EP1228048A1 - Sordaricinderivate mit antifungaler wirkung - Google Patents

Sordaricinderivate mit antifungaler wirkung

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Publication number
EP1228048A1
EP1228048A1 EP00972905A EP00972905A EP1228048A1 EP 1228048 A1 EP1228048 A1 EP 1228048A1 EP 00972905 A EP00972905 A EP 00972905A EP 00972905 A EP00972905 A EP 00972905A EP 1228048 A1 EP1228048 A1 EP 1228048A1
Authority
EP
European Patent Office
Prior art keywords
compound
alkyl
methyl
straight
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.)
Withdrawn
Application number
EP00972905A
Other languages
English (en)
French (fr)
Inventor
Jose Maria Bueno
Jose Maria Fiandor
Araceli Mallo
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.)
BASF Enzymes LLC
Original Assignee
Glaxo Wellcome SA
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 Glaxo Wellcome SA filed Critical Glaxo Wellcome SA
Priority to EP00972905A priority Critical patent/EP1228048A1/de
Publication of EP1228048A1 publication Critical patent/EP1228048A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms

Definitions

  • This invention relates to novel carbocydic derivatives having antifungal activity. More particularly it relates to novel sordaricin derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine, more particularly in the prevention or treatment of diseases in animals, including humans, caused by fungal infection.
  • British Patent Specification No. 1 ,162,027 describes the preparation of an antibiotic, SL2266, by the cultivation of the strain NRRL 3196 of the fungus species Sordaria araneosa.
  • SL 2266 later named sordarin, is reported to have fungistatic activity.
  • the same research group also described in Helvetica Chimica Acta (1971 ), 51 ⁇ , 119-120 the degradation of sordarin to sordaricin.
  • Published Japanese Patent Application No. J6 2040292A describes the preparation of an antibiotic, zofimarin, which is reported to have antifungal activity.
  • Sordarin, sordaricin and zofimarin may be represented by formula (A) below
  • OR as sordarin; OR as OH describes sordaricin; and OR as
  • sordarin and zofimarin exhibit antifungal activity, both compounds are only moderately active and have limited spectra of action when tested against a battery of fungal organisms.
  • WO96/14326 and WO96/14327 describe novel sordarin derivatives which exhibit useful antifungal activity.
  • WO99/09974 and WO99/09975 describe 4- cyano-4-deformyl sordarin and sordaricin derivatives which exhibit antifungal activity.
  • R represents a group selected from CXR 2 , CXOR 3 , CONHR 4 or SO ⁇ ;
  • X is oxygen or sulphur
  • R 2 is a group selected from C ⁇ straight or branched chain alkyl, C 2 ⁇ straight or branched chain alkenyl, C 2 ⁇ straight or branched chain alkynyl, C, ⁇ straight or branched chain alkyl substituted by a group selected from (C ⁇ alkoxy, hydroxy, halogen, C ⁇ alkoxycarbonyl, carboxy or optionally substituted phenyl), optionally substituted phenyl, or optionally substituted 5 or 6 membered heteroaryl group or optionally substituted C ⁇ cycloalkyl or C ⁇ alkoxycarbonyl
  • R 3 is a group selected from C ⁇ straight or branched alkyl, C 2 ⁇ straight or branched alkenyl or alkynyl or C straight or branched alkyl substituted by a group selected from C ⁇ 4 alkoxy, hydroxy, halogen, carboxy, C lJt alkoxycarbonyl or optionally substituted phenyl;
  • R 4 represents C
  • Physiologically acceptable salts of the compounds of formula (I) include salts formed with physiologically acceptable bases as well as internal salts.
  • Suitable physiologically acceptable salts of the compounds of formula (I) with bases include inorganic base salts such as alkali metal salts (for example sodium and potassium salts) and ammonium salts and organic base salts.
  • Suitable organic base salts include amine salts such as trialkylamine (e.g. triethylamine), dialkylamine (e.g. dicyclohexylamine), optionally substituted benzylamine (e.g.
  • phenylbenzylamine or p-bromobenzylamine procaine, ethanolamine, diethanolamine, N-methylglucosamine and tri(hydroxymethyl)methylamine salts and amino acid salts (e.g. lysine and arginine salts).
  • references hereinafter to a compound of formula (I) includes that compound and physiologically acceptable salts thereof.
  • Metabolically labile derivatives of compounds of formula (I) are compounds which are converted in the body into compounds of formula (I).
  • examples of such derivatives include conventional metabolically labile esters formed from the free carboxylic acid in the molecule. It is well known in the field of medicinal chemistry that there is a wide range of structurally distinct esters of carboxylic acid which are readily hydrolysed in the body to yield the parent carboxylic acid or a salt thereof and it is to be understood that the present invention encompasses all such esters.
  • esters examples include phthalidyl, (2-oxo-5-methyl-1 ,3-dioxolen-4- yl) methyl or those derived from the alcohol HOCH(R a ) OCO(0) pR b , wherein R a is hydrogen or C ⁇ alkyl, p is zero or 1 and R b is a group selected from C ⁇ alkyl (optionally substituted by one or two groups selected from amino, C,.
  • R b is a 5 to 8 membered heterocyclic ring containing one or 2 hetero groups selected from oxygen or NH e.g. piperedino-4-yl or tetrahydropyran-2-yl.
  • straight or branched chain alkyl (C 1-4 or C ⁇ alkyl) includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tertiary butyl, pentyl, isopentyl, 1-ethylpropyl, hexyl or isohexyl.
  • C ⁇ alkoxy as a group or part of a group refers to straight or branched alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy or isobutoxy.
  • C 2 ⁇ alkenyl as a group or part of a group include such groups as ethenyl, 1-methylethenyl, 2-methylethenyl, or allyl.
  • phenylalkyl includes phenyl or phenyl substituted by 1 , 2 or 3 groups which may be the same or different and selected from C ⁇ alkyl, halogen (fluorine, chlorine, bromine or iodine), hydroxy, C lJt alkoxy, methylenedioxy, trifluoromethyl or acetylamino.
  • optionally substituted C ⁇ cycloalkyl includes cyclopentyl, cyclohexyl or cycloheptyl group which may be substituted by 1 or 2 methyl, methoxy, hydroxy or phenyl groups.
  • straight or branched C ⁇ alkynyl includes ethynyl, 2-methyI-ethynyl or propynyl.
  • 5 or 6 membered heteroaryl group refers to a heteroaryl group wherein the 5 membered group contains a single heteroatom selected from oxygen, sulphur or nitrogen and optionally contains 1 or 2 further nitrogen atoms, and the 6 membered group contains from 1 to 3 nitrogen atoms.
  • heteroaryl groups include furanyl, thienyl, pyrrolyl, oxazolyl, iso-oxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrimidiyl, pyridazinyl, pyrazinyl or triazinyl.
  • the said heteroaryl groups may be substituted by one or two groups selected from C1-4alkyl e.g. methyl, hydroxyalkyl e.g. heteroaryl, acyloxyalkyl e.g. acetoxy methyl, halogen, or phenyl or the heteroaryl ring may be fused to a phenyl ring e.g. a benzothienyl or benzofuranyl.
  • R 2 groups include C ⁇ alkyl (e.g. methyl, ethyl, isopropyl, butyl or 2,2-dimethylpropyl), C 1 , alkyl substituted by methoxy (e.g. methoxymethyl), C, ⁇ alkyl substituted by optionally substituted phenyl (e.g. benzyl), C ⁇ alkyl substituted by C lJt alkoxycarbonyl (e.g. ethoxycarbonylmethyl), C 2 ⁇ alkenyl (e.g. ethenyl or 1-methylethenyl), optionally substituted phenyl (e.g.
  • phenyl optionally substituted by halogen (such as fluorine), or methoxy, C ⁇ cycloalkyl (e.g. cyclohexyl), heteroaryl, e.g. furanyl, thienyl, oxazolyl, triazolyl, e.g. 2-phenyl-4-methyl, 1,2,3-triazol-5yl, benzofuranyl, benzothienyl, or pyridyl, or R 2 is C ⁇ alkoxycarbonyl group e.g. ethyloxycarbonyl group.
  • halogen such as fluorine
  • methoxy C ⁇ cycloalkyl
  • heteroaryl e.g. furanyl, thienyl, oxazolyl, triazolyl, e.g. 2-phenyl-4-methyl, 1,2,3-triazol-5yl, benzofuranyl, benzothienyl, or pyridyl
  • R 2 is C ⁇
  • R is the group CXOR 3
  • suitable R 3 groups include alkyl e.g. methyl, ethyl or C 2 ⁇ alkenyl e.g. ethenyl or 1-methylethenyl.
  • R t is the group CONHR 4
  • suitable R 4 group include alkyl e.g. ethyl or optionally substituted phenyl e.g. phenyl.
  • R T is the group SO 2
  • suitable R 5 groups include alkyl e.g. methyl, optionally substituted phenyl e.g. phenyl or phenyl substituted by acetylamino, or R 5 is a dialkylamino group e.g. dimethylamino.
  • R is a group selected from CXR 2 or CXOR 3 .
  • R 8 is C 1-6 alkyl examples of suitable groups include methyl, ethyl, propyl, butyl or t-butyl.
  • R 8 is optionally substituted phenyl
  • an example of a suitable groups includes phenyl.
  • R 2 is a group selected from C ⁇ alkyl such as methyl, ethyl, isopropyl, butyl or 2,2 dimethylpropyl, C ⁇ alkenyl such as ethenyl, C ⁇ alkyl substituted by methoxy e.g. methoxy methyl. C ⁇ alkyl substituted by halogen (such as chlorine e.g. chloromethyl), C ⁇ alkyl substituted by alkoxycarbonyl (e.g. alkoxycarbonylmethyl such as ethoxycarbonylmethyl), C ⁇ alkyl substituted by optionally substituted phenyl (e.g. benzyl), C ⁇ alkoxycarbonyl e.g.
  • ethoxycarbonyl optionally substituted phenyl such as phenyl, fluorophenyl, methoxyphenyl or trimethoxyphenyl, C ⁇ -cycloalkyl such as cyclohexyl or heteroaryl such as furanyl, thienyl, isoxazole, pyridyl, a 1 ,2,3 triazole such as 4- methyl-2-phenyl-1 ,2,3-triazolyl, or benzothienyl.
  • phenyl such as phenyl, fluorophenyl, methoxyphenyl or trimethoxyphenyl
  • C ⁇ -cycloalkyl such as cyclohexyl or heteroaryl
  • furanyl, thienyl isoxazole
  • pyridyl a 1 ,2,3 triazole
  • a 1 ,2,3 triazole such as 4- methyl-2-phenyl-1 ,2,3-triazolyl, or
  • R 3 is a group selected from C ⁇ alkyl e.g. methyl or C 2 alkenyl e.g. 1-methylethenyl.
  • the group R 4 is conveniently C ⁇ alkyl e.g. ethyl or optionally substituted phenyl e.g. phenyl.
  • the group R 5 is conveniently C ⁇ alkyl e.g. methyl optionally substituted phenyl e.g. phenyl or 4-acetylaminophenyl or NReR 7 such as dimethylamino.
  • the group R 8 is conveniently C ⁇ alkyl such as methyl, ethyl, propyl, butyl or t- butyl or phenyl.
  • a preferred class of compounds of formula (I) are those wherein R, is the group CXR 2 or CXOR 3 and X is oxygen.
  • a further preferred class of compounds of formula (I) are those wherein Rg is a formyl group. Yet a further preferred class of compounds are those wherein Re is a methyl group.
  • a preferred group of compounds of formula (I) are those wherein R 8 is methyl and R 9 is formyl. Within this group particularly preferred compounds are those wherein R is CXR 2 or CXOR 3 and X is oxygen.
  • the compounds of formula (I) are useful in combating fungal and or protozoal infections in animals, including humans.
  • they may be used in the treatment of fungal infections including those caused by one or more organisms such as species of Candida (e.g. Candida albicans, Candida glabrata, (Torulopsis glabrata), Candida tropicalis, Candida parapsilosis and Candida pseudotropicalis), Cryptococcus neoformans, Aspergillus Spp (e.g. Aspergillus flavus and Aspergillus fumigatus), Coccidioides (e.g. Coccidioides immitis), Paracoccidioides (e.g. Paracoccidioides brasiliensis), Histoplasma (e.g.
  • Histoplasma capsulatum or Blastomyces (e.g. Blastomyces dermatitidis). They may also be used to treat other fungal infections caused by species of Trichophyton, Microsporum or Epidermophyton (e.g. Trichophyton mentagrophytes, Trichophyton rubrum, Microsporum canis or Epidermophyton floccosum), or in mucosal infections caused by Candida albicans.
  • Trichophyton e.g. Trichophyton mentagrophytes, Trichophyton rubrum, Microsporum canis or Epidermophyton floccosum
  • Compounds of formula (I) may also be used to treat other infections caused by other fungi such as Geotrichum (e.g. Geotrichum clavatum), Trichosporon (e.g. Trichosporon beigelii), Blastoschizomyces (e.g. Blastoschizomyces capitatus), Sporothrix (e.g. Sporothrix schenckii), Scedosporium (e.g. Scedosporium apiosperum), Cladosporium (e.g. Cladosporium carrionii) and Pityrosporum ovale.
  • Geotrichum e.g. Geotrichum clavatum
  • Trichosporon e.g. Trichosporon beigelii
  • Blastoschizomyces e.g. Blastoschizomyces capitatus
  • Sporothrix e.g. Sporothrix schenckii
  • Scedosporium e.g. Scedo
  • the compounds of formula (I) may also be used to treat infections caused by protozoa such as Toxoplasma, Cryptosporidium, Leishmania, Tripanosoma, Giardia and Trichomonas.
  • the compounds of formula (I) may also be used to treat infections caused by Pneumocystis Carinii.
  • the antifungal activity of the compounds of formula (I) may be determined using conventional in vitro and in vivo screens. Thus, the in vitro evaluation of the anti-fungal activity of compounds of the invention was performed on liquid or solid medium by the anti-fungal two-fold serial dilution technique of determining the minimum inhibitory concentration (MIC) of anti-fungal agent that inhibited development of growth after 24 to 48 hours of incubation at 37°C.
  • MIC minimum inhibitory concentration
  • a series of agar plates or broth microdilution panels containing two-fold dilutions of anti-fungal agent tested were inoculated with a standard culture of a clinically relevant pathogen, for example, Candida albicans.
  • the agar plates or broth microdulution panels were then examined for the presence or absence of growth of the fungus and the appropriate MIC values were noted.
  • MFC values (defined as the lowest anti-fungal concentration that killed at least 99.9% of the initial inoculum in liquid medium) may also be determined by sub- culturing 0.01 and 0.1 ⁇ l of broth from the drug-free control well, the first well containing growth and each clear well on agar plates.
  • the fungicidal activity of the compounds of formula (I) may also be determined in conventional tests in animals e.g. rats and mice. For example the lethal systems candidiasis test in mice.
  • the compounds of formula (I) may also be useful in the control and or eradication of phytopathogenic fungi.
  • Compounds of the invention show particularly useful activity against one or more of the organisms selected from Candida albicans, Candida glabrata, Candida tropicalis, Candida parapsilosis, Pneumocystis carinii Coccidioides immitis, Paracoccidioides brasiliensis, Histoplasma capsulatum and Blastomyces dermatitides.
  • compounds of formula (I) recommend themselves for the treatment of a variety of fungal and or protozoal infections in human beings and animals.
  • infections include superficial, cutaneous, subcutaneous and systemic mycotic infections such as respiratory tract infections, gastrointestinal tract infections, cardiovascular infections, urinary 10
  • CNS infections CNS infections, candidiasis and chronic mucocandidiasis (e.g. thrush and vaginal candidiasis) and skin infections caused by fungi, cutaneous and mucocutaneous candidiasis, dermatophytoses including ringworm and tinea infections, athletes foot, paronychia, pityriasis versicolor, erythrasma, intertrigo, fungal nappy rash, Candida vulvitis, Candida balanitis and otitis externa. They may also be used as prophylactic agents to prevent systemic and topical fungal infections.
  • candidiasis and chronic mucocandidiasis e.g. thrush and vaginal candidiasis
  • skin infections caused by fungi, cutaneous and mucocutaneous candidiasis, dermatophytoses including ringworm and tinea infections, athletes foot, paronychia, pityriasis versicolor, erythra
  • prophylactic agents may, for example, be appropriate as part of a selective gut decontamination regimen in the prevention of infection in immunocompromised patients (e.g. AIDS patients, patients receiving cancer therapy or transplant patients). Prevention of fungal overgrowth during antibiotic treatment may also be desirable in some disease syndromes or iatrogenic states. They may also be used in the prophylaxis and or treatment of infections caused by Pneumocystis carinii.
  • immunocompromised patients e.g. AIDS patients, patients receiving cancer therapy or transplant patients.
  • Prevention of fungal overgrowth during antibiotic treatment may also be desirable in some disease syndromes or iatrogenic states. They may also be used in the prophylaxis and or treatment of infections caused by Pneumocystis carinii.
  • the invention provides a method of the treatment of human or non human animal body to prevent or treat fungal and or protozoal diseases, which method comprises administering to solid body an effective amount of a compound of formula (I).
  • the invention also provides for the use of a compound of formula (I) in the manufacture of a medicament for the treatment or prevention of fungal and or protozoal infections.
  • compositions of the invention include those in a form especially formulated for oral, buccal, parenteral, implant, rectal, topical, ophthalmic or genito-urinary administration or in a form suitable for administration by inhalation or insufflation.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch or sodium starch glycollate or crosscarmellose sodium; wetting agents such as sodium lauryl sulphate and pH modifiers for example citric acid, malic acid, tartaric acid, sodium carbonate, sodium bicarbonate, triethanolamine or trometamol.
  • binding agents for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone
  • the capsule may contain powders, tablets, pellets, granules, liquids, waxes, surfactants or any combination of the former, which may be coated according to the methods well known to the art.
  • the content of the capsules can be made of: binding agents, fillers, lubricants, desintegrants, wetting agents and pH modifiers, as described above.
  • the tablets which include chewable, dispersible or effervescent tablets may be coated according to methods well known in the art.
  • 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 constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethyJcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives, for example, methyl or propyl p- hydroxybenzoates or sorbic acid and flavouring agent.
  • suspending agents for example, sorbitol syrup,
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the composition according to the invention may be formulated for parenteral administration by injection or continuous infusion.
  • Formulations for injection may be presented in unit dose form in ampoules, or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • compositions according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurised packs with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, or from a nebuliser.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas
  • the dosage unit
  • compositions according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch or as a modified physical form of the drug substance alone.
  • the powder composition may be presented in unit dosage form in, for example, capsules or cartridges of e.g. gelatin, or blister packs from which the powder may be administered with the aid of an inhaler or insufflator.
  • compositions may take the form of a suppository, e.g. containing a conventional suppository base, or a pessary, e.g. containing a conventional pessary base.
  • compositions may also be formulated for topical administration in the form of ointments, creams, gels, lotions, shampoos, powders (including spray powders), pessaries, tampons, sprays, dips, aerosols, drops (e.g. eye, ear or nose drops) or pour-ons.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening 13
  • Ointments for administration to the eye may be manufactured in a sterile manner using sterilised components.
  • Pour-ons may, for example, be formulated for veterinary use in oils containing organic solvents, optionally with formulatory agents, e.g. stabilising and solubilising agents.
  • Pessaries and tampons for vaginal insertion may be formulated using conventional techniques and, where appropriate, may contain an effervescent vehicle.
  • Such compositions may also contain other active ingredients such as corticosteroids, antibiotics or antiparasitics as appropriate.
  • Liquid preparations for intranasal delivery may take the form of solutions or suspensions and may contain conventional excipients such as tonicity adjusting agents, for example, sodium chloride, dextrose or mannitol; preservatives, for example benzalkonium chloride, thiomersal, phenylethyl alcohol; and other formulating agents such as suspending, buffering, stabilising, dispersing and or flavouring agents.
  • tonicity adjusting agents for example, sodium chloride, dextrose or mannitol
  • preservatives for example benzalkonium chloride, thiomersal, phenylethyl alcohol
  • other formulating agents such as suspending, buffering, stabilising, dispersing and or flavouring agents.
  • Transdermal administration may be affected by the design of a suitable system which promotes absorption of the active compound through the skin and would typically consist of a base formulation enclosed within an adhesive stick-on patch comprising backing films, membranes and release liners.
  • a suitable system which promotes absorption of the active compound through the skin and would typically consist of a base formulation enclosed within an adhesive stick-on patch comprising backing films, membranes and release liners.
  • Such systems may include absorption enhancers such as alcohols or work by promoting ionotophoresis.
  • composition according to the invention may also be formulated as a depot preparation.
  • Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • a compound of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions comprise dosage units
  • each unit will preferably contain
  • the daily dosage as employed for adult human treatment will preferably range from 0.001 mg to 5000mg of active ingredient, most preferably from 0.01 mg to 2000mg which may be administered in 1 to 4 daily doses, for example, depending on the route of administration and on the condition of the patient and the disease to be treated.
  • the compound may be administered by intravenous infusion using, for example, up to 50mg/kg/day of the active ingredient.
  • the duration of treatment will be dictated by the rate of response rather than by arbitrary numbers of days.
  • Compounds of the invention may also be used in combination with other therapeutic agents, and the invention thus provides, in a further aspect, a combination comprising a compound of the invention together with another therapeutical ly active agent.
  • the compounds of the invention may be used in combination with one or more other antifungal agents, such as a polyenic derivative e.g. (Amphotericin B, Nystatin, a lipid formulation of Amphotericin B) an azole derivative e.g. (Fluconazole, Intraconazole, Ketoconazole, Miconazole, Clotrimazole, ZD-08070, UK-109496), 5-Fluorocytosine, a Pneumocandin or Echinocandin derivative (such as Cilofungin, LY-303366, L-733560), an allylamine derivative (e.g.
  • a polyenic derivative e.g. (Amphotericin B, Nystatin, a lipid formulation of Amphotericin B)
  • an azole derivative e.g. (Fluconazole, Intraconazole, Ketoconazole, Miconazole, Clotrimazole, ZD-08070,
  • Terbinafine, Butenafine or Naftifine and/or one or more immunomodulating agents such as an interferon e.g. (IFN- ⁇ ), interleukine e.g. (IL-1 , IL-2, IL-3 and IL-8) and colony stimulating factors, [(G)-CSF, (M)-CSF and (GM)-CSF] and defensines.
  • IFN- ⁇ interferon e.g.
  • interleukine e.g. (IL-1 , IL-2, IL-3 and IL-8
  • colony stimulating factors [(G)-CSF, (M)-CSF and (GM)-CSF] and defensines.
  • Particularly advantageous compounds for use with compounds of the invention include Intraconazole, Flucytosine, Fluconazole, Terbinafine or Amphotericin B.
  • the compounds of the invention When the compounds of the invention are administered in combination with another antifungal agent the compounds of the invention and the other fungal agent can be administered at the recommended maximum clinical dosage or at lower doses.
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier thereof comprise a further aspect of the invention.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • each compound of the invention When a compound of the invention is used in combination with a second therapeutic agent against the same condition the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
  • a compound of formula (I) or a physiologically acceptable salt thereof or a pharmaceutical composition comprising a compound of formula (I) or a physiologically acceptable salt thereof as defined above for use in therapy, particularly for the treatment of fungal infections in animals (especially humans).
  • a method of treatment of the human or non-human animal body to combat fungal diseases comprises administering to said body an effective amount of a compound of formula (I) or a physiologically acceptable salt thereof.
  • references herein to treatment extend to prophylaxis as well as the treatment of established conditions or infections.
  • the compounds may be formulated in conventional manner.
  • the invention also provides processes for the preparation of compounds of formula (I).
  • the invention provides a process for the preparation of compounds of formula (I) or a physiologically acceptable salt thereof which comprises reacting a compound of formula (II) wherein R 8 has the meaning given in formula 1 , R 10 is cyano formyl, or a protected formyl group and RNase is hydrogen, a carboxyl protecting or a cation of a salt,
  • R 10 is a protected formyl group this is conveniently an acetal thereof such as those formed with a C, ⁇ alkanol e.g. methanol or ethanol or a 1 ,2 or 1 ,3 diol such as ethylene glycol, 1 ,2-propanediol or 1 ,3-propanediol.
  • a C, ⁇ alkanol e.g. methanol or ethanol or a 1 ,2 or 1 ,3 diol
  • ethylene glycol 1 ,2-propanediol or 1 ,3-propanediol.
  • R is a carboxyl protecting group this is conveniently a substituted methyl group such as optionally substituted benzyl, diphenylmethyl, allyl or trialklsilylalkyloxy-methyl e.g. trimethylsilylethyloxymethyl.
  • Suitable reagents capable of introducing the group R ⁇ include activated derivatives of the acids R 2 CXOH, R 3 OCXOH, R 4 NHC02H, or R 5 SO2OH or the isocyanate R 4 NCO, wherein the groups R 2 , R 3 , R 4 and R 5 have the meaning given in formula 1.
  • the activated derivative of the above acids are the corresponding acid halides e.g. chlorides such as R 2 CXCI, R 3 OCXCI, R 4 NHCOCI or R 5 SO 2 CI.
  • R ⁇ is the group R 2 CO alternative suitable activated derivatives of the acid R 2 C0 2 H include those derived from the couping agents commonly used in peptide synthesis, for example activated derivatives formed with carbodimides or carbonyldiimidazole or a mixed acid anhydride.
  • the reaction with the activated acid derivatives is preferably carried out in an aprotic solvent e.g. a hydrocarbon, halohydrocarbon e.g. dichloromethane, or an ether and in the presence of a base such as an alkali metal carbonate, or bicarbonate or a tertiary organic amine, e.g. a trialkylamine or an optionally substituted pyridine.
  • an aprotic solvent e.g. a hydrocarbon, halohydrocarbon e.g. dichloromethane, or an ether
  • a base such as an alkali metal carbonate, or bicarbonate or a tertiary organic amine, e.g. a trialkylamine or an optionally substituted pyridine.
  • the carboxyl protecting group R n ⁇ may be removed by conventional means.
  • R reactive group R n ⁇ may be removed by hydrogenolysis using hydrogen and a suitable catalyst e.g. Palladium on charcoal in a suitable solvent e.g. ethyl acetate.
  • a suitable catalyst e.g. Palladium on charcoal in a suitable solvent e.g. ethyl acetate.
  • R Marinac is a trimethylsilylethyloxymethyl group this may be cleaved by reaction with fluoride ions e.g. tetrabutylammonium fluoride in a suitable aprotic solvent such as an ether e.g. tetrahydrofuran.
  • fluoride ions e.g. tetrabutylammonium fluoride
  • a suitable aprotic solvent such as an ether e.g. tetrahydrofuran.
  • R 10 When R 10 is a protected formyl group this may be converted into the formyl group by conventional means. Thus if R 10 is an acetal group it may be converted into the formyl group by treatment with an acid e.g. organic acid such as trifluoroacetic acid or an aqueous mineral acid e.g. aqueous hydrochloric acid.
  • an acid e.g. organic acid such as trifluoroacetic acid or an aqueous mineral acid e.g. aqueous hydrochloric acid.
  • Salts of compounds of formula (I) with inorganic or organic bases may be prepared by treating a solution or suspension of the compound of formula (I) e.g. a suspension in methanol with an equivalent amount of the base e.g sodium hydroxide optionally in a solvent e.g. water.
  • the salts may be isolated by removal of the organic solvent followed by lyophilisation.
  • the compound of formula (II) may be prepared by the processes described and/or excemplified in WO99/58512 which is incorporated herein by reference.
  • the compound of formula (III) wherein R 10 is CN may be prepared from the corresponding compound wherein R 10 is CHO by reaction with hydroxylamine in a solvent such as toluene and then treatment of the resultant oxime with acetic anhydride and with heating.
  • compounds of formula (I) wherein R 9 is CN may be prepared from the corresponding compound of formula (I) wherein R 9 is CHO by reaction with hydroxylamine in a solvent such as toluene and then treatment of the resultant oxime with acetic anhydride and with heating.
  • Metabolically labile esters of compounds of formula (I) may be prepared by reacting the corresponding acid or a base addition salt thereof e.g. the sodium salt with an activated derivative for the required alcohol e.g. a halide or a sulphonate derivative.
  • an activated derivative for the required alcohol e.g. a halide or a sulphonate derivative.
  • Intermediate 3 may also be prepared using the above proceedurre but using intermediate 2 as the starting material.
  • EXAMPLE 1b r 1 R-(1 ⁇ .3a ⁇ .4 ⁇ .4a ⁇ .7 ⁇ .7a .8aB l 8a-[(2R.6R)-(6-Methyl. 4-pentanoyl) morpholin-2-yl-oxymethyl]-4-(formyl)-4,4a,5,6,7,7a,8,8a-octahydro-7-methyl-3- (1 -methylethyl)-1 ,4-methano-s-indacene-3a(1 H)-carboxylic acid.
  • EXAMPLE 1c ⁇ R-(1 ⁇ .3a ⁇ .4B.4a ⁇ .7 ⁇ .7a ⁇ .8a ⁇ )1 8a-r(2R.6R)-(4-Acryloyl. 6-methyl)morpholin- 2-yl-oxymethyfl-4-formyl-4,4a,5,6,7,7a,8,8a-octahydro-7-methyl-3-(1-methyl- ethyl)-1 ,4-methano-s-indacene-3a(1 H)-carboxylic acid.
  • H-8a 2.90 (m, 1 H, H-3'), 2.65 (m, 1 H, H-1), 2.50 (m, 1 H, H-5'), 2.34 (m, 1 H, CH(CH 3 ) 2 ).
  • EXAMPLE 1d ⁇ R-(1 ⁇ .3a ⁇ .4 ⁇ .4a ⁇ .7 ⁇ .7a ⁇ .8a ⁇ l 8a-r(2R.6Rr-(4-Methoxyacetyl. 6-methyl) morpholin-2-yl-oxymethyl]-4-formyl-4,4a,5,6,7,7a,8,8a-octahydro-7-methyl-3-(1- methylethyl)-1 ,4-methano-s-indacene-3a(1 H)-carboxylic acid.
  • EXAMPLE 1e R-(1 ⁇ .3a ⁇ .4 ⁇ .4a ⁇ .7 ⁇ .7a ⁇ .8a ⁇
  • EXAMPLE 1f riR-(1 ⁇ .3a ⁇ .4 ⁇ .4a ⁇ .7 ⁇ .7a ⁇ .8a ⁇ V
  • EXAMPLE 1i R-(1 .3a ⁇ .4 ⁇ .4a ⁇ .7 ⁇ .7a ⁇ .8a ⁇ )1 8a-r(2R.6R)-(6-Methv1.
  • EXAMPLE 2f R-(1 ⁇ .3a ⁇ ,4B.4a ⁇ .7 ⁇ .7a ⁇ .8a ⁇ Y
  • EXAMPLE 2j ⁇ R-(1 ⁇ .3a ⁇ .4 ⁇ ,4a ⁇ .7 ⁇ .7a ⁇ .8a ⁇ )1 8a-r(2R.6R)-(4-(Methoxy-carbonyl). 6- methyl)mo ⁇ holin-2-yl-oxymethyl]-4-formyl-4,4a,5,6,7,7a,8,8a-octahydro-7- methyl-3-(1-methylethyl)-1 ,4-methano-s-indacene-3a(1 H)-carboxylic acid.
  • EXAMPLE 21 ⁇ R-f 1 ⁇ .3a ⁇ .4 ⁇ .4a ⁇ .7 ⁇ .7a ⁇ .8a ⁇ l 8a-r(2R.6R)-(4-Ethyloxallyl. 6-methyl) morpholin-2-yl-oxymethyl]-4-formyl-4,4a,5,6,7,7a,8,8a-octahydro-7-methyl-3-(1- methylethyl)-1 ,4-methano-s-indacene-3a(1 H)-carboxylic acid.
  • EXAMPLE 2s ⁇ R-(1 ⁇ ,3a ⁇ .4 ⁇ .4a ⁇ .7 ⁇ .7a ⁇ .8a ⁇ )l 8a-r(2R.6R)-(6-Methyl,4-phenylsulphonyl) morpholin-2-yl-oxymethyl]-4-formyl-4,4a,5,6,7,7a,8,8a-octahydro-7-methyl-3-(1- methylethyl)-1 ,4-methano-s-indacene-3a(1 H)-carboxylic acid.
  • Magnesium stearate 5 mg The drug substance is blended with microcrystalline cellulose, crosscarmellose sodium and magnesium stearate, then compressed into tablets.
  • the drug substance is blended with the lactose and the magnesium stearate and then filled into appropriate capsules.

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EP00972905A 1999-11-11 2000-11-10 Sordaricinderivate mit antifungaler wirkung Withdrawn EP1228048A1 (de)

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