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WO2006037185A1 - Nouveaux sulfénamides et oxydes de sulfénamide - Google Patents

Nouveaux sulfénamides et oxydes de sulfénamide Download PDF

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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
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oso
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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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Griffith University
Monash University
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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

La présente invention décrit un composé de formule générale (I) : où R1, R2, X1, X1', X2, X2', X3, X3', X4, X4' et X5 représentent divers substituants et p est égal à 0, 1 ou 2. La présente invention décrit également l'utilisation desdits composés en tant qu'agents anti-microbiens.
PCT/AU2005/001548 2004-10-07 2005-10-07 Nouveaux sulfénamides et oxydes de sulfénamide Ceased WO2006037185A1 (fr)

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AU2004905781A AU2004905781A0 (en) 2004-10-07 Novel sulfenamides and sulfenamide oxides
AU2004905781 2004-10-07

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12116382B2 (en) 2022-11-28 2024-10-15 Hongene Biotech Corporation Functionalized N-acetylgalactosamine analogs

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE CA [online] MAEHREL ET AL: "Structural studies of the melibiose permease of Escherichia coli by fluorescence resonance energy transfer. I. Evidence for ion-induced conformational change.", Database accession no. (130:164488) *
ILLYES, TUNDE-ZITA ET AL: "Novel approaches to the syntheses of N-substituted S-glycosyl-sulfenamides.", CARBOHYDR RES., vol. 339, no. 8, 2004, pages 1651 - 1564 *
J BIOL CHEM., vol. 273, no. 50, 1998, pages 33192 - 33197 *
OWEN D J ET AL: "A one-pot synthesis of novel N,N-dialkyl-S-glycosylsulfenamides.", CARBOHYDR RES., vol. 328, no. 3, 2000, pages 287 - 292 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12116382B2 (en) 2022-11-28 2024-10-15 Hongene Biotech Corporation Functionalized N-acetylgalactosamine analogs

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