ZA200406672B - An antimicrobial agent. - Google Patents

Description

AN ANTIMICROBIAL AGENT

Technical Field

The present invention relates to novel "5 sulfenamides that have an antimicrobial action, methods for their synthesis, pharmaceutical compositions containing them and method of treatment of patients suffering microbial infection.

Background Art

Many bacterial diseases once thought to be on the decline are beginning to re-emerge and annually devastate populations in many countries. This problem is amplified by the emergence of many new drug resistant strains of the microorganisms that cause these diseases. Our interest in glycofuranose chemistry (Owen & von Itzstein, 2000) has led to the discovery of a new class of antimicrobial agents described below. Although significant chemistry and biology has been published (see, for example, Marino,

Marino, Miletti, Alves, Colli, & de Lederkremer, 1998;

Miletti, Marino, Marino, de Lederkremer, Colli & Alves, 1999; zhang & Liu, 2001; Brimacombe, Gent & Stacey, 1968;

Brimacombe, Da’aboul & Tucker, 1971; Lemieux & Stick, 1975; de Lederkremer, Cirelli & Sznaidman, 1986; Shin &

Perlin, 1979; de Lederkremer, Cicero & Varela, 1990; de

Lederkremer, Marino & Marino, 2002; Pathak, Pathak,

Suling, Gurcha, Morehouse, Besra, Maddry & Reynolds, 2002;

Ernst, Hart & Sinay, 2000) in the area of glycofuranose chemistry and biology none to date provides compounds that have significant antimicrobial activity.

Disclosure of the Invention

The present invention is concerned generally with novel sulfenamides that have antimicrobial action. )

In a first aspect of the present invention there is provided a compound of general formula (I):

Xa Ri nT

Xs AN

Ra

Xs X4 wherein R; and R; may be the same or different and are selected from the group consisting of hydrogen, 5 optionally substituted C4.3; alkyl and optionally substituted C4-39 alkenyl, provided that R; and R; may not both be hydrogen, or R; and R, 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, or R; and R; together with . the nitrogen atom from which they depend form an optionally substituted lactam moiety;

X; is selected from the group consisting of ORs,

SR3, NR3R’;, hydrogen, halogen, CN, C(O)NR3R’3, C(O)ORj3,

OSO3R3, OPO3R3R’3, NNR3R’3, SNR;3R’;, NHSR3, SSR; and substituted alkyl;

Xz is selected from the group consisting of OR,

SRq, NR4R's, hydrogen, halogen, CN, C(O)NRsR’s, C(O)OR,,

OSO3R4, OPO3R4R’,, NNR4R',, SNR4R’4, NHSR4, SSR; and substituted alkyl;

X3 is selected from the group consisting of ORs,

SRs, NRsR’s, hydrogen, halogen, CN, C(O)NRsR’s5, C(O)ORs,

OS03Rs, OPO3RsR’s, NNRsR’s, SNRsR's, NHSRs5, SSRs and substituted alkyl;

Xs is selected from the group consisting of ORg,

SRe, NRe¢R’s, hydrogen, halogen, CN, C(O)NRgR’g, C(O)ORg,

OSO3Rs, OPO3R¢R’s, NNRe¢R’'s, SNReR's, NHSRs, SSR; and substituted alkyl;

Ris, R's, Ra, R's, Rs, R's, Rg and R’; are the same or different and are selected from the group consisting of

- 3 = hydrogen, optionally substituted alkyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted acyl and a carbohydrate moiety; or a pharmaceutically acceptable salt thereof.

The term “alkyl” used either alone or in a compound word such as “optionally substituted alkyl” or woptionally substituted cycloalkyl” denotes straight chain, branched or mono- or poly- cyclic alkyl. Examples of straight chain and branched C4.3p alkyl include butyl, isobutyl, sec-butyl, tert-butyl, amyl, isocamyl, sec-amyl, 1,2-dimethylpropyl, 1,l-dimethylpropyl, hexyl, 4- methylpentyl, l-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-trimethylpropyl, heptyl, 5- methylhexyl, l-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, l-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, 1l-2-pentylheptyl and the like. Examples of Cy-30 cycloalkyl include 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 Cy4.39 alkenyl include butenyl, iso-butenyl, 3-methyl-2-butenyl, l-pentenyl, .cyclopentenyl, l-methyl-cyclopentenyl, 1- hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl, l-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, l-decenyl, 3-decenyl, 1,3-butadienyl, 1-4,pentadienyl, 1,3-cyclopentadienyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,3- cyclohexadienyl, 1,4-cyclohexadienyl, 1,3- cycloheptadienyl, 1,3,5-cycloheptatrienyl and 1,3,5,7- cyclooctatetraenyl.

The term “acyl” used either alone or in compound words such as “optionally substituted acyl” or “optionally substituted acyloxy” denotes an aliphatic acyl group or an acyl group containing an aromatic ring, which is referred to as aromatic acyl, or a heterocyclic ring, which is referred to as heterocyclic acyl, preferably Ci 3p 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 naphthylalkanoyl (e.g. naphthylacetyl, naphthylpropanoyl and naphthylbutanoyl); aralkenoyl such as phenylalkenoyl (e.g. rhenylpropenoyl, phenylbutenoyl, phenylmethacrylyl, phenylpentenoyl and phenylhexenoyl and naphthylalkenoyl (e.g. naphthylpropenoyl, naphthylbutenoyl and naphthylpentenoyl) ; heterocycliccarbonyl; heterocyclicalkanoyl such as thienylacetyl, thienylpropanoyl, thienylbutanoyl, thienylpentanoyl, ~ thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl and

- 5 = 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 or aromatic heterocyclic ring systems. Examples of aryl include phenyl, biphenyl, terphenyl, quaterphenyl, phenoxyphenyl, naphtyl, tetrahydronaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl, fluorenyl, pyrenyl, indenyl, azulenyl, chrysenyl, pyridyl, 4-phenylpyridyl, 3-phenylpyridyl, thienyl, furyl, pyrryl, pyrrolyl, furanyl, imadazolyl, 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, O and S and up to 9 carbon atoms in the ring.

The term “heterocyclyl” or equivalent terms such as “heterocyclic” used either alone or in compound words such as “optionally substituted saturated or unsaturated heterocyclyl” denotes monocyclic or polycyclic heterocyclyl groups containing at least one heteroatom atom selected from nitrogen, sulphur and oxygen. Suitable heterocyclyl groups include N-containing heterocyclic groups, such as, unsaturated 3 to 6 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, 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. Oxygen atoms may be replaced by hydrogen or bonds to a halogen, nitrogen, sulfur or carbon atoms, or

. = 7 = carbon-oxygen bonds such as in: ethers or esters may be introduced. Examples of carbohydrates include but are not limited to D-galactofuranose, N-acetyl-p-galactofuranose, b-glucofuranose, N-acetyl-b-glucofuranose, D- galactopyranose N-acetyl-b-galactopyranose, D-glucopyranose and N-acetyl-b-glucopyranose and their equivalents where oxygen atoms have been replaced in selected positions with hydrogen or bonds to halogen, nitrogen, sulfur or carbon, as well as oligosaccharides containing these moieties.

In this specification “optionally substituted” means that a group may or may not be further substituted with one or more groups selected from alkyl, alkenyl, alkynyl, aryl, halo, haloalkyl, halocalkenyl, 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, provided that none of the substituents outlined above interferes with the formation of the subject compound. .~

Any of the moieties whose length is defined in terms of the number of carbon atoms present may possess any number of carbon atoms within the specified 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 containing 4 to 24 carbon atoms, . preferably 6 to 12 carbon atoms, more preferably 8 to 10 carbon atoms and most preferably 8 carbon atoms are preferred for reasons of cost and availability of precursors, ease of synthesis and efficacy.

In a particularly preferred embodiment of the present invention one of Ry; or Rp; is C430 alkyl and the other is hydrogen or Cy.3p alkyl or R; and R, together with nitrogen atom from which they depend form a saturated or unsaturated heterocyclic ring containing said nitrogen atom as the single heteroatom.

More preferably, one of R; or R; is Css, ’ preferably C¢-12, alkyl and other is hydrogen or Cs-34, preferably, Cs.12, alkyl. More preferably still, one of R; or Ry is Cg.39 alkyl and the other is hydrogen or Cs.ig alkyl. Advantageously, both R; and R, are Cs-30 alkyl, preferably Ci.z4, more preferably Ce¢.i, alkyl and more preferably still Cg; alkyl, and most preferably Cg alkyl.

The alkyl groups are the same or different but most conveniently the same.

X1, Xz, X3 and X; may be any combination of substituents, but it is preferred that at least two of these moieties be other than hydrogen or a group linked to the ring through a carbon-carbon bond. Preferably, at least two of X;, Xp, ¥X3 and X; are moieties linked to the ring through a carbon-oxygen bond, for example, in the case of X;, OR3, OSO3R; and OPO3R3R’;.

Preferably X; is OR;. Advantageously R; is hydrogen or acyl, preferably Ci-3p acyl.

Preferably X; is OR... Advantageously R, is hydrogen or acyl, preferably Cis acyl.

Preferably X3 is ORs. Advantageously Rs is hydrogen or acyl, preferably C3 acyl.

Preferably X; is OR¢. Advantageously Rg is hydrogen or acyl preferably Ci-30 acyl.

Typically the compounds of the invention are galactofuranosyl compounds, and therefore have the configuration illustrated in general formula (Ia):

Xa Ry

IN

Xs ST “Ra

Xs X4

Alternatively, the compounds of the invention are glucofuranosyl derivatives having the general formula (Ib): _

Xa Ry

LL o / te — ‘, Rs

Xs X4

Advantageously the sulfenamide of general formula (I) is selected from the group consisting of N,N-Didecyl- 5-(2,3,5,6-tetra-0-benzoyl-1-thio-B-p- galactofuranosyl)sulfenamide, N, N-Dioctyl-S-(2,3,5, 6- tetra-0O-benzoyl-1-thio-f-p-galactofuranosyl) sulfenamide,

N,N-Dihexyl-5-(2,3,5, 6-tetra-0-benzoyl-1-thio-B-p— galactofuranosyl)sulfenamide, N,N-Didecyl-S-(l-thio-fB-p- galactofuranosyl)sulfenamide, N,N-Dioctyl-S-(l-thio-fB-b- galactofuranosyl)sulfenamide, N,N-Dihexyl-S-(l-thio-f-b- galactofuranosyl)sulfenamide, N,N-Dioctyl-S-(2,3,5,6- tetra-O-acetyl-1-thio-B-D-glucofuranosyl)sulfenamide and

N,N-Dioctyl-S-(1-thio-B-D~glucofuranosyl)sulfenamide.

In a particularly preferred embodiment of the invention the sulfenamide of general formula (I) is N,N-

Didecyl-S-(1-thio-P-pD-galactofuranosyl)sulfenamide, N, N-

Dioctyl-S-(1-thio-B-p~galactofuranosyl)sulfenamide or N,N-

Dihexyl~S-{(1l-thio-B-p-galactofuranosyl)sulfenamide, most particularly, N,N-Dioctyl-S-(l-thio-f-p- galactofuranosyl)sulfenamide.

According to a second aspect of the present invention there is provided a method of preparation of a compound of general formula (I):

Xa o y R 1 —_ in REN

Ro

Xo X4 . comprising reacting a compound of general formula (II):

Xa 0 ts —Z

Xz X wherein Z is an acyl group, preferably acetyl and

X1, Xz, X3 and X4 are as defined above with the proviso that none of R3, R’3, Rg, R’4, Rs, R's, Rg and R's is hydrogen : but, instead, is a protecting group; with a compound of general formula (III):

Ri : H—N_

Ro wherein R; and R; are as defined above; in the presence of a bis-activated alkyl halide; and, optionally removing the protecting groups.

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, or mixtures of such solvents, at a temperature from 20°C to 60°C, preferably 25°C to 40°C, under an atmosphere of nitrogen or argon. The reaction mixture may be left to stir typically for 2 to 160 hours, preferably greater than 24 hours, prior to isolation and

- 11 =- purification, or deprotection. Suitable protecting groups are well known to the person skilled in the art and in this case the benzoyl group is preferred. Benzoyl protecting groups are typically removed through hydrolysis with sodium methoxide in methanol. The compounds of the present invention may also be synthesised through the condensation of sulfenyl halides with a secondary amine of general formula (III), the reaction of the relevant thiols and amines in the presence of oxidising reagents or via the reaction of disulfides and amines in the presence of silver or mercuric salts. An extensive array of methodologies has been developed to manipulate each position of the furanose template as disclosed, for . example, in Marino, Marino, Miletti, Alves, Colli, & de

Lederkremer, 1998; Miletti, Marino, Marino, de

Lederkremer, Colli & Alves, 1999; Zhang & Liu, 2001;

Brimacombe, Gent & Stacey, 1968; Brimacombe, Da’aboul &

Tucker, 1971; Lemieux & Stick, 1975; de Lederkremer,

Cirelli & Sznaidman, 1986; Shin & Perlin, 1979; de

Lederkremer, Cicero & Varela, 19290; de Lederkremer, Marino & Marino, 2002; Pathak, Pathak, Suling, Gurcha, Morehouse,

Besra, Maddry & Reynolds, 2002; Ernst, Hart & Sinay, 2000; the contents of which are incorporated herein by reference.

According to a third aspect of the present invention there is provided a method for the treatment of a patient with a microbial infection, comprising administering to said patient a therapeutically effective amount of a compound of general formula (I).

According to a fourth aspect of the present invention there is provided the use of a compound of general formula (I) in the manufacture of a medicament for use in the treatment of a microbial infection.

As used herein, the term “therapeutically effective amount” means an amount of a compound of the present invention effective to yield a desired therapeutic response, for example to prevent or treat a disease which by administration of a pharmaceutically-active agent.

The specific "therapeutically effective amount" will, obviously, vary with such factors as the particular condition being treated, the physical condition and clinical history of the subject, the type of animal being treated, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed and the structure of the compound or its derivatives.

As used herein, a "pharmaceutical carrier" is a pharmaceutically acceptable solvent, suspending agent, excipient or vehicle for delivering the compound of general formula (I) to the subject. The carrier may be liquid or solid, and is selected with the planned manner of administration in mind.

The compound of general formula (I) may be administered orally, topically, or parenterally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intrathecal, intracranial, injection or infusion techniques.

The invention also provides suitable topical, oral, aerosol, and parenteral pharmaceutical formulations for use in the novel methods of treatment of the present invention. The compounds of the invention may be administered orally as tablets, aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions, capsules, syrups or elixirs. The composition for oral use may contain one or more agents selected from the group of sweetening agents, flavouring agents, colouring agents and preserving agents in order to produce pharmaceutically elegant and palatable preparations. The tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.

These excipients may be, for example, inert diluents, such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, such as starch, gelatin or acacia; or lubricating agents, such as magnesium stearate, stearic acid or talc. The tablets may be uncoated, or may be coated by known techniques.to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be employed.

Coating may also be performed using techniques described " in the U. S. Pat. Nos. 4,256,108; 4,160,452; and 4,265,874 to form osmotic therapeutic tablets for control release.

The compound of general formula (I) of the invention can be administered, for in vivo application, parenterally by injection or by gradual perfusion over time independently or together. Administration may be intravenously, intra-arterial, intraperitoneally, intramuscularly, subcutaneously, intracavity, or transdermally. For in vitro studies the agents may be added or dissolved in an appropriate biologically acceptable buffer and added to a cell or tissue.

Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/agqueous solutions, emulsions or suspensions, including saline and buffered media.

Parenteral vehicles include sodium chloride solution,

Ringer's dextrose, dextrose and sodium chloride, lactated

Ringer's intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present such as, for example, anti-microbials, anti-oxidants, chelating agents, growth factors and inert gases and the like.

The compounds of general formula (I) are antimicrobial agents which are active, in particular but not limited to, against Mycobacterium including

Mycobacterium tuberculosis, M. avium intracellulare, M. fortuitum, M. abscessus and rapid growing atypical

Mycobacterial strains, Nocardia, particularly Nocardia asteroides and N. nova, Staphylococcus including

Staphylococcus aureus and S. aureus (Coagulas-negative) and Enterococci species. The compounds of general formula (I) are particularly useful in treating infections involving these organisms.

Generally, the terms "treating", "treatment" and the like are used herein to mean affecting a subject, tissue or cell to obtain a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of completely or partially preventing infection, and/or may be therapeutic in terms of a partial or complete cure of an infection. "Treating" as used herein covers any treatment of, or prevention of infection in a vertebrate, a mammal, particularly a human, and includes: preventing the infection from occurring in a subject that may have been exposed to the infectious agent, but has not yet been diagnosed as affected; inhibiting the infection, ie., arresting its development; or relieving or ameliorating the effects of the infection, ie., cause regression of the effects of the infection.

According to a fifth aspect of the present invention there is provided a pharmaceutical composition comprising a compound of general formula (I) and a pharmaceutically acceptable carrier.

The pharmaceutical compositions according to one embodiment of the invention are prepared by bringing a compound of general formula (I) into a form suitable for

Claims (26)

Claims:

1. A compound of general formula (I): Xa Ry 0) / tan . Rs Xs X4 wherein R; and R, may be the same or different and are selected from the group consisting of hydrogen, optionally substituted C4.30 alkyl and optionally substituted C439 alkenyl, provided that R; and R; may not both be hydrogen, or R; and R; 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, or R; and R; together with the nitrogen atom from which they depend form an optionally substituted lactam moiety; X; is selected from the group consisting of ORs, - SR3, NR3R’3, hydrogen, halogen, CN, C(O)NR3R’3, C(O)ORj, OSO3R3, OPO3R3R’3, NNR3R’3, SNRiR’3, NHSR3, SSR3; and substituted alkyl; X; is selected from the group consisting of OR4, SRg, NR4R’4, hydrogen, halogen, CN, C(O)NRgR’4, C(O)ORy4, OSO3Ry4, OPO3R4R’4, NNRgR'’ys, SNR4R’4, NHSR4, SSRs and substituted alkyl; X3; is selected from the group consisting of ORs, SRs, NRsR's hydrogen, halogen, CN, C(O)NRsR’s, C(O)ORs, OSO3Rs5, OPO3RsR’s5, NNRsR’s, SNRsR'’s, NHSRs, SSRs and substituted alkyl; Xy is selected from the group consisting of ORg, : SR¢, NR¢R’s hydrogen, halogen, CN, C(O)NR¢R’s, C(0)ORg, 0OSO3Rgs, OPO3RgR’s, NNRgR'’s, SNRgR's, NHSRg, SSRg and substituted alkyl; Ri, R’3, Rg, R’4, Rs, R's, Rg and R's are the same or different and are selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted acyl and a carbohydrate moiety; or a pharmaceutically acceptable salt thereof.

2. A compound as claimed in claim 1 wherein one of R; or Ry is Cy.24 alkyl and the other is hydrogen or Ci_a4 alkyl.

3. A compound as claimed in claim 2 wherein one of R; or Ry is Cg-12 alkyl and the other is hydrogen or Ce-1: alkyl.

4. A compound as claimed in claim 3 wherein one of Ry or Ry is Cg1p alkyl and the other is hydrogen or Cs-io alkyl. -

5. A compound as claimed in claim 1 wherein both R; or R; are Cy4-30 alkyl. -

6. A compound as claimed in any one of claims 1 to 5 wherein X; is ORs.

7. A compound as claimed in claim 6 wherein Rj; is hydrogen or Ci-zp acyl.

8. A compound as claimed in any one of claims 1 to 7 wherein X; is OR4.

9. A compound as claimed in claim 8 wherein Ry is hydrogen or Ci-3p acyl.

10. A compound as claimed in any one of claims 1 to 9 wherein X3 is ORs.

11. A compound as claimed in claim 10 wherein Rs is hydrogen or Ci-3p acyl.

12. A compound as claimed in any one of claims 1 to 11 wherein X; is ORs.

13. A compound as claimed in claim 12 wherein Rg is hydrogen or Cj-3zp acyl.

14. A compound as claimed in any one of claims 1 to 13 having the general formula (Ia):

Xa R, J FE Xa joy AN ’%, Ro Xs Xi

15. A compound as claimed in any one of claims 1 to 13 having the general formula (Ib): Xs R; As ~N d : Xs N ‘ R> X3 X4

16. A compound selected from the group consisting of: N,N-Didecyl-5-(2,3,5, 6-tetra-0O-benzoyl-1-thio-f- D-galactofuranosyl)sulfenamide - N,N-Dioctyl-$-(2,3,5, 6-tetra-O-benzoyl-1-thio-fB- D-galactofuranosyl)sulfenamide N,N-Dihexyl-S-(2,3,5, 6-tetra-0O-benzoyl-1-thio-f- p-galactofuranosyl)sulfenamide N, N-Didecyl-S-(1-thio-B-p- galactofuranosyl)sulfenamide N, N-Dioctyl-S-(1-thio-pf-p~ galactofuranosyl) sul fenamide N, N-Dihexyl-S-(1-thio-B-D- galactofuranosyl) sulfenamide N,N-Dioctyl-5-(2,3,5,6~tetra-0-acetyl-1-thio-B-p- glucofuranosyl)sulfenamide - N, N-Dioctyl-S-(1-thio-B-p- glucofuranosyl)sulfenamide.

17. A method of preparation of a compound of general formula (I):

Xs R, : : J i San R: Xs - X comprising reacting a compound of general formula (II): Xq ) O _—te — Xg “X1 wherein is an acyl group, preferably acetyl and X3, Xz, X; and X; are as defined above with the proviso that none of Ri, R’3, Rs, R's, Rs, R’s, Rs and R’s is hydrogen but, instead, is a protecting group; ) with a compound of general formula (III): . A, HN] : “Re wherein R; and Raz as defined above; } in the presence of a bis-activated alkyl halide; and, optionally . . removing the protecting groups.

18. A compound of general formula (I) as claimed in any one of claims 1 to 16 for use in the treatment of a patient with a microbial infection.

19. The use of a compound of general formula (I) as claimed in any one of claims 1 to 16 in the manufacture of a medicament for use in the treatment of a microbial “infection. ]

20. A pharmaceutical composition comprising a compound of general formula (I) as claimed in any one of claims 1 to 16 and a pharmaceutically acceptable carrier.

21. A compound of general formula (I) as claimed in any one of claims 1 to 16 for use in killing a microorganism.

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22. A compound according to claim 1 or 16, substantially as herein described and exemplified.

23. A method according to claim 17, substantially as herein described and exemplified.

24. A compound according to claim 18 or 21, substantially as herein described and exemplified.

25. Use according to claim 19, substantially as herein described and exemplified.

26. A pharmaceutical composition according to claim 20, substantially as herein described and exemplified.