EP1351701A2 - Metabolite actif de compose antifongique - Google Patents

Metabolite actif de compose antifongique

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Publication number
EP1351701A2
EP1351701A2 EP02708948A EP02708948A EP1351701A2 EP 1351701 A2 EP1351701 A2 EP 1351701A2 EP 02708948 A EP02708948 A EP 02708948A EP 02708948 A EP02708948 A EP 02708948A EP 1351701 A2 EP1351701 A2 EP 1351701A2
Authority
EP
European Patent Office
Prior art keywords
compound
recited
pharmaceutical composition
formula
administered
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Withdrawn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
EP02708948A
Other languages
German (de)
English (en)
Inventor
James F. Dropinski
Patricia Scott Hicks
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.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
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 Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP1351701A2 publication Critical patent/EP1351701A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to the identification of a metabolite compound of
  • Caspofungin acetate is a semisynthetic antifungal agent developed for the parenteral treatment of Candida, Aspergillus, Pneumocystis carinii and other mycotic infections. Its activity is mediated by inhibition of the synthesis of ⁇ -(l,3)-glucan, an integral component in the cell wall of the target organisms.
  • Caspofungin is a macrocyclic peptide with a molecular weight of 1094 disclosed in US Patent No. 5,378,804. This compound possesses a variety of potentially reactive functionalities that include an aminal moiety.
  • the metabolite is formed by the hydrolysis of the aminal in the ornithine residue, ring opening and recyclization to form two isomeric 5-membered cyclic hemiaminal products. These two isomers are not easily separable by high performance liquid chromatography and thus are isolated together as a single product and collectively termed "the metabolite".
  • Recent disclosures discuss the formation of a metobolite/degradation byproduct of caspofungin. See XU, X., DELUNA, F., YUANG, A., CYLC, D., DAVIS, M., SAHLY, Y. and LIN, J.H. Slow hepatic uptake and elimination play an important role in the disposition of L-743,872, a potent antifungal agent, in rats. For presentation at: American Association of Pharmaceutical Principles 10th Annual Meeting (AAPS), Seattle, Washington, 10/26/1996 - 10/31/1996; KAUFMAN, M.J. and NERURKAR, M.
  • Degradation of the macrocyclic antifungal agent L-743,872 Reaction products and kinetics, and stabilization strategies. For presentation at: American Chemical Society 31st Middle Atlantic Regional Meeting, Desiville, New York, 05/27/1997 - 05/30/1997; KAUFMAN, M.J. and NERURKAR, M. Degradation of the macrocyclic antifungal agent L-743,872: Reaction products and kinetics, and stabilization strategies.
  • Metabolites of caspofungin acetate, a potent antifungal agent, in human plasma and urine For submission to: Drug Metabolism and Disposition; and MCQUADE, M.S., FORSYTH, R.J., ZIMMERMAN, J. and ROBERTS, J.C. Stability of reconstituted CancidasTM (caspofungin acetate) in commonly used i.v. solutions and flexible polyvinyl chloride containers.
  • CancidasTM caspofungin acetate
  • a method for treating a fungal infection comprising administering to a mammalian subject in need of such treatment, an effective amount of a compound of Formula I or its pharmaceutically acceptable salt,
  • Additional aspects of the invention include: 1) a method for controlling mycotic infections comprising administering to an immune-comprised patient in need of such treatment, an effective amount of a compound of Formula I or its pharmaceutically acceptable salt; 2) a method for controlling Pneumocystis pneumonia comprising administering to an immune-comprised patient in need of such treatment, an effective amount of a compound of Formula I or its pharmaceutically acceptable salt; 3) a pharmaceutical composition comprising a compound of Formula I or its pharmaceutically acceptable salt and a second antifungal agent selected from the group consisting of: azoles or polyenes, purine or pyrimidine nucleotide inhibitors, chitin synthesis inhibitors, elongation factor inhibitors, mannan-binding antifungal agents, bactericidal/permeability-inducing (BPI) protein products, and complex carbohydrate antifungal agents; and 4) a method of treating a fungal infection comprising administering to a mammalian subject in need of such treatment an effective amount of
  • a method for treating fungal infections comprising administering to a mammalian subject in need of such treatment, an effective amount of a compound of Formula I or its pharmaceutically acceptable salt,
  • a method for controlling mycotic infections comprising administering to a mammalian subject in need of such treatment, an effective amount of a compound of Formula I or its pharmaceutically acceptable salt,
  • a method for controlling Pneumocystis pneumonia comprising administering to an immune-comprised patient in need of such treatment, an effective amount of a compound of Formula I or its pharmaceutically acceptable salt,
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of the compound of Formula I and a second antifungal agent, as well as an antifungal combination therapy comprising the administration of the antifungal compound of Formula I and a second antifungal agent. It is understood that this combination therapy would involve the sequential, simultaneous or concomitant administration of these two agents.
  • the invention relates to antifungal combination therapy comprising the use of a second antifungal agent such as: azoles or polyenes, purine or pyrimidine nucleotide inhibitors, chitin synthesis inhibitors, elongation factor inhibitors, mannan-binding antifungal agents, bactericidal/permeability-inducing (BPI) protein products, and complex carbohydrate antifungal agents.
  • a second antifungal agent such as: azoles or polyenes, purine or pyrimidine nucleotide inhibitors, chitin synthesis inhibitors, elongation factor inhibitors, mannan-binding antifungal agents, bactericidal/permeability-inducing (BPI) protein products, and complex carbohydrate antifungal agents.
  • Such second antifungal agents are: azoles, such as fluconazole, voriconazole, itraconazole, ketoconazole, miconazole, ravuconazole, posaconazole; polyenes such as amphotericin B, nystatin or liposomal and lipid forms thereof such as ABELCET, AMBISOME and AMPHOCIL; purine or pyrimidine nucleotide inhibitors such as flucytosine; or polyoxins such as nikkomycins, in particular nikkomycin Z or other chitin synthesis inhibitors, elongation factor inhibitors such as sordarin and analogs thereof, mannan-binding antifungal agents such as the pradamicins, bactericidal/permeability-inducing (BPI) protein products such as XMP.97 orXMP.127 or complex carbohydrate antifungal agents such as CAN-296.
  • azoles such as fluconazole, voricon
  • this combination therapy has been shown to be useful against such opportunistic pathogens as Cryptococcus spp., Candida spp., Aspergillus spp., Histoplasma spp., Coccidioides spp., Paracoccidioides spp. Blastomyces spp., Fusarium spp., Sporothrix spp., Trichosporon spp., Rhizopus spp., Pseudallescheria spp., dermatophytes, Paeciliomyces spp., Alternaria spp.,
  • Curvularia spp. Curvularia spp., Exophiala spp., Wangiella spp., Penicillium spp., Saccharomyces spp., Dematiaceous fungi and Pneumocystis carinii.
  • CANCIDASTM (Caspofungin acetate) is disclosed in U.S. Patent No. 5,378,804 and its preparation is described in that patent, as well as U.S. Patent No. 5,552,521.
  • the azole, polyene or other antifungal agent may be administered orally or parenterally.
  • the compound of Formula I is preferably administered parenterally, but is not limited to that route and may also be administered by other routes such as oral, intramuscular or subcutaneous.
  • Combination therapy results in enhanced effects using sub-inhibitory concentrations of all agents. These effects may be demonstrated in vitro and in vivo using clinical and environmental strains of C. neoformans, C. albicans and A. fumigatus.
  • the compound of Formula I is formed from caspofungin by hydrolysis of the aminal group, followed by ring opening and recyclization onto N2 of the ornithine group.
  • the compound of Formula I may be prepared from pneumocandin B 0 (Compound I) following the procedures outlined in SCHEME 1. Briefly, the 3- hydroxyglutamine residue of pneumocandin B 0 may be reduced to give Compound 2. Borane dimethylsulfide complex is a preferred reducing agent. Compound 2 may be treated with a base such as triethylamine, to effect ring opening and subsequent recyclization to give the compound of Formula I.
  • the compound of Formula I is formed as a mixture of two isomers at the newly formed hemiaminal group. The isomers are not easily separable by standard chromatographic techniques and thus may be used as a mixture.
  • the invention also embraces acid addition salts.
  • the compound of Formula I in the normal course of isolation is obtained as an acid addition salt.
  • the salt thus obtained may be dissolved in water and passed through an anion exchange column bearing the desired anion.
  • the eluate containing the desired salt may be concentrated to recover the salt as a solid product.
  • the compound of Formula I was tested for yeast susceptibility following protocol M27-A.
  • This protocol is the standard by which all hospital clinical laboratories test their yeast isolates for susceptibility to antifungal agents. See J.N. Galgiani et al. Reference Method for Broth Dilution Antifungal Susceptibility Testing: Approved Standard M27-A (Reference F-7), National Committee for Clinical Laboratory Standardsl997; 17(9):l-29.
  • the inoculum was standardized with a spectrophotometer (optical density, 550 nm) and was diluted to a final concentration of 0.5 x 10 3 to 2.5 x 10 3 in RPMI 1640 medium with L-glutamine, without sodium bicarbonate, buffered with 0.165 M MOPS (morpholinepropanesulfonic acid) (BioWhittaker, Walkersville, MD).
  • a spectrophotometer optical density, 550 nm
  • MOPS morpholinepropanesulfonic acid
  • the compound of Formula I along with appropriate control standards were prepared as concentrated stock solutions in sterile deionized water and diluted in RPMI 1640 medium, and tested at concentrations ranging from 128 ⁇ g/mL down to 0.06 ⁇ g/mL in two-fold serial dilutions.
  • the Minimum Inhibitory Concentration (MIC) was defined as the lowest concentration of compound which completely inhibited visible growth after incubation at 35°C for 24 or 48 hr.
  • the compound of Formula I also shows in vivo effectiveness against fungi which may be demonstrated using the following in vivo assay.
  • the assay then was carried out by administering aqueous solutions of compound of Formula I at various concentrations intraperitoneally (I.P.), thrice daily (t.i.d.) for one day to 18 to 20 gram female DBA/2 mice, which previously had been infected with Candida albicans in the manner described above.
  • Deionized water was administered I.P. to C. albicans challenged mice as controls. After 24 hours, the mice were sacrificed by carbon dioxide gas, paired kidneys were removed aseptically and placed in sterile polyethylene bags containing 5 milliliters of sterile saline. The kidneys were homogenized in the bags, serially diluted in sterile saline and aliquots spread on the surface of SDA plates.
  • the compound of Formula I is also useful for inhibiting or alleviating Pneumocystis carinii infections in immune-compromised patients.
  • the efficacy of the compounds of the present invention for therapeutic or anti-infection purposes may be demonstrated in studies on immunosuppressed rats.
  • Sprague-Dawley rats (weighing approximately 250 grams) are immunosuppressed with dexamethasone in the drinking water (2.0 mg L) and maintained on a low protein diet for seven weeks to induce the development of Pneumocystis pneumonia from a latent infection.
  • PCP Pneumocystis carinii pneumonia
  • Five rats (weighing approximately 150 grams) are injected twice daily for four days subcutaneously (sc) with compound of Formula I in 0.25 ml of vehicle (distilled water).
  • sc subcutaneously
  • vehicle distilled water
  • compositions suitable for oral administration may contain at least a therapeutic antifungal or antipneumocystis amount of the active compound.
  • the composition contains at least 1 % by weight of the compound of Formula I.
  • Concentrate compositions suitable for dilutions prior to use may contain 90% or more by weight.
  • the compositions include compositions suitable for oral, topical, parenteral (including intraperitoneal, subcutaneous, intramuscular, and intravenous), nasal, and suppository administration, or insufflation.
  • the compositions may be prepacked by intimately mixing the compound of Formula I with the components suitable for the medium desired.
  • Compositions formulated for oral administration may be a liquid composition or a solid composition.
  • the therapeutic agent may be formulated with liquid carriers such as water, glycols, oils, alcohols, and the like, and for solid preparations such as capsules and tablets, with solid carriers such as starches, sugars, kaolin, ethyl cellulose, calcium and sodium carbonate, calcium phosphate, kaolin, talc, lactose, generally with lubricant such as calcium stearate, together with binders disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage form. It is especially advantageous to formulate the compositions in unit dosage form (as hereinafter defined) for ease of administration and uniformity of dosage. Compositions in unit dosage form constitute an aspect of the present invention.
  • compositions may be formulated for injection and may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles such as 0.85 percent sodium chloride or 5 percent dextrose in water and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Buffering agents as well as additives such as saline or glucose may be added to make the solutions isotonic.
  • the compound may also be solubilized in alcohol/propylene glycol or polyethylene glycol for drip intravenous administration.
  • These compositions also may be presented in unit dosage form in ampoules or in multidose containers, preferable with added preservative.
  • the active ingredients may be in powder form for reconstituting with a suitable vehicle prior to administration.
  • unit dosage form refers to physically discrete units, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the pharmaceutical carrier.
  • unit dosage forms are tablets, capsules, pills, powder packets, wafers, measured units in ampoules or in multidose containers and the like.
  • a unit dosage of the present invention will generally contain from 100 to 200 milligrams of one of the compounds.
  • any method of administration may be employed.
  • oral or intravenous administration is usually employed.
  • the compounds of the present inventions are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulizers.
  • the preferred delivery system for inhalation is a metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution of compound of Formula I in suitable propellants, such as fluorocarbons or hydrocarbons.
  • MDI metered dose inhalation
  • the compounds of the present invention may be employed as tablets, capsules, topical compositions, insufflation powders, suppositories and the like, the solubility of the compounds of the present invention in water and aqueous media render them adaptable for use in injectable formulations and also in liquid compositions suitable for aerosol sprays.
  • Pneumocandin B 0 (also referred to as compound I) is disclosed in U.S.
  • Patent No. 5,202,309 which issued April 13, 1993 and is produced by cultivating the fungus Glarea lozoyensis (formerly identified as Zalerion arboricola) under aerobic conditions.
  • a process for the production of Pneumocandin Bo is disclosed in U.S. Patent 5,194,377 which issued March 16, 1993.
  • Pneumocandin B 0 is produced by cultivating Glarea lozoyensis, ATCC No. 20868, deposited under the Budapest Treaty in the Culture Collection of American Type Culture Collection at 12301 Parklawn Drive, Rockville, Md. 20852.
  • Pneumocandin Bo can also be prepared following the procedures described in US Patent No. 5,939,384. Alternatively, Pneumocandin Bo can be isolated following the procedure described below.
  • the fungus Glarea lozoyensis (ATCC 74030) is used to produce Compound I and the structurally related analogues.
  • This improved production strain was derived ultimately from the wild-type organism, ATCC 20868, (isolated from a sample of fresh water) by sequential steps of N-methyl-N'-nitro-N-nitrosoguanidine mutagenesis. The culture was maintained as aliquots of a mycelial suspension in 5% (v/v) glycerol stored at -70°C.
  • a 250 ml Erlenmeyer flask containing 50 ml of LYCP-5 medium was inoculated aseptically with 1 ml of a thawed culture stock. This first stage seed culture was incubated at 25°C with 220 rpm agitation for 3-5 days. A 1 ml aliquot of the first stage seed was transferred to a second 250 ml Erlenmeyer flask containing 50 ml of LYCP-5 medium. This second stage seed culture was incubated as above for 3 days.
  • each treatment group For each variable tested (i.e., treatment group), several 250 ml Erlenmeyer flasks each containing 25 ml FGY medium (Table 2) or a variation thereof (described below) were inoculated at 5% (v/v) with second stage seed. The flasks were incubated at 25°C with 220 rpm agitation for 14 days. The pH for each treatment group was adjusted as required by removing one flask from the group, adding acid or base to return the pH to 5.0-5.5, and then adding this same volume of sterile titrant to the remaining flasks in the group. Where required, a volume of a sterile fructose solution was added during the fermentation to maintain the residual concentration within a specific range.
  • proline concentration in the base medium (0-15 gm 1) resulted in a dose-dependent reduction in the levels of Compounds X and XI while the level of Compound VI increased as a function of proline concentration (Table 3).
  • Amino acids such as glutamine, arginine, and ornithine which can be metabolized to ⁇ pyrroline-S-carboxylate (P5C) also appear to have an impact on the analogues which are defined by the specific amino acid incorporated at the position "occupied" by 3-hydroxyproline in pneumocandin B 0 (Table 5).
  • osmolarity can be controlled by maintaining the residual fructose concentration at high (>75 gm/L) or low ( ⁇ 30 gm L).
  • the initial fructose concentration in the control process is 125 gm/L and is kept high by making two 50 gm L additions during the 14 cycle.
  • the initial fructose concentration can be lowered to 40 gm/L and several 25 gm/L additions made during the course of the fermentation to maintain a low residual sugar level.
  • hydroxylation patterns of amino acids of Pneumocandin Bo are sensitive to zinc, cobalt and nickel. Additionally, amino acid additions to the production medium have a direct effect on the pneumocandins produced by the fermentation. Supplementation of the production medium with proline, trans-3- hydroxyproline and tran.y-4-hydroxyproline effects the incorporation of trans- or trans-4-hydroxyproline residues in Pneumocandin Bo- The addition of threonine to the fermentation controls the level of the serine analogue, Compound JN.
  • Pneumocandin B 0 (15.9 g, 89% area % pure, 3.4 wt % water, 0.0128 mol) was added to dry THF (0.64 L) and the suspension was dried to ⁇ 10 moI% water by refluxing through a bed of 3 A molecular sieves. Additional dry THF was added to reconstitute the mixture to the original volume and the suspension was cooled to ⁇ 4° C. with an ice/water/methanol bath.
  • Neat BH 3 'SMe 2 (10.91 g, 0.144 mol) was added over ten minutes and the reaction mixture was monitored by HPLC until the ratio of starting material to product was 1 : 1 indicating the end of the reaction (3.5 h).
  • the rich cuts (>80 area %) were combined and diluted with water to a 1:7.3 v/v acetonitrile/water (1.70 L total). This mixture was loaded to the same column described above, and the column was washed with 0.57 L of water. The desired compound was eluted with 0.57 L methanol. The rich cut fractions (>85 area %) were combined and concentrated by rotary evaporation and static high vacuum to give 6.81 g (87 wt % pure, 6.8 wt % water) containing 5.92 g of Compound 2 hydrochloride salt for an isolated yield of 43%.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
  • Oncology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une technique de traitement d'infection fongique qui consiste à administrer à un sujet mammifère une quantité efficace d'un composé représenté par la formule (I) ou d'un sel de ce composé répondant aux normes pharmaceutiques. D'autres aspects de cette invention comprennent une technique de traitement d'infection fongique utilisant une combinaison de ce composé représenté par la formule (I) et d'un second agent antifongique et des compositions pharmaceutiques constituées de ces combinaisons.
EP02708948A 2001-01-09 2002-01-04 Metabolite actif de compose antifongique Withdrawn EP1351701A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US26060301P 2001-01-09 2001-01-09
US260603P 2001-01-09
PCT/US2002/000160 WO2002055022A2 (fr) 2001-01-09 2002-01-04 Metabolite actif de compose antifongique

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EP1351701A2 true EP1351701A2 (fr) 2003-10-15

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JP (1) JP2004521102A (fr)
CA (1) CA2433652A1 (fr)
WO (1) WO2002055022A2 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006182672A (ja) * 2004-12-27 2006-07-13 Meiji Seika Kaisha Ltd 新規抗真菌物質、その製造方法、及び医薬組成物
EP1785432A1 (fr) * 2005-11-15 2007-05-16 Sandoz AG Procédé et produits intermédiaires pour la synthèse du caspofungin.
CN102488886B (zh) * 2011-09-26 2014-03-26 上海天伟生物制药有限公司 一种低杂质含量的卡泊芬净制剂及其制备方法和用途
FR2986970A1 (fr) * 2012-02-17 2013-08-23 Agronomique Inst Nat Rech Activite anti-oomycetes des lipopolysaccharides (lps)-binding proteins/bactericidal/permeability-increasing proteins
EP2948145A1 (fr) 2013-01-28 2015-12-02 Pola Pharma Inc. Composition pharmaceutique destinées à des maladies provoquées par des microorganismes pathogènes tels qu'aspergillus
WO2014185542A1 (fr) 2013-05-17 2014-11-20 Pola Pharma Inc. Composition pharmaceutique pour traiter une vaginite ou une pneumonie
CN112110991A (zh) * 2014-12-24 2020-12-22 上海天伟生物制药有限公司 一种含氮杂环六肽前体的组合物及其制备方法和用途
CN113564057B (zh) * 2021-08-17 2023-06-20 湖北省农业科学院植保土肥研究所 一株解毒抑菌生防菌及其应用

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Publication number Priority date Publication date Assignee Title
US5219985A (en) * 1990-10-31 1993-06-15 Merck & Co., Inc. Antifungal agent

Non-Patent Citations (1)

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Title
See references of WO02055022A2 *

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CA2433652A1 (fr) 2002-07-18
JP2004521102A (ja) 2004-07-15
WO2002055022A3 (fr) 2003-02-27
WO2002055022A2 (fr) 2002-07-18

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