[go: up one dir, main page]

WO2003070239A1 - Benzylidene-thiazolidinediones et leur utilisation en tant qu'agents antimycosiques - Google Patents

Benzylidene-thiazolidinediones et leur utilisation en tant qu'agents antimycosiques Download PDF

Info

Publication number
WO2003070239A1
WO2003070239A1 PCT/GB2003/000752 GB0300752W WO03070239A1 WO 2003070239 A1 WO2003070239 A1 WO 2003070239A1 GB 0300752 W GB0300752 W GB 0300752W WO 03070239 A1 WO03070239 A1 WO 03070239A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
alkyl
phenylethoxy
methoxy
optionally substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB2003/000752
Other languages
English (en)
Inventor
Judi Charlotte Neuss
Michael Glen Orchard
David Ian Carter Scopes
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Oxford Glycosciences UK Ltd
Original Assignee
Oxford Glycosciences UK Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Oxford Glycosciences UK Ltd filed Critical Oxford Glycosciences UK Ltd
Priority to AU2003214367A priority Critical patent/AU2003214367A1/en
Publication of WO2003070239A1 publication Critical patent/WO2003070239A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • 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
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel thiazolidine derivatives, which are useful as antifungal agents.
  • the invention also relates to methods for their preparation, pharmaceutical compositions containing them and their use in medicine, specifically in the treatment of an individual susceptible to or suffering from a fungal infection.
  • the compounds find use in the treatment of fungal infections, such as, topical infections caused by species such as Candida, Trichophyton, Microsporum and Epidermophyton, mucosal infections caused by fungi such as Candida albicans (e.g. thrush and vaginal candidiasis) and systemic infections caused by species such as Candida (e.g. Candida albicans), Aspergillus (e.g. Aspergillus flavus and Aspergillus fumigatus), Cryptococcus (e.g. Cryptococcus neoformans), Coccidioides, Paracoccidioides, Histoplasma or Blastomyces.
  • fungal infections such as, topical infections caused by species such as Candida,
  • the cell wall of pathogenic fungal organisms is an essential component for their survival. Defects in the cell wall structure will result in cell swelling and ultimately death through cell rupture. The unique nature of the fungal cell wall has made its synthesis and re-modelling a focus for the development of novel antifungal agents.
  • the wall consists of three major components: complex ⁇ l-3 and ⁇ l-6 linked glucan chains, chitin and cell wall mannoproteins.
  • the ⁇ -glucans represent 50-60% of the cell wall mass, forming a rigid skeletal structure responsible for shape and physical 'strength.
  • the chitin is only a minor component (>3%), but forms a structure to which the ⁇ -glucan is linked and is essential for bud scar formation during cell division.
  • agents that are being developed as antifungal treatments targeted against the synthesis of ⁇ -glucans (e.g. lipopeptides, such as echinocandins and pneumocandins, see Kurtz, M.B. & Douglas, CM. (1997) J. Med. Vet. Myc. 35, 79-86.) or chitin (e.g. nikkomycin Z, see Obi, K. et al., (2000) Bioorg. Med- Chem. Lett. 10, 1451-4).
  • the mannoproteins represent the remaining content of the wall. They form radially extending fibrillae at the outside of the cell wall and are believed to confer the cell surface properties involved in adhesion and host interactions.
  • a number of classes of mannoproteins have been identified (e.g. Sedl, Floll, Agal, Pir2, Alsl, Axl2) and these have been separated into groups dependent upon the nature of their attachment to the other cell wall components (Kapteyn, J.C. et al., (2000) Mol. Microbiol. 35, 601- 11). During their secretion from the cell some receive a GPI anchor and all become mannosylated. Mannosylation of these proteins is divided into two categories: O- and N-linked.
  • the N-linked are attached via asparagine residues and form extensive branched structures consisting of an ⁇ l,6 backbone to which ⁇ l,2-, ⁇ l,3- and ⁇ l,2- side chains are attached.
  • the O-linked are attached via serine or threonine residues and consist of short linear chains.
  • the extension of both chain types is catalysed by a family of mannosyltransferases.
  • the initial mannose residue is added to serine or threonine by a protein:mannosyl transferase (PMT) which uses dolicholphospho-mannose as a donor of the mannose. Seven PMT's have been reported in S. cerevisiae (Strahl-Bolsinger, S.
  • Fungal infections can affect animals including humans. These can include infections of the joints and skin. Some fungal infections occur as a result of opportunistic infection of a weakened or immune- suppressed individual. The incidence of life-threatening fungal infections has increased dramatically as the population of immunocompromised individuals (including cancer, organ transplant and AIDS patients) has increased. Present therapeutic options for the treatment of these infections are largely limited to two classes of compound: polyenes and azoles. The utility of polyenes is limited by nephrotoxicity and resistance is emerging to azoles. There is therefore a need for new antifungal compounds with novel mechanisms of action for use in treating or preventing such fungal infections.
  • W094/29287 discloses arylidene-4-oxo-2-thioxo-3 -thiazolidine carboxylic acids of the formula
  • WO00/18747 discloses rhodanine carboxylic acid derivatives of the formula
  • WO02/22612 and WO02/17915 disclose thiazolidine derivatives having antifungal activity.
  • A is O or S
  • Q is CCHa ⁇ n -CHOR'HCHz),,; m is 0, 1, 2 or 3; n is 0, 1 or 2; q is O or 1;
  • R is OR 6 orNHR 8 ;
  • R 1 is hydrogen or Cr-C 6 alkyl optionally substituted with one or more of hydroxyl, COR, C1-C 3 alkylphenyl or phenyl; one or both of R 2 and R 3 is independently (CH 2 ) n -CH(R ⁇ )-(CH 2 ) q -aryl where aryl is phenyl, pyridyl, thienyl, or furyl wherein phenyl is optionally substituted by one or more substituents selected' from F, CI, Br, CF 3 , OCF 3 , OR 7 , C r C 6 alkyl, COR, CN, S0 2 R 9 and S0 2 NR 8 R 9 , and pyridyl, thienyl or furyl are optionally substituted by F, CI, Br, CF 3 , OR 6 or C r C 6 alkyl; the other of R 2 and R 3 is hydrogen, C
  • R 4 is hydrogen, F, CI, Br, CF 3 , OR 6 , C C 6 alkyl or O(CH 2 ) n -CH(R 10 )-(CH 2 ) q -aryl where aryl is phenyl, pyridyl, thienyl, or furyl, wherein phenyl is optionally substituted by one or more substituents selected from F, CI, Br, CF 3 , OCF 3 , OR 7 , C r C 6 alkyl, COR, CN, S0 2 R 9 and S0 2 NR 8 R 9 , and pyridyl, thienyl or furyl are optionally substituted by F, CI, Br, CF , OR 6 or C ⁇ -C 6 alkyl;
  • R 5 is hydrogen, Q-C ⁇ alkyl or phenyl optionally substituted by one or more substituents selected fromF, CI, Br, CF 3 , OCF 3 , OR 6 , C,-C 6 alkyl, COR, CN and S0 2 R 9 ;
  • R 6 and R 7 are independently hydrogen, - alkyl, C 3 -C 6 cycloalkyl, or phenyl optionally substituted by one or more substituents selected from F, CI, Br, CF 3 , OCF 3 , C C 6 alkyl, COR, CN and S0 2 R 9 ;
  • R 8 is hydrogen or C 1 -C 3 alkyl
  • R 9 is C ⁇ -C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl or C 1 -C 3 alkylphenyl;
  • R 10 is hydrogen, C0 2 R 6 , CONR 6 R 9 or C r C 6 alkyl optionally substituted by hydroxy, CF 3 , C0 2 R 6 or CONR 6 R 9 ; wherein R 6 and R 9 together with the nitrogen atom to which they are attached may form a 5- or 6- membered ring, optionally incorporating one or more additional heteroatoms selected from oxygen, nitrogen and sulfur, wherein the ring may be optionally substituted by one or more of C ⁇ -C 6 alkyl, aryl, or C ⁇ -C 6 alkylaryl;
  • R" is Ci- alkyl substituted by C C 6 alkoxy, C(0)OR 12 or OC(0)R 12 , or when n > 1, R ⁇ may be Ci-C ⁇ alkoxy, C(0)OR 12 or OC(0)R 12 ; or R ⁇ may be linked to the aryl group in (CH 2 ) friendship-CrI(R ⁇ )-(CH 2 ) q -aryl to form a fused 5- or 6- membered ring containing one O atom; and
  • R 12 is hydrogen or - alkyl.
  • A is preferably S.
  • Q is preferably C ⁇ R 1 ).
  • m is preferably 0, 1 or 2.
  • n is preferably 0 or 1.
  • q is preferably 0.
  • R is preferably OR 6 or NH 2 . More preferably R is OH.
  • R 1 is preferably hydrogen, or Q-Q alkyl. More preferably R 1 is hydrogen.
  • R 2 is preferably (CH 2 ) n -CH(R n )-(CH 2 ) q -aryl, Q-Q 0 alkyl optionally substituted with Q-Q cycloalkyl; (CH 2 ) m -(CF 2 ) n CF 3 , or (CH 2 ) n -CH(R 10 )-(CH 2 ) q -aryl.
  • R 2 is Q-Q 0 alkyl optionally substituted with Q-Q cyclohexyl; (CH 2 ) m -(CF 2 ) intuitionCF 3 , (CH 2 ) n -CH(R n )-(CH 2 ) q - ⁇ henyl, CH(R 10 )-phenyl or CH 2 CH(R 10 )-phenyl, where phenyl is optionally substituted by one or more substituents selected from F, CI, CF 3 , OCF 3 , Q-Q alkyl, OR 7 or S0 2 R 9 .
  • R 2 is CH(R ⁇ )- pheny ⁇ , CH 2 CH(R n )-phenyl, CH(R 10 )-phenyl or CH 2 CH(R l0 )-phenyl, where phenyl is optionally substituted by one or more substituents selected from F, CI, CF 3 , OCF 3 , Q-Q alkyl, OR 7 or S0 2 R 9 .
  • R 2 is CH(R 10 )-phenyl or CH 2 CH(R 10 )-phenyl where phenyl is optionally substituted by one or more substituents selected fromF, CI, CF 3 , OCF 3 , Q-Q alkyl, OR 7 or S0 2 R 9 .
  • R 2 is preferably in the para position relative to the methylene-3 -thiazolidine group.
  • R 3 is preferably (CH 2 ) folk-CH(R n )-(CH 2 ) q -aryl. More preferably R 3 is (CH 2 ) hinder-CH(R ⁇ )-(CH 2 ) q - phenyl, where phenyl is optionally substituted by one or more substituents selected from F, CI, CF 3 , OCF 3 , Q-Q alkyl, OR 7 or SO z R 9 but is preferably unsubstituted.
  • R 3 is preferably (CH 2 ) n -CH(R 10 )-(CH 2 ) q -aryl, more preferably CH(R 10 )-phenyl or CH 2 CH(R 10 )-phenyl, where phenyl is optionally substituted by one or more substituents selected from F, CI, CF 3 , OCF 3 , Q-Q alkyl, OR 7 or S0 2 R 9 but is preferably unsubstituted.
  • R 4 is preferably hydrogen F, CI, Br, CF 3 , OR 6 , Q-Q alkyl or 0-CH 2 -phenyl wherein phenyl is optionally substituted by one or more substituents selected from F, CI, Br, CF 3 , OCF 3 , OR 6 , Q-Q alkyl, COR, CN, S0 2 R 9 and S0 2 NR 8 R 9 . More preferably R 4 is hydrogen or 0-CH 2 -phenyl.
  • R 5 is preferably hydrogen or Q-Q alkyl. More preferably R 5 is hydrogen.
  • R 6 is preferably hydrogen or Q-Q alkyl. More preferably R 6 is hydrogen.
  • R 7 is preferably hydrogen or Q-Q alkyl.
  • R 7 is Q-Q alkyl.
  • R 9 is preferably Q-Q alkyl or phenyl. More preferably R 9 is Q-Q alkyl.
  • R 10 is preferably hydrogen, C0 2 R 6 , CONR 6 R 9 , or Q-Q alkyl optionally substituted by hydroxy.
  • R 10 is hydrogen or Q-Q alkyl optionally substituted by hydroxy.
  • R 6 and R 9 together with the nitrogen atom to which they are attached form a ring, this is preferably a piperidine ring, optionally incorporating one or more additional heteroatoms selected from oxygen, nitrogen and sulfur, (e.g. a piperazine ring) wherein the ring may be optionally substituted by one or more of Q-Q alkyl or phenyl.
  • a piperidine ring optionally incorporating one or more additional heteroatoms selected from oxygen, nitrogen and sulfur, (e.g. a piperazine ring) wherein the ring may be optionally substituted by one or more of Q-Q alkyl or phenyl.
  • R 11 is preferably Q-Q alkyl substituted by Q-Q alkoxy ⁇ or OC(0)R 12 , or when n > 1, R 11 may be Q-Q alkoxy, or OC(0)R 12 . More preferably R 11 is Q-Q alkyl substituted by Q-Q alkoxy.
  • R 11 When R 11 is linked to the aryl group in (CH 2 ) folk-CH(R n )-(CH 2 ) q -aryl to form a fused 5- or 6- membered ring containing one O atom, the resulting group R 2 and/or R 3 may be of the formula:
  • the compounds of the invention preferably have a molecular weight of less than 800, more preferably less than 600.
  • alkyl as used herein whether on its own or as part of a larger group e.g. "alkylaryl” or “alkoxy”, includes both straight and branched chain radicals, including but not limited to methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl and tert-butyl.
  • alkyl also includes those radicals wherein one or more hydrogen atoms are replaced by fluorine.
  • cycloalkyl as used herein includes cyclic radicals such as cyclopropyl, cyclopentyl and cyclohexyl.
  • aryl as used herein includes 5- to 10-membered aromatic, mono- or bi-cyclic ring systems. Aryl groups may contain up to 3 heteroatoms selected from oxygen, nitrogen and sulfur. Examples of aryl groups include phenyl, pyridyl, thienyl, and furyl. A preferred aryl group is phenyl.
  • antifungal agent as used herein at all occurrences includes a compound or composition which alleviates or reduces the symptoms of a fungal infection or an agent which causes harm to fungus allowing the destruction of a fungus either by the agent, a second agent or the hosts natural defences (e.g. the immune system).
  • Another compound of the invention is 5-[[3-(2-methoxy-l-phenylethoxy)-4-[(4- trifluoromethoxyphenyl)ethoxy]phenyl]methylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid.
  • a particularly preferred compound of the invention is 5-[[3-(2-methoxy-l-phenylethoxy)-4-[(4- trifluoromethoxyphenyl)methoxy]phenyl]methyle ⁇ e]-4-oxo-2-thioxo-3-thiazolidineacetic acid.
  • Suitable pharmaceutically acceptable salts of the compounds include those derived from inorganic and organic bases.
  • suitable inorganic bases for the formation of salts of compounds for this invention include the hydroxides, carbonates, and bicarbonates of ammonia, lithium, sodium, calcium, potassium, aluminium, iron, magnesium, zinc and the like. Salts can also be formed with suitable organic bases.
  • Such organic bases are already well known in the art and may include amino acids such as arginine and lysine, mono-, di-, or tri-hydroxyalkylamines, such as ethanolamine or choline, mono-, di-, and tri-alkylamines, such as methylamine, dimethylamine or trimethylamine, guanidine, N- methylglucosamine, N-methylpiperazine, morpholine, ethylenediamine, N-benzylphenethylamine, tris(hydroxymethyl) aminomethane, meglumine and the like.
  • amino acids such as arginine and lysine, mono-, di-, or tri-hydroxyalkylamines, such as ethanolamine or choline, mono-, di-, and tri-alkylamines, such as methylamine, dimethylamine or trimethylamine, guanidine, N- methylglucosamine, N-methylpiperazine, morpholine, ethylenediamine, N-benzylphene
  • salts can also be formed with organic acids such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, or mineral acids such as hydrochloric acid, sulfuric acid and the like, giving methanesulfonate, benzenesulfonate, p-toluenesulfonate, hydrochloride and sulfate salts, and the like, respectively.
  • organic acids such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid
  • mineral acids such as hydrochloric acid, sulfuric acid and the like
  • Salts may be prepared in a conventional manner using methods well known in the art.
  • the compounds of this invention may be crystallised or recrystallised from solvents such as aqueous and organic solvents. In such cases solvates may be formed.
  • This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.
  • the invention also includes prodrugs of the aforementioned compounds.
  • a prodrug is commonly described as an inactive or protected derivative of an active ingredient or a drug, which is converted to the active ingredient or drug in the body.
  • prodrugs include pharmaceutically acceptable esters, including Q-Q alkyl esters and pharmaceutically acceptable amides, including secondary Q-Q alkylamides.
  • the invention extends to active derivatives of the aforementioned compounds.
  • the compounds of the invention may exist in the form of optical isomers, e.g. diastereoisomers and mixtures of isomers in all ratios, e.g. racemic mixtures.
  • the invention includes in particular the isomeric forms (R or S).
  • the different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.
  • a compound contains an alkene moiety, the alkene can be presented as a cis or trans isomer or a mixture thereof.
  • an isomeric form of a compound of the invention When an isomeric form of a compound of the invention is provided substantially free of other isomers, it will preferably contain less than 5% w/w, more preferably less than 2% w/w and especially less than 1% w/w of the other isomers.
  • the compounds of the invention are intended for use in pharmaceutical compositions, it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more suitably at least 5%, e.g. 10 to 59% of a compound of the formula (I).
  • the compounds of formula (I) can be prepared by art-recognized procedures from known or commercially available starting materials. If the starting materials are unavailable from a commercial source, their synthesis is described herein, or they can be prepared by procedures known in the art.
  • the compounds of the invention may be prepared by condensation of rhodanine-3- acetic acid, or 2,4-dioxo-3-thiazolidineacetic acid or an analogue or derivative thereof, with the appropriate substituted benzaldehyde derivative (or alkylphenone derivative) under general acid-base catalysis conditions using typical reagents for such a process, e.g. sodium acetate in acetic acid or ammonium acetate in a suitable solvent such as toluene or DMF, usually with the application of heat
  • Rhodanine-3 -acetic acid is commercially available and its analogues can be prepared by methods known to one skilled in the art.
  • the benzaldehyde derivatives can be prepared by the methods outlined in the Examples.
  • the compounds of formula (I) may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000 compounds, and more preferably 10 to 100 compounds of formula (I).
  • Libraries of compounds of formula (I) may be prepared by a combinatorial 'split and mix' approach or by multiple parallel synthesis using either solution phase or solid phase chemistry, by procedures known to those skilled in the art.
  • a compound library comprising at least 2 compounds of formula (I).
  • the compounds of the invention may be administered in conventional dosage forms prepared by combining one of the aforementioned compounds ("active ingredient") with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, excipient and/or diluent.
  • the compounds or pharmaceutical compositions may be administered to a subject by any of the routes conventionally used for drug administration, for example they may be adapted for oral (including buccal, sublingual), topical (including transdermal), nasal (including inhalation), rectal, vaginal or parenteral
  • compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) excipient(s) or diluent(s).
  • carrier(s) excipient(s) or diluent(s) Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulfate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for. reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives, such as suspending agents, for example— sorbitol, methyl cellulose ⁇ - glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
  • suspending agents for example— sorbitol, methyl cellulose ⁇ - glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monoo
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, impregnated dressings, sprays, aerosols or oils and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • Such applications include those to the eye or other external tissues, for example the mouth and skin and the compositions are preferably applied as a topical ointment or cream.
  • the active ingredient may be employed, for example, a paraffinic or a water-miscible ointment base.
  • the active ingredient may be formulated in a cream with an oil- in-water cream base or a water-in-oil base.
  • the composition may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • compositions adapted for topical administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • compositions adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318, (1986).
  • Pharmaceutical compositions adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size, for example, in the range 20 to 500 microns, which is administered by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable compositions wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops include aqueous or oil solutions of the active ingredient.
  • Pharmaceutical compositions adapted for administration by inhalation include fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulizers or insufflators.
  • compositions adapted for rectal administration may be presented as suppositories or enemas.
  • Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray compositions.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • The, compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • fluid unit dosage forms are prepared utilizing the active ingredient and a sterile vehicle, water being preferred.
  • the active ingredient depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the active ingredient can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • the dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions are prepared in substantially the same manner except that the active ingredient is suspended in the vehicle instead of being dissolved and sterilization, cannot be accomplished by filtration.
  • the active ingredient can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active ingredient.
  • the pharmaceutical compositions according to the invention are preferably adapted for oral or topical administration.
  • compositions may also include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents. They may also contain therapeutically active agents in addition to the compounds of the invention.
  • compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of the active ingredient, depending on the method of administration.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per dose.
  • a unit may contain for example O.lmg/kg to 750mg/kg, more preferably O.lmg kg to lOmg/kg depending on the condition being treated, the route of administration and the age, weight and condition of the subject.
  • Preferred unit dosage compositions are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • the optimal quantity and spacing of individual dosages of the compounds of the invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular subject being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e. the number of doses of the aforementioned compounds given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
  • the compounds of the present invention are useful as antifungal agents.
  • the compounds of the invention can be used in the treatment of various fungal infections such as, topical infections caused by species such as Candida, Trichophyton, Microsporum and Epidermophyton, mucosal infections caused by fungi such as Candida albicans (e.g. thrush and vaginal candidiasis) and systemic infections caused by species such as Candida (e.g. Candida albicans), Aspergillus (e.g. Aspergillus flavus and Aspergillus fumigatus), Cryptococcus (e.g. Cryptococcus neoformans), Coccidioides, Paracoccidioides, Histoplasma or Blastomyces.
  • fungal infections such as, topical infections caused by species such as Candida, Trichophyton, Microsporum and Epidermophyton, mucosal infections caused by fungi such as Candida albicans (e.g. thrush and vaginal candidiasis
  • the compounds of the invention can be used in the treatment of fungal infections in humans and animals, especially domestic animals such as dogs, cats, horses etc.
  • the compounds of the invention can also find use in the treatment of fungal infections in subjects who are immunosuppressed e.g. as a result of a therapy (e.g. chemotherapy or radiotherapy), organ transplant or an infection (e.g. HTV).
  • a therapy e.g. chemotherapy or radiotherapy
  • organ transplant e.g. HTV
  • the compounds or pharmaceutical compositions can be administered simultaneously, separately or sequentially with one or more other antifungal treatment.
  • treatment is meant either prophylactic or therapeutic i.e. curative therapy.
  • the present invention provides: i) the use of a compound of formula (I) as an antifungal agent. ii) the use of a compound of formula (I) in the manufacture of a medicament for the treatment of fungal infections such as, topical infections caused by species such as Candida, Trichophyton, Microsporum and Epidermophyton, mucosal infections caused by fungi such as Candida albicans (e.g. thrush and vaginal candidiasis) and systemic infections caused by species such as Candida (e.g. Candida albicans), Aspergillus (e.g. Aspergillus flavus and Aspergillus fumigatus), Cryptococcus (e.g.
  • fungal infections such as, topical infections caused by species such as Candida, Trichophyton, Microsporum and Epidermophyton, mucosal infections caused by fungi such as Candida albicans (e.g. thrush and vaginal candidiasis) and systemic infections caused by species such as
  • a compound of formula (I) in the manufacture of a medicament for the treatment of fungal infections in a subject who is immunosuppressed, for example as a result of a therapy (e.g. chemotherapy or radiotherapy), organ transplant or an infection (e.g. HIV).
  • a method for the treatment of fungal infections in a subject such as, topical infections caused by species such as Candida, Trichophyton, Microsporum and Epidermophyton, mucosal infections caused by fungi such as Candida albicans (e.g.
  • Candida e.g. Candida albicans
  • Aspergillus e.g. Aspergillus flavus and Aspergillus fumigatus
  • Cryptococcus e.g. Cryptococcus neoformans
  • Coccidioides e.g. Paracoccidioides, Histoplasma or Blastomyces
  • a method for the treatment of fungal infections in a subject who is immunosuppressed for example as a result of a therapy (e.g. chemotherapy or radiotherapy), organ transplant or an infection (e.g.
  • HIV which comprises the step of administering to the subject an effective amount of a compound of the invention.
  • Example 1 5-[[3-(PhenyImethoxy)-4-[(R)-2-methoxy-2-phenylethoxy]phenyI]methylene]-4-oxo-2- thioxo-3-thiazolidineacetic acid (a) (R)-2-Methoxy-2-phenylethyl methanesulfonate
  • This compound was prepared from (S)-2-methoxy-2-phenylethyl methanesulfonate following the same procedure as that which was used to prepare 3-(phenylmethoxy)-4-[(R)-2-methoxy-2- phenylethoxyjbenzaldehyde (Example 1(e)).
  • the product was obtained as a colourless, viscous oil (33%) R F (petroleum ethe ⁇ ethyl acetate, 3:1) 0.33.
  • This compound was prepared from 3-(phenylmethoxy)-4-[(S)-2-methoxy-2- phenylethoxyjbenzaldehyde using a similar procedure as that described for 5-[[3-(phenylmethoxy)-4- [(R)-2-methoxy-2-phenylethoxy]phenyl]methylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid (Example 1(f)), except that attempts to crystallize the product failed. Instead, it was chromatographed on silica and eluted with ethyl acetate/methanol (9:1).
  • (a) (S)-2-Phenyl ⁇ ropyl methanesulfonate was prepared from (S)-2-phenylpropanol as described in Example 1(a).
  • (b) 3-Hydroxy-4-[(S)-2-phenylpropoxy]benzaldehyde (S)-2-Phenylpropyl methanesulfonate (8.0g, 37.3mmol, leq) was added to a stirred solution of 3,4-dihydroxybenzaldehyde (5.15g, 37.3mmol, leq) and cesium carbonate (12.16g, 37.3mmol, leq) in N,N-dimethylformamide (lOOmL).
  • This compound was synthesised from 3-(2-methoxy-l-phenylethoxy)-4-[(S)-2- phenylpropoxy]benzaldehyde following the same procedure as that described in Example 3(c), except that the reaction required 17h.
  • the final product was obtained as a yellow foam, isolated as a 1: 1 mixture of diastereoisomers (87%) mp 64°C.
  • This compound was synthesized from 3-(2-methoxy-l-phenylethoxy)-4-[(R)-2- phenylpropyloxyjbenzaldehyde following the same procedure as that described for Example 3(c), except that the reaction required 4h.
  • the final product was obtained as yellow foam, isolated as a 1:1 mixture of diastereoisomers (24%) mp 69-75°C.
  • This compound was prepared from 3-(2-methoxy-l-phenylethoxy)-4-[2-(4- fluorophenyl)ethoxy]benzaldehyde following the same procedure as that described for Example 3(c), except that the reaction required 4h.
  • Manganese dioxide (2.52g, 29mmol, lOeq) was added to a solution of 3-(2-methoxy-l- phenylethoxy)-4-[(4-trifluoromethoxyphenyl)methoxy]benzyl alcohol (1.3g, 2.9mmol, leq) in dichloromethane (50mL). The reaction mixture was heated to reflux and stirred for lh. It was cooled to room temperature, filtered through celite and concentrated in vacuo.
  • the assay method is based upon the transfer of a radiolabelled mannose moiety from dolicholphosphomannose onto a threonine hydroxyl residue in a short peptide, as catalysed by the Candida albicans PMT-1 enzyme.
  • Dolicholphospho-[ 3 H] -mannose is synthesised enzymatically from GDP-[ 3 H] -mannose and purified by chloroform: methanol extraction. 100000 Dpm of the generated substrate is incubated with 400 ⁇ g phosphatidylcholine, 25 ⁇ g of peptide (DYATAV) and 25 ⁇ g of Candida albicans membrane protein in a final volume of 50 ⁇ l in lOOmM Tris/lmM MgCl 2 buffer, pH 8.0.
  • Test compounds dissolved in DMSO, are added to a final concentration of up to lOO ⁇ M, with a maximal solvent concentration of 1%. After 60 min at 25 °C, the reaction is stopped with 50 ⁇ l of methanol. The unreacted radiolabel is removed by the addition of 150 ⁇ l of 0.4g/ml octadecyl-functionalised silica (C18) in methanol. The C18 material is removed by centrifugation and the activity transferred to the peptide is counted in the supernatant.
  • This assay is based upon the observed increased sensitivity of the pmtl-/- Candida strain to Geneticin (G418).
  • lOO ⁇ l of a 0.1 OD 6 oo nm culture of Candida albicans (strain SC5314) is placed into a 96 well plate in the presence or absence of varying concentrations of test compound.
  • the compounds are initially dissolved in DMSO and added to the cultures at a final DMSO concentration of 1%.
  • G418 is added to a final concentration of lOO ⁇ g/ml. In the absence of PMT-1 inhibition, this concentration of G418 has no effect on the proliferation of the organism.
  • the cultures are grown overnight at 37°C and cell density is then estimated by an OD 6 oo nm measurement.
  • the effect of the test compound is calculated as the concentration that gives a 50% reduction in cell growth relative to the culture with G418 alone.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention a trait à des dérivés de la thiazolidine représentés par la formule (I), à leurs procédés de préparation, à des compositions pharmaceutiques les contenant, et à leur utilisation en médecine, en particulier pour le traitement d'infections fongiques. Dans ladite formule (I), A représente O ou S ; Q représente (CH2)m-CH(R1)-(CH2)n ; m est 0, 1, 2 ou 3 ; n est 0, 1 ou 2 ; R représente OR6 ou NHR8 ; et R1 à R5 représentent divers substituants.
PCT/GB2003/000752 2002-02-23 2003-02-21 Benzylidene-thiazolidinediones et leur utilisation en tant qu'agents antimycosiques Ceased WO2003070239A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003214367A AU2003214367A1 (en) 2002-02-23 2003-02-21 Benzylidene thiazolidinediones and their use as antimycotic agents

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0204252.1A GB0204252D0 (en) 2002-02-23 2002-02-23 Novel compounds
GB0204252.1 2002-02-23

Publications (1)

Publication Number Publication Date
WO2003070239A1 true WO2003070239A1 (fr) 2003-08-28

Family

ID=9931614

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2003/000752 Ceased WO2003070239A1 (fr) 2002-02-23 2003-02-21 Benzylidene-thiazolidinediones et leur utilisation en tant qu'agents antimycosiques

Country Status (3)

Country Link
AU (1) AU2003214367A1 (fr)
GB (1) GB0204252D0 (fr)
WO (1) WO2003070239A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009143041A1 (fr) * 2008-05-20 2009-11-26 Merck & Co., Inc. Production efficace de protéines hétérologues à l'aide d'inhibiteurs de la mannosyl transférase
WO2021123145A1 (fr) 2019-12-19 2021-06-24 Universite De Strasbourg Ligands de récepteurs sigma-1 et leurs utilisations

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001002377A1 (fr) * 1999-07-01 2001-01-11 Geron Corporation Inhibiteurs de telomerase et leurs procedes d'utilisation
WO2002017915A1 (fr) * 2000-08-31 2002-03-07 Oxford Glycosciences (Uk) Limited Thiazolidinediones de benzylidene et leur utilisation en tant qu'agents antifongiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001002377A1 (fr) * 1999-07-01 2001-01-11 Geron Corporation Inhibiteurs de telomerase et leurs procedes d'utilisation
WO2002017915A1 (fr) * 2000-08-31 2002-03-07 Oxford Glycosciences (Uk) Limited Thiazolidinediones de benzylidene et leur utilisation en tant qu'agents antifongiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LIMA M C A ET AL.: "Synthesis and antimicrobial activity of chlorobenzyl benzylidine imidazolidinediones and substituted thiazolidinediones", PHARMAZIE, vol. 47, no. 3, 1992, VEB VERLAG VOLK UND GESUNDHEIT. BERLIN., DD, pages 182 - 184, XP001152531, ISSN: 0031-7144 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009143041A1 (fr) * 2008-05-20 2009-11-26 Merck & Co., Inc. Production efficace de protéines hétérologues à l'aide d'inhibiteurs de la mannosyl transférase
CN102036974A (zh) * 2008-05-20 2011-04-27 默沙东公司 利用甘露糖基转移酶抑制剂有效生产异源蛋白质
JP2011520968A (ja) * 2008-05-20 2011-07-21 メルク・シャープ・エンド・ドーム・コーポレイション マンノシルトランスフェラーゼ阻害剤を使用した異種蛋白質の効率的生産
US8765409B2 (en) 2008-05-20 2014-07-01 Merck Sharp & Dohme Corp. Efficient production of heterologous proteins using mannosyl transferase inhibitors
CN102036974B (zh) * 2008-05-20 2014-07-23 默沙东公司 利用甘露糖基转移酶抑制剂有效生产异源蛋白质
WO2021123145A1 (fr) 2019-12-19 2021-06-24 Universite De Strasbourg Ligands de récepteurs sigma-1 et leurs utilisations

Also Published As

Publication number Publication date
AU2003214367A1 (en) 2003-09-09
GB0204252D0 (en) 2002-04-10

Similar Documents

Publication Publication Date Title
EP3483142B1 (fr) Composé aromatique d'acétylène ou d'éthylène, produit intermédiaire, procédé de préparation, composition pharmaceutique et leur utilisation
EP1313471B1 (fr) Thiazolidinediones de benzylidene et leur utilisation en tant qu'agents antifongiques
JP4869072B2 (ja) Ａｔｐ結合カセットトランスポーターのモジュレーターとして有用なチアゾールおよびオキサゾール
JP3356751B2 (ja) 糖尿病合併症治療用および予防用組成物
RU2125565C1 (ru) Производные фенокси- или феноксиалкилпиперидина и антивирусная композиция на их основе
EP1426046A1 (fr) Nouvelle utilisation de composes tricycliques
AU2014204831C1 (en) Benzylideneguanidine derivatives and therapeutic use for the treatment of protein misfolding diseases
WO2004092123A2 (fr) Inhibiteurs d'invasion fongique
JP2019527717A (ja) アミノピリミジンｓｓａｏ阻害剤
EP1313731B1 (fr) Derives de thiazolidine et leur utilisation comme agents antifongiques
CN102803223A (zh) 具有取代苯基的环状化合物
CN113784950A (zh) 新型拟甲状腺素药
JP2002517385A (ja) カリウムチャネル阻害剤
US20230119894A1 (en) Therapeutic or prophylactic method for diabetes using combination medicine
JP2002510623A (ja) 抗糖尿病薬
CN101282926A (zh) S1p3受体拮抗剂
US11708353B2 (en) Inhibitors of prolyl-tRNA-synthetase
WO2003070239A1 (fr) Benzylidene-thiazolidinediones et leur utilisation en tant qu'agents antimycosiques
CN102807575A (zh) 3-芳基-5-噻吩基-5H-噻唑并[3,2-a]嘧啶类衍生物及其应用
WO2003070238A1 (fr) Agents antifongiques a base de thiazolidine
EP1919867B1 (fr) Analogues d'une lisofylline et procedes d'utilisation de ceux-ci
EP3423448A1 (fr) Composés de médiation des récepteurs cannabinoïdes
EP4021898B1 (fr) Inhibition de la sécrétion mycobactérienne de type vii
EP1491537B1 (fr) Derive de l'hydroxymorpholinone et ses utilisations medicales
US10961211B2 (en) Isotopically-stabilized tetronimide compounds

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP