WO2007029076A1 - Isoindole derivatives as antimicrobial agents - Google Patents

Isoindole derivatives as antimicrobial agents Download PDF

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Publication number
WO2007029076A1
WO2007029076A1 PCT/IB2006/002368 IB2006002368W WO2007029076A1 WO 2007029076 A1 WO2007029076 A1 WO 2007029076A1 IB 2006002368 W IB2006002368 W IB 2006002368W WO 2007029076 A1 WO2007029076 A1 WO 2007029076A1
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compound
formula
methylethyl
isoindol
dihydro
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PCT/IB2006/002368
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French (fr)
Inventor
Shahadat Ahmed
Biswajit Das
Dilip J. Upadhyay
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Ranbaxy Laboratories Limited
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Publication of WO2007029076A1 publication Critical patent/WO2007029076A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • substituted aromatic compounds which are tRNA synthetase inhibitors, and hence can be used as antimicrobial agents.
  • Compounds disclosed herein can be used for the treatment or prevention of a condition caused by or contributed to by gram positive, gram negative, anaerobic bacteria or fungal organisms, more particularly against bacterium, for example, Staphylococci, Enterococci, Streptococci, Haemophilus, Moraxalla, Escherichia, Chlamydia, Rickettsiae, Mycoplasm, Legionella, Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus or Enterobactericeae, and fungal organisms, for example, Aspergillus, Blastomyces, Candida, Coccidiodes, Cryptococcus, Epidermophyton, Hendersonula, Histoplasma, Microsporum, Paecilomyces, Paracoccidiodes, Pneumoc
  • Antibiotics are of immense value for combating infectious diseases, hi recent decades, the effectiveness of antibiotics has been threatened by an inexorable rise in the prevalence of microbial drug resistance. Some important pathogens have serious resistance problems. Staphylococcus aureus is perhaps the most significant of these pathogens. It causes community and hospital acquired infections and is associated with high morbidity and mortality rates. Vancomycin has been used as the antibiotic of last resort to treat methicillin-resistance staphylococcus aureus infections (MRSA) with multiple resistance. Strains with some level of resistance to vancomycin (Vancomycin- intermediates-resistant S.
  • VISA highly resistant strain
  • VRE vancomycin resistant enterococci
  • ESBLs extended spectrum ⁇ - lactamases
  • Antimicrobial resistance among respiratory pathogens has become a common clinical problem, currently over 90% of Morexella catarrhalis and 25% of Haemophilus influenzae produce ⁇ lactamases, requiring treatment with a ⁇ lactamase stable cephalosporin or combination drugs.
  • amino acyl tRNA synthetases are essential enzymes found in all living organisms. These enzymes have emerged as an attractive target for the development of new antibiotics. Amino acyl tRNA synthetases charge tRNA molecules with their corresponding amino acid, an essential step in protein synthesis. There are 20 tRNA synthetases, most of which correspond to attractive broad- spectrum antibacterial targets.
  • pseudomonic acid A also known as mupirocin
  • mupirocin a natural product from Pseudominas fluorescens, inhibits isoleucyl tRNA synthtase and is marketed as a topical antibiotic Bactropan.
  • Other known natural products directed against amino acyl tRNA synthetases include borrelidin, furanomycin, granaticin, indolmycin, ochartoxin A, and cispentacin, none of them has been developed as antibiotic compounds.
  • U.S. Patent Application Nos. 2004/0224981 and 2003/0013724 disclose tRNA synthetase inhibitors.
  • WO 00/18772 discloses condensed imidazolidinone as tRNA synthetase inhibitors.
  • U.S. Patent Nos. 5,191,093 and 4,916,155 disclose crystalline pseudomonate, process for its production and its use in human and veterinary medicines.
  • U.S. Patent No. 4,916,155 discloses crystalline calcium pseudomonate or the hydrate thereof, and their use in human and veterinary medicine.
  • Novel synthetic compounds which target tRNA synthetases, offer clear advantages as useful therapeutic agents to curb the threat of drug resistance.
  • substituted aromatic compounds which are tRNA synthetase inhibitors, and hence can be used for the treatment of microbial infections, and processes for the synthesis of these compounds.
  • Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, prodrugs, metabolites, polymorphs and N-oxides of these compounds having same type of activity are also provided.
  • Pharmaceutical compositions containing the disclosed compounds (Formula I) together with pharmaceutically acceptable carriers, excipients or diluents which can be used for the treatment of microbial infections.
  • Cy can be cycloalkyl or heterocyclyl;
  • X can be alkylene;
  • X 1 and X 2 can be independently CO, CS or CH 2 ;
  • R 3 and R 4 can, together with the nitrogen to which they are attached, form a heterocyclic ring.
  • Bacterium for example, Staphylococci, Enterococci, Streptococci, Haemophilus, Moraxalla, Escherichia, Chlamydia, Rickettsiae, Mycoplasm, Legionella, Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus or Enterobactericeae may cause the bacterial infections.
  • Organisms for example, Aspergillus, Blastomyces, Candida, Coccidiodes, Cryptococcus, Epidermophyton, Hendersonula, Histoplasma, Microsporum, Paecilomyces, Paracoccidiodes, Pneumocystis, Trichophyton, or Trichosporium, Enterobactericeae may cause the fungal infections.
  • the conditions may be, for example, community acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, hospital acquired lung infections or bone and joint infections, and other bacterial infections, for example, mastitis, catheter infection, foreign body, prosthesis infections or peptic ulcer disease.
  • alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms.
  • Rx and R 7T are independently selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or carboxy ⁇ , nitro or -SO m R ⁇ (wherein m is an integer from 0-2 and R ⁇ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, aryl, heterocyclyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl).
  • substituents maybe substituted further by 1-3 substituents selected from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, -NR x R 7 T, hydroxy, alkoxy, halogen, CF 3 , cyano, and -SO m R ⁇ (wherein R x , R 7n , m and R ⁇ are the same as defined earlier); or an alkyl group as defined above that has both substituents as defined above and is also interrupted by 1-5 atoms or groups as defined above.
  • alkylene refers to a diradical branched or unbranched saturated hydrocarbon chain having from 1 to 6 carbon atoms and one or more hydrogen can optionally be substituted with alkyl, hydroxy, halogen or oximes. This term can be exemplified by groups such as methylene, ethylene, propylene isomers (e.g., -CH 2 CH 2 CH 2 and -CH(CH 3 )CH 2 ) and the like.
  • cycloalkyl refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, which may optionally contain one or more olefinic bonds, unless otherwise constrained by the definition.
  • Such cycloalkyl groups can include, for example, single ring structures, including cyclopropyl, cyclobutyl, cyclooctyl, cyclopentenyl, and the like or multiple ring structures, including adamantanyl, andbicyclo [2.2.1] heptane or cyclic alkyl groups to which is fused an aryl group, for example, indane, and the like.
  • Cycloalkylalkyl refers to alkyl-cycloalkyl group linked through alkyl portion, wherein the alkyl and cycloalkyl are the same as defined earlier.
  • aryl unless otherwise specified, refers to aromatic system having 6 to 14 carbon atoms, wherein the ring system can be mono-, bi- or tricyclic and are carbocyclic aromatic groups.
  • Aryl groups optionally may be fused with a cycloalkyl group, wherein the cycloalkyl group may optionally contain heteroatoms selected from O, N or S.
  • Groups such as phenyl, naphthyl, anthryl, biphenyl, and the like exemplify this term.
  • the substituents are attached to a ring atom, i.e., carbon or heteroatom in the ring.
  • heteroaryl groups include oxazolyl, imidazolyl, pyrrolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzthiazinyl, benzthiazinonyl, benzoxazinyl, benzoxazinonyl, quinazonyl, carbazolyl phenothiazinyl, phenoxazinyl, benzothiazolyl or be
  • halogen e.g.,
  • Heterocyclyl can optionally include rings having one or more double bonds. Such ring systems can be mono-, bi- or tricyclic. Carbonyl or sulfonyl group can replace carbon atom(s) of heterocyclyl. Unless otherwise constrained by the definition, the substituents are attached to the ring atom, i.e., carbon or heteroatom. in the ring. Also, unless otherwise constrained by the definition, the heterocyclyl ring optionally may contain one or more olefinic bond(s).
  • heterocyclyl groups include oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, benzoxazinyl, benzthiazinyl, imidazolyl, benzimidazolyl, tetrazolyl, carbaxolyl, indolyl, phenoxazinyl, phenothiazinyl, dihydropyridinyl, dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl, thiazolidinyl, dihydroindolyl, pyridinyl, isoindole 1,3-dione, piperidinyl, tetrahydropyranyl, piper azinyl, 3H-imidazo[4,5-b]pyridine, isoquinolinyl, lH-pyrrolo[2,3-b]pyridine or piperazinyl and the like.
  • solvates refers to solvates with either water (e.g., hydrates, hemihydrate or sesquihydrate), or pharmaceutically acceptable solvents, for example solvates with common organic solvents as ethanol and the like. Such solvates are also encompassed within the scope of the disclosure.
  • prodrugs of these agents also includes within its scope prodrugs of these agents.
  • prodrugs will be functional derivatives of these compounds, which are readily convertible in vivo into the required compound.
  • Conventional procedure for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H Bundgaard and, Elsevier, 1985.
  • prodrugs refers to the compounds that are rapidly transformed in vivo to yield the parent compound of Formula I, for example by hydrolysis in blood.
  • polymorphs includes all crystalline form as well as amorphous forms for compounds described herein and as such are included in the present invention.
  • phrases "pharmaceutically acceptable carriers” is intended to include non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • pharmaceutically acceptable salts refer to a salt prepared from pharmaceutically acceptable monovalent, divalent or trivalent non-toxic metal or organic base.
  • metal salts include, but are not limited to, lithium, sodium, potassium, calcium, magnesium, zinc, aluminum and the like.
  • organic bases include, but are not limited to, amino acid, ammonia, mono-alkyl ammonium, dialkyl ammonium, trialkyl ammonium and N-methyl glucamine and the like.
  • the free acid forms of compounds of the present invention may be prepared from the salt forms, if desired, by contacting the salt with dilute aqueous solution of an acid, such as hydrochloric acid.
  • the base addition salts may differ from the free acid forms of the compounds of this invention in such physical characteristics as solubility and melting point.
  • pharmaceutically acceptable salts can further refer to salts prepared from pharmaceutically acceptable non-toxic inorganic or organic acids.
  • inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, nitrous, nitric, carbonic, sulfuric, phosphoric acid, and the like.
  • organic acids include, but are not limited to aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classes of organic acids, for example, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic, benzenesulfonic, panthenic, toluenesulfonic, 2-hydroxyethanesulfonic acid and the like.
  • stereoisomer refers to compounds, which have identical chemical composition, but differ with regard to arrangement of the atoms and the groups in space. These include enantiomers, diastereomers, geometrical isomers, atropisomer and conformational isomers as defined by the IUPAC 1974 Recommendations for Section E. All these stereoisomers are included within the scope of this invention.
  • subject refers to human or lower mammal.
  • treatment includes the treatment or prevention of a bacterial or fungal infection as provided in the method of the present invention.
  • pharmaceutically acceptable means approved by regulatory agency of the federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
  • the compounds disclosed herein may be prepared by techniques well known in the art and familiar to the average synthetic organic chemist, hi addition, the compounds of the present invention may be prepared by the following reaction sequences as depicted in, for example, Schemes I and II.
  • Compounds of Formula 2 can be reacted in one or more solvents, for example, chlorinated solvents (e.g., chloroform, dichloromethane, carbon tetrachloride or dichloroethane), polar aprotic solvents (e.g,. dimethylsulfoxide, dimethylformamide, acetone, tetrahydrofuran or acetonitrile) or mixtures thereof.
  • solvents for example, chlorinated solvents (e.g., chloroform, dichloromethane, carbon tetrachloride or dichloroethane), polar aprotic solvents (e.g,. dimethylsulfoxide, dimethylformamide, acetone, tetrahydrofuran or acetonitrile) or mixtures thereof.
  • Compounds of Formula 2 can also be reacted in one or more reducing agents, for example, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, cata
  • Compounds of Formula 8 can be prepared, for example, according to Scheme II.
  • compound of Formula 2 can be reacted with a compound of Formula 5 to form compounds of Formula 6.
  • Compounds of Formula 6 can be reduced to form compounds of Formula 7.
  • Compounds of Formula 2 can be reacted in one or more solvents, for example, chlorinated solvents (e.g,. chloroform, dichloromethane, carbon tetrachloride or dichloroethane).
  • the reaction can also be carried out in one or more reagents, which can act as dehydrating agents, for example, glacial acetic acid, sulfuric acid, perchloric acid or mixtures thereof.
  • Compounds of Formula 6 can be reduced in the presence of one or more reducing agents, for example, catalytic reducing agents (e.g,. hydrogen/nickel, hydrogen/palladium or hydrogen/platinum), boron/tetrahydrofuran or mixtures thereof.
  • the reduction can also be carried out in one or more solvents, for example, polar protic solvents (e.g,. methanol, ethanol or isopropanol) in the presence of a base, for example, triethylamine, trimethylamine or ammonia.
  • Compounds of Formula 7 can be reacted in one or more solvents, for example, aprotic polar solvents (e.g., pyridine, dimethylformamide, dimethylacetamide, acetonitrile or dimethylsulfoxide) and in presence of one or more bases, for example, triethylamine, trimethylamine, tributylamine, 4-N-dimethylaminopyridine or mixtures thereof.
  • aprotic polar solvents e.g., pyridine, dimethylformamide, dimethylacetamide, acetonitrile or dimethylsulfoxide
  • bases for example, triethylamine, trimethylamine, tributylamine, 4-N-dimethylaminopyridine or mixtures thereof.
  • compositions of the present invention comprise a pharmaceutically effective amount of compounds described herein formulated together with one or more pharmaceutically acceptable carriers.
  • Solid form preparations for oral administration include capsules, tablets, pills, powders, granules, cachets and suppositories.
  • the active compound can be mixed with at least one inert, pharmaceutically acceptable excipients or carrier, for example, sodium citrate, dicalcium phosphate and/or a filler or extenders, for example, starches, lactose, sucrose, glucose, mannitol and silicic acid; binders, for example, carboxymethylcellulose, alginates, gelatins, polyvinylpyrrolidinone, sucrose, or acacia; disintegrating agents, for example, agar-agar, calcium carbonate, potato starch, alginic acid, certain silicates and sodium carbonate; absorption acceletors, for example, quaternary ammonium compounds; wetting agents, for example, cetyl alcohol, or glycerol mono stearate; adsorbants, for example, Kaolin; lubricants , for example, talc, calcium stearate, magnesium stearate, solid polyethyleneglycol, sodium luaryl sulphate and mixture thereof,
  • Liquid form preparations for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the active compound can be mixed with water or other solvent, solubilizing agents and emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils, for example, cottonseed, groundnut, corn, germ, olive, castor and sesame oil), glycerol, and fatty acid esters of sorbitan and mixture thereof.
  • the oral composition can also include adjuvants, for example, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavouring agents and perfuming agents.
  • aqueous suspensions may be formulated according to the art using suitable dispersing or wetting and suspending agent.
  • suitable dispersing or wetting and suspending agent include water, Ringer's solution and isotonic sodium chloride.
  • Dosage forms for tropical or transdermal administration of compounds provided herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active compound can be admixed under sterile condition with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulations, eardrops, eye ointments, powder and solution are also contemplated as being within the scope of this invention.
  • the pharmaceutical preparation can be provided in a unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be packaged preparation, the package containing discrete capsules, powders, in vials or ampoules, and ointments capsule, sachet, tablet, gel, cream itself or it can be the appropriate number of any of these packaged forms. Examples set forth below demonstrate general synthetic procedures for the preparation of representative compounds. The examples are provided to illustrate particular aspect of the disclosure and do not constrain the scope of the present invention as defined by the claims.
  • 2-carboxy benzaldehyde (0.5 equiv.) of Formula 3 was added to a solution of compounds of Formula 2 (1 equiv.) in dichloroethane and the reaction mixture was stirred at room temperature for about 1 hour.
  • Molecular sieves (1 gm) and sodium triacetoxy borohydride (1 equiv.) were added and the reaction mixture was stirred overnight at an ambient temperature, filtered, and the mother liquor was washed with aqueous sodium bicarbonate solution. The organic layer was dried and evaporated under reduced pressure. The residue was purified by column chromatography to form compounds of Formula 4.
  • N-acetamido phenyl sulfonyl chloride (1 equiv.) and triethylamine (5 equiv.) were added to a solution of compound of Formula 7 (1.1 equiv.) in pyridine (5 mL).
  • the reaction mixture was stirred at room temperature for about 12 hours. Volatiles were removed in vacuo and the content was dissolved in dichloromethane. It was then washed with aqueous sodium bicarbonate solution. Dichloromethane layer collected was dried over anhydrous sodium sulfate. The solvent was removed and the solid obtained was purified over silica gel column, using dichloromethane as eluant to afford compounds of Formula 8.
  • Microbroth minimum inhibitory concentration is performed using NCCLS method in Cation adjusted Mueller ⁇ inton broth for facultative cultures (S.aureus, Enterococcus) and Cation adjusted Mueller ⁇ inton broth +2.5% lysed horse blood for S.pneumoniae.
  • MIC against H.influenzae strains is performed by NCCLS broth dilution method using ⁇ TM broth. Overnight grown cultures are adjusted to 0.5 Mcfarland using normal saline and diluted 100 times. 1 mg/ml concentration of stock solution of drug in DMSO/ distilled water/ solvent given in NCCLS manual is prepared. NCCLS double dilutions are done to get the required concentration range of the drugs in the 96-well microtiter plates using the respective media.

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Abstract

Provided herein are substituted aromatic compound of Formula (I), which are tRNA synthetase inhibitors, and hence can be used as antimicrobial agents. Compounds disclosed herein can be used for the treatment or prevention of a condition caused by or contributed to by gram positive, gram negative, anaerobic bacteria or fungal organisms, more particularly against bacterium, for example, Staphylococci, Enterococci, Streptococci, Haemophilus, Moraxalla, Escherichia, Chlamydia, Rickettsiae, Mycoplasm, Legionella, Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus or Enterobactericeae, and fungal organisms, for example, Aspergillus, Blastomyces, Candida, Coccidiodes, Cryptococcus, Epidermophyton, Hendersonula, Histoplasma, Microsporum, Paecilomyces, Paracoccidiodes, Pneumocystis, Trichophyton, or Trichosporium. Processes for the preparation of these compounds, pharmaceutical compositions thereof, and method of treating microbial infections are also provided.

Description

ISOINDOLE DERIVATIVES AS ANTIMICROBIAL AGENTS
Field of the Invention
Provided herein are substituted aromatic compounds, which are tRNA synthetase inhibitors, and hence can be used as antimicrobial agents. Compounds disclosed herein can be used for the treatment or prevention of a condition caused by or contributed to by gram positive, gram negative, anaerobic bacteria or fungal organisms, more particularly against bacterium, for example, Staphylococci, Enterococci, Streptococci, Haemophilus, Moraxalla, Escherichia, Chlamydia, Rickettsiae, Mycoplasm, Legionella, Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus or Enterobactericeae, and fungal organisms, for example, Aspergillus, Blastomyces, Candida, Coccidiodes, Cryptococcus, Epidermophyton, Hendersonula, Histoplasma, Microsporum, Paecilomyces, Paracoccidiodes, Pneumocystis, Trichophyton, or Trichosporium. Processes for the preparation of these compounds, pharmaceutical compositions thereof, and method of treating microbial infections are also provided. Background of the Invention
Antibiotics are of immense value for combating infectious diseases, hi recent decades, the effectiveness of antibiotics has been threatened by an inexorable rise in the prevalence of microbial drug resistance. Some important pathogens have serious resistance problems. Staphylococcus aureus is perhaps the most significant of these pathogens. It causes community and hospital acquired infections and is associated with high morbidity and mortality rates. Vancomycin has been used as the antibiotic of last resort to treat methicillin-resistance staphylococcus aureus infections (MRSA) with multiple resistance. Strains with some level of resistance to vancomycin (Vancomycin- intermediates-resistant S. aureus, VISA) have been known since 1996, but the newly identified highly resistant strain (VRSA) heralds a new stage in the battle with this pathogen. Other serious treatment problems include multidrug resistance in tuberculosis, vancomycin resistant enterococci (VRE), resistance owing to extended spectrum β- lactamases (ESBLs) in Enterobacteriaceae and Pseudomonas aeruginosa, and penicillin resistance in Streptococcus pneumoniae. A nation wide epidemic of multi drug resistant Salmonell typhi occurred in 1990 and has not yet fully subsided. Antimicrobial resistance among respiratory pathogens has become a common clinical problem, currently over 90% of Morexella catarrhalis and 25% of Haemophilus influenzae produce β lactamases, requiring treatment with a β lactamase stable cephalosporin or combination drugs. In the last several years, there has been a rapid increase in the number of strains resistant to penicillin, cephalosporins, macrolides and fluoroquinolones.
These circumstances have prompted efforts to develop new antibiotics that overcome the emerging antibiotic resistance bacteria. The amino acyl tRNA synthetases are essential enzymes found in all living organisms. These enzymes have emerged as an attractive target for the development of new antibiotics. Amino acyl tRNA synthetases charge tRNA molecules with their corresponding amino acid, an essential step in protein synthesis. There are 20 tRNA synthetases, most of which correspond to attractive broad- spectrum antibacterial targets. This is a validated target class in that pseudomonic acid A, also known as mupirocin, a natural product from Pseudominas fluorescens, inhibits isoleucyl tRNA synthtase and is marketed as a topical antibiotic Bactropan. Other known natural products directed against amino acyl tRNA synthetases include borrelidin, furanomycin, granaticin, indolmycin, ochartoxin A, and cispentacin, none of them has been developed as antibiotic compounds.
U.S. Patent Application Nos. 2004/0224981 and 2003/0013724 disclose tRNA synthetase inhibitors. WO 00/18772 discloses condensed imidazolidinone as tRNA synthetase inhibitors. U.S. Patent Nos. 5,191,093 and 4,916,155 disclose crystalline pseudomonate, process for its production and its use in human and veterinary medicines. U.S. Patent No. 4,916,155 discloses crystalline calcium pseudomonate or the hydrate thereof, and their use in human and veterinary medicine.
Novel synthetic compounds, which target tRNA synthetases, offer clear advantages as useful therapeutic agents to curb the threat of drug resistance.
Summary of the Invention
Herein are provided substituted aromatic compounds, which are tRNA synthetase inhibitors, and hence can be used for the treatment of microbial infections, and processes for the synthesis of these compounds. Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, prodrugs, metabolites, polymorphs and N-oxides of these compounds having same type of activity are also provided. Pharmaceutical compositions containing the disclosed compounds (Formula I) together with pharmaceutically acceptable carriers, excipients or diluents, which can be used for the treatment of microbial infections. Other aspects will be set forth in the accompanying description which follows and in part will be apparent from the description or may be learnt by the practice of the invention. hi one aspect, there are provided compounds having the structure of Formula I,
Figure imgf000004_0001
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, prodrugs, metabolites and N-oxide thereof, wherein:
Cy can be cycloalkyl or heterocyclyl; X can be alkylene; X1 and X2 can be independently CO, CS or CH2; R can be hydrogen, hydroxy, nitro, halogen, OR1, OCONHR1, OCONHSO2R1, SR2 (wherein R1 can be aryl or heteroaryl and R2 can be hydrogen, alkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl) or NR3R4 {wherein R3 and R4 can be independently hydrogen, SO2R5, COR5, CSR5, or COOR5 [wherein R5 can be alkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroarylalkyl, heterocycloalkyl, OR6, NHR6, NHSO2R6, NHCOR6, NHCSR6, or NH2C=NHSO2R6 (wherein R6 can be alkyl, aryl, heteroaryl or heterocyclyl)]}. Also, R3 and R4 can, together with the nitrogen to which they are attached, form a heterocyclic ring. hi another aspect, there is provided a method for treating or preventing a subject suffering from a condition caused by or contributed to by Gram-positive, Gram-negative, anaerobic bacteria or fungal organisms, comprising administering to the subject, a therapeutically effective amount of a compound or a pharmaceutical composition disclosed herein.
Bacterium, for example, Staphylococci, Enterococci, Streptococci, Haemophilus, Moraxalla, Escherichia, Chlamydia, Rickettsiae, Mycoplasm, Legionella, Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus or Enterobactericeae may cause the bacterial infections. Organisms, for example, Aspergillus, Blastomyces, Candida, Coccidiodes, Cryptococcus, Epidermophyton, Hendersonula, Histoplasma, Microsporum, Paecilomyces, Paracoccidiodes, Pneumocystis, Trichophyton, or Trichosporium, Enterobactericeae may cause the fungal infections. The conditions may be, for example, community acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, hospital acquired lung infections or bone and joint infections, and other bacterial infections, for example, mastitis, catheter infection, foreign body, prosthesis infections or peptic ulcer disease.
In a further aspect, there are provided processes for the preparation of compounds as disclosed herein.
The following definitions apply to terms as used herein:
The term "alkyl," unless otherwise specified, refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. Alkyl groups can be optionally interrupted by atom(s) or group(s) independently selected from oxygen, sulfur, a phenylene, sulphinyl, sulphonyl group or -NR0T, wherein Ra can be hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, acyl, aralkyl, -C(=O)ORχ, SO1nR,/, or
Figure imgf000005_0001
This term can be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n- decyl, tetradecyl, and the like. Alkyl groups may be substituted further with one or more substituents selected from alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, oxo, thiocarbonyl, carboxy, carboxyalkyl, aryl, heterocyclyl, heteroaryl, (heterocyclyl)alkyl, cycloalkoxy, -CH=N-O(C1-6alkyl), -CH=N-NH(C 1-6alkyl), -CH=N-NH(C1-6alkyl)-C1- 6alkyl, arylthio, thiol, alkylthio, aryloxy, nitro, aminosulfonyl, aminocarbonylamino, -
Figure imgf000005_0002
-C(=O)heteroaryl,
C(=O)heterocyclyl,
Figure imgf000005_0003
{wherein Rx and R7T are independently selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or carboxy}, nitro or -SOmRø (wherein m is an integer from 0-2 and Rψ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, aryl, heterocyclyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl). Unless otherwise constrained by the definition, alkyl substituents may be further substituted by 1-3 substituents selected from alkyl, alkenyl, alkynyl, carboxy, - NRxR7T3 -C(=O)NRλRτr, -OC(=O)NRxRT)-NHC(=O)NRxR7r, hydroxy, alkoxy, halogen, CF3, cyano, and -SOmR^; or an alkyl group also may be interrupted by 1-5 atoms of groups independently selected from oxygen, sulfur or -NR0T (wherein Ro, Rx, R% m and R^ are the same as defined earlier). Unless otherwise constrained by the definition, all substituents maybe substituted further by 1-3 substituents selected from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, -NRxR7T,
Figure imgf000006_0001
hydroxy, alkoxy, halogen, CF3, cyano, and -SOmRψ (wherein Rx, R7n, m and R^ are the same as defined earlier); or an alkyl group as defined above that has both substituents as defined above and is also interrupted by 1-5 atoms or groups as defined above.
The term "alkylene," as used herein, refers to a diradical branched or unbranched saturated hydrocarbon chain having from 1 to 6 carbon atoms and one or more hydrogen can optionally be substituted with alkyl, hydroxy, halogen or oximes. This term can be exemplified by groups such as methylene, ethylene, propylene isomers (e.g., -CH2CH2CH2 and -CH(CH3)CH2) and the like. Alkylene may further be substituted with one or more substituents such as alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryloxy, heteroaryloxy, aminosulfonyl, -COORø, -NHCC=O)Rx, - NRxR1T, -Q=O)NRxR7T, -NHCC=O)NRxR7T, -C(=O)heteroaryl, C(=O)heterocyclyl, -O- C(=O)NRxR7r, nitro, -S(O)mRx (wherein Rx, Rπ> m and R^ are the same as defined earlier): Unless otherwise constrained by the definition, all substituents may be further substituted by 1-3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, -COOR^, -NRxR7T, - Q=O)NRxR7T, -OQ=O)NRxR7T, -NHC(=0)NRxR7r, hydroxy, alkoxy, halogen, CF3, cyano, and -S(O)mR,/, (wherein Rx, R71-, m and R^ are the same as defined earlier). Alkylene can also be optionally interrupted by 1-5 atoms of groups independently chosen from oxygen, sulfur and -NRa (wherein R0 is the same as defined earlier). Unless otherwise constrained by the definition, all substituents may be further substituted by 1-3 substituents selected from hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, acyl, aralkyl, alkoxy, hydroxy, carboxy, -Q=0)0Rψ, halogen, CF3, cyano, -NRxR7T, -S(O)mRψ, -Q=O)NRxR7T, -
Figure imgf000006_0002
-CONH-, -C=O or -C=NOH (wherein Rx, Rx, m and Rψ are the same as defined earlier). The term "cycloalkyl," unless otherwise specified, refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, which may optionally contain one or more olefinic bonds, unless otherwise constrained by the definition. Such cycloalkyl groups can include, for example, single ring structures, including cyclopropyl, cyclobutyl, cyclooctyl, cyclopentenyl, and the like or multiple ring structures, including adamantanyl, andbicyclo [2.2.1] heptane or cyclic alkyl groups to which is fused an aryl group, for example, indane, and the like. Spiro and fused ring structures can also be included. Cycloalkyl groups may be substituted further with one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylarmno, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, carboxyalkyl, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, aminocarbonylamino, -NRxR7T, -NHCt=O)NRxR7T, -NHC(^O)Rx, - CC=O)NRxR7T, -0-CC=O)NRxR7T, nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or SOmRψ (wherein Rx, R^m and Rψ are the same as defined earlier). Unless otherwise constrained by the definition, cycloalkyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkoxy, halogen, CF3, -NRxR7T, -CC=O)NRxR7T, -NHCC=O)NRxR7T,- OCC=O)NRxR7T, cyano or -SOmR^ (wherein Rx, R% m and Rψ are the same as defined earlier). "Cycloalkylalkyl" refers to alkyl-cycloalkyl group linked through alkyl portion, wherein the alkyl and cycloalkyl are the same as defined earlier. term "aryl," unless otherwise specified, refers to aromatic system having 6 to 14 carbon atoms, wherein the ring system can be mono-, bi- or tricyclic and are carbocyclic aromatic groups. For example, aryl groups include, but are not limited to, phenyl, biphenyl, anthryl or napthyl ring and the like, optionally substituted with 1 to 3 substituents selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, acyl, aryloxy, CF3, cyano, nitro, COOR,/,, NHCC=O)Rx, -NRxR7T, - CC=O)NRxR7T, -NHCC=O)NRxR7T, -0-CC=O)NRxR7T, -SOmRψ, carboxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or amino carbonyl amino, mercapto, haloalkyl, optionally substituted aryl, optionally substituted heterocyclylalkyl, thioalkyl, - CONHR7T, -OCOR7T, -COR7T, -NHSO2R7T or -S O2NHR7T (wherein Rx, Rτ, m and R^ are the same as defined earlier). Aryl groups optionally may be fused with a cycloalkyl group, wherein the cycloalkyl group may optionally contain heteroatoms selected from O, N or S. Groups such as phenyl, naphthyl, anthryl, biphenyl, and the like exemplify this term.
The term "heteroaryl," unless otherwise specified, refers to an aromatic ring structure containing 5 or 6 ring atoms or a bicyclic or tricyclic aromatic group having from 8 to 10 ring atoms, with one or more heteroatom(s) independently selected from N, O or S optionally substituted with 1 to 4 substituent(s) selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, carboxy, aryl, alkoxy, aralkyl, cyano, nitro, lieterocyclyl, heteroaryl, -NRxR1T, CH=NOH, -(CH2)WC(=O)R^ {wherein w is an integer from 0-4 and R,, is hydrogen, hydroxy, ORx, NRχRπ, -NHOR0, or -NHOH}, - C(-O)NRxR,r -NHC(^O)NRxR7T, -SOmR^, -0-C(^O)NRxR7T, -O-C(=O)Rχ, or -O-C(=O)ORλ (wherein m, R^, Rx and Rv are as defined earlier and R0, is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl). Unless otherwise constrained by the definition, the substituents are attached to a ring atom, i.e., carbon or heteroatom in the ring. Examples of heteroaryl groups include oxazolyl, imidazolyl, pyrrolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzthiazinyl, benzthiazinonyl, benzoxazinyl, benzoxazinonyl, quinazonyl, carbazolyl phenothiazinyl, phenoxazinyl, benzothiazolyl or benzoxazolyl, and the like. The The term "heterocyclyl," unless otherwise specified, refers to a non-aromatic monocyclic or bicyclic cycloalkyl group having 5 to 10 atoms wherein 1 to 4 carbon atoms in a ring are replaced by heteroatoms selected from O, S or N, and optionally are benzofused or fused heteroaryl having 5-6 ring members and/or optionally are substituted, wherein the substituents are selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, optionally substituted aryl, alkoxy, alkaryl, cyano, nitro, oxo, carboxy, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, -O-C(=O)Rχ, -O-C(=O)ORχ, -Ct=O)NRxR7T, SOmRø, -O- C(=O)NRXR,T, -MKX=O)NRxR71-, -NRxR7T, mercapto, haloalkyl, thioalkyl, -COOR^, - COONHRx, -CORx, -NHSO2Rx or S O2NHRx (wherein m, Rψ, Rx and Rπ are as defined earlier) or guanidine. Heterocyclyl can optionally include rings having one or more double bonds. Such ring systems can be mono-, bi- or tricyclic. Carbonyl or sulfonyl group can replace carbon atom(s) of heterocyclyl. Unless otherwise constrained by the definition, the substituents are attached to the ring atom, i.e., carbon or heteroatom. in the ring. Also, unless otherwise constrained by the definition, the heterocyclyl ring optionally may contain one or more olefinic bond(s). Examples of heterocyclyl groups include oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, benzoxazinyl, benzthiazinyl, imidazolyl, benzimidazolyl, tetrazolyl, carbaxolyl, indolyl, phenoxazinyl, phenothiazinyl, dihydropyridinyl, dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl, thiazolidinyl, dihydroindolyl, pyridinyl, isoindole 1,3-dione, piperidinyl, tetrahydropyranyl, piper azinyl, 3H-imidazo[4,5-b]pyridine, isoquinolinyl, lH-pyrrolo[2,3-b]pyridine or piperazinyl and the like. The groups "aryl, heteroaryl and heterocyclyl" can optionally be substituted with substituent(s) selected from alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heteroarylalkyl, heterocycloalkyl, halogen, hydroxy, alkoxy, cyano, nitro, aryloxy, haloalkoxy, CORb, CSRb, COORb, S(O)aRb, OCOORb, NHSO2Rb, MϊC0Rb, NHCSRb, (CH)o-2C(=0)NRcRd or NR0Rd (wherein Rb, R0 and Rd are independently selected from hydrogen, alkyl, aryl, heteroaryl, heterocyclyl and a is an integer of from 0-2. Unless otherwise constrained, all substituents may optionally be further substituted by substituent(s) defined earlier.
The term "pharmaceutically acceptable solvates" refers to solvates with either water (e.g., hydrates, hemihydrate or sesquihydrate), or pharmaceutically acceptable solvents, for example solvates with common organic solvents as ethanol and the like. Such solvates are also encompassed within the scope of the disclosure.
The present invention also includes within its scope prodrugs of these agents. In general, such prodrugs will be functional derivatives of these compounds, which are readily convertible in vivo into the required compound. Conventional procedure for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H Bundgaard and, Elsevier, 1985. As used herein the term "prodrugs" refers to the compounds that are rapidly transformed in vivo to yield the parent compound of Formula I, for example by hydrolysis in blood.
The disclosed compounds may get metabolized in vivo and these metabolites are also encompassed within the scope of this invention. The term "polymorphs" includes all crystalline form as well as amorphous forms for compounds described herein and as such are included in the present invention.
The phrase "pharmaceutically acceptable carriers" is intended to include non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
The term "pharmaceutically acceptable salts" refer to a salt prepared from pharmaceutically acceptable monovalent, divalent or trivalent non-toxic metal or organic base. Examples of such metal salts include, but are not limited to, lithium, sodium, potassium, calcium, magnesium, zinc, aluminum and the like. Examples of such organic bases include, but are not limited to, amino acid, ammonia, mono-alkyl ammonium, dialkyl ammonium, trialkyl ammonium and N-methyl glucamine and the like. The free acid forms of compounds of the present invention may be prepared from the salt forms, if desired, by contacting the salt with dilute aqueous solution of an acid, such as hydrochloric acid. The base addition salts may differ from the free acid forms of the compounds of this invention in such physical characteristics as solubility and melting point.
The term "pharmaceutically acceptable salts" can further refer to salts prepared from pharmaceutically acceptable non-toxic inorganic or organic acids. Examples of such inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, nitrous, nitric, carbonic, sulfuric, phosphoric acid, and the like. Appropriate organic acids include, but are not limited to aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classes of organic acids, for example, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic, benzenesulfonic, panthenic, toluenesulfonic, 2-hydroxyethanesulfonic acid and the like.
The compounds of present invention include stereoisomers. The term "stereoisomer" refers to compounds, which have identical chemical composition, but differ with regard to arrangement of the atoms and the groups in space. These include enantiomers, diastereomers, geometrical isomers, atropisomer and conformational isomers as defined by the IUPAC 1974 Recommendations for Section E. All these stereoisomers are included within the scope of this invention.
The term "subject" as used herein refers to human or lower mammal.
The term "treatment", as used herein, unless otherwise indicated, includes the treatment or prevention of a bacterial or fungal infection as provided in the method of the present invention.
The term "pharmaceutically acceptable" means approved by regulatory agency of the federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
Detailed Description of the Invention
The compounds disclosed herein may be prepared by techniques well known in the art and familiar to the average synthetic organic chemist, hi addition, the compounds of the present invention may be prepared by the following reaction sequences as depicted in, for example, Schemes I and II.
Scheme I
Figure imgf000011_0001
Formula 3
Figure imgf000011_0002
Formula 4 (Formula I5 wherein X]=CH2, X2=CO, R=H)
Compounds of Formula 4 can be prepared, for example, according to Scheme I. Thus, compounds of Formula 2 can be reacted with a compound of Formula 3 to form compounds of Formula 4 (wherein Cy can be cycloalkyl or heterocyclyl and X can be alkylene).
Compounds of Formula 2 can be reacted in one or more solvents, for example, chlorinated solvents (e.g., chloroform, dichloromethane, carbon tetrachloride or dichloroethane), polar aprotic solvents (e.g,. dimethylsulfoxide, dimethylformamide, acetone, tetrahydrofuran or acetonitrile) or mixtures thereof. Compounds of Formula 2 can also be reacted in one or more reducing agents, for example, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, catalytic reducing agents, like hydrogen/Nickel, hydrogen/palladium, hydrogen/platinum or mixtures thereof.
Figure imgf000012_0001
Formula 5 Formula 6
Figure imgf000012_0002
Formula 8
(Formula I, wherein, X1=X2=CO, R=NR3R4; R3=H1 R4=SO2R5)
Compounds of Formula 8 can be prepared, for example, according to Scheme II. Thus, compound of Formula 2 can be reacted with a compound of Formula 5 to form compounds of Formula 6. Compounds of Formula 6 can be reduced to form compounds of Formula 7. Compounds of Formula 7 can be treated with compounds of Formula RsSO2Cl (wherein R5 can be alkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroarylalkyl, heterocycloalkyl, OR6, NHR6, NHSO2R6, NHCOR6, NHCSR6, OrNH2C=NHSO2R6 (wherein R6 can be alkyl, aryl, heteroaryl or heterocyclyl) to form compounds of Formula 8.
Compounds of Formula 2 can be reacted in one or more solvents, for example, chlorinated solvents (e.g,. chloroform, dichloromethane, carbon tetrachloride or dichloroethane). The reaction can also be carried out in one or more reagents, which can act as dehydrating agents, for example, glacial acetic acid, sulfuric acid, perchloric acid or mixtures thereof.
Compounds of Formula 6 can be reduced in the presence of one or more reducing agents, for example, catalytic reducing agents (e.g,. hydrogen/nickel, hydrogen/palladium or hydrogen/platinum), boron/tetrahydrofuran or mixtures thereof. The reduction can also be carried out in one or more solvents, for example, polar protic solvents (e.g,. methanol, ethanol or isopropanol) in the presence of a base, for example, triethylamine, trimethylamine or ammonia.
Compounds of Formula 7 can be reacted in one or more solvents, for example, aprotic polar solvents (e.g., pyridine, dimethylformamide, dimethylacetamide, acetonitrile or dimethylsulfoxide) and in presence of one or more bases, for example, triethylamine, trimethylamine, tributylamine, 4-N-dimethylaminopyridine or mixtures thereof.
Particular illustrative compounds include those listed below:
2-[(15)-2-cyclohexyl-l-methylethyl]isoindolin-l-one (Compound No. 1);
4-ammo-2-[(l£)-2-cyclohexyl- 1 -methylethyl]- lH-isoindole- 1 ,3(2H)-dione (Compound
No. 2);
2-[(15)-2-cyclohexyl- 1 -methylethyl] -4-nitro- lH-isoindole- 1 ,3(2H)-dione (Compound No. 3);
/V-{4.[({2-[(l(S)-2-cyclohexyl-l-methylethyl]-l,3-dioxo-2,3-dihydro-lH-isoindol-4- yl}amino)sulfonyl]phenyl}acetamide (Compound No. 4); 2-[(16)-2-cyclohexyl-l-methylethyl]-lH-isoindole-l,3(2H)-dione (Compound No. 5);
7V-{4-[({2-[(15)-2-cyclohexyl-l-methylethyl]-2,3-dihydro-lH'-isoindol-4- yl}amino)sulfonyl]phenyl}acetamide (Compound No. 6); iV-{4-[({2-[(15)-2-cyclohexyl-l-methylethyl]-3-oxo-2,3-dihydro-lH"-isoindol-4- yl}amino)sulfonyl]phenyl}acetamide (Compound No. 7);
7V-{2-[(l,S)-2-cyclohexyl-l-methylethyl]-l,3-dioxo-2,3-dihydro-lH-isomdol-4-yl}-4-(lH- pyrrol-l-yl)benzenesulfonamide (Compound No. 8);
N- {2-[(l<S)-2-cyclohexyl- 1 -methylethyl]- 1 ,3-dioxo-2,3-dihydro- lH-isoindol-4-yl} -6-(1H"- pyrrol-l-yl)pyridine-3-sulfonamide (Compound No. 9);
N-{2-[(l1S)-2-cyclopentyl-l-methylethyl]-l,3-dioxo-2,3-dihydro-lH"-isoindol-4-yl}-4-(lH"- pyrrol- l-yl)benzenesulfonamide (Compound No. 10); 7V"-{2-[(16)-2-cyclopentyl-l-methylethyl]-l,3-dioxo-2,3-dihydro-lH"-isoindol-4-yl}-3- fluoro-4-(lH-pyrrol-l-yl)benzenesulfonamide (Compound No. 11); N- {2-[(lS)-2-cycloρentyl- 1 -methylethyl]- 1 ,3-dioxo-2,3-dihydro-lH-isoindol-4-yl} -4-(1H"- l,2,4-triazol-l-yl)benzenesulfonamide (Compound No. 12);
N-{2-[(l»S)-2-cyclopentyl-l-methylethyl]-l,3-dioxo-2,3-dihydro-lH"-isoindol-4-yl}-4- (l,2,3-thiadiazol-4-yl)benzenesulfonamide (Compound No. 13);
N- {2-[(l£)-2-cyclopentyl-l -methylethyl]-3-oxo-2,3-dihydro- l/f-isoindol-4-yl} -4-(l ,2,3- thiadiazol-4-yl)benzenesulfonamide (Compound No. 14);
N-{2-[(l(S)-2-cyclopentyl-l-methylethyl]-2,3-dihydro-lH-isoindol-4-yl}-4-(l,2,3- thiadiazol-4-yl)benzenesulfonamide (Compound No. 15); and pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereo isomers, prodrugs, metabolites and N-oxides thereof.
Because of their antimicrobial activity, the compounds described herein may be administered to an animal for treatment orally, topically, rectally, internasally, or by a parenteral route. The pharmaceutical compositions of the present invention comprise a pharmaceutically effective amount of compounds described herein formulated together with one or more pharmaceutically acceptable carriers. Solid form preparations for oral administration include capsules, tablets, pills, powders, granules, cachets and suppositories. For solid form preparations, the active compound can be mixed with at least one inert, pharmaceutically acceptable excipients or carrier, for example, sodium citrate, dicalcium phosphate and/or a filler or extenders, for example, starches, lactose, sucrose, glucose, mannitol and silicic acid; binders, for example, carboxymethylcellulose, alginates, gelatins, polyvinylpyrrolidinone, sucrose, or acacia; disintegrating agents, for example, agar-agar, calcium carbonate, potato starch, alginic acid, certain silicates and sodium carbonate; absorption acceletors, for example, quaternary ammonium compounds; wetting agents, for example, cetyl alcohol, or glycerol mono stearate; adsorbants, for example, Kaolin; lubricants , for example, talc, calcium stearate, magnesium stearate, solid polyethyleneglycol, sodium luaryl sulphate and mixture thereof, hi the case of capsules, tablets, or pills, the dosage form may also comprise buffering agents. The solid preparation of tablets, capsules, pills and granules can be prepared with coating and shells, for example, enteric coating and other coatings well known in the pharmaceutical formulating art.
Liquid form preparations for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. For liquid form preparations, the active compound can be mixed with water or other solvent, solubilizing agents and emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils, for example, cottonseed, groundnut, corn, germ, olive, castor and sesame oil), glycerol, and fatty acid esters of sorbitan and mixture thereof. Besides inert diluents, the oral composition can also include adjuvants, for example, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavouring agents and perfuming agents.
Injectible preparations, for example, sterile injections, aqueous suspensions may be formulated according to the art using suitable dispersing or wetting and suspending agent. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride.
Dosage forms for tropical or transdermal administration of compounds provided herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active compound can be admixed under sterile condition with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulations, eardrops, eye ointments, powder and solution are also contemplated as being within the scope of this invention.
The pharmaceutical preparation can be provided in a 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 packaged preparation, the package containing discrete capsules, powders, in vials or ampoules, and ointments capsule, sachet, tablet, gel, cream itself or it can be the appropriate number of any of these packaged forms. Examples set forth below demonstrate general synthetic procedures for the preparation of representative compounds. The examples are provided to illustrate particular aspect of the disclosure and do not constrain the scope of the present invention as defined by the claims.
EXAMPLES General Procedures Example 1: Preparation of compounds of Formula 4
2-carboxy benzaldehyde (0.5 equiv.) of Formula 3 was added to a solution of compounds of Formula 2 (1 equiv.) in dichloroethane and the reaction mixture was stirred at room temperature for about 1 hour. Molecular sieves (1 gm) and sodium triacetoxy borohydride (1 equiv.) were added and the reaction mixture was stirred overnight at an ambient temperature, filtered, and the mother liquor was washed with aqueous sodium bicarbonate solution. The organic layer was dried and evaporated under reduced pressure. The residue was purified by column chromatography to form compounds of Formula 4.
Example 2: Preparation of compounds of Formula 6
A solution of compounds of Formula 2 (1 equiv.) and 3-nitrophthalic anhydride (1 equiv.) of Formula 5 in acetic acid was stirred at about 100 0C for about 20 hours. Volatile matter was removed in vacuo, and the residue obtained was dissolved in dichloromethane. The solution was washed with sodium bicarbonate solution and with water. The dichloromethane layer was separated and the solvent was evaporated. The solid then obtained was purified over silica column using dichloromethane as eluent to form compounds of Formula 6.
Example 3: Preparation of compounds of Formula 7
To a solution of compound of Formula 6 (1 equiv.) in methanol (50 mL) was added raney nickel (3 equiv.). To the stirred reaction mixture at room temperature hyrdazine hydrate (3 equiv.) added slowly in about 1 hour and the reaction mixture was allowed to stir at room temperature for about 3 hours. Filtered through a celite pad. The solid thus formed was purified by column chromatography to afford compounds of Formula 7.
Example 4: Preparation of compounds of Formula 8
N-acetamido phenyl sulfonyl chloride (1 equiv.) and triethylamine (5 equiv.) were added to a solution of compound of Formula 7 (1.1 equiv.) in pyridine (5 mL). The reaction mixture was stirred at room temperature for about 12 hours. Volatiles were removed in vacuo and the content was dissolved in dichloromethane. It was then washed with aqueous sodium bicarbonate solution. Dichloromethane layer collected was dried over anhydrous sodium sulfate. The solvent was removed and the solid obtained was purified over silica gel column, using dichloromethane as eluant to afford compounds of Formula 8.
The following compounds were prepared analogously, following the above general procedures:
Compound No. 1 : 2-[(l£y2-cyclohexyl-l-methylethyl1isoindolin-l-one
1HNMR (CDCl3): δ 7.86 (d;lH), 7.53(d;lH), 7.45 (t; 2H), 4.68 (m;lH), 4.28 (dd, 2H), 1.95 (d, IH), 1.58 (m, 5H), 1.42 ( m, IH). 1.25 (d, 3H), 1.17(m, 4H), 1.12 (m, IH) Mass (m/z): 258.2 (M+H);
Compound No. 2: 4-amino-2-[(15)-2-cvclohexyl-l-methylethvn-lH-isoindole-l 3(2H)- dione
1HNMR (CDCl3): δ 7.41 (t; IH), 7.12 (d;lH), 6.12 (d, IH), 5.30 (bs, 2H), 4.44 (m; IH),
2.04 (m, IH)5 1.8 (d. 2H), 1.62 (m, 4H), 1.51 (m, IH). 1.42 (d, 3H). 1.12(m, 4H), 0.90 (m,
2H)
Mass (m/z): 287.2 (M+H);
Compound No. 3: 2-r(lS)-2-cvclohexyl-l-methylethyll-4-nitro-lH-isoindole-1.3('2H")- dione
1HNMR (CDCl3): δ 8.10 (d; 2H), 7.90 (t;lH), 4.53 (m; IH), 2.02 (m, IH), 1.8 (d. 2H), 1.58 (m, 5H), 1.42 (d, 3H). 1.17(m, 3H), 0.85 (m, 2H) Mass (m/z): 317.1(M+H);
Compound No. 4: iy-{4-rC(2-rd^-2-cvclohexyl-l-methylethyll-1.3-dioxo-2,3-dihvdro- lH-isoindol-4-yl) ammoisulfonyl]phenyl> acetamide
1HNMR (CDCl3): δ 9.01 (bs, IH), 7.89 (d, 2H), 7.82(d, IH), 7.62 (t; 2H), 7.56 (t, IH),
7.41 (d;lH), 7.35 (bs, IH), 4.39 (m; IH), 2.19 (s, 3H), 1.96 (m, IH), 1.80 (d. 2H), 1.60 (m,
5H)5 1.40 (d, 3H). 1.12 (m, 4H)5 0.90 (m, 2H)
Mass (m/z): 484.1 (M+H);
The following compounds can be prepared following the above general procedures
Compound No. 5: 2-[(l,S)-2-cyclohexyl-l-methylethyl]-lH-isoindole-l,3(2H)-dione;
Compound No. 6: N-{4-[({2-[(l,S)-2-cyclohexyl-l-methylethyl]-2,3-dihydro-lH"-isoindol- 4-yl} amino)sulfonyl]phenyl} acetamide;
Compound No. 7: N-{4-[({2-[(15)-2-cyclohexyl-l-methylethyl]-3-oxo-2,3-dihydro-lH- isoindol-4-yl} amino)sulfonyl]phenyl} acetamide; Compound No. 8: N-{2-[(lS)-2-cycloliexyl-l-methylethyl]-l,3-dioxo-2,3-diliydro-lH'- isoindol-4-yl} -4-( lH-pyrrol- 1 -yl)benzenesulfonamide;
Compound No. 9: N-{2-[(15)-2-cyclohexyl-l-methylethyl]-l,3-dioxo-2,3-dihydro-lH- isoindol-4-yl} -6-(lH-pyrrol- 1 -yl)pyridine-3 -sulfonamide;
Compound No. 10: N-{2-[(lS)-2-cycloρentyl-l-methylethyl]-l,3-dioxo-2,3-dihydro-lH- isoindol-4-yl} -4-(lH-pyrrol- 1 -yl)benzenesulfonamide; CompoundNo. 11: N-{2-[(lS)-2-cyclopentyl-l-methylethyl]-l,3-dioxo-2,3-dihydro-lH"- isoindol-4-yl}-3-fluoro-4-(lH-pyrrol-l-yl)benzenesulfonamide;
Compound No. 12: N-{2-[(lJS)-2-cycloρentyl-l-methylethyl]-l,3-dioxo-2,3-dihydro-lH- isoindol-4-yl} -4-(1H"- 1 ,2,4-triazol- 1 -yl)benzenesulfonamide;
Compound No. 13: N-{2-[(l;S)-2-cyclopentyl-l-methylethyl]-l,3-dioxo-2,3-diliydro-lH- isoindol-4-yl} -4-(l ,2,3 -thiadiazol-4-yl)benzenesulfonamide;
Compound No. 14: N-{2-[(15)-2-cyclopentyl-l-methylethyl]-3-oxo-2,3-dihydro-lH- isoindol-4-yl}-4-(l,2,3-thiadiazol-4-yl)benzenesulfonamide;
Compound No. 15: iV-{2-[(lS)-2-cyclopentyl-l-methylethyl]-2,3-dihydro-lH-isoindol-4- yl} -4-(l ,2,3-thiadiazol-4-yl)benzenesulfonamide;
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.
Microbiological activity
Microbroth minimum inhibitory concentration (MIC) is performed using NCCLS method in Cation adjusted Mueller Ηinton broth for facultative cultures (S.aureus, Enterococcus) and Cation adjusted Mueller Ηinton broth +2.5% lysed horse blood for S.pneumoniae. MIC against H.influenzae strains is performed by NCCLS broth dilution method using ΗTM broth. Overnight grown cultures are adjusted to 0.5 Mcfarland using normal saline and diluted 100 times. 1 mg/ml concentration of stock solution of drug in DMSO/ distilled water/ solvent given in NCCLS manual is prepared. NCCLS double dilutions are done to get the required concentration range of the drugs in the 96-well microtiter plates using the respective media. 100 μl of culture broth is added in wells already containing 100 μl of broth containing antibiotic to get approximately 3-7x10^ CFU/ml. The plates are incubated at 370C for about 18- 24 hours. The concentration of drag at which there is complete disappearance of growth was considered as MIC. Compounds 1-4 were tested for activity against S.pneum strains 3579, AB34, 49619 and 6303; against H.influenza strains 49427 and jS-lac; against S.pyo. 19615; against S.aureus 25923; and against MRSA. The compounds gave MIC (μg/ml) of between about 8 and about 32.

Claims

We claim: 1. A compound having the structure of Formula I,
Figure imgf000020_0001
7
8 pharmaceutically acceptable salts, pharmaceutically acceptable solvates,
9 stereoisomers, prodrugs, metabolites and N-oxide thereof, wherein: 0 Cy is cycloalkyl or heterocyclyl; X is alkylene; X1 and X2 are independently CO, 1 CS or CH2; and R is hydrogen, hydroxy, nitro, halogen, OR1, OCONHR1,
2 OCO]SlHSO2R1, SR2 (wherein Ri is aryl or heteroaryl and R2 is hydrogen, alkyl,
3 cycloalkyl, heterocyclyl, heteroaryl or aryl) or NR3R4 {wherein R3 and R4 is 4 independently hydrogen, SO2R5, COR5, CSR5, or COOR5 [wherein R5 is alkyl, 5 aryl, heteroaryl, heterocyclyl, aralkyl, heteroarylalkyl, heterocycloalkyl, OR6, 6 NHR6, NHSO2R6, NHCOR6, NHCSR6, or NH2C=NHSO2R6 (wherein R6 is alkyl, 7 aryl, heteroaryl or heterocyclyl)] } , or R3 and R4, together with the nitrogen to 8 which they are attached, form a heterocyclic ring.
1 2. A compound selected from the group consisting of:
2 2-[(15)-2-cyclohexyl-l-methylethyl]isoindolin-l-one (Compound No. 1); 3
4 4-amino-2-[(16)-2-cyclohexyl-l-methylethyl]-lH-isoindole-l,3(2H)-dione
5 (Compound No. 2); 6
7 2-[(15)-2-cyclohexyl-l-methylethyl]-4-nitro-lH-isoindole-l,3(2H)-dione
8 (Compound No. 3); 9 0 N-{4-[({2-[(lJS)-2-cyclohexyl-l-methylethyl]-l,3-dioxo-2,3-dihydro-lH-isoindol- 1 4-yl} amino)sulfonyl]phenyl} acetamide (Compound No. 4); 2 3 2-[(16)-2-cyclohexyl- 1 -methylethyl]- lH-isoindole- 1 ,3(2H)-dione (Compound 4 No. 5); 5 6 N- {4-[( {2-[(15)-2-cyclohexyl- 1 -methylethyl]-2,3-dihydro- lH-isoindol-4- 7 yl} amino)sulfonyl]phenyl} acetamide (Compound No. 6); 8 N- {4-[( {2-[(l<S)-2-cyclohexyl- 1 -methylethyl]-3-oxo-2,3-dihydro- lH-isoindol-4- yl}amino)sulfonyl]phenyl}acetamide (Compound No. 7); N- {2-[(l«S)-2-cyclohexyl- 1 -methylethyl]- 1 ,3-dioxo-2,3-dihydro- lH-isoindol-4-yl} - 4-(lH-pyπOl-l-yl)benzenesulfonamide (Compound No. 8); N- {2-[( 15)-2-cyclohexyl- 1 -methylethyl]- 1 ,3 -dioxo-2,3 -dihydro- lH-isoindol-4-yl} - 6-(lH-pyrrol-l-yl)pyridine-3-sulfonamide (Compound No. 9); N- {2-[(15)-2-cyclopentyl- 1 -methylethyl]- 1 ,3-dioxo-2,3-dihydro- l/f-isoindol-4- yl}-4-(lH-pyrrol-l-yl)benzenesulfonamide (Compound No. 10); N- {2-[(l>S)-2-cycloρentyl- 1 -methylethyl]- 1 ,3-dioxo-2,3-dihydro- lH-isoindol-4- yl}-3-fluoro-4-(lH-pyrrol-l-yl)benzenesulfonamide (Compound No. 11); N-{2-[(l1S)-2-cyclopentyl-l-methylethyl]-l,3-dioxo-2,3-dihydro-lH-isoindol-4- yl}-4-(lH-l,2,4-triazol-l-yl)beiizenesulfonamide (Compound No. 12); N-{2-[(15)-2-cycloρentyl-l-methylethyl]-l,3-dioxo-2,3-dihydro-lHr-isoindol-4- yl}-4-(l,2,3-thiadiazol~4-yl)benzenesulfonamide (Compound No. 13); N-{2-[(lJS)-2-cycloρentyl-l-methylethyl]-3-oxo-233-dihydro-lH-isoindol-4-yl}-4- (l,2,3-thiadiazol-4-yl)benzenesulfonamide (Compound No. 14); N-{2-[(l1S)-2-cycloρentyl-l-methylethyl]-2,3-dihydro-lH-isoindol-4-yl}-4-(l,2,3- thiadiazol-4-yl)benzenesulfonamide (Compound No. 15); 3. A pharmaceutical composition comprising therapeutically effective amounts of one or more compounds of claim 1, together with pharmaceutically acceptable carrier, excepients, diluents or mixtures thereof. 4. A method for treating or preventing a subject suffering from a condition caused by or contributed to by bacterial infection or fungal infection, comprising administering to subject, a therapeutically effective amount of one or more compounds of claim 1. 5. A method according to claim 4 wherein bacterium is selected from Staphylococci, Enterococci, Streptococci, Haernophilus, Moraxalla, Escherichia, Chlamydia, Rickettsiae, Mycoplasm, Legionella, Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus or Enterobactericeae, and fungal organism, is selected from, Aspergillus, Blastomyces, Candida, Coccidiodes, Cryptococcus, Epidermophyton, Hendersonula, Histoplasma, Microsporum, Paecilomyces, Paracoccidiodes, Pneumocystis, Trichophyton, or Trichosporium.
6. A method for preparing the compounds of Formula 4,
Figure imgf000022_0001
Formula 4 wherein Cy is cycloalkyl or heterocyclyl; and X is alkylene the method comprising: : reacting a compound of Formula 2 with a compound of Formula 3
Figure imgf000022_0002
Formula 2 Formula 3 to form a compound of Formula 4.
7. A method of preparation of compounds of Formula 8,
Figure imgf000022_0003
Formula 8 wherein Cy is cycloalkyl or heterocyclyl; X is alkylene; and R5 is alkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroarylalkyl, heterocycloalkyl the method comprising: a) reacting a compound of Formula 2 with a compound of Formula 5
Figure imgf000022_0004
Formula 2 Formula 5 to give a compound of Formula 6;
Figure imgf000023_0001
Formula 6
b) reducing the compound of Formula 6 to give a compound of Formula 7; and
Figure imgf000023_0002
Formula 7 c) reacting a compound of Formula 7 with a compound OfR5SO2Cl to give a compound of Formula 8.
PCT/IB2006/002368 2005-09-05 2006-08-30 Isoindole derivatives as antimicrobial agents WO2007029076A1 (en)

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