[go: up one dir, main page]

EP1664072A1 - Novel sulfenamides - Google Patents

Novel sulfenamides

Info

Publication number
EP1664072A1
EP1664072A1 EP04761152A EP04761152A EP1664072A1 EP 1664072 A1 EP1664072 A1 EP 1664072A1 EP 04761152 A EP04761152 A EP 04761152A EP 04761152 A EP04761152 A EP 04761152A EP 1664072 A1 EP1664072 A1 EP 1664072A1
Authority
EP
European Patent Office
Prior art keywords
optionally substituted
group
compound
alkyl
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04761152A
Other languages
German (de)
French (fr)
Inventor
Laurence Mark Von Itzstein
Christopher Bonner Davis
Robin Joy Thomson
Regan David Hartnell
Paul David Orr Madge
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Griffith University
Original Assignee
Griffith University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from AU2003904500A external-priority patent/AU2003904500A0/en
Application filed by Griffith University filed Critical Griffith University
Publication of EP1664072A1 publication Critical patent/EP1664072A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/14—Acyclic radicals, not substituted by cyclic structures attached to a sulfur, selenium or tellurium atom of a saccharide radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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

Definitions

  • the present invention relates to novel sulfenamides that have an antimicrobial action, methods or their synthesis , pharmaceutical compositions containing them and method of treatment of patients suffering microbial infection .
  • T are independently selected from the group consisting of O, S, and NR ⁇ 0 ;
  • alkyl used either alone or in a compound word such as "optionally substituted alkyl” or “optionally substituted cycloalkyl” denotes straight chain, branched or mono- or poly- cyclic alkyl. Examples of straight chain and branched C alkyl include methyl .
  • cycloalkyl examples include cyclopropyl , cyclobutyl, cyclopentyl , cyclohexyl , cycloheptyl , cyclooctyl , cyclononyl and cyclodecyl and the like .
  • alkenyl used either alone or in compound words such as "alkenyloxy” denotes groups formed from straight chain, branched or cyclic alkenes including ethylenically mono-, di- or poly-unsaturated alkyl or cycloalkyl groups as defined above .
  • C 4 _ 30 alkenyl examples include butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl , 1-methyl-cyclopentenyl, 1- hexenyl, 3-hexenyl, cyclohexenyl , 1-heptenyl, 3-heptenyl, 1-octenyl, cyclooctenyl , 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl , 1 , 3-butadienyl , 1-4 ,pentadienyl, 1 , 3-cyclopentadienyl , 1 , 3-hexadienyl, 1 , 4-hexadienyl, 1,3- cyclohexadienyl , 1 , 4-cyclohexadienyl, 1,3- cycloheptadienyl ,
  • acyl used either alone or in compound words such as "optionally substituted acyl” or “optionally substituted acyloxy” denotes an aliphatic acyl group or an acyl group containing an aromatic ring, which is referred to as aromatic acyl, or a heterocyclic ring, which is referred to as heterocyclic acyl, preferably C ⁇ -. 30 acyl.
  • acyl examples include straight chain or branched alkanoyl such as ormyl , acetyl, propanoyl, butanoyl, 2- methylpropanoyl , pentanoyl , 2,2-dimethylpropanoyl , hexanoyl , heptanoyl , octanoyl , nonanoyl , decanoyl , undecanoyl , dodecanoyl , tridecanoyl , pentadecanoyl , hexadecanoyl , heptadecanoyl , octadecanoyl , nonadecanoyl and icosanoyl; cy ⁇ loalkylcarbonyl such as cyclopropylcarbonyl cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl; aroyl
  • phenylacetyl phenylpropanoyl , phenylbutanoyl , phenylisobutyl, phenylpentanoyl and phenylhexanoyl
  • naphthylalkanoyl e.g. naphthylacetyl , naphthylpropanoyl and naphthylbutanoyl
  • aralkenoyl such as phenylalkenoyl (e.g.
  • phenylpropenoy1 phenylbutenoyl , phen lmethacrylyl , phen lpentenoyl and phenylhexenoyl and naphthylalkenoyl (e.g.
  • heterocycliccarbonyl heterocyclicalkanoyl such as thienylacetyl , thienylpropanoyl , thienylbutanoyl , thienylpentanoyl , thienylhexanoyl , thiazolylacetyl , thiadiazolylacetyl and tetrazolylacetyl
  • heterocyclicalkenoyl such as heterocyclicpropenoyl , heterocyclicbutenoyl , heterocyclicpentenoyl and heterocyclichexenoyl .
  • aryl used either alone or in compound words such as “optionally substituted aryl”, “optionally substituted aryloxy” or “optionally substituted heteroaryl” denotes single, polynuclear, conjugated and fused residues of aromatic hydrocarbons (“carbocyclic aryl” or “carboaryl”) or aromatic heterocyclic (heteroaryl”) ring systems.
  • carbocyclic aryl examples include phenyl , biphenyl , terphenyl , quaterphenyl , phenoxyphenyl , naphtyl , tetrahydronaphthyl , anthracenyl , dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl , fluorenyl , pyrenyl , indenyl , azulenyl , chrysenyl,
  • heteroaryl examples include pyridyl , 4- phenylpyridyl , 3-phenylpyridyl , thienyl, furyl, pyrryl , pyrrolyl , furanyl , imadazolyl , pyrrolydinyl , pyridinyl , piperidinyl, indolyl, pyridaziny
  • a carbocyclic aromatic ring system contains 6-10 carbon atoms and an aromatic heterocyclic ring system contains 1 to 4 heterato s independently selected from N, O and S and up to 9 carbon atoms in the ring.
  • heterocyclyl or equivalent terms such as “heterocyclic” used either alone or in compound words such as "optionally substituted saturated or unsaturated heterocyclyl” denotes monocyclic or polycyclic heterocyclyl groups containing at least one heteroatom atom selected from nitrogen, sulphur and oxygen.
  • Suitable heterocyclyl groups include N-containing heterocyclic groups , such as , unsaturated 3 to 6 me bered heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl , pyrrolinyl , imidazolyl , pyrazolyl , pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as, pyrrolidinyl, imidazolidinyl , piperidino or piperazinyl; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl , isoquinolyl, indazolyl, benzotriazolyl or te
  • carbohydrate denotes a carbohydrate residue or a functionalised or deoxygenated carbohydrate residue, and includes monosaccharides and oligosaccharides .
  • a carbohydrate residue is an acyclic polyhydroxy-aldehyde or ketone, or one of their cyclic tautomers , and includes a compound resulting from reduction of the aldehyde or keto group such as alditols .
  • Oxygen atoms may be replaced by hydrogen or bonds to a halogen, nitrogen, sulfur or carbon atoms, or carbon- oxygen bonds such as in ethers or esters may be introduced.
  • carbohydrates include but are not limited to D-galactofuranose, N-acetyl-D-galactofuranose, D-glucofuranose, JY-acetyl-D-glucofuranose, D- galactopyranose W-acetyl-D-galactopyranose, D-glucopyranose and iV-acetyl-D-glucopyranose and their equivalents where oxygen atoms have been replaced in selected positions with hydrogen or bonds to halogen , nitrogen , sulfur or carbon , as well as oligosaccharides containing these moieties.
  • a group may or may not be further substituted with one or more functional groups such as alkyl, alkenyl, alkynyl , aryl , halo , haloalkyl , haloalkenyl , haloalkynyl , haloaryl , hydroxy, alkoxy, alkenyloxy, aryloxy, benzyloxy, haloalkoxy, haloalkenyloxy , haloaryloxy, nitro, nitroalkyl, nitroalkenyl , nitroalkynyl , nitroaryl, nitroheterocyclyl, amino, alkylamino, dialkylamino , alkenylamino , alkynylamino , arylamino , diarylamino , benzylamino, dibenzylamino, acyl, alkenylacyl , alkyn
  • any of the moieties whose length is defined in terms of the number of carbon atoms present may possess any number of carbon atoms within the specified rang . Nevertheless , within this range certain species will be preferred due to factors such as availability and cost of precursors and ease of synthesis, as well as efficacy.
  • A is O and q is 1 and one of Ri and R 2 is selected from the group consisting of hydrogen, optionally substituted C 1 -.
  • Ri and R 2 are independently C 4 _ 30 alkyl , and may be C 6 - ⁇ 2 alkyl and or C 8 _ ⁇ 0 alkyl . If one or both Ri and R 2 is alkenyl it may be C 4 _ 3 o alkenyl , in a further embodiment C 6 _ ⁇ 2 alkenyl and, in a further embodiment still, C 8 _ ⁇ o alkenyl. In the case of one or both Ri and R 2 being or including alkyl or alkenyl interrupted by one or more of heteroatoms or functional groups, the heteroatom is typically oxygen, and Ri and/or R 2 may have the formula CH 3 (CH 2 ) X O (CH 2 ) y O (CH 2 ) z .
  • R 3 , R' 3 , R'' 3 , R 4 , R' 4 , R" 4 , R 5 , R's, R"s, Re, R'e, R'' 6 , R 7 , R 8 , R 9 , R' 9 , Rio, Rii and R' n is alkyl, alkenyl or alkyl or alkenyl interrupted by one or more of heteroatoms or functional groups the preferred forms are as set out for Ri and R 2 .
  • the amine portion of the sulfenamide is tethered to the carbohydrate moiety through an additional linkage, for example, if the amine per se were toxic in order to ensure it is not released by in -vivo cleavage of the sulfenamide linkage.
  • the amine moiety may be tethered by linkage to any position in the carbohydrate moiety, linkage to the C 2 position through either Ri or R 2 forming a ring together with i is preferred.
  • the linkage may take the form of an optionally substituted alkyl chain being linked to end of a functional group located in position 2 of the carbohydrate ring and linked to a functional group located within Ri or R 2.
  • Xi is OR 3 .
  • R 3 is hydrogen or optionally substituted acyl.
  • X 2 is OR 4 .
  • R is hydrogen or optionally substituted acyl .
  • X 3 is OR 5 .
  • R 5 is hydrogen or optionally substituted acyl.
  • X 4 when present, is OR ⁇ .
  • R 6 is hydrogen or optionally substituted acyl .
  • any one of the substituents R 3 , R 4 , R 5 and R 6 is optionally substituted acyl, in particular, optionally substituted acyl where the substituent on the acyl group effects, the lipophilicity or water solubility of the compound.
  • preferred compounds include amino acid esters where the amino acid side chain is selected to provide a predetermined lipophilicity for the compound.
  • the amino acid side chains envisaged include all of the natural occurring amino acid side chains as well as common synthetic amino acids.
  • the compounds maybe succinnyl esters terminating in amides that improve water solubility.
  • the compounds of the invention are galactofuranosyl compounds , and therefore have the con iguration illustrated in general formula (la) :
  • the compounds of the invention are arabinofuranosyl derivatives having the general formula (lb) :
  • (I) is selected from the group consisting of N-benzyl-S- (2,3,5, 6-tetra-O-benzoyl- ⁇ -D-galactofuranosyl) -sulfenamide , N / IV-dibenzyl-S- (2,3,5, 6-tetra-O-acetyl- ⁇ -D- galactofuranosyl) sulfenamide, iV,iV-dicyclohexyl-S- (2,3,5, 6-tetra-O-acetyl- ⁇ -D-galacto uranosyl) sulfenamide,
  • the compound of general formula (I) is N,N ⁇ dibenzyl-S- ( ⁇ -D-galactofuranosyl) sulfenamide or N,N-di(2- methoxyethoxyethyl) -S- ( ⁇ -D-galactofuranosyl) sulfenamide.
  • L is a leaving group, preferably acetyl and Xi , X x ' , X 2 , X 2 ' , X 3 , X 3 ' , X 4 , X 4 ' , X 5 and X 5 ' , are as defined above; with a compound of general formula (III) :
  • R x and R 2 are as defined above; in the presence of a bis-activated alkyl halide.
  • the bis-activated alkyl halide is diethyl bromomalonate , trimethyl bromophosphonoacetate or N-bromosuccinimide .
  • the reaction is performed in the presence of an excess of the secondary amine of general formula (III) in an inert solvent such as DMF or THF, in an alcoholic solvent such as methanol or ethanol , or in mixtures of such solvents , at a temperature from 20 °C to 60 °C, preferably 25 °C to 40 °C, under an atmosphere of nitrogen or argon.
  • the reaction mixture may be left to stir typically for 2 to 160 hours, preferably greater than 12 hours , prior to isolation and purification, or deprotection .
  • R 2 , R' 2 , R" 2 , R 3 , R' 3 , R" 3 , R 4 , R' 4 , R" 4 , R 5 , R' 5 , R" 5 , 6 , ' 6 and R' ' 6 may be a protecting group and the process then further comprises removing the protecting groups .
  • Suitable protecting groups are well known to the person skilled in the art and in this case the acetyl or benzoyl groups are preferred. Acetyl and benzoyl protecting groups are typically removed through hydrolysis with sodium methoxide in methanol .
  • the compounds of the present invention may also be synthesised through the condensation of sulfenyl halides with a secondary amine of general formula (III) , the reaction of the relevant thiols and amines in the presence of oxidising reagents , or via the reaction of the relevant disulfides or thiosulfonates and amines in the presence of silver or mercuric salts, such as are disclosed in Craine & Raban, 1989; Koval ' , 1996; Illyes, 2004; the contents of which are incorporated herein by reference.
  • a method for the treatment of a patient with a microbial infection comprising administering to said patient a therapeutically effective amount of a compound of general formula (I) .
  • a compound of general formula (I) in the manufacture of a medicament for use in the treatment of a microbial infection.
  • therapeutically effective amount means an amount of a compound of the present invention effective to yield a desired therapeutic response, for example to prevent or treat a disease which by administration of a pharmaceutically-active agent.
  • a "pharmaceutical carrier” is a pharmaceutically acceptable solvent, suspending agent, excipient or vehicle for delivering the compound of general formula (I) to the subject.
  • the carrier may be liquid or solid, and is selected with the planned manner of administration in mind.
  • the compound of general formula (I) may be administered orally, topically, or parenterally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles .
  • parenteral as used herein includes subcutaneous , intravenous , intramuscular , intrathecal , intracranial , injection or infusion techniques.
  • the invention also provides suitable topical , oral , aerosol , and parenteral pharmaceutical formulations for use in the novel methods of treatment of the present invention .
  • the compounds of the invention may be administered orally as tablets , aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions , capsules , syrups or elixirs .
  • the composition for oral use may contain one or more agents selected from the group of sweetening agents , flavouring agents , colouring agents and preserving agents in order to produce pharmaceutically elegant and palatable preparations.
  • the tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets .
  • excipients may be , for example , inert diluents, such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, such as starch, gelatin or acacia; or lubricating agents, such as magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated, or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time-delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • Coating may also be performed using techniques described in the U. S. Pat. Nos. 4,256,108; 4,160,452; and 4,265,874 to form osmotic therapeutic tablets for control release .
  • the compound of general formula (I) of the invention can be administered, for in vivo application, parenterally by injection or by gradual perfusion over time independently or together. Administration may be intravenously, intra-arterial, intraperitoneally, intramuscularly, subcutaneously, intracavity, or transdermally . For in vitro studies the agents may be added or dissolved in an appropriate biologically acceptable buffer and added to a cell or tissue.
  • Preparations for parenteral administration include sterile aqueous or non-aqueous solutions , suspensions , and emulsions .
  • non-aqueous solvents are propylene glycol , polyethylene glycol , vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate .
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride
  • lactated Ringer ' s intravenous vehicles include fluid and nutrient replenishers , electrolyte replenishers such as those based on Ringer's dextrose, and the like.
  • Preservatives and other additives may also be present such as, for example, anti-microbials , anti-oxidants , chelating agents, growth factors and inert gases and the like .
  • the compounds of general formula (I) are antimicrobial agents which are active, in particular but not limited to, against Mycobacterium including Mycobacterium tuberculosis , M. avium intracellulare, M. fortuitum, M.
  • the effect may be prophylactic in terms of completely or partially preventing infection, and/or may be therapeutic in terms of a partial or complete cure of an infection.
  • Treating covers any treatment of, or prevention of infection in a vertebrate , a mammal , particularly a human , and includes : preventing the infection from occurring in a subject that may have been exposed to the infectious agent, but has not yet been diagnosed as affected; inhibiting the infection, ie., arresting its development; or relieving or ameliorating the effects of the infection , ie . , cause regression of the effects of the infection.
  • a pharmaceutical composition comprising a compound of general formula (I) and a pharmaceutically acceptable carrier .
  • compositions according to one embodiment of the invention are prepared by bringing a compound of general formula (I) into a form suitable for administration to a subject using carriers, excipients and additives or auxiliaries.
  • carriers or auxiliaries include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins , cellulose and its derivatives , animal and vegetable oils, polyethylene glycols and solvents, such as sterile water, alcohols, glycerol and polyhydric alcohols.
  • Intravenous vehicles include fluid and nutrient replenishers .
  • Preservatives include antimicrobial , anti- oxidants , chelating agents and inert gases .
  • compositions include aqueous solutions, non-toxic excipients, including salts, preservatives, buffers and the like, as described, for instance, in Remington's Pharmaceutical Sciences, 15th ed. Easton: Mack Publishing Co., 1405-1412,1461-1487 (1975) and The National Formulary XIV., 14th ed. Washington: American Pharmaceutical Association (1975) , the contents of which are hereby incorporated by reference .
  • the pH and exact concentration of the various components of the pharmaceutical composition are adjusted according to routine skills in the art. See Goodman and Gilman's The Pharmacological Basis for Therapeutics (7th ed.).
  • the pharmaceutical compositions are preferably prepared and administered in dosage units .
  • Solid dosage units include tablets , capsules and suppositories .
  • different daily doses can be used depending on activity of the compound, manner of administration, nature and severity of the disorder, age and body weight of the subject. Under certain circumstances, however, higher or lower daily doses may be appropriate.
  • the administration of the daily dose can be carried out both by single administration in the form of an individual dose unit or else several smaller dose units and also by multiple administration of subdivided doses at specific intervals .
  • the pharmaceutical compositions according to the invention may be administered locally or systemically in a therapeutically effective dose . Amounts ef ective for this use will, of course, depend on the severity of the microbial infection and the weight and general state of the subject.
  • dosages used in vitro may provide useful guidance in the amounts useful for in situ administration of the pharmaceutical composition, and animal models may be used to determine effective dosages for treatment of the cytotoxic side ef ects .
  • animal models may be used to determine effective dosages for treatment of the cytotoxic side ef ects .
  • Formulations for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin . They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions normally contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspension .
  • excipients may be suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethylcellulose , sodium alginate, polyvinylpyrrolidone , gum tragacanth and gum acacia; dispersing or wetting agents, which may be (a) naturally occurring phosphatide such as lecithin; (b) a condensation product of an alkylene oxide with a fatty acid,, for example, polyoxyethylene stearate; (c) a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadecaethylenoxycetanol; (d) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate, or (e) a condensation product of ethylene oxide
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as those mentioned above.
  • the sterile injectable preparation may also a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1 , 3-butanediol .
  • the acceptable vehicles and solvents which may be employed are water , Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed, including synthetic mono-or diglycerides .
  • fatty acids such as oleic acid find use in the preparation of injectables .
  • Compounds of general formula (I) may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles , large unilamellar vesicles , and multilamellar vesicles .
  • Liposomes can be formed from a variety of phospholipids , such as cholesterol, stearylamine, or phosphatidylcholines .
  • Compounds of general formula (I) may also be administered in combination with cyclodextrins for enhanced aqueous solubility.
  • Dosage levels of the compound of general formula (I) of the present invention will usually be of the order of about 0.05mg to about 20mg per kilogram body weight, with a preferred dosage range between about 0.05mg to about lOmg per kilogram body weight per day (from about 0. lg to about 3g per patient per day) .
  • the amount of active ingredient which may be combined with the carrier materials to produce a single dosage will vary, depending upon the host to be treated and the particular mode of administration.
  • a formulation intended for oral administration to humans may contain about lmg to lg of an active compound with an appropriate and convenient amount of carrier material , which may vary from about 5 to 95 percent of the total composition.
  • Dosage unit forms will generally contain between from about 5mg to 500mg of active ingredient . It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • some of the compounds of the invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of the invention .
  • the compounds of the invention may additionally be combined with other compounds to provide an operative combination.
  • a method of killing a microorganism comprising exposing said microorganism to a compound of general formula (I) as defined above.
  • the microorganism is selected from the group consisting of MycoJacterium including Mycobacterium tuberculosis , M. avium intracellulare, M. fortuitum, M. abscessus and rapid growing atypical Mycobacterial strains, Nocardia, particularly Nocardia asteroides and N.
  • R 1 /R 2 -C(CH 3 ) 2 CH 2 CH 2 CH 2 C(CH 3 ) 2 - 3e
  • R 1 CH 2 Ph
  • R 2 H
  • Example 1 iV,N-Dibenzyl ⁇ S- (2,3,5, 6-tetra-O-acetyl- ⁇ -D- galactofuranosyl) sulfenamide (3a) : l-S-Acetyl-2 ,3,5, 6-tetra-O-acetyl-l-thio- ⁇ -D- galactofuranose (2) (1.01 g, 2.50 mmol) was dissolved in methanol (75 mL) . Diethylbromomalonate (630 ⁇ L, 3.75 mmol) and dibenzylamine (1.20 mL, 6.3 mmol) were added and the reaction stirred at room temperature.
  • Example 6 l,2,3-Tri-0-acetyl-5-0- ( ert-butyldiphenylsilyl) - ⁇ / ⁇ -D- arabinofuranose (6) : 5-0- (Tert-butyldiphenylsilyl) - ⁇ / ⁇ -D-arabinose (5) (2.10 g, 5.40 mmol) was dissolved in dry pyridine (20 mL) and stirred with acetic anhydride (20 mL, excess) at 0 °C for 1 h, and then at room temperature for 18 h under N 2 .
  • Example 7 ( ⁇ -D-galactofuranosyl) sulfenamide (4a) : WV-KT-Dibenzyl-S- (2,3,5, 6-tetra-O-acetyl- ⁇ -D- galactofuranosyl) sulfenamide (3a) (275 mg, 0.49 mmol) was de-O-acetylated to yield the product (4a) (47%) as a white solid. R f 0.21 (8.5:1.5 EtOAc/methanol) .
  • the compounds of general formula (I) are useful as pharmaceuticals , particularly antimicrobial agents .
  • de Lederkremer R. M. Cirelli, A.; Sznaidman, M. L. Carbohydr. Res . 1986, 146, 233-240. Shin, J.; Perlin, A. Carbohydr. Res . 1979, 76, 165-176.
  • de Lederkremer R. M. Cicero, D.; Varela, 0. Tetrahedron 1990, 46, 1131-1144.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Molecular Biology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

Abstract

Sulfenamide compounds of general formula (I) are disclosed wherein A, R1, R2, X1, X1’, X2, X2’, X3, X3’, X4, X4’, X5 and X5’ define a variety of variables and q is 0 or 1. The compounds of the examples are galactofuranosyl and arabinofuranosyl compounds wherein the variable A is oxygen. Methods for the synthesis of compounds of general formula (I), pharmaceutical compositions them and methods of using them to treat patients suffering a microbial infection are also disclosed.

Description

NOVEL SULFENAMIDES
Technical Field The present invention relates to novel sulfenamides that have an antimicrobial action, methods or their synthesis , pharmaceutical compositions containing them and method of treatment of patients suffering microbial infection .
Background Art Many bacterial diseases once thought to be on the decline are beginning to re-emerge and annually devastate populations in many countries . This problem is amplified by the emergence of many new drug resistant strains of the microorganisms that cause these diseases. Our interest in glycofuranose chemistry (Owen & von Itzstein, 2000) has led to the discovery of a new class of antimicrobial agents described below. Although significant chemistry and biology has been published (see, for example, Marino, Marino, Miletti , Alves , Colli, & de Lederkremer, 1998; Miletti, Marino, Marino, de Lederkremer, Colli & Alves, 1999; Zhang & Liu, 2001; Brimacombe, Gent & Stacey, 1968; Brimacombe, Da'aboul & Tucker, 1971; Lemieux & Stick, 1975; de Lederkremer, Cirelli & Sznaidman, 1986; Shin & Perlin, 1979; de Lederkremer, Cicero & Varela, 1990; de Lederkremer, Marino & Marino, 2002; Pathak, Pathak, Suling, Gurcha, Morehouse, Besra, Maddry & Reynolds, 2002; Ernst, Hart & Sinay, 2000) in the area of glycofuranose chemistry and biology none to date have provided compounds that are clinically useful antimicrobial medicines.
Disclosure of the Invention The present invention is concerned generally with novel sulfenamides . In a first aspect of the present invention there is provided a compound of general formula (I) : wherein A is selected from the group consisting of O, S, SO, S02, Se, Te, NR8, CR9R' 9, N → O and C (O) ; and, when A is O and q is 1, one of Ri and R2 is selected from the group consisting of hydrogen, optionally substituted Cι_3 or >C30 alkyl, alkyl when interrupted by one or more heteroatoms or functional groups selected from the group consisting of O, S, -N=, NR7 and -(Y)mC=(Z) (T)n-, optionally substituted C2-3 or >C30 alkenyl, alkenyl when interrupted by one or more heteroatoms or functional groups selected from the group consisting of O, S, -N=, NR and -(Y)mC=(Z) (T)n-, optionally substituted aralkyl which may be interrupted within the alkyl moiety by one or more heteroatoms or functional groups selected from the group consisting of O, S, -N=, NR7 and - (Y)mC= (Z) (T)n-, optionally substituted acyl, optionally substituted aryl, optionally substituted heterocyclic and a carbohydrate moiety, while the other of Ri and R2 is selected from the group consisting of hydrogen, optionally substituted alkyl which may be interrupted by one or more heteroatoms or functional groups selected from the group consisting of O, S, -N=, NR7 and - (Y) mC= (Z) (T) n- , optionally substituted alkenyl which may be interrupted by one or more heteroatoms or functional groups selected from the group consisting of O, S, -N=, NR7 and - (Y)mC= (Z) (T) n- , optionally substituted aralkyl which may be interrupted within the alkyl moiety by one or more heteroatoms or functional groups selected from the group consisting of O, S, -N=, NR7 and - (Y)mC= (Z) (T) n- , optionally substituted aryl, optionally substituted heterocyclic, optionally substituted acyl and a carbohydrate moiety; but, when A is S, SO, S02 , Se, Te, NR8 , CR9R9' , N -» O or C (O) and q is 1 or A is O, S, SO, S02 , Se , Te, NR8 , CR9R9' , N → O or C (O) and q is O, then Ri and R2 are independently selected from the group consisting of hydrogen, optionally substituted alkyl which may be interrupted by one or more heteroatoms or functional groups selected from the group consisting of O, S, -N=, NR and -(Y)mC=(Z) (T)n-, optionally substituted alkenyl which may be interrupted by one or more heteroatoms or functional groups selected from the group consisting of O, S, ~N=, NR7 and - (Y)mC= (Z) (T)n-, optionally substituted aralkyl which may be' interrupted within the alkyl moiety by one or more heteroatoms or functional groups selected from the group consisting of O, S, -N=, NR7 and - (Y)mC=(Z) (T)n-, optionally substituted aryl, optionally substituted acyl and a carbohydrate moiety, or Ri and R2 together with the nitrogen atom from which they depend form a saturated or unsaturated, optionally substituted heterocyclic group which may include additional heteroatoms selected from the group consisting of O, N and S; i is selected from the group consisting of OR3, SR3, NR3R'3, hydrogen, halogen, - (Y)mC= (Z) (T) nR3, - N(C=(Z) (T)nR3)2, N3, CN, OCN, SCN, OS03R3, OS02R3, OP03R3R' 3 , OP02R3R'3/ S(0)R3, S(0)2R3, S(0)2OR3, P03R3R' 3 , NR3NR' 3R" 3 , SNR3R'3, NR3SR'3, SSR3 and R3 , or is an oxo group, =S, =NOR3 or =CR3R' 3 and Xx ' is absent; X2 is selected from the group consisting of OR4, SR4, NR4R' , hydrogen, halogen, - (Y) mC= (Z) (T) nR4, - N(C=(Z) (T)nR4)2, N3, CN, OCN, SCN, OS03R4 , OS02R4 , OP03R4R'4, OP02R4R' 4 , S (O) R4 , S (O) 2R4 , S (O) 20R4 , P03R4R' 4 , NR4NR' 4R' ' 4 ,
SNR4R'4, NR4SR'4, SSR4 and R4, or is an oxo group, =S, =NOR4 or =CR4R' and X2 ' is absent; X3 and X3 ' are independently selected from the group consisting of OR5, SR5, NR5R'5, hydrogen, halogen, - (Y)mC=(Z) (T)nR5, -N(C=(Z) (T)nR5)2, N3 , CN, OCN, SCN, OS03R5, OS02R5, OPθ3R5R'5, OP02R5R'5, S(0)R5, S(0)2R5, S(0)2OR5, P03R5R'5, NR5NR' 5R' '5, SNR5R'5, NR5SR' 5 , SSR5 and RΞ , or X3 is =0, =S, =NOR5 or =CR5R'5 and X3 ' is absent; X4 is selected from the group consisting of OR6, SR6, NR6R'6, hydrogen, halogen, - (Y)mC= (Z) (T)nR6, - N(C=(Z) (T)nR6)2, N3, CN, OCN, SCN, OS03R6, OS02R6, OP03R6R'6, OP02R6R'6, S(0)R6, S(0)2R6, S(0)2OR6, P03R6R'6, NR6NR'6R"6, SNR6R'6, NR6SR'6, SSR6 and R6, or is an oxo group, =S, =NOR6 or =CReR' 6 and X4 ' is absent; X5 is selected from the group consisting of hydrogen, CN, -C= (Z) (T)nRu, S(0)Rllf S(0)2RX1, S(0)2ORn, 03RnR'ii, optionally substituted alkyl, optionally substituted alkaryl , optionally substituted aryl, optionally substituted aralkyl, and optionally substituted acyl ; Xi ' , X2 ' , X4 ' and X5 ' are the same or different and are selected from the group consisting of hydrogen, CN, optionally substituted alkyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted aralkyl, and optionally substituted acyl; or one of Xi and X2, X2 and X ' , X5' and A when A contains a carbon or nitrogen atom, X5 and A when A contains a carbon or nitrogen atom, and X5 and Xi together constitute a double bond, or X5' and X4 or X3 and X4 together constitute a double bond, or Ri and Xi, R2 and Xi, Ri and X2 , R2 and X2 , Ri and X5 , R2 and X5 , Ri and X5' , R2 and X5' , Xi and X2, X2 and X3, X2 and X4 , X3 and X4, Xi and Xt' , X2 and X2' , X3 and X3' or X4 and X4' together form part of a ring structure which optionally includes at least one heteroatom selected from O, S and N and is optionally substituted; m, n and q are independently 0 or 1 and Y, Z and
T are independently selected from the group consisting of O, S, and NRι0; R3, R'3, R"3, R4, R'4, R"4, R5, R'5, R"s, R6, R' 6 , R''6, R7, Rg, R9, R' 9, Rio, R11 and R' n are the same or different and are selected from the group consisting of hydrogen, optionally substituted alkyl which may be interrupted by one or more heteroatoms or functional groups selected from the group consisting of O, S, -N=, NR and -(Y)mC=(Z) (T)n-, optionally substituted alkenyl which may be interrupted by one or more heteroatoms or functional groups selected from the group consisting of O, S, -N=, NR7 and - (Y) mC= (Z) (T) n- , optionally substituted aryl , optionally substituted aralkyl which may be interrupted within the alkyl moiety by one or more heteroatoms or functional groups selected from the group consisting of O, S, -N=, NR7 and - (Y)mC= (Z) (T) n- , optionally substituted acyl and a carbohydrate moiety; with the proviso that at least two of Xi, X2, X3 and X4 are other than hydrogen or a group linked to the ring through a carbon-carbon bond and the further proviso that the compound of general formula (I) is not 1-(9H- purinyl) -S- (3-deoxy-pentafuranosyl) sulfenamide 5-formamido-2 ' , 3 ' , 5 ' -tri-O-formyl-1- (β-D- ribofuranosylthio) imidazole-4-carboxamide , N-phenyl-S- (2,3:5, 6-di-O-isopropylidenyl-β-D- mannofuranosyl) sulfenamide or N,tf-diethyl-S- (2,3,5, 6-tetra-O-benzoyl-β-D- galactofuranosyl) sulfenamide; or a pharmaceutically acceptable salt thereof . It will be appreciated that the manner of representing substituents in the foregoing general formula does imply any particular stereochemistry or orientation for the substituents . The term "alkyl" used either alone or in a compound word such as "optionally substituted alkyl" or "optionally substituted cycloalkyl" denotes straight chain, branched or mono- or poly- cyclic alkyl. Examples of straight chain and branched C alkyl include methyl . ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl , amyl , isoamyl, sec-amyl, 1 , 2-dimethylpropyl, 1 , 1-dimethylpropyl , hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl , 3-methylpentyl , 1 , 1-dimethylbutyl , 2,2- dimethylbutyl , 3 , 3-dimethylb tyl , 1 , 2-dimethylb tyl , 1,3- dimethylbutyl , 1 ,2 , 2-trimethylpropyl, 1,1,2- trimethylpropyl , heptyl, 5-methylhexyl, 1-methylhexyl, 2 ,2-dimethylpentyl , 3 , 3-dimethylpentyl , 4,4- dimethylpentyl , 1,2-dimethylpentyl , 1 , 3-dimethyIpentyl , 1 , 4-dimethylpentyl, 1 ,2 , 3-trimethylbutyl, 1,1,2- trimethylbutyl , nonyl, 1-, 2-, 3-, 4-, 5-, 6- or 7- methyloctyl, 1-, 2-, 3-, 4- or 5-ethylheptyl, 1-2- or 3- propylhexyl, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- and 8- methylnonyl, 1-, 2-, 3-, 4-, 5- or 6-ethyloctyl, 1-, 2-, 3- or 4-propylheptyl, undecyl 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-methyldecyl, 1-, 2-, 3-, 4-, 5-, 6- or 7- ethylnonyl, 1-, 2-, 3-, 4- or 5-propyloctyl , 1-, 2- or 3- butylheptyl, 1-pentylhexyl, dodecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-methylundecyl, 1-, 2-, 3-, 4-, 5-, 6- , 7- or 8-ethyldecyl , 1-, 2-, 3-, 4-, 5- or 6-propylnonyl, 1-, 2-, 3- or 4-butyloctyl, 1-2-pentylheptyl and the like. Examples of cycloalkyl include cyclopropyl , cyclobutyl, cyclopentyl , cyclohexyl , cycloheptyl , cyclooctyl , cyclononyl and cyclodecyl and the like . The term "alkenyl" used either alone or in compound words such as "alkenyloxy" denotes groups formed from straight chain, branched or cyclic alkenes including ethylenically mono-, di- or poly-unsaturated alkyl or cycloalkyl groups as defined above . Examples of C4_30 alkenyl include butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl , 1-methyl-cyclopentenyl, 1- hexenyl, 3-hexenyl, cyclohexenyl , 1-heptenyl, 3-heptenyl, 1-octenyl, cyclooctenyl , 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl , 1 , 3-butadienyl , 1-4 ,pentadienyl, 1 , 3-cyclopentadienyl , 1 , 3-hexadienyl, 1 , 4-hexadienyl, 1,3- cyclohexadienyl , 1 , 4-cyclohexadienyl, 1,3- cycloheptadienyl , 1 , 3 ,5-cycloheptatrienyl and 1,3,5,7- cyclooctatetraenyl . The term "acyl" used either alone or in compound words such as "optionally substituted acyl" or "optionally substituted acyloxy" denotes an aliphatic acyl group or an acyl group containing an aromatic ring, which is referred to as aromatic acyl, or a heterocyclic ring, which is referred to as heterocyclic acyl, preferably Cι-.30 acyl. Examples of acyl include straight chain or branched alkanoyl such as ormyl , acetyl, propanoyl, butanoyl, 2- methylpropanoyl , pentanoyl , 2,2-dimethylpropanoyl , hexanoyl , heptanoyl , octanoyl , nonanoyl , decanoyl , undecanoyl , dodecanoyl , tridecanoyl , pentadecanoyl , hexadecanoyl , heptadecanoyl , octadecanoyl , nonadecanoyl and icosanoyl; cyσloalkylcarbonyl such as cyclopropylcarbonyl cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl; aroyl such as benzoyl , toluoyl and naphthoyl ; aralkanoyl such as phenylalkanoyl (e.g. phenylacetyl , phenylpropanoyl , phenylbutanoyl , phenylisobutyl, phenylpentanoyl and phenylhexanoyl) and naphthylalkanoyl (e.g. naphthylacetyl , naphthylpropanoyl and naphthylbutanoyl) ; aralkenoyl such as phenylalkenoyl (e.g. phenylpropenoy1 , phenylbutenoyl , phen lmethacrylyl , phen lpentenoyl and phenylhexenoyl and naphthylalkenoyl (e.g. naphth lpropenoyl , naphthylbutenoyl and naphthylpentenoyl) ; heterocycliccarbonyl ; heterocyclicalkanoyl such as thienylacetyl , thienylpropanoyl , thienylbutanoyl , thienylpentanoyl , thienylhexanoyl , thiazolylacetyl , thiadiazolylacetyl and tetrazolylacetyl ; and heterocyclicalkenoyl such as heterocyclicpropenoyl , heterocyclicbutenoyl , heterocyclicpentenoyl and heterocyclichexenoyl . The term "aryl" used either alone or in compound words such as "optionally substituted aryl", "optionally substituted aryloxy" or "optionally substituted heteroaryl" denotes single, polynuclear, conjugated and fused residues of aromatic hydrocarbons ("carbocyclic aryl" or "carboaryl") or aromatic heterocyclic (heteroaryl") ring systems. Examples of carbocyclic aryl include phenyl , biphenyl , terphenyl , quaterphenyl , phenoxyphenyl , naphtyl , tetrahydronaphthyl , anthracenyl , dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl , fluorenyl , pyrenyl , indenyl , azulenyl , chrysenyl, Examples of heteroaryl include pyridyl , 4- phenylpyridyl , 3-phenylpyridyl , thienyl, furyl, pyrryl , pyrrolyl , furanyl , imadazolyl , pyrrolydinyl , pyridinyl , piperidinyl, indolyl, pyridazinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzo uranyl, benzothienyl , purinyl, quinazolinyl , phenazinyl , aσridinyl , benzoxazolyl , benzothiazolyl and the like. Preferably, a carbocyclic aromatic ring system contains 6-10 carbon atoms and an aromatic heterocyclic ring system contains 1 to 4 heterato s independently selected from N, O and S and up to 9 carbon atoms in the ring. The term "heterocyclyl" or equivalent terms such as "heterocyclic" used either alone or in compound words such as "optionally substituted saturated or unsaturated heterocyclyl" denotes monocyclic or polycyclic heterocyclyl groups containing at least one heteroatom atom selected from nitrogen, sulphur and oxygen. Suitable heterocyclyl groups include N-containing heterocyclic groups , such as , unsaturated 3 to 6 me bered heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl , pyrrolinyl , imidazolyl , pyrazolyl , pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as, pyrrolidinyl, imidazolidinyl , piperidino or piperazinyl; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl , isoquinolyl, indazolyl, benzotriazolyl or tetrazolopyridazinyl ; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, such as, oxiranyl, pyranyl or furyl ; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms, such as, thienyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, oxazolyl , isoxazolyl or oxadiazolyl; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms , such as , morpholinyl ; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms , such as , benzoxazolyl or benzoxadiazolyl ; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms , such as , thiazolyl or thiadiazolyl ; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms , such as , thiazolidinyl ; and unsaturated condensed heterocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms , such as, benzothiazolyl or benzothiadiazolyl . The term "carbohydrate" denotes a carbohydrate residue or a functionalised or deoxygenated carbohydrate residue, and includes monosaccharides and oligosaccharides . A carbohydrate residue is an acyclic polyhydroxy-aldehyde or ketone, or one of their cyclic tautomers , and includes a compound resulting from reduction of the aldehyde or keto group such as alditols . Oxygen atoms may be replaced by hydrogen or bonds to a halogen, nitrogen, sulfur or carbon atoms, or carbon- oxygen bonds such as in ethers or esters may be introduced. Examples of carbohydrates include but are not limited to D-galactofuranose, N-acetyl-D-galactofuranose, D-glucofuranose, JY-acetyl-D-glucofuranose, D- galactopyranose W-acetyl-D-galactopyranose, D-glucopyranose and iV-acetyl-D-glucopyranose and their equivalents where oxygen atoms have been replaced in selected positions with hydrogen or bonds to halogen , nitrogen , sulfur or carbon , as well as oligosaccharides containing these moieties. In this speci ication "optionally substituted" means that a group may or may not be further substituted with one or more functional groups such as alkyl, alkenyl, alkynyl , aryl , halo , haloalkyl , haloalkenyl , haloalkynyl , haloaryl , hydroxy, alkoxy, alkenyloxy, aryloxy, benzyloxy, haloalkoxy, haloalkenyloxy , haloaryloxy, nitro, nitroalkyl, nitroalkenyl , nitroalkynyl , nitroaryl, nitroheterocyclyl, amino, alkylamino, dialkylamino , alkenylamino , alkynylamino , arylamino , diarylamino , benzylamino, dibenzylamino, acyl, alkenylacyl , alkynylacyl, arylacyl , acylamino, diacylamino, acyloxy, alkylsulphonyloxy, arylsulphenyloxy , heterocyclyl, heterocycloxy , heterocyclamino , haloheterocyclyl , alkylsulphenyl , arylsulphenyl, carboalkoxy, carboaryloxy , mercapto, alkylthio, benzylthio, acylthio, phosphorus- containing groups and the like, and including groups such as =0, =S , =N-, where appropriate, particularly as substituents in ring structures such as lactones , lactams and cyclic i ides, provided that none of the substituents outlined above interferes with the formation of the subject compound. Any of the moieties whose length is defined in terms of the number of carbon atoms present may possess any number of carbon atoms within the specified rang . Nevertheless , within this range certain species will be preferred due to factors such as availability and cost of precursors and ease of synthesis, as well as efficacy. In an embodiment A is O and q is 1 and one of Ri and R2 is selected from the group consisting of hydrogen, optionally substituted C1-.3 or >C30 alkyl , alkyl when interrupted by one or more heteroatoms or functional groups selected from the group consisting of O, S, -N=, NR7 and -(Y)mC=(Z) (T)n-/ optionally substituted C2_3 or >C30 alkenyl , alkenyl when interrupted by one or more heteroatoms or functional groups selected from the group consisting of O, S, -N=, NR7 and -(Y)mC=(Z) (T)n-, optionally substituted aralkyl which may be interrupted within the alkyl moiety by one or more heteroatoms or functional groups selected from the group consisting of O, S, -N=, NR7 and - (Y)mC= (Z) (T) n- , optionally substituted acyl, optionally substituted aryl, optionally substituted heterocyclic and a carbohydrate moiety, while the other of Ri and R2 is selected from the group consisting of hydrogen, optionally substituted alkyl which may be interrupted by one or more heteroatoms or functional groups selected from the group consisting of O, S, ~N=, NR and ~(Y)mC=(Z) (T)n-, optionally substituted alkenyl which may be interrupted by one or more heteroatoms or functional groups selected from the group consisting of O, S, -N=, NR7 and -(Y)mC=(Z) (T)n-, optionally substituted aralkyl which may be interrupted within the alkyl moiety by one or more heteroatoms or functional groups selected from the group consisting of O, S, ~N=, NR7 and - (Y)mC=(Z) (T)n-, optionally substituted aryl, optionally substituted heterocyclic, optionally substituted acyl and a carbohydrate moiet . In an alternative embodiment A is S, SO, S02 , Se, Te, NR8, CR9R9' , N -» O or C (O) and q is 1 or A is O, S, SO, S02, Se, Te, NR8 , CR9R9' , N -> O or C (O) and q is O, and Ri and R2 are independently selected from the group consisting of hydrogen, optionally substituted alkyl which may be interrupted by one or more heteroatoms or functional groups selected from the group consisting of O, S, -N=, NR7 and -(Y)mC=(Z) (T)n-, optionally substituted alkenyl which may be interrupted by one or more heteroatoms or functional groups selected from the group consisting of O, S, -N=, NR7 and - (Y) mC= (Z) (T) n- , optionally substituted aralkyl which may be interrupted within the alkyl moiety by one or more heteroatoms or functional groups selected from the group consisting of O, S, -N=, NR7 and - (Y)mC=(Z) (T)n~, optionally substituted aryl, optionally substituted acyl and a carbohydrate moiety, or Rx and R2 together with the nitrogen atom from which they depend form a saturated or unsaturated, optionally substituted heterocyclic group which may include additional heteroatoms selected from the group consisting of O, N and S . In an embodiment when i and R2 are independently C4_30 alkyl , and may be C6-ι2 alkyl and or C8_ι0 alkyl . If one or both Ri and R2 is alkenyl it may be C4_3o alkenyl , in a further embodiment C6_ι2 alkenyl and, in a further embodiment still, C8_ιo alkenyl. In the case of one or both Ri and R2 being or including alkyl or alkenyl interrupted by one or more of heteroatoms or functional groups, the heteroatom is typically oxygen, and Ri and/or R2 may have the formula CH3 (CH2)X O (CH2)yO (CH2) z. Equally, if one of R3, R'3, R''3, R4, R'4, R"4, R5, R's, R"s, Re, R'e, R''6, R7, R8, R9, R'9, Rio, Rii and R' n is alkyl, alkenyl or alkyl or alkenyl interrupted by one or more of heteroatoms or functional groups the preferred forms are as set out for Ri and R2. In an embodiment the amine portion of the sulfenamide is tethered to the carbohydrate moiety through an additional linkage, for example, if the amine per se were toxic in order to ensure it is not released by in -vivo cleavage of the sulfenamide linkage. While the amine moiety may be tethered by linkage to any position in the carbohydrate moiety, linkage to the C2 position through either Ri or R2 forming a ring together with i is preferred. By way of example only, the linkage may take the form of an optionally substituted alkyl chain being linked to end of a functional group located in position 2 of the carbohydrate ring and linked to a functional group located within Ri or R2. In an embodiment Xi is OR3. Advantageously R3 is hydrogen or optionally substituted acyl. In an embodiment X2 is OR4. Advantageously, R is hydrogen or optionally substituted acyl . In an embodiment X3 is OR5. Advantageously, R5 is hydrogen or optionally substituted acyl. In an embodiment X4, when present, is ORβ.
Advantageously, R6 is hydrogen or optionally substituted acyl . In an embodiment any one of the substituents R3, R4 , R5 and R6 is optionally substituted acyl, in particular, optionally substituted acyl where the substituent on the acyl group effects, the lipophilicity or water solubility of the compound. By way of example, preferred compounds include amino acid esters where the amino acid side chain is selected to provide a predetermined lipophilicity for the compound. The amino acid side chains envisaged include all of the natural occurring amino acid side chains as well as common synthetic amino acids.
Alternatively, the compounds maybe succinnyl esters terminating in amides that improve water solubility. In an embodiment the compounds of the invention are galactofuranosyl compounds , and therefore have the con iguration illustrated in general formula (la) :
In a further embodiment the compounds of the invention are arabinofuranosyl derivatives having the general formula (lb) :
Advantageously the sulfenamide of general formula
(I) is selected from the group consisting of N-benzyl-S- (2,3,5, 6-tetra-O-benzoyl-β-D-galactofuranosyl) -sulfenamide , N/IV-dibenzyl-S- (2,3,5, 6-tetra-O-acetyl-β-D- galactofuranosyl) sulfenamide, iV,iV-dicyclohexyl-S- (2,3,5, 6-tetra-O-acetyl-β-D-galacto uranosyl) sulfenamide,
N,N-d± (2-methoxyethoxyethyl) -S- (2,3,5, 6-tetra-O-acetyl-β-D- galactofuranosyl) sulfenamide, 1- (2 ,2 , 6, 6-tetram.ethyl- piperidinyl) -S- (2,3,5, 6-tetra-O-acetyl-β-D- galactof ranosyl) sulfenamide, N, W-dioctyl-S- (2 , 3-di-O- acetyl-5-O- [ fcert-butyldiphenylsilyl] - α-D- arabinofuranosyl) sulfenamide, 27,N-dibenzyl-S- (β-D- galactofuranosyl) sulfenamide, and N,_>7~di(2- methoxyethoxyethyl) -S- (β-D-galactof ranosyl) sulfenamide. In a particularly preferred embodiment of the invention the compound of general formula (I) is N,N~ dibenzyl-S- (β-D-galactofuranosyl) sulfenamide or N,N-di(2- methoxyethoxyethyl) -S- (β-D-galactofuranosyl) sulfenamide. According to a second aspect of the present invention there is provided a method of preparation of a compound of general formula (I) :
comprising reacting a compound of general formula
(ID
wherein L is a leaving group, preferably acetyl and Xi , Xx ' , X2 , X2 ' , X3 , X3 ' , X4 , X4 ' , X5 and X5 ' , are as defined above; with a compound of general formula (III) :
wherein Rx and R2 are as defined above; in the presence of a bis-activated alkyl halide. Typically the bis-activated alkyl halide is diethyl bromomalonate , trimethyl bromophosphonoacetate or N-bromosuccinimide . In general terms the reaction is performed in the presence of an excess of the secondary amine of general formula (III) in an inert solvent such as DMF or THF, in an alcoholic solvent such as methanol or ethanol , or in mixtures of such solvents , at a temperature from 20 °C to 60 °C, preferably 25 °C to 40 °C, under an atmosphere of nitrogen or argon. The reaction mixture may be left to stir typically for 2 to 160 hours, preferably greater than 12 hours , prior to isolation and purification, or deprotection . In an embodiment, R2, R'2, R"2, R3, R'3, R"3, R4, R'4, R" 4 , R5, R' 5 , R" 5 , 6, ' 6 and R' ' 6 may be a protecting group and the process then further comprises removing the protecting groups . Suitable protecting groups are well known to the person skilled in the art and in this case the acetyl or benzoyl groups are preferred. Acetyl and benzoyl protecting groups are typically removed through hydrolysis with sodium methoxide in methanol . The compounds of the present invention may also be synthesised through the condensation of sulfenyl halides with a secondary amine of general formula (III) , the reaction of the relevant thiols and amines in the presence of oxidising reagents , or via the reaction of the relevant disulfides or thiosulfonates and amines in the presence of silver or mercuric salts, such as are disclosed in Craine & Raban, 1989; Koval ' , 1996; Illyes, 2004; the contents of which are incorporated herein by reference. An extensive array of methodologies has been developed to manipulate each position of the furanose template as disclosed, for example, in Marino, Marino, Miletti, Alves, Colli, & de Lederkremer, 1998; Miletti, Marino, Marino, de Lederkremer, Colli & Alves, 1999; Zhang & Liu, 2001; Brimacombe, Gent & Stacey, 1968; Brimacombe, Da'aboul & Tucker, 1971; Lemieux & Stick, 1975; de Lederkremer, Cirelli & Sznaidman, 1986; Shin & Perlin, 1979; de Lederkremer, Cicero & Varela, 1990; de Lederkremer, Marino & Marino, 2002; Pathak, Pathak, Suling, Gurcha, Morehouse, Besra, Maddry & Reynolds, 2002; Ernst, Hart & Sinay, 2000; the contents of which are incorporated herein by reference . According to a third aspect of the present invention there is provided a method for the treatment of a patient with a microbial infection, comprising administering to said patient a therapeutically effective amount of a compound of general formula (I) . According to a fourth aspect of the present invention there is provided the use of a compound of general formula (I) in the manufacture of a medicament for use in the treatment of a microbial infection. As used herein, the term "therapeutically effective amount" means an amount of a compound of the present invention effective to yield a desired therapeutic response, for example to prevent or treat a disease which by administration of a pharmaceutically-active agent. The specific "therapeutically effective amount" will, obviously, vary with such factors as the particular condition being treated, the physical condition and clinical history of the subject, the type of animal being treated, the duration of the treatment, the nature of concurrent therapy (if any) , and the specific formulations employed and the structure of the compound or its derivatives . As used herein, a "pharmaceutical carrier" is a pharmaceutically acceptable solvent, suspending agent, excipient or vehicle for delivering the compound of general formula (I) to the subject. The carrier may be liquid or solid, and is selected with the planned manner of administration in mind. The compound of general formula (I) may be administered orally, topically, or parenterally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles . The term parenteral as used herein includes subcutaneous , intravenous , intramuscular , intrathecal , intracranial , injection or infusion techniques. The invention also provides suitable topical , oral , aerosol , and parenteral pharmaceutical formulations for use in the novel methods of treatment of the present invention . The compounds of the invention may be administered orally as tablets , aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions , capsules , syrups or elixirs . The composition for oral use may contain one or more agents selected from the group of sweetening agents , flavouring agents , colouring agents and preserving agents in order to produce pharmaceutically elegant and palatable preparations. The tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets . These excipients may be , for example , inert diluents, such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, such as starch, gelatin or acacia; or lubricating agents, such as magnesium stearate, stearic acid or talc. The tablets may be uncoated, or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be employed.
Coating may also be performed using techniques described in the U. S. Pat. Nos. 4,256,108; 4,160,452; and 4,265,874 to form osmotic therapeutic tablets for control release . The compound of general formula (I) of the invention can be administered, for in vivo application, parenterally by injection or by gradual perfusion over time independently or together. Administration may be intravenously, intra-arterial, intraperitoneally, intramuscularly, subcutaneously, intracavity, or transdermally . For in vitro studies the agents may be added or dissolved in an appropriate biologically acceptable buffer and added to a cell or tissue. Preparations for parenteral administration include sterile aqueous or non-aqueous solutions , suspensions , and emulsions . Examples of non-aqueous solvents are propylene glycol , polyethylene glycol , vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate . Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer ' s intravenous vehicles include fluid and nutrient replenishers , electrolyte replenishers such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present such as, for example, anti-microbials , anti-oxidants , chelating agents, growth factors and inert gases and the like . The compounds of general formula (I) are antimicrobial agents which are active, in particular but not limited to, against Mycobacterium including Mycobacterium tuberculosis , M. avium intracellulare, M. fortuitum, M. abscessus and rapid growing atypical Mycobacterial strains, Nocardia, particularly Nocardia asteroides and N. nova, Staphylo coccus including Staphylococcus aureus and S . aureus (Coagulas-negative) , Streptococcus spp . and Enterococci species. The compounds of general formula (I) are particularly useful in treating infections involving these organisms . Generally, the terms "treating", "treatment" and the like are used herein to mean affecting a subject, tissue or cell to obtain a desired pharmacological and/or physiological effect . The effect may be prophylactic in terms of completely or partially preventing infection, and/or may be therapeutic in terms of a partial or complete cure of an infection. "Treating" as used herein covers any treatment of, or prevention of infection in a vertebrate , a mammal , particularly a human , and includes : preventing the infection from occurring in a subject that may have been exposed to the infectious agent, but has not yet been diagnosed as affected; inhibiting the infection, ie., arresting its development; or relieving or ameliorating the effects of the infection , ie . , cause regression of the effects of the infection. According to a fifth aspect of the present invention there is provided a pharmaceutical composition comprising a compound of general formula (I) and a pharmaceutically acceptable carrier . The pharmaceutical compositions according to one embodiment of the invention are prepared by bringing a compound of general formula (I) into a form suitable for administration to a subject using carriers, excipients and additives or auxiliaries. Frequently used carriers or auxiliaries include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins , cellulose and its derivatives , animal and vegetable oils, polyethylene glycols and solvents, such as sterile water, alcohols, glycerol and polyhydric alcohols. Intravenous vehicles include fluid and nutrient replenishers . Preservatives include antimicrobial , anti- oxidants , chelating agents and inert gases . Other pharmaceutically acceptable carriers include aqueous solutions, non-toxic excipients, including salts, preservatives, buffers and the like, as described, for instance, in Remington's Pharmaceutical Sciences, 15th ed. Easton: Mack Publishing Co., 1405-1412,1461-1487 (1975) and The National Formulary XIV., 14th ed. Washington: American Pharmaceutical Association (1975) , the contents of which are hereby incorporated by reference . The pH and exact concentration of the various components of the pharmaceutical composition are adjusted according to routine skills in the art. See Goodman and Gilman's The Pharmacological Basis for Therapeutics (7th ed.). The pharmaceutical compositions are preferably prepared and administered in dosage units . Solid dosage units include tablets , capsules and suppositories . For treatment of a subject, depending on activity of the compound, manner of administration, nature and severity of the disorder, age and body weight of the subject, different daily doses can be used. Under certain circumstances, however, higher or lower daily doses may be appropriate. The administration of the daily dose can be carried out both by single administration in the form of an individual dose unit or else several smaller dose units and also by multiple administration of subdivided doses at specific intervals . The pharmaceutical compositions according to the invention may be administered locally or systemically in a therapeutically effective dose . Amounts ef ective for this use will, of course, depend on the severity of the microbial infection and the weight and general state of the subject. Typically, dosages used in vitro may provide useful guidance in the amounts useful for in situ administration of the pharmaceutical composition, and animal models may be used to determine effective dosages for treatment of the cytotoxic side ef ects . Various considerations are described, eg., in Langer, Science, 249: 1527, (1990) . Formulations for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin . They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil. Aqueous suspensions normally contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspension . Such excipients may be suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethylcellulose , sodium alginate, polyvinylpyrrolidone , gum tragacanth and gum acacia; dispersing or wetting agents, which may be (a) naturally occurring phosphatide such as lecithin; (b) a condensation product of an alkylene oxide with a fatty acid,, for example, polyoxyethylene stearate; (c) a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadecaethylenoxycetanol; (d) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate, or (e) a condensation product of ethylene oxide with a partial ester derived from fatty acids and hexitol anhydrides , for example polyoxyethylene sorbitan monooleate . The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as those mentioned above. The sterile injectable preparation may also a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1 , 3-butanediol . Among the acceptable vehicles and solvents which may be employed are water , Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed, including synthetic mono-or diglycerides . In addition, fatty acids such as oleic acid find use in the preparation of injectables . Compounds of general formula (I) may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles , large unilamellar vesicles , and multilamellar vesicles . Liposomes can be formed from a variety of phospholipids , such as cholesterol, stearylamine, or phosphatidylcholines . Compounds of general formula (I) may also be administered in combination with cyclodextrins for enhanced aqueous solubility. Dosage levels of the compound of general formula (I) of the present invention will usually be of the order of about 0.05mg to about 20mg per kilogram body weight, with a preferred dosage range between about 0.05mg to about lOmg per kilogram body weight per day (from about 0. lg to about 3g per patient per day) . The amount of active ingredient which may be combined with the carrier materials to produce a single dosage will vary, depending upon the host to be treated and the particular mode of administration. For example, a formulation intended for oral administration to humans may contain about lmg to lg of an active compound with an appropriate and convenient amount of carrier material , which may vary from about 5 to 95 percent of the total composition. Dosage unit forms will generally contain between from about 5mg to 500mg of active ingredient . It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. In addition, some of the compounds of the invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of the invention . The compounds of the invention may additionally be combined with other compounds to provide an operative combination. It is intended to include any chemically compatible combination of pharmaceutically-active agents , as long as the combination does not eliminate the activity of the compound of general formula (I) of this invention. According to a sixth aspect of the present invention there is provided a method of killing a microorganism, comprising exposing said microorganism to a compound of general formula (I) as defined above. Advantageously, although not limited to, the microorganism is selected from the group consisting of MycoJacterium including Mycobacterium tuberculosis , M. avium intracellulare, M. fortuitum, M. abscessus and rapid growing atypical Mycobacterial strains, Nocardia, particularly Nocardia asteroides and N. nova, Staphylococcus including Staphylococcuε aureus, Streptococcus spp . and S. aureus (Coagulas-negative) and Enterococci species. Throughout this specification and the claims , the words "comprise", "comprises" and "comprising" are used in a non-exclusive sense, except where the context requires otherwise . It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art, in Australia or in any other country .
Modes for Performing the Invention The synthetic schemes employed to prepare compounds in accordance with preferred embodiments of the invention are now described in more detail. The synthesis of protected (compounds 3a- ; Examples 1-5) and deprotected (compounds 4a,b; Examples 7&8) galactofuranosyl sulfenamides is shown in Scheme 1. For the preparation of these examples, 1 ,2 , 3 , 5 , 6-penta-O- acetyl-D-galactofuranose (compound 1, Acyl = acetyl;
Bakinovskii et al . , 1988) and l-S-acetyl-2 , 3 , 5 , 6-tetra-O- benzoyl-1-thio-β-D-galactofuranose (compound 2, Acyl = benzoyl; Owen and von Itzstein, 2000) were prepared according to known literature methods and are shown in Scheme 1 without modification. The synthesis of a protected (compound 8; Example 6) arabinofuranosyl sulfenamide is shown in Scheme 2. For the preparation of this example, 5-0- (t-butyldiphenylsilyl) -D-arabinofuranose (compound 5) was prepared according to known literature methods (Ikeda and Bando, 1995) and is shown in Scheme 2 without modification . All new compounds gave the expected spectroscopic data.
D-Galactose 1 Acyl = Ac, Bz 2 Acyl = Ac, Bz
3b R1 = R2 = CBjCHaOCHzCHzOCHa 4b R1 = R2 = CHjCHjOCHzCHgOCHa 3c R = R2 = C6H11 3d R1 /R2 = -C(CH3)2CH2CH2CH2C(CH3)2- 3e R1 = CH2Ph , R2 = H
Scheme 1 Reagents and Conditions : a) Acyl = acetyl, according to
Bakinovskii et al . , 1988; Acyl = benzoyl, according to D'Accorso et al . , 1983; b) SnCl4 or BF3.Et20, HSAc, CH2C12, 0 °C to rt, 1 to 6 h, N2; c) BrCH(COOEt)2, H ^R2 , DMF, THF, or MeOH, rt, 17 to 44 h; d) NaOMe, MeOH, rt, 2 h, N2. D-Arabinose 5 6
8 R = R = GQH-]7
Scheme 2 Reagents and Conditions : a) According to Ikeda and Bando, 1995; b) pyridine, Ac20, 0 °C, 1 h, N2; c) BF3.Et20, CH2C12, HSAc, rt, 5 h, Ar; d) BrCH (COOEt) 2, HNRXR2, MeOH, rt, 3 h, Ar; e) i . TBAF, AcOH, THF, rt, 6 h, N2 ; ii . NaOMe , MeOH, rt, 2 h, N2.
l-S-Acetyl-2 ,3,5, 6-tetra-O-acetyl-l-thio-β-D- galactofuranose (2, Acyl = acetyl) : 1,2,3,5, 6-Penta-O-acetyl-D-galactofuranose (1) (10.0 g, 25.6 mmol) was dissolved in anhydrous dichloromethane under N2 and the solution cooled to 0 °C . Thioacetic acid (3.6 mL, 2 equivalents) and distilled borontrifluoride etherate (3.8 mL, 1.2 equivalents) were added dropwise and the reaction warmed to room temperature . After 6 hr the reaction was diluted with dichloromethane and quenched with saturated sodium bicarbonate. The organic phase was dried (Na2S0 ) , concentrated under reduced pressure, and the resulting yellow residue was chromatographed (3:2 hexanes/EtOAc) to give the product (2) (lO.Og, 96%) as a yellow syrup. 1H NMR (300 MHz, CDC13) : δ 2.03, 2.04, 2.11, 2.12 (4 x 3H, 4 x s, 4 x OAc), 2.38 (3H, s, SAσ) , 4.07-4.23 (2H, m, H-4, H- 6), 3.32 (1H, dd, J6, ;5 4.2, «J6,,6 12.0 Hz, H-6' ) , 5.07 (1H, m, H-2) , 5.22 (1H, t, J2, χ ~ J2,3 1.8 Hz, H-2) , 5.37 (1H, m, H-5) , 5.97 (1H, app. t, Jϊ,2 0.9 Hz, H-l) .
Example 1 iV,N-Dibenzyl~S- (2,3,5, 6-tetra-O-acetyl-β-D- galactofuranosyl) sulfenamide (3a) : l-S-Acetyl-2 ,3,5, 6-tetra-O-acetyl-l-thio-β-D- galactofuranose (2) (1.01 g, 2.50 mmol) was dissolved in methanol (75 mL) . Diethylbromomalonate (630 μL, 3.75 mmol) and dibenzylamine (1.20 mL, 6.3 mmol) were added and the reaction stirred at room temperature. After 44 h the solvent was removed and the residue purified by column chromatography on silica (1:1 EtOAc/hexanes) to yield the product (3a) (1.19 g, 86%) as a clear syrup. Rf 0.58 (1:2 EtOAc/hexanes) . 1H NMR (300 MHz, CDC13) : δ 2.01, 2.05, 2.09, 2.15 (each 3H, s, OAc), 3.82 (4H, s, CH2Ph) , 4.17- 4.40 (3H, m, H-4, H-6 and H-6'), 5.00-5.10 (2H, m, H-2 and H-3) , 5.38 (1H, , H-5) , 5.48 (1H, d, J 2 = 3.0 Hz, H-l) , 7.20-7.40 (10H, m, ArH) ; LRMS (ESI): m/z 559.9 [(M)+, 100%) .
Example 2 jV,iV-Di (2-methoxyethoxyethyl) -S- (2,3,5, 6-tetra-O-acetyl-β-D- galactofuranosyl) sulfenamide (3b): l-S-Acetyl-2 ,3,5, 6-tetra-O-acetyl-l-thio-β-D- galactofuranose (2) (350 mg, 0.9 mmol) was dissolved in methanol (25 mL) . Diethylbromomalonate (273 μL, 1.7 mmol) and N, JW-di (2-methoxyethoxyethyl) amine (479 mg, 2.4 mmol) were added and the reaction stirred at room temperature. After 19 h the solvent was removed under reduced pressure and the residue purified by column chromatography on silica (EtOAc) to yield the product (3b) (360 mg, 72 %) as a light golden oil. Rf 0.32 (EtOAc) . E NMR (300 MHz, CDC13) : δ 1.91, 1.93, 1.96, 1.99 (4 x 3H, 4 x s, 4 x OAc), 3.08 (4H, t, J = 6 Hz, NCH2CH2) , 3.23 (6H, s, OMe) , 3.30- 3.60 (12H, m, OCH2) , 4.00-4.25 (3H, m, H-5, H-6, H-6 ), 4.92 (2H, m, H-2, H-3), 5.19 (1H, m, H-5), 5.29 (1H, d, i,2 3.3 Hz, H-l) .
Example 3
N/ IV-dicyclohexyl -S- (2 , 3 , 5 , 6-tetra-O-acetyl-β-D- galactofuranosyl) sulfenamide (3c) : l-S-Acetyl-2 ,3,5, 6-tetra-O-acetyl-l-thio-β-D- galactofuranose (2) (750 mg, 1.85 mmol) was dissolved in methanol (25 mL) . Diethylbromomalonate (466 μL, 2.78 mmol) and dicyclohexylamine (920 μiL, 4.63 mmol) were added and the reaction stirred at room temperature. After 90 min the solvent was removed and the residue purified by column chromatography on silica (1:2 EtOAc/hexanes) to yield the product (3c) (688 mg, 69%) as a clear syrup. Rf 0.68 (1:2 EtOAc/hexanes). XH NMR (300 MHz, CDC13) : δ 0.9-1.7 (20H,m, cyclohexyl), 1.95, 1.97, 2.01, 2.04 (each 3H, s, OAc), 2.62 (2H, m, cyclohexyl), 4.00-4.30 (3H, m, H-4, H-6 and H-6'), 4.94 (3H, m, H-l, H-2 and H-3), 5.28 (1H, m, H-5); LRMS (ESI): m/z 565.8 [ (M + Na) + , 100%).
Example 4
1- (2 , 2 , 6 , 6 -Tetramethylpiperidine) -S- (2 , 3 , 5 , 6-tetra-O- acetyl-β-D-galactof uranosyl) sulfenamide (3d) : l-S-Acetyl-2 , 3 , 5 , 6-tetra-O-acetyl-l-thio-β-D- galactofuranose (2) (472 mg, 1.12 mmol) was dissolved in methanol (15 mL) and tetrahydrofuran (15 mL) . Diethylbromomalonate (293 μL, 2.62 mmol) and 2,2,6,6- tetramethylpiperidine (782 μL, 4.5 mmol) were added and the reaction stirred at room temperature. After 20 h the solvent was removed and the residue purified by column chromatography on silica (1:1 EtOAc/hexanes) to yield the product (3d) (356 mg, 61%) as a clear syrup. JRf 0.67 (1:1 EtOAc/hexanes). 1H NMR (300 MHz, CDC13) : δ 1.10, 1.12, 1.21, 1.23 (each 3H, s, Me), 1.3-1.6 (6H, m, piperidine) , 2.03, 2.04, 2.08, 2.12 (each 3H, s, OAc), 4.10-4.30 (3H, m, H-4, H-6 and H-6'), 5.01 (1H, dd, -J2 3 6.3 Hz, -J3,4 3.0 Hz, H-3), 5.13 (2H, m, H-l, H-2), 5.33 (1H, m, H-5); LRMS (ESI): m/z 525.9 [ (M + Na) +, 100%).
Example 5
W-Benzyl-S- (2,3,5, 6-tetra-O-benzoyl-β-D- galactofuranosyl) sulfenamide (3e) : l-S-Acetyl-2 ,3,5, 6-tetra-O-benzoyl-l-thio-β-D- galactofuranose (2) (330 mg, 0.50 mmol) was dissolved in methanol (15 mL) . Diethylbromomalonate (256 μL, 0.75 mmol) and benzylamine (218 μiL, 2.1 mmol) were added and the reaction stirred at room temperature. After 17 h the solvent was removed under reduced pressure and the residue purified by column chromatography on silica (1:1 EtOAc/hexanes) to yield the product (3e) (254 mg, 77 %) as a clear syrup. Rf 0.48 (1:1 EtOAc/hexanes). XH NMR (300 MHz, CDC13) : δ 3.13 (IH, t, J 5.7 Hz, NH) , 4.24 (2H, d, J 1.5 Hz, CH2Ph) , 4.85 (3H, m, H-6, H-6' and H-4), 5.71 (IH, d, Ji2 3.0 Hz, H-l), 5.74 (IH, app. t, J1/2 3.0, «72,3 2.1 Hz, H-2), 5.82 (IH, dd, «72,3 2.1, «J3,4 4.8 H-3), 6.13 (IH, m, H-5), 7.2-7.7 (17H, m, m,p-ArH of benzoyl groups and ArH of Benzyl group), 7.9- 8.2 (4 x 2H, 4x m, o-ArH of benzoyl groups) .
Example 6 l,2,3-Tri-0-acetyl-5-0- ( ert-butyldiphenylsilyl) -α/β-D- arabinofuranose (6) : 5-0- (Tert-butyldiphenylsilyl) - α/β-D-arabinose (5) (2.10 g, 5.40 mmol) was dissolved in dry pyridine (20 mL) and stirred with acetic anhydride (20 mL, excess) at 0 °C for 1 h, and then at room temperature for 18 h under N2. After this time the solvent removed under reduced pressure and the residue was chromatographed on silica (4:1 hexanes/EtOAc) to furnish the product (6) (2.67 g, 96%) as a clear syrup. Rf 0.45 (4:1 hexanes/EtOAc) . XH NMR (300 MHz, CDC13) : δ 7.33-7.22 (m, 10 H, SiPh) , 6.37 (d, 1 H, Ji,2 4.7 Hz, H-lβ) , 6.19 (bs , 1 H, H-lα) , 5.63 (dd, 1 H, «J3,4
6.1, J3|27.2 Hz, H-3β) , 5.38 (m, 1 H, H-3α) , 5.33 (dd, 1 H, a,! 4.8, J2,37.2 Hz, H-2β) , 5.21 (app d, 1 H, J 1.6 Hz, H- 2α) , 4.24 (dd, 1 H, J 4.0, J 8.8 Hz, H-4 ) , 4.12 (m, 1 H, H-4β) , 3.87 (m, 2 H, H-5 and H-5 ' α) , 3.81 (m, 2 H, H-5β and H-5'β), 2.02-2.13 (6 x s, 18 H, 6 x OAc α and β) , 1.07 (bs , 18 H, terfc-butyl α and β) . l-S-Acetyl-2 , 3-di-0-acetyl-5- - ( ert-butyldiphenylsilyl) - 1-thio-α-D-arabinofuranose (7) : To a solution of 5-0- ( ert-butyldiphenylsilyl) - 1,2,3-tri-O-acetyl-α/β-D-arabinofuranose (6) (2.10 g, 4.08 mmol) in dry DCM (20 mL) at 0 °C, under Ar was added
BF3.OEt2 (1.2 equivalents, 4.90 mmol). After 10 minutes thiolacetic acid (1.5 equivalents, 4.33 mL, 6.12 mmol) was added and the reaction was stirred for 5 h at room temperature under Ar . After this time the reaction was diluted with EtOAc (150 mL) and sat. aq. NaHC03 (150 mL) . The organic layer was washed sat. aq. NaHC03 (150 mL) and aq. NaCl (150 mL) , dried (Na2S04) , filtered, and concentrated under reduced pressur . The residue was chromatographed on silica (3:1 hexanes/EtOAc) to furnish the product (7) (1.88 g, 87%) as a clear syrup. Rf 0.30 (4:1 hexanes/EtOAc) . 1H NMR (300 MHz, CDC13) : δ 7.65-7.73 (m, 4 H, Si(Ph)2), 7.34-7.46 (m, 6 H, Si(Ph)2), 6.00 (bs , 1 H, H-l), 5.37 (m, 1 H, H-2), 5.25 (app t, 1 H, J1.6 Hz, H-3), 4.14 (m, 1 H, H-4), 3.85 (m, 2 H, H-5 and H-5'), 2.39 (s, 3 H, SCOCH3) , 2.11 (s, 3 H, 1 x OCOCH3) , 2.02 (s, 3 H, 1 x OCOCH3) , 1.06 (s, 9 H, -C(CH3)3).
N, N-Dioctyl-S- (2 , 3-di-0-acetyl-5-0- [ tert- butyldiphenylsilyl] -1-thio-α-D-arabinofuranosyl) sulfenamide (8, R1 = R2 = C8Hι7) : l-S-Acetyl-2 , 3-di-0-acetyl-5-0- ( tert- butyldiphenylsilyl) -1-thio-α-D-arabinofuranose (7) (1.48 g,
2.79 mmol) was dissolved in dry methanol (20 ml) .
Diethylbromomalonate (938 μL, 5.58 mmol, 2 molar equiv.) was then added, and the mixture was stirred for 10 minutes at room temperature under Ar . Dioctylamine (3.36 mL,
11.15 mmol, 4 molar equiv.) was then added and the reaction stirred for 3 h at room temperature under Ar .
The reaction was concentrated and the residue was taken up in EtOAc (100 ml) , washed with sat. NaCl, dried (Na2S04) , filtered, and the solvent removed under reduced pressure.
The residue was chromatographed on silica (6:1 hexanes/EtOAc) to furnish the product (8) (1.30 g, 64%) as a pale yellow syrup. Rf 0.70 (4:1 hexanes/EtOAc) . 1H NMR (300 MHz, CDC13) : δ 7.66-7.73 (m, 4 H, Si(Ph)2), 7.33-7.47 (m, 6 H, Si(Ph)2), 5.44 (d, 1 H, J1 / 2 4.1 Hz, H-l), 5.34 (dd, 1 H, J3,4 5.4, J3 / 2 3.2 Hz, H-3), 5.12 (dd, 1 H, J2,3
3.2, «72fι 4.0 Hz, H-2), 4.22 (m, 1 H, H-4), 3.85 (d, 2 H, J 3.9 Hz, H-5 and H-5'), 2.90 (m, 4 H, N(CH2)2), 2.05 (s, 6 H, 2 x OCOCH3) , 1.18-1.63 ( , 24 H, 12 x CH2 dioctyl chain), 1.06 (s, 9 H, -C(CH3)3), 0.87 (m, 6 H, 2 x CH3) .
General procedure for the deprotection of benzoate and acetate protecting- groups : To a solution of the protected sulfenamide (0.5 mmol) in dry methanol (10 mL) under an atmosphere of N is added one equivalent of sodium methoxide (IM solution in dry methanol) . The reaction is left to stir at room temperature for 2 h. After this time the reaction is neutralized with Amberlite (H+) resin. The resin is removed by filtration, washed with methanol, and the solvent evaporated under reduced pressure. The residue is chromatographed on silica to yield the deprotected compound .
General procedure for the deprotection of tert- butyldiphenylsilyl protecting- groups : To a solution of the silyl protected sulfenamide (0.5 mmol) in dry THF (5 L) at °C under an atmosphere of N2 is added one and a half equivalents of tetrabutylammonium fluoride (1 M solution in THF) and acetic acid (0.1 mL) . The reaction is left to stir at room temperature for 15 h, then additional acetic acid (0.5 mL) is added and the reaction is left to stir for a further 1 h. After this time the reaction mixture is evaporated under reduced pressure. The residue is chromatographed on silica to yield the desilylated compound. Example 7 (β-D-galactofuranosyl) sulfenamide (4a) : WV-KT-Dibenzyl-S- (2,3,5, 6-tetra-O-acetyl-β-D- galactofuranosyl) sulfenamide (3a) (275 mg, 0.49 mmol) was de-O-acetylated to yield the product (4a) (47%) as a white solid. Rf 0.21 (8.5:1.5 EtOAc/methanol) . XH NMR (300 MHz, CD3OD) : δ.3.60-3.80 (4H, m, H-2, H-5, H-6, H-6'), 3.90 (IH, dd, J3r 4 7.8 Hz, J3f 4 2.7 Hz, H-4), 4.07 (IH, m, H-3), 4.11 (4H, s, CH2-Ph) , 5.31 (IH, d, «Tlf2 5.1 Hz, H-l), 7.10- 7.40 (10H, m, ArH) ; LRMS (ESI): m/z 413.9 [ (M + Na)+, 100%] .
Example 8
N,N-Oi (2-methoxyethoxyethyl) -S- (β-D- galactofuranosyl) sulfenamide (4b): N, N-O± (2-methoxyethoxyethyl) -S- (2,3,5, 6-tetra-O- acetyl-β-D-galacto uranosyl) sulfenamide (3b) was de-O- acetylated to give the product (4b) (55%) as a waxy solid. Rf 0.24 (14:5:1 EtOAc/methanol/H20) . 1H NMR (300 MHz, D20) : δ 3.13 (4H, m, NCH2CH2) , 3.38 (6H, s, OMe), 3.50-3.75 (15H, overlapping m, OCH2, H-5, H-6 and H-6 ), 3.79 (IH, t, -73,4 3 Hz, H-4), 3.92 (IH, dd, -2 3 7.5 Hz J3/4 3 Hz, H-3), 4.07 (IH, dd, Ji,2 5.4 Hz «J2 3 7.5 Hz, H-2), 5.20 (IH, d, i2 5.4 Hz, H-l); LRMS (ESI): m/z 438.4 [ (M + Na) + , 100%).
Biological Data
Example 9 Inhibition of various bacteria by compound (4a) (R1 = R2 = CH2Ph) is described in Table 1. Data for the previously reported compound N,N-dioctyl-S- (β-D- galactofuranosyl) sulfenamide (10) (R1 = R2 = C8Hι ; von Itzstein et al., 2003) is provided for comparison. The biological data were determined by a Zone Inhibition Assay method. Compounds were tested by spotting 100 μg of compound as a solution in methanol onto a sterile filter disc placed on a lawn of bacteria on the surface of an LB agar plate. After incubation at 37 °C for 72 h (M. smegmatis) or overnight (other species) , the zone of inhibition was measured using an arbitrary scale: +++ = relatively large zone of inhibition, - = no zone of inhibitio .
Table 1
4a R1 = R2= CH2Ph 10 R1 = R2= C8Hi7
Industrial Applicability The compounds of general formula (I) are useful as pharmaceuticals , particularly antimicrobial agents .
References
The disclosure of the following documents is incorporated herein by reference :
Owen, D. J. ; von Itzstein, M. Carbohyr. .Res. 2000, 328, 287-292. Marino, C . ; Marino, K. ; Miletti, L. C; Alves, M. J. M. ; Colli, . ; de Lederkremer, R. M. Glycobiology 1998, 8, 901-904. Miletti, L. C; Marino, C; Marino, K. ; de Lederkremer, R. M. ; Colli, . ; Alves, M. J. M. Carbohydr. Res . 1999, 320, 176-182. Zhang, Q.; Liu, H. J. Am. Chem. Soc . 2001, 123, 6756-6766. Brimacombe, J. ; Gent, P.; Stacey, M. J. Chem. Soc . Org. 1968, 567-569. Brimacombe, J. ; Da'aboul, I.; Tucker, L. J. Chem. Soc . Org. 1971, 3762. Lemieux, R. U. ; Stick, R. V. Aust . J. Chem.
1975, 28, 1799-1801. de Lederkremer R. M. ; Cirelli, A.; Sznaidman, M. L. Carbohydr. Res . 1986, 146, 233-240. Shin, J.; Perlin, A. Carbohydr. Res . 1979, 76, 165-176. de Lederkremer R. M. ; Cicero, D.; Varela, 0. Tetrahedron 1990, 46, 1131-1144. de Lederkremer , R. M. ; Marino , K . ; Marino , C . Anal . Biochem. 2002, 301 , 325-328. Pathak, A. K. ; Pathak, V.; Suling, W. J. ;
Gurcha, S. S.; Morehouse, C. B.; Besra, G. S.; Maddry, J. A.; Reynolds, R. C. Bioorg. Med. Chem. 2002, 10, 923-928. Ernst, B.; Hart, G. W. ; Sinay, P. (Eds), Carbohydrates in Chemistry and Biology, Wiley-VCH, Weinheim, 2000, Vols 1 - 4. Craine, L.; Raban, M. Chem. Rev. 1989, 89, 689- 712. Koval', I.V. Russ . Chem. Rev. 1996, 65, 421-440. Illyes, T.-Z.; Molnar-Gabor , D.; Szilagyi, L. Carbohydr. Res . 2004, 339, 1561-1564. Backinovskii, L.V.; Nepogod'ev, S.A.; Kochetkov, N.K. Bioorg. Khim. 1988, 14 , 1234-1241. Ikeda, M; Bando, H. Production of Synthetic Intermediate of Vitamin Derivative . (Sumitomo Pharmaceutical Co. Ltd.) JP7145093, 1995. D'Accorso, N.B.; Thiel , I.M.E.; Schueller, M. Carbohdr. Res . 1983, 124 , 177-184. von Itzstein, L.M.; Coppel, R.L.; Davis, C.B.; Thomson, R.J.; Owen, D.J. An antimicrobial agent . WO 03/070715, 2003.

Claims

Claims 1. A compound of general formula (I) :
wherein A is selected from the group consisting of O, S, SO, S02, Se, Te, NR8, CR9R'9, N → O and C (O) ; and, when A is O and q is 1 , one of Ri and R2 is selected from the group consisting of hydrogen, optionally substituted Cι_3 or >C30 alkyl, alkyl when interrupted by one or more heteroatoms or functional groups selected from the group consisting of O, S, -N=, NR7 and - (Y) mC= (Z) (T) n- , optionally substituted C2_3 or >C30 alkenyl , alkenyl when interrupted by one or more heteroatoms or functional groups selected from the group consisting of O, S, -N=, NR and -(Y)mC=(Z) (T)n-, optionally substituted aralkyl which may be interrupted within the alkyl moiety by one or more heteroatoms or functional groups selected from the group consisting of O, S, -N=, NR7 and -(Y)mC=(Z) (T)n-, optionally substituted acyl, optionally substituted aryl, optionally substituted heterocyclic and a carbohydrate moiety, while the other of Ri and R2 is selected from the group consisting of hydrogen, optionally substituted alkyl which may be interrupted by one or more heteroatoms or functional groups selected from the group consisting of O, S, -N=, NR7 and - (Y)mC= (Z) (T)n- , optionally substituted alkenyl which may be interrupted by one or more heteroatoms or functional groups selected from the group consisting of O, S, -N=, NR7 and -(Y)mC=(Z) (T)n-, optionally substituted aralkyl which may be interrupted within the alkyl moiety by one or more heteroatoms or functional groups selected from the group consisting of O, S, -N=, NR7 and - (Y) mC= (Z) (T) n- , optionally substituted aryl, optionally substituted heterocyclic, optionally substituted acyl and a carbohydrate moiety; but, when A is S, SO, S02 , Se, Te, NR8 , CR9R9' , N - O or C (O) and q is 1 or A is O, S, SO, S02 , Se, Te , NR8 , CR9Rg' , N —» O or C (O) and q is O, then Ri and R2 are independently selected from the group consisting of hydrogen, optionally substituted alkyl which may be interrupted by one or more heteroatoms or functional groups selected from the group consisting of O, S, -N=, NR7 and ~(Y)mC=(Z) (T)n-, optionally substituted alkenyl which may be interrupted by one or more heteroatoms or functional groups selected from the group consisting of O, S, -N=, NR7 and -(Y)mC=(Z) (T)n-, optionally substituted aralkyl which may be interrupted within the alkyl moiety by one or more heteroatoms or functional groups selected from the group consisting of O, S, -N=, NR7 and - (Y)mC=(Z) (T)n-, optionally substituted aryl, optionally substituted acyl and a carbohydrate moiety, or Ri and R2 together with the nitrogen atom from which they depend form a saturated or unsaturated, optionally substituted heterocyclic group which may include additional heteroatoms selected from the group consisting of 0, N and S; Xi is selected from the group consisting of OR3, SR3, NR3R'3, hydrogen, halogen, - (Y) mC= (Z) (T) nR3 , -
N(C=(Z) (T)nR3)2, N3, CN, OCN, SCN, OS03R3, OS02R3, OP03R3R' 3 , OP02R3R'3, S(0)R3, S(0)2R3, S(0)2OR3, P03R3R' 3 , NR3NR' 3R" 3 , SNR3R'3, NR3SR'3, SSR3 and R3 , or is an oxo group, =S, =NOR3 or =CR3R' 3 and Xi ' is absent; X2 is selected from the group consisting of OR4,
SR4, NR4R'4, hydrogen, halogen, - (Y)raC= (Z) (T) nR4, - N(C=(Z) (T)nR4)2, N3, CN, OCN, SCN, OS03R4 , OS02R4 , OP03R4R' 4 , OP02R4R'4, S(0)R4, S(0)2R4, S(0)2OR4, P03R4R'4, NR4NR' 4R' ' 4 , SNR4R'4, NR4SR'4, SSR and R4 , or is an oxo group, =S , =NOR or =CR4R' 4 and X2 ' is absent; X3 and X3 ' are independently selected from the group consisting of OR5, SR5 , NR5R' 5 , hydrogen, halogen, - (Y)mC=(Z) (T)nR5, -N(C=(Z) (T)nR5)2, N3, CN, OCN, SCN, OS03R5 , OS02R5, OP03R5R'5, OP02R5R'5/ S(0)R5, S(0)2R5, S(0)2OR5, P03R5R'5, NR5NR'5R''5, SNR5R' 5 , NR5SR'5, SSR5 and R5, or X3 is =0, =S, =NOR5 or =CR5R'5 and X3 ' is absent; X4 is selected from the group consisting of OR6,
SR6/ NR6R'6, hydrogen, halogen, - (Y)mC= (Z) (T)nR6, - N(C=(Z) (T)nR6)2, N3, CN, OCN, SCN, OS03R6, OS02R6, OP03R6R'6, OP02R6R'6, S(0)R6, S(0)2R6, S(0)2OR6, P03R6R'6, NR6NR'6R"6, SNR6R'6, NR6SR'6, SSR6 and R6, or is an oxo group, =S, =NOR6 or =CR6R' 6 and X4 ' is absent; X5 is selected from the group consisting of hydrogen, CN, -C= (Z) (T)nRu, S(0)Rn, S(0)2Rn, S(0)2ORn, P03RiiR'n, optionally substituted alkyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted aralkyl, and optionally substituted acyl ; Xi ' r X2 ' Xa ' and X5 ' are the same or di erent and are selected from the group consisting of hydrogen, CN, optionally substituted alkyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted aralkyl, and optionally substituted acyl; or one of i and X2, X2 and X5' , X5' and A when A contains a carbon or nitrogen atom, X5 and A when A contains a carbon or nitrogen atom, and X5 and X together constitute a double bond, or X5' and X4 or X3 and X4 together constitute a double bond, or Ri and Xi, R2 and Xi, Ri and X2, R2 and X2 , Ri and X5, R2 and X5 , Rx and X5' , R2 and X5' , Xi and X2, X2 and X3, X2 and X4, X3 and X4, Xx and Xi' , X2 and X2' , X3 and X3' or X4 and X4' together form part of a ring structure which optionally includes at least one heteroatom selected from 0, S and N and is optionally substituted; m, n and q are independently 0 or 1 and Y, Z and T are independently selected from the group consisting of O, S, and NRi0; R3, R'3/ R"3, R4, R'4, R" , R5, R's, R"s, Re, R'e, R''6, R , Rs, 9, R' 9, Rio, R11 and R' n are the same or different and are selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted acyl and a carbohydrate moiety; with the proviso that at least two of Xi, X2, X3 and X4 are other than hydrogen or a group linked to the ring through a carbon-carbon bond and the further proviso that the compound of general formula (I) is not 1-(9H- purinyl) -S- (3-deoxy-pentafuranosyl) sulfenamide 5-formamido-2 ' , 3 ' , 5 ' -tri-O-formyl-1- (β-D- ribofuranosylthio) imidazole-4-carboxamid , N-phenyl-S- (2,3:5, 6-di-O-isopropylidenyl-β-D- annofuranosyl) sulfenamide or N,-V-diethyl-S- (2,3,5, 6-tetra-O-benzoyl-β-D- galactofuranosyl) sulfenamide; or a pharmaceutically acceptable salt thereof. 2. A compound as claimed in claim 1 wherein q is 0 or q is 1 and A is selected from S, SO, S02, Se, Te, NR8, CR9R'9, N →- O or C(O) and one or both of Ri and R2 is alkyl . 3. A compound as claimed in claim 2 wherein one or both of Ri and R2 is C_3o alkyl . 4. A compound as claimed in claim 3 wherein one or both of Ri and R2 is C6-ι2 alkyl. 5. A compound as claimed in claim 4 wherein one or both of Ri and R2 is C8_0 alkyl . 6. A compound as claimed in claim 1 wherein one or both or Ri and R2 is aralkyl . 7. A compound as claimed in claim 6 wherein one or both Ri and R2 is (CH2)rPh where Ph is phenyl and r is an integer in the range 1 to 12 inclusive. 8. A compound as claimed in claim 1 wherein one or both of Ri and R2 is alkyl interrupted by one or more heteroatoms or functional groups selected from the group consisting of O, S, -N=, NR7 , and -(Y)mC=(Z) (T)n. 9. A compound as claimed in claim 8 wherein one or both of Ri and R2 is alkyl interrupted by one or more oxygen atoms . 10. A compound as claimed in claim 9 wherein one or both of Rx and R2 is CH3 (CH2) x O (CH2) γO(CH2) 2 wherein x is an integer in the range 0 to 12 inclusive and y and z are independently integers in the range 1 to 12 inclusive. 11. A compound as claimed in claim 1 wherein q is 0 or q is 1 and A is selected from S, SO, S02, Se, Te, NR8, CRgR'g, N - O or C (O) and one or both of Ri and R2 is alkenyl . 12. A compound as claimed in claim 1 wherein Ri and
R2 together with the nitrogen atom from which they depend form an optionally substituted saturated or unsaturated heterocyclic group . 13. A compound as claimed in claim 12 wherein Ri and
R2 together with the nitrogen atom from which they depend orm a cyclic imide or a lacta . 1 . A compound as claimed in any one of claims 1 to
13 wherein Xx is OR3. 15. A compound as claimed in claim 14 wherein R3 is hydrogen or optionally substituted acyl . 16. A compound as claimed in any one of claims 1 to 15 wherein X2 is OR . 17. A compound as claimed in claim 16 wherein R4 is hydrogen or optionally substituted acyl. 18. A compound as claimed in any one of claims 1 to 17 wherein X3 is OR5. 19. A compound as claimed in claim 18 wherein R5 is hydrogen or optionally substituted acyl . 20. A compound as claimed in any one of claims 1 to 19 wherein X , when present, is 0R6. 21. A compound as claimed in claim 20 wherein Rε is hydrogen or optionally substituted acyl. 22. A compound selected from the group consisting of: N~benzyl-S- (2,3,5, 6-tetra-O-benzoyl-β-D- galactofuranosyl) sulfenamide N N-dibenzyl-S- (2,3,5, 6-tetra-O-acetyl-β-D- galactofuranosyl) sulfenamide N,N~d±cyclohexyl -S- (2,3,5, 6-tetra-O-acetyl-β-D- galactofuranosyl) sulfenamide N,N-di (2-methoxyethoxyethyl) -S- (2,3,5, 6-tetra- - acetyl-β-D-galactof ranosyl) sulfenamide 1- (2 , 2 , 6 , 6-tetramethylpiperidinyl) -S- (2,3,5,6- tetra- - cetyl-β-D-galactof ranosyl) sulfenamide iV,W-dioctyl-S-(2,3-di-0-acetyl-5-0-[te.c:t- butyldiphenylsilyl] - α-D-arabinofuranosyl) sulfenamide J7,N-Dibenzyl-S- (β-D-galactofuranosyl) sulfenamide N,N-Oi (2-methoxyethoxyethyl) -S- (β-D- galactofuranosyl) sulfenamide 23. A method of preparation of a compound of general formula (I) :
comprising reacting a compound of general formula (II) :
wherein L is a leaving group, preferably acetyl and Xl f Xx ' , X2, X2 ' , X3, X3 ' , X4, X4 ' , X5 and X5 ' , are as defined; with a compound of general formula (III) :
wherein Ri and R2 are as defined above; in the presence of a bis-activated alkyl halide. 24. A method for the treatment of a microbial infection, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of general formula (I) as claimed in any one of claims 1 to 22. 25. The use of a compound of general formula (I) as claimed in any one of claims 1 to 22 in the manufacture of a medicament for use in the treatment of a microbial infection . 26. A pharmaceutical composition comprising a compound of general formula (I) as claimed in any one of claims 1 to 22 and a pharmaceutically acceptable carrier. 27. A method of killing a microorganism, comprising exposing said microorganism to a compound of general formula (I) as claimed in any one of claims 1 to 22.
EP04761152A 2003-08-21 2004-08-20 Novel sulfenamides Withdrawn EP1664072A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
AU2003904500A AU2003904500A0 (en) 2003-08-21 Novel compounds II
AU2003904501A AU2003904501A0 (en) 2003-08-21 Novel compounds III
AU2003904509A AU2003904509A0 (en) 2003-08-21 Novel Compounds
PCT/AU2004/001115 WO2005019237A1 (en) 2003-08-21 2004-08-20 Novel sulfenamides

Publications (1)

Publication Number Publication Date
EP1664072A1 true EP1664072A1 (en) 2006-06-07

Family

ID=34221925

Family Applications (1)

Application Number Title Priority Date Filing Date
EP04761152A Withdrawn EP1664072A1 (en) 2003-08-21 2004-08-20 Novel sulfenamides

Country Status (6)

Country Link
EP (1) EP1664072A1 (en)
JP (1) JP2007502779A (en)
BR (1) BRPI0413684A (en)
CA (1) CA2535802A1 (en)
MX (1) MXPA06001976A (en)
WO (1) WO2005019237A1 (en)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2015151857A (en) 2008-12-02 2019-01-15 Уэйв Лайф Сайенсес Джапан, Инк. METHOD FOR SYNTHESIS OF NUCLEIC ACIDS MODIFIED BY PHOSPHOR ATOMIC
MX342945B (en) 2009-07-06 2016-10-18 Ontorii Inc * Novel nucleic acid prodrugs and methods use thereof.
US10428019B2 (en) 2010-09-24 2019-10-01 Wave Life Sciences Ltd. Chiral auxiliaries
EP3248982A1 (en) 2011-07-19 2017-11-29 Wave Life Sciences Ltd. Thiosulfonate reagents for the synthesis of functionalized nucleic acids
CA2879023C (en) 2012-07-13 2017-03-28 Wave Life Sciences Japan Asymmetric auxiliary group
MX2016009290A (en) 2014-01-16 2017-02-28 Wave Life Sciences Ltd Chiral design.
KR20190058477A (en) 2016-08-17 2019-05-29 솔스티스 바이올로직스, 리미티드 Polynucleotide construct
WO2019006455A1 (en) 2017-06-30 2019-01-03 Solstice Biologics, Ltd. Chiral phosphoramidite auxiliaries and methods of their use
PH12022551379A1 (en) 2019-12-06 2023-05-03 Vertex Pharma Substituted tetrahydrofurans as modulators of sodium channels
BR112022024071A2 (en) 2020-05-27 2022-12-20 Axial Therapeutics Inc TLR2 MODULATOR COMPOUNDS, PHARMACEUTICAL COMPOSITIONS AND THEIR USES
DK4347031T3 (en) 2021-06-04 2025-12-01 Vertex Pharma N-(HYDROXYALKYL-(HETERO)ARYL)-TETRAHYDROFURAN-CARBOXAMIDES AS MODULATORS OF SODIUM CHANNELS

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2489498A1 (en) * 2002-02-22 2003-08-28 Griffith University An antimicrobial agent

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2005019237A1 *

Also Published As

Publication number Publication date
CA2535802A1 (en) 2005-03-03
WO2005019237A1 (en) 2005-03-03
MXPA06001976A (en) 2006-05-31
JP2007502779A (en) 2007-02-15
BRPI0413684A (en) 2006-10-24

Similar Documents

Publication Publication Date Title
WO2005019237A1 (en) Novel sulfenamides
US20120202877A1 (en) Anti-influenza agents
EP1664071A1 (en) Novel sulfenamide oxides
US8093227B2 (en) Monosaccharide compounds and methods therefor
US10864261B2 (en) Synthetic vaccines against Streptococcus pneumoniae serotype 2
US20050124559A1 (en) Antimicrobial agent
US7312194B2 (en) Delivery systems
US20060014702A1 (en) Antimicrobial agent
AU2004266177A1 (en) Novel sulfenamides
WO2006037185A1 (en) Novel sulfenamides and sulfenamide oxides
AU2004266176A1 (en) Novel sulfenamide oxides
AU2003246615A1 (en) An antimicrobial agent
AU2003225343A1 (en) An antimicrobial agent
ZA200406672B (en) An antimicrobial agent.
JP5283033B2 (en) Sialyl α (2 → 6) lactose-containing compound and use thereof
CN1871247A (en) Novel sulfenamides

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20060317

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PL PT RO SE SI SK TR

DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20080301