WO1997017365A1 - Compose de cyclohexapeptidyle bisamine, compositions contenant ce compose et procedes d'utilisation - Google Patents

Compose de cyclohexapeptidyle bisamine, compositions contenant ce compose et procedes d'utilisation Download PDF

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Publication number
WO1997017365A1
WO1997017365A1 PCT/US1996/017715 US9617715W WO9717365A1 WO 1997017365 A1 WO1997017365 A1 WO 1997017365A1 US 9617715 W US9617715 W US 9617715W WO 9717365 A1 WO9717365 A1 WO 9717365A1
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WIPO (PCT)
Prior art keywords
compound
patient
treating
effective amount
water
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Application number
PCT/US1996/017715
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English (en)
Inventor
James M. Balkovec
Frances A. Bouffard
James F. Dropinski
Original Assignee
Merck & 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
Priority claimed from GBGB9603241.2A external-priority patent/GB9603241D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to JP9518271A priority Critical patent/JP2000501076A/ja
Priority to CA002235824A priority patent/CA2235824A1/fr
Priority to EP96937905A priority patent/EP0862579A1/fr
Priority to AU75540/96A priority patent/AU707664B2/en
Publication of WO1997017365A1 publication Critical patent/WO1997017365A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
    • 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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to an antifungal and anti- pneumocystis agent of the pneumocandin class, in which the aryl side chain on the 5-aminoethyloxy-4-hydroxyornithine subunit of the hexapeptide consists of a naphthoyl group with an OC7H15 substituent.
  • Pending US Patent Application Serial No. 07/936,558 filed September 3, 1992 generally discloses pneumocandins containing an aminoethyl ether at the C-5 ornithine position as well as an amine group at the 5th position of the hexapeptide, as having antifungal activity.
  • EP Publication No. 0 535 967 published April 7, 1993 also discloses these pneumocandins.
  • the compound of the present invention is characterized by an antibiotic spectrum which is largely focused on Candida, Aspergillus, and Pneumocystis carinii. Also, the present compound has safety and pharmacokinetic properties which are superior to other compounds in the class.
  • the present invention relates to a novel cyclohexapeptidyl bisamine compound of the formula:
  • the present invention also relates to a pharmaceutical composition comprised of the compound in combination with a pharmaceutically acceptable carrier.
  • the present invention relates to a method for treating fungal infections, in particular those caused by Candida, Aspergillus and Pneumocystis carinii which comprises administering the compound of formula I to a patient in need of such treatment in an amount effective to treat the fungal infection.
  • the invention additionally relates to a method for preventing Pneumocystis carinii infections in a patient which comprises administration of a preventative amount of the compound of formula I.
  • Pharmaceutically acceptable salts suitable as acid addition salts as well as salts providing the anion of the quaternary salt are those from acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, maleic, citric, acetic, tartaric, succinic, oxalic, malic, glutamic, pamoic and the like, and include other acids related to the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977).
  • the compound When the compound is a free amine, it is soluble in lower alcohols and polar aprotic solvents such as dimethylformamide (DMF) and pyridine. It is insoluble in solvents such as ether and acetonitrile. When the compound is a quaternary ammonium salt or protonated amine, it is soluble in water and polar solvents.
  • polar aprotic solvents such as dimethylformamide (DMF) and pyridine. It is insoluble in solvents such as ether and acetonitrile.
  • solvents such as ether and acetonitrile.
  • the compound When the compound is a quaternary ammonium salt or protonated amine, it is soluble in water and polar solvents.
  • the compound of the present invention is useful as an antibiotic, especially as an antifungal agent or as an antiprotozoal agent.
  • an antifungal agent it is useful for the control of both filamentous fungi and yeast. It is especially adaptable to be employed for the treatment of mycotic infections in mammals, especially those caused by Candida species such as C. albicans, C. tropicalis, C. krusei, C. glabrata and C . pseudotropicalis, and Aspergillus species such as A. fumigatus, A.flavus and A. niger. It is also useful for the treatment and/or prevention of Pneumocystis carinii pneumonia to which immune compromised patients are especially susceptible as hereinafter described.
  • solubility properties are advantageous for utilization in therapeutic applications, especially in injectible compositions.
  • the compound of the present invention may be obtained from natural products or derivatives of natural products through a sequence of reactions seen in the accompanying reaction schemes or from one of the intermediates which are claimed in concurrently filed copending applications.
  • the compound of the present invention may be prepared by two different methods.
  • the starting material which is represented by formula (E) is a natural product disclosed in US Patent No. 5,202,309 issued April 13, 1993.
  • the 3-hydroxyglutamine residue may be reduced to a 3- hydroxyornithine residue (Compound F) using any suitable reducing agent.
  • preferred agents include a borane complex such as borane with tetrahydrofuran or dimethylsulfide or BH2C1 with dimethylsulfide or a metal boride such as ZrCl4/NaBH4.
  • Compound F has been described in copending application serial number 07/936,561 filed September 3, 1992.
  • Etherification at the 5-position of the 4,5- dihydroxyornithine residue of Compound F may be carried out with ethanolamine and a suitable acid catalyst to give bis-amine Compound G.
  • Compound G has been described in copending application serial number 07/936,558 filed September 3, 1992.
  • the dimethylmyristoyl side chain of Compound G may be deacylated enzymatically with Comamonas acidovorans to give triamine Compound H.
  • Compound H is the subject of copending application serial number 08/295,176 filed August 23, 1994.
  • Other suitable enzymatic preparations from a variety of organisms may also be employed for the deacylation. Selective protection of two of the three amine groups of Compound H may be accomplished by any number of reagents.
  • Benzyl 4- nitrophenylcarbonate illustrates this protection step to give Compound J and is shown in Scheme 1.
  • Treatment of Compound J with an activated acylating form of 6-n-heptyloxy-2-naphthoic acid gives the reacylated cyclopeptide K.
  • the preferred activated form is the pentafluorophenyl naphthoate ester.
  • the protecting groups are removed by a suitable method, that being hydrogenolysis for CBz, to give the compound of the present invention.
  • the compound of the present invention may be obtained by subjecting Compound E to enzymatic reaction with a preparation of Comamonas acidovorans or any suitable organism to give the deacylated cyclopeptide Compound L.
  • Compound L is the subject of US Patent 5,310,873 issued May 10, 1994.
  • Acylation of the free amine group of Compound L may be accomplished using an activated acylating form of 6-n-heptyloxy-2- naphthoic acid.
  • the pentafluorophenyl ester of 6-n-heptyloxy-2- naphthoic acid illustrates the transformation of Compound L to Compound M and is preferred.
  • the compounds of the present invention are active against many fungi and particularly against Candida, Aspergillus and Cryptococcus species.
  • the antifungal properties may be illustrated with the minimum fungicidal concentration (MFC) determination against certain Candida and Cryptococcus organisms in a microbroth dilution assay carried out in a Yeast Nitrogen Base (Difco) medium with 1 percent dextrose (YNBD).
  • MFC minimum fungicidal concentration
  • DMSO dimethyl sulfoxide
  • the drug stock was brought to a concentration of 512 ⁇ g/ml by dilution in water such that the final DMSO concentration was about 10 percent.
  • the solution was then dispensed via a multichannel pipetter into the first column of a 96-well plate (each well containing 0.075 ml of YNBD), resulting in a drug concentration of 256 ⁇ g/ml.
  • Compounds in the first column were diluted 2-fold across the rows yielding final drug concentrations ranging from 256 ⁇ g/ml to 0.12 ⁇ g/ml.
  • Compound I also shows in vivo effectiveness against fungi.
  • the assay then was carried out by administering aqueous solutions of Compound I at various concentrations intraperitoneally (I.P.), twice daily (b.i.d.) for two consecutive days to 18 to 20 gram female DBA/2 mice, which previously had been infected with Candida albicans in the manner described above. Distilled water was administered I.P. to C. albicans challenged mice as controls. After four days, the mice were sacrificed by carbon dioxide gas, paired kidneys were removed aseptically and placed in sterile polyethylene bags containing 5 milliters of sterile saline. The kidneys were homogenized in the bags, serially diluted in sterile saline and aliquots spread on the surface of SDA plates.
  • I.P. intraperitoneally
  • b.i.d. twice daily
  • CFU colony forming units
  • the compound of the present invention may also be useful for inhibiting or alleviating Pneumocystis carinii infections in immune compromised patients.
  • the efficacy of the compound of the present invention for therapeutic or anti-infective purposes may be demonstrated in studies on immunosuppressed mice.
  • mice were 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. Before drug treatment, two mice were sacrificed to confirm the presence of Pneumocystis carinii pneumonia (PCP); both mice were found to have infections. Five mice (weighing approximately 20 grams) were injected twice daily for four days subcutaneously (sc) with the compound in 0.25 ml of vehicle (distilled water). A vehicle control was also carried out. All animals continued to receive dexamethasone in the drinking water and low protein diet during the treatment period.
  • PCP Pneumocystis carinii pneumonia
  • the compound of the present invention has surprising and unexpected safety benefits in that there is markedly improved acute tolerability in mammals than with other related compounds.
  • laboratory test animals rhesus monkeys
  • no notable response was observed for the compound of the present invention when dosed at identical levels of related compounds that do cause cardiovascular effects.
  • the acute tolerability of the compound of the present invention in mice has been shown to be superior to that of related compounds.
  • compositions contain at least a therapeutic antifungal or antipneumocystis amount of the active compound of the present invention. Generally, the composition contains at least 1 percent by weight of Compound I. Concentrate compositions suitable for dilutions prior to use may contain 90 percent 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 Compound 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 a lubricant such as calcium stearate, together with binders disintegrating agents and the like.
  • liquid carriers such as water, glycols, oils, alcohols, and the like
  • 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 a lubricant such as calcium stearate, together with binders disintegrating agents and the like.
  • solid carriers such as starches, sugars,
  • compositions may be formulated for injection and for injection 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. Compound I 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, preferably with added preservative. Altematively, 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 10 to 500 milligrams of the compound.
  • any method of administration may be employed.
  • the compounds of the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulisers.
  • the preferred delivery system for inhalation is a metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution of the compound in suitable propellants, such as fluorocarbons or hydrocarbons.
  • MDI metered dose inhalation
  • the compound 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 injectible formulations and also in liquid compositions suitable for aerosol sprays.
  • Compound E (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 mol% 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 BH3»SMe2 (10.91 g, 0.144 mol) was added over ten minutes and the reaction mixture was maintained at 0-4°C. The reaction progress was monitored by HPLC until the ratio of starting material to product was 1 : 1 indicating the end of the reaction (3.5 h). At 4 hours, the mixture was cooled to -12°C and slowly quenched with 2N HCl (0.036 L). This solution was diluted to 1.14 L with water. The assay yield of Compound F was 6.60 g (47%).
  • the quenched solution was diluted to 4 L and loaded onto a medium-pressure column of LiChroprep RP-C18 adsorbent (158 g). After loading, the column was washed with 1.2 L water and the amine was eluted with 1.9 L of 1 :4 v/v acetonitrile/water, and then 0.38 L of 1 :3 v/v acetonitrile/water.
  • the rich cuts (> 80 area%) were combined and diluted with water to a 1 :7.3 v/v acetonitrile/water solution (1.70 L total). This mixture was loaded to the same column described above, and the column was washed with 0.57 L 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 F (where R 1 is dimethyltridecyl) hydrochloride salt for an isolated yield of 43%.
  • a loopful of cells from an LB agar slant of the organism was used to inoculate 50 mL of Lauria-Bertani (LB) medium in a 250-mL unbaffled Erlenmeyer flask.
  • the flask was incubated at 25°C with agitation at 220 rpm for about 18 hours and 0.1 mL of this culture was used to inoculate each of three 250-mL Erlenmeyer flasks containing 50 mL of LB medium.
  • Deacylation was set up in two 15 -liter Microferm fermentors (New Brunswick Scientific).
  • 10 g of Compound G dissolved in 250 mL of distilled water was added to 5 liters of the washed and buffered C. acidovorans cells while in the second vessel (B), 8.2 g of Compound G dissolved in 200 mL of distilled water was added to 4 liters of the cells.
  • Addition of Compound G to each vessel was accomplished with a pipette over a 5-minute period.
  • To reduce foaming about 2 mL and 1.5 mL of P2000 were added to vessels A and B respectively.
  • Each fermentor was operated with stirring at 100 rpm, aeration at 1.5 L/min and temperature at 37°C for the first 2.5 hours and 30°C for the last 21.5 hours. After 24 hours, - 16 -
  • the pentaflourophenyl 6-n- heptyloxy-2-napthoate (6.65 g, 0.015 mol) was then added and stirred for 18 hours.
  • HPLC indicated consumption of Compound J and formation of acylated product, Compound K.
  • the reaction was diluted with water (75 mL) and loaded onto a RP Cl8 flash column (50 g) packed in 30% CH 3 CN/H 2 0; rinsed with 6 x 50 mL of 50% CH 3 CN/H 2 0; and lastly 10 x 50 mL 100% methanol.
  • the product- containing methanol fractions were combined and concentrated to give 1 1.1 g of crude Compound K (80% pure).
  • Compound K was further purified on Zorbax Rx-Cl8 (21.2 x 250 mm) eluting with 70% CH 3 CN/H 2 0 at a flow rate of 10 mL/min.
  • the product-containing fractions, as determined by HPLC (75% A/B, t 3.1 min),were combined and lyophilized to give > 98% pure Compound K.
  • a loopful of Comamonas acidovorans ATCC 53942 is inoculated into 50 milliliters of Luria Bertani medium of the following composition: per liter Bacto-Trypton, 10 g; Bacto- Yeast Extract, 5 g and sodium chloride 10 g and solidified with 2 percent agar and incubating for 24 hours with shaking to obtain a seed culture.
  • Cells for the deacylation are then grown by diluting a 50 milliliter portion of seed culture 1 :500 into fresh Luria-Bertani medium and incubating at 25 °C with shaking for 16 hours. Cells are then harvested by centrifugation, washed by resuspending in 1 percent sodium chloride and centrifuged and then resuspended in potassium phosphate buffer at pH 6.5.
  • a solution of pneumocandin Bo (Compound E) in dimethylsulfoxide is then added to a stirred suspension of the cells of C. acidovorans thus obtained and the mixture maintained at 37 °C for 18 hours to obtain the deacylated product, Compound L, which is recovered in the supernatant after centrifugation.
  • Pentafluorphenyl 6-n-heptyloxy-2-naphthoate is prepared as follows. To a suspension of 6-n-heptyloxy-2-naphthoic acid (10.5 mmol) and dicyclohexylcarbodiimide (10.5 mmol) in ethyl acetate at 0°C is added pentafluorophenol (1 1.5 mmol). The mixture is stirred at 25 °C for a period of 18 h. Any precipitate is removed by filtration. The filtrate is washed twice with water and brine and dried with magnesium sulfate.
  • Pentafluorophenyl 6-n-heptyloxy-2-naphthoate (1.1 mmol) prepared as above is added to a solution of Compound L from Part A (1.0 mmol) in anhydrous N,N-dimethylformamide. The resulting solution is stirred at room temperature for a period of 12 to 24 h. The mixture is subsequently diluted with water.
  • a reaction vessel is outfitted with an addition funnel charged with 3-4 angstrom molecular sieves and a reflux condenser above the addition funnel.
  • Compound M is suspended in dry tetrahydrofuran and heated to reflux under a nitrogen atmosphere. The mixture is refluxed for 12-24 hours, then cooled to 0°C.
  • Borane-methylsulf ⁇ de complex (10-20 equivalents) is added dropwise over 1 -2 hours. The mixture is stirred at 0°C for 2-5 hours and then carefully quenched with 2N hydrochloric acid. Stirring is continued for 1 hour after the final addition of hydrochloric acid.
  • the mixture is concentrated to 40-50 percent of the original volume and then diluted with 6-7 volumes of distilled water.
  • reaction mixture is diluted with five to ten volumes of water and the resulting mixture applied to a reverse phase flash silica gel column using Lichroprep C18 (particle size 40-63 microns). The mixture is then eluted initially with 5%-15% acetonitrile in water to remove the excess DMSO and 2-aminoethanol hydrochloride, then with 10-50% acetonitrile in water to elute the product. Fractions containing the desired product are combined, concentrated and lyophilized to afford the product.
  • Subsequent exchange for chloride ion may be accomplished by dissolving the residue in water and passing through a BioRad AG2-X8, Cl- resin column to give the desired Compound I as the dihydrochloride with a molecular weight of 1 197.2.

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Abstract

La présente invention concerne un composé représenté par la formule générale (I). Ce composé convient au traitement des mycoses et au traitement des infections provoquées par Pneumocystis carinii.
PCT/US1996/017715 1995-11-09 1996-11-06 Compose de cyclohexapeptidyle bisamine, compositions contenant ce compose et procedes d'utilisation WO1997017365A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP9518271A JP2000501076A (ja) 1995-11-09 1996-11-06 シクロヘキサペプチジルビスアミン化合物、その化合物を含む組成物とその使用方法
CA002235824A CA2235824A1 (fr) 1995-11-09 1996-11-06 Compose de cyclohexapeptidyle bisamine, compositions contenant ce compose et procedes d'utilisation
EP96937905A EP0862579A1 (fr) 1995-11-09 1996-11-06 Compose de cyclohexapeptidyle bisamine, compositions contenant ce compose et procedes d'utilisation
AU75540/96A AU707664B2 (en) 1995-11-09 1996-11-06 Cyclohexapeptidyl bisamine compound, compositions containing said compound and methods of use

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US650595P 1995-11-09 1995-11-09
US60/006,505 1995-11-09
GBGB9603241.2A GB9603241D0 (en) 1996-02-16 1996-02-16 Cyclohexapeptidyl bisamine compound, compositions containing said compound and methods of use
GB9603241.2 1996-02-16

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Publication Number Publication Date
WO1997017365A1 true WO1997017365A1 (fr) 1997-05-15

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PCT/US1996/017715 WO1997017365A1 (fr) 1995-11-09 1996-11-06 Compose de cyclohexapeptidyle bisamine, compositions contenant ce compose et procedes d'utilisation

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EP (1) EP0862579A1 (fr)
JP (1) JP2000501076A (fr)
AR (1) AR001314A1 (fr)
AU (1) AU707664B2 (fr)
CA (1) CA2235824A1 (fr)
CO (1) CO4770984A1 (fr)
HR (1) HRP960521A2 (fr)
PE (1) PE16198A1 (fr)
WO (1) WO1997017365A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000035945A1 (fr) * 1998-12-16 2000-06-22 Eli Lilly And Company Agents antifongiques de peptide cyclique possedant un substituant sucre

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0535967A2 (fr) * 1991-10-01 1993-04-07 Merck & Co. Inc. Cyclohexapeptides bisaminés
WO1994021677A1 (fr) * 1993-03-16 1994-09-29 Merck & Co., Inc. Composes d'aza cyclohexapeptide
EP0644199A1 (fr) * 1993-05-17 1995-03-22 Fujisawa Pharmaceutical Co., Ltd. Peptides antimicrobiens cycliques et leur préparation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0535967A2 (fr) * 1991-10-01 1993-04-07 Merck & Co. Inc. Cyclohexapeptides bisaminés
WO1994021677A1 (fr) * 1993-03-16 1994-09-29 Merck & Co., Inc. Composes d'aza cyclohexapeptide
EP0644199A1 (fr) * 1993-05-17 1995-03-22 Fujisawa Pharmaceutical Co., Ltd. Peptides antimicrobiens cycliques et leur préparation

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000035945A1 (fr) * 1998-12-16 2000-06-22 Eli Lilly And Company Agents antifongiques de peptide cyclique possedant un substituant sucre

Also Published As

Publication number Publication date
EP0862579A1 (fr) 1998-09-09
JP2000501076A (ja) 2000-02-02
AR001314A1 (es) 1997-10-22
HRP960521A2 (en) 1998-04-30
PE16198A1 (es) 1998-04-11
CO4770984A1 (es) 1999-04-30
AU7554096A (en) 1997-05-29
AU707664B2 (en) 1999-07-15
CA2235824A1 (fr) 1997-05-15

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