WO2000063239A1 - Nouveaux composes antifongiques - Google Patents

Nouveaux composes antifongiques Download PDF

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Publication number
WO2000063239A1
WO2000063239A1 PCT/JP2000/002465 JP0002465W WO0063239A1 WO 2000063239 A1 WO2000063239 A1 WO 2000063239A1 JP 0002465 W JP0002465 W JP 0002465W WO 0063239 A1 WO0063239 A1 WO 0063239A1
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Prior art keywords
compound
ion
exchanged water
group
column
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PCT/JP2000/002465
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English (en)
Japanese (ja)
Inventor
Takao Ohyama
Yuko Kurihara
Tomio Ishikawa
Shunichi Miyakoshi
Kiyoshi Hamano
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Sankyo Company, Limited
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Priority to AU38376/00A priority Critical patent/AU3837600A/en
Publication of WO2000063239A1 publication Critical patent/WO2000063239A1/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
    • 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 novel antifungal compounds, their use, medicaments containing them as an active ingredient, antifungal agents containing them as an active ingredient, and the like.
  • a drug that inhibits the synthesis of 1,3- ⁇ -glucan, a major cell wall component of fungi, ie, a 1,3 -— / 3-glucan synthase (1,3— / 3-glucansynthase) inhibitor Is expected to be a safe and effective antifungal drug because the enzyme is specifically present in fungi and a bactericidal action can be expected.
  • Examples of the enzyme inhibitor include papracandins (see, Römme 1 e, G. eta 1. (1 983) Journal of Antibiotics, 36, p15 39 and below), Carrots (see Debono, M. eta 1. (1995) Journal of Medicine and hemistry, 38, p3 271 and below), and dumocandins (Hensens, O. D. eta. 1. (1992) Journalof Antibiotics, 45, p1875 et seq., And acreasins (Takeshima, H. eta, (1 989) Journalo ⁇ Biochemistry, 105, p 606 and below).
  • papracandins see, Römme 1 e, G. eta 1. (1 983) Journal of Antibiotics, 36, p15 39 and below
  • Carrots see Debono, M. eta 1. (1995) Journal of Medicine and hemistry, 38, p3 271 and below
  • the inventors isolated many microorganisms from nature in order to obtain a novel bioactive compound. While examining the biological activity of the product, they isolated from plant leaves newly collected in Ube City, Yamaguchi Prefecture. It has been found that a compound having strong antifungal activity is produced in a culture of the resulting non-spore-forming filamentous fungus SANK173977. Furthermore, the present invention has been completed by producing derivatives of these compounds.
  • the present invention relates to novel compounds having 1,3- / 3-glucan synthase inhibitory activity and useful as a therapeutic agent for mycosis in humans or animals, their use, and containing them as effective components. It is an object of the present invention to provide medicaments and antifungal agents containing them as active ingredients.
  • the present invention is a.
  • the nuclear magnetic resonance spectrum (90 MHz) measured in diuterium-substituted dimethyl sulfoxide using the solvent spectrum of diuterium-substituted dimethyl sulfoxide as an internal standard is as follows. As shown below:
  • the nuclear magnetic resonance spectrum (90 MHz) measured in diuterium-substituted dimethyl sulfoxide using the solvent spectrum of diuterium-substituted dimethyl sulfoxide as an internal standard is as follows. As shown below:
  • a compound I VB or a prodrug thereof or a salt thereof A compound I VB or a prodrug thereof or a salt thereof,
  • a medicament comprising the compound according to any one of (1) to (12) as an active ingredient
  • an antifungal agent comprising the compound according to any one of (1) to (12) as an active ingredient
  • the compounds of the present invention have antifungal activity against fungi such as Candida albicans (Candida albicans), which show pathogenicity infecting humans and animals. Further, the compound of the present invention inhibits the glucan synthesis activity of a 1,3- ⁇ -glucan synthase solubilized sample prepared from Aspergillus fumigatus (Aspergii11usfmigatus) at a low concentration.
  • the compound of the present invention has the following general formula (m):
  • R is 3-arsenide Dorokishi dodecyl group and R 2 is 8 - arsenide Dorokishi compound dodecyl compounds IA
  • R is 3-hydroxycarboxylic dodecyl group and R 2 is 8-arsenide de Rokishite Toradeshiru group Is a compound IIA
  • R i is a 3-hydroxydodecyl group and R 2 is an 8-hydroxytridecyl group
  • a compound is a compound II IA
  • R i is a 3-hydroxydodecyl group and R 2 is 8 year old
  • Kisote Toradeshiru a is of compound group compounds I VA, compounds wherein R 3 human Dorokishi preparative Rideshiru group and R 2 is 8-arsenide Doroki Cite Toradeshiru group compound VA, R, but 3 - human Dorokishite
  • R i is 3-hydroxycarboxylic dodecyl group and compounds wherein R 2 is 8-hydroxycarboxylic dodecyl group compound IB, but 3-hydroxycarboxylic dodecyl group and R 2 is 8-arsenide de port Kishite
  • a compound having a trdecyl group is compound IIB, a compound having 3-hydroxyhydrdecyl group and R 2 is 8 -hydroxyridyl compound is a compound IIIB, and a compound having R: 3-hydroxydecyl group and R 2 is 8 -oxote.
  • a compound having a trdecyl group is compound I VB, a compound having a 3-hydroxytridecyl group and R 2 being an 8-hydroxytradecyl group is a compound VB, and a compound having R i being a 3-hydroxytradecyl group and R A compound in which 2 is an 8-hydroxytradecyl group is a compound VIB.
  • Compound IA, compound IB, compound IIA, compound IIB, compound IIIA, compound IIIB, compound IVA, compound IVB, compound VA, compound VB, compound VIA, and compound VIA of the present invention each have several asymmetric carbon atoms. Having. Therefore, various optical isomers exist. In the present invention, all isomers of these compounds are represented by a single formula. However, the present invention relates to all of these isomers including racemic compounds and mixtures of these isomers. Including.
  • Compound IA, Compound IB, Compound IIA, Compound IIB, Compound IIIA, Compound IIIB, Compound IVA, Compound IVB, Compound VA, Compound VB, Compound V of the present invention IA and compound VIB can be salified using methods well known to those skilled in the art.
  • the present invention also includes salts of such compounds.
  • salts include sodium salt, potassium salt, and lithium salt.
  • alkali metal salts such as, calcium salts, magnesium salts, alkaline earth metal salts such as, aluminum salts, iron salts, zinc salts, copper salts, nickel salts, metal salts such as cobalt salts, etc .
  • Inorganic salts such as salts, tert-octylamine salts, dibenzylamine salts, morpholinate salts, dalcosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methyldalcamine salts, guanidine salts, getylamine salts, triethylamine salts, dicyclomine salts Hexylamine salt, N, ⁇ 'dibenzylethylenediamine salt, Organic salts such as thiophene salts,
  • Compound I of the present invention Compound I, Compound II, Compound II, Compound III, Compound III, Compound IVA, Compound IVB, Compound VA, Compound VB, Compound VIA, or Compound VIB is a solvate (eg, Hydrate) are all included in the present invention.
  • a solvate eg, Hydrate
  • the compound IA, compound IB, compound IIA, compound IIB, compound IIIA, compound IIIB, compound IVA, compound IVB, compound VA, compound VB, compound VIA, or compound VIB of the present invention is left in the air, or By recrystallization, water may be absorbed, adsorbed water may adhere, or hydrates may be formed.
  • the present invention includes such a solvate.
  • the present invention also includes a prodrug of the compound of the present invention, a salt or a solvate of the prodrug.
  • a prodrug refers to a compound IA of the present invention, which is cleaved by a chemical or biological method such as hydrolysis in a human or animal body to form a compound of the present invention or a salt thereof.
  • Compound IB, Compound IIA, Compound IIB, Compound IIIA, Compound IIIB, Compound IVA, Compound IVB, Compound VA, Compound VB, Compound V It is a derivative in which the functional group of IA or compound VIB is protected.
  • Whether such a derivative is a prodrug is determined by detecting the compound of the present invention or a salt thereof in a body fluid of an animal after oral administration or intravenous administration to an experimental animal such as a rat mouse. It can be determined by whether or not it is performed.
  • Compound IA, Compound IB, Compound IIA, Compound IIB, Compound IIIA, Compound IIIB, Compound IVA, Compound IVB, Compound VA, Compound VB, Compound VIA, or Compound VIB of the present invention has a functional group such as a carboxyl group or a hydroxyl group.
  • pharmacologically acceptable derivatives include derivatives in which a hydroxyl group is esterified, derivatives in which a hydroxyl group is substituted with an acyl group, and the like.
  • Examples of the group that forms an ester with a carboxyl group include an alkyl group having 1 to 16 carbon atoms, an aryl group having 6 to 18 carbon atoms, and an aralkyl group having 7 to 23 carbon atoms. Can be. These alkyl group, aryl group, aralkyl group and the like may be substituted with a hydroxyl group, a carboxyl group, a phosphate group and the like.
  • alkyl group having 1 to 16 carbon atoms examples include methyl, ethyl, isopropyl, butynole, isobutynole, pentinole, pinoquinole, hexinole, heptinole, octyl, noninole, decyl, 3-Methyneno ninole, 8-methylno ninole, 3-ethylooctyl, 3,7-dimethyloctyl, pendecyl, dodecyl, tridecyl, tetradecyl, pentadecinole, hexadecyl, 1-methylpentadecyl, 14-methinoledentadecyl, Groups such as 13, ⁇ 13 -dimethylpentadecyl can be mentioned.
  • the aryl group having 6 to 18 carbon atoms examples include groups such as phenyl, tolyl, and naphthy
  • Examples of the aralkyl group having 7 to 23 carbon atoms include groups such as benzyl and phenethyl.
  • acyl group that substitutes a hydroxyl group examples include an aliphatic acyl group, an aromatic acyl group, an alkoxycarbonyl group, an aralkyloxycarbonyl group, an aminoacyl group, and a phosphoric acid group.
  • Examples of the aliphatic acetyl group include formyl, acetyl, propionyl, and petit Linole, Isobu-Cyrinole, Penta Noinole, Pinot Loinore, Valerinole, I Sonoku Relinole, Octanyl, Nonanoyl, Decanoyl, 3-Methylnonanoyl, 8-Methylnonanoyl, 3-Methylnonanoyl, 3,7-Dimethylo Kutanoyl, Pendecanoyl, Dodecanoyl, Tridecanoyl, Tetradecanoyl, Pentadecanoyl, Hexadecanoyl, 1-Methylpentadecanoyl, 14-Methylpentadecanoyl, 13-, 13-Dimethyltetradecanol, 1-Dimethyltetradecanol Examples thereof include alkanoyl groups having 1 to
  • aliphatic acyl groups may have 1 to 3 multiple bonds, and may be substituted with a hydroxyl group, a carboxyl group, a phosphoric acid group or a carboxyl group.
  • aromatic acyl group include an arylcarbonyl group having 7 to 11 carbon atoms such as benzoyl, ⁇ -naphthoyl, and naphthyl.
  • the aryl ring of these aromatic acyl groups includes an alkyl group having 1 to 4 carbon atoms, a halogen atom, an alkoxy group, a hydroxyl group, a carboxyl group, an alkoxyl group having 1 to 4 carbon atoms, It may be substituted with a hydroxyalkyl group having 1 to 4 carbon atoms, an alkyl phosphate group having 1 to 4 carbon atoms or a carboxyalkyl group having 2 to 5 carbon atoms.
  • alkoxycarbonyl group or aralkyloxycarbonyl group examples include alkoxycarbonyl groups having 2 to 20 carbon atoms such as methoxycarbonyl, ethoxycanoleboninole, tert-butoxycarbonyl, and isobutoxycarbonyl groups.
  • the alkyl moiety of the alkoxycarbonyl group or the aryl ring of the aralkyloxycarbonyl group includes an alkyl group having 1 to 4 carbon atoms, a nitrogen atom, an alkoxy group having 1 to 4 carbon atoms, a hydroxyl group, and a phosphoric acid.
  • Examples of the phosphate group include: phosphoric acid; methylphosphoric acid, ethylphosphoric acid, propylphosphoric acid, Monoalkyl phosphate groups having 1 to 20 carbon atoms such as tyl phosphoric acid, decyl phosphoric acid, and octadecyl phosphoric acid; 1 to 2 carbon atoms such as dimethyl phosphoric acid, getyl phosphoric acid, dipropyl phosphoric acid, dibutyl phosphoric acid, didecyl phosphoric acid, and dioctadecyl phosphoric acid And zero dialkyl phosphate groups.
  • the compound of the present invention is obtained by culturing a non-spore-forming filamentous fungus S ANK 173997, and using the culture solution to obtain the following general formula (o):
  • R i is 3—hydroxy dodecyl group and R 2 is 8—hydroxy dodecyl group
  • Compound I R i is a 3-hydroxy dodecyl group and R 2 is 8—hydr Kishite Toradeshiru a group compound compound II, R is 3 - human Dorokishidodeshi Le group and compound a compound where R 2 is 8-arsenide Dorokishito Rideshiru group III, R 1 is 3-hydroxycarboxylic dodecyl group and R 2 is 8 - Okisote Toradeshiru group, compound compound IV, R E 3 - human Dorokishito Rideshiru group and R 2 is 8 - heat Dorokishite Toradeshiru group in which the compound compound V, R E is 3-arsenide Dorokishite Toradeshiru Moto ⁇ one R 2 Is defined as compound VI.
  • a compound represented by the formula (1) is purified and isolated, and subjected to hydrolysis reaction under acidic conditions to produce the compound.
  • Compounds IA and IB are compound I and compound IIA and compound IIB are From compound II, compound IIIA and compound IIIB are from compound III, compound IVA and compound IVB are from compound IV, compound VA and compound VB are from compound V, and compound VIA and compound VIB are from compound VI. Manufactured.
  • SANK17397 strain Spore-free spore-forming fungus S ANK173997 strain (hereinafter referred to as "SANK17397 strain"), which is a suitable producing bacterium for compound I, compound II, compound III, compound IV, compound V and compound VI Has the following properties.
  • the growth on the medium is extremely suppressed, and the diameter reaches 23 ° (: 19 mm in 14 days)
  • the colony is thick and velvety, wool-like at the center and rises by about 2 to 3 mm, the colony surface becomes olive (1F5), and the rise and the white side become white.
  • a radial groove is formed from the center to the edge
  • the back surface of the colony is dark blue-green (24F3)
  • Growth on WSH medium is extremely inhibitory and the diameter is 23 ° (:, Reach 17 mm in 14 days. Basal hyphae are thin, aerial hyphae are bundled from wool-like, slightly prominent at the center, and a long part of hyphae exists concentrically from the center.
  • the surface is olive (1E3), grayish white (1B1) at the prominence, and the back is gray (1F1)
  • the growth on Miura medium is extremely suppressed, the diameter is 23 and reaches 18 mm in 14 days.
  • the basal hyphae is thin, and the aerial hyphae is wool-like.
  • the colony surface is orange-white (5A2), the prominence is light orange (5A3), and the back is black-brown (5F4) in the center. It becomes orange-white (5A2) toward the margin.
  • Cornmealagar (hereafter referred to as “CMA”) is extremely inhibited from growing on the medium, reaching a diameter of 23 ° (: 15 mm in 14 days).
  • the aerial mycelium is wool-like and protrudes about 1 to 2 mm at the center.
  • the colony surface is yellow-brown (5E6), the protuberance is white, and the back is gray-brown (5F3). It is orange-gray (5B2) at the edge.
  • Hyphae are colorless to brown in any medium, the surface is smooth to rough, branched, with septum, l ⁇ 3 // m in diameter, often clustered in bundles. No sexual spores or conidia were formed even after 2 weeks in the tested medium.
  • the SANK 1739 7 strain can grow on PDA medium at 5 to 30 and does not grow at 37.
  • the optimum temperature is between 17 and 27.
  • the SANK 17397 strain was identified as a non-spore-free filamentous fungus.
  • composition of each medium used here is described below.
  • PDA medium 39 g Nissi potato dextrose agar medium (manufactured by Nissui Pharmaceutical Co., Ltd.), 1 L distilled water
  • sterilization of the above medium was all performed at 121 C for 20 minutes.
  • Compound I, compound II, compound III, compound IV, compound V, and compound VI are obtained by culturing bacteria producing the compound such as S ANK 173997 in a liquid medium containing a carbon source, a nitrogen source, and the like. Can be obtained.
  • the liquid medium may contain inorganic salts, vitamins, trace metals, sulfur compounds, defoamers and the like. The culturing is preferably performed under aerobic conditions.
  • Examples of the carbon source contained in the liquid medium include glucose, starch, dextrin, glycerin, fructose, maltose, lactose, sucrose, mannitol, oat flour, rye flour, corn starch, potato, Maize flour, soy flour, malt extract, and combinations of two or more of these can be mentioned, and glucose, starch, dextrin and glycerin are preferred.
  • the upper limit is 5% ⁇ 1 ⁇ 2 to 10% by weight
  • the lower limit is 0.1% to 0.5% by weight
  • the preferred range is 0.5% by weight. 5 to ⁇ 5.
  • Nitrogen sources in the liquid medium include, for example, glutamine, cystine, alanine, glycine, proline, threonine, other amino acids, bran, peanut flour, casein hydrolyzate, fish meal, malt Extracts, soy flour, soy casein, casamino acids, pharma media (Southern 'cotton' oil), cottonseed flour, wheat germ, meat kiss, peptone, corn steep liquor, self-digesting yeast, Dried yeast, yeast extract, ammonium salt, a mixture of two or more of these, and the like. Is amino acid, bran, peanut powder, casein.
  • the inorganic salts are not particularly limited as long as they can be ionized. Examples thereof include sodium, potassium, magnesium, ammonium, calcium, phosphate, sulfate, chloride, and lithium carbonate. And the like.
  • vitamins examples include vitamin B1, biotin, thiamine and the like.
  • Examples of the trace metals include iron, copper, manganese, iron, molybdenum, zinc, and the like.
  • sulfur compounds examples include sulfates such as zinc sulfate, copper sulfate, ferrous sulfate, and ammonium sulfate; thiosulfates such as ammonium thiosulfate; sulfites such as ammonium sulfite; Inorganic sulfur compounds; sulfur-containing amino acids such as cystine, cysteine, L-thiazolidine-14-carboxylic acid; and organic sulfur compounds such as sulfur-containing peptides such as hypotaurine and glutathione. it can.
  • antifoaming agent examples include silicon oil, polyalkylene glycol, vegetable oil, animal oil, surfactant and the like.
  • a preferred method for producing III, compound IV, compound V or compound VI is SANK 173 Spores or mycelium of the bacterium producing the compound, such as 9 strains, are cultured under aerobic conditions after inoculation in the above-mentioned liquid medium, and the compound is collected from the culture.
  • seed culture a step of inoculating a seed culture medium with the bacteria grown on the inclined agar medium, and thereafter growing a microorganism that becomes a seed microorganism for the production bacterium of the compound of the present invention (hereinafter, this step is referred to as “seed culture”).
  • seed culture any of the aforementioned liquid media can be used. Bacteria grown on a gradient agar medium are inoculated into a liquid medium in a sterilized flask, and the flask is kept warm while shaking.
  • the lower limit of the shaking speed is 50 to 190 revolutions / minute (reVo1utionsperminute: hereinafter, referred to as “rpm”), and the upper limit is 220 to 400 rpm.
  • the range is 190 to 220 rpm.
  • the lower limit of the heat retention temperature is 15 to 20 : 'C, the upper limit is 26 to 30, and the preferable range is 20 to 26.
  • the lower limit of the number of days of the inoculum culture is 2 to 3 days, the upper limit is 5 to 10 days, and the preferred range is 3 to 5 days. Seed culture can be performed multiple times as needed, and the culture scale can be gradually expanded. In this case, it is also possible to shorten the cultivation time of the second or subsequent seed culture.
  • the inoculum is used to inoculate the culture medium for producing the starting compound (hereinafter referred to as “production medium”).
  • production medium the above-mentioned liquid medium can be used.
  • the same medium as the medium used for inoculum culture or a medium having a slightly different composition is used.
  • the culture method for producing the raw material compounds is not particularly limited as long as it is a culture method usually used for large-scale culture of microorganisms, and examples thereof include a stirring culture method, a shaking culture method, and an aeration culture method. be able to. It is preferable to carry out any of the culturing methods mentioned here under aerobic conditions. For industrial culturing, aeration and stirring culturing methods are suitable. Inoculate the seed culture into the production medium in a sterilized flask, and incubate the flask with or without shaking. The lower limit of the shaking speed is 50 to 190 rpm, the upper limit is 220 to 400 rpm, and the preferable range is 190 to 220 rpm.
  • the range of the culture days is a lower limit of 3 to 5 days, an upper limit of 14 to 20 days, and a preferred range is 5 to 14 days. is there.
  • the pH range of the production medium has a lower limit of pH 3.5 to 4.5, an upper limit of 7.0 to 8.0, and a preferable range of 4.5 to 7.0.
  • the range of the pH after the modification is such that the lower limit is pH 3 to 5, the upper limit is pH 7 to 9, and the preferable range is pH 5 to 7.
  • a water-miscible solvent is mixed with a water-miscible solvent and the mycelium is filtered.
  • a solvent miscible with water is not particularly limited so long as the solvent usually miscible with microbial broth of aqueous, for example, acetone, methanol, ethanol and c the culture mixture, and the like thereof
  • the ratio of the water and the solvent miscible with water is usually from 2: 1 to 1: 5, and preferably 1: 1. From the collected filtrate, compound I, compound II, compound III, compound IV, compound V or compound VI can be purified and isolated using the method described below.
  • aqueous filtrate is extracted with a water-immiscible solvent such as methyl ethyl ketone, ethyl acetate, dichloromethane, butyl acetate, and butanol, preferably after adjusting the pH to neutral.
  • a water-immiscible solvent such as methyl ethyl ketone, ethyl acetate, dichloromethane, butyl acetate, and butanol
  • an aqueous filtrate is added to a column packed with a resin such as Amberlite XAD-11 (manufactured by Rohm and Haas) and Diaion HP-20 (manufactured by Mitsubishi Chemical Corporation).
  • a resin such as Amberlite XAD-11 (manufactured by Rohm and Haas) and Diaion HP-20 (manufactured by Mitsubishi Chemical Corporation).
  • the fraction obtained using these methods can be dried under reduced pressure to obtain a partially purified surface fraction. Thereafter, the partially purified fraction is subjected to several separation steps, such as adsorption and partition chromatography.
  • Chromatographic separation uses a nonionic adsorbent, etc. This can be performed by column chromatography, which is commonly used in Japan.
  • a nonionic adsorbent such as silica gel
  • methanol, chloroform, acetic acid, water, or the like can be used alone or in combination as an eluent.
  • C8 or C18 stationary phase silica gel is preferably used as the adsorbent.
  • a solvent such as water, methanol and acetonitrile, or a mixture thereof is used.
  • the fraction containing the target compound obtained through each purification means as described above is supplied to the next purification step with or without distilling off the solvent contained in the fraction.
  • the method for distilling off the solvent is not particularly limited as long as it is a method for distilling off the solvent, but examples thereof include concentration under reduced pressure using a rotary evaporator.
  • the isolated fraction can also be obtained by distilling off the solvent.
  • Compound IA, Compound IB, Compound IIA, Compound IIB, Compound IIIA, Compound IIIB, Compound IVA, Compound IVB, Compound VA, Compound VB, Compound VIA or Compound VIB of the present invention can be obtained by the above-mentioned purification means.
  • Compound I, Compound II, Compound III, Compound IV, Compound V or Compound VI can be produced by subjecting it to a hydrolysis reaction under acidic conditions, and the compounds I, Compound II, and Compounds subjected to the hydrolysis reaction can be produced.
  • the extract of the culture of the SANK17397 culture can be obtained by mixing the culture of the strain cultured by the above method with a water-miscible solvent and extracting the mixture.
  • the solvent that is miscible with water is not particularly limited as long as it is generally used for extracting a microorganism culture solution. Examples thereof include 1-propanol, acetone, and methanol.
  • the ratio of the mixture of the solvent and the solvent is usually from 2: 1 to 1: 5, preferably 1: 1.
  • the extraction method is not particularly limited as long as it is a method of performing a normal liquid-liquid extraction, and includes, for example, stirring.
  • the extraction time ranges from 10 minutes to 1 hour at a lower limit and from 2 hours to 5 hours at an upper limit. Yes, the preferred range is 1-2 hours.
  • Extracts, crude fractions, partially purified fractions or isolated fractions of the culture containing compound I, compound II, compound III, compound IV, compound V and / or compound VI do not dilute the above extract.
  • it can be obtained by diluting with ion-exchanged water and using the above purification means.
  • IA or compound VIB is obtained by subjecting compound I, compound II, compound III, compound IV, compound V or compound VI in the respective purification steps as described above to a hydrolysis reaction under acidic conditions. From compound IA, compound IB, compound of the present invention
  • the acidic condition used for the hydrolysis reaction is obtained by allowing an acid to exist in the reaction system.
  • the acid used in the reaction is not particularly limited as long as it is an acid generally used for hydrolyzing an organic compound, and examples thereof include hydrochloric acid.
  • the range of the normality of the acid used in the reaction depends on the kind of the acid used, etc., but the lower limit is usually from 0.01 to 0.05, and the upper limit is from 0.2 to 1 norm. The proper range is 0.55 to 0.2.
  • the compound I, compound II, compound III, compound IV, compound V or compound VI in each purification step as described above is dried, and this is added to a mixture of a solvent and an acid used in the reaction. This is achieved by dissolving and maintaining a constant temperature.
  • the solvent to be mixed with the above-mentioned acid is not particularly limited as long as it is a solvent capable of dissolving the raw material compound in each of the purification steps as described above, and examples thereof include 1-propanol.
  • the ratio of mixing the solvent and the acid used in the reaction (the solvent: acid) is usually from 2: 1 to 1: 5, preferably 1: 1.
  • the range of the reaction temperature is as follows.
  • Type is acid, the concentration, the amount of the compound used for the reaction depends on the reaction time and the like, the lower limit is 2 5 to 5 0 C, the upper limit is I 0: 'C to 1 0 0:' is C, preferably The range of the reaction time is from 50 to 70 C.
  • the range of the reaction time depends on the kind of the acid used, the degree of normality, the amount of the starting compound, the reaction temperature, etc., but the lower limit is usually 30 minutes to 10 hours, the upper limit is 20 to 50 hours, and the preferred range is 10 to 20 hours.
  • the behavior of the target compound is determined by measuring the 1,3 —
  • HPL high performance 1 lquidchromatography
  • Glucan synthase inhibitory activity was determined by the method of Beaulieu et al. (Beaueauieu, D., et al., Antimicro Dial Agents and C hemotherapy, 38, 93 7-94 199 4) It can be measured according to)).
  • the physiologically acceptable salts are administered in various forms.
  • the dosage forms include, for example, oral administration by tablets, capsules, granules, powders, syrups, etc., or non-administration by injections (intravenous, intramuscular, subcutaneous), drops, suppositories, etc. Oral administration can be mentioned.
  • compositions can be added to the active ingredient in the form of excipients, binders, disintegrants, lubricants, flavoring agents, Solution adjuvants, suspending agents, c which may be formulated using known Tosuke agents which have been conventionally used in the pharmaceutical formulating art, such as co-one tee ing agent
  • carriers for forming into tablets, a wide variety of carriers conventionally known in this field can be used as carriers, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, and the like.
  • Excipients such as microcrystalline cellulose, citric acid, etc .; water, ethanol, propanol, single syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, cerac, methinoresenol, potassium phosphate
  • Binders such as polyvinylpyrrolidone: dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearyl Disintegrators such as monoglyceric acid, starch, lactose; sucrose, stealine, cocoa Disintegration inhibitors for hydrogenated oils, etc .: Quaternary ammonium bases, sodium lauryl s
  • the tablet can be a tablet coated with a usual coating, if necessary, such as a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet or a double tablet or a multilayer tablet.
  • carriers for molding into pill form, a wide variety of carriers conventionally known in this field can be used as carriers, such as glucose, lactose, cacao butter, starch, hydrogenated vegetable oil, kaolin, talc, etc.
  • Binders such as arabic gum powder, tragacanth powder, gelatin and ethanol, and disintegrants such as laminaran agar.
  • liquid preparations and suspensions are preferably sterilized and isotonic with hemostatic fluid.
  • diluents Any of the agents commonly used in this field can be used, for example, water, ethanol, propylene glycol, ethoxylated isostear linoleic alcohol.
  • polyoxyethylene chi Sosutea Lil alcohol 3 still capable polyoxyethylene sorbitan fatty acid esters, in this case, a sufficient amount of salt to Seisuru regulating isotonicity of the solution, glucose or Glycerin may be included in the pharmaceutical preparation, and ordinary dissolution aids, buffers, soothing agents, etc. may be added.
  • the pharmaceutical composition may further contain a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent, and the like and other pharmaceuticals as necessary.
  • a coloring agent e.g., a FD&C, FD&C, FD&C, FD&C, FD&C, FD&C, FD&C, FD&C, FD&C, FD&C, FD&C Red No.
  • the preferred range is 1 to 30% by weight.
  • the administration method of the above pharmaceutical preparation is not particularly limited, and is determined according to various preparation forms, patient age, gender and other conditions, degree of disease, and the like.
  • tablets, pills, solutions, suspensions, emulsions, granules and capsules are orally administered.
  • they are administered intravenously, alone or mixed with normal rehydration fluids such as glucose and amino acids, and, if necessary, intramuscularly, intradermally, subcutaneously or intraperitoneally. Is done.
  • suppositories they are administered rectally.
  • the range of the daily dose of the pharmaceutical composition for an adult depends on the symptoms, age, body weight, administration method and dosage form, but the lower limit is usually 0.1 to 1 mg, and the upper limit is 10 to 2 mg. The preferred range is from 1 to 10 mg. It can be administered once or in several divided doses.
  • the non-spore-forming filamentous fungus SAK173-97 was grown on potato dextrose gradient agar (PDA) at 23 : 'C for 7 days or more, and the resulting mycelium was replaced with 2% starch and 2% starch.
  • PDA potato dextrose gradient agar
  • FFA-1 medium consisting of 3% lysine, 3% glucose, 1_% soy flour, 0.25% gelatin, 0.25% yeast extract, 0.25% ammonium nitrate was inoculated into two those sterilized for 30 minutes at the L volume Erlenmeyer one placed in a flask 1 2 1, 2 1 0 cultured in r P m rotary oice earthenware pots 4 days in culture machine 2 3 C seed culture
  • 15 L of the above-mentioned FFA-1 medium was added to two 30 L-volume jar fermenters, and sterilized with 121 : 'C for 30 minutes.
  • the elution fraction containing Compound IIA was diluted with an equal volume of ion-exchanged water, and this was equilibrated with ion-exchanged water.
  • the eluted fraction containing compound IIA was diluted with an equal volume of ion-exchanged water, and this was applied to a column of 20 O ml of Diaion HP-20 (Mitsubishi Chemical Corporation) equilibrated with ion-exchanged water. After flooding, the column was washed with ion-exchanged water and eluted with 500 ml of methanol. The eluted surface was concentrated to dryness under reduced pressure using a rotary evaporator, dissolved in 1-propanol: ion-exchanged water (50:50), and supplied to a preparative HPLC under the following conditions.
  • the eluted fraction containing compound IIA was adjusted to pH 4 with 1N sodium hydroxide, diluted with an equal volume of ion-exchanged water, and equilibrated with ion-exchanged water. Donate to column 2000 ml and wash the column with ion-exchanged water. After washing, the residue was eluted with 1 L of methanol, and the eluted fraction was concentrated under reduced pressure using a rotary evaporator to isolate 118 mg of Compound IIA.
  • the spore-free filamentous fungus SAK173997 was grown on potato dextrose gradient agar (PDA) at 23 t for 7 days or more, and the resulting mycelium was reduced to 2% starch and 3% glycerin.
  • PDA potato dextrose gradient agar
  • FFA — 1 medium 450 ml, 2 L Erlenmeyer flask Put in 1 2 1.
  • Two strains sterilized with C for 30 minutes were inoculated, and cultured at 23 t for 4 days on a rotary shaker at 210 rpm to obtain a seed culture solution.
  • the eluted fraction containing compound IIB was diluted with an equal volume of ion-exchanged water, and this was applied to a column of 20 O ml of Diaion HP-20 (manufactured by Mitsubishi Chemical Corporation) equilibrated with ion-exchanged water. After flooding, the column was washed with ion-exchanged water and eluted with 500 ml of methanol. The eluted fraction was concentrated to dryness under reduced pressure using a rotary evaporator, then dissolved in 1-propanol: ion-exchanged water (50:50), and supplied to preparative HPLC under the following conditions. .
  • the eluted fraction containing compound IIB was adjusted to pH 4 with 1N sodium hydroxide, Diluted with an equal volume of ion-exchanged water and ion-exchanged. Diaion HP—20 (manufactured by Mitsubishi Chemical Corporation) equilibrated with water. After eluted with 1 L of methanol, the eluted fraction was concentrated to dryness under reduced pressure by a rotary evaporator. This was dissolved in 1-propanol: ion-exchanged water (50:50) and supplied to preparative HPLC under the following conditions.
  • the eluted fraction containing compound IIB was diluted with an equal volume of ion-exchanged water, and applied to a column of 5 Oml of Diaion HP-20 (manufactured by Mitsubishi Chemical Corporation) equilibrated with ion-exchanged water.
  • a column of 5 Oml of Diaion HP-20 manufactured by Mitsubishi Chemical Corporation
  • ion-exchanged water was washed with ion-exchanged water, eluted with 300 ml of methanol, and the eluted fraction was concentrated under reduced pressure using a rotary evaporator to isolate 15 mg of Compound IIB.
  • ? ⁇ 1 medium (Composition: 2% flour, glyce (3% of phosphorus, 3% of glucose, 1% of soybean flour, 1% of gelatin, 0.25% of yeast, 0.25% of yeast, 0.25% of ammonium nitrate) And inoculated into four tubes that were sterilized with 120 : C for 20 minutes, and cultured on a rotary shaker at 210 rpm for 5 days at 23 to obtain a seed culture solution. . Next, 80 ml of FFA-1 medium was placed in a 500 ml Erlenmeyer flask, sterilized at 120 C for 20 minutes, and 60 seeds were inoculated with the above seed culture solution at 4% (v / v). Then, the cells were cultured at 23 C for 14 days on a rotary shaker at 210 rpm.
  • Acetone (4.8 L) was added to the culture solution (4.8 L), and the mixture was stirred for 30 minutes, and the obtained acetone extract was filtered. Acetone was distilled off from this extract under reduced pressure using a rotary evaporator, and the pH was adjusted to 7 with 6N sodium hydroxide.
  • Acetonitrile The fraction eluted with ion-exchanged water (40:60) was concentrated to dryness under reduced pressure using a rotary evaporator, and then supplied to preparative HPLC under the following conditions. Using acetonitrile containing water as the mobile phase, elution was performed with the acetonitrile content (VV) changed linearly from 20% to 80% in 30 minutes.
  • VV acetonitrile content
  • the active fraction was concentrated to dryness under reduced pressure by a rotary evaporator to isolate 4.0 mg of Compound I.
  • the non-spore-forming filamentous fungus S ANK173977 was grown on a PDA gradient medium at 23 : C for 7 days or more, and the resulting mycelium was added to 50 ml of FA-1 medium 80 ml. 0 ml 1 Erlenmeyer flask; inoculate 4 bottles that have been sterilized and sterilized at 120 C for 20 minutes. To prepare a seed culture was incubated at C;. 5 days between 2 3 a rotary oice Cormorants culture onboard 2 1 0 rpm. Next, place 80 ml of FFA-1 medium into a 500 ml Erlenmeyer flask.
  • Acetone (4.8 L) was added to the culture solution (4.8 L), the mixture was stirred for 30 minutes, and the obtained acetone extract was filtered. Acetone was distilled off from this extract under reduced pressure by a rotary evaporator, and the pH was adjusted to 7 with 6N sodium hydroxide. This was flooded onto a column 40 Om1 of Diaion HP-20 (manufactured by Mitsubishi Chemical Corporation) equilibrated with ion-exchanged water, and 1 L of water, methanol: ion-exchanged water (30: 7 0), methanol: ion-exchanged water
  • the active fraction was concentrated to dryness under reduced pressure using a rotary evaporator, and 7.6 mg of Compound II was isolated.
  • the asporogenous filamentous fungus S ANK 173,977 was grown on a PDA gradient medium at 23 for at least 7 days, and the resulting mycelium was transformed into 450 ml of FFA-1 medium.
  • Seed culture by inoculating 4 tubes in a L-volume Erlenmeyer flask, sterilized with 1 2 : C for 30 minutes, and culturing at 23 C for 4 days on a rotating shaker at 210 rpm. Liquid. Subsequently, 15 L of the above-mentioned FFA-1 medium was added to four 30 L volume fermenters, and sterilized with 121 : C for 30 minutes. Add 3% (V / V) of each of the aforementioned seed cultures to these. The cells were cultured at 23 : 'C for 12 days at an aeration rate of 15 L / min while controlling the stirring speed to maintain the dissolved oxygen concentration at 5 ppm.
  • methanol: ion-exchanged water (20:80) is 8 L
  • methanol: ion-exchanged water (50:50) is 20 L
  • methanol is ion-exchanged water (60:40).
  • 15 B methanol: ion-exchanged water (70: 30)
  • 15 L methanol: ion-exchanged water
  • acetonitrile: ion-exchanged water (30:70) was used for column equilibration, and acetonitrile: ion-exchanged water (45:70) was used for elution of compound I. 55) was used, and acetonitrile: ion-exchanged water (50:50) was used for elution of compound II, respectively.
  • the column was supplied to a column 60 L of Diaion HP-20 (manufactured by Mitsubishi Chemical Corporation) equilibrated with methanol: ion-exchanged water (50: 50), and the column was subjected to methanol: ion-exchanged water (6 After washing with 0:40) 300 L, the mixture was eluted with 280 L of acetonitrile: ion-exchanged water (40:60). 250 L of the eluted fraction was diluted with water, and 400 L of diluent was equilibrated with methanol: ion-exchanged water (50: 50).
  • Diaion HP-20 (manufactured by Mitsubishi Chemical Corporation) Column was applied to 5 L. The column was washed with 40 L of methanol: ion-exchanged water (65:35), and then eluted with 29 L of methanol: ion-exchanged water (90: 10). Among these, 20 L of the fraction containing the target compound was concentrated under reduced pressure using a rotary evaporator to obtain a crude fraction. To this was added 550 ml of dimethyl sulfoxide to dissolve, and the solution was supplied to preparative HPLC under the following conditions. Elution was performed stepwise using acetonitrile: ion-exchanged water (45:55) and acetonitrile: ion-exchanged water (50:50) as mobile phases. The fractionation was performed in six batches.
  • the cells were cultured at 23 C for 5 days on a rotary shaker at 0 rpm to obtain a seed culture solution. Then, add 30 L of the above FFA-1 medium to a 60 L volume
  • the column was treated with methanol: After washing with 40 L of ion-exchanged water (65:35), the column was eluted with 29 L of methanol: ion-exchanged water (90:10). Of these, 20 L of the fraction containing the target compound was concentrated under reduced pressure using a rotary evaporator to obtain a crude fraction. To this was added 550 ml of dimethylsulfoxide, dissolved and supplied to preparative HPLC under the following conditions ( acetonitrinole: ion-exchanged water (45 : 55) and acetonitrile: ion-exchanged water (50: 50) were eluted in a stepwise manner.
  • compound IIA of the present invention exhibited excellent antifungal activity.
  • Example 2 For the compounds obtained in Example 1 and Example 2, a paper disc method using agar plates (Nobuo Tanaka and Shoshiro Nakamura, Overview of Antibiotics Chemistry and Biological Activity, 4th edition, The antifungal activity was measured based on page 16, published by The University of Tokyo Press, 1992).
  • the agar plate was prepared by using a sub-mouthed agar medium (manufactured by Eiken Chemical Co., Ltd.) inoculated with a spore count of the test bacterium at a final concentration of 1 ⁇ 10 4 at ZmI.
  • Compound IIA or compound IIB 100 mg, lactose 100 mg, corn starch 144.88 mg, magnesium stearate 1.2 mg, mix each powder, and sieve 60 mesh Then, 350 mg of this powder is put into a gelatin capsule to make a capsule.c
  • Compound IA, compound IB, compound IIA, compound IIB, compound IIIA, compound IIIB, compound IVA, compound IVB, compound VA, compound VB, compound VIA, and compound VIB disclosed in the present invention are human or animal. It has an excellent antifungal activity against fungal pathogens that infect bacteria, and is useful as an agent for preventing or treating fungal infections in humans or animals.

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Abstract

La présente invention concerne un composé représenté par la formule (a), des promédicaments de celui-ci, des sels du composé et des promédicaments, ou analogues, exerçant des effets antifongiques et utilisés dans le traitement ou la prévention de diverses mycoses.
PCT/JP2000/002465 1999-04-16 2000-04-14 Nouveaux composes antifongiques WO2000063239A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0084826A2 (fr) * 1982-01-15 1983-08-03 Bristol-Myers Company Composé antibiotique
EP0360760A2 (fr) * 1988-09-23 1990-03-28 Sandoz Ag Peptolides cycliques qui contiennent de l'acide pipecolique, leur préparation et compositions pharmaceutiques les contenant
JPH07278186A (ja) * 1994-03-30 1995-10-24 Hoechst Ag リポペプチド誘導体、その製造法およびその使用
WO1996012732A1 (fr) * 1994-10-25 1996-05-02 Sekisui Chemical Co., Ltd. Nouveau peptide et agent therapeutique
WO1996030399A1 (fr) * 1995-03-29 1996-10-03 Fujisawa Pharmaceutical Co., Ltd. Noyaux de peptides cycliques et leurs derives
WO1999020651A1 (fr) * 1997-10-21 1999-04-29 Sankyo Company, Limited Nouveaux composes antifongiques

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0084826A2 (fr) * 1982-01-15 1983-08-03 Bristol-Myers Company Composé antibiotique
EP0360760A2 (fr) * 1988-09-23 1990-03-28 Sandoz Ag Peptolides cycliques qui contiennent de l'acide pipecolique, leur préparation et compositions pharmaceutiques les contenant
JPH07278186A (ja) * 1994-03-30 1995-10-24 Hoechst Ag リポペプチド誘導体、その製造法およびその使用
WO1996012732A1 (fr) * 1994-10-25 1996-05-02 Sekisui Chemical Co., Ltd. Nouveau peptide et agent therapeutique
WO1996030399A1 (fr) * 1995-03-29 1996-10-03 Fujisawa Pharmaceutical Co., Ltd. Noyaux de peptides cycliques et leurs derives
WO1999020651A1 (fr) * 1997-10-21 1999-04-29 Sankyo Company, Limited Nouveaux composes antifongiques

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