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WO2001060395A2 - Procedes servant a traiter une inflammation de la muqueuse non invasive provoquee par un champignon au moyen d'agents antifongiques de cyclohexapeptides - Google Patents

Procedes servant a traiter une inflammation de la muqueuse non invasive provoquee par un champignon au moyen d'agents antifongiques de cyclohexapeptides Download PDF

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Publication number
WO2001060395A2
WO2001060395A2 PCT/US2001/000685 US0100685W WO0160395A2 WO 2001060395 A2 WO2001060395 A2 WO 2001060395A2 US 0100685 W US0100685 W US 0100685W WO 0160395 A2 WO0160395 A2 WO 0160395A2
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Prior art keywords
hydroxy
hydrogen
echinocandin
methyl
alkyl
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PCT/US2001/000685
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English (en)
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WO2001060395A3 (fr
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Jeffrey Alan Radding
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Eli Lilly And Company
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Publication of WO2001060395A3 publication Critical patent/WO2001060395A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • 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

Definitions

  • the present invention relates to the treatment or prevention of non-invasive fungus-induced mucositis with cyclohexapeptide antifungal agents, in particular, echinocandins .
  • the present invention provides a method for treating a non-invasive fungus-induced mucositis in a mammal in need thereof comprising the step of contacting an echinocandin compound with fungi residing in the mucus of said mammal.
  • the method is particularly useful for the treatment of non- invasive fungus-induced chronic rhinosinusitis, chronic asthma symptoms, chronic otitis media, chronic colitis and Crohn's disease.
  • a method for preventing non-invasive fungus-induced mucositis in a mammal by mucoadministrating an echinocandin such that it contacts mucus in an amount, at a frequency, and for a duration effective to prevent non-invasive fungus- induced mucositis (e.g., non-invasive fungus-induced chronic rhinosinusitis, chronic asthma symptoms, chronic otitis media, chronic colitis and Crohn's disease) .
  • a medicament is provided for the treatment or prevention of non-invasive fungus-induced mucositis comprising an echinocandin .
  • mucusitis refers to an inflammation, as opposed to an infection, of a mucus membrane.
  • echinocandin refers to a compound having the following general structure:
  • R is an alkyl group, an alkenyl group, an alkynyl group, an aryl group, heteroaryl group, or combinations thereof;
  • R , R 3/ R 6 , R 7 , and R ⁇ 0 are independently hydroxy or hydrogen;
  • R 2 is hydroxy, aminoalkylamine (e.g., -NHCH 2 CH 2 NH 2 ) , or hydrogen;
  • R is hydrogen, methyl or alkylamido (e . g. , -CH 2 C (0)NH 2 ) ;
  • R 5 is alkylamine (e.g., -CHCH 2 NH 2 ) , alkylamido (e.g., -CH 2 C(0)NH 2 ) , methyl or hydrogen;
  • R 8 is -OH, -OS0 3 H, -OP0 3 H 2 , -OP0 3 HR a , or -OP0 2 HR , where R a is hydroxy, Ci-C ⁇ alkyl, C]_-Cg alkoxy, phenyl, phenoxy, p-halophenyl, p-halophenoxy, p-nitrophenyl, p-nitrophenoxy, benzyl, benzyloxy, p-halobenzyl , p-halobenzyloxy, p- nitrobenzyl, or p-nitrobenzyloxy; R 9 is
  • Examples of compounds encompassed by the term “echinocandin” specifically include all of the compounds described in U.S. Patent Nos . 4,293,489; 5,965,525; US 5,693,750; 5,569,646; 5,502,033; 5,792,746; 5,378,804; 5,854,213; 5,684,128; 5,646,245; 5,516,757; 5,514,650; 5,386,009; 5,378,804; 5,310,726; 5,166,135; 5,159,059; 5,049,546; and 4,931,352, all of which are incorporated herein by reference .
  • Further examples of compounds encompassed by the term “echinocandin” also include those compounds described in PCT applications WO 98/23637 and WO 96/11210; and EP application EP 788511.
  • Echinocandin B or “ECB” refers to an echinocandin compound as described above where R x , R 2 , R 3 , R 6 , R, Rs and Rio are hydroxy groups; R 4 , R 5 and Ru are methyl groups; R 9 is a hydrogen.
  • R is a linoleoyl group.
  • R has both a rigid and a flexible component, for example where R is represented by the following formula
  • terphenylpentoxy semisynthetic derivative also known as LY303366
  • the term "Caspofungin” or “MK-991” refers to an echinocandin compound as described above where Ri, R 3 , R ⁇ , R 7 , R 8 and Rio are hydroxy groups; R 2 is -NHCH 2 CH 2 NH 2 ; R 4 and Ru are methyl groups; R 5 is -CH2CH2 H 2 ; R 9 is a hydrogen and R is -(CH 2 ) 8 CH(CH 3 )CH 2 CH(CH 3 )CH 2 CH 3 .
  • Preparation of Caspofungin and other useful derivatives may be found in U.S. Patent Nos. 5,792,746 and 5,378,804, each of which are incorporated herein by reference.
  • FR-901379 refers to an echinocandin compound as described above where Ri, R 2 , R 3 , R 5 , R 7 , R 8 and R ⁇ 0 are hydroxy groups; R 4 and Ru are methyl groups; R 5 is -CH 2 C(0)NH 2 ; R 9 is a -OS0 3 " Na + and R is -(CH 2 ) ⁇ CH 3 .
  • the preparation of FR-901379 and its derivatives may be found in U.S. Patent Nos. US 5,693,750; 5,569,646; and 5,502,033, all of which are incorporated herein by reference.
  • FK-463 refers to an echinocandin compound as described above where R x , R 2 , R 3 , R 6 , R , R 8 and Rio are hydroxy groups; R and Ru are methyl groups; R 5 is -CH 2 C(0)NH 2 ; R 9 is a -0S0 3 " Na + and R is represented by the following structure:
  • FK-463 The preparation of FK-463 and its derivatives may be found in PCT applications WO 98/23637 and WO 96/11210; and EP application EP 788511.
  • alkyl refers to a hydrocarbon radical of the general formula C n H 2n+ ⁇ containing from 1 to 30 carbon atoms unless otherwise indicated.
  • the alkane radical may be straight, branched/ cyclic, or multi-cyclic.
  • the alkane radical may be substituted or unsubstituted.
  • the alkyl portion of an alkoxy group or alkanoate have the same definition as above.
  • alkenyl refers to an acyclic hydrocarbon containing at least one carbon-carbon double bond.
  • the alkene radical may be straight, branched, cyclic, or multi- cyclic.
  • the alkene radical may be substituted or unsubstituted.
  • alkynyl refers to an acyclic hydrocarbon containing at least one carbon carbon triple bond.
  • the alkyne radical may be straight, or branched.
  • the alkyne radical may be substituted or unsubstituted.
  • aryl refers to aromatic moieties having single (e.g., phenyl) or fused ring systems (e.g., naphthalene, anthracene, phenanthrene, etc.).
  • the aryl groups may be substituted or unsubstituted.
  • Substituted aryl groups include a chain of aromatic moieties (e.g., biphenyl, terphenyl, phenylnaphthalyl , etc.)
  • heteroaryl refers to aromatic moieties containing at least one heteratom within the aromatic ring system (e.g., pyrrole, pyridine, indole, thiophene, furan, benzofuran, imidazole, pyrimidine, purine, benzimidazole, quinoline, etc.) .
  • the aromatic moiety may consist of a single or fused ring system.
  • the heteroaryl groups may be substituted or unsubstituted.
  • alkyl group allows for substituents which -1- is a classic alkyl, such as methyl, ethyl, isopropyl, isobutyl, tertiary butyl, hexyl, isooctyl, dodecyl, stearyl, etc.
  • alkyls which are common in the art, such as hydroxy, halogen, alkoxy, carbonyl, keto, ester, carbamato, etc., as well as including the unsubstituted alkyl moiety.
  • substituents should be selected so as to not adversely affect the pharmacological characteristics of the compound or adversely interfere with the use of the medicament.
  • Suitable substituents for any of the groups defined above include alkyl, alkenyl, alkynyl, aryl, halo, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, mono- and di-alkyl amino, quaternary ammonium salts, aminoalkoxy, hydroxyalkylamino , aminoalkylthio, carbamyl, carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanyl, and combinations thereof .
  • DETAILED DESCRIPTION Evidence exists to support the theory that at least a subset of diseases diagnosed as chronic rhinosinusitis (CRS) , asthma and irritable bowel syndrome is caused by colonization of the mucus membranes by a variety of species of fungi which in some populations triggers an inappropriate and massive eosinophil infiltration of the surrounding mucosa and tissue. (See, i.e., Ponikau, J., et al .
  • echinocandin antifungal agents such as LY303366, MK-991 and FR-901379 and related compounds are potent inhibitors of cell wall biosynthesis in fungi.
  • current existing antifungal agents such as amphotericin B and itraconazole
  • the echinocandins have broader spectrum, greater potency and • better toxicological properties.
  • echinocandins are active against azole resistant fungal organisms . Based on the foregoing observations, the echinocandins provide a unique set of antifungal agents for treatment or prevention of non-invasive fungus-induced mucositis.
  • the cyclic peptides used in the present invention may be produced by culturing various microorganisms. Suitable natural product starting materials belonging to the echinocandin cyclic peptide family include Echinocandin B, Echinocandin C, Echinocandin D, Aculeacin A ⁇ , Mulundocandin, Sporiofungin A, Pneumocandin A 0 , WF11899A, and Pneumocandin Bo- In general, the cyclic peptides may be characterized as a cyclic hexapeptide nucleus with an acylated amino group on one of the amino acids. The amino group on the naturally- occurring cyclic peptide is typically acylated with a fatty acid group forming a side chain off the nucleus . Examples of naturally-occurring acyl groups include linoleoyl
  • Semi-synthetic derivatives may be prepared by removing the fatty acid side chain from the cyclic peptide nucleus to produce a free amino group (i.e., no pendant acyl group -C(O)R) .
  • the fatty acid side chain may be removed using an echinocandin B-deacylase isolated from Actinoplanes Utahensis .
  • the free amine is then reacylated with a suitable acyl group using conventional acylation chemistry well-known to those skilled in the art.
  • the echinocandin B nucleus has been re-acylated with certain nonnaturally occurring side chain moieties to provide a number of antifungal agents.
  • the various free hydroxyl groups pendant to the peptide units of the core ring may be modified to enhance activity .and/or solubility. See, e.g., European Patent Applications EP 943,623 and EP 906,915; and U.S. Patent Nos. 4,293,489; 5,629,290; 5,786,325; 5,693,611; 5,618,787; 5,646,111; 5,932,543; and 5,965,525, each of which are incorporated herein by reference.
  • N- acyl side chain encompasses a variety of side chain moieties known in the art. Suitable side chain moieties include substituted and unsubstituted alkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups and combinations thereof. Preferably, the side chain contains both a linearly rigid section and a flexible alkyl section to maximize antifungal potency. Compounds having a side chain containing both a rigid and flexible section are described in U.S. Patent No. 5,965,525, incorporated herein by reference . Representative examples of preferred acyl side chains include R groups having the following structures : ( ⁇ - . ⁇ »
  • A, B, C and D are independently hydrogen, C ⁇ -C 12 alkyl, C 2 -C 12 alkynyl, C 1 -C 12 alkoxy, C 1 -C 12 alkylthio, halo, or -0-(CH 2 ) m -[0-(CH 2 ) n ] p -0-(C 1 -C 12 alkyl) or -0- (CH 2 ) q -X-E; m is 2, 3 or 4; n is 2, 3 or 4; p is 0 or 1; q is 2, 3 or 4; X is pyrrolidino, piperidino or piperazino; and E is hydrogen, C1-C12 alkyl, C3-C12 cycloalkyl, benzyl or C3-C12 cycloalkylmethyl .
  • MK-991 and related derivatives are described in U.S. Patent Nos. 5,792,746; 5,378,804; 5,854,213; 5,684,128; 5,646,245; 5,516,757; 5,514,650; 5,386,009; 5,378,804; 5,310,726; 5,166,135; 5,159,059; 5,049,546; and 4,931,352, all of which are incorporated herein by reference.
  • FR- 901379 and related derivatives are described in U.S. Patent Nos.
  • the cyclic peptides described herein may be prepared by fermentation of known microorganisms as described in the art.
  • the subsequent deacylation is typically carried out enzymatically using a deacylase enzyme by known materials and procedures described in the art.
  • U.S. Patent No. 3,293,482 (Abbott et al . ) , incorporated herein by reference, describes the deacylation and preparation of the cyclic peptide of formula I where R 4 , R 5 , and Ru are methyl, R 9 is hydrogen, and Ri, R 2 , R 3 , Re , R 7 , R 8 - and R ⁇ 0 are each hydroxy.
  • Cyclic peptides where R 2 and R 7 are each hydrogen may be prepared by subjecting the corresponding compound (where R 2 and R are each hydroxy; the ornithine alpha-amino group may be a free amino group or acylated) to a strong acid and a reducing agent at a temperature of between -5°C and 70°C, in a suitable solvent.
  • Suitable strong acids include trichloroacetic acid, trifluoroacetic acid or boron trifluoride etherate.
  • a preferred strong acid is trifluoroacetic acid.
  • Suitable reducing agents include sodium cyanoborohydride or triethylsilane .
  • a preferred reducing agent is triethylsilane.
  • Suitable solvents include methylene chloride, chloroform or acetic acid, preferably methylene chloride.
  • the strong acid is present in an amount from about 2 to 60 mol per mol of substrate, and the reducing agent is present in an amount from about 2 to 60 mol per mol of substrate.
  • the acid reduction process selectively removes the a inal (R 2 ) and benzylic (R) hydroxy groups .
  • the amino group may be acylated by reaction with an appropriately substituted acyl halide, preferably in the presence of an acid scavenger such as a tertiary amine (e.g., triethylamine) .
  • an acid scavenger such as a tertiary amine (e.g., triethylamine)
  • the reaction is typically carried out at a temperature between about -20°C to 25°C.
  • Suitable reaction solvents include polar aprotic solvents, such as dioxane or dimethylformamide . Solvent choice is not critical so long as the solvent employed is inert to the ongoing reaction and the reactants are sufficiently solubilized to effect the desired reaction.
  • the amino group may also be acylated by reaction with an appropriately substituted carboxylic acid, in the presence of a coupling agent.
  • Suitable coupling agents include dicyclohexylcarbodiimide (DCC) , N,N'- carbonyldiimidazole, bis (2-oxo-3-oxazolidinyl)phosphinic chloride (B0P-C1) , N-ethoxycarbonyl-2-ethoxy-l, 2- dihydroquinoline (EEDQ) , benzotriazole-1-yloxy- tripyrrolidinophosphonium hexafluorophosphate (PyBOP) and the like.
  • the amino group may be acylated with an activated ester of a carboxylic acid such as p-nitrophenyl, 2 , 4, 5-trichlorophenyl, hydroxybenzotriazole hydrate
  • acylating moieties are the 2 , 4, 5-trichlorophenyl and HOBT carboxylate esters.
  • the reaction is typically ran 1 to 65 hours at a temperature from about 0°C to 30°C in an aprotic solvent.
  • the reaction is generally complete after about 24 to 48 hours when carried out at a temperature between about 15°C to 30°C.
  • Suitable solvents include tetrahydrofuran and dimethylformamide or mixtures thereof.
  • the amino group is generally present in equimolar proportions relative to the
  • nitrile and ester intermediates may be prepared using procedures known in the art.
  • the nitrile and ester intermediates where R is an alkoxy aryl moiety may be prepared using Procedure A or Procedure B, described below.
  • nitrile and ester intermediates where R is an alkynyl aryl moiety may be prepared using Procedure C, below.
  • Procedure C A mixture containing Et 2 0 (2 equiv. ) , palladium dichloride (0.05 equiv.), triphenylphosphine (0.1 equiv.), cuprous iodide (0.025 equiv.) and an alkyne (1 equiv.) is added to one equivalent of an aryl bromide, iodide, or trifluoromethanesulfonate in CH 3 CN (600ml/0. lmol of aryl reactant) , under nitrogen (N 2 ) .
  • the resulting mixture is refluxed for 17h and then the solvent is removed in vacuo to provide a residue which is slurried in 300 ml of Et2 ⁇ and then filtered.
  • the filtrate is washed with a IN HCl solution, dried over MgS0 4 , filtered and then dried to provide the product.
  • Butyl lithium (1.2 equivalents) is added to one equivalent of a cold (-78°C) aryl halide in THF . After 15 minutes, triisopropyl borate (2 equiv.) is added. After 10 minutes, the reaction mixture is warmed to room temperature and quenched by the addition of water (H 2 0) , followed by the addition of IN HCl. The resulting layers are separated and the organic layer is concentrated in vacuo to provide a solid which is collected by filtration and washed with hexane .
  • Tetrakis (triphenylphosphine) palladium (0.03 equiv.) is added to a mixture containing an aryl boronic acid (1 equiv.), K 2 C0 3 (1.5 equiv.) and methyl 4-iodobenzoate (1 equiv. ) (or trichlorophenyl ester of iodobenzoate) in N 2 - purged toluene.
  • the reaction mixture is refluxed for 7h and then decanted to remove the K 2 C0 3 and dried in vacuo to provide a residue. This residue is triturated in CH 3 CN and filtered to provide the product.
  • Procedure F An excess of 2N NaOH is added to an aryl ester in MeOH, and the resulting solution is refluxed for 5h and then acidified by the addition of excess HCl. Water is added to the reaction mixture until a solid (carboxylic acid) precipitates . The carboxylic acid is collected by filtration and dried in vacuo .
  • the carboxylic acids may be converted to the corresponding 2 , 4, 5-trichlorophenyl esters using Procedure G, below.
  • the activated esters are then used to acylate the amino nucleus .
  • Procedure G A mixture containing an aryl carboxylic acid (1 equiv.), 2 , 4, 5-trichlorophenol (1 equiv.) and DCC (1 equiv.) in CH 2 Cl 2 is stirred for 17h and then filtered. The filtrate is concentrated to provide a residue which is dissolved in Et 2 0, filtered, and then pentane is added until crystallization begins. The crystals are collected by filtration and dried in vacuo .
  • the carboxylic acid may be activated by conversion to the corresponding hydroxybenzotriazole ester using Procedure H, below.
  • the echinocandin compound may be isolated and used per se or in the form of its pharmaceutically acceptable salt, solvate and/or hydrate.
  • pharmaceutically acceptable salt refers to non-toxic acid addition salts derived from inorganic and organic acids .
  • Suitable salt derivatives include halides, thiocyanates, sulfates, bisulfates, sulfites, bisulfites, arylsulfonates, alkylsulfates, phosphonates , monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphonates, alkanoates, cycloalkylalkanoates, arylalkonates, adipates, alginates, aspartates, benzoates, fumarates, glucoheptanoates, glycerophosphates, lactates, maleates, nicotinates, oxalates, palmitates, pectinates, picrates, pivalates, succinates, tartarates, citrates, camphorates, camphorsulfonates, digluconates, trifluoroacetates, and the like .
  • a typical solution formulation is prepared by mixing the echinocandin and a carrier, diluent or excipient .
  • Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • the particular carrier, diluent or excipient used will depend upon the means and purpose for which the active ingredient is being applied.
  • Solvents are generally selected based on solvents recognized by persons in the art as safe (GRAS) to be administered to a mammal.
  • safe solvents are non-toxic aqueous solvents such as, water and other non- toxic solvents that are soluble or miscible in water.
  • Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300) , etc. and mixtures thereof.
  • a preferred solvent is water.
  • the formulations may also include one or more buffers, stabilizing agents, surfactants (preferably a micelle- forming surfactant), wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug.
  • stabilizing agent refers to a pharmaceutically acceptable excipient that enhances the chemical and physical stability of the active ingredient in the formulation.
  • Suitable stabilizing agents include polyols (e.g., polyethylene and propylene glycols and carbohydrates such as sucrose, trehalose, fructose, lactose and mannitol) , amino acids and surfactants such as polysorbates and bile salts.
  • most preferred stabilizing agents are the bile salts, polyethylene glycols and propylene glycol.
  • the formulation may also optionally contain a buffer.
  • the buffer is generally present at a concentration in the range from about 0.03% to about 5% (wgt . /vol . ) , more preferably at a concentration in the range from about 0.1% to about 1%.
  • the term "buffer” refers to a pharmaceutically acceptable excipient that maintains the pH of the solution within a particular range specific to the buffering system.
  • a suitable pH range is from pH 3.0 to 7.0.
  • the preferred range is from 4.0 to 5.5, more preferably 4.0 to 5.0.
  • Suitable buffers include acetates, citrates, phosphates, tartrates, lactates, succinates, amino acids and the like.
  • Preferred buffers for the solution formulation include acetate, citrate, tartrates, phosphate salts and combinations thereof.
  • the formulations may be prepared using conventional dissolution and mixing procedures.
  • the bulk drug substance e.g., echinocandin
  • the active ingredient is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product .
  • the term "unit dose” or "unit dosage” refers to physically discrete units that contain a predetermined quantity of active ingredient calculated to produce a desired therapeutic effect.
  • the dosage to be administered may vary depending upon the physical characteristics of the patient, the severity of the patient's symptoms, and the means used to administer the drug. The specific dose for a given patient is usually set by the judgment of the attending physician.
  • a pharmaceutical composition may be administered using a variety of methods.
  • a unit dose When a unit dose is administered, it is typically provided in the form of an aerosol, powder, topical composition (ointment or spray) or other known form which allows placement of the active ingredient in contact with the fungus residing in the mucus.
  • An aerosol may be inhaled or sprayed in liquid or dry form.
  • the particular treatment method used will depend upon the inflammation being addressed. For example, in treating a mammal having asthma, at least a portion of the airways (e.g., nasal- paranasal airways and lung airways) of the mammal is treated with a medicament containing the echinocandin in an amount, at a frequency, and for a duration effective to reduce or eliminate asthma symptoms.
  • the mucoadministration of an agent to the nasal- paranasal anatomies can be any type of administration that places the agent in contact with nasal-paranasal mucus.
  • Direct mucoadministration to the nasal-paranasal anatomies can include, nasal irrigations, nasal sprays, nasal inhalations, and nasal packs with, for example, saturated gauze provided the administered agent contacts nasal- paranasal mucus prior to crossing epithelium.
  • injections into the nasal-paranasal cavities using, for example, a needle or catheter tube is considered a direct mucoadministration provided the administered agent contacts nasal-paranasal mucus after leaving the needle or catheter tube and prior to crossing epithelium.
  • Any device can be used to directly mucoadminister an agent to the nasal- paranasal anatomy including, a syringe, bulb, inhaler, canister, spray can, nebulizer, and mask.
  • mucoadministration of an agent to the lung airways can be any type of administration that places the agent in contact with mucosa of the lung (including the bronchi and bronchial tubes) .
  • Direct mucoadministration to the lung airways can include, inhalations, nasal sprays, and nasal irrigations provided the administered agent contacts lung airway mucus prior to crossing epithelium.
  • injections into lung airways using, for example, a needle or catheter tube is considered a direct mucoadministration provided the administered agent contacts lung airway mucus after leaving the needle or catheter tube and prior to crossing epithelium.
  • Any device can be used to directly mucoadminister an agent to the lung airway including, a syringe, bulb, inhaler, nebulizer, aerosol canister, spray can, and mask.
  • Mucoadministration of an agent to the middle ear can be any type of administration that places the agent in contact with middle ear mucus.
  • the direct mucoadministration to the middle ear can include ear drops and ear flushes provided the administered agent contacts middle ear mucus prior to crossing epithelium.
  • an ear flush would be considered a direct mucoadministration provided the administered agent contacts middle ear mucus.
  • injections into the middle ear using, for example, a needle or myringotomy tube is considered a direct mucoadministration provided the administered agent contacts middle ear mucus after leaving the needle or tube and prior to crossing epithelium.
  • Any device can be used to directly mucoadminister an agent to the middle ear including, a syringe and bulb .
  • Mucoadministration of an agent to the intestines can be any type of administration that places the agent in contact with intestinal mucus .
  • the direct mucoadministration to the intestines can include oral and enema administrations provided the administered agent contacts intestinal mucus prior to crossing epithelium.
  • injections into the digestive tract using, for example, a needle or catheter tube is considered a direct mucoadministration provided the administered agent contacts intestinal mucus after leaving the needle or catheter tube and prior to crossing epithelium.
  • Any device can be used to directly mucoadminister an agent to the intestines including a syringe and regulated release capsule .
  • the echinocandin compound can be formulated into a regulated release capsule such that the antifungal agent is released after passing, for example, the stomach (e.g., pH regulated release capsules and time regulated release capsules) .
  • Echinocandin compounds have been shown to exhibit antifungal activity such as growth inhibition of various infectious fungi including Candida spp. (i.e., C. Albicans , C. Parapsilosis, C. Krusei , C. Glabrata, C. Tropicalis, or C. Lusi taniaw) ; Torulopus spp. (i.e., T. Glabrata) ; Aspergillus spp. (i.e., A .
  • Fumigatus Fumigatus
  • Histoplasma spp. i.e., H. Capsulatum
  • Cryptococcus spp. i.e., C. Neoformans
  • Blastomyces spp. i.e., B. Dermati tidis
  • Fusarium spp. Trichophyton spp., Pseudallescheria boydii , Coccidioides i mi ts , Sporothrix schenckii , etc.
  • the formulations containing echinocandin compounds described herein are useful in treating or preventing non-invasive fungus-induced mucositis by preventing, eradicating or inhibiting the growth of fungus in the mucus.
  • the echinocandin antifungal agent may be used in the manufacture of a medicament for the therapeutic applications described herein.
  • fungal activity which induces inflammation may be inhibited by contacting the echinocandin antifungal agent with the inflammation-inducing fungus.
  • the term "contacting" includes a union or junction, or apparent touching or mutual tangency of a compound of the invention with a fungus. The term does not imply any further limitations to the process.
  • the methods are defined to encompass the inhibition of fungal activity by the action of the compounds and their inherent antifungal properties.
  • the method for treating or preventing non-invasive ⁇ fungus-induced mucositis comprises administering an effective amount of a pharmaceutical formulation containing an echinocandin compound to a host in need of such treatment.
  • effective amount refers to an amount of active compound which is capable of inhibiting fungal activity.
  • the dose, frequency and duration will vary depending on such factors as the nature and severity of the inflammation, the age and general health of the host and the tolerance of the host to the antifungal agent.
  • the medicament may be given in a single daily dose or in multiple doses during the day.
  • the regimen may last from about 2-3 days to several weeks, months, or a year or longer.
  • a typical daily dose (administered in single or divided doses) contains a dosage level sufficient to reduce inflammation caused by the presence of the fungal organisms, generally between about 0.001 mg/kg to 500 mg/kg of body weight of an active compound.
  • the resultant mixture was degassed 2 times for 20-30 seconds each under a positive pressure of N 2 , followed by the addition of palladium (II) acetate (0.24g, l.lmmol) and triphenylphosphine (0.84g, 3.2mmol) and then degassed 2 more times.
  • the reaction mixture was then refluxed under N 2 for 5h resulting in a light-yellow mixture.
  • This paste was poured into MTBE (500ml) which resulted in the precipitation of a fine powder which was collected by vacuum filtration and dried to provide 27g of crude material. This material was crushed to a powder with a mortar and pestle, slurried for 5 minutes in toluene
  • Tables I & II summarize the test results for Compound 6 (a) against a broad spectrum of fungal strains using the NCCLS Standard Reference Method M27-T (Table I and the agar dilution test (Table II) .
  • Table I summarizes the test results for Compound 6 (a) against a broad spectrum of fungal strains using the NCCLS Standard Reference Method M27-T (Table I and the agar dilution test (Table II) .
  • Test Organism MIC Range ( ⁇ g/ml) (No. of Strains) Compound 6(a) Amphotericin B
  • Torulopsis glabrata (19) 0.001-2.5* 2.5-20
  • the echinocandin compound provided better antifungal activity than the comparative Amphotericin B compound. Unlike the azole antifungal agents, it is believed that the echinocandins have a lower potential for the development of resistant strains. In addition, the echinocandins generally have less side effects and a superior toxicity profile than the comparative Amphotericin B.
  • Compound 6(a) has an acute toxicity in a murine model of greater than 100 mg/kg when administered by the IV route; whereas, Amphotericin B has an acute toxicity, as measured in a murine model, of 4 mg/kg (LD 50 ) •

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Abstract

L'invention concerne un procédé de traitement ou de prévention d'une inflammation de la muqueuse non invasive provoquée par un champignon, ce qui consiste à administrer à la muqueuse d'un mammifère un agent antifongique à base de cyclohexapeptides dans le but de traiter ou de prévenir l'inflammation provoquée par une réponse immune à un champignon résidant dans le mucus.
PCT/US2001/000685 2000-02-18 2001-02-08 Procedes servant a traiter une inflammation de la muqueuse non invasive provoquee par un champignon au moyen d'agents antifongiques de cyclohexapeptides WO2001060395A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001236448A AU2001236448A1 (en) 2000-02-18 2001-02-08 Methods of treatment for non-invasive fungus-induced mucositis with cyclohexapeptide antifungal agents

Applications Claiming Priority (2)

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US18358000P 2000-02-18 2000-02-18
US60/183,580 2000-02-18

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WO2001060395A3 WO2001060395A3 (fr) 2002-02-21

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7048953B2 (en) 2000-04-03 2006-05-23 Inhalation, Inc. Methods and apparatus to prevent, treat and cure infections of the human respiratory system by pathogens causing severe acute respiratory syndrome (SARS)
US7150888B1 (en) 2000-04-03 2006-12-19 Inhalation, Inc. Methods and apparatus to prevent colds, influenzaes, tuberculosis and opportunistic infections of the human respiratory system

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5166135A (en) * 1988-09-12 1992-11-24 Merck & Company, Inc. Method for the control of pneumocystis carinii
KR20010031363A (ko) * 1997-10-22 2001-04-16 젠스 포니카우 진균류에 의한 점막염을 국소 치료하기 위한 항진균제의용도

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7048953B2 (en) 2000-04-03 2006-05-23 Inhalation, Inc. Methods and apparatus to prevent, treat and cure infections of the human respiratory system by pathogens causing severe acute respiratory syndrome (SARS)
US7150888B1 (en) 2000-04-03 2006-12-19 Inhalation, Inc. Methods and apparatus to prevent colds, influenzaes, tuberculosis and opportunistic infections of the human respiratory system

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Publication number Publication date
WO2001060395A3 (fr) 2002-02-21
AU2001236448A1 (en) 2001-08-27

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