EP1594852A1 - Oxazolidinone derivatives as antimicrobials - Google Patents

Oxazolidinone derivatives as antimicrobials

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Publication number
EP1594852A1
EP1594852A1 EP03701664A EP03701664A EP1594852A1 EP 1594852 A1 EP1594852 A1 EP 1594852A1 EP 03701664 A EP03701664 A EP 03701664A EP 03701664 A EP03701664 A EP 03701664A EP 1594852 A1 EP1594852 A1 EP 1594852A1
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EP
European Patent Office
Prior art keywords
alkyl
methyl
formula
compound
cycloalkyl
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.)
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Application number
EP03701664A
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German (de)
French (fr)
Inventor
Anita Mehta
Sonali Rudra
Ajjarapu Venkata Subrahmanya Raja Rao
Ajay Singh Yadav
Ashok Rattan
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Ranbaxy Laboratories Ltd
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Ranbaxy Laboratories Ltd
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Publication of EP1594852A1 publication Critical patent/EP1594852A1/en
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to certain substituted phenyl oxazolidinones and to the processes for the synthesis of the same.
  • This invention also relates to pharmaceutical compositions containing the compounds of the present invention as antimicrobials.
  • the compounds are useful antimicrobial agents, effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply-resistant staphylococci, streptococci and enterococci as well as anaerobic organisms such as Bacterioides spp. and Clostridia spp. species, and acid fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp.
  • Nancomycin which inspite of its various drawbacks, has become the drug of choice for
  • Streptococcus pneumoniae is a major pathogen causing pneumonia, sinusitis and meningitis. Until very recently it was highly susceptible to penicillin.
  • Oxazolidinones are a new class of synthetic antimicrobial agents which kill gram positive pathogens by inhibiting a very early stage of protein synthesis. Oxazolidinones inhibit the formation of ribosomal initiation complex involving 30S and 50S ribosomes leading to prevention of initiation complex formation. Due to their novel mechanism of action, these compounds are active against pathogens resistant to other clinically useful antibiotics.
  • WO 02/06278 application discloses phenyloxazolidinone derivatives as antimicrobials.
  • WO 01/46164 discloses piperidinyloxy and pyrrolidinyloxyphenyl oxazolidinones as antimicrobials.
  • WO 99/37630 discloses oxazolidinone combinatorial libraries.
  • WO 93/23384 application discloses phenyloxazolidinones containing a substituted diazine moiety and their uses as antimicrobials.
  • WO 93/09103 application discloses substituted aryl and heteroaryl- phenyloxazolidinones useful as antibacterial agents
  • WO 90/02744 application discloses 5-indolinyl-5 ⁇ -amidomethyloxazolidinones, 3- (fused ring substituted) phenyl-5 ⁇ -amidomethyloxazolidinones which are useful as antibacterial agents.
  • European Patent Publication 352,781 discloses phenyl and pyridyl substituted phenyl oxazolidinones.
  • European Patent Application 312,000 discloses phenylmethyl and pyridinylmethyl substituted phenyl oxazolidinones.
  • U.S. Patent No. 5,254,577 discloses nitrogen heteroaromatic rings attached to phenyloxazolidinone.
  • the invention involves the synthesis, identification and profiling of oxazolidinone molecules which have good activity against multiply resistant gram positive pathogens like MRSA, NRE and PRSP. Some of these molecules have activity against MDR-TB and MAI strains, while others have significant activity against important anaerobic bacteria.
  • the invention provides processes for phenyloxazolidinones derivatives which can exhibit significant antibacterial activity against multiply resistant gram positive pathogens like MRSA, VRE and P ⁇ ISP against MDR-TB and MAI strains, in order to provide safe and effective treatment of bacterial infections.
  • T is a five to seven membered heterocyclic ring, aryl, substituted aryl, bound to the ring C with a linker W.
  • X is H, CH, CH-S, CH-O, N, CHNRn, wherein R ⁇ is hydrogen, optionally substituted Ci. 2 alkyl, C 3 . 12 cycloalkyl, C ⁇ - 6 alkoxy, C ⁇ - 6 alkyl, C ⁇ _ 6 alkylcarbonyl, C ⁇ - 6 alkyl carboxy, aryl or heteroaryl;
  • X 2 CH or N; Y and Z are independently selected from hydrogen, C-_ 6 alkyl, C 3 12 cycloalkyl or C 0 _ 3 bridging group;
  • U and V are independently selected from hydrogen, optionally substituted C alkyl, F, Cl, Br, C._ 12 alkyl substituted with one or more of F, Cl, Br, I, preferably U and V are hydrogen or fluoro;
  • W is selected from CH 2 , CO, CH 2 NH, -NHCH 2 , -CH 2 NHCH 2 , -CH 2 N(R ⁇ )CH 2 -, CH 2 ( R ⁇ )N-, CH(R n ), CH 2 (CO), NH, O, S, N(R ⁇ ), (CO)CH 2 , N(R ⁇ )CON(Rn), N(Rn)CSN(Rii), SO 2 , SO, wherein R n is the same as defined above; and
  • U and V are independently selected from hydrogen, optionally substituted C ⁇ - 6 alkyl, F, Cl, Br, Ci- 12 alkyl substituted with one or more of F, Cl, Br, I; preferably U and V are hydrogen and fluoro;
  • Y and Z are independently selected from hydrogen, C ⁇ - 6 alkyl, C . ⁇ 2 cycloalkyl, Co- bridging group;
  • X is selected from H, CH, CH-S, CH-O or N;
  • X 2 CH or N
  • Qi is selected from O, S or NR ⁇ , wherein R ⁇ is as defined above;
  • G, J, L are independently selected from H, C ⁇ . 6 alkyl, F, Cl, Br,I, -CN, COR 5 ,COOR 5 ,
  • R 5 are independently selected from H, C ⁇ - 12 alkyl, C 3 _ ⁇ 2 cycloalkyl, C ⁇ - 6 alkoxy, C ⁇ - 6 alkyl substituted with one or more of F, Cl, Br, I or OH, aryl, heteroaryl;
  • Rg and R are independently selected from H, optionally substituted C -n alkyl, C3-12 cycloalkyl, C ⁇ - 6 alkoxy;
  • R 8 and R 9 are independently selected from H, C ⁇ - 6 alkyl, F, Cl, Br, I, C 1 - 1 2 alkyl substituted with one or more of F, Cl, Br, I, OR 5 , SRj, N(Re,R 7 );
  • ring C may be 6-8 membered in size and the ring may have either two or three carbon atoms between each nitrogen atom, for example:
  • the ring C may be bridged to form a bicyclic system as shown below:
  • ring C is optionally substituted at positions Y and Z with alkyl groups, cycloalkyl groups, fluoro group, carboxylic and corresponding esters, amides, substituted alkyls or bridging alkyl groups are as shown below:
  • ring C also includes the following structures:
  • U and V are independently selected from hydrogen, optionally substituted C ⁇ - 6 alkyl, F, Cl, Br, C ⁇ _ ⁇ 2 alkyl substituted with one or more of F, Cl, Br, I; preferably U and V are hydrogen and fluoro;
  • Y and Z are independently selected from hydrogen, C ⁇ . 6 alkyl, C 3 - ⁇ 2 cycloalkyl, Co- 3 bridging group;
  • X is selected from H, CH, CH-S, CH-O or N;
  • R 6 and R 7 are independently selected from H, optionally substituted - 12 alkyl, C -i 2 cycloalkyl, C ⁇ - 6 alkoxy;
  • R 8 and R 9 are independently selected from H, C ⁇ - 6 alkyl, F, Cl, Br, I, C ⁇ - ⁇ 2 alkyl substituted with one or more of F, Cl, Br, I, OR 5 , SR- t , N(R 6 ,R 7 );
  • R ⁇ o H, optionally substituted C ⁇ - ⁇ 2 alkyl, G 3 - 12 cycloalkyl, C ⁇ _ 6 alkoxy, C ⁇ _ 6 alkyl, aryl, heteroaryl; and
  • n is an integer in the range from 0 to 3;
  • Particular G, J and L substitutions can include nitro, aldehydes and halides.
  • U and V are independently selected from hydrogen, optionally substituted C ⁇ - 6 alkyl, F, Cl, Br, C ⁇ - 12 alkyl substituted with one or more of F, Cl, Br, I; preferably U and V are hydrogen and fluoro;
  • Y and Z are independently selected from hydrogen, C ⁇ _ 6 alkyl, C 3 _i2 cycloalkyl, C0-3 bridging group;
  • X is selected from C, CH, CH-S, CH-O or N;
  • Another particular compound of Formula IN is as follows:
  • Y and Z are independently selected from hydrogen, C ⁇ _ 6 alkyl, C -i 2 cycloalkyl, Co- 3 bridging group;
  • X is selected from H, CH, CH-S, CH-O, or N;
  • a particular compound of Formula V is as follows: (S)-N-[[3-[3-Fluoro-4-[ J- ⁇ 2-furyl-(5-nitro)-methyl ⁇ piperidmyl-4-oxy]phenyl]-2-oxo-5- oxozolidinyljmethyl] acetamide.
  • Compounds of the present invention can be useful antimicrobial agents, effective against a number of human and veterinary pathogens, particularly aerobic Gram-positive bacteria, including multiply-antibiotic resistant staphylococci and streptococci, as well as anaerobic organisms such as Mycobacterium tuberculosis and other mycobacterium species.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, suppositories, and ointments.
  • a solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, or tablets disintegrating agents; it can also be as finely divided solid which is in admixture with the finely divided active compound.
  • the active compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from about 5 to about 70 percent of the active ingredient.
  • suitable solid carriers are lactose, pectin, dextrin, starch, gelatin, tragacanth, low melting wax, cocoa butter, and the like.
  • preparation is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component (with or without other carriers) is surrounded by carrier, which is thus in association with it.
  • capsules can be used as solid dosage forms suitable for oral administration.
  • Liquid form preparations include solutions, suspensions, and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Such solutions are prepared so as to be acceptable to biological systems
  • Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilizing, and thickening agents as desired.
  • Aqueous suspension suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e., natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other well-known suspending agents.
  • Ointment preparations contain heavy metal salts of a compound of Formula I with a physiologically acceptable carrier.
  • the carrier is desirably a conventional water- dispersible hydrophilic or oil-in-water carrier, particularly a conventional semi-soft or cream-like water-dispersible or water soluble, oil-in-water emulsion infected surface with a minimum of discomfort.
  • Suitable compositions may be prepared by merely incorporating or homogeneously admixing finely divided compounds with the hydrophilic carrier or base or ointment.
  • the pharmaceutical preparations can be in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete capsules, powders in vials or ampoules, and ointments capsule, cachet, tablet, gel, or cream itself or it can be the appropriate number of any of these packaged forms.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from less than 1 mg to several grams according to the particular application and the potency of the active ingredient.
  • the compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 3 mg to about 40 mg per kilogram daily.
  • the dosages may be varied depending upon the requirements of the patient and the compound being employed. Determination of the proper dosage for a particular situation is within the smaller dosages which are less than the optimum dose. Small increments until the optimum effect under the daily dosage may be divided and administered in portions during the day if desired.
  • the invention provides processes for the synthesis of compounds of Formulae I, II, III, IN and V.
  • Pharmaceutically acceptable non-toxic acid addition salts of the compounds of the present invention of Formulae I, II, III, TV and N may be formed with inorganic or organic acids, by methods well known in the art.
  • the present invention also includes within its scope prodrugs of the compounds of
  • prodrugs will be functional derivatives of these compounds which readily get converted in vivo into defined compounds.
  • the invention also includes pharmaceutically acceptable salts, the enantiomers, diastereomers, N-oxides, prodrugs, metabolites in combination with a pharmaceutically acceptable carrier and optionally included excipients.
  • Mi is NH, NHRi 4 , CH 2 NHR ⁇ 4 , CH-CH 2 NHR ⁇ 4 , -CCH 2 -NHR ⁇ 4 wherein R 14 is H, ethyl, methyl, isopropyl, acetyl, cyclopropyl, or alkoxy and
  • X 2 CH or N
  • Y and Z are independently selected from hydrogen, Q, alkyl, C 3 _ 12 cycloalkyl or C 0 _ 3 bridging group;
  • U and V are independently selected from hydrogen, optionally substituted C._ 6 alkyl, F, Cl, Br, C . alkyl substituted with one or more of F, Cl, Br, I, preferably U and V are hydrogen or fluoro; and
  • W is selected from CH 2 , CO, CH 2 NH, -NHCH 2 , -CH 2 NHCH 2 , -CH 2 N(R ⁇ )CH 2 -, CH 2 ( R ⁇ )N-, CH(R ⁇ ), CH 2 (CO), NH, O, S, N(R ⁇ ), (CO)CH 2 , N(R ⁇ )CON(R ⁇ ), N(R ⁇ )CSN(R ⁇ ), SO 2 , SO, wherein R is the same as defined above; and
  • R 1 2 is a suitable leaving group well known to one of ordinary skill in the art such as fluoro, chloro, bromo, iodo, SCH 3 , -SO 2 CH 3 , -SO 2 CF 3 , Tos or OC 6 H 5 etc.
  • the reaction can be carried out in a suitable solvent in the presence of a suitable base selected from the group consisting of potassium carbonate, N-ethyldiisopropylamine and dipotassium hydrogen phosphate.
  • a suitable base selected from the group consisting of potassium carbonate, N-ethyldiisopropylamine and dipotassium hydrogen phosphate.
  • the corresponding aldehyde can be used through a process of reductive amination and is attached to the amine of Formula VI.
  • the corresponding acid can be used and the amino compound of Formula VI can be acylated through activated esters in the presence of condensing agents such as 1,3- dicyclohexylcarbodiimide (DCC) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlori.de (EDC).
  • DCC 1,3- dicyclohexylcarbodiimide
  • EDC l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlori.de
  • Other methods of acylation can also be employed.
  • the compounds having carbonyl link can also be made by reacting heteroaromatic compound of the Formula VII (wherein G, J, L, Qi & R ⁇ 2 are the same as defined earlier),
  • Formula VII such as N-methyl pyrrole, with the intermediate amine of Formula VI in the presence of triphosgene or phosgene.
  • the carbonyl linkers may also be introduced between heteroaromatic compound, such as 3-bromothiophene and the amine of Formula VI with carbon monoxide in the presence of a catalyst such as Pd (PPli 3 ) 2 Cl .
  • the extended chain pyrroles having dicarbonyl linkers can also be obtained from treatment with oxalyl chloride and the amine of the Formula VI.
  • the heteroaromatic compound of the Formula VII such as 2-bromo-thiophene is reacted with the intermediate amine of Formula VI in the presence of ligands such as palladium dibenzylidene acetone Pd 2 (dba) 3 or Pd(OAc) 2 with 2,2'-bis-(di ⁇ henylphosphino)-l,l'-bina ⁇ hthyl (BINAP) and bases such as cesium carbonate or sodium t-butoxide (Ref: J. Org. Chem. 1999, 64, 6019- 6022 and J. Org. Chem. 2000, 65, 1144-1157).
  • ligands such as palladium dibenzylidene acetone Pd 2 (dba) 3 or Pd(OAc) 2 with 2,2'-bis-(di ⁇ henylphosphino)-l,l'-bina ⁇ hthyl (BINAP) and bases such as cesium carbonate or sodium t-butoxide
  • the compounds having carbonyl link can also be made by reacting heteroaromatic compound of the Formula VII, (wherein G, J, L, Qi and R ⁇ 2 are as defined earlier) such as N- methyl pyrrole with the intermediate amine of Formula VI in the presence of triphosgene or phosgene.
  • the carbonyl linkers may also be introduced between heteroaromatic compound, such as 3-bromothiophene and the amine of Formula VI with carbon monoxide in the presence of a catalyst such as Pd (PPh 3 ) 2 Cl 2 .
  • the extended chain pyrroles having dicarbonyl linkers can also be obtained from treatment with oxalyl chloride and the amine of the Formula VI.
  • the reaction can be carried out in a suitable solvent such as dimethylformamide, dimethylacetamide, ethanol, dimethylsulfoxide, acetonitrile, or ethylene glycol at a suitable temperature in the range of about -70°C to 180° C to afford compounds of Formula II.
  • a suitable base such as tri ethylamine, N-ethyldiisopropyl amine, potassium carbonate, sodium bicarbonate, dipotassium hydrogen phosphate is useful in some cases to improve the yield of the reaction.
  • Formula VI identified as three different cores, namely
  • optically pure amines of Formula VI could be obtained either by one of a number of assymetric synthesis or alternatively by resolution from a racemic mixture by selective crystallization of a salt prepared, with an appropriate optically active acid such as dibenzoyl tartarate or 10-camphorsulfonic acid, followed by treatment with base to afford the optically pure amine.
  • an appropriate optically active acid such as dibenzoyl tartarate or 10-camphorsulfonic acid
  • the title compound was prepared from (S)-N-[[3-[3-Fluoro-4-(piperidinyl-4-oxy)phenyl]- 2-oxo-5-oxozolidinyl]methyl] acetamide and 4-(N-4-methyl-piperazin- 1 -yl)-5-nitro-2- thiophenecarboxaldehyde using Method A.
  • the title compound was prepared from (S)-N-[[3-[3-Fluoro-4-(piperidinyl-4-oxy)phenyl]- 2-oxo-5-oxozolidinyl]methyl]acetamide and 2-nitro-3-thiophenecarboxaldehyde using Method A.
  • the reaction is carried out in a suitable solvent such as dimethylformamide, dimethylacetamide, ethanol or ethylene glycol at a suitable temperature in the range of - 78°C to 180°C to afford compounds of Formula II.
  • a suitable base such as triethylamine, diisopropyl amine, potassium carbonate, sodium bicarbonate is useful in some cases to improve the yield of the reaction.
  • the tiltle compound was prepared from (S)-N-[[3-[3-Fluoro-4-(piperidinyl-4-oxy)phenyl]- 2-oxo-5 -oxozolidinyl]methyl] acetamide and 5-nitro-2-( - trifluoromethylsulfonate)ethylfuran using Method B.
  • DCC 1,3- dicyclohexylcarbodiimide
  • EDC l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • Other methods of acylation can also be employed.
  • the following compounds were prepared using this method:
  • reaction mixture was quenched with water and extracted with ethyl acetate (100 ml).
  • organic layer was dried over anhydrous sodium sulfate and concentrated to get the crude product which was purified by column chromatography using 2-3% methanol in dichloromethane as eluent to yield 150 mg of the title compound.
  • the title compound was prepared from (S)-N-[[3-[3-Fluoro-4-(piperidinyl-4-oxy)phenyl]- 2-oxo-5-oxozolidinyl]methyl]acetamide and 5-nitro-2-thiophenecarboxylic acid using Method C.
  • Step-c Preparation of 3- fluoro- 4-[ ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-3-tert-butoxycarbonyl-3-azabicyclo- [3.1.0]hexan-6-yl ⁇ -methyloxy]mtrobenzene:
  • Step-d Preparation of 3-Fluoro-4-[ ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-3-tetrabutoxycarbonyl-3- azabicyclo[3.1.0]hexan-6-yl ⁇ methyloxy]aniline: To a solution of 3-fluoro-4-[ ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-3-tert-butoxycarbonyl-3-azabicyclo- [3.1.0]hexan-6-yl ⁇ -methyloxy]nitrobenzene obtained in step-c (6gm) in methanol (100), 5% wet Pd/C (8gm) was added and shaken in a parr hydrogenation apparatus under 50 psi of hydrogen gas for 3h . Then the rection mixture was filtered over celite bed and washed with 50 ml of methanol. The filtrate was evaporated in vacuo to yield 5.5 gm of the title compound.
  • Step-e Preparation of 3-Fluoro-4-[ ⁇ (l ,5 ⁇ ,6 ⁇ )-3-tetrabutoxycarbonyl-3- azabicyclo[3.1.0]-hexan-6-yl ⁇ methyloxy] benzyloxy carbonyl aniline: To a solution of 3-Fluoro-4-[ ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-3-tetrabutoxycarbonyl-3- azabicyclo[3.1.0]hexan-6-yl ⁇ methyloxy]aniline obtained in step-d (D, 5.0 gm, 0.015 mole) in THF (150ml) cooled to 5°C, sodium bicarbonate (3.92 gm, 0.046 mole), was added and then benzylchloroformate (3.94 gm, 0.02 mole) was added dropwise at the same temperature .
  • reaction mixture was stirred at room temperature for 4 hrs and then filtered, washed with THF (50 ml). The filtrate was evaporated in vacuo. The residue obtained was triturated with hexane. The solid was filtered and dried to get the 5.0 gm of the title compound.
  • Step-f Preparation of R(-)-3-[3-fluoro-4-[ ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-3-tetrabutoxycarbonyl-3- azabicyclo[3.1.0]hexan-6-yl ⁇ methyloxy]phenyl]5-hydroxymethyl-2-oxazolidinone :
  • reaction mixture was stirred at -78°C for 1.5hr, then R-glycidyl butyrate (1.70 gm, 0.0118 mole) was added and the reaction mixture was stirred at -78°C for lhr and then at RT for 18 hr.
  • the reaction mixture was quenched with saturated ammonium chloride solution (25 ml) and the organic layer was separated. The aqueous layer was again extracted with 200ml of ethyl acetate. The combined organic layer was dried over anhydrous Na SO 4 and evaporated in vacuo.
  • the crude product was purified by column chromatography (eluent is 2% methanol in dichloromethane) to yield 3.5 gm of the title compound.
  • Step-g Preparation of R(-)-3-[3-fluoro-4-[ ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-3-tetrabutoxycarbonyl-3- azabicyclo[3.1.0] hexan-6-yl ⁇ methyloxy]phenyl]5-methanesulphonyloxy-methyl-2- oxazolidinone:
  • Step-h Preparation of S(-)-3-[3-fluoro-4-[ ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-3-tert-butoxycarbonyl-3- azabicyclo[3.1.0]hexa-6-yl ⁇ methyloxy]phenyl]5-azidomethyl-2-oxazolidinone:
  • Step-i Preparation of S(-)-3-[3-fluoro-4-[ ⁇ (l ,5 ⁇ ,6 ⁇ )-3-tert-butoxycarbonyl-3- azabicyclo[3.1.0]hexan-6-yl]phenyl]-5-aminomethyl-2-oxazolidinone: To a solution of S(-)-3-[3-fluoro-4-[ ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-3-tert-butoxycarbonyl-3- azabicyclo[3.1.0]hexa-6-yl ⁇ methyloxy]phenyl]5-azidomethyl-2-oxazolidinone (2.0 gm, 0.0045 mole) in THF, triphenylphosphine was added and stirred for 2hr at RT.
  • Step-j Preparation of (S)-N-[[3-[3-Fluoro-4-[ ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-3-t-butoxycarbonyl-3- azabicyclo [3.1.0]hexan-6-yl ⁇ -methyloxy]phenyl] -2-oxo-5 -oxozolidinyl]methyl] acetamide.
  • reaction mixture was diluted with dichloromethane (25 ml) and washed with saturated sodium bicarbonate, followed by brine. The combined organic layer was dried over anhydrous sodium sulfate and evaporated under vacuo to get the 1.3 gm of the title compound.
  • Step-k Preparation of (S)-N-[[3-[3-Fluoro-4-[ ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-3-azabicyclo[3.1.0]hexan-6- yl ⁇ -methyloxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide.
  • the title compound was prepared from (S)-N-[[3-[3-Fluoro-4-[ ⁇ (l ,5 ⁇ ,6 )-3- azabicyclo[3.1.0]hexan-6-yl ⁇ -methyloxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide and 5-nitro-2-thiophenecarboxaldehyde using Method A.
  • the title compound was prepared from (S)-N-[[3-[3-Fluoro-4-[N-l-(N-l- piperazinylcarbonyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide Trifluorocaetate and 5-nitro-2-thiophenecarboxaldehyde using Method A.
  • the title compound was prepared from (S)-N-[[3-[3-Fluoro-4-[N-l-(N-l- pi ⁇ erazinylcarbonyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide trifluoroacetate and 5-nitro-2-bromothiophene using Method B.
  • the compounds of the invention display antibacterial activity when tested by the agar incorporation method.
  • the following minimum inhibitory concentrations ( ⁇ g/ml) were obtained for representative compounds of the invention which are given below in Table- 1.
  • MRSA 15187 Metalicillin Resistant Staphylococcus aureus 3
  • MRSA 15187 Metalicillin Resistant Staphylococcus aureus 3
  • ATCC 6303 Streptococcus pneumoniae ATCC 6303

Abstract

The present invention relates to certain substituted phenyl oxazolidinones of the formula h wherein T is a ring and to the processes for the synthesis of the same. The compounds are useful antimicrobial agents, effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply-resistant staphylococci, streptococci and enterococci as well as anaerobic organisms such as Bactericides spp. and Clostridia spp. species, and acid fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp.

Description

OXAZOLIDINONE DERIVATIVES AS ANTIMICROBIALS
FIELD OF THE INVENTION
The present invention relates to certain substituted phenyl oxazolidinones and to the processes for the synthesis of the same. This invention also relates to pharmaceutical compositions containing the compounds of the present invention as antimicrobials. The compounds are useful antimicrobial agents, effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply-resistant staphylococci, streptococci and enterococci as well as anaerobic organisms such as Bacterioides spp. and Clostridia spp. species, and acid fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp.
BACKGROUND OF THE INVENTION
Increasing antibacterial resistance in Gram positive bacteria has presented a formidable treatment problem. The enterococci, although traditionally non virulent pathogens, have been shown, when associated with Nancomycin resistance, to have an attributable mortality of approximately 40%. Staphylococcus aureus, the traditional pathogen of post operative wounds, has been resistant to Penicillin due to production of penicillinases. This resistance was overcome by the development of various penicillinase stable β lactams. But the pathogen responded by synthesizing a modified target penicillin binding protein- 2' leading to less affinity for β lactam antibiotics and a phenotype known as Methicillin Resistant S. aureus (MRS A). These strains, till recently were susceptible to
Nancomycin, which inspite of its various drawbacks, has become the drug of choice for
MRSA infections. Streptococcus pneumoniae is a major pathogen causing pneumonia, sinusitis and meningitis. Until very recently it was highly susceptible to penicillin.
Recently though, different PBP 2' strains with different susceptibility to penicillin have been reported from across the globe.
Oxazolidinones are a new class of synthetic antimicrobial agents which kill gram positive pathogens by inhibiting a very early stage of protein synthesis. Oxazolidinones inhibit the formation of ribosomal initiation complex involving 30S and 50S ribosomes leading to prevention of initiation complex formation. Due to their novel mechanism of action, these compounds are active against pathogens resistant to other clinically useful antibiotics.
WO 02/06278 application discloses phenyloxazolidinone derivatives as antimicrobials. WO 01/46164 discloses piperidinyloxy and pyrrolidinyloxyphenyl oxazolidinones as antimicrobials.
Bioorganic &Medicinal Chemistry Letters 11 (2001) 1829-1832 discloses piperidinyloxy oxazolidinone anitimicrobial agents
WO 99/37630 discloses oxazolidinone combinatorial libraries. WO 93/23384 application discloses phenyloxazolidinones containing a substituted diazine moiety and their uses as antimicrobials.
WO 93/09103 application discloses substituted aryl and heteroaryl- phenyloxazolidinones useful as antibacterial agents
WO 90/02744 application discloses 5-indolinyl-5β-amidomethyloxazolidinones, 3- (fused ring substituted) phenyl-5β-amidomethyloxazolidinones which are useful as antibacterial agents.
European Patent Publication 352,781 discloses phenyl and pyridyl substituted phenyl oxazolidinones.
European Patent Application 312,000 discloses phenylmethyl and pyridinylmethyl substituted phenyl oxazolidinones.
U.S. Patent No. 5,254,577 discloses nitrogen heteroaromatic rings attached to phenyloxazolidinone.
U.S. Patents No. 5,547,950 and 5,700,799 also disclose the phenyl piperazinyl oxazolidinones. Other references disclosing various phenyloxazolidinones include U.S. Patent Nos.
4,801,600 and 4,921,869; Gregory W.A., et al, J.Med.Chem., 1989; 32: 1673-81; Gregory W.A., et al, J.MedChem., 1990; 33: 2569-78; Wang C, et al, Tetrahedron, 1989; 45: 1323-26.; Brittelli, et al, J.Med. Chem., 1992; 35: 1156; and Bio-organic and Medicinal Chemistry Letters, 1999; 9: 2679-2684; Antibacterial & Antifungal Drug Discovery & Development Summit, Strategic Research Institute, June 28-29, 2001, Amsterdam, The Netherlands; Posters No. 1822, 1823, 1824, 1825, 1826, 1827, 1828, 1829, 1830, 1831, 1832, 1833, and 1834, 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Sept 17-20, 2000, Toronto, Canada; and Posters No 1023, 1040, 1041, 1042, 1043, 1044,1045, 1046, 1047, 1048, 1049, 1050, and 1051, 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, Sept 22-25, 2001, Chicago, USA.
SUMMARY OF THE INVENTION
The invention involves the synthesis, identification and profiling of oxazolidinone molecules which have good activity against multiply resistant gram positive pathogens like MRSA, NRE and PRSP. Some of these molecules have activity against MDR-TB and MAI strains, while others have significant activity against important anaerobic bacteria.
The invention provides processes for phenyloxazolidinones derivatives which can exhibit significant antibacterial activity against multiply resistant gram positive pathogens like MRSA, VRE and PΪISP against MDR-TB and MAI strains, in order to provide safe and effective treatment of bacterial infections.
In accordance with one aspect of the present invention, there are provided compounds having the structure of Formula I
R
and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, Ν-oxides, polymorphs, prodrugs, or metabolites, wherein T is a five to seven membered heterocyclic ring, aryl, substituted aryl, bound to the ring C with a linker W. Preferred forms of T are selected from aryl and five membered heteroaryl which are further substituted by a group represented by R, wherein R is selected from the group consisting of H, Cι-6 alkyl, F, Cl, Br,I, -CΝ, COR5,COOR5, Ν(Rδ,R7), NHCOC(R8, R9, Rio), CON (Rg, R7), CH2NO2, NO2, CH2R8, CHR9, -CH = N-ORio, - C=CH-R5, OR5, SR5, -C(R9)=C(R9)NO2, Cm alkyl substituted with one or more of F, Cl, Br, I, OR4, S , wherein ι and R5 are independently selected from H, C1-12 alkyl, C3.ι2 cycloalkyl, Cι_6 alkoxy, Cι-6 alkyl substituted with one or more of F, Cl, Br, I or OH, aryl, heteroaryl; Re and R7, are independently selected from H, optionally substituted Cι-ι2 alkyl, C3-ι2 cycloalkyl, Cι-6 alkoxy; R8 and R9 are independently selected from H, Cι-6 alkyl, F, Cl, Br, I, C1-12 alkyl substituted with one or more of F, Cl, Br, I, OR5, SRi, N(R6,R7); Rιo= H, optionally substituted -12 alkyl, C3-ι2 cycloalkyl, Cι.6 alkoxy, Cι_6 alkyl, aryl or heteroaryl; n is an integer in the range from 0 to 3;
X is H, CH, CH-S, CH-O, N, CHNRn, wherein Rπ is hydrogen, optionally substituted Ci. 2 alkyl, C3.12 cycloalkyl, Cι-6 alkoxy, Cι-6 alkyl, Cι_6 alkylcarbonyl, Cι-6 alkyl carboxy, aryl or heteroaryl;
Xi is (CH2)nS, (CH2)nO, where n = 0 to 3; NRn wherein Rπ is the same as defined above; CO, or C=S;
X2 = CH or N; Y and Z are independently selected from hydrogen, C-_6 alkyl, C3 12 cycloalkyl or C0_3 bridging group;
U and V are independently selected from hydrogen, optionally substituted C alkyl, F, Cl, Br, C._12 alkyl substituted with one or more of F, Cl, Br, I, preferably U and V are hydrogen or fluoro; W is selected from CH2, CO, CH2NH, -NHCH2, -CH2NHCH2, -CH2N(Rπ)CH2-, CH2( Rπ)N-, CH(Rn), CH2(CO), NH, O, S, N(Rπ), (CO)CH2, N(Rπ)CON(Rn), N(Rn)CSN(Rii), SO2, SO, wherein Rn is the same as defined above; and
Ri is selected from -NHC(=O)R2 , N(R3, R4), -NR2C(=S)R3, -NR2C(=S)SR3) wherein R2 is hydrogen, aryl, heteroaryl, C-_12 alkyl, C3_12 cycloalkyl, C._6 alkoxy, C._6 alkyl substituted with one or more of F, Cl, Br, I or OH; or thioCι-6 alkyl; R3, R.j are independently selected from hydrogen, aryl, heteroaryl, C._12 alkyl, C3_12 cycloalkyl, C. 6 alkoxy, C -_6 alkyl substituted with one or more of F, Cl, Br, I or OH.
In accordance with a second aspect of the present invention, there are provided compounds represented by Formula II containing D ring as furanyl, thienyl, and pyrrolyl ring systems and further substituted by substitutions G, J and L,
Formula II and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs, or metabolites, wherein
Rx is selected from -NHC(=O)R2, -N(R3, R0), -NR2C(=S)R3> -NR2C(=S)SR3 wherein R2, R , Rj are independently hydrogen, aryl, heteroaryl, C 2 alkyl, C3-ι2 cycloalkyl, Cι_6 alkoxy, Cι-6 alkyl substituted with one or more of F, Cl, Br, I, OH; preferably Ri is of the formula -NH(C=O)X3 wherein X3 is CH3, CH2F, CHF2, CF3, CH2C1, CHC12 or CC13;
U and V are independently selected from hydrogen, optionally substituted Cι-6 alkyl, F, Cl, Br, Ci-12 alkyl substituted with one or more of F, Cl, Br, I; preferably U and V are hydrogen and fluoro;
Y and Z are independently selected from hydrogen, Cι-6 alkyl, C .ι2 cycloalkyl, Co- bridging group;
X is selected from H, CH, CH-S, CH-O or N;
Xi is (CH2)nS, (CH2)nO, where n = 0 to 3; NRπ, wherein Rn is hydrogen, optionally substituted Cι-2 alkyl, C .ι2 cycloalkyl, Cι-6 alkoxy, Cι-6 alkyl, Cι.6 alkylcarbonyl, Cι-6 alkyl carboxy, aryl or heteroaryl; C=O, C=S;
X2 = CH or N;
W is independently selected from CH2, C=O, CH2NH, NHCH2, CH2NHCH2, CH2N(Rn)CH2, CH2N(Rn), CH(Rπ), CH2(C=0), NH, O, S, (CO)CH2, N(Rii)CON(Rn), SO2, SO, N(Rn), N(Rn)C(=S)N(Rn), wherein Rn is the same as defined above;
Qi is selected from O, S or NRπ, wherein Rπ is as defined above;
G, J, L are independently selected from H, Cι.6 alkyl, F, Cl, Br,I, -CN, COR5,COOR5,
N(R6,R7), NHCOC(R8, R9, Rio), CON (R6, R7), CH2NO2, NO2, CH2R8, CHR9, -CH - N- ORio, -C=CH-R5, OR5, SR5, -C(R9)=C(R9)NO2, Cι.12 alkyl substituted with one or more of
F, Cl, Br, I, OIL]., SR^ wherein i, R5 are independently selected from H, Cι-12 alkyl, C3_ι2 cycloalkyl, Cι-6 alkoxy, Cι-6 alkyl substituted with one or more of F, Cl, Br, I or OH, aryl, heteroaryl; Rg and R are independently selected from H, optionally substituted C -n alkyl, C3-12 cycloalkyl, Cι-6 alkoxy; R8 and R9 are independently selected from H, Cι-6 alkyl, F, Cl, Br, I, C1-12 alkyl substituted with one or more of F, Cl, Br, I, OR5, SRj, N(Re,R7); Rιo= H, optionally substituted CM2 alkyl, C3.12 cycloalkyl, Ci-e alkoxy, Cι-6 alkyl, aryl, heteroaryl; except when W=CO, Qι=O, S, X=N, X2=CH, X^O and G, J, L=H.
In some compounds represented by Formula II, ring C may be 6-8 membered in size and the ring may have either two or three carbon atoms between each nitrogen atom, for example:
The ring C may be bridged to form a bicyclic system as shown below:
When ring C is optionally substituted at positions Y and Z with alkyl groups, cycloalkyl groups, fluoro group, carboxylic and corresponding esters, amides, substituted alkyls or bridging alkyl groups are as shown below:
-X γ2-X, X-2-X1- -jζ rSfc-X. rJS2-X1-
When ring C is 6 membered in size and X is -CH-(NHR), or >CCH2NHR-, the following rings are preferred ones wherein Rn is the same as defined earlier.
In addition to the above, ring C also includes the following structures:
In accordance with a third aspect of the present invention, there are provided compounds represented by Formula III
FORMULA III wherein
Ri is selected from -NHC(=O)R2) -N(R3, R4), -NR2C(=S)R3) -NR2C(=S)SR3 wherein R2, R3, R4 are independently hydrogen, aryl, heteroaryl, C1-12 alkyl, C3-12 cycloalkyl, Cι-6 alkoxy, Cι-6 alkyl substituted with one or more of F, Cl, Br, I, OH; preferably Rx is of the formula -NH(C=O)X3 or NH(C=S)X3 wherein X3 is CH3, CH2F, CHF2, CF3, CH2C1, CHC12 or CC13;
U and V are independently selected from hydrogen, optionally substituted Cι-6 alkyl, F, Cl, Br, Cι_ι2 alkyl substituted with one or more of F, Cl, Br, I; preferably U and V are hydrogen and fluoro;
Y and Z are independently selected from hydrogen, Cι.6 alkyl, C3-ι2 cycloalkyl, Co-3 bridging group;
X is selected from H, CH, CH-S, CH-O or N;
Xi is (CH )nS, (CH2)nO, where n = 0 to 3; NRπ, wherein Rn is hydrogen, optionally substituted Cι.2 alkyl, C3_ι2 cycloalkyl, Cι-6 alkoxy, Cι_6 alkyl, Cι-6 alkylcarbonyl, Cι-6 alkyl carboxy, aryl or heteroaryl; C=O, C=S;
X2 = CH or N; is independently selected from CH2, CO, CH-.NH, -NHCH2, -CH2NHCH2, -CH2-N(Rπ) CH2 -, CH2 ( Rn)N -, CH( Rn), CH2( CO), NH, O, S, N(Rπ), (CO)CH2, N(Rπ)CON(Rπ), N(Rιι)C(=S)N(Rπ), SO2, SO, wherein R. is the same as defined above;
G, J, L are independently selected from H, Cι-6 alkyl, F, Cl, Br,I, -CN, COR5,COOR5, N(R6,R7), NHCOC(R8, R9, Rι0), CON (R6, R7), CH2NO2, NO2, CH2R8, CHR9, -CH = N- ORio, -C=CH-R5, OR5, SR5, -C(R9)=C(R9)NO2, Cm alkyl substituted with one or more of F, Cl, Br, I, ORi, SR ) wherein R , R5 are independently selected from H, C1-12 alkyl, C -i2 cycloalkyl, Cι-6 alkoxy, Cι.6 alkyl substituted with one or more of F, Cl, Br, I or OH, aryl, heteroaryl; R6 and R7 are independently selected from H, optionally substituted -12 alkyl, C -i2 cycloalkyl, Cι-6 alkoxy; R8 and R9 are independently selected from H, Cι-6 alkyl, F, Cl, Br, I, Cι-ι2 alkyl substituted with one or more of F, Cl, Br, I, OR5, SR-t, N(R6,R7); Rιo= H, optionally substituted Cι-ι2 alkyl, G3-12 cycloalkyl, Cι_6 alkoxy, Cι_6 alkyl, aryl, heteroaryl; and n is an integer in the range from 0 to 3;
Particular G, J and L substitutions can include nitro, aldehydes and halides.
Preferably W is selected from the group consisting of CH-,, C(=O), C(=O)-C(=O), CH2NH, -NHCH2, -CH2NHCH2, -CH2-N(CH3)CH2-, CH2 ( CH3)N -, CH ( CH3), S and CH2( C=O), -NH.
In accordance with a fourth aspect of the present invention, there are provided compounds represented by Formula IN
FORMULA IV wherein
Ri is selected from -ΝHC(=O)R2, -N(R3, Rj), -NR2C(=S)R3, -NR2C(=S)SR3 wherein R2, R3, i are independently hydrogen, aryl, heteroaryl, C1-12 alkyl, C3.12 cycloalkyl, Cι-6 alkoxy, Cι-6 alkyl substituted with one or more of F, Cl, Br, I, OH; preferably Ri is of the formula -NH(C=O)X3 wherein X3 is CH3, CH2F, CHF2, CF3, CH2C1, CHC12, CC13;
U and V are independently selected from hydrogen, optionally substituted Cι-6 alkyl, F, Cl, Br, Cι-12 alkyl substituted with one or more of F, Cl, Br, I; preferably U and V are hydrogen and fluoro;
Y and Z are independently selected from hydrogen, Cι_6 alkyl, C3_i2 cycloalkyl, C0-3 bridging group;
X is selected from C, CH, CH-S, CH-O or N;
Xi is (CH2)nS, (CH2)nO, where n = 0 to 3; NRπ; wherein Rn is hydrogen, optionally substituted C1-2 alkyl, C3.i2 cycloalkyl, Cι-6 alkoxy, Cι_6 alkyl, Cι-6 alkylcarbonyl, Cι_6 alkyl carboxy, aryl or heteroaryl; C=O, C=S;
X2 = CH orN;
W is independently selected from CR,, CO, CH2NH, -NHCH2, -CH2NHCH2, -CH2-N (Rπ)CH2 -, CH2( Rπ)N-, CH( Rπ), CH2( CO), NH, O, S, N(Rπ), (CO)CH2, N(Rιι)CON(Rπ), N(Rn)C(=S)N(Ru), SO2, SO, wherein R-- is the same as defined above;
G, J, L are independently selected from H, Cι-6 alkyl, F, Cl, Br,I, -CN, COR5,COOR5, N(R6,R7), NHCOC(R8, R9, Rio), CON (R6, R7), CH2NO2, NO2, CH2R8, CHR9, -CH = N- ORio, -C=CH-R5, OR5, SR5, -C(R9)=C(R9)NO2, Cι-i2 alkyl substituted with one or more of F, Cl, Br, I, OR , SR4; wherein j, R5 are independently selected from H, C1-12 alkyl, C3-ι2 cycloalkyl, Cι-6 alkoxy, Cι-6 alkyl substituted with one or more of F, Cl, Br, I or OH, aryl, heteroaryl; R6 and R7 are independently selected from H, optionally substituted Cι-ι2 alkyl, C3-ι cycloalkyl, Cι-6 alkoxy; R8 and R9 are independently selected from H, Cι-6 alkyl, F, Cl, Br, I, C1-12 alkyl substituted with one or more of F, Cl, Br, I, OR5, SR*, N(Re, R7); Rio^ H, optionally substituted C1-12 alkyl, C3-ι2 cycloalkyl, Cι.6 alkoxy, Cι.6 alkyl, aryl, heteroaryl; except when W=CO, X=N, X2=CH, Xι=O, G, J, L=H; and n is an integer in the range from 0 to 3;
Particular G, J and L substitutions include nitro, aldehydes or halides;
Preferably W is selected from the group consisting of CH2, C(=O), C(=O)-C(=O), CH2NH, -NHCH2, -CH2NHCH2, -CH2-N(CH3)CH2-, CH2 ( CH3)N -, CH ( CH3), S and CH2( C=O), -NH.
Another particular compound of Formula IN is as follows:
(S)-Ν-[[3-[3-Fluoro-4-[Ν-{2-thienyl-(5-nitro) methyl}piperidinyl-4-oxy]phenyl]-2-oxo-5- oxozolidinyl]methyl] acetamide.
In accordance with a fifth aspect of the present invention, there are provided compounds represented by Formula V
FORMULA V wherein Ri is selected from -NHC(=O)R2, -N(R3, R ), -NR2C(=S)R3, -NR2C(=S)SR3 wherein R2, R3, i are independently hydrogen, aryl, heteroaryl, C1-12 alkyl, C3_i2 cycloalkyl, Cι_6 alkoxy, Cι.6 alkyl substituted with one or more of F, Cl, Br, I, OH; preferably Ri is of the formula -NH(C=O)X3 wherein X3 is CH3, CH2F, CHF2, CF3, CH2C1, CHC12 or CC13; U and V are independently selected from hydrogen, optionally substituted Cι-6 alkyl, F, Cl, Br, Cι-12 alkyl substituted with one or more of F, Cl, Br, I; preferably U and V are hydrogen and fluoro;
Y and Z are independently selected from hydrogen, Cι_6 alkyl, C -i2 cycloalkyl, Co-3 bridging group; X is selected from H, CH, CH-S, CH-O, or N;
Xi is (CH2)nS, (CH2)nO, where n = 0 to 3; NRπ, wherein Rn is hydrogen, optionally substituted Cι.2 alkyl, C3-i2 cycloalkyl, Cι-6 alkoxy, Cι_6 alkyl, Cι_6 alkylcarbonyl, Cι-6 alkyl carboxy, aryl or heteroaryl; C=O, C=S;
X2 = CH orN; W is independently selected from CH2, CO, CH2NH, -NHCH2, -CH2NHCH2, -CH2-N (Rπ)CH2 -, CH2( Rπ)N -, CH ( Rπ), CH2( CO), NH, O, S, N(Rπ), (CO)CH2, N(RΠ)CON(RΠ), N(Rπ)C(=S)N(Rπ), SO2, SO, wherein R.- is the same as defined above;
G, J, L are independently selected from H, Cι.6 alkyl, F, Cl, Br,I, -CN, COR5,COOR5, N(R6,R7), NHCOC(R8, R9, Rι0), CON (Re, R7), CH2NO2, NO2, CH2R8, CHR9, -CH = N- OR10, -C=CH-R5, OR5, SR5, -C(R9)=C(R9)NO2, C1.12 alkyl substituted with one or more of F, Cl, Br, I, OR4, SR4; wherein i, R5 are independently selected from H, C1-12 alkyl, C3-12 cycloalkyl, Cι-6 alkoxy, Cι_6 alkyl substituted with one or more of F, Cl, Br, I or OH, aryl, heteroaryl; R6 and R , are independently selected from H, optionally substituted C1-12 alkyl, C3-12 cycloalkyl, -6 alkoxy; R8 and R9 are independently selected from H, Cι-6 alkyl, F, Cl, Br, I, C1-12 alkyl substituted with one or more of F, Cl, Br, I, OR5, SR4, N(Re-R7); Rιo= H, optionally substituted C1.12 alkyl, C3_i2 cycloalkyl, Cι-6 alkoxy, Ci-e alkyl, aryl or heteroaryl; except when W=CO, X=N, X2=CH, Xι=O, G, J, L=H; and n is an integer in the range from 0 to 3. Particular G, J and L substitutions are nitro, aldehydes and halides. Preferably W is selected from the group consisting of CH , C(=O), C(=O)-C(=O), CH2NH, -NHCH2, -CH2NHCH2, -CH2-N(CH3)CH2-, CH2 ( CH3)N -, CH ( CH3), S and CH2( C=O), -NH.
A particular compound of Formula V is as follows: (S)-N-[[3-[3-Fluoro-4-[ J-{2-furyl-(5-nitro)-methyl}piperidmyl-4-oxy]phenyl]-2-oxo-5- oxozolidinyljmethyl] acetamide.
Compounds of the present invention can be useful antimicrobial agents, effective against a number of human and veterinary pathogens, particularly aerobic Gram-positive bacteria, including multiply-antibiotic resistant staphylococci and streptococci, as well as anaerobic organisms such as Mycobacterium tuberculosis and other mycobacterium species.
For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, suppositories, and ointments. A solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, or tablets disintegrating agents; it can also be as finely divided solid which is in admixture with the finely divided active compound. For the preparation of tablets, the active compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about 5 to about 70 percent of the active ingredient. Suitable solid carriers are lactose, pectin, dextrin, starch, gelatin, tragacanth, low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component (with or without other carriers) is surrounded by carrier, which is thus in association with it. Similarly, capsules can be used as solid dosage forms suitable for oral administration.
Liquid form preparations include solutions, suspensions, and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Such solutions are prepared so as to be acceptable to biological systems
(isotonicity, pH, etc.). Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilizing, and thickening agents as desired. Aqueous suspension suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e., natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other well-known suspending agents.
Ointment preparations contain heavy metal salts of a compound of Formula I with a physiologically acceptable carrier. The carrier is desirably a conventional water- dispersible hydrophilic or oil-in-water carrier, particularly a conventional semi-soft or cream-like water-dispersible or water soluble, oil-in-water emulsion infected surface with a minimum of discomfort. Suitable compositions may be prepared by merely incorporating or homogeneously admixing finely divided compounds with the hydrophilic carrier or base or ointment.
The pharmaceutical preparations can be in unit dosage form. In such forms, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete capsules, powders in vials or ampoules, and ointments capsule, cachet, tablet, gel, or cream itself or it can be the appropriate number of any of these packaged forms.
The quantity of active compound in a unit dose of preparation may be varied or adjusted from less than 1 mg to several grams according to the particular application and the potency of the active ingredient.
In therapeutic use as agents for treating bacterial infections the compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 3 mg to about 40 mg per kilogram daily. The dosages, however, may be varied depending upon the requirements of the patient and the compound being employed. Determination of the proper dosage for a particular situation is within the smaller dosages which are less than the optimum dose. Small increments until the optimum effect under the daily dosage may be divided and administered in portions during the day if desired.
In one aspect, the invention provides processes for the synthesis of compounds of Formulae I, II, III, IN and V. Pharmaceutically acceptable non-toxic acid addition salts of the compounds of the present invention of Formulae I, II, III, TV and N may be formed with inorganic or organic acids, by methods well known in the art. The present invention also includes within its scope prodrugs of the compounds of
Formulae I, II, III, IV and V. In general, such prodrugs will be functional derivatives of these compounds which readily get converted in vivo into defined compounds.
Conventional procedures for the selection and preparation of suitable prodrugs are known to the artisan of ordinary skill in the art.
The invention also includes pharmaceutically acceptable salts, the enantiomers, diastereomers, N-oxides, prodrugs, metabolites in combination with a pharmaceutically acceptable carrier and optionally included excipients.
Other advantages of the invention will be set forth in the description which follows, and in part will be apparent from the description, or may be learned by the practice of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The compounds described herein represented by general Formula I may be prepared by the reaction sequence as shown in Scheme I:
SCHEME-I
FORMULA VI
R— T-W-R 12
FORMULA
In Scheme I, the amine of structure of Formula VI wherein
Mi is NH, NHRi4, CH2NHRι4, CH-CH2NHRι4, -CCH2-NHRι4 wherein R14 is H, ethyl, methyl, isopropyl, acetyl, cyclopropyl, or alkoxy and
Xi is (CH2)nS, (CH2)nO, where n = 0 to 3; n wherein Rn is the same as defined above; C=O, C=S;
X2 = CH or N;
Y and Z are independently selected from hydrogen, Q, alkyl, C3_12 cycloalkyl or C0_3 bridging group; U and V are independently selected from hydrogen, optionally substituted C._6 alkyl, F, Cl, Br, C . alkyl substituted with one or more of F, Cl, Br, I, preferably U and V are hydrogen or fluoro; and
Ri is selected from -NHC(=O)R2 , N(R3, Rt), -NR2C(=S)R3, -NR2C(=S)SR3 wherein R2 is hydrogen, aryl, heteroaryl, C._12 alkyl, C3_12 cycloalkyl, C. _6 alkoxy, C. 6 alkyl substituted with one or more of F, Cl, Br, I or OH; or thioCι-6 alkyl; R3, R4 are independently selected from hydrogen, aryl, heteroaryl, C._12 alkyl, C3 _n cycloalkyl, C. 6 alkoxy, C . 6 alkyl substituted with one or more of F, Cl, Br, I or OH, is reacted with a heteroaromatic compound of Formula R-T-W-R12 wherein T is a five to seven membered heterocyclic ring, aryl, substituted aryl, bound to the ring C with a linker W. Preferred forms of T are selected from aryl and five membered heteroaryl which are further substituted by a group represented by R, wherein R is selected from the group comsisting of H, Cι-6 alkyl, F, Cl, Br,I, -CN, COR5,COOR5, N(R6,R7), NHCOC(R8, R9, Rio), CON (R6, R7), CH2NO2, NO2„ CH2R8, CHR9, -CH = N-OR10, - C=CH-R5, OR5, SR5, -C(R9)=C(R9)NO2, Cm alkyl substituted with one or more of F, Cl, Br, I, OR4, SR4; wherein i and R5 are independently selected from H, C1-12 alkyl, C3-ι2 cycloalkyl, Cι-6 alkoxy, Cι-6 alkyl substituted with one or more of F, Cl, Br, I or OH, aryl, heteroaryl; R6 and R , are independently selected from H, optionally substituted Cι-ι2 alkyl, C3-ι2 cycloalkyl, Cι- alkoxy; R8 and R9 are independently selected from H, -6 alkyl, F, Cl, Br, I, Cι-ι2 alkyl substituted with one or more of F, Cl, Br, I, OR5, SR4, N(Rβ,R ); Rιo= H, optionally substituted C1-12 alkyl, C3-i2 cycloalkyl, Ci-e alkoxy, Cι-6 alkyl, aryl or heteroaryl;
W is selected from CH2, CO, CH2NH, -NHCH2, -CH2NHCH2, -CH2N(Rπ)CH2-, CH2( Rπ)N-, CH(Rπ), CH2(CO), NH, O, S, N(Rπ), (CO)CH2, N(Rπ)CON(Rπ), N(Rπ)CSN(Rιι), SO2, SO, wherein R is the same as defined above; and
R12 is a suitable leaving group well known to one of ordinary skill in the art such as fluoro, chloro, bromo, iodo, SCH3, -SO2CH3, -SO2CF3, Tos or OC6H5 etc. The reaction can be carried out in a suitable solvent in the presence of a suitable base selected from the group consisting of potassium carbonate, N-ethyldiisopropylamine and dipotassium hydrogen phosphate. For the preparation of compounds of Formula I when W is equal to CH2, the corresponding aldehyde can be used through a process of reductive amination and is attached to the amine of Formula VI.
Similarly, for the preparation of compound of Formula I wherein W is equal to C = O, the corresponding acid can be used and the amino compound of Formula VI can be acylated through activated esters in the presence of condensing agents such as 1,3- dicyclohexylcarbodiimide (DCC) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlori.de (EDC). Other methods of acylation can also be employed.
Alternatively, the compounds having carbonyl link can also be made by reacting heteroaromatic compound of the Formula VII (wherein G, J, L, Qi & Rι2 are the same as defined earlier),
Formula VII such as N-methyl pyrrole, with the intermediate amine of Formula VI in the presence of triphosgene or phosgene. The carbonyl linkers may also be introduced between heteroaromatic compound, such as 3-bromothiophene and the amine of Formula VI with carbon monoxide in the presence of a catalyst such as Pd (PPli3)2Cl . The extended chain pyrroles having dicarbonyl linkers can also be obtained from treatment with oxalyl chloride and the amine of the Formula VI.
Alternatively, for the preparation of compounds of Formula I, the heteroaromatic compound of the Formula VII, such as 2-bromo-thiophene is reacted with the intermediate amine of Formula VI in the presence of ligands such as palladium dibenzylidene acetone Pd2(dba)3 or Pd(OAc)2 with 2,2'-bis-(diρhenylphosphino)-l,l'-binaρhthyl (BINAP) and bases such as cesium carbonate or sodium t-butoxide (Ref: J. Org. Chem. 1999, 64, 6019- 6022 and J. Org. Chem. 2000, 65, 1144-1157). Other ligands such as ethylenediamine or TMEDA along with bases such as cesium carbonate or potassium phosphate may also be used (Synlett, 2002, 3, 427-430) The reduction of the carbonyl linkers using the standard reducing agents results in the formation of methylene linkers. The preparation of the compound of Formula II can be accomplished as exemplified below by three methods A, B and C as shown in Scheme II:
Scheme-II
Formula VI
Formula VII
Formula II
Method A:
The reductive alkylation of the amine intermediate of Formula VI with the corresponding heterocyclic aldehydes of the Formula VII, such as 5-nitro-2-furaldehyde (Qi = O; G=NO2, J, L = H; Rι2 is CHO) using reducing agents well known to one of ordinary skill in the art such as sodium triacetoxyborohydride or sodium cyanoborohydride gives the products of Formula II wherein W=CH2 as shown in Scheme II.
Alternatively, the compounds having carbonyl link can also be made by reacting heteroaromatic compound of the Formula VII, (wherein G, J, L, Qi and Rι2 are as defined earlier) such as N- methyl pyrrole with the intermediate amine of Formula VI in the presence of triphosgene or phosgene. The carbonyl linkers may also be introduced between heteroaromatic compound, such as 3-bromothiophene and the amine of Formula VI with carbon monoxide in the presence of a catalyst such as Pd (PPh3)2Cl2. The extended chain pyrroles having dicarbonyl linkers can also be obtained from treatment with oxalyl chloride and the amine of the Formula VI.
The reduction of the carbonyl linkers using the standard reducing agents results in the formation of methylene linkers.
Method B:
The amine of Formula VI is reacted with a heteroaromatic compound of Formula VII, such as 2-bromo-5-nitro thiophene where Qi = S, G = NO , J, L = H, R12 = Br, and Rι2 is a suitable leaving group which is the same as defined earlier for Scheme I.
The reaction can be carried out in a suitable solvent such as dimethylformamide, dimethylacetamide, ethanol, dimethylsulfoxide, acetonitrile, or ethylene glycol at a suitable temperature in the range of about -70°C to 180° C to afford compounds of Formula II. The presence of a suitable base such as tri ethylamine, N-ethyldiisopropyl amine, potassium carbonate, sodium bicarbonate, dipotassium hydrogen phosphate is useful in some cases to improve the yield of the reaction.
Method C:
The acylation of intermediate amines of Formula VI with a heterocyclic acid of Formula VII, such as 5-nitro-2- furoic acid ( Qi = O; G=NO2, J, L = H; RJ2 =COOH) gives products of Formula II, wherein W=CO as shown in the Scheme II wherein U, V, Y, Z, X, W, Qi, G, J, L and R12 are the same as defined earlier.
Mainly three different amines of Formula VI
Formula VI identified as three different cores, namely
(S)-N-[[3- {3-Fluoro-4-(ρiperidinyl-4-oxy)phenyl} -2-oxo-5- oxozolidinyl]methyl]acetamide (core I); (S)-N-[[3-[3-Fluoro-4-[{(l ,5α,6 )-3-azabicyclo[3.1.0]hexan-6-yl}-methyloxy]phenyl]- 2-oxo-5-oxozolidinyl]methyl]acetamide (Core II);
(S)-N-[[3-[3-Fluoro-4-[N-l-(N-l-piperazinylcarbonyl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-acetamide (Core III); were used for analoguing purposes wherein M, U, V, Y, Z, Ri, X1; X2 and n are as defined earlier.
The key intermediate amines of Formula VI for the analogue preparation were prepared from commercially available reagents. Some amines of Formula VI are already known in the literature and are given by reference and if they have been made for the first time or by different procedures or variation of known procedure they are described in detail in the experimental section.
The optically pure amines of Formula VI could be obtained either by one of a number of assymetric synthesis or alternatively by resolution from a racemic mixture by selective crystallization of a salt prepared, with an appropriate optically active acid such as dibenzoyl tartarate or 10-camphorsulfonic acid, followed by treatment with base to afford the optically pure amine.
The transformations effected are described in the experimental section. In the above synthetic methods where specific acids, bases, solvents, catalysts, oxidising agents, reducing agents etc. are mentioned, it is to be understood that the other acids, bases, solvents, catalysts, oxidising agents, reducing agents etc. may be used. Similarly, the reaction temperature and duration of the reaction may be adjusted according to the need.
An illustrative list of particular compounds according to the invention and capable of being produced by the above mentioned schemes include:
Compound No. Chemical Name 1. (S)-N-[[3-[3-Fluoro-4-[N-l-{2-furyl-(5-nitro) methyl}piρeridinyl-4-oxy]ρhenyl]-2- oxo-5-oxozolidinyl]methyl]acetamide (Compound No.l)
2. (S)-N-[[3-[3-Fluoro-4-[N-l - {2-thienyl-(5 -nitro) methyl}ρiρeridinyl-4-oxy]ρhenyl]-2- oxo-5-oxozolidinyl]methyl]acetamide (Compound No.2)
3. (S)-N-[[3-[3-Fluoro-4-| -l-{2-ftιryl-(4-bromo-5-nitro) methyl}ρiperidinyl-4- oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide (Compound No.3) 4. (S)-N-[[3-[3-Fluoro-4-[N-l- {2-thienyl-(4-bromo-5-nitro) methyl}piperidinyl-4- oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide (Compound No.4)
5. (S)-N-[[3-[3-Fluoro-4-[N-l- {2-thienyl-(4-morpholino-5-nitro) methyl}ρiρeridinyl-4- oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide (Compound No.5) 6. (S)-N-[[3-[3-Fluoro-4-[N-l-[2-thienyl-{4-(N-4-methyl piperazin-l-yl)-5-nitro} methyl]piperidinyl-4-oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide (Compound No.6)
7. (S)-N-[[3-[3-Fluoro-4-pSf-l-{2-thienyl-(4-dimethylamino-5-nitro) methyl}piρeridinyl- 4-oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide (Compound No.7) 8. (S)-N-[[3-[3-Fluoro-4-[N-l-{2-furyl-(4-isopropyl-5-nitro) methyl}piperidinyl-4- oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide (Compound No.8)
9. (S)-N-[[3-[3-Fluoro-4-[N-l-[2-furyl-{5-(2-nitro)phenyl} methyl]piperidinyl-4- oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide (Compound No.9)
10. (S)-N-[[3-[3-Fluoro-4-P^-l-[2-furyl-{5-(3-nitro)phenyl} methyl]ρiperidinyl-4- oxyjphenyl] -2-oxo-5 -oxozolidinyljmethyl] acetamide (Compound No .10)
11. (S)-N-[[3-[3-Fluoro-4-[N-l- {3-thienyl-(2-nitro) methyl}piρeridinyl-4-oxy]phenyl]-2- oxo-5-oxozolidinyl]methyl]acetamide (Compound No.l 1)
12. (S)-N-[[3-[3-Fluoro-4-[N-l-{2-furyl-(5-nitro) methyl}piperidinyl-4-oxy]phenyl]-2- oxo-5-oxozolidinyl]methyl]thioacetamide (Compound No.12) 13. (S)-N-[[3-[3-Fluoro-4-[N-l- {(benzo(b)furan-2-yl)methyl}ρiperidinyl-4-oxy]ρhenyl]- 2-oxo-5-oxozolidinyl]methyl]acetamide (Compound No.13)
14. (S)-N-[[3-[3-Fluoro-4-[N-l-{2-thienyl-(5-nitro)}ρiρeridinyl-4-oxy]ρhenyl]-2-oxo-5- oxozolidinyl]methyl] acetamide (Compound No.14)
15. (S)-N-[[3-[3-Fluoro-4-[N-l -[ 1 - {2-furyl-(5-nitro)} -ethyl] piperidinyl-4-oxy]phenyl]-2- oxo-5-oxozolidinyl]methyl]acetamide (Compound No.15)
16. (S)-N-[[3-[3-Fluoro-4-|Η-l-{2-furyl-(5-nitro)carbonyl}ρiperidinyl-4-oxy]ρhenyl]-2- oxo-5-oxozolidinyl]methyl]acetamide (Compound No.16)
17. (S)-N-[[3-[3-Fluoro-4-[ f-l-{(benzo(b)furan-2-yl)carbonyl}piρeridinyl-4-oxy]phenyl]- 2-oxo-5-oxozolidinyl]methyl]acetamide (Compound No.17) 18. (S)-N-[[3-[3-Fluoro-4-[N-l- {2-thienyl-(5-nitro)carbonyl}piperidinyl-4-oxy]phenyl]-2- oxo-5-oxozolidinyl]methyl]acetamide (Compound No.18)
19. (S)-N-[[3-[3-Fluoro-4-[N-l-{2-thienyl-(5-nitro)thiocarbonyl}piperidinyl-4- oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]thioacetamide (Compound No.19) 20. (S)-N-[[3-[3-Fluoro-4-[{(lα,5α,6α)-3-t-butoxycarbonyl-3-azabicyclo[3.1.0]hexan-6- yl}-methyloxyl]phenyl]-2-oxo-5-oxozolidinyl]methyl] acetamide (Compound No.20)
21. (S)-N-[[3-[3-Fluoro-4-[[(lα,5α,6α)-3-{2-furyl(5-nitro)methyl}-3- azabicyclo[3.1.0]hexan-6-yl]-methyloxyl]phenyl]-2-oxo-5- oxozolidinyljmethyl] acetamide (Compound No.21) 22. (S)-N-[[3-[3-Fluoro-4-[[(lα,5α,6α)-3-{2-thienyl(5-nitro)methyl}-3- azabicyclo[3.1.0]hexan-6-yl]-methyloxyl]phenyl]-2-oxo-5- oxozolidinyljmethyl] acetamide (Compound No.22)
23. (S)-N-[[3-[3-Fluoro-4-[{(l ,5α,6α)-3-(5-nitro-2-thienyl)-3-azabicyclo[3.1.0]hexan-6- yl}-methyloxyl]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide (Compound No.23) 24. (S)-N-[[3-[3-Fluoro-4-[N-l-(4-t-butoxycarbonyl)piperazinylcarbonyl] phenyl] -2-oxo- 5-oxazolidinyl]methyl]-acetamide (Compound No.24)
25. (S)-N-[[3-[3-Fluoro-4-[N-l-[4-{2-furyl-(5-nitro)methyl}]piperazinylcarbonyl] phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide (Compound No.25)
26. (S)-N-[[3-[3-Fluoro-4-[N-l-[4-{2-thienyl-(5-nitro)methyl}]ρiρerazinylcarbonyl] phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide (Compound No.26)
27. (S)-N-[[3-[3-Fluoro-4-[N-l-[4-{2-thienyl-(5-nitro)}]piperazinylcarbonyl]phenyl]-2- oxo-5-oxazolidinyl]methyl]-acetamide (Compoimd No.27)
Most of the compounds were characterized using NMR, IR and were purified by chromatography. Crude products were subjected to column chromatographic purification using silica gel (100-200 or 60-120 mesh) as stationary phase.
The examples mentioned below demonstrate the general synthetic procedure as well as the specific preparation for the preparation for the preferred compound. The examples are given to illustrate the details of the invention and should not be constrained to limit the scope of the present invention. EXAMPLE 1
Analogues of (S)-N-[[3-[3-FIuoro-4-(piperidinyI-4-oxy)phenyI]-2-oxo-5- oxozolidinyl] methyl] acetamide (core I)
(S)-N-[ [3 - [3 -Fluoro-4-(piperidinyl-4-oxy)phenyl] -2-oxo-5 -oxozolidinyl]methyl] acetamide 5 (core I) was prepared according to the procedure in Bioorganic & Medicinal Chemistry Letters 11 (2001) 1829-1832. The heteroaromatic group with the corresponding appendage can be introduced on the nitrogen atom of ring C of compounds of Formula I by one of the methods described below:
Method A l o General Procedure :
The reductive alkylation of the amine intermediate of Formula VI with the corresponding heterocyclic aldehydes of the Formula VII, using known reducing agents well known to one of ordinary skill in the art such as sodium triacetoxyborohydride or sodium cyanoborohydride gave the products of Formula II wherein W=CH2.
15 The following compounds were made using this method:
Compound No.l (S)-N-[[3-[3-Fluoro-4-[N-l-{2-furyl-(5-nitro) methyl}piperidinyl-4- oxy] phenyl] -2-oxo-5-oxozolidinyl] methyl] acetamide.
To a solution of compound (S)-N-[[3-[3-Fluoro-4-(piperidinyl-4-oxy)phenyl]-2-oxo-5- oxozolidinyl]methyl]acetamide (1.81 mmole) in THF, 5-nitro-furan-2-carboxaldehyde
20 (2.36mmole) and molecular seive (4A)were added at RT with stirring. After stirring for 15 min., sodium triacetoxy borohydride (5.45 mmole) was added and further stirred for 6-7hr at RT. The reaction mixture was filtered through celite bed and washed with THF. The filtrate was concentrated under reduced pressure. The residue obtained was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution (100ml) followed by 5 brine wash (100ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography using 2-3% methanol in dichloromethane as eluent to yield 515 mg of the title compound. tfNMR (CDCl3)δ PPM: 7.47-7.43 (d,lH), 7.05-6.97 (m,2H), 6.49-6.47 (d,lH), 6.10(m,lH), 4.78(m,lH), 4.38(m,lH), 4.01-3.98(t,lH), 3.77-3.62(m,5H), 2.79- 2.76(m,2H), 2.45-2.42(m,2H), 2.02(s,3H), 1.97-1.94(m,2H).
Compound No.2 (S)-N-[[3-[3-Fluoro-4-[N-l-{2-thienyl-(5-nitro) methyl}piperidinyl-4- oxy] phenyl] -2-oxo-5-oxozoIidinyl] methyl] acetamide
The title compound was prepared from (S)-N-[[3-[3-Fluoro-4-(piperidinyl-4-oxy)phenyl]- 2-oxo-5 -oxozolidinyl]methyl] acetamide and 5-nitro-2-thioρhenecarboxaldehyde using Method A.
H!NMR (CDCl3)δ PPM: 7.8(S,1H), 7.49-7.45(d,lH), 7.08-6.96(m,3H), 6.09(m,lH), 4.76(m,lH), 4.36 (m,lH), 4.05-3.99(t,lH), 3.78-3.57(m,5H), 2.85(m,2H), 2.51(m,2H),2.03(s, 3H), 1.95(m,4H).
Compound No. 3 (S)-N-[[3-[3-Fluoro-4-[N-l-{2-furyl-(4-bromo-5-nitro) methyl}piperidinyl-4-oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide
The title compound was prepared from (S)-N-[[3-[3-Fluoro-4-(piperidinyl-4-oxy)phenyl]- 2-oxo-5-oxozolidinyl]methyl] acetamide and 4-bromo-5-nifro-2-furaldehyde using Method A. tfNMR (CDCl3)δ PPM: 7.47-7.43(d,lH), 7.09-7.05(d,lH), 7.005-6.94(m,lH), 6.62(s,lH), 6.02-6.00(m,lH), 4.77-4.75(m,lH), 4.28(m,lH), 4.01(t,lH), 3.77-3.62(m,5H), 2.79- 2.77(m,2H), 2.44(m,2H), 2.02(s,3H), 1.97-1.93(m,2H), 1.90-1.87(m,2H). Compound No. 4 (S)-N-[[3-[3-Fluoro-4-[N-lτ{2-thienyl-(4-bromo-5-nitro) methyl}piperidinyl-4-oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl] acetamide
The title compound was made with (S)-N-[[3-[3-Fluoro-4-(piperidinyl-4-oxy)phenyl]-2- oxo-5-oxozolidinyl]methyl]acetamide and 4-bromo-5-nitro-2-thiophenecarboxaldehyde using Method A. H1NMR (CDCl3)δ PPM: 7.48-7.44(d,lH), 7.08 7.06(d,lH), 7.01-6.98(d,lH), 6.92(s,lH), 6.00(m,lH), 4.77(m,lH), 4.33(m, 1H) . Compound No. 5 (S)-N-[[3-[3-Fluoro-4-[N-l-{2-thienyl-(4-morpholino-5-nitro) methyl}piperidinyl-4-oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide
The title compound was prepared from (S)-N-[[3-[3-Fluoro-4-(piperidinyl-4-oxy)phenyl]- 2-oxo-5-oxozolidinyl]methyl]acetamide and 4-morpholino-5-nitro-2- thiophenecarboxaldehyde using Method A.
H*NMR (CDCl3)δ PPM: 7.47-7.43 (d, IH ), 7.05-6.98 (d, IH ), 6.57(s,lH), 6.00 (m,lH), 4.70 (m, IH), 4.30 (m,lH), 4.01 (t, IH), 3.89-3.86 (m,3H), 3.77-3.71 (m,2H), 3.64-3.60 (m,2H), 3.39-3.36 (m,5H), 2.75 (m,2H), 2.45 (m,2H), 2.02 (s,3H), 1.93 (m, 4H) .
Compound No. 6 (S)-N-[[3-[3-FIuoro-4-[N-l-[2-thienyl-{4-(N-4-methyl piperazin-1- yl)-5-nitro} methyl]piperidinyl-4-oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide
The title compound was prepared from (S)-N-[[3-[3-Fluoro-4-(piperidinyl-4-oxy)phenyl]- 2-oxo-5-oxozolidinyl]methyl] acetamide and 4-(N-4-methyl-piperazin- 1 -yl)-5-nitro-2- thiophenecarboxaldehyde using Method A. tfNMR (CDCl3)δ PPM: 7.47-7.43 (d,lH), 7.07-6.95 (d,2H), 6.56 (s,lH), 6.02 (m,lH), 4.77-4.75 (m,lH), 4.31(m,lH), 4.04-3.98 (t,lH), 3.77-3.59 (m,5H), 3.41-3.40 (m,4H), 2.77 (m,2H), 2.60 (m,4H), 2.44 (m,2H), 2.36 (s,3H), 2.11 (s,3H), 2.02-1.89 (m,4H) .
Compound No. 7 (S)-N-[[3-[3-Fluoro-4-[N-l-{2-thienyI-(4-dimethylamino-5-nitro) methyl} piperidinyl-4-oxy]phenyl]-2-oxo-5-oxozoIidinyl]methyl]acetamide
The title compound was prepared from (S)-N-[[3-[3-Fluoro-4-(piperidinyl-4-oxy)phenyl]- 2-oxo-5-oxozolidinyl]methyl]acetamide and 4-dimethylamino-5-nitro-2- thiophenecarboxaldehyde using Method A. tfNMR (CDCl3)δ PPM: 7.48-7.44 (d,lH), 7.08-6.5 (m,2H), 6.54 (s,lH), 6.04 (m,lH), 4.77 (m,lH), 4.32 (m,lH), 4.05-3.99 (t,lH), 3.77-3.69 (m,5H), 3.11 (s,6H), 2.77 (m,2H), 2.45 (m,2H), 2.02 (s,3H), 1.96-1.91 (m,4H) . Compound No. 8 (S)-N-[[3-[3-Fluoro-4-[N-l-{2-furyl-(4-isopropyl-5-nitro) methyl}piperidinyl-4-oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide
The title compound was prepared from (S)-N-[[3-[3-Fluoro-4-(piperidinyl-4-oxy)phenyl]- 2-oxo-5-oxozolidinyl]methyl]acetamide and 4-isopropyl-5-nitro-2- thiophenecarboxaldehyde using Method A. H NMR (CDCl3)δ PPM: 7.47-7.42 (d,lH), 7.07-6.95 (m,2H), 6.45 (s,lH), 6.11 (m,lH), 4.76 (m,lH), 4.28 (m,lΗ), 4.05-3.99 (t,lH), 3.77-3.58 (m,5H), 2.8 (m,2H), 2.44 (m,2H), 2.17 (m,lH), 2.02 (s,3H), 1.98-1.87 (m,4H), 1.71 (s,6H) .
Compound No. 9 (S)-N-[[3-[3-Fluoro-4-[N-l-[2-furyl-{5-(2-nitro)phenyI} methyl]piperidinyl-4-oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide
The title compound was prepared from (S)-N-[[3-[3-Fluoro-4-(piperidinyl-4-oxy)phenyl]- 2-oxo-5 -oxozolidinyl]methyl] acetamide and 5-(2-nitro)phenyl-2-furaldehyde using Method A.
H1NMR (CDCl3)δ PPM: 7.70-7.68 (d,2H), 7.67 (t,lH), 7.56-7.40 (m,2H), 7.04-6.98 (m,lH), 4.04-3.98 (t,lH), 3.75-3.59 (m,5H), 2.81-2.78 (m,2H), 2.39 (m,2H), 2.02 (s,3H), 1.87-1.85 (m,4H) .
Compound No. 10 (S)-N-[[3-[3-Fluoro-4-[N-l-[2-furyl-{5-(3-nitro)phenyl} methyl]piperidinyl-4-oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide
The title compound was prepared from (S)-N-[[3-[3-Fluoro-4-(piperidinyl-4-oxy)phenyl]- 2-oxo-5 -oxozolidinyl]methyl] acetamide and 5-(3-nitro)phenyl-2-furaldehyde using Method A.
H NMR (CDCl3)δ PPM: 8.47 (s,lH), 8.09-8.06 (d,lH), 7.96-7.94 (d,lH), 7.56-7.51 (t,lH), 7.46-7.411 (d,lH), 7.04-6.97 (m,2H), 6.76-6.75 (d,lH), 6.36-6.34 (d,lH), 5.98 (m,lH),
Compound No. ll(S)-N-[[3-[3-Fluoro-4-[N-l-{3-thienyl-(2-nitro) methyl}piperidinyl- 4-oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide
The title compound was prepared from (S)-N-[[3-[3-Fluoro-4-(piperidinyl-4-oxy)phenyl]- 2-oxo-5-oxozolidinyl]methyl]acetamide and 2-nitro-3-thiophenecarboxaldehyde using Method A.
H!NMR (CDCl3)δ PPM: 7.49-7.45 (m,lH), 7.20 (m,lH), 7.10-6.97 (m,2H), 6.04-6.03 (m,lH), 4.78-4.74 (m,lH), 4.32 (m,lH), 4.06-4.00 (m,2H), 3.78-3.56 (m,4H), 2.89 (m,2H), 2.42 (2H,m), 2.03 (s,3H), 1.94-1.82 (m,4H) .
Compound No. 12 (S)-N-[[3-[3-FIuoro-4-[N-{2-furyl-(5-nitro) methyI}piperidinyl-4- oxy] phenyl] -2-oxo-5-oxozolidinyl] methyl] thioacetamide
To a solution of compound (S)-N-[[3-[3-Fluoro-4-[N-{2-furyl-(5- nitro)methyl}piperidinyl-4-oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide
16 (0.48mmole) in toluene (20ml), Lawesson's reagent was added and it was heated to 70- 80°C for 4-5 hr. The reaction mixture was cooled to RT and quenched with water and then extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was triturated with ether. The solid was filtered and dried to yield 30 mg of the title compound.
H1NMR (CDCl3)δ PPM: 7.94 (m,lH), 7.46-7.41 (d,lH), 7.29-7.28 (s,lH), 7.06-6.94 (m,2H), 6.51 (d,lH), 4.97-4.95 (m,lH), 4.30-4.23 (m,2H), 4.10-4.00 (m,2H), 3.83-3.80 (t,lH), 3.78-3.70 (m,2H), 2.81 (m,2H), 2.59 (s,3H), 2.47 (m,2H), 1.90 (m,4H). Compound No. 13 (S)-N-[[3-[3-Fluoro-4-[N-{(benzo(b)furan-2-yl)methyl}piperidinyl- 4-oxy] phenyl] -2-oxo-5-oxozolidinyl] methyl] acetamide
The title compound was prepared from (S)-N-[[3-[3-Fluoro-4-(piperidinyl-4-oxy)phenyl]- 2-oxo-5-oxozolidinyl]methyl]acetamide and benzo(b)furan-2-carboxaldehyde using Method A. H1NMR (CDCl3)δ PPM: 7.54-7.46 (m,4H), 7.28-7.26 (s,lH), 7.05-6.99 (m,2H), 6.62 (s,lH), 6.30 (m,lH), 4.77-4.74 (m,lH), 4.28 (m,lH), 4.03-3.97 (t,lH), 3.71-3.60 (m,5H), 2.84 (m,2H), 2.48 (m,2H), 2.01 (s,3H), 1.92-1.91 (m,4H).
Method-B:
General procedure: The amine of structure of Formula VI is reacted with a heteroaromatic compound of Formula VII having corresponding Rι2 appendages such as Rι3, -CH2R13, -COR13 or - CH(CH3)Ri3 wherein R 13 is a suitable leaving group well known to one of ordinary skill in the art such as fluoro, chloro, bromo, SCH3, -SO2CH3; -SO2CF , Tos or OC6H5 etc.
The reaction is carried out in a suitable solvent such as dimethylformamide, dimethylacetamide, ethanol or ethylene glycol at a suitable temperature in the range of - 78°C to 180°C to afford compounds of Formula II. The presence of a suitable base such as triethylamine, diisopropyl amine, potassium carbonate, sodium bicarbonate is useful in some cases to improve the yield of the reaction.
The following compounds were made following this method: Compound No. 14 (S)-N-[[3-[3-Fluoro-4-[N-l-{2-thienyl-(5-nitro)}piperidinyl-4- oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide
To a solution of compound (S)-N-[[3-[3-Fluoro-4-(piperidinyl-4-oxy)phenyl]-2-oxo-5- oxozolidinyl]methyl] acetamide (0.665mmole) in DMSO (8ml), potassium carbonate (1.330mmole) and 2-bromo-5-nitro-thiophene (0.789mmole) were added and stirred for 14 hr at RT. The reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography using 1-2% methanol in dichloromethane as eluent to get the product, and triturated with ether. The solid obtained was filtered and dried to yield 130 mg of the title compound. rfNMR (CDCl3)δ PPM: 7.80-7.78 (m,lH), 7.50 (dd,lH), 7.05 (t,lH), 6.03-5.97 (m,2H), 4.78-4.77 (m,lH), 4.55-4.52 (m,lH), 4.03 (t,lH), 3.77 (t,lH), 3.74-3.62 (m,4H), 3.44-3.36 (m,2H), 2.07-2.05 (m,4H), 2.03 (s,3H). Compound No. 15 (S)-N-[[3-[3-Fluoro-4-[N-l-[l-{2-furyl-(5-nitro)-}-ethyl] piperidinyl-4-oxy] phenyl] -2-oxo-5-oxozolidinyl] methyl] acetamide.
The tiltle compound was prepared from (S)-N-[[3-[3-Fluoro-4-(piperidinyl-4-oxy)phenyl]- 2-oxo-5 -oxozolidinyl]methyl] acetamide and 5-nitro-2-( - trifluoromethylsulfonate)ethylfuran using Method B. H*NMR (CDCl3)δ PPM: 7.51-7.45 (lH,d), 7.26 (lH,s), 7.07-7.02 (lH,d), 6.99-6.97 (lH,d), 6.42-6.41(lH,s), 6.05 (lH,m), 4.77-4.76(lH,m), 4.32 (lH,m), 4.05-3.99 (lH,t), 3.79-3.68 (4H,m), 3.1(2H,m), 2.61 (2H,m), 2.03-2.01 (3H,s), 1.97-1.94(4H,m), 1.30(3H,d).
Method C: General Procedure:
The compound of Formula I wherein W is equal to C= is prepared from the corresponding acid of Formula VII and the amine of Formula VI is acylated through activated esters in the presence of condensing agents such as 1,3- dicyclohexylcarbodiimide (DCC) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), along with 1-hydroxybenzotriazole. Other methods of acylation can also be employed. The following compounds were prepared using this method:
Compound No. 16 (S)-N-[[3-[3-Fluoro-4-[N-l-{2-furyl-(5-nitro)carbonyl}piperidinyl- 4-oxy] phenyl] -2-oxo-5-oxozolidinyl] methyl] acetamide
To SL solution of compound (S)-N-[[3-[3-Fluoro-4-(piperidinyl-4-oxy)phenyl]-2-oxo-5- oxozolidinyl]methyl] acetamide in DMF, N-methyl morpholine (NMM) (1.064mmole), 1- hydroxybenzotriazole (HOBT) (1.064mmole), & 5-nitro-2-furoic acid (0.975mmole) were added at 0°C and stirred at the same temperature for lhr. EDC (1.064mmole) was added at 0°C and the temperature was brought to room temperature over a period of lhr and then stirred the reaction mixture for 14 hr at room temperature. The reaction mixture was quenched with water and extracted with ethyl acetate (100 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated to get the crude product which was purified by column chromatography using 2-3% methanol in dichloromethane as eluent to yield 150 mg of the title compound. tfNMR (CDCl3)δ PPM: 7.92 (dd,lH), 7.68(d,lH), 7.24(m,lH,-NH), 7.16 (d,lH), 7.15- 7.00 (m, 2H), 4.78 (m,lH), 4.57(m,lH), 4.02 (t,2H), 3.88-3.82 (m,4H), 3.64-3.62 (m,2H), 3.10 (m,4H), 2.01 (s,3H).
M+l= 513
Compound No. 17 (S)-N-[[3-[3-Fluoro-4-[N-l-{(benzo(b)furan-2- yl)carbonyl}piperidinyl-4-oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide The title compound was prepared from (S)-N-[[3-[3-Fluoro-4-(piperidinyl-4-oxy)phenyl]- 2-oxo-5-oxozolidinyl]methyl]acetamide and benzo(b)-furan-2-carboxylic acid using Method C.
^ MR (CDCl3)δ PPM: 7.66-7.63 (d,lH), 7.53-7.37 (m,3H), 7.31-7.29 (m,2H), 7.08-7.02 (m,2H), 6.16 (m,lH), 4.76 (m,lH), 4.55 (m,lH), 4.06-4.00 (m,2H), 3.89-3.84 (m,2H), .41 (m,4H),2.03 (s,3H), 2.00-1.96 (m,4H).
Compound No. 18 (S)-N-[[3-[3-Fluoro-4-[N-l-{2-thienyl-(5- nitro)carbonyl}piperidinyl-4-oxy] phenyl] -2-oxo-5-oxozolidinyl] methyl] acetamide
The title compound was prepared from (S)-N-[[3-[3-Fluoro-4-(piperidinyl-4-oxy)phenyl]- 2-oxo-5-oxozolidinyl]methyl]acetamide and 5-nitro-2-thiophenecarboxylic acid using Method C. H'lSIMR (CDC13 +DMSO)δ PPM: 7.87 (d,lH), 7.69(m,lH), 7.52(dd,lH), 7.22 (d,lH), 7.11-7.00 (m,2H), 4.77 (m,lH),4.56 (m,lH), 4.02 (t,lH), 3.83-3.78 (m,5H), 3.67 (m,2H), 3.21 (m,4H), 1.99 (s,3H).
M+l = 513 Compound No. 19 (S)-N-[[3-[3-Fluoro-4-[N-l-{2-thienyl-(5- nitro)thiocarbonyl}piperidinyl-4-oxy]phenyl]-2-oxo-5- oxozolidinyl]methyl]thioacetamide
The title compound was prepared with (S)-N-[[3-[3-fluoro-4-(piρeridinyl-4-oxy)phenyl]- 2-oxo-5-oxazolidinyl]methyl]thioacetamide and 5-nitro-2-thiophenecarboxylic acid using Method C.
H!NMR (CDCl3)δ PPM: 7.96 (m,lH),7.76 (d,lH), 7.48(dd,lH), 7.12-6.97 (m,3H), 5.00- 4.98 (m,lH),4.63 (m,lH), 4.30-4.25(m,lH), 4.12-4.06( m,4H), 3.84 (t,lH), 3.71 (m,lH), 3.52-3.45 (m,lH), 2.60 (s,3H), 2.05 (m,4H).
EXAMPLE 2
Analogues of (S)-N-[[3-[3-Fluoro-4-[{(lα,5α,6α)-3-azabicyclo[3.1.0]hexan-6-yl}- methyloxy]phenyl]-2-oxo-5-oxozolidinyl]methyl] acetamide (Core II)
(S)-N-[[3-[3-Fluoro-4-[{(l ,5α,6α)-3-azabicyclo[3.1.0]hexan-6-yl}-methyloxy]phenyl]- 2-oxo-5-oxazolidinyl]methyl]acetamide (Core II) was prepared according to the following procedure:
Step-a: Preparation of (lα,5α,6 )-6-hydroxymethyl-3-azabicyclo[3.1.0]-hexane:
To a solution of (lα,5α,6α)-3-benzyl-6-hydroxymethyl-3-azabicyclo[3.1.0]-hexane (20gm, 0.098 mole) in methanol (300), was added ammonium formate (15.5 gm, 0.246 mole) and Pd/C (8 gm, wet 5%) and the rection mixture was heated to 50°C for 8 hrs. It was then filtered through celite bed (hyflo), and washed with methanol (100ml). The filtrate was evaporated in vacuo to yield 1 lgm of the title compound.
1H NMR (DMSO-d6) δ PPM: 3.27 (d,2H), 2.82 (d,2H), 2.64 (d,2H), 1.20 (m,2H), 0.85 (m,lH) . Step-b: Preparation of (l ,5α,6α)-3-tert-butoxycarbonyl-6-hydroxymethyl-3- azabicyclo[3.1.0]-hexane:
To a solution of [lα,5α,6α]6-hydroxymethyl-3-azabicyclo[3.1.0]hexane (llgm, 0.097 mole) in dichloromethane (200ml), triethylamine (17.5mL, 0.126 mole) was added and cooled to 0°C. It was followed by the dropwise addition of di tert- butoxydicarbonate (25.4gm, 0.116 mole) at 0 to 5°C and then stirred at room temperature for 4 hrs. The reaction mixture was diluted with dichloromethane (100ml), washed with saturated sodium bicarbonate solution (2 x 200ml), followed by brine wash (2x 100ml). The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to yield the crude product which was purified by column chromatography, using 10% ethylacatate in hexane as eluent to yield 8.0 gm of the desired compound.
1H NMR (CDCI3) δ PPM : 3.63-3.60 (d,2H), 3.53-3.47 (m,2H), 3.43-3.33 (m,2H), 1.75- 1.64 (m,2H), 1.43 (s,9H) 0.97-0.90 (m,lH).
Step-c: Preparation of 3- fluoro- 4-[{(lα,5α,6α)-3-tert-butoxycarbonyl-3-azabicyclo- [3.1.0]hexan-6-yl}-methyloxy]mtrobenzene:
To a solution of potassium tert-butoxide (t- KOBu) (5.13 gm, 0.045 mole) in THF (100ml), (1 α,5 ,6α)-3-tert-butoxycarbonyl-6-hydroxymethyl-3-azabicyclo[3.1.0]hexane obained in step-b dissolved in (50ml) THF was added and cooled to 0 to 5°C. Then, 3,4, diflouro nitrobenzene (5.6 gm, 0.0352 mole) was added dropwise and stirred for 2h at room temperature. The reaction mixture was quenched with saturated NH4C1 solution (50ml). The organic layer was separated. The aqueous layer was again extracted with ethyl acetate (200ml), the combined organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by column chromatography (15% ethyl acetate : hexane ) to yield 6.5 gm of the title compound. 1H NMR (CDC13) δ PPM : 8.06-7.97 (m,2H), 7.02-6.96 (t,lH), 4.14-4.12 (m,lH), 4.00- 3.94 (m,lH), 3.71-3.61 (m,2H), 3.41-3.38 (m,2H), 1.64 (m,2H), 1.34 (s,9H), 1.23-1.18 (m,lH).
Step-d: Preparation of 3-Fluoro-4-[{(lα,5α,6α)-3-tetrabutoxycarbonyl-3- azabicyclo[3.1.0]hexan-6-yl}methyloxy]aniline: To a solution of 3-fluoro-4-[{(lα,5α,6α)-3-tert-butoxycarbonyl-3-azabicyclo- [3.1.0]hexan-6-yl}-methyloxy]nitrobenzene obtained in step-c (6gm) in methanol (100), 5% wet Pd/C (8gm) was added and shaken in a parr hydrogenation apparatus under 50 psi of hydrogen gas for 3h . Then the rection mixture was filtered over celite bed and washed with 50 ml of methanol. The filtrate was evaporated in vacuo to yield 5.5 gm of the title compound.
1H NMR (CDC13) δ PPM: 6.80-6.77 (t, IH, Ar), 6.45-6.41 (d, Ar), 6.34-6.32 (d, lH-ArH), 3.89-3.86 (m, IH), 3.76-3.74 (m, IH), 3.70-3.56 (m, 2H), 3.53-3.51 (d, 2H), 3.34-3.32 (m, 2H, NH2), 1.48 (m, 2H), 1.41 (s, 9H), 1.09-1.05 (m, IH).
Step-e: Preparation of 3-Fluoro-4-[{(l ,5α,6α)-3-tetrabutoxycarbonyl-3- azabicyclo[3.1.0]-hexan-6-yl}methyloxy] benzyloxy carbonyl aniline: To a solution of 3-Fluoro-4-[{(lα,5α,6α)-3-tetrabutoxycarbonyl-3- azabicyclo[3.1.0]hexan-6-yl}methyloxy]aniline obtained in step-d (D, 5.0 gm, 0.015 mole) in THF (150ml) cooled to 5°C, sodium bicarbonate (3.92 gm, 0.046 mole), was added and then benzylchloroformate (3.94 gm, 0.02 mole) was added dropwise at the same temperature . The reaction mixture was stirred at room temperature for 4 hrs and then filtered, washed with THF (50 ml). The filtrate was evaporated in vacuo. The residue obtained was triturated with hexane. The solid was filtered and dried to get the 5.0 gm of the title compound.
1H NMR (CDC13) δ PPM: 7.38-7.33 (5H, Ar), 7.28 (d, IH, Ar), 6.77-6.84 (m, 2H), 6.60 (m, IH, -NH), 5.19 (d, 2H, -COH2-Ar), 3.98-3.96 (m, IH), 3.83-3.81 (m, IH), 3.66-3.56 (m, 2H), 3.37-3.36 (m, 2H), 1.57 (m, 2H), 1.43 (s, 9H), 1.11-1.08 (m, IH).
Step-f: Preparation of R(-)-3-[3-fluoro-4-[{(lα,5α,6α)-3-tetrabutoxycarbonyl-3- azabicyclo[3.1.0]hexan-6-yl}methyloxy]phenyl]5-hydroxymethyl-2-oxazolidinone :
To a solution of 3-Fluoro-4-[{(lα,5α,6α)-3-tetrabutoxycarbonyl-3-azabicyclo[3.1.0]- hexan-6-yl}methyloxy]benzyloxycarbonylaniline obtained in step-e (4.5 gm, 0.0098 mole) in dry THF (50ml) cooled to -78°C, butyl lithium (8.39 ml 15% soln in hexane, 0.0199 mole) was added under the presence of nitrogen. The reaction mixture was stirred at -78°C for 1.5hr, then R-glycidyl butyrate (1.70 gm, 0.0118 mole) was added and the reaction mixture was stirred at -78°C for lhr and then at RT for 18 hr. The reaction mixture was quenched with saturated ammonium chloride solution (25 ml) and the organic layer was separated. The aqueous layer was again extracted with 200ml of ethyl acetate. The combined organic layer was dried over anhydrous Na SO4 and evaporated in vacuo. The crude product was purified by column chromatography (eluent is 2% methanol in dichloromethane) to yield 3.5 gm of the title compound.
1H NMR (CDCI3) δ PPM: 7.46 (d, IH, Ar), 7.12 (d, IH), 6.93 (t, IH Ar), 4.76-4.71 (, IH), 4.03-3.73 (m, 6H), 3.66-3.57 (m, 2H), 3.36-3.35 (m, 2H), 2.41 (m, IH, -OH), 1.56 (m, 2H), 1.43 (s, 9H), 1.14-1.10 (m, IH).
Step-g: Preparation of R(-)-3-[3-fluoro-4-[{(lα,5α,6α)-3-tetrabutoxycarbonyl-3- azabicyclo[3.1.0] hexan-6-yl}methyloxy]phenyl]5-methanesulphonyloxy-methyl-2- oxazolidinone:
To a solution of R(-)-3-[3-fluoro-4-[{(lα,5α,6α)-3-tetrabutoxycarbonyl-3- azabicyclo [3.1.0]hexan-6-yl} methyloxyjphenyl] 5-hydroxymethyl-2-oxazolidinone
(3.0gm, 0.0071 mole) in dichloromethane (25 ml) cooled to 0-5°C, triethylamine (1.077 gm, 0.0106 mole) and methanesulfonyl chloride (1.058 gm, 0.0092 mole) were added, and the reaction mixture was stirred for 4 hr. The reaction mixture was diluted with dichloromethane (25 ml) and washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to yield 3.5 gm of the title compound.
Step-h: Preparation of S(-)-3-[3-fluoro-4-[{(lα,5α,6α)-3-tert-butoxycarbonyl-3- azabicyclo[3.1.0]hexa-6-yl}methyloxy]phenyl]5-azidomethyl-2-oxazolidinone:
To a solution of R(-)-3-[3-fluoro-4-[{(lα,5α,6α)-3-tetrabutoxycarbonyl-3- azabicyclo[3.1.0]hexan-6-yl}methyloxy]phenyl]5-methanesulphonyloxy-methyl-2- oxazolidinone (3.0 gm, 0.006 mole) in DMF (20 ml), sodium azide (1.20 gm, 0.018 mole) was added and the reaction mixture heated to 80°C for 4-5 hrs . The reaction mixture was filtered off and the filtrate was evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and washed with water (2 x50 ml). The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to yield 2.2 gm of the title compound.
1H NMR (CDC13) δ PPM: 7.45 (dd, IH, Ar), 7.11 (d, IH, Ar), 6.95 (t, IH, Ar), 4.79-4.75 (m, IH), 4.07-3.98 (q, 2H), 3.87-3.81 (q, 2H), 3.72-3.5 (m, 4H), 3.38-3.35 (m, 2H), 1.56 (m, 2H), 1.43 (s, 9H), 1.160-1.10 (m, IH).
Step-i: Preparation of S(-)-3-[3-fluoro-4-[{(l ,5α,6α)-3-tert-butoxycarbonyl-3- azabicyclo[3.1.0]hexan-6-yl]phenyl]-5-aminomethyl-2-oxazolidinone: To a solution of S(-)-3-[3-fluoro-4-[{(lα,5α,6α)-3-tert-butoxycarbonyl-3- azabicyclo[3.1.0]hexa-6-yl}methyloxy]phenyl]5-azidomethyl-2-oxazolidinone (2.0 gm, 0.0045 mole) in THF, triphenylphosphine was added and stirred for 2hr at RT. Water (1.28 ml) was added to the reaction mixture and heated to 40°C and stirred for 4hr. The reaction mixture was further stirred at RT for 14 hr. The reaction mixture was concentrated under reduced pressure. To the residue, water (100 ml) was added and acidified with IN HC1 (aq. solution) up to pH 2. It was washed with ether (3 χ50 ml). The aqueous layer was basified with IN NaOH solution up to pH 12 and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to get the 1.5 gm of the title compound.
H1 NMR (CDC13) δ PPM: 7.65 (dd, IH, Ar), 7.13 (d, IH, ar), 6.94 (t, IH, Ar), 4.67-4.65 (m, IH), 4.01 (t, 2H), 3.85-3.79 (m, 2H), 3.65-3.57 (m, 2H), 3.38-3.35 (m, 2H), 3.13-3.09 (m, IH), 3.01-2.96 (m, IH), 1.52 (m, 2H), 1.43 (s, 9H), 1.15-1.10 (m, IH)
Step-j: Preparation of (S)-N-[[3-[3-Fluoro-4-[{(lα,5α,6α)-3-t-butoxycarbonyl-3- azabicyclo [3.1.0]hexan-6-yl} -methyloxy]phenyl] -2-oxo-5 -oxozolidinyl]methyl] acetamide.
To a solution of S(-)-3-[3-fluoro-4-[{(lα,5 ,6α)-3-tert-butoxycarbonyl-3- azabicyclo[3.1.0]hexan-6-yl]phenyl]-5-aminomethyl-2-oxazolidinone (I, 1.4 gm, 0.003 mole ) in dichloromethane (50ml) cooled to 0-5°C, triethylamine (0.7 ml, 0.005 mole) and acetic anhydride (0.45 ml, 0.0043 mole ) were added and stirred at RT for 4-6 hrs. The reaction mixture was diluted with dichloromethane (25 ml) and washed with saturated sodium bicarbonate, followed by brine. The combined organic layer was dried over anhydrous sodium sulfate and evaporated under vacuo to get the 1.3 gm of the title compound.
H1 NMR (CDC13) δ PPM: 7.46 (dd, IH, Ar), 7.06 (d, IH, ar), 6.93 (t, IH, Ar), 6.18-6.14 (m, IH-NH), 4.78-4.75 (m, IH), 4.04-3.98 (m, 2H), 3.77-3.75 (t, IH), 3.75-3.57 (m, 5H0, 3.38-3.35 (m, 2H), 2.02 (s, 3H), 1.56 (m, 2H), 1.43 (s, 9H), 1.15-1.10 (m, IH).
Step-k: Preparation of (S)-N-[[3-[3-Fluoro-4-[{(lα,5α,6α)-3-azabicyclo[3.1.0]hexan-6- yl}-methyloxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide.
To a solution of compound (S)-N-[[3-[3-Fluoro-4-[{(lα,5α,6α)-3-t-butoxycarbonyl-3- azabicyclo [3.1.0] hexan-6-yl}-methyloxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide in dichloromethane, trifluoroacetic acid (20% of the solvent used) was added at 0°C and stirred at 0-25°C for 2-4 hr. The reaction mixture was concentrated under reduced pressure to get (S)-N-[[3-[3-Fluoro-4-[{(lα,5α,6α)-3-azabicyclo[3.1.0]hexan-6-yl}- methyloxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide.
Compound No. 20: (S)-N-[[3-[3-Fluoro-4-[{(lα,5α,6α)-3-t-butoxycarbonyl-3- azabicyclo[3.1.0]hexan-6-yl}-methyloxyl]phenyl]-2-oxo-5- oxozolidinyl] methyl] acetamide.
The title compound was prepared as described in step-j, Example 2.
H!NMR (CDCl3)δ PPM: 7.48 (d,lH, Ar), 7.04(d,lH, Ar), 6.93(t,lH, Ar), 6.18-6.14(m,lH, -NH), 4.78-4.75(m,lH), 4.04-3.98(m,2H), 3.75(t,lH), 3.72-3.57(m,5H), 3.38-3.35(m,2H), 2.02(s,3H), 1.56 (m,2H), 1.43(s,9H), 1.14(m,lH).
Compound No. 21: (S)-N-[[3-[3-Fluoro-4-[[(lα,5α,6 )-3-{2-furyl(5-nitro)methyl}-3- azabicyclo[3.1.0]hexan-6-yl]-methyIoxyl]phenyl]-2~oxo-5- oxozolidinyl] methyl] acetamide.
The title compound was prepared from (S)-N-[[3-[3-Fluoro-4-[{(lα,5α,6α)-3- azabicyclo[3.1.0]hexan-6-yl}-methyloxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide and 5-nitro-2-furaldehyde using Method A.
^NMR (CDCl3)δ PPM: 7.77(d,lH, Ar), 7.48(d,lH, Ar), 7.03(d,lH, Ar), 6.92(t,lH, Ar), 6.45(d,lH, Ar), 6.14(m,lH, -NH), 4.76(m,lH), 4.01(t,lH), 3.89-3.76(m,2H), 3.71- 3.60(m,5H), 3.19-3.16(m,2H), 2.65-2.62(m,2H),2.02(s,3H), 1.70(m,lH), 1.53(m,2H). Compound No. 22 (S)-N-[[3-[3-Fluoro-4-[[(lα,5α,6α)-3-{2-thienyl(5-nitro)methyl}-3- azabicy clo [3.1.0] hexan-6-yl] -methoxyl] phenyl] -2-oxo-5- oxozolidinyl] methyl] acetamide.
The title compound was prepared from (S)-N-[[3-[3-Fluoro-4-[{(l ,5α,6 )-3- azabicyclo[3.1.0]hexan-6-yl}-methyloxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide and 5-nitro-2-thiophenecarboxaldehyde using Method A.
H!NMR (CDCl3)δ PPM: 7.77(d,lH Ar), 7.48(d,lH Ar), 7.07(d,lH, Ar), 6.96(t,lH, Ar), 6.81(d,lH, Ar), 6.05 m,lH, -NH), 4.77 (m,lH), 4.02(t,lH), 3.90-3.77(m,2H), 3.75- 3.61(m,5H), 3.15(m,2H), 2.48(m,2H), 2.02(s,3H), 1.72 (m,lH), 1.48(m,2H). Compound No. 23 (S)-N-[[3-[3-Fluoro-4-[{(lα,5 ,6α)-3-(5-nitro-2-thienyl)-3- azabicy clo [3.1.0] hexan-6-yl}-methyloxyl] phenyl] -2-oxo-5- oxozolidinyl] methyl] acetamide.
The title compound was prepared from (S)-N-[[3-[3-Fluoro-4-[{(lα,5α,6α)-3- azabicyclo[3.1.0]hexan-6-yl}-methyloxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide and 5-nitro-2-bromothiophene using Method B.
H' MR (CDCl3)δ PPM: 7.77(d,lH, Ar), 7.48(d,lH, Ar), 7.07(d,lH,Ar), 6.94(t,lH,Ar), 6.00(m,lH,-NH), 5.74(d,lH, Ar), 4.76(m,lH), 4.04-3.97(m,3H), 3.78-3.72(m,2H), 3.65- 3.49(m,5H), 2.02(s,3H), 1.89(m,2H), 1.23(m,lH).
EXAMPLE 3
Analogues of (S)-N-[[3-[3-Fluoro-4-[N-l-(N-l-piperazinylcarbonyl)phenyl]-2-oxo-5- oxazolidinyI]methyI]-acetamide (Core III)
(S)-N-[[3-[3-Fluoro-4-[N-l-(N-l-piperazinylcarbonyl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-acetamide trifluorocaetate
To (S)-N-[[3-[3-Fluoro-4-[N-l-(4-t-butoxycarbonyl)piperazinylcarbonyl] phenyl] -2-oxo- 5-oxazolidinyl]methyl]-acetamide (0.4g, 0.86 mmol) in dichloromethane (8 ml) was added trifluoroacetic acid (2 ml). The reaction mixture was stirred for 2 hrs and evaporated in vacuo to give the title compound. This product was used as such in the subsequent steps without further characterization.
Compound No. 24 (S)-N-[[3-[3-Fluoro-4-[N-l-(4-t- butoxycarbonyl)piperazinylcarbonyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - acetamide
To (S)-N-[[3-[3-Fluoro-4-[N-l-(4-carboxy)piperazinylcarbonyl] phenyl]-2-oxo-5- oxazolidinyl]methyl]-acetamide (1.87 g, 5.7 mmol; prepared following the procedures disclosed in WO 99/37630) in N,N-dimethylformamide (50ml), N-l-t- butoxycarbonylpiperazine (1.06g, 5.7 mmol) was added and cooled to 5 °C. To this suspension, N-methylmorpholine (0.63 g, 6.3 mmol) and 1-hydroxybenzotriazole (0.77g, 5.7 mmol) were added. It was stirred for 15 min, then EDC was added and further stirred at RT for 17hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with satd.sodium bicarbonate solution, water and brine, dried over anhyd.sodium sulphate and evaporated in vacuo. The product was triturated with diethylether and filtered to give 1.6 g of the final product.
H!NMR (CDCl3)δ PPM: 7.52 (dd, IH), 7.42 (t, IH), 7.22 (m,lH), 6.04 (t, IH), 4.81 (m,lH), 4.06 (t, IH), 3.81-3.2 (m,HH), 2.02 (s,3H), 1.47 (s,9H)
M+l = 465, M-tBu - 409
Compound No. 25 (S)-N-[[3-[3-FIuoro-4-[N-l-[4-{2-furyI-(5- nitro)methyl}]piperazinylcarbonyl] phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide
The title compound was prepared from (S)-N-[[3-[3-Fluoro-4-[N-l-(N-l- piperazinylcarbonyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide Trifluorocaetate and 5-nitro-2-furaldehyde using Method A. m.p. 141-146°C, 1HNMR (DMSO) δppm 8.25 (t, IH), 7.67 (d, IH), 7.55 (dd, IH), 7.40 (m, 2H), 6.81 (d, IH), 4.75 (m, IH), 4.14 (t, IH), 3.76 (m, 6H), 2.73 (m, 2H), 1.83 (s, 3H)
M+l = 490 Compound No. 26 (S)-N-[[3-[3-Fluoro-4-[N-l-[4-{2-thienyl-(5- nitro)methyl}]piperazinylcarbonyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -acetamide
The title compound was prepared from (S)-N-[[3-[3-Fluoro-4-[N-l-(N-l- piperazinylcarbonyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide Trifluorocaetate and 5-nitro-2-thiophenecarboxaldehyde using Method A. 1HNMR (CDCI3) δppm 7.79 (d, IH), 7.53 (dd, IH), 7.24 (m, IH), 6.88 (d, IH), 5.94 (t, IH), 4.81 (rn-lH), 4.06 (t, IH), 3.9-3.6 (m, 8H), 3.38 (m, 2H), 2.63 (m, 2H), 2.51 (m, 2H), 2.02 (s, 3H)
M+l = 506
Compound No. 27 (S)-N-[[3-[3-Fluoro-4-[N-l-[4-{2-thienyI-(5- nitro)}]piperazinyIcarbonyl] phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide
The title compound was prepared from (S)-N-[[3-[3-Fluoro-4-[N-l-(N-l- piρerazinylcarbonyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide trifluoroacetate and 5-nitro-2-bromothiophene using Method B.
1HNMR (CDCI3) δppm 8.25 (t, IH), 7.94 (d, IH), 7.62-7.35 (m, 3H), 6.36 (d, IH), 4.77 (m, IH), 4.18 (t, IH), 3.8 (m, 4H), 1.84 (s, 3H) M+l = 492
Pharmacological Testing
The compounds of the invention display antibacterial activity when tested by the agar incorporation method. The following minimum inhibitory concentrations (μg/ml) were obtained for representative compounds of the invention which are given below in Table- 1.
GUIDE TO TABLE ABBREVIATIONS:
1) S.aureus ATCC 25923 — taphylococus aureus ATCC 25923
2) MRSA 15187 —Methicillin Resistant Staphylococcus aureus 3) Ent. faecalis ATCC 29212 -Enterococcus faecalis ATCC 29212
4) Ent. faecium 6A ~ Enterococcus faecium 6A Van®, Cipro®
5) Strep, pne. ATCC 6303 —Streptococcus pneumoniae ATCC 6303
6) Strep.pyog. ATCC 19615 Streptococcus pyogenes
7) S. epidermidis - Staphylococcus epidermidis ATCC 12228
Table-1
MIC OF THE SYNTHESIZED COMPOUNDS AGAINST 60 BACTERIAL CULTURES
The in vitro antibacterial activities of the compounds were demonstrated by the agar incorporation method (NCCLS M 7 and M 100-S8 documents). Briefly, the compounds were dissolved in DMSO and doubling dilution of the compounds were incorporated into Meer Hilton agar before solidification. Inoculum was prepared by suspending 4 to 5 colonies into 5 ml of normal saline solution and adjusting the turbility to 0.5 Macfarland turbidity standard tables (1.5 x 10^ CFU/ml), after appropriate dilutions, 10^ CFU/spot was transfered into the surface of dried plate and incubated for 18 hours (24 hours for MRSN studies). The concentration showing no growth of the inoculated culture was recorded as the MIC. Appropriate ATCC standard strains were simultaneously tested and result recorded only when the MIC's against standard antibiotics were within the acceptable range.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Claims

We Claim:
1. Compounds having the structure of Formula I:
and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs, or metabolites, wherein
T is a five to seven membered heterocyclic ring, aryl, substituted aryl, bound to the ring C with a linker W, and the aryl and five membered heteroaryl rings are further substituted by a group represented by R, wherein R is selected from the group consisting of H, Cι_6 alkyl, F, Cl, Br,I, -CN, COR5,COOR5, N(R6,R7), NHCOC(R8, R9, Rio), CON (R6, R7), CH2NO2, NO2, CH2R8, CHR9, -CH = N-
ORio, -C=CH-R5, OR5, SR5, -C(R9)=C(R9)NO2, C1.12 alkyl substituted with one or more of F, Cl, Br, I, ORj, S t, wherein R4 and R5 are independently selected from H, Cι-12 alkyl, C3.ι2 cycloalkyl, Cι_6 alkoxy, Cι-6 alkyl substituted with one or more of F, Cl, Br, I or OH, aryl, heteroaryl; R6 and R7, are independently selected from H, optionally substituted Cι-12 alkyl, C3-ι2 cycloalkyl, Cι-6 alkoxy; R8 and R9 are independently selected from H, Cι-6 alkyl, F, Cl, Br, I, Cι-ι alkyl substituted with one or more of F, Cl, Br, I, OR5, S i, N(Re,R7); Rιo= H, optionally substituted Cι_ ι2 alkyl, C3_ι2 cycloalkyl, Ci-6 alkoxy, Cι-6 alkyl, aryl or heteroaryl; n is an integer in the range from 0 to 3; X is H, CH, CH-S, CH-O, N, CHNRn, wherein Rn is hydrogen, optionally substituted Cι-2 alkyl, C3_ι2 cycloalkyl, Cι_6 alkoxy, Cι_6 alkyl, Cι-6 alkylcarbonyl, Ci-6 alkyl carboxy, aryl or heteroaryl;
Xi is (CH2)nS, (CH2)nO, where n = 0 to 3; NR wherein Rn is the same as defined above, C=O, or C=S; X2 = CH orN; Y and Z are independently selected from hydrogen, C- _6 alkyl, C3_12 cycloalkyl or C0 3 bridging group;
U and V are independently selected from hydrogen, optionally substituted C-_6 alkyl, F, Cl, Br, C. 12 alkyl substituted with one or more of F, Cl, Br, I;
W is selected from CH2, CO, CK.NH, -NHCH2, -CH2NHCH2, -CH2N(Rπ)CH2-,
CH2( Rπ)N-, CH(Rn), CH2(CO), NH, O, S, N(Rn), (CO)CH2, N(Rn)CON(Rn), N(Rn)CSN(Rn), SO2, SO, wherein R is the same as defined above; and
Ri is selected from the group consisting of -NHC(=O)R , N(R3, R0), - NR2C(=S)R3, -NR2C(=S)SR3) wherein R2 is hydrogen, aryl, heteroaryl, C._12 alkyl, C3 12 cycloalkyl, C. 6 alkoxy, C. 6 alkyl substituted with one or more of F, Cl, Br, I or OH; or thioCι-6 alkyl; R3, are independently selected from hydrogen, aryl, heteroaryl, C._12 alkyl, C3 12 cycloalkyl, C. 6 alkoxy, C -_6 alkyl substituted with one or more of F, Cl, Br, I or OH. 2. Compounds having the structure of Formula II:
and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs, or metabolites, wherein
Ri is selected from the group consisting of -NHC(=O)R2, -NQi^ , - NR2C(=S)R3, -NR2C(=S)SR3 wherein R2, R3, i are independently hydrogen, aryl, heteroaryl, Cι_ι2 alkyl, C3-ι2 cycloalkyl, Cι.6 alkoxy, Cι_6 alkyl substituted with one or more of F, Cl, Br, I, OH;
U and V are independently selected from hydrogen, optionally substituted Cι-6 alkyl, F, Cl, Br, -12 alkyl substituted with one or more of F, Cl, Br, I; Y and Z are independently selected from hydrogen, Cι-6 alkyl, C3-ι2 cycloalkyl, C0.3 bridging group;
X is selected from H, CH, CH-S, CH-O or N;
Xi is (CH2)nS, (CH2)nO, where n = 0 to 3; NRn, wherein Rn is hydrogen, optionally substituted Cι-2 alkyl, C3.ι2 cycloalkyl, Cι_6 alkoxy, Cι-6 alkyl, Cι.6 alkylcarbonyl, Cι-6 alkyl carboxy, aryl or heteroaryl, C=O, or C=S;
X2 = CH or N;
W is independently selected from CH2, C=O, CH2NH, NHCH2, CH2NHCH2, CH2N(Rπ)CH2, CH2N(Rπ), CH(R„), CH2(C=O), NH, O, S, (CO)CH2, N(Rπ)CON(Rn), SO2, SO, N(Rn), N(Rn)C(=S)N(Rn), wherein Rn is the same as defined above;
Qi is selected from O, S or NRn, wherein Rn is as defined earlier;
G, J, L are independently selected from H, Cι-6 alkyl, F, Cl, Br,I, -CN, COR5,COOR5, N(R6,R7), NHCOC(R8, R9, Rio), CON (R6, R7), CH2NO2, NO2, CH2Rs, CHR9, -CH = N-ORio, -C=CH-R5, OR5, SR5, -C(R9)=C(R9)NO2, Cι-ι2 alkyl substituted with one or more of F, Cl, Br, I, OR4, SR4, wherein R4, R5 are independently selected from H, Cι-ι2 alkyl, C3-ι2 cycloalkyl, Cι_6 alkoxy, Cι.6 alkyl substituted with one or more of F, Cl, Br, I or OH, aryl, heteroaryl; R6 and R7, are independently selected from H, optionally substituted C1-12 alkyl, C3-ι2 cycloalkyl, Cι-6 alkoxy; R8 and R9 are independently selected from H, C 6 alkyl, F, Cl, Br, I,
Cι-12 alkyl substituted with one or more of F, Cl, Br, I, OR5, SR.}, N(Rό,R ); R10- H, optionally substituted .12 alkyl, C3-ι2 cycloalkyl, Cι-6 alkoxy, Cι-6 alkyl, aryl, heteroaryl; except when W=CO, Q O, S, X=N, X =CH, Xι=O, and G, J, L=H.
3. The compound according to claim 2 wherein in Formula II, ring C is 6-8 membered in size and the ring may have either two or three carbon atoms between each nitrogen atom comprising of:
and the ring C may be bridged to form a bicyclic system as shown below,
4. The compound according to claim 2 wherein in Formula II, ring C is substituted at positions Y and Z with alkyl groups, cycloalkyl groups, fluoro group, carboxylic and corresponding esters, amides, substituted alkyls or bridging alkyl group as shown below,
-X X2-X1 X1 X rSx,2"Xι-
5. The compound according to claim 2 wherein in Formula II, ring C is 6 membered in size and X is -CH-(NHR), or >CCH2NHR-, the ring C is selected from the group consisting of the following rings wherein Rn is the same as defined earlier,
or in addition to the above, the ring C includes the following structures:
The compound according to claim 2 having the structure of Formula III,
FORMULA III wherein U, N, Y, Z, X, Xi, X2, Ri, Rn, W, G, J, L and n are as defined earlier.
7. The compound according to claim 2 having the structure of Formula IN,
FORMULA IV wherein U, N, Y, Z, X, Xi, X2, Ri, W, G, J, L and n are as defined earlier. 8. The compound according to claim 2 having the structure of Formula N,
FORMULA N wherein U, N, Y, Z, X, Xi, X2, Ri, W, G, J, L and n are as defined earlier.
A compound selected from the group consisting of :
(S)-Ν-[[3-[3-Fluoro-4-| I-l-{2-furyl-(5-nitro) methyl}piperidinyl-4-oxy]phenyl]- 2-oxo-5 -oxozolidinyljmethyl] acetamide (Compound No.l)
(S)-N-[[3-[3-Fluoro-4-[N-l-{2-thienyl-(5-nitro) methyl}piperidinyl-4- oxy]phenyl] -2-0X0-5 -oxozolidinyl]methyl] acetamide (Compound No.2)
(S)-N-[[3-[3-Fluoro-4-|^-l-{2-furyl-(4-bromo-5-nitro) methyl}piperidinyl-4- oxyjphenyl] -2-0X0-5 -oxozolidinyljmethyl] acetamide (Compound No.3)
(S)-N-[[3-[3-Fluoro-4-[N- 1 - {2-thienyl-(4-bromo-5 -nitro) methyl} ρiperidinyl-4- oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide (Compound No.4)
(S)-N-[[3-[3-Fluoro-4-[N- 1 - {2-thienyl-(4-morpholino-5-nitro) methyl}piperidinyl- 4-oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide (Compound No.5)
(S)-N-[[3-[3-Fluoro-4-rN-l-[2-thienyl-{4-(N-4-methylρiρerazin-l-yl)-5-nitro} methyl]piperidinyl -4-oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide (Compound No.6) (S)-N-[[3-[3-Fluoro-4-[N-l-{2-thienyl-(4-dimethylamino-5-nitiO) methyl}piperidinyl-4-oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide (Compound No.7)
(S)-N-[[3-[3-Fluoro-4-| J-l-{2-furyl-(4-isopropyl-5-nitτo) methyl}piperidinyl-4- oxyjphenyl] -2-oxo-5-oxozolidinyl]methyl] acetamide (Compound No .8)
(S)-N-[[3-[3-Fluoro-4-|Η-l-[2-furyl-{5-(2-ιιitro)phenyl} methyl]piperidinyl-4- oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide (Compound No.9)
(S)-N-[[3-[3-Fluoro-4-[N- 1 -[2-furyl- {5-(3-nitro)phenyl} methyl]piperidinyl-4- oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl] acetamide (Compound No.10) (S)-N-[[3-[3-Fluoro-4-[N-l- {3-thienyl-(2-nitro) methyl}piperidinyl-4- oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl] acetamide (Compound No.l 1)
(S)-N-[[3-[3-Fluoro-4-[N-l-{2-furyl-(5-nitro) methyl}piperidinyl-4-oxy]phenyl]- 2-oxo-5-oxozolidinyl]methyl]thioacetamide (Compound No.12)
(S)-N-[[3-[3-Fluoro-4-|^-l-{(benzo(b)furan-2-yl)methyl}piperidinyl-4- oxyjphenyl] -2-oxo-5-oxozolidinyl]methyl] acetamide (Compound No.13)
(S)-N-[[3-[3-Fluoro-4-[N-l-{2-thienyl-(5-nitro)}piperidinyl-4-oxyJphenylJ-2-oxo- 5-oxozolidinyl]methyl]acetamide (Compound No.14)
(S)-N-[[3-[3-Fluoro-4-[N-l-[l- {2-furyl-(5-nitro)-} -ethyl] piperidinyl-4- oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl] acetamide (Compound No.15) (S)-N- [ [3 - [3 -Fluoro-4- [N- 1 - {2-furyl-(5 -nitro)carbonyl}piperidinyl-4-oxy]phenyl] -
2-oxo-5-oxozolidinyl]methyl]acetamide (Compound No.16)
(S)-N-[[3-[3-Fluoro-4-|Η-l-{(ber-zo(b)furan-2-yl)carbonyl}piperidinyl-4- oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide (Compound No.17)
(S)-N-[[3-[3-Fluoro-4-[N-l-{2-thienyl-(5-nitro)carbonyl}ρiρeridinyl-4- oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide (Compound No.18)
(S)-N-[[3-[3-Fluoro-4-[N-l-{2-thienyl-(5-nitro)thiocarbonyl}piperidinyl-4- oxy]phenyl]-2-oxo-5-oxozolidinyl]methyl]thioacetamide (Compound No.19) (S)-N-[[3-[3-Fluoro-4-[ {(1 α,5α,6α)-3-t-butoxycarbonyl-3-azabicyclo[3.1.0]hexan- 6-yl}-methyloxyl]phenyl]-2-oxo-5-oxozolidinyl]methyl]acetamide (Compound No.20)
(S)-N-[[3-[3-Fluoro-4-[[(l α,5α,6 )-3- {2-furyl(5-nitro)methyl} -3- azabicyclo[3.1.0]hexan-6-yl]-methyloxyl]phenyl]-2-oxo-5- oxozolidinyl]methyl] acetamide (Compound No.21)
(S)-N-[[3-[3-Fluoro-4-[[(lα,5α,6α)-3-{2-thienyl(5-nitro)methyl}-3- azabicyclo[3.1.0]hexan-6-yl]-methyloxyl]phenyl]-2-oxo-5- oxozolidinyl]methyl] acetamide (Compound No.22) (S)-N-[[3-[3-Fluoro-4-[ {(1 α,5α,6α)-3-(5-nitro-2-thienyl)-3- azabicyclo[3.1.0]hexan-6-yl} -methyloxyl]phenyl]-2-oxo-5- oxozolidinyl]methyl] acetamide (Compound No.23)
(S)-N-[[3-[3-Fluoro-4-[N-l-(4-t-butoxycarbonyl)piperazinylcarbonyl] phenyl]-2- oxo-5-oxazolidinyl]methyl] -acetamide (Compound No.24) (S)-N-[[3-[3-Fluoro-4-[N-l-[4-{2-furyl-(5-nitro)methyl}]ρiρerazinylcarbonyl] phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide (Compound No.25)
(S)-N-[[3-[3-Fluoro-4-[N-l-[4-{2-thienyl-(5-nitro)methyl}]piρerazinylcarbonyl] phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide (Compound No.26)
(S)-N-[[3-[3-Fluoro-4-[N-l -[4- {2-thienyl-(5-nitro)}]piperazinylcarbonyl] phenyl]- 2-oxo-5-oxazolidinyl]methyl]-acetamide (Compound No.27).
10. A pharmaceutical composition comprising the compound of claims 1, 2 or 9 and a pharmaceutical acceptable carrier.
11. A pharmaceutical composition comprising a pharmaceutically effective amount of compound according to claims 1, 2 or 9 or a physiologically acceptable acid addition salt thereof with a pharmaceutically acceptable carrier for treating microbial infections.
12. A method of treating or preventing microbial infections in a mammal comprising administering to said mammal, the pharmaceutical composition according to claim 11.
13. The method according to claim 12 wherein the microbial infections are caused by gram-positive and gram-negative bacteria.
14. The method according to claim 13 wherein the gram-positive bacteria are selected from the group consisting of staphylococcus spp., streptococcus spp., listeria spp. and legionella spp.
15. A method of treating or preventing aerobic and anaerobic bacterial infections in a mammal comprising administering to said mammal, a therapeutically effective amount of a compound having the structure of Formula I
FORMULA I or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs, metabolites, wherein
T is a five to seven membered heterocyclic ring, aryl, substituted aryl, bound to the ring C with a linker W, and the aryl and five membered heteroaryl rings are further substituted by a group represented by R, wherein R is selected from the group consisting of H, C 6 alkyl, F, Cl, Br,I, -CN, COR5,COOR5, N(R6,R7),
NHCOC(R8, R9, Rio), CON (R6, R7), CH2NO2, NO2, CH2R8, CHR9, -CH = N- ORio, -C=CH-R5, OR5, SR5, -C(R9)=C(R9)NO2, CM alkyl substituted with one or more of F, Cl, Br, I, O i, S j, wherein i and R5 are independently selected from H, Ci-12 alkyl, C .ι2 cycloalkyl, Cι-6 alkoxy, Cι-6 alkyl substituted with one or more of F, Cl, Br, I or OH, aryl, heteroaryl; R6 and R , are independently selected from
H, optionally substituted Cι-ι alkyl, C -ι2 cycloalkyl, Cι-6 alkoxy; R8 and R are independently selected from H, Cι-6 alkyl, F, Cl, Br, I, Cι-ι2 alkyl substituted with one or more of F, Cl, Br, I, OR5, SRi, N(R6,R7); Rιo= H, optionally substituted C\. \2 alkyl, C3.ι2 cycloalkyl, Cι-6 alkoxy, C1.6 alkyl, aryl or heteroaryl; n is an integer in the range from 0 to 3; X is H, CH, CH-S, CH-O, N, CHNRn, wherein Rπ is hydrogen, optionally substituted Cι_2 alkyl, C3-ι2 cycloalkyl, Cι_6 alkoxy, Cι-6 alkyl, Cι_6 alkylcarbonyl, Ci-6 alkyl carboxy, aryl or heteroaryl;
Xi is (CH2)nS, (CH2)nO, where n = 0 to 3; NRn wherein Rn is the same as defined above, C=O, or C=S;
X2 = CH or ;
Y and Z are independently selected from hydrogen, C. 6 alkyl, C3 12 cycloalkyl or C0 3 bridging group;
U and V are independently selected from hydrogen, optionally substituted C alkyl, F, Cl, Br, C. _- alkyl substituted with one or more of F, Cl, Br, I;
W is selected from CH2; CO, CH2NH, -NHCH2, -CH2NHCH2, -CH2N(Rn)CH2-, CH2( Rπ)N-, CH(Rn), CH2(CO), NH, O, S, N(Rn), (CO)CH2, N(Rn)CON(Rn), N(Rιι)CSN(Rn), SO2, SO, wherein R - is the same as defined above; and
Ri is selected from the group consisting of -1SIHC(::=0)R2 , N(R3, R0), - NR2C(=S)R3, -NR2C(=S)SR3> wherein R2 is hydrogen, aryl, heteroaryl, C._12 alkyl,
C3 12 cycloalkyl, C._6 alkoxy, C. 6 alkyl substituted with one or more of F, Cl, Br, I or OH; or thioCι-6 alkyl; R3, Ri are independently selected from hydrogen, aryl, heteroaryl, C._12 alkyl, C3 _. cycloalkyl, C. 6 alkoxy, C._6 alkyl substituted with one or more of F, Cl, Br, I or OH. 16. A method of treating or preventing aerobic and anaerobic bacterial infections in a mammal comprising administering to said mammal, a therapeutically effective amount of a compound having the structure of Formula II
FORMULA II or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs, or metabolites, wherein
Ri is selected from the group consisting of -NHC(=O)R2, -N(R3,R4), - NR2C(=S)R3, -NR2C(=S)SR3 wherein R2, R3, j are independently hydrogen, aryl, heteroaryl, Cι-12 alkyl, C3.12 cycloalkyl, Cι_6 alkoxy, Cι_6 alkyl substituted with one or more of F, Cl, Br, I, OH;
U and V are independently selected from hydrogen, optionally, substituted Cι_6 alkyl, F, Cl, Br, Cι-ι alkyl substituted with one or more of F, Cl, Br, I; Y and Z are independently selected from hydrogen, Cι-6 alkyl, C3_ι2 cycloalkyl,
Co-3 bridging group;
X is selected from H, CH, CH-S, CH-O or N;
Xi is (CH )nS, (CH2)nO, where n = 0 to 3; NRn, wherein Rn is hydrogen, optionally substituted Cι_2 alkyl, C3.1 cycloalkyl, Cι_6 alkoxy, Cι-6 alkyl, Cι-6 alkylcarbonyl, Cι-6 alkyl carboxy, aryl or heteroaryl, C=O, or C=S;
X2 = CH orN; is independently selected from CH2, C=O, CH2NH, NHCH2, CH2NHCH2, CH2N(Rn)CH2, CH2N(Rn), CH(Rn), CH2(C=O), NH, O, S, (CO)CH2, N(Rιι)CON(Rn), SO2, SO, N(Rπ), N(Rπ)C(=S)N(Rn), wherein Rn is the same as defined above;
Qi is selected from O, S or NRn, wherein Rn is as defined earlier;
G, J, L are independently selected from H, Cι-6 alkyl, F, Cl, Br,I, -CN, COR5,COOR5, N(R6,R7), NHCOC(R8, R9, Rio), CON (R6, R7), CH2NO2, NO2, CH2R8, CHR9, -CH = N-ORio, -C=CH-R5, OR5, SR5, -C(R9)=C(R9)NO2, Ci-12 alkyl substituted with one or more of F, Cl, Br, I, ORi, SRt; wherein R4, R5 are independently selected from H, Cn2 alkyl, C3_ι2 cycloalkyl, Cι-6 alkoxy, Cι.6 alkyl substituted with one or more of F, Cl, Br, I or OH, aryl, heteroaryl; R6 and R , are independently selected from H, optionally substituted Cι-ι2 alkyl, C3-ι2 cycloalkyl, Cι-6 alkoxy; R8 and R9 are independently selected from H, Cι-6 alkyl, F, Cl, Br, I, Cι-ι2 alkyl substituted with one or more of F, Cl, Br, I, OR5, SR, N(R<5,R7); Rιo= H, optionally substituted Cι-12 alkyl, C3-ι2 cycloalkyl, Cι-6 alkoxy, Cι-6 alkyl, aryl, heteroaryl; except when W=CO, Qι=O, S, X=N, X2=CH, Xι=O, and G, J, L=H.
17. The method according to claim 16 wherein in Formula II, ring C is 6-8 membered in size and the ring may have either two or three carbon atoms between each nitrogen atom comprising of:
and ring C may be bridged to form a bicyclic system as shown below,
18. The method according to claim 16 wherein in Formula II, ring C is substituted at positions Y and Z with alkyl groups, cycloalkyl groups, fluoro group, carboxylic and corresponding esters, amides, substituted alkyls or bridging alkyl groups as shown below,
-)* r_JS2-X. X rj-S2-X
19. The method according to claim 16 wherein in Formula π, ring C is 6 membered in size and X is -CH-(NHR), or >CCH2NHR-, the ring C is selected from the group consisting of the following rings wherein Rn is the same as defined earlier,
or in addition to the above, the ring C includes the following structures:
20. The method according to claim 16 having the structure of Formula III,
FORMULA III wherein U, V, Y, Z, X, XI, X2, Ri, Rn, W, G, J, L and n are as defined earlier. 21. The method according to claim 16 having the structure of Fonnula IN,
FORMULA IV wherein U, N, Y, Z, X, Xi, X2, Ri, W, G, J, L and n are as defined earlier.
22. The compound according to claim 16 having the structure of Formula N,
FORMULA V wherein U, N, Y, Z, X, X1} X2, Ri, W, G, J, L and n are as defined earlier.
23. A process for preparing a compoxmd of Formula I,
FORMULA I and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, Ν-oxides, polymorphs, prodrugs, or metabolites, wherein
T is a five to seven membered heterocyclic ring, aryl, substituted aryl, bound to the ring C with a linker W, and the aryl and five membered heteroaryl rings are further substituted by a group represented by R, wherein R is selected from the group consisting of H, Cι-6 alkyl, F, Cl, Br,I, -CΝ, COR5,COOR5, Ν(R6,R7), NHCOC(R8, R9, Rio), CON (R6, R7), CH2NO2, NO2, CH2R8, CHR9, -CH = N- OR10, -C=CH-R5, OR5, SR5, -C(R9)=C(R9)NO2, C 2 alkyl substituted with one or more of F, Cl, Br, I, O i, SR4; wherein R4 and R5 are independently selected from H, Cι-ι2 alkyl, C3-ι2 cycloalkyl, Cι.6 alkoxy, Cι.6 alkyl substituted with one or more of F, Cl, Br, I or OH, aryl, heteroaryl; R6 and R , are independently selected from H, optionally substituted Cι-ι2 alkyl, C3-ι2 cycloalkyl, Cι-6 alkoxy; R8 and R9 are independently selected from H, Cι-6 alkyl, F, Cl, Br, I, Cι-ι2 alkyl substituted with one or more of F, Cl, Br, I, OR5, SRt, N(R6,R ); Rιo= H, optionally substituted Ci. ι2 alkyl, C3_ι2 cycloalkyl, Cι_6 alkoxy, Cι_6 alkyl, aryl or heteroaryl; n is an integer in the range from 0 to 3; X is H, CH, CH-S, CH-O, N, CHNRn, wherein Rn is hydrogen, optionally substituted C1-2 alkyl, C3.ι2 cycloalkyl, d-6 alkoxy, Cι-6 alkyl, Cι_6 alkylcarbonyl, Ci-6 alkyl carboxy, aryl or heteroaryl;
Xi is (CH2)nS, (CH2)nO, where n = 0 to 3; NRn wherein Rn is the same as defined above, C=O, or C=S;
X2 = CH orN;
Y and Z are independently selected from hydrogen, C._6 alkyl, C3_12 cycloalkyl or C0 3 bridging group;
U and V are independently selected from hydrogen, optionally substituted C. 6 alkyl, F, Cl, Br, C. 12 alkyl substituted with one or more of F, Cl, Br, I;
W is selected from CH2, CO, CH-.NH, -NHCR,, -CH2NHCH2, -CH2N(Rn)CH2-, CH2( Rn)N-, CH(Rn), CH2(CO), NH, O, S, N(Rn), (CO)CH2, N(Rn)CON(Rn), N(Rιι)CSN(Rn), SO2, SO, wherein R is the same as defined above; and
Ri is selected from the group consisting of -NHC(=O)R2 , N(R3, Rj), - NR2C(=S)R3, -NR2C0=S)SR3, wherein R2 is hydrogen, aryl, heteroaryl, C._12 alkyl,
C3 12 cycloalkyl, C. , alkoxy, C. 6 alkyl substituted with one or more of F, Cl, Br, I or OH; or thioCι-6 alkyl; R3, i are independently selected from hydrogen, aryl, heteroaryl, C. alkyl, C3 12 cycloalkyl, C-_6 alkoxy, C . 6 alkyl substituted with one or more of F, Cl, Br, I or OH, which comprises reacting an amine of Formula VI
Formula VI with a heteroatomic group of Formula R-T-W-Rι2 wherein T, W, Ri, U, V, Y, Z,
X2, Xi, and n are the same as defined earlier and Mi is selected from the group consisting of NH, NHRι4, CH2NHRι4, CH-CH2NHR14, -CCH2-NHRι4 wherein Ru is H, ethyl, methyl, isopropyl, acetyl, cyclopropyl, or alkoxy and Rι2 is a suitable leaving group selected from the group consisting of fluoro, chloro, bromo, iodo, SCH3, -SO2CH3, -SO2CF3, Tos and OC6H5.
24. The process of claim 23 wherein the amine of Formula NI reacts with a heteroaromatic compound of Formula R-T-W-Rι2 in the presence of a base selected from the group consisting of potassium carbonate, Ν- ethyldiisopropylamine and dipotassium hydrogen phosphate.
25. The process of preparing a compound of Formula I of claim 23, wherein W=CH2 and R-T-W-Ri2 is a five membered heterocyclic ring with aldehyde group and the compound of Formula I is produced by reductive amination. 26. The process for preparing a compound of Formula I of claim 23 wherein W=CO and R-T-W-R12 is a five membered heterocyclic ring with carboxylic acid and amino compound of Formula NI is acylated with activated esters in the presence of condensing agents consisting of 1,3-dicyclohexyl carbodiimide (DCC) and l-(3- dimethylaminopropyl)-3 -ethyl carbodiimide (EDC). 27. A process for preparing a compound having the structure of Formula II:
FORMULA II and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, enantiomers, diastereomers, Ν-oxides, prodrugs or metabolites, wherein
Ri is selected from the group consisting of -ΝHC(=O)R2; -Nø^ ; - NR2C(=S)R3; -NR2C(=S)SR3 wherein R2, R3, R4 are independently hydrogen, aryl, heteroaryl, Cι_ι2 alkyl, C .ι2 cycloalkyl, Cι-6 alkoxy, Cι-6 alkyl substituted one or more of F, Cl, Br, I, OH,
U and V are independently selected from hydrogen, optionally substituted Cι.6 alkyl, F, Cl, Br, C1.12 alkyl substituted with one or more of F, Cl, Br, I; Y and Z are independently selected from hydrogen, Cι-6 alkyl, C3.12 cycloalkyl, C0-3 bridging group;
X is selected from H, CH, CH-S, CH-O or N;
Xi is (CH2)nS, (CH2)nO, where n = 0 to 3; NRn, wherein Rn is hydrogen, optionally substituted Cι_2 alkyl, C3-J2 cycloalkyl, Cι_6 alkoxy, Cι-6 alkyl, Cι_6 alkylcarbonyl, Cι_6 alkyl carboxy, aryl or heteroaryl, C=O, or C=S;
X2 = CH orN; is independently selected from CH2, C=O, CH2NH, NHCH2, CH2NHCH2, CH2N(Rn)CH2, CH2N(Rn), CH(Rn), CH2(C=O), NH, O, S, (CO)CH2, N(Rιι)CON(Rn), SO2, SO, N(Rn), N(Rπ)C(=S)N(Rn), wherein Rn is the same as defined above;
Qi is selected from O, S or NRn, wherein Rn is as defined above;
G, J, L are independently selected from H, Cι-6 alkyl, F, Cl, Br,I, -CN, COR5,COOR5, N(R6,R7), NHCOC(R8, R9, Rio), CON (R6, R7), CH2NO2, NO2, CH2R8, CHR9, -CH = N-ORio, -C=CH-R5, OR5, SR5, -C(R9)=C(R9)NO2, C 2 alkyl substituted with one or more of F, Cl, Br, I, OR4, S i, wherein Rt, R5 are independently selected from H, Cπ2 alkyl, C3_ι2 cycloalkyl, Cι-6 alkoxy, Cι_6 alkyl substituted with one or more of F, Cl, Br, I or OH, aryl, heteroaryl; Rg and R , are independently selected from H, optionally substituted Cι-ι2 alkyl, C3-ι cycloalkyl, Cι-6 alkoxy; R8 and R9 are independently selected from H, Cι-6 alkyl, F, Cl, Br, I,
Ci-12 alkyl substituted with one or more of F, Cl, Br, I, OR5, SRi, N(R6,R7); Rιo= H, optionally substituted Cι_ι2 alkyl, C3.1 cycloalkyl, Cι-6 alkoxy, Cι-6 alkyl, aryl, heteroaryl; except when W=CO, Qι=O, S, X=N, X2=CH, Xι=O and G, J, L=H, comprising reacting a compoxmd Formula NI
Formula VI with a heteroaromatic compound of Formula Nil
Formula VII wherein Ri, U, N, Xi, X2, Mi, Y, Z, n, Rι2, Qi, G, J and L are as defined earlier.
28. The process according to claim 27 wherein in Formula II, ring C is 6-8 membered in size and the ring may have either two or three carbon atoms between each nitrogen atom comprising of:
and ring C may be bridged to form a bicyclic system as shown below,
29. The process according to claim 27 wherein in Formula II, ring C is substituted at positions Y and Z with alkyl groups, cycloalkyl groups, fluoro group, carboxylic and corresponding esters, amides, substituted alkyls or bridging alkyl groups as shown below,
0. The process according to claim 27 wherein in Formula π, ring C is 6 membered in size and X is -CH-(NHR), or >CCH2NHR-, ring C is sleeted from the group consisting of the following rings wherein Rn is the same as defined earlier,
or in addition to the above, the ring C includes the following structures:
31. The process according to claim 27 having the structure of Formula III,
FORMULA III wherein U, V, Y, Z, X, Xi, X2, Ri, Rn, W, G, J, L, and n are as defined earlier.
32. The process according to claim 27 having the structure of Formula IN,
FORMULA IV wherein U, N, Y, Z, X, Xi, X , Rl9 W, G, J, L, and n are as defined earlier.
33. The process 34. according to claim 27 having the structure of Formula N,
FORMULA V wherein U, N, Y, Z, X, Xi, X2, R1? W, G, J, L, and n are as defined earlier. 34. The process of claim 27 wherein the reaction is carried out in a suitable solvent selected from the group consisting of dimethylformamide, dimethylacetamide, ethanol, dimethylsulfoxide, acetonitrile or ethyleneglycol at a suitable temperature in the range of about -70°C to about 180°C in the presence of a suitable base selected from the group consisting of triethylamine, Ν-ethyl diisopropylamine, potassium carbonate, sodium carbonate and dipotassium hydrogen phosphate.
35. The process of claim 27 wherein Formula Nil is 5-nitro-2-furaldehyde and the reductive alkylation of the amine of Formula NI is performed with a reducing agent.
36. The process of claim 27 wherein Formula Nil is 5-nixro-2-furoic acid.
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