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WO2006037185A1 - Novel sulfenamides and sulfenamide oxides - Google Patents

Novel sulfenamides and sulfenamide oxides Download PDF

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Publication number
WO2006037185A1
WO2006037185A1 PCT/AU2005/001548 AU2005001548W WO2006037185A1 WO 2006037185 A1 WO2006037185 A1 WO 2006037185A1 AU 2005001548 W AU2005001548 W AU 2005001548W WO 2006037185 A1 WO2006037185 A1 WO 2006037185A1
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Prior art keywords
optionally substituted
group
hydrogen
opo
oso
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PCT/AU2005/001548
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French (fr)
Inventor
Laurence Mark Von Itzstein
Ross Leon Coppel
Christopher Bonner Davis
Robyn Joy Thomson
Regan David Hartnell
David James Owen
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Griffith University
Monash University
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Priority claimed from AU2004905781A external-priority patent/AU2004905781A0/en
Application filed by Griffith University, Monash University filed Critical Griffith University
Publication of WO2006037185A1 publication Critical patent/WO2006037185A1/en

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    • 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
    • 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 and their oxides that have physiological activity, particularly an antimicrobial action, methods for their synthesis, pharmaceutical compositions containing them and method of treatment of patients, in particular, those suffering a microbial infection.
  • the present invention is concerned generally with novel sulfenamides and their oxides that have physiologic activity, in particular, an antimicrobial action.
  • a compound of the following general formula (I) is provided.
  • A is selected from the group consisting of 0, S, SO, SO 2 , Se, Te, NR 8 , CR 9 R' 9 , N->O, and C(0) ;
  • X 1 ' , X 2 ' , X 3 ' and X 4 ' 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 X 1 and X 2 , X 2 and X 31 X 3 and X 4 ' , X 4 ' and A when A contains a carbon or nitrogen atom, X 5 and A when A contains a carbon or
  • 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 _ 3 o 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, 1,3,5-cycloheptatrienyl
  • 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 acy ⁇ , or a heterocyclic ring, which is referred to as heterocyclic acyl, preferably Ci_ 3 o acyl.
  • acyl examples include straight chain or branched alkanoyl such as formyl, acetyl, propanoyl, butanoyl, 2- methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl and icosanoyl; cycloalkylcarbonyl such as cyclopropylcarbonyl cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl; aroyl such as benzoyl, toluoyl and naphthoy
  • phenylacetyl phenylpropanoyl, phenylbutanoyl, phenylisobutyl, phenylpentanoyl and phenylhexanoyl
  • naphthy1alkanoyl e.g. naphthylacetyl, naphthylpropanoyl and naphthyIbutanoyl
  • aralkenoyl such as phenylalkenoyl (e.g.
  • phenylpropenoyl e.g., phenylbutenoyl, phenylmethacrylyl, phenylpentenoyl and phenylhexenoyl and naphthylalkenoyl (e.g.
  • heterocycliccarbonyl such as thienylacetyl, thienylpropanoyl, thienyIbutanoyl, 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, iinadazolyl, pyrrolydinyl, pyridinyl, piperidinyl, indolyl, pyridazinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, purinyl, quinazolinyl, phenazinyl, acridinyl, benzoxazolyl, benzothiazolyl and the like.
  • a carbocyclic aromatic ring system contains 6-10 carbon atoms and an aromatic heterocyclic ring system contains 1 to 4 heteratoms independently selected from N, 0 and S and up to 9 carbon atoms
  • 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 membered 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 tetrazolopyridazin
  • 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-galactose, D-galactofuranose, N-acetyl-D- galactofuranose, D-galactopyranose, N-acetyl-D- galactopyranose, D-glucose, D-glucofuranose, I7-acetyl-D- glucofuranose, D-glucopyranose and JW-acetyl-D- glucopyranose, D-mannose, D-mannofuranose, D-mannopyranose, W-acetyl-D-mannopyranose, D-arabinofuranose, D- arabinopyranose, L-rhamnopyranose, D-ribose, D-fucose, N- acylneuraminic acid, 2-keto-3-deoxy-nonulosonic acid, 2- keto-3-deoxy-octulosonic acid, D-galacturonic acid, D- glucuronic acid
  • 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, diacyl, alken
  • 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 range. 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.
  • such moieties may contain 1 to 24 carbon atoms, advantageously 1 to 12 carbon atoms, and typically 1 to 10 carbon atoms
  • R 1 and R 2 is alkyl.
  • one or both of Ri and R 2 is C 4 -3o alkyl, and may be C6-12 alkyl or C 8 -I 0 alkyl, advantageously C 8 alkyl.
  • Ri and R 2 being alkyl interrupted by one or more heteroatoms or functional groups
  • the heteroatom may be oxygen
  • Ri and/or R 2 may have the formula CH 3 (CH 2 ) x 0(CH 2 ) y O(CH 2 ) z or
  • R x and/or R 2 may have the formula CH 3 (CH 2 ) Y O(CH 2 ) z where y is in the range 3 to 9, typically 7, and x is in the range 2 to 6, typically 2.
  • R 3 , R' 3, R"3, R4, R' 4, R"4, R 5 , R'5, R'' 5 , R 6 , R' 6 , R" 6/ R 7 , R 8 , R 9 , R' 9, Rio, Rn, R' 11, R12, R'12 or R' ' 1 2 is alkyl, alkenyl, aralkyl or alkyl or alkenyl interrupted by one or more heteroatoms or functional groups, embodiments are as set out for R x and R 2 .
  • the amine portion of the sulfenamide or its oxide is tethered to the carbohydrate moiety through an additional linkage. While the amine moiety may be tethered by linkage to any position in the carbohydrate moiety, linkage to the position bearing Xi through either Ri or R 2 forming a ring together with Xi is preferred.
  • the linkage may take the form of an optionally substituted alkyl chain being linked to the end of a functional group located in the position bearing Xi of the carbohydrate ring and linked to a functional group located within Ri or R 2.
  • X x is OR 3 .
  • R 3 is hydrogen or optionally substituted acyl.
  • X 2 is OR 4 .
  • R 4 is hydrogen or optionally substituted acyl.
  • X3 is OR5.
  • R 5 is hydrogen or optionally substituted acyl.
  • X 4 is CH 2 OR 12 , CHOR 12 CH 2 OR 12 or CHOR 12 CHOR 12 CH 2 OR 12 where each R 12 may be any of the groups recited above. Typically X 4 is CH 2 OR 12 .
  • any one of the substituents R 3 , R 4 , R 5 , R 6 and R 12 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.
  • p is 2 and the compounds are sulfonamides.
  • p is 1 and the compounds are sulfinamides .
  • the compounds of the invention are galactopyranosyl compounds.
  • the compounds of the invention are glucopyranosyl compounds .
  • the compounds of general formula (I) are selected from the group consisting of: N,N-dioctyl-S- (2,3,5,6-tetra-O-acetyl- ⁇ -D- galactopyranosyl) sulfenamide,
  • the compound of general formula (I) is selected from the group consisting of N,27-dioctyl- S- ( ⁇ -D-galactopyranosyl) sulfenamide, N,N-d ⁇ (2- octyloxyethyl) -S- ( ⁇ -D-galactopyranosyl) sulfenamide, N,N- dioctyl-S- ( ⁇ -D-glucopyranosyl) sulfenamide and N,N-d ⁇ (2- octyloxyethyl) -S- ( ⁇ -D-glucopyranosyl) sulfenamide, and their oxides.
  • L is an acyl group, preferably acetyl and Xi, X 2 , X3, X4, Xi' , X 2 ' , X3' X-' and X5 are as defined above; with a compound of general formula (III) :
  • Ri and R 2 are as defined above; in the presence of a bis-activated alkyl halide; and, optionally, reacting the product with an oxidising agent.
  • 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 2O 0 C to 60 0 C, preferably 25 0 C to 4O 0 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 3 , R' 3 , R' ' 3 , R 4 , R' 4, R" 4, R 5 , R'5, R' '5, Re, R' e, R" ⁇ , R7, Rs, Rio, Rn, R' 1 1, R12, R' 12 and R' ' 12 may be a protecting group, and the process may include the further step of removing the protecting groups .
  • Protecting groups may not always be required. Suitable protecting groups for hydroxyl groups are well known to the person skilled in the art, and in this case the acetyl and benzoyl groups are preferred.
  • Acetyl and benzoyl protecting groups are typically removed through hydrolysis with sodium methoxide in methanol. Suitable protecting groups for nitrogen atoms are well known to the person skilled in the art.
  • the sulfenamides 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 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.
  • oxidising agent is 3-chloroperbenzoic acid.
  • An extensive array of methodologies has been developed to manipulate different positions on carbohydrate templates as disclosed, for example, Ernst, Hart & Sinay, 2000; Chapleur, 1998; Stick, 2001; the contents of which are incorporated herein by reference.
  • 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) :
  • A is selected from the group consisting of 0, S, SO, SO 2 , Se, Te, NR 8 , CR 9 R' 9 , N->O, and C(O) ;
  • Xi is selected from the group consisting of OR 3 ,
  • Xi' , X2' , X3' anc * X4' 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 X 2 , X 2 and X 3 , X 3 and X 4 ' , X 4 ' and A when A contains a carbon or nitrogen atom, X5 and A when A contains a carbon or nitrogen atom, and X 5 and Xi together constitute a double bond, or Ri and Xi, R 2 and Xi, Ri and X 2 , R 2 and X 2 , Ri and X 3 , R 2 and X 3 , R x and X 4 , R 2 and X 4 , R 1 and X 4 ' , R 2 and X 4 ' , X 1 and X 2
  • A is selected from the group consisting of O, S, SO, SO 2 , Se, Te, NR 8 , CR 9 R' 9 , N->0, and C(O) ;
  • Xi' i X2' t X3' and X 4 ' 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 X 1 and X 2 , X 2 and X 3 , X 3 and X 4 ' , X 4 ' and A when A contains a carbon or nitrogen atom, X 5 and A when A contains a carbon or nitrogen atom, and X 5 and Xi together constitute a double bond, or R 1 and X 1 , R 2 and X 1 , R 1 and X 2 , R 2 and X 2 , R 1 and X 3 , R 2 and X 3 , R 1 and X 4 , R 2 and X 4 , R 1 and X 4 ' , R 2 and X 4 ' , X 1 and
  • terapéuticaally 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 ex ⁇ ipients 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 Staphylococcus including Staphylococcus aureus and S. aureus (Coagulas-negative) , Streptococcus species, Enterococci species, Mycobacterium including Mycobacterium tuberculosis, M. avium intracellulare, M. fortuitum, M. abscessus and rapid growing atypical Mycobacterial strains and Nocardia, particularly Nocardia asteroid.es and N. nova.
  • the compounds of general formula (I) are particularly useful in treating infections involving these organisms .
  • 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) :
  • A is selected from the group consisting of O, S, SO, SO 2 , Se, Te, NR 8 , CR 9 R' 9 , N->0, and C(O) ;
  • X 1 ' , X 2 ' , X 3 ' and X 4 ' 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 X 2 , X 2 and X 31 X 3 and X 4 ' , X 4 ' and A when A contains a carbon or nitrogen atom, X 5 and A when
  • 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.
  • 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.
  • compositions according to the invention may be administered locally or systemically in a therapeutically effective dose. Amounts effective 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 effects. 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.
  • excipients may be suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl ⁇ ellulose, 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
  • 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.Ig 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 Ig 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.
  • 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. 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.
  • a method of killing a microorganism comprising exposing said microorganism to a compound of general formula (I) :
  • A is selected from the group consisting of O, S,, SO, SO 2 , Se, Te, NR 8 , CR 9 R' 9 , N->O, and C(O);
  • Xi' , X2' , X3' and X 4 ' 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 X 1 and X 21 X 2 and X 3 , X 3 and X 4 ' , X 4 ' and A when A contains a carbon or nitrogen atom, X 5 and A when A contains a carbon or nitrogen atom, and X 5 and Xi together constitute a double bond, or Ri and X 1 , R 2 and Xi, Ri and X 2 , R 2 and X 2 , R x and X 3 , R 2 and X 3 , R x and X 4 , R 2 and X 4 , Ri and X 4 ' , R 2 and X 4 ' , X 1 and X 2
  • the microorganism is selected from the group consisting of Staphylococcus including Staphylococcus aureus and S. aureus (Coagulase-negative) , Streptococcus species,
  • Mycobacterium including Mycobacterium tuberculosis, M. avium lntracellulare, M. fortultum, M. abscessus and rapid growing atypical Mycobacterial strains and Nocardla, particularly Nocardia asterold.es and N. nova.
  • N,.NHDioctyl-S- (2,3,5, 6-tetra-O-acetyl- ⁇ -D- galactopyranosyl) sulfenamide (2) was de-O-acetylated according to the general procedure to give the desired product. Yield: 74%. R f 0.38 (EtOAc) .
  • N,JV-Dioctyl-S- (2,3,5,6-tetra-O-acetyl- ⁇ -D- galactopyranosyl) sulfonamide (4) was de-O-acetylated according to the general procedure to give the desired product. Yield: 80%. R f 0.26 (EtOAc) .
  • N,N-Oi (2-octyloxyethyl) -S- (2,3,5,6-tetra-O- acetyl- ⁇ -D-galactopyranosyl) sulfonamide (5) was de-O- acetylated according to the general procedure to give the desired product. Yield: 82%. R £ 0.34 (EtOAc) .
  • Example 8 N,N-Diocfcyl-S- (2,3,5, 5-tetra.-O-acetyl-/?-!>- glucopyranosyl)sulfenamide: l-S-Acetyl-2,3,5,6-tetra-O-acetyl-l-thio- ⁇ -D- glucopyranose (9) (2.31 g, 5.69 mmol) was dissolved in MeOH (100 mL) . Diethylbromomalonate (1.46 mL, 8.54 mmol) and 27,N-dioctylamine (5.10 mL, 17.10 mmol) were added and the reaction stirred at room temperature for 4 hours.
  • N,N-Di(2-octyloxyeth ⁇ l) -S- (2,3,5,6-t ⁇ tra-O-a.cetyl- ⁇ -D- glucopyra.nosyl)sulfenaxnide l-S-Acetyl-2,3,5, 6 ⁇ tetra-O-acetyl-l-thio- ⁇ -D- glucopyranose (9) (446 mg, 1.1 ⁇ unol) was dissolved in methanol (20 mL) . Diethyl bromomalonate (280 ⁇ L) and di(2- octyloxyethyl)amine (904 mg) were added and the reaction stirred at room temperature for 16 h.
  • Inhibition of Bacillus subtilis by compounds (7) and (12) is described in Table 2.
  • the biological data were determined by Minimum Inhibitory Concentration (MIC) Serial Dilution Assay. Standard solutions of the compounds were prepared in MeOH. Assays were carried out in a final volume of 2 mL LB Broth with a maximum 2% MeOH concentration, in 10 mL Falcon tubes with 5 ⁇ L of saturated culture. Tubes were incubated at 37 °C with shaking for 18 to 20 hours. The MIC BO was then determined as the concentration in which there was 80% or greater reduction in growth as compared to the control.
  • MIC Minimum Inhibitory Concentration
  • MIC data against Enterococcus and Streptococcus spp. for compounds (6) , (7) , (8) , (12) and (13) is described in Table 3.
  • the MIC assays were carried-out according to NCCLS (National Committee for Clinical Laboratory Standards) guidelines. Standard solutions of the compounds were prepared in DMSO. Assays were carried out in Mueller Hinton II Broth in 96-well microdilution plates with a final cell concentration of 5 x 10 5 colony-forming- units/ml. Plates incubated at 35°C for approximately 20 h. The MIC was recorded as the lowest concentration of drug that inhibited visible growth of the organism.
  • the compounds of general formula (I) are useful as pharmaceutical agents, particularly anti-microbial agents .

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Abstract

A compound of the general formula (I): wherein R1, R2, X1, X1', X2, X2', X3, X3', X4, X4' and X5 define various substituents and p is 0, 1 or 2. The invention also relates to use of the compounds as anti-microbial agents.

Description

NOVEL SULFENAMIDES AND SULFENAMIDE OXIDES
Technical Field
The present invention relates to novel sulfenamides and their oxides that have physiological activity, particularly an antimicrobial action, methods for their synthesis, pharmaceutical compositions containing them and method of treatment of patients, in particular, those suffering a 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 the development of carbohydrate-based antimicrobial agents (see, for example, von Itzstein, Wu, et al. , 1993; Kok, Campbell, Mackey, & von Itzstein, 1996; Fazli, Bradley et al. , 2001) has led to the discovery of a new class of antimicrobial agents described below. A large amount of work has been published (see, for example Ernst, Hart & Sinay, 2000) in the area of carbohydrate chemistry and biology. In addition, carbohydrate mimics based on isosteres of the ring structure are well known in the literature and often present interesting biological activities (see, for example, Chapleur, 1998; Lillelund, Jensen, Liang, & BoIs, 2002; Kok, Campbell, Mackey, & von Itzstein, 1996) . Despite this large body of work little to date has provided compounds that are clinically useful antimicrobial medicines. There remains a need for the identification of new antimicrobial agents.
Disclosure of the Invention The present invention is concerned generally with novel sulfenamides and their oxides that have physiologic activity, in particular, an antimicrobial action. In a first aspect of the present invention there is provided a compound of the following general formula (I) =
Figure imgf000003_0001
wherein R1 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 0, S, -N=, NR7 and -(Y)1nC=(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)1nC=(Z) (T)n-, optionally substituted heterocyclic, 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;
A is selected from the group consisting of 0, S, SO, SO2, Se, Te, NR8, CR9R' 9, N->O, and C(0) ;
Xi is selected from the group consisting of OR3, SR3, NR3R'3, hydrogen, halogen, -(Y)1nC=(Z) (T)nR3, - N(C=(Z) (T)nR3)2, N3, CN, OCN, SCN, OSO3R3, OSO2R3, OPO3R3R'3, OPO2R3R'3, S(O)R3, S(O)2R3, S(O)2OR3, PO3R3R'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, or Xx is C=(Z) and R2 is a bond thereto so as to form a cyclic moiety -C=(Z)NRxS (O)p-/ X2 is selected from the group consisting of OR4, SR4, NR4R'4, hydrogen, halogen, - (Y) mC= (Z) (T)nR4, - N(C=(Z) (T)nR4J2, N3, CN, OCN, SCN, OSO3R4, OSO2R4, OPO3R4R'4, OPO2R4R' 4, S(O)R4, S(O)2R4, S(O)2OR4, PO3R4R' 4 , NR4NR' 4R' '4, SNR4R' 4, NR4SR' 4, SSR4 and R4, or is an oxo group, =S, =N0R4 or =CR4R' 4 and X2 1 is absent;
X3 is selected from the group consisting of OR5, SR5, NR5R'5, hydrogen, halogen, -(Y)1nC=(Z) (T)nR5, - N(C=(Z) (T)nRs)2, N3, CN, OCN, SCN, OSO3R5, OSO2R5, OPO3R5R'5, OPO2R5R' 5, S(O)R5, S(O)2Rs, S(O)2OR5, PO3R5R' 5 , NR5NR' 5R"5,
SNR5R' 5, NR5SR' 5, SSR5 and R5, or is an oxo group, =S, =NOR5 or =CR5R' 5 and X3' is absent;
X4 is selected from the group consisting of OR6, SR6, NR6R'6, hydrogen, halogen, -(Y)1nC=(Z) (T)nR6, - N(C=(Z) (T)nRg)2, N3, CN, OCN, SCN, OSO3R6, OSO2R6, OPO3R6R'6, OPO2R6R' 6, S(O)R6, S(O)2R6, S(O)2OR6, PO3R6R' 6, NR6NR' 6R' '6, SNR6R' 6, NR6SR' 6, SSR6 , R6, or is an oxo group, =S , =N0R6 or =CR6R'6 and X4' is absent, and -( CX6X6 ') VCX7X7 ' X7 " wherein v is an integer in the range of 0 to 6 inclusive and, when v is in the range of 1 to 6, may include a double bond or epoxide group, each of X6, X7 and X7' is independently selected from the group consisting of ORχ2, SRi2, NRi2R' 12, hydrogen, halogen, -(Y)1nC=(Z) (T)nR12, -N(C=(Z) (T)nRi2J2, N3, CN, OCN, SCN, OSO3Ri2, OSO2Ri2, OPO3Ri2R' 12, OPO2Ri2R' 12 , S(O)Ri2, S(O)2Ri2, S(O)2ORi2, PO3Ri2R' 12 , NR12NR' 12R" i2 ,
SNR12R' i2/ NRi2SR'12, SSR12 and Ri2, or is an oxo group, =S, =N0Ri2 or =CRi2R' i2 and X6' or X7'' , respectively, is absent; and each of X6' and X7' ' is independently selected from the group hydrogen, CN, optionally substituted alkyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted aralkyl, and optionally substituted acyl;
X5 is selected from the group consisting of hydrogen, CN, -C=(Z) (T)nRn, S(O)Rn, S(O)2Rn, S(O)2ORn, PO3R11R'n, optionally substituted alkyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted aralkyl, and optionally substituted acyl; X1' , X2' , X3' and X4' 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 X1 and X2, X2 and X31 X3 and X4' , X4' 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 Ri and Xi, R2 and X1, Ri and X2, R2 and X2, Ri and X3, R2 and X3, Ri and X4, R2 and X4, Ri and X4' , R2 and X4' , Xi and X2, X2 and X3, X2 and X4, X3 and X4, Xi and X1' , 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 and n are independently zero or one and Y, Z and T are independently selected from the group consisting of 0, S, and NRi0 p is zero, one or two; R3, R'3, R"3, R4, R'4, R"4, R5, R'5, R"5, R6, R'6,
R" 6, R7, R8, R9, R' 9, Rio, Rn, R'n, Ri2, R'12 and R' '12 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=, 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 0, S, -N=, NR7 and -(Y)mC=(Z) (T)n-, optionally substituted aryl, optionally substituted heterocyclic, 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)1nC=(Z) (T)n-, optionally substituted acyl and a carbohydrate moiety; with the proviso that at least two of X1, X2, X3, X4, Xg and X7 are other than hydrogen or a group linked to the ring through a carbon-carbon bond and the further proviso that the compound is not N,27-diethyl-S- (2,3,4, 6- tetra-O-acetyl-β-D-galactopyranosyl) sulfenamide, 27,JP7— diethyl-S- (2-acetamido-3,4, 6-tri-0-acetyl-2-deoxy-β-D- glucopyranosyl) sulfenamide, methyl JV-acetyl-4,7,8,9-tetra- O-acetyl-2-S- (diethylamino) -2-thio-α-neuraminate, N,N- di (isopropyl) -S- (2,3,4, 6-tetra-O-acetyl-β-D- glucopyranosyl) sulfenamide, 1- [(2,3,4, 6-tetra-O-acetyl-β-D- galactopyranosyl) thio]piperidine, 1- [ (2,3,4,6-tetra-O- acetyl-β-D-glucopyranosyl)thio]piperidine, 4-[(2,3,4,6- tetra-O-acetyl-β-D-galactopyranosyl) thio]morpholine, N-(I- adamantyl) -S- (2,3,4, 6-tetra-O-acetyl-β-D- glucopyranosyl) sulfenamide, jV-benzyl-S- (2,3,4,6-tetra-O- acetyl-β-D-glucopyranosyl) sulfenamide, W-phenyl-S- (2,3,4,6- tetra-O-acetyl-β-D-glucopyranosyl) sulfenamide, £7-phenyl-S- (D-glucopyranosyl) sulfenamide, N- (4-methylphenyl) -S-
(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl) sulfenamide, N- (2-chlorophenyl) -S- (2,3,4, 6-tetra-O-acetyl-β-D- glucopyranosyl) sulfenamide, JV- (4-hydroxypheny1) -S- (2,3,4, 6-tetra-O-acetyl-β-D-glucopyranosyl) sulfenamide, 2- [(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl) thio] -1 (2H) - isoquinoline, methyl 1-deoxy-l- [ (4-thioxo-l (4H) - pyrimidinyl) thio] -β-D-glucopyranuronate, 1- (galactopyranosylthio) -lH-tetrazole, 1- (glucopyranosylthio) -lH-tetrazole, or 1,1'- [sulfonylbis (4,1-phenyleneiminosulfonyl) ]bis [1-deoxy-β-D- glucopyranuronic acid] tetrasodium salt; or a pharmaceutically acceptable salt thereof.
It will be appreciated that the manner of representing substituents in the foregoing general formula does not 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-dimethylbutyl, 1,2-dimethylbutyl, 1,3- dimethylbutyl, 1,2,2-trimethylpropyl, 1,1,2- trimethylpropy1, heptyl, 5-methylhexyl, 1-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4- dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 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_3o 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 acyϊ, or a heterocyclic ring, which is referred to as heterocyclic acyl, preferably Ci_3o acyl. Examples of acyl include straight chain or branched alkanoyl such as formyl, acetyl, propanoyl, butanoyl, 2- methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl and icosanoyl; cycloalkylcarbonyl 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 naphthy1alkanoyl (e.g. naphthylacetyl, naphthylpropanoyl and naphthyIbutanoyl) ; aralkenoyl such as phenylalkenoyl (e.g. phenylpropenoyl, phenylbutenoyl, phenylmethacrylyl, phenylpentenoyl and phenylhexenoyl and naphthylalkenoyl (e.g. naphthylpropenoyl, naphthylbutenoyl and naphthylpentenoyl) ; heterocycliccarbonyl; heterocyclicalkanoyl such as thienylacetyl, thienylpropanoyl, thienyIbutanoyl, 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, iinadazolyl, pyrrolydinyl, pyridinyl, piperidinyl, indolyl, pyridazinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, purinyl, quinazolinyl, phenazinyl, acridinyl, 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 heteratoms independently selected from N, 0 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 membered 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-galactose, D-galactofuranose, N-acetyl-D- galactofuranose, D-galactopyranose, N-acetyl-D- galactopyranose, D-glucose, D-glucofuranose, I7-acetyl-D- glucofuranose, D-glucopyranose and JW-acetyl-D- glucopyranose, D-mannose, D-mannofuranose, D-mannopyranose, W-acetyl-D-mannopyranose, D-arabinofuranose, D- arabinopyranose, L-rhamnopyranose, D-ribose, D-fucose, N- acylneuraminic acid, 2-keto-3-deoxy-nonulosonic acid, 2- keto-3-deoxy-octulosonic acid, D-galacturonic acid, D- glucuronic acid, D-muramic acid, D-fructose, D-galactitol, D-glucitol, D-mannitol, D-laσtitol, 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 specification "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 oxo, =S, =N-, where appropriate, particularly as substituents in ring structures such as lactones, lactams and cyclic imides, provided that none of the substituents outlined above interferes with the formation or activity 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 range. 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 particular, such moieties may contain 1 to 24 carbon atoms, advantageously 1 to 12 carbon atoms, and typically 1 to 10 carbon atoms
In an embodiment one or both of R1 and R2 is alkyl. In a further embodiment one or both of Ri and R2 is C4-3o alkyl, and may be C6-12 alkyl or C8-I0 alkyl, advantageously C8 alkyl. Furthermore one or both of Ri and R2 may be aralkyl, alkyl interrupted by one or more heteroatoms or functional groups selected from the group consisting of O, S, -N=, NR7, and -(Y)1nC=(Z) (T)n, alkenyl or Ri and R2 together with a nitrogen atom from which they depend may form an optionally substituted saturated or unsaturated heterocyclic group, for example, a cyclic imide or a lactam. If one or both Ri and R2 is alkenyl it may be C4_3o alkenyl, in a further embodiment,C6-I2 alkenyl and in a still further embodiment C8_io alkenyl. In the case of one or both Ri and R2 being alkyl interrupted by one or more heteroatoms or functional groups, the heteroatom may be oxygen, and, in an embodiment, Ri and/or R2 may have the formula CH3(CH2)x 0(CH2)yO(CH2)z or
CH3 (CH2)YO(CH2)z 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. Advantageously Rx and/or R2 may have the formula CH3 (CH2)YO(CH2) z where y is in the range 3 to 9, typically 7, and x is in the range 2 to 6, typically 2. Equally, if one of R3, R' 3, R"3, R4, R' 4, R"4, R5, R'5, R''5, R6, R' 6, R"6/ R7, R8, R9, R' 9, Rio, Rn, R' 11, R12, R'12 or R' ' 12 is alkyl, alkenyl, aralkyl or alkyl or alkenyl interrupted by one or more heteroatoms or functional groups, embodiments are as set out for Rx and R2.
In an embodiment the amine portion of the sulfenamide or its oxide is tethered to the carbohydrate moiety through an additional linkage. While the amine moiety may be tethered by linkage to any position in the carbohydrate moiety, linkage to the position bearing Xi through either Ri or R2 forming a ring together with Xi is preferred. By way of example only, the linkage may take the form of an optionally substituted alkyl chain being linked to the end of a functional group located in the position bearing Xi of the carbohydrate ring and linked to a functional group located within Ri or R2.
In an embodiment Xx is OR3. Advantageously R3 is hydrogen or optionally substituted acyl. In an embodiment X2 is OR4. Advantageously, R4 is hydrogen or optionally substituted acyl.
In an embodiment X3 is OR5. Advantageously, R5 is hydrogen or optionally substituted acyl. In an embodiment X4 is - (CX6X6' )VCX7X7'X7' ' wherein v is an integer in the range of 0 to 6 inclusive, preferably 0, 1 or 2, and each of X6, X7 and X7' is independently selected from the group consisting of OR12, SR12, NR12R'12, hydrogen, halogen, -(Y)1nC=(Z) (T)nR12, - N(C=(Z) (T)nR12J2, N3, CN, OCN, SCN, OSO3R12, OSO2R12, OPO3R12R' 12, OPO2R12R' i2/ S(O)R12, S(O)2R12, S(O)2OR12, PO3R12R' 12, NR12NR'12R' '12, SNR12R' 12, NR12SR'12, SSR12 and R12, or is an oxo group, =S, =NOR12 or =CR12R'12 and X6' or X7' ' , respectively, is absent; and each of X6' and X7' ' is independently selected from the group hydrogen, CN, optionally substituted alkyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted aralkyl, and optionally substituted acyl; and R12, R' 12 and R' '12 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 0, S, -N=, NR7 and -(Y)1nC=(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)1nC=(Z) (T)n-, optionally substituted aryl, optionally substituted heterocyclic, 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)1nC=(Z) (T)n-, optionally substituted acyl and a carbohydrate moiety.
In an embodiment, X4 is CH2OR12, CHOR12CH2OR12 or CHOR12CHOR12CH2OR12 where each R12 may be any of the groups recited above. Typically X4 is CH2OR12.
In an embodiment any one of the substituents R3, R4, R5, R6 and R12 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 p is 2 and the compounds are sulfonamides. Alternatively, p is 1 and the compounds are sulfinamides .
In an embodiment the compounds of the invention are galactopyranosyl compounds.
In an embodiment the compounds of the invention are glucopyranosyl compounds .
Advantageously the compounds of general formula (I) are selected from the group consisting of: N,N-dioctyl-S- (2,3,5,6-tetra-O-acetyl-β-D- galactopyranosyl) sulfenamide,
N1N-d± (2-octyloxyethyl) -S- (2,3,5, 6-tetra-O-acetyl-β-D- galactopyranosyl) sulfenamide, 2V,JV-dioctyl-S- (2,3,5, 6-tetra-O-acetyl-β-D- glucopyranosyl) sulfenamide,
N,N-d±(2-octyloxyethyl) -S- (2,3,5,6-tetra-O-acetyl-β-D- glucopyranosyl) sulfenamide, iV,27-dioctyl-S- (β-D-galactopyranosyl) sulfenamide,
N,N-d±(2-octyloxyethyl) -S- (β-D- galactopyranosyl) sulfenamide,
N,W-dioctyl-S- (β-D-glucopyranosyl) sulfenamide, and iV,iV-di(2-octyloxyethyl) -S- (β-D-glucopyranosyl) sulfenamide, and their oxides.
In an embodiment the compound of general formula (I) is selected from the group consisting of N,27-dioctyl- S- (β-D-galactopyranosyl) sulfenamide, N,N-d± (2- octyloxyethyl) -S- (β-D-galactopyranosyl) sulfenamide, N,N- dioctyl-S- (β-D-glucopyranosyl) sulfenamide and N,N-d±(2- octyloxyethyl) -S- (β-D-glucopyranosyl) sulfenamide, and their oxides.
In an embodiment the compound is a thio- (A = S) or aza- (A = NR8) analogue of W,N-dioctyl-S- (β-D- galactopyranosyl) sulfenamide and its oxides.
According to a second aspect of the present invention there is provided a method of preparation of a compound of general formula (I) :
Figure imgf000015_0001
comprising reacting a compound of general formula
(II) :
Figure imgf000015_0002
wherein L is an acyl group, preferably acetyl and Xi, X2, X3, X4, Xi' , X2' , X3' X-' and X5 are as defined above; with a compound of general formula (III) :
Figure imgf000015_0003
wherein Ri and R2 are as defined above; in the presence of a bis-activated alkyl halide; and, optionally, reacting the product with an oxidising agent. 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 2O0C to 600C, preferably 250C to 4O0C, 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 R3, R'3, R' '3, R4, R' 4, R" 4, R5, R'5, R' '5, Re, R' e, R"β, R7, Rs, Rio, Rn, R'11, R12, R' 12 and R' ' 12 may be a protecting group, and the process may include the further step of removing the protecting groups . Protecting groups may not always be required. Suitable protecting groups for hydroxyl groups are well known to the person skilled in the art, and in this case the acetyl and benzoyl groups are preferred.
Acetyl and benzoyl protecting groups are typically removed through hydrolysis with sodium methoxide in methanol. Suitable protecting groups for nitrogen atoms are well known to the person skilled in the art. The sulfenamides 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 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 number of methods have been developed to oxidise sulfenamides as disclosed, for example, in Craine and Raban, 1989; Glass & Swedo, 1977; Haake, Gebbing, & Benack, 1979; the contents of which are incorporated herein by reference. Typically the oxidising agent is 3-chloroperbenzoic acid. An extensive array of methodologies has been developed to manipulate different positions on carbohydrate templates as disclosed, for example, Ernst, Hart & Sinay, 2000; Chapleur, 1998; Stick, 2001; 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 microbial infection, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of general formula (I) :
Figure imgf000017_0001
wherein 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)111C=(Z) (T)n-, optionally substituted alkenyl which may be interrupted by one or more heteroatoms or functional groups selected from the group consisting of 0, 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 heterocyclic, 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;
A is selected from the group consisting of 0, S, SO, SO2, Se, Te, NR8, CR9R' 9, N->O, and C(O) ; 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, OSO3R3, OSO2R3, OPO3R3R'3, OPO2R3R'3, S(O)R3, S(O)2R3, S(O)2OR3, PO3R3R'3, NR3NR'3R"3, SNR3R'3, NR3SR'3, SSR3 and R3, or is an oxo group, =S, =NOR3 or =CR3R'3 and X1 1 is absent, or X1 is C=(Z) and R2 is a bond thereto so as to form a cyclic moiety -C=(Z)NR1S(O)P-;
X2 is selected from the group consisting of OR4, SR4, NR4R' 4, hydrogen, halogen, -(Y)1nC=(Z) (T)nR4, - N(C=(Z) (T)nR4J2, N3, CN, OCN, SCN, OSO3R4, OSO2R4, OPO3R4R'4, OPO2R4R' 4, S(O)R4, S(O)2R4, S(O)2OR4, PO3R4R' 4, NR4NR' 4R"4, SNR4R' 4/ NR4SR' 4, SSR4 and R4, or is an oxo group, =S, =N0R4 or =CR4R' 4 and X2 1 is absent;
X3 is selected from the group consisting of OR5, SR5, NRsR's, hydrogen, halogen, -(Y)1nC=(Z) (T)nR5, -
N(C=(Z) (T)nRs)2, N3, CN, OCN, SCN, OSO3R5, OSO2R5, OPO3R5R'5, OPO2R5R'5, S(O)R5, S(O)2R5, S(O)2OR5, PO3R5R'5, NR5NR'5R''5, SNR5R'5, NR5SR'5, SSR5 and R5, or is an oxo group, =S, =N0R5 or =CR5R'5 and X3' is absent; X4 is selected from the group consisting of OR6,
SR6, NR6R'6, hydrogen, halogen, -(Y)1nC=(Z) (T)nR6, - N(C=(Z) (T)nR6)2, N3, CN, OCN, SCN, OSO3R6, OSO2R6, OPO3RSR'6, OPO2R6R' 6, S(O)R6, S(O)2R6, S(O)2OR6, PO3R6R' 6, NR6NR' 6R"6, SNR6R' 6, NR6SR' 6, SSR6 , R6, or is an oxo group, =S, =N0R6 or =CR6R'6 and X4' is absent, and -(CX6X6' )VCX7X7'X7' ' wherein v is an integer in the range of 0 to 6 inclusive and, when v is in the range of 1 to 6, may include a double bond or epoxide group, each of X6, X7 and X7' is independently selected from the group consisting of OR12, SR12, NR12R' 12, hydrogen, halogen, -(Y)1nC=(Z) (T)nR12, -N(C=(Z) (T)nR12J2, N3, CN, OCN, SCN, OSO3R12, OSO2Ri2, OPO3R12R' 12, OPO2R12R' 12, S(O)R12, S(O)2R12, S(O)2OR12, PO3R12R' 12, NR12NR' 12R' '12, SNR12R'χ2, NR12SR' 12, SSR12 and Ri2, or is an oxo group, =S, =N0R12 or =CR12R' 12 and X6' or X7'' , respectively, is absent; and each of X6' and X7' ' is independently selected from the group hydrogen, CN, optionally substituted alkyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted aralkyl, and optionally substituted acyl; X5 is selected from the group consisting of hydrogen, CN, -C=(Z) (T)nR11, S(O)R1x, S(O)2R11, S(O)2ORu, PO3R11R']^, optionally substituted alkyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted aralkyl, and optionally substituted acyl;
Xi' , X2' , X3' anc* X4' 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 X3, X3 and X4' , X4' 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 Ri and Xi, R2 and Xi, Ri and X2, R2 and X2, Ri and X3, R2 and X3, Rx and X4, R2 and X4, R1 and X4' , R2 and X4' , X1 and X2, X2 and X3, X2 and X4, X3 and X4, Xi and X1' , 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 and n are independently zero or one and Y, Z and T are independently selected from the group consisting of O, S, and NR10 p is zero, one or two;
R3, R'3, R"3, R4, R'4, R"4, R5, R's, R" 5/ R5, R'e, R'' 6, R7, R8, R9, R'9, Rio, Rn, R'n, RX2, R'X2 and R' '12 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=, NR7 and -(Y)1nC=(Z) (T)n-, optionally substituted alkenyl which may be interrupted by one or more heteroatoms or functional groups selected from the group consisting of 0, S, -N=, NR7 and -(Y)1nC=(Z) (T)n-, optionally substituted aryl, optionally substituted heterocyclic, 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 0, S, -N=, NR7 and -(Y)1nC=(Z) (T)n-, optionally substituted acyl and a carbohydrate moiety; with the proviso that at least two of X1, X2, X3, X4, Xe and X7 are other than hydrogen or a group linked to the ring through a carbon-carbon bond; or a pharmaceutically acceptable salt thereof.
According to a fourth aspect of the present invention there is provided the use of a compound of general formula (I) :
Figure imgf000020_0001
wherein 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 0, S, -N=, NR7 and -(Y)1nC=(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)1nC=(Z) (T)n-, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted acyl and a carbohydrate moiety; or R1 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;
A is selected from the group consisting of O, S, SO, SO2, Se, Te, NR8, CR9R' 9, N->0, and C(O) ;
Xi is selected from the group consisting of OR3, SR3, NR3R' 3, hydrogen, halogen, -(Y)1nC=(Z) (T)nR3, - N(C=(Z) (T)nR3J2, N3, CN, OCN, SCN, OSO3R3, OSO2R3, OPO3R3R'3, OPO2R3R' 3, S(O)R3, S(O)2R3, S(O)2OR3, PO3R3R' 3 , NR3NR' 3R" 3 , SNR3R'3, NR3SR'3, SSR3 and R3, or is an oxo group, =S, =NOR3 or =CR3R'3 and Xi1 is absent, or X1 is C=(Z) and R2 is a bond thereto so as to form a cyclic moiety -C=(Z)NRxS (0)p-;
X2 is selected from the group consisting of OR4, SR4, NR4R'4, hydrogen, halogen, -(Y)111C=(Z) (T)nR4, -
N(C=(Z) (T)nR4)2, N3, CN, OCN, SCN, OSO3R4, OSO2R4, OPO3R4R'4, OPO2R4R' 4, S(O)R4, S(O)2R4, S(O)2OR4, PO3R4R' 4, NR4NR' 4R' '4, SNR4R' 4/ NR4SR'4, SSR4 and R4, or is an oxo group, =S, =N0R4 or =CR4R' 4 and X2' is absent; X3 is selected from the group consisting of OR5,
SR5, NRsR's, hydrogen, halogen, -(Y)1nC=(Z) (T)nR5, - N(C=(Z) (T)nR5J2, N3, CN, OCN, SCN, OSO3R5, OSO2R5, OPO3R5R'S, OPO2R5R'5, S(O)R5, S(O)2R5, S(O)2OR5, PO3R5R'5, NR5NR'5R"5, SNR5R'5, NR5SR'5, SSR5 and R5, or is an oxo group, =S, =NOR5 or =CR5R'5 and X3' is absent;
X4 is selected from the group consisting of OR6, SR6, NR6R'6, hydrogen, halogen, -(Y)nC=(Z) (T)nR6, - N(C=(Z) (T)nRg)2, N3, CN, OCN, SCN, OSO3R6, OSO2R6, OPO3R6R'6, OPO2R6R' 6, S(O)R6, S(O)2R6, S(O)2OR6, PO3R6R' 6, NR6NR' 6R"6, SNR6R' sr NR6SR' 6, SSR6 , R6, or is an oxo group, =S, =NOR6 or =CR6R'6 and X4' is absent, and -(CX6X6' )VCX7X7'X7' ' wherein v is an integer in the range of 0 to 6 inclusive, and when v is in the range of 1 to 6, may include a double bond or epoxide group, and each of X6, X7 and X7' is independently selected from the group consisting of OR12, SRi2, NRi2R'i2, hydrogen, halogen, -(Y)1nC=(Z) (T)nRi2, -N(C=(Z) (T)nRi2J2, N3, CN, OCN, SCN, OSO3Ri2, OSO2Ri2, OPO3Ri2R' 12, OPO2RX2R' 12, S(O)Ri2, S(O)2R12, S(O)2OR12, PO3R12R' 12, NR12NR'i2R" 12, SNR12R'12, NR12SR' 12, SSR12 and R12, or is an oxo group, =S, =NOR12 or =CRi2R'12 and X6' or X7'' , respectively, is absent; and each of X6' and X7' ' is independently selected from the group hydrogen, CN, optionally substituted alkyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted aralkyl, and optionally substituted acyl;
X5 is selected from the group consisting of hydrogen, CN, -C=(Z) (T)nRn, S(O)Rn, S(O)2R11, S(O)2ORn, PO3RiiR'ii, optionally substituted alkyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted aralkyl, and optionally substituted acyl;
Xi' i X2' t X3' and X4' 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 X1 and X2, X2 and X3, X3 and X4' , X4' 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 R1 and X1, R2 and X1, R1 and X2, R2 and X2, R1 and X3, R2 and X3, R1 and X4, R2 and X4, R1 and X4' , R2 and X4' , X1 and X2, X2 and X3, X2 and X4, X3 and X4, X1 and X1' , 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 and n are independently zero or one and Y, Z and T are independently selected from the group consisting of 0, S, and NR10 p is zero, one or two;
R3, R'3, R"3, R4, R'4, R"4, R5, R'5, R"5, R6, R'6, R'' 6, R7, R8, R9, R' 9, R10, R11, R'n, R12, R' 12 and R"12 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=, NR7 and -(Y)1nC=(Z) (T)n-, optionally substituted alkenyl which may be interrupted by one or more heteroatoms or functional groups selected from the group consisting of 0, S, -N=, NR7 and -(Y)1nC=(Z) (T)n-, optionally substituted aryl, optionally substituted heterocyclic, 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)1nC=(Z) (T)n-, optionally substituted acyl and a carbohydrate moiety; with the proviso that at least two of X1, X2, X3, X4, XQ and X7 are other than hydrogen or a group linked to the ring through a carbon-carbon bond; or a pharmaceutically acceptable salt thereof; 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 exσipients 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 Staphylococcus including Staphylococcus aureus and S. aureus (Coagulas-negative) , Streptococcus species, Enterococci species, Mycobacterium including Mycobacterium tuberculosis, M. avium intracellulare, M. fortuitum, M. abscessus and rapid growing atypical Mycobacterial strains and Nocardia, particularly Nocardia asteroid.es and N. nova. 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) :
Figure imgf000026_0001
wherein 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 0, S, -N=, NR7 and -(Y)111C=(Z) (T)n-, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted acyl and a carbohydrate moiety; or R1 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;
A is selected from the group consisting of O, S, SO, SO2, Se, Te, NR8, CR9R' 9, N->0, and C(O) ;
Xi is selected from the group consisting of OR3, SR3, NR3R'3, hydrogen, halogen, -(Y)1nC=(Z) (T)nR3, - N(C=(Z) (T)nR3J2, N3, CN, OCN, SCN, OSO3R3, OSO2R3, OPO3R3R'3, OPO2R3R'3, S(O)R3, S(O)2R3, S(O)2OR3, PO3R3R'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, or X1 is C=(Z) and R2 is a bond thereto so as to form a cyclic moiety -C=(Z)NR1S (O)p-; X2 is selected from the group consisting of OR4, SR4, NR4R'4, hydrogen, halogen, - (Y)mC=(Z) (T)nR4, - N(C=(Z) (T)nR4J2, N3, CN, OCN, SCN, OSO3R4, OSO2R4, OPO3R4R'4, OPO2R4R'4/ S(O)R4, S(O)2R4, S(O)2OR4, PO3R4R' 4, NR4NR'4R''4, SNR4R'4, NR4SR'4, SSR4 and R4, or is an oxo group, =S, =NOR4 or =CR4R'4 and X2 1 is absent;
X3 is selected from the group consisting of. OR5, SR5, NRsR's, hydrogen, halogen, -(Y)1nC=(Z) (T)nR5, - N(C=(Z) (T)nR5)2, N3, CN, OCN, SCN, OSO3R5, OSO2R5, OPO3R5R'5, OPO2R5R'5, S(O)R5, S(O)2R5, S(O)2OR5, PO3R5R'5, NR5NR'5R''5,
SNR5R'5r NR5SR'5, SSR5 and R5, or is an oxo group, =S, =N0R5 or =CR5R'5 and X3' is absent;
X4 is selected from the group consisting of OR6, SR6, NR6R'6, hydrogen, halogen, -(Y)1nC=(Z) (T)nR6, - N(C=(Z) (T)nRg)2, N3, CN, OCN, SCN, OSO3R6, OSO2R6, OPO3R6R'6, OPO2R6R' 6, S(O)R6, S(O)2R6, S(O)2OR6, PO3R6R' 6, NR6NR' 6R"6, SNR6R' s, NR6SR' 6, SSR6 , R6, or is an oxo group, =S, =N0R6 or =CR6R' 6 and X4' is absent, and -(CX6X6')VCX7X7'X7'' wherein v is an integer in the range of 0 to 6 inclusive and, when v is in the range of 1 to 6, may include a double bond or epoxide group, and each of X6, X7 and X7' is independently selected from the group consisting of ORi2, SRi2, NRi2R' i2, hydrogen, halogen, -(Y)nC=(Z) (T)nR12, -N(C=(Z) (T)nRi2J2, N3, CN, OCN, SCN, OSO3R12, OSO2R12, OPO3R12R'12, OPO2Ri2R' 12, S(O)Ri2, S(O)2Ri2, S(O)2ORi2, PO3Ri2R'12/ NR12NR' 12R"12,
SNR12R' 12, NR12SR'12, SSR12 and R12, or is an oxo group, =S, =N0R12 or =CR12R'12 and X6' or X7' ' , respectively, is absent; and each of X6' and X7' ' is independently selected from the group hydrogen, CN, optionally substituted alkyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted aralkyl, and optionally substituted acyl;
X5 is selected from the group consisting of hydrogen, CN, -C=(Z) (T)nR11, S(O)R11, S(O)2R11, S(O)2OR11, PO3Ri1R' ii, optionally substituted alkyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted aralkyl, and optionally substituted acyl; X1' , X2' , X3' and X4' 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 X31 X3 and X4' , X4' 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 R1 and X1, R2 and Xi, Ri and X2, R2 and X2, Ri and X3, R2 and X3, Ri and X4, R2 and X4, Rx and X4' , R2 and X4' , Xx and X2, X2 and X3, X2 and X4, X3 and X4, Xi and X1' , 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 and n are independently zero or one and Y, Z and T are independently selected from the group consisting of O, S, and NRi0 p is zero, one or two; R3, R'3/ R"3, R4, R'4, R"4, R5, R's, R"s, R6, R'e,
R'' 6, R7, R8, R9, R' 9, Rio, Rn, R' n, Ri2, R'12 and R' '12 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 0, S, -N=, NR7 and -(Y)1nC=(Z) (T)n-, optionally substituted alkenyl which may be interrupted by one or more heteroatoms or functional groups selected from the group consisting of 0, S, -N=, NR7 and -(Y)1nC=(Z) (T)n-, optionally substituted aryl, optionally substituted heterocyclic, 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 0, S, -N=, NR7 and -(Y)1nC=(Z) (T)n-, optionally substituted acyl and a carbohydrate moiety; with the proviso that at least two of Xi, X2, X3, X4, Xe and X7 are other than hydrogen or a group linked to the ring through a carbon-carbon bond; or a pharmaceutically acceptable salt thereof; 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 effective 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 effects. 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, hydroxypropylmethylσellulose, 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.Ig 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 Ig 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) :
Figure imgf000032_0001
wherein 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)1nC=(Z) (T)n-, optionally substituted alkenyl which may be interrupted by one or more heteroatoms or functional groups selected from the group consisting of 0, S, -N=, NR7 and -(Y)1nC=(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 0, S, -N=, NR7 and - (Y)mC=(Z) (T)n-, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted acyl and a carbohydrate moiety; or R1 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;
A is selected from the group consisting of O, S,, SO, SO2, Se, Te, NR8, CR9R'9, N->O, and C(O);
Xi is selected from the group consisting of OR3, SR3, NR3R'3, hydrogen, halogen, - (Y)mC=(Z) (T)nR3, -
N(C=(Z) (T)nR3J2, N3, CN, OCN, SCN, OSO3R3, OSO2R3, OPO3R3R'3, OPO2R3R' 3, S(O)R3, S(O)2R3, S(O)2OR3, PO3R3R'3, NR3NR'3R" 3, SNR3R'3, NR3SR'3, SSR3 and R3, or is an oxo group, =S, =N0R3 or =CR3R' 3 and Xi' is absent, or Xi is C=(Z) and R2 is a bond thereto so as to form a cyclic moiety -C=(Z)NR1S(O)P-;
X2 is selected from the group consisting of OR4, SR4, NR4R'4, hydrogen, halogen, - (Y)mC=(Z) (T)nR4, - N(C=(Z) (T)nR4)2, N3, CN, OCN, SCN, OSO3R4, OSO2R4, OPO3R4R' 4, OPO2R4R' 4, S(O)R4, S(O)2R4, S(O)2OR4, PO3R4R'4, NR4NR'4R' ' 4, SNR4R' 4, NR4SR' 4, SSR4 and R4, or is an oxo group, =S, =N0R4 or =CR4R' 4 and X2' is absent;
X3 is selected from the group consisting of OR5, SR5, NR5R'5, hydrogen, halogen, -(Y)nC=(Z) (T)nR5, - N(C=(Z) (T)nRs)2, N3, CN, OCN, SCN, OSO3R5, OSO2R5, OPO3R5R'5, OPO2R5R'5, S(O)R5, S(O)2R5, S(O)2OR5, PO3R5R'5, NR5NR'5R"5,
SNR5R'5, NR5SR'5, SSR5 and R5, or is an oxo group, =S, =NOR5 or =CR5R'5 and X3' is absent;
X4 is selected from the group consisting of OR5, SR6, NR6R' 6, hydrogen, halogen, - (Y)mC=(Z) (T)nR6, - N(C=(Z) (T)nRs)2, N3, CN, OCN, SCN, OSO3R6, OSO2R6, OPO3R6R'6, OPO2R6R' 6, S(O)R6, S(O)2Re, S(O)2OR6, PO3R6R' 6, NR6NR' 6R"6, SNR6R' 6, NR6SR' 6, SSR6 , R6, or is an oxo group, =S, =N0R6 or =CR6R'6 and X4' is absent, and -(CX6X6')VCX7X7'X7" wherein v is an integer in the range of 0 to 6 inclusive and, when v is in the range of 1 to 6, may include a double bond or epoxide group, each of X6, X7 and X7' is independently selected from the group consisting of OR12, SRi2, NR12R']^, hydrogen, halogen, -(Y)1nC=(Z) (T)nR12, -N(C=(Z) (T)nR12) 2, N3, CN, OCN, SCN, OSO3R12, OSO2R12, OPO3R12R'12, OPO2R12R' 12, S(O)R12, S(O)2R12, S(O)2OR12, PO3R12R'12, NR12NR'12R"12, SNR12R'i2, NR12SR' 12, SSR12 and R12, or is an oxo group, =S, =N0Ri2 or =CR12R' 12 and X6' or X7'' , respectively, is absent; and each of X6' and X7' ' is independently selected from the group hydrogen, CN, optionally substituted alkyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted aralkyl, and optionally substituted acyl; X5 is selected from the group consisting of hydrogen, CN, -C=(Z) (T)nR11, S(O)R11, S(O)2R11, S(O)2OR11, PO3Ri1R'].]., optionally substituted alkyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted aralkyl, and optionally substituted acyl;
Xi' , X2' , X3' and X4' 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 X1 and X21 X2 and X3, X3 and X4' , X4' 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 Ri and X1, R2 and Xi, Ri and X2, R2 and X2, Rx and X3, R2 and X3, Rx and X4, R2 and X4, Ri and X4' , R2 and X4' , X1 and X2, X2 and X3, X2 and X4, X3 and X4, X1 and X1' , 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 and n are independently zero or one and Y, Z and T are independently selected from the group consisting of 0, S, and NRi0 p is zero, one or two;
R3, R'3, R"3, R4, R'β/ R"4, R5, R's, R"s, R6, R'e, R'' 6, R7, R8, R9, R' g, R10, Rn, R'n, R12, R' 12 and R' ' 12 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=, NR7 and -(Y)1nC=(Z) (T)n-, optionally substituted alkenyl which may be interrupted by one or more heteroatoms or functional groups selected from the group consisting of 0, S, -N=, NR7 and -(Y)mC=(Z) (T)n-, optionally substituted aryl, optionally substituted heterocyclic, 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 0, S, -N=, NR7 and -(Y)1nC=(Z) (T)n-, optionally substituted acyl and a carbohydrate moiety; with the proviso that at least two of Xi, X2, X3, X4, X6 and X7 are other than hydrogen or a group linked to the ring through a carbon-carbon bond; or a pharmaceutically acceptable salt thereof.
Advantageously, although not limited to, the microorganism is selected from the group consisting of Staphylococcus including Staphylococcus aureus and S. aureus (Coagulase-negative) , Streptococcus species,
Enterococcl species, Mycobacterium including Mycobacterium tuberculosis, M. avium lntracellulare, M. fortultum, M. abscessus and rapid growing atypical Mycobacterial strains and Nocardla, particularly Nocardia asterold.es and N. nova.
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 scheme employed to prepare compounds in accordance with preferred embodiments of the invention is now described in more detail. The synthesis of protected (compounds 2-5; Examples 1-4) and deprotected (compounds 6-8; Examples 5-7) galactopyranosyl derivatives is shown in Scheme 1. For the preparation of these examples, l-S-acetyl-2,3,4,6-tetra-O-acetyl-l-thio-β-D- galactopyranose (compound 1; Holland et al. , 1967) was prepared according to known literature methods and is shown in Scheme 1 without modification. Similarly prepared, from l-S-acetyl-2,3,4,6-tetra-O-acetyl-l-thio-β- D-glucopyranose (compound 9; Holland et al., 1967) as shown in Scheme 2, were the protected (compounds 10 and 11; Examples 8 and 9) and deprotected (compounds 12 and 13; Examples 10 and 11) glucopyranosyl derivatives. All new compounds gave the expected spectroscopic data.
Figure imgf000036_0001
1 2 R1 = R2 = C8H17 6 R1 = R2 = C8H17
3 R1 = R2 = C2H4OC8H17
Figure imgf000036_0002
4 Rt = R2 = C8H17 7 R1 = R2 = C8H17
5 R1 = R2 = C2H4OC8H17 8 R1 = R2 = C2H4OC8H1 7 Scheme 1
Reagents and Conditions: a) BrCH(COOEt)2, HNR1R2, DMF, THF, or
MeOH, rt, 24 h to 7 d; b) MCPBA, CH2Cl2, reflux, 20 h; c) NaOMe, MeOH, rt, 2 h, N2.
Figure imgf000037_0001
12 R1 = R2 = C8H17
13 R1 = R2 = C2H4OC8H17
Scheme 2 Reagents and Conditions: a) BrCH(COOEt)2, HNR1R2, DMF, THF, or MeOH, rt, 24 h to 7 d; b) MCPBA, CH2Cl2, reflux, 20 h; c) NaOMe, MeOH, rt, 2 h, N2.
General procedure for the oxidation of sulfenamides to the corresponding sulfonamides:
To a solution of the protected sulfenamide (0.5 mmol) in dichloroitiethane (20 mL) is added meta- chloroperoxybenzoic acid (3 equiv.) and the mixture is heated under reflux. Upon completion of the reaction, the reaction mixture is diluted to 60 mL with EtOAc and quenched with saturated aqueous sodium hydrogen carbonate. The organic phase is separated, dried, filtered, and concentrated under reduced pressure, and the residue is chromatographed on silica.
General procedure for the deprotection of acetate protecting groups: To a solution of the acetylated derivative (0.5 mmol) in dry MeOH (10 mL) under an atmosphere of N2 is added one equivalent of sodium methoxide (IM solution in dry MeOH) . 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, the solvent removed under reduced pressure, and the residue purified by column chromatography on silica.
Example 1
N,JV-Dioctyl-S- (2,3,5,6-tetra-O-acetyl-β-D- galactopyranosyl) sulfenamide (2; Ri = R2 = C8Hi7) • l-S-Acetyl-2,3,5, 6-tetra-O-acetyl-l-thio-β-D- galactopyranose (1) (1.0 g, 2.5 mmol) was dissolved in dry THF (25 mL) under an inert atmosphere. Diethylbromomalonate (1.3 mL, 7.5 mmol) and N,N- dioctylamine (6 mL, 20 mmol) were added and the solution stirred at room temperature for 7 days . The reaction mixture was concentrated and the residue purified by flash chromatography on silica (1:9 —» 1:2 EtOAc/hexanes) to give the desired product (0.63 g, 42%) . Rf 0.56 (1:2 EtOAc/hexanes) . 1H NMR (300 MHz, CDCl3) : δ 0.87 (6H, m, CH3) , 1.10-1.30 (2OH, m, CH2) , 1.52 (4H, m, CH2) , 1.94, 2.00, 2.03, 2.11 (4 x 3H, 4 x s, 4 x OAc), 2.81 (4H, m,
CH2) , 3.93 (IH, dt, J4,5 0.9, J5,6 7.2 Hz, H-5) , 4.17 (2H, m, H-6, H-6' ) , 4.67 (IH, m, H-2) , 5.00 (2H, m, H-3 and H-I) , 5.42 (IH, d, J4/3 1.5 Hz, H-4) .
Example 2
N,N-Di (2-octyloxyβthyl) -N-trityl amine:
To a solution of N-trityl-diethanolamine (3.0 g, 8.6 mmole) in dry THF (40 mL) under an atmosphere of nitrogen was added tosyl-n-octanol (9.8 g, 34.4 mmol) and finely ground potassium hydroxide (5.8 g, 103 mmole) . The solution was refluxed for 20 h then cooled to room temperature. The reaction mixture was diluted with EtOAc, washed twice with saturated NaCl, water and the organic phase dried and concentrated. The residue was purified by column chromatography on silica (10% EtOAc/hexanes) to give iMV-V-di (2-octyloxyethyl) -iV-trityl amine (4.92 g, 83%) . Rf 0.65 (10% EtOAc/hexanes) . 1H NMR (300 MHz, CDCl3) : δ 0.87 (6H, t, J 6.0 Hz, CH3) , 1.28 (20H, m, CH2), 1.55 (4H, m, CH2), 2.54 (4H, t, J 6.0 Hz, EtO) , 3.38 (4H, t, J 6.0 Hz, O-octyl) , 3.57 (4H, t, J 6.0 Hz, EtO), 7.10-7.60 (15H, m, trityl ArH) .
N,N-Di (2-octyloxyethyl)amine:
To a solution of N,N-d± (2-octyloxyethyl) -W-trityl amine (3.70 g, 6.5 mmole) in a mixture of CH2Cl2 (10 mL) and MeOH (25 mL) , was added 5% HCl (aq.) (15 mL) and the solution stirred for 5 min. The reaction mixture was diluted with CH2Cl2 and washed twice with saturated aqueous sodium bicarbonate, water and the organic phase dried (sodium sulphate) and concentrated. The residue was purified by column chromatography on silica (1:1 EtOAc/hexanes → 15% MeOH/EtOAc) to give N,.V-di(2- octyloxyethyl)amine (1.76 g, 83%) . R£ 0.35 (10%
MeOH/EtOAc) . 1H NMR (300 MHz, CDCl3) : δ 0.87 (6H, t, J 6.0 Hz, CH3) , 1.26 (20H, m, CH2) , 1.53 (4H, m, CH2), 2.00 (IH, bs, NH) 2.79 (4H, t, J 6.0 Hz, EtO) , 3.41 (4H, t, J 6.0 Hz, O-octyl) , 3.53 (4H, t, J 6.0 Hz, EtO) .
N,27-Di (2-octyloxyethyl) -S- (2,3,5, 6-tetra-O-acetyl-β-D- galactopyranosyl) sulfenamide (3; Ri = R2 = C2H4OC8Hi7) : l-S-acetyl-2,3,5,6-tetra-O-acetyl-l-thio-β-D- galactopyranose (1) (399 mg, 0.98 mmol) was dissolved in methanol (10 mL) . Diethylbromomalonate (280 μL, 1.5 mmol) and N,iV-di(2-octyloxyethyl)amine (824 mg, 2.5 mmol) were added and the reaction stirred at room temperature for 16 days . The reaction was concentrated and the residue purified by column chromatography on silica (1:3 EtOAc/hexanes) to give the desired product (428 mg, 63%) . Rf 0.18 (3:1 hexanes/EtOAc) . 1H NMR (300 MHz, CDCl3) : δ 0.87 (6H, t, CH3) , 1.30 (2OH, m, octyl) , 1.55 (4H, m, octyl) , 1.97, 2.04, 2.06, 2.14 (4 x 3H, 4 x s, 4 x OAc) , 3.15 (4H, m, EtO), 3.40 (4H, t, J 6.0 Hz, O-octyl) , 3.56 (4H, t, J 6.0 Hz, EtO), 3.89 (IH, dt, -J4,5 0.9, J5,6 7.2 Hz, H-5) , 4.10 (2H, m, H-6, H-6' ) , 4.69 (IH, m, H-2) , 5.05 (2H, m, H-3 and H-I) , 5.40 (IH, d, J4,3 1.5, H-4) .
Example 3
W,27-Dioctyl-S- (2,3,5, 6-tetra-O-acetyl-β-D- galactopyranosyl) sulfonamide (4; Ri = R2 = C8Hi7) :
-V^iV-Dioctyl-S- (2,3,5,6-tetra-O-acetyl-β-D- galactopyranosyl) sulfenamide (2) was oxidised according to the general procedure and the residue purified by column chromatography on silica (EtOAc) to give the desired product. Yield: 26%. Rf 0.19 (3:1 hexanes/EtOAc) . 1H NMR (300 MHz, CDCl3) : δ 0.80 (6H, m, CH3) , 1.10-1.30 (2OH, m, CH2) , 1.50 (4H, m, CH2) , 1.94, 1.98, 2.02, 2.13 (4 x 3H, 4 x s, 4 x OAc) , 3.1 and 3.3 (each 2H, m, CH2) , 3.95 (IH, dd, J4,5 0.9, J5,6 6.9 Hz, H-5), 4.09 (2H, m, H-6, H-6'), 4.38 (IH, d, J1,2 9.9 Hz, H-I) , 5.05 (IH, dd, J3,43.3, <J2/3 9.9 Hz, H-3) , 5.39 (IH, d, J3,4 3.3 Hz, H-4) , 5.52 (IH, app. t, J2,3 9.9, Jlr2 9-9 Hz/ H-2) .
Example 4
N,W-Di (2-octyloxyethyl) -S- (2,3,5,6-tetra-O-acetyl-β-D- galactopyranosyl) sulfonamide (5; R1 = R2 = C2H4OC8Hi7) : N,N-Di (2-octyloxyethyl) -S- (2,3,5,6-tetra-O- acetyl-β-D-galactopyranosyl) sulfonamide (3) was oxidised according to the general procedure and the residue purified by column chromatography on silica (2:1 hexanes/EtOAc) to give the desired product. Yield: 95%. JRf 0.45 (3:1 hexanes/EtOAc) . 1H NMR (300 MHz, CDCl3) : δ 0.87 (6H, t, CH3) , 1.30 (2OH, m, octyl) , 1.55 (4H, m, octyl) , 1.97, 2.04, 2.06, 2.14 (4 x 3H, 4 x s, 4 x OAc) , 3.30-3.80 (12H, m, 2 x EtO and O-octyl), 3.97 (IH, dt, Ji)S 0.9, J5,6 6.0 Hz, H-5), 4.13 (2H, m, H-6, H-6'), 4.75 (IH, d, Ji,2 9.6 Hz, H-I) , 4.70 (IH, dd, J2,3 9.9, J3,4 3.3 Hz, H- 3), 5.46 (IH, dd, J3,4 3.3, J4,5 0.9 Hz, H-4) , 5.61 (IH, app. t, Ji,2 9.6, J2,3 9.9 Hz, H-2) . Example 5
N,N~O±octγl-S- (β-D-galactopyranosyl) sulfenamide (6 ; R1 = R2
= C8H17) :
N,.NHDioctyl-S- (2,3,5, 6-tetra-O-acetyl-β-D- galactopyranosyl) sulfenamide (2) was de-O-acetylated according to the general procedure to give the desired product. Yield: 74%. Rf 0.38 (EtOAc) . 1H NMR (300 MHz, CD3OD) : δ 0.91 (6H, m, CH3), 1.20-1.40 (2OH, m, CH2), 1.59 (4H, m, CH2), 2.85 (4H, m, CH2), 3.48 (IH, dd, J3,4 3.3, J2,3 9.3 Hz, H-3) , 3.51 (IH, m, H-5) , 3.68 (IH, app. t J2,3 9.3, Ji,2 9.3 Hz, H-2) , 3.72 (2H, m, H-6, H-6' ) , 3.91 (IH, d, J3,4 2.7, H-4) , 4.39 (IH, d, J1,2 9.3, H-I) .
Example 6 -V^N-Dioctyl-S- (β-D-galactopyranosyl) sulfonamide (7; R1 = R2 = CsH17) :
N,JV-Dioctyl-S- (2,3,5,6-tetra-O-acetyl-β-D- galactopyranosyl) sulfonamide (4) was de-O-acetylated according to the general procedure to give the desired product. Yield: 80%. Rf 0.26 (EtOAc) . 1H NMR (300 MHz, CD3OD) : δ 0.90 (6H, m, CH3) , 1.20-1.40 (2OH, m, CH2) , 1.59 (4H, m, CH2) , 3.20 and 3.35 (each 2H, m, CH2) , 3.55 (IH, dd, J3,4 3.3, J2,3 9.3 Hz, H-3) , 3.51 (IH, m, H-5) , 3.72 (2H, m, H-6, H-61) , 3.91 (IH, d, J3,A 3.3, H-4), 3.99 (IH, app. t, J2,3 9.3, J1,, 9.3, H-2) , 4.31 (IH, d, J1,2 9.3, H-I) .
Example 7
N,N-Oi. (2-octyloxyethyl) -S- (β-D-galactopyranosyl) sulfonamide (8; R1 = R2 = C2H4OC8H17) :
N,N-Oi (2-octyloxyethyl) -S- (2,3,5,6-tetra-O- acetyl-β-D-galactopyranosyl) sulfonamide (5) was de-O- acetylated according to the general procedure to give the desired product. Yield: 82%. R£ 0.34 (EtOAc) . 1H NMR (300 MHz, CD3OD) : δ 0.87 (6H, t, CH3) , 1.30 (2OH, m, octyl) , 1.55 (4H, m, octyl) , 3.40-3.80 (16H, m, 2 x EtO, O-octyl, H-3, H-5, H-6 and H-61) , 3.88 (IH, d, J3,4 3.0 Hz, H-4) , 3.99 (IH, app. t, J2, 3 9.3, J1, 2 9-3 Hz, H-2) , 4.43 (IH, d, J1, 2 9.3 Hz, H-I) .
Example 8 N,N-Diocfcyl-S- (2,3,5, 5-tetra.-O-acetyl-/?-!>- glucopyranosyl)sulfenamide: l-S-Acetyl-2,3,5,6-tetra-O-acetyl-l-thio-β-D- glucopyranose (9) (2.31 g, 5.69 mmol) was dissolved in MeOH (100 mL) . Diethylbromomalonate (1.46 mL, 8.54 mmol) and 27,N-dioctylamine (5.10 mL, 17.10 mmol) were added and the reaction stirred at room temperature for 4 hours. The reaction was concentrated and the residue purified by column chromatography on silica (4:1 hexanes/EtOAc) to give the desired product (2.75 g, 80%) . Bf 0.18 (4:1 hexanes/EtOAc) . 1H NMR (300 MHz, CDCl3) : δ 0.87 (6H, t, 2 x CH3) , 1.20-1.32 (2OH, m, 10 x CH2) , 1.48-1.60 (4H, m, 2 x CH2) , 2.00, 2.02, 2.05, 2.08 (4 x 3H, 4 x s, 4 x COCH3) , 2.85-2.90 (4H, m, 2 x CH2), 3.64-3.71 (IH, m, H-5) , 4.09- 4.29 (2H, obscured m, H-6, H-6' ) , 4.63 (IH, d, J1,2 10.2 Hz, H-I) , 4.82-4.92 (IH, m, H-2) , 5.03 (IH, t, J4,3 ~ J4,5 9.6 Hz, H-4) , 5.23 (IH, t, J3,2 ~ J3,4 9.3 Hz, H-3) .
N,W-Dioctyl-S- (2,3,5,6-tetra-O-acetyl-β-D- glucopyranosyl) sulfonamide (10; R1 = R2 = CsH1V) : N,N-Dioctyl-S- (2,3,4, 6-tetra-O-acetyl-β-D- glucopyranosyl) sulfenamide was oxidized according to the general procedure to give the desired product. Yield: 42%. Ef 0.21 (3:1 hexanes/EtOAc) . 1H NMR (300 MHz, CDCl3) : δ 0.87 (6H, t, CH3), 1.21-1.34 (2OH, m, 10 x CH2), 1.44-1.63 (4H, m, 2 x CH2) , 2.01, 2.03, 2.06, 2.08 (4 x 3H, 4 x s, 4 x COCH3) , 3.09-3.16 (2H, m, CH2) , 3.30-3.40 (2H, m, CH2) , 3.70-3.76 (IH, m, H-5) , 4.18-4.22 (2H, m, H-6, H- 6') , 4.44 (IH, d, J1,2 9.6 Hz, H-I) , 5.08 (IH, t, J4,3 ~ J4,5 9.6 Hz, H-4) , 5.27 (IH, t, J3,2 ~ J3,4 9.3 Hz, H-3) , 5.39 (IH, t, J2/1 ~ J2,3 9.6, H-2) . Example 9
N,N-Di(2-octyloxyethγl) -S- (2,3,5,6-tβtra-O-a.cetyl-β-D- glucopyra.nosyl)sulfenaxnide: l-S-Acetyl-2,3,5, 6~tetra-O-acetyl-l-thio-β-D- glucopyranose (9) (446 mg, 1.1 πunol) was dissolved in methanol (20 mL) . Diethyl bromomalonate (280 μL) and di(2- octyloxyethyl)amine (904 mg) were added and the reaction stirred at room temperature for 16 h. The reaction was concentrated and the residue purified by column chromatography on silica (3:1 hexanes/EtOAc) to give the desired product (557 mg, 73%) . R£ 0.18 (3:1 hexanes/EtOAc) . 1H NMR (300 MHz, CDCl3) : δ 0.87 (6H, t, CH3) , 1.20-1.35 (2OH, m, 10 x CH2) , 1.50-1.60 (4H, m, 2 x CH2) , 1.99, 2.02, 2.04, 2.07 (4 x 3H, 4 x s, 4 x COCH3) , 3.11-3.21 (4H, m, 2 x NCH2 (ethyl)) , 3.40 (4H, t, 2 x OCH2
(octyl) ) , 3.56 (4H, t, 2 x CH2O (ethyl)) , 3.64-3.71 (IH, m, H-5) , 4.11 (IH, dd (obscured) , H-6) , 4.23 (IH, dd, J6, ,5 5.1, J6, /6 12.3 Hz, H-6') , 4.63 (IH, d, J1/2 10.5 Hz, H-I) , 4.91 (IH, dd, J2/3 9.0, J2/1 10.5, H-2) , 5.04 (IH, t, J4/3 ~ J4, 5 9.6 Hz, H-4) , 5.23 (IH, t, J3, 2 ~ J3, 4 9.3 Hz, H-3) .
N,N-D± (2-octyloxyethyl) -S- (2,3,4, 6-tetra-O-acetyl-β-D- glucopyranosyl) sulfonamide (11; R1 = R2 = C2H4OC8H17) : N,N-O± (2-octyloxyethyl) -S- (2,3,4, 6-tetra-O- acetyl-β-D-glucopyranosyl) sulfenamide was oxidised according to the general procedure to give the desired product. Yield: 95%. R£ 0.27 (2:1 hexanes/EtOAc) . 1H NMR (300 MHz, CDCl3) : δ 0.88 (6H, t, CH3) , 1.20-1.37 (2OH, m, 10 x CH2) , 1.52-1.62 (4H, m, 2 x CH2) , 2.01, 2.03, 2.05, 2.09 (4 x 3H, 4 x s, 4 x COCH3) , 3.33-3.78 (13H, m, 2 x NCH2 (ethyl) , 2 x OCH2 (octyl) , 2 x CH2O (ethyl) , H-5) , 4.13-4.23 (2H, m, H-6, H-6'), 4.77 (IH, d, J1/2 9.6 Hz, H- 1), 5.07 (IH, t, J4,3 ~ J4,5 9.6 Hz, H-4), 5.24 (IH, t, J3,2 ~ J3,4 9.3 Hz, H-3), 5.43 (IH, t, J2,3 ~ J2,! 9.3, H-2) .
Example 10
NVN-Dioctyl-S- (β-D-glucopyranosyl) sulfonamide (12; R1 = R2
= C8H17) : jV,iV-Dioctyl-S- (2,3,4, 6-tetra-O-aσetyl-β-D- glucopyranosyl)sulfonamide (10) was de-O-acetylated according to the general procedure to give the desired product. Yield: 75%. R£ 0.21 (EtOAc) . 1H NMR (300 MHz, CD3OD) : 6 0.91 (6H, t, CH3), 1.25-1.38 (2OH, br. s, 10 x CH2), 1.51-1.67 (4H, m, 2 x CH2) , 3.15-3.28 (2H, m, CH2) , 3.32-3.44 (5H, obscured m, CH2, H-3, H-4, H-5,) , 3.63-3.69 (2H, m, H-2, H-6) , 3.88 (IH, dd, J6, ,5 1.8, J6,,6 12.3 Hz, H- 6') , 4.32 (IH, d, J1,2 9.3 Hz, H-I) .
Example 11 iV,iY-Di (2-octyloxyethyl) -S- (β-D-glucopyranosyl) sulfonamide (13; R1 = R2 = C2H4OC8H17) : JNViV-Di (2-octyloxyethyl) -S- (2,3,4,6-tetra-O-acetyl-β-D- glucopyranosyl) sulfonamide (11) was de-O-acetylated according to the general procedure to give the desired product after purification by chromatography on silica (EtOAc) . Yield: 89%. 1H NMR (300 MHz, CD3OD) : δ 0.91 (6H, t, CH3) , 1.23-1.42 (2OH, m, 10 x CH2) , 1.52-1.63 (4H, m, 2 x CH2) , 3.32-3.71 (17H, m, 2 x NCH2 (ethyl) , 2 x OCH2
(octyl) , 2 x CH2O (ethyl) , H-2, H-3, H-4, H-5, H-6) , 3.89 (IH, dd, J6, ,5 1-2, J6',6 12.0 Hz, H-6') , 4.51 (IH, d, J1,2 9.6, H-I) .
Biological Data
Example 12
Inhibition of various bacteria by compound (6) where R1 = R2 = C8H17 is described in Table 1. The biological data were determined by a Zone Inhibition Assay method. The compound was 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 0C overnight (or for 3 days for M. smegiaat±s) , the zone of inhibition was measured using an arbitrary scale: +++ = relatively large zone of inhibition, - = no zone of inhibition. Table 1
Figure imgf000045_0001
Example 13
Inhibition of Bacillus subtilis by compounds (7) and (12) is described in Table 2. The biological data were determined by Minimum Inhibitory Concentration (MIC) Serial Dilution Assay. Standard solutions of the compounds were prepared in MeOH. Assays were carried out in a final volume of 2 mL LB Broth with a maximum 2% MeOH concentration, in 10 mL Falcon tubes with 5 μL of saturated culture. Tubes were incubated at 37 °C with shaking for 18 to 20 hours. The MICBO was then determined as the concentration in which there was 80% or greater reduction in growth as compared to the control.
Table 2
Figure imgf000045_0002
Example 14
MIC data against Enterococcus and Streptococcus spp. for compounds (6) , (7) , (8) , (12) and (13) is described in Table 3. The MIC assays were carried-out according to NCCLS (National Committee for Clinical Laboratory Standards) guidelines. Standard solutions of the compounds were prepared in DMSO. Assays were carried out in Mueller Hinton II Broth in 96-well microdilution plates with a final cell concentration of 5 x 105 colony-forming- units/ml. Plates incubated at 35°C for approximately 20 h. The MIC was recorded as the lowest concentration of drug that inhibited visible growth of the organism.
Table 3
Figure imgf000046_0001
ND = not determined
Industrial Applicability
The compounds of general formula (I) are useful as pharmaceutical agents, particularly anti-microbial agents .
References
The disclosure of the following documents is incorporated herein by reference:
von Itzstein, M.; Wu, W-Y.; Kok, G.B.; Pegg,
M.S.; Dyason, J.C; Jin, B.; Phan, T.V.; Smythe, M.L.; White, H.F.; Oliver, S.W.; Colman, P.M.; Varghese, J.N. ; Ryan, D.M.; Woods, J.M. ; Bethell, R.C; Hotham, V.J.; Cameron, J.M. ; Penn, CR. Nature 1993, 363, 418-423. Kok, G.B.; Campbell, M.; Mackey, B.; von
Itzstein, M. J. Chem. Soc. r Perkin Trans. 1 1996, 2811- 2815.
Fazli, A.; Bradley, S.J.; Kiefel, M.J.; Jolley, C; Holmes, I.H.; von Itzstein, M. J. Med. Chem. 2001, 44, 3292-3301.
Ernst, B.; Hart, G. W.; Sinay, P. (Eds) , Carbohydrates in Chemistry and Biology, Wiley-VCH, Weinheim, 2000, VoIs 1 - 4.
Chapleur, Y. Carbohydrate Mimics, Wiley-VCH, Weinheim, 1998.
Lillelund, V.H.; Jensen, H.H.; Liang, X.; BoIs, M. Chem. Rev. 2002, 102, 515-553.
Craine, L.; Raban, M. Chem.Rev. 1989, 89, 589- 712. Koval', I.V. RVLSS. Chem. Rev. 1996, 65, 421-440.
Illyes, T. -Z.; Molnar-Gabor, D.; Szilagyi, L. Carbohydr. Res. 2004, 339, 1561-1564.
Glass, R.S.; Swedo, R.J. Synthesis 1977, 798- 800. Haake, M.; Gebbing, H.; Benack, H. Synthesis
1979, 97.
Stick, R.V. Carbohydrates - The sweet molecules of life, Academic Press, San Diego, 2001.
Holland, CV. ; Horton, D.; Miller, M.J.; Bhacca, N.S. J. Org. Chem. 1967, 32, 3077-3086.

Claims

Claims :
1. A compound of the general formula (I) :
Figure imgf000048_0001
wherein 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)1nC=(Z) (T)n-, optionally substituted alkenyl which may be interrupted by one or more heteroatoms or functional groups selected from the group consisting of 0, S, -N=, NR7 and -(Y)1nC=(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 0, S, -N=, NR7 and ~(Y)mC=(Z) (T)n-, optionally substituted heterocyclic, 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; A is selected from the group consisting of O, S,
SO, SO2, Se, Te, NR8, CR9R' 9, N->O, and C(O);
Xi is selected from the group consisting of OR3, SR3, NR3R'3, hydrogen, halogen, - (Y)1nC=(Z) (T)nR3, - N(C=(Z) (T)nR3)2, N3, CN, OCN, SCN, OSO3R3, OSO2R3, OPO3R3R'3, OPO2R3R'3, S(O)R3, S(O)2R3, S(O)2OR3, PO3R3R'3, NR3NR'3R''3,
SNR3R'3, NR3SR'3, SSR3 and R3, or is an oxo group, =S, =N0R3 or =CR3R'3 and X1 1 is absent, or Xx is C=(Z) and R2 is a bond thereto so as to form a cyclic moiety -C=(Z)NRxS (O)p-; X2 is selected from the group consisting of OR4, SR4, NR4R'4, hydrogen, halogen, - (Y)mC=(Z) (T)nR4, - N(C=(Z) (T)nR4J2, N3, CN, OCN, SCN, OSO3R4, OSO2R4, OPO3R4R'4, OPO2R4R'4, S(O)R4, S(O)2R4, S(O)2OR4, PO3R4R' 4, NR4NR' 4R''4, SNR4R' 4/ NR4SR'4, SSR4 and R4, or is an oxo group, =S, =N0R4 or =CR4R' 4 and X2' is absent;
X3 is selected from the group consisting of OR5, SR5, NR5R'5/ hydrogen, halogen, - (Y)mC=(Z) (T)nR5, - N(C=(Z) (T)nRs)2, N3, CN, OCN, SCN, OSO3R5, OSO2R5, OPO3R5R'5, OPO2R5R'5, S(O)R5, S(O)2R5, S(O)2OR5, PO3R5R'5, NR5NR'5R"5, SNR5R'5, NR5SR' 5, SSR5 and R5, or is an oxo group, =S, =N0R5 or =CR5R'5 and X3' is absent;
X4 is selected from the group consisting of OR6, SR6, NR6R'6, hydrogen, halogen, -(Y)1nC=(Z) (T)nR6, - N(C=(Z) (T)nR6)2, N3, CN, OCN, SCN, OSO3R6, OSO2R6, OPO3R6R'6, OPO2R6R' 6, S(O)R6, S(O)2R6, S(O)2OR6, PO3R6R' 6, NR6NR' 6R"6,
SNR6R' s, NR6SR' 6, SSR6 , R6, or is an oxo group, =S, =NOR6 or =CR6R'6 and X4' is absent, and -(CX6X6' )VCX7X7'X7' ' wherein v is an integer in the range of 0 to 6 inclusive and, when v is in the range of 1 to 6, may include a double bond or epoxide group, each of X6, X7 and X7' is independently selected from the group consisting of ORi2, SRi2, NRi2R'i2, hydrogen, halogen, -(Y)1nC=(Z) (T)nRi2, -N(C=(Z) (T)nR12J2, N3, CN, OCN, SCN, OSO3Ri2, OSO2R12, OPO3Ri2R'12, OPO2Ri2R' 12, S(O)Ri2, S(O)2Ri2, S(O)2ORi2, PO3Ri2R'12, NRX2NR' 12R"12, SNRi2R'i2, NRi2SR' i2, SSRX2 and Ri2, or is an oxo group, =S,
=NORi2 or =CRi2R'i2 and X6' or X7'' , respectively, is absent; and each of X6' and X7' ' is independently selected from the group hydrogen, CN, optionally substituted alkyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted aralkyl, and optionally substituted acyl;
X5 is selected from the group consisting of hydrogen, CN, -C=(Z) (T)nRn, S(O)Rn, S(O)2R1x, S(O)2ORn, PO3RnR'11, optionally substituted alkyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted aralkyl, and optionally substituted acyl;
Xi' , X2' , X3' and X4' 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 X1 and X2, X2 and X3, X3 and X4' , X4' 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 Ri and Xi, R2 and Xi, Ri and X2, R2 and X2, Ri and X3, R2 and X3, Ri and X4, R2 and X4, Ri and X4' , R2 and X4' , Xx and X2, X2 and X3, X2 and X4, X3 and X4, Xx and X1' , 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 and n are independently zero or one and Y, Z and T are independently selected from the group consisting of O, S, and NRi0 p is zero, one or two;
R3, R'3, R"3, R4, R'4, R"4, R5, R's, R"5, R6, R'e, R'' 6, R?, R8, Rg, R' 9, Rio, R11, R'11, R12, R' 12 and R' ' 12 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=, NR7 and -(Y)1nC=(Z) (T)n-, optionally substituted alkenyl which may be interrupted by one or more heteroatoms or functional groups selected from the group consisting of 0, S, -N=, NR7 and -(Y)1nC=(Z) (T)n-, optionally substituted aryl, optionally substituted heterocyclic, 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 0, S, -N=, NR7 and -(Y)1nC=(Z) (T)n-, optionally substituted acyl and a carbohydrate moiety; with the proviso that at least two of X1, X2, X3,
X4, Xe and X7 are other than hydrogen or a group linked to the ring through a carbon-carbon bond and the further proviso that the compound is not _V,iV-diethyl-S- (2,3,4,6- tetra-O-acetyl-β-D-galactopyranosyl) sulfenamide, N,N- diethyl-S- (2-aσetamido-3,4,6~tri-0-acetyl-2-deoxy-β-D- glucopyranosyl) sulfenamide, methyl 27-acetyl-4,7,8, 9-tetra- O-acetyl-2-S- (diethylamino) -2-thio-α-neuraminate, N,N- di (isopropyl) -S- (2,3,4,6-tetra-O-acetyl-β-D- glucopyranosyl) sulfenamide, 1-[ (2,3,4,6-tetra-O~acetyl-β-D- galactopyranosyl)thio]piperidine, 1-[ (2,3,4,6-tetra-O- acetyl-β-D-glucopyranosyl) thio]piperidine, 4-[ (2,3,4, 6- tetra-O-acetyl-β-D-galactopyranosyl) thio]morpholine, N- (1- adamantyl) -S- (2,3,4, 6-tetra-O-acetyl-β-D- glucopyranosyl) sulfenamide, iV-benzyl-S- (2,3,4,6-tetra-O- acetyl-β-D-glucopyranosyl) sulfenamide, iV-phenyl-S- (2,3,4,6- tetra-O-acetyl-β-D-glucopyranosyl) sulfenamide, N-phenyl-S- (D-gluσopyranosyl) sulfenamide, N- (4-methylphenyl) -S- (2,3,4, 6-tetra-O-acetyl-β-D-glucopyranosyl) sulfenamide, N- (2-chlorophenyl) -S- (2,3,4, 6-tetra-O-acetyl-β-D- glucopyranosyl) sulfenamide, N- (4-hydroxypheny1) -S- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl) sulfenamide, 2- [ (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)thio] -1 (2H) - isoquinoline, methyl 1-deoxy-l-[ (4-thioxo-l (4H) - pyrimidinyl) thio] -β-D-glucopyranuronate, 1- (galactopyranosylthio) -lH-tetrazole, 1- (glucopyranosylthio) -lH-tetrazole, or 1,1'- [sulfonylbis (4,1-phenyleneiminosulfonyl) ]bis [1-deoxy-β-D- glucopyranuronic acid] tetrasodium salt; or a pharmaceutically acceptable salt thereof.
2. A compound as claimed in claim 1 wherein one or both of Ri and R2 is C4-30 alkyl.
3. A compound as claimed in claim 2 wherein one or both of Ri and R2 is Cδ-i2 alkyl.
4. A compound as claimed in claim 3 wherein one or both of Ri and R2 is Cs-io alkyl.
5. 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, alkenyl or R1 and R2 together with the nitrogen atom from which they depend form an optionally substituted saturated or unsaturated heterocyclic group.
6. A compound as claimed in claim 5 wherein one or both of R1 and R2 is alkyl interrupted by one or more oxygen atoms.
7. A compound as claimed in claim 6 wherein one or both of R1 and R2 has the formula CH3 (CH2)x 0(CH2)yO(CH2) z or
CH3 (CH2)γθ(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.
8. A compound as claimed in any one of claims 1 to 7 wherein X1 is OR3.
9. A compound as claimed in claim 8 wherein R3 is hydrogen or optionally substituted acyl.
10. A compound as claimed in any one of claims 1 to 9, wherein X2 is OR4.
11. A compound as claimed in claim 10 wherein R4 is hydrogen or optionally substituted acyl.
12. A compound as claimed in any one of claims 1 to 11 wherein X3 is OR5.
13. A compound as claimed in claim 12 wherein R5 is hydrogen or optionally substituted acyl.
14. A compound as claimed in any one of claims 1 to 13 wherein X4 is -(CX6X6' )VCX7X7'X7' ' wherein v is an integer in the range of 0 to 6 inclusive, and each of X6, X7 and X7' is independently selected from the group consisting of OR12, SRi2, NRi2R'i2, hydrogen, halogen, -(Y)1nC=(Z) (T)nR12, - N(C=(Z) (T)nR12J2, N3, CN, OCN, SCN, OSO3Ri2, OSO2Ri2, OPO3Ri2R'12, OPO2Ri2R' i2, S(O)Ri2, S(O)2Ri2, S(O)2OR12, PO3R12R'12, NRi2NR'12R' '12, SNR12R'3.2, NR12SR'12, SSR12 and R12, or is an oxo group, =S, =N0Ri2 or =CRi2R'12 and X6' or X7'' , respectively, is absent; and each of X6' and X7' ' is independently selected from the group hydrogen, CN, optionally substituted alkyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted aralkyl, and optionally substituted acyl.
15. A compound as claimed in claim 14 wherein X4 is CH2ORi2, CHORi2CH2OR12 or CHOR12CHORI2CH2ORI2.
16. A compound as claimed in claim 15 wherein X4 is CH2OR12.
17. A compound as claimed in any one of claims 1 to 16 wherein p is zero.
18. A compound as claimed in any one of claims 1 to 16 wherein p is one.
19. A compound as claimed in any one of claims 1 to 16 wherein p is two.
20. A compound selected from the group consisting of: 27,27-dioctyl-S- (2,3,5, 6-tetra-O-acetyl-β-D- galactopyranosyl) sulfenamide, N,N-d± (2-octyloxyethyl) -S- (2,3,5, 6-tetra-O-acetyl-β-D- galactopyranosyl) sulfenamide, N,N-d±octyl-S- (2,3,5,6-tetra-O-acetyl-β-D- glucopyranosyl) sulfenamide, N,N-d± (2-octyloxyethyl) -S- (2,3,5, 6-tetra-O-acetyl-β-D- glucopyranosyl) sulfenamide,
N,N-dioctyl-S- (β-D-galactopyranosyl) sulfenamide, N,N-d± (2-octyloxyethyl) -S- (β-D- galactopyranosyl) sulfenamide, N,-V-dioctyl-S- (β-D-glucopyranosyl) sulfenamide, and N,N-d± (2-octyloxyethyl) -S- (β-D- glucopyranosyl) sulfenamide, and their oxides, and pharmaceutically acceptable salts thereof.
21. A method of preparation of a compound of general formula (I) :
Figure imgf000054_0001
comprising reacting a compound of general formula
(H) :
Figure imgf000054_0002
wherein L is an acyl group, preferably acetyl and Xx, X2, X3, X4, Xi' , X2' , Xs' X4' and X5 are as defined in claim 1; with a compound of general formula (III) :
Figure imgf000054_0003
wherein Rx and R2 are as defined in claim 1; in the presence of a bis-activated alkyl halide; and, optionally, reacting the product with an oxidising agent.
22. 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) :
Figure imgf000055_0001
wherein 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)1nC=(Z) (T)n-, optionally substituted alkenyl which may be interrupted by one or more heteroatoms or functional groups selected from the group consisting of 0, S, -N=, NR7 and -(Y)1nC=(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)1nC=(Z) (T)n-, optionally substituted heterocyclic, 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; A is selected from the group consisting of O, S,
SO, SO2, Se, Te, NR8, CR9R' 9/ N->0, and C(O);
Xi is selected from the group consisting of OR3, SR3, NR3R'3, hydrogen, halogen, -(Y)11C=(Z) (T)nR3, - N(C=(Z) (T)nR3J2, N3, CN, OCN, SCN, OSO3R3, OSO2R3, OPO3R3R'3, OPO2R3R'3, S(O)R3, S(O)2R3, S(O)2OR3, PO3R3R'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, or Xx is C=(Z) and R2 is a bond thereto so as to form a cyclic moiety -C=(Z)NRxS(O)p-; X2 is selected from the group consisting of OR4, SR4, NR4R' 4, hydrogen, halogen, -(Y)1nC=(Z) (T)nR4, - N(C=(Z) (T)nR4J2, N3, CN, OCN, SCN, OSO3R4, OSO2R4, OPO3R4R'4, OPO2R4R'4, S(O)R4, S(O)2R4, S(O)2OR4, PO3R4R' 4/ NR4NR' 4R''4, SNR4R'4, NR4SR'4, SSR4 and R4, or is an oxo group, =S, =N0R4 or =CR4R' 4 and X2' is absent;
X3 is selected from the group consisting of OR5, SR5, NR5R'5, hydrogen, halogen, -(Y)1nC=(Z) (T)nR5, - N(C=(Z) (T)nRs)2, N3, CN, OCN, SCN, OSO3R5, OSO2R5, OPO3R5R'5, OPO2R5R'5, S(O)R5, S(O)2R5, S(O)2OR5, PO3R5R' 5, NR5NR'5R''5, SNR5R'5, NR5SR'5, SSR5 and R5, or is an oxo group, =S, =N0R5 or =CR5R'5 and X3 1 is absent;
X4 is selected from the group consisting of 0R6, SR6, NR6R'6, hydrogen, halogen, -(Y)1nC=(Z) (T)nR6, - N(C=(Z) (T)nRg)2, N3, CN, OCN, SCN, OSO3R6, OSO2R6, OPO3R6R'6, OPO2R6R' 6, S(O)R6, S(O)2R6, S(O)2OR6, PO3R6R' 6, NR6NR' 6R"6,
SNR6R' 6, NR6SR' 6, SSR6 , R6, or is an oxo group, =S, =N0R6 or =CR6R' 6 and X4' is absent, and - (CX6X6' )VCX7X7'X7' ' wherein v is an integer in the range of 0 to 6 inclusive and, when v is in the range of 1 to 6, may include a double bond or epoxide group, each of X6, X7 and X7' is independently selected from the group consisting of OR12, SRi2, NRi2R' 12, hydrogen, halogen, - (Y)mC=(Z) (T)nR12/ -N(C=(Z) (T)nRi2J2, N3, CN, OCN, SCN, OSO3R12, OSO2R12, OPO3R12R' 12, OPO2R12R'12, S(O)R12, S(O)2R12, S(O)2OR12, PO3Ri2R'I2, NR12NR' 12R"12, SNRi2R' 12, NRi2SR' i2, SSRi2 and R12, or is an oxo group, =S,
=NORi2 or =CRi2R' i2 and X6' or X7' ' , respectively, is absent; and each of X6' and X7' ' is independently selected from the group hydrogen, CN, optionally substituted alkyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted aralkyl, and optionally substituted acyl;
X5 is selected from the group consisting of hydrogen, CN, -C=(Z) (T)nR1x, S(O)R11, S(O)2R11, S(O)2OR1I, PO3R11R'11, optionally substituted alkyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted aralkyl, and optionally substituted acyl;
Xi' , X2' , X3' and X4' 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 X3, X3 and X4' , X4' 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 Ri and X1, R2 and Xi, Ri and X2, R2 and X2, Ri and X3, R2 and X3, R1 and X4, R2 and X4, Ri and X4' , R2 and X4' , X1 and X2, X2 and X3, X2 and X4, X3 and X4, Xi and X1' , 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 and n are independently zero or one and Y, Z and T are independently selected from the group consisting of O, S, and NRi0 p is zero, one or two;
R3, R'3, R"3, R4, R'4, R"4, R5, R's, R"s, R5, R'β, R" 6, Rv, R8, Rg, R' 9, Rio, R11, R'11, R12, R' 12 and R' ' 12 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=, NR7 and -(Y)1nC=(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)1nC=(Z) (T)n-, optionally substituted aryl, optionally substituted heterocyclic, 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 0, S, -N=, NR7 and -(Y)1nC=(Z) (T)n-, optionally substituted acyl and a carbohydrate moiety; with the proviso that at least two of Xi, X2, X3,
X4, Xg and X7 are other than hydrogen or a group linked to the ring through a carbon-carbon bond; or a pharmaceutically acceptable salt thereof.
23. The use of a compound of general formula (I)
Figure imgf000058_0001
wherein R1 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)1nC=(Z) (T)n-, optionally substituted alkenyl which may be interrupted by one or more heteroatoms or functional groups selected from the group consisting of 0, S, -N=, NR7 and -(Y)1nC=(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 0, S, -N=, NR7 and -(Y)mC=(Z) (T)n-, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted acyl and a carbohydrate moiety; or R1 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;
A is selected from the group consisting of 0, S, SO, SO2, Se, Te, NR8, CR9R'9, N->0, and C(O);
X1 is selected from the group consisting of OR3, SR3, NR3R' 3, hydrogen, halogen, -(Y)1nC=(Z) (T)nR3, - N(C=(Z) (T)nRa)2, N3, CN, OCN, SCN, OSO3R3, OSO2R3, OPO3R3R'3, OPO2R3R' 3, S(O)R3, S(O)2R3, S(O)2OR3, PO3R3R' 3 , NR3NR' 3R" 3, SNR3R^, NR3SR'3, SSR3 and R3, or is an oxo group, =S, =NOR3 or =CR3R'3 and Xi' is absent, or Xi is C=(Z) and R2 is a bond thereto so as to form a cyclic moiety -C=(Z)NR1S(O)P-;
X2 is selected from the group consisting of OR4, SR4, NR4R' 4, hydrogen, halogen, -(Y)1nC=(Z) (T)nR4, -
N(C=(Z) (T)nR4J2, N3, CN, OCN, SCN, OSO3R4, OSO2R4, OPO3R4R'4, OPO2R4R'4, S(O)R4, S(O)2R4, S(O)2OR4, PO3R4R' 4, NR4NR'4R''4, SNR4R' 4, NR4SR' 4, SSR4 and R4, or is an oxo group, =S, =N0R4 or =CR4R' 4 and X2' is absent; X3 is selected from the group consisting of OR5,
SR5, NR5R'5, hydrogen, halogen, -(Y)1nC=(Z) (T)nR5, - N(C=(Z) (T)nRs)2, N3, CN, OCN, SCN, OSO3R5, OSO2R5, OPO3R5R'5, OPO2R5R'5, S(O)R5, S(O)2R5, S(O)2OR5, PO3R5R'5, NR5NR'5R' ' 5, SNR5R'5, NR5SR'5, SSR5 and R5, or is an oxo group, =S, =N0R5 or =CR5R'5 and X3' is absent; >
X4 is selected from the group consisting of OR6, SR6, NR6R's, hydrogen, halogen, -(Y)1nC=(Z) (T)nR6, - N(C=(Z) (T)nR6)2, N3, CN, OCN, SCN, OSO3R6, OSO2R6, OPO3R6R'6, OPO2R6R' 6, S(O)R6, S(O)2R6, S(O)2OR6, PO3R6R' 6, NR6NR' 6R"6, SNR6R' 6, NR6SR' 6, SSR6 , R6, or is an oxo group, =S, =N0R6 or =CR6R' 6 and X4' is absent, and -(CX6X6')VCX7X7'X7'' wherein v is an integer in the range of 0 to 6 inclusive and, when v is in the range of 1 to 6, may include a double bond or epoxide group, each of X6, X7 and X7' is independently selected from the group consisting of OR12, SRi2, NRi2R' 12, hydrogen, halogen, -(Y)1nC=(Z) (T)nRi2, -N(C=(Z) (T)nRi2J2, N3, CN, OCN, SCN, OSO3Ri2, OSO2R12, OPO3Ri2R'12, OPO2Ri2R' 12, S(O)Ri2, S(O)2Ri2, S(O)2ORi2, PO3Ri2R'12, NR12NR'12R" 12, SNR12R' 12, NRi2SR' i2, SSR12 and R12, or is an oxo group, =S, =NORi2 or =CR12R' 12 and X6' or X7'' , respectively, is absent; and each of X6' and X7' ' is independently selected from the group hydrogen, CN, optionally substituted alkyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted aralkyl, and optionally substituted acyl;
X5 is selected from the group consisting of hydrogen, CN, -C=(Z) (T)nRn, S(O)R11, S(O)2R11, S(O)2ORn, PO3R11R' 11, optionally substituted alkyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted aralkyl, and optionally substituted acyl;
X1' , X2' , X3' and X4' 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 X3, X3 and X4' , X4' 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 Ri and Xi, R2 and Xi, Ri and X2, R2 and X2, R1 and X3, R2 and X3, Ri and X4, R2 and X4, Ri and X4' , R2 and X4' , X1 and X2, X2 and X3, X2 and X4, X3 and X4, X1 and X1' , 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 and n are independently zero or one and Y, Z and T are independently selected from the group consisting of 0, S, and NRi0 p is zero, one or two;
R3, R'3, R"3, R4, R'4, R"4, R5, R's, R"5, R6, R'6, R'' 6, R7, R8, R9, R' 9, Ri0, Ru, R'u, R12, R'i2 and R' ' i2 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 0, S, -N=, NR7 and -(Y)1nC=(Z) (T)n-, optionally substituted alkenyl which may be interrupted by one or more heteroatoms or functional groups selected from the group consisting of 0, S, -N=, NR7 and -(Y)1nC=(Z) (T)n-, optionally substituted aryl, optionally substituted heterocyclic, 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 0, S, -N=, NR7 and -(Y)1nC=(Z) (T)n-, optionally substituted acyl and a carbohydrate moiety; with the proviso that at least two of X1, X2, X3, X4, X6 and X7 are other than hydrogen or a group linked to the ring through a carbon-carbon bond; or a pharmaceutically acceptable salt thereof; in the manufacture of a medicament for use in the treatment of a microbial infection.
24. A pharmaceutical composition comprising a compound of general formula (I) :
Figure imgf000061_0001
wherein 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)1nC=(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)1nC=(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)1nC=(Z) (T)n-, optionally substituted heterocyclic, 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;
A is selected from the group consisting of 0, S, SO, SO2, Se, Te, NR8, CR9R' 9, N->0, and C(O) ;
Xi is selected from the group consisting of OR3, SR3, NR3R' 3, hydrogen, halogen, - (Y)mC=(Z) (T)nR3, - N(C=(Z) (T)nRa)2, N3, CN, OCN, SCN, OSO3R3, OSO2R3, OPO3R3R'3, OPO2R3R' 3, S(O)R3, S(O)2R3, S(O)2OR3, PO3R3R' 3, NR3NR' 3R"3, SNR3R' 3, NR3SR' 3, SSR3 and R3, or is an oxo group, =S, =NOR3 or =CR3R'3 and X1' is absent, or X1 is C=(Z) and R2 is a bond thereto so as to form a cyclic moiety -C=(Z)NR1S(O)P-;
X2 is selected from the group consisting of OR4, SR4, NR4R' 4, hydrogen, halogen, -(Y)1nC=(Z) (T)nR4, - N(C=(Z) (T)nR4) 2, N3, CN, OCN, SCN, OSO3R4, OSO2R4, OPO3R4R' 4, OPO2R4R' 4, S (O)R4, S (O) 2R4, S (O) 2OR4, PO3R4R' 4, NR4NR' 4R' ' 4,
SNR4R' 4, NR4SR' 4, SSR4 and R4, or is an oxo group, =S, =N0R4 or =CR4R' 4 and X2' is absent;
X3 is selected from the group consisting of OR5, SR5, NR5R' 5, hydrogen, halogen, -(Y)1nC=(Z) (T)nR5, - N(C=(Z) (T)nRs)2, N3, CN, OCN, SCN, OSO3R5, OSO2R5, OPO3R5R'5, OPO2R5R' 5, S(O)R5, S(O)2R5, S(O)2OR5, PO3R5R' 5, NR5NR' 5R" 5, SNR5R' sr NR5SR' 5, SSR5 and R5, or is an oxo group, =S, =N0R5 or =CR5R' 5 and X3 1 is absent;
X4 is selected from the group consisting of OR6, SR6, NR6R'6, hydrogen, halogen, -(Y)1nC=(Z) (T)nR6, -
N(C=(Z) (T)nRg)2, N3, CN, OCN, SCN, OSO3R6, OSO2R6, OPO3R6R'6, OPO2R6R' 6, S(O)R6, S(O)2R6, S(O)2OR6, PO3R6R' 6, NR6NR' 6R"6, SNR6R' sr NR6SR' 6, SSR6 , R6, or is an oxo group, =S, =NOR6 or =CR6R'6 and X4' is absent, and -(CX6X6')VCX7X7'X7'' wherein v is an integer in the range of 0 to 6 inclusive and, when v is in the range of 1 to 6, may include a double bond or epoxide group, each of X6, X7 and X7' is independently selected from the group consisting of OR12, SR12, NR12R' 12 r hydrogen, halogen, -(Y)1nC=(Z) (T)nR12, -N(C=(Z) (T)nR12J2, N3, CN, OCN, SCN, OSO3R12, OSO2R12, OPO3R12R' 12, OPO2R12R' 12, S(O)R12, S(O)2R12, S(O)2OR12, PO3R12R' 12, NR12NR' 12R" 12, SNR12R' 12, NR12SR' 12, SSR12 and R12, or is an oxo group, =S, =NOR12 or =CR12R'12 and X6' or X7'' , respectively, is absent; and each of X6' and X7' ' is independently selected from the group hydrogen, CN, optionally substituted alkyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted aralkyl, and optionally substituted acyl; X5 is selected from the group consisting of hydrogen, CN, -C=(Z) (T)nR11, S(O)R11, S(O)2R11, S(O)2OR11, PO3R11R' xx, optionally substituted alkyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted aralkyl, and optionally substituted acyl;
Xi' , X2' / X3' and X4' 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 X1 and X2, X2 and X3, X3 and X4' , X4' and A when A contains a carbon or nitrogen atom, X5 and A when A contains a carbon or nitrogen atom, and X5 and X1 together constitute a double bond, or R1 and X1, R2 and X1, R1 and X2, R2 and X2, R1 and X3, R2 and X3, R1 and X4, R2 and X4, R1 and X4' , R2 and X4' , X1 and X2, X2 and X3, X2 and X4, X3 and X4, X1 and X1' , 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 and n are independently zero or one and Y, Z and T are independently selected from the group consisting of O, S, and NRi0 p is zero, one or two;
R3, R'3, R"3, R4, R'4, R"4, Rs, R'5, R"s, R6, R'e, R'' 6, R7, R8, R9, R' 9, R10, R11, R'U, RI2, R' 12 and R' '12 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 0, S, -N=, NR7 and -(Y)1nC=(Z) (T)n-, optionally substituted alkenyl which may be interrupted by one or more heteroatoms or functional groups selected from the group consisting of 0, S, -N=, NR7 and -(Y)1nC=(Z) (T)n-, optionally substituted aryl, optionally substituted heterocyclic, 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)1nC=(Z) (T)n-, optionally substituted acyl and a carbohydrate moiety; with the proviso that at least two of X1, X2, X3, X4, Xe and X7 are other than hydrogen or a group linked to the ring through a carbon-carbon bond; or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
25. A method of killing a microorganism, comprising exposing said microorganism to a compound of general formula (I) :
Figure imgf000064_0001
wherein 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 0, 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)1nC=(Z) (T)n-, optionally substituted heterocyclic, 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; A is selected from the group consisting of O, S, SO, SO2, Se, Te, NR8, CR9R' 9, N->0, and C(O) ;
Xi is selected from the group consisting of OR3, SR3, NR3R'3, hydrogen, halogen, - (Y)mC=(Z) (T)nR3, - N(C=(Z) (T)nR3J2, N3, CN, OCN, SCN, OSO3R3, OSO2R3, OPO3R3R'3, OPO2R3R'3, S(O)R3, S(O)2R3, S(O)2OR3, PO3R3R'3, NR3NR'3R''3, SNR3R'3, NR3SR' 3, SSR3 and R3, or is an oxo group, =S, =N0R3 or =CR3R' 3 and Xi' is absent, or X1 is C=(Z) and R2 is a bond thereto so as to form a cyclic moiety -C=(Z)NRiS (O)p-; X2 is selected from the group consisting of OR4,
SR4, NR4R' 4, hydrogen, halogen, -(Y)1nC=(Z) (T)nR4, - N(C=(Z) (T)nR4J2, N3, CN, OCN, SCN, OSO3R4, OSO2R4, OPO3R4R' 4, OPO2R4R' 4, S(O)R4, S(O)2R4, S(O)2OR4, PO3R4R' 4, NR4NR' 4R' ' 4, SNR4R'4, NR4SR'4, SSR4 and R4, or is an oxo group, =S, =N0R4 or =CR4R' 4 and X2' is absent;
X3 is selected from the group consisting of OR5, SR5, NR5R's, hydrogen, halogen, -(Y)1nC=(Z) (T)nR5, - N(C=(Z) (T)nR5)2, N3, CN, OCN, SCN, OSO3R5, OSO2R5, OPO3R5R'5, OPO2R5R'5, S(O)R5, S(O)2R5, S(O)2OR5, PO3R5R'5, NR5NR' 5R' '5, SNR5R' 5/ NR5SR'5, SSR5 and R5, or is an oxo group, =S, =NOR5 or =CR5R'5 and X3' is absent;
X4 is selected from the group consisting of OR6, SR6, NR6R'6, hydrogen, halogen, -(Y)1nC=(Z) (T)nR6, - N(C=(Z) (T)nR6)2, N3, CN, OCN, SCN, OSO3R6, OSO2R6, OPO3R6R' 6, OPO2R6R' s, S(O)R6, S(O)2R6, S(O)2OR6, PO3R6R' 6, NR6NR' 6R"6,
SNR6R' 6, NR6SR' 6, SSR6 , R6, or is an oxo group, =S, =N0R6 or =CR6R' 6 and X4' is absent, and -(CX6X6')VCX7X7'X7" wherein v is an integer in the range of 0 to 6 inclusive and, when v is in the range of 1 to 6, may include a double bond or epoxide group, each of X6, X7 and X7' is independently selected from the group consisting of ORi2, SRi2, NRi2R' i2, hydrogen, halogen, -(Y)1nC=(Z) (T)nR12, -N(C=(Z) (T)nRi2)2, N3, CN, OCN, SCN, OSO3R12, OSO2R12, OPO3R12R' 12, OPO2R12R' 12, S(O)Ri2, S(O)2R12, S(O)2ORi2, PO3R12R' 12, NR12NR' 12R" 12, SNR12R' i2/ NR12SR' i2, SSR12 and Rx2, or is an oxo group, =S,
=N0Ri2 or =CR12R' i2 and X6' or X7'' , respectively, is absent; and each of X6' and X7' ' is independently selected from the group hydrogen, CN, optionally substituted alkyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted aralkyl, and optionally substituted acyl;
X5 is selected from the group consisting of hydrogen, CN, -C=(Z) (T)nR11, S(O)R11, S(O)2R11, S(O)2OR11, PO3R11R'!.]., optionally substituted alkyl, optionally substituted alkaryl, optionally substituted aryl, optionally substituted aralkyl, and optionally substituted acyl; X1' , X2' , X3' and X4' 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 X1 and X2, X2 and X3, X3 and X4' , X4' and
A when A contains a carbon or nitrogen atom, X5 and A when A contains a carbon or nitrogen atom, and X5 and X1 together constitute a double bond, or R1 and X1, R2 and X1, R1 and X2, R2 and X2, R1 and X3, R2 and X3, R1 and X4, R2 and X4, R1 and X4' , R2 and X4' , X1 and X2, X2 and X3, X2 and X4, X3 and X4, X1 and X1' , 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 and n are independently zero or one and Y, Z and T are independently selected from the group consisting of 0, S, and NR10 p is zero, one or two;
R3, R's, R"3, R4, R'4, R"4, R5, R's, R"s, R6, R'e, R' '6, R?, Rs, Rg, R' 9, Rio, Rn, R' 11, R12, R' i2 and R" 12 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=, NR7 and -(Y)1nC=(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 heterocyclic, 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 0, 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, X4, X6 and X7 are other than hydrogen or a group linked to the ring through a carbon-carbon bond; or a pharmaceutically acceptable salt thereof.
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