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EP0217923A1 - Antibiotique 10381a 1? - Google Patents

Antibiotique 10381a 1?

Info

Publication number
EP0217923A1
EP0217923A1 EP86902633A EP86902633A EP0217923A1 EP 0217923 A1 EP0217923 A1 EP 0217923A1 EP 86902633 A EP86902633 A EP 86902633A EP 86902633 A EP86902633 A EP 86902633A EP 0217923 A1 EP0217923 A1 EP 0217923A1
Authority
EP
European Patent Office
Prior art keywords
antibiotic
avg
brd
growth
hydrogen
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Withdrawn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
EP86902633A
Other languages
German (de)
English (en)
Inventor
Alexander D. Argoudelis
Alice L. Laborde
Oldrich K. Sebek
Scott E. Truesdell
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.)
Pharmacia and Upjohn Co
Original Assignee
Upjohn Co
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 Upjohn Co filed Critical Upjohn Co
Publication of EP0217923A1 publication Critical patent/EP0217923A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/195—Antibiotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • C12N1/205—Bacterial isolates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/465—Streptomyces

Definitions

  • This invention concerns a cytosine-containing antibiotic and isolation of this antibiotic from the fermentation beer of a new species of Streptomyces, S. arginensis.
  • Cytosine-containing antibiotics are known in the art. Congerotin, Fox, J.J., et al., Tett. Let., p. 3765, (1968); Plicacetin, Stevens, C.L., et al., J. Org. Chem., 31:2822 (1966); and blasticidin, Yonehara, H. and Otake, N., Tett. Let., p. 3785, (1966). None of the prior art antibiotics known to applicant teaches or suggests the specific invention disclosed herein. In addition, there are accordingly unexpected and advantageous properties associated with this new antibiotic, e.g., greatly reduced toxicity.
  • R is hydrogen or an alkyl of 1 to 4 carbon atoms, inclusive.
  • the compounds are active in vitro against Gram-positive bacteria, yeasts, and fungi.
  • the compounds are particularly active against Candida albicans (UC R 1392), Penicillium oxalicum (UC 1268), and Saccharorayces cerevisiae (UC 1342) and have a low toxicity in mammals.
  • UC is a registered trademark of The Upjohn Company).
  • this invention concerns both a pure form of a naturally occurring cytosine-containing antibiotic named 10381a 1 and synthetically derived alkyl esters.
  • the antibiotic of the present invention is produced by a naturally occuring microorganism. As such, the antibiotic may be produced by this organism as it exists in its natural state.
  • the present invention as it is directed to this antibiotic does not encompass any composition thereof as might have or does exist or occur in nature. Rather, the present invention provides for the production and isolation of this antibiotic in a manner rendering it practically useful, e.g., for pharmacological and other antimicrobial purposes.
  • the invention includes a process for culturing and purifying 10381a 1 .
  • the antibiotics described herein can be used alone or in combination with other antimicrobial agents to prevent the growth or reduce the numbers of microorganisms in various environments .
  • the compounds could be used to disinfect surfaces or as an additive to paint to prevent excess growth of microorganisms .
  • Antibiotics of formula I where R is hydrogen are obtainable from the cultivation of S. arginensis .
  • This antibiotic is designated 10381 a 1 .
  • Compound 10381a 1 has broad spectrum antibiotic properties having an especially strong growth inhibitory effect upon yeasts and fungi .
  • 10381a 1 has less toxicity than blasticidin, a known antibiotic of similar structure .
  • microorganism used for the production of 10381 a 1 is a new species of streptomyces , Streptomyces arginensis bietz sp. , NRRL-15941. The organism was isolated from soil screening conducted by The Upjohn
  • accession number is NRRL- 15941 .
  • Aeri al mycelium is predominantly blue; Melanin-positive .
  • the color pattern on Ektachrome is given in Table 1 .
  • Reference color characteristics are given in Table 2. The culture may be placed in the
  • Antibiotic 10381a 1 (Formula I) is produced when S. arginensis is grown in an aqueous nutrient medium under submerged aerobic conditions .
  • the microorganism is grown in a nutrient medium containing a carbon source and an assimilable nitrogen compound or proteinaceous material.
  • Preferred carbon sources incl ude glucose , brown sugar , sucrose, glycerol , starch , cornstarch, lactose , dextrin, molasses , and the like.
  • Preferred nitrogen sources include corn steep liquor , yeast , autolyzed brewer' s yeast with milk solids , soybean meal , cottonseed meal , cornmeal , milk solids , pancreatic digest of casein , distillers' solids , animal peptone liquors , meat and bone scraps , and the like . Combinations of these carbon and nitrogen sources can be used advantageously.
  • Trace metals for example , zinc, magnesium, manganese , cobalt, iron and the like need not be added to the fermentation medium since tap water and unpurified ingredients are used as medium components .
  • Production of Antibiotic 10381a 1 can be induced at any temperature conducive to satisfactory growth of the microorganism preferably between about 20° and 32° C . Ordinarily, optimum production of the compound is obtained in about 2 to 10 days.
  • the medium normally remains weakly basic (pH 7.4 - 9.0) during the fermentation.
  • the final pH is dependent , in part , on the buffers present , if any , and in part , on the initial pH of the culture medium which is advantageously adj usted to about pH 7.2 prior to sterilization.
  • the vegetative form, rather than the spore form, of the microorganism for inoculation to avoid a pronounced lag in the production of the new compound and the attendant inefficient utilization of the equipment . Accordingly, it is desirable to produce a vegetative inoculum in a nutrient broth culture by inoculating this broth culture with an aliquot from a soil or a slant culture. When a young, active vegetative inoculum has thus been secured , it is transferred aseptically to large vessels or tanks .
  • the medium in which the vegetative inoculum is produced can be the same as , or different from, that utilized for the production of the new compound, as long as it is such that adequate growth of the microorganism is obtained .
  • a variety of procedures can be employed to isolate and purify 10381a 1 , for example, chromatographic absorbtion procedures followed by elution with a suitable solvent , column chromatography , partition chromatography , and crystallization from solvents and combinations thereof .
  • the clear filtrate is used to extract 1038l a-
  • Column chromatography techniques preferably IRC-50(H + ) , and Amberlite XAD-4 , (Rohm and Haas ; Phil , PA, USA) are used to perform the initial purification. Final purif ication of 10381 a 1 is achieved by counter current distribution.
  • Bioassays on separate, or combined fractions can be conducted on Micrococcus luteus or Streptococcus pyogenes .
  • Bioassays are conducted by applying 80 ⁇ l of test solution to a 1 /2 inch paper disc and applying the disc to a growing plate of either test organism.
  • a biounit of activity (BU) is defined as the quantity of antibiotic necessary to achieve a 20 mm zone of growth inhibition around the 1 /2 inch paper disc.
  • Antibiotic 10381 a 1 is an amphoteric compound forming salts with acids , alkaline metals (including ammonia) alkaline earth metals (including magnesium and aluminum, and amines ) .
  • Metal salts can be formed by dissolving 10381 a 1 in water and adding a dilute metal base until the pH is between 7 and 8.
  • Metal salts include sodium, potassium and calcium salts.
  • Amine salts, including those with organic bases such as primary, tertiary, mono-, di-, and polyamines can also be formed using the above-described or other commonly used procedures. Further, ammonium salts can be made by well-known procedures.
  • Acid salts can be made by neutralizing 10381 a 1 with the appropriate acid to below pH 7.0, and preferably to between pH 2 and 6. Suitable acids for this purpose include hydrochloric, sulfuric, phosphoric, sulfamic, hydrobromic, and the like. Acid and base salts of 10381a 1 can be used for the same biological purposes as the parent compound. Antibiotic 10381a 1 can be esterified under standard esterification conditions. Most preferably compounds of formula I can be treated with alcohol, such as methanol, ethanol, n-propanol, or isopropanol and at reflux temperatures in the presence of hydrogen chloride to yield the (C 1 -C 3 ) alkyl esters of Formula I. Both the free base and pharmaceutically acceptable salts as defined above can be used for the same biologicalpurposes as antibiotic 10381a 1 .
  • Antibiotic 10381a is active against Candida albicans (UC 1392), Penicillium oxalicum (UC 1268), Saccaromyces cerevisiae (UC 1342), Streptococcus pyogenes (UC 152), and Streptococcus faecalis (UC 694).
  • the compounds of formula I are effective for treating bacterial infections in mammals, including humans.
  • compositions of the present invention are presented for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, eye drops, oral solutions or suspensions, and water-in-oil emulsions containing suitable quantities of compounds of Formula I.
  • either solid or fluid unit dosage forms can be prepared.
  • the compounds of formula I are mixed with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methyl cellulose, and functionally similar materials as pharmaceutical diluents or carriers.
  • Capsules are prepared by mixing the compound with an inert pharmaceutical diluent and filling the mixture into a hard gelatin capsule of appropriate size.
  • Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compound wi th an acceptable vegetable oil , light liquid petrolatum or other inert oil .
  • Fluid unit dosage forms for oral administration such as syrups , elixirs , and suspensions can be prepared.
  • the water-soluble forms can be dissolved in an aqueous vehicle together with sugar , aromatic flavoring agents and preservatives to form a syrup.
  • An elixir is prepared by using a hydroalcoholic (ethanol ) vehicle with suitable sweeteners such as sugar and saccharin , together with an aromatic flavoring agent .
  • Suspensions can be prepared with an aqueous vehicle with the aid of a suspending agent such as acacia , tragacanth , methylcellullose and the like .
  • a suspending agent such as acacia , tragacanth , methylcellullose and the like .
  • fluid unit dosage forms are prepared utilizing the compounds and a sterile vehicle , water being preferred .
  • the compounds depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle .
  • the compound can be dissolved in water for inj ection and filtered sterilized before filling into a suitable vial or ampoule and sealing .
  • adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • the dry lyophilized powder is then sealed in the vial and an accompanying vial of water for inj ection is supplied to reconstitute the liquid prior to use.
  • Parenteral sus pensions can be prepared in substantially the same manner except that the compounds are suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
  • the compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • a rectal suppository can be employed to deliver the active compound.
  • This dosage form is of particular interest where the mammal cannot be treated conveniently by means of other dosage forms, such as orally or by insufflation, as in the case of young children or debilitated persons.
  • the active compound can be incorporated into any of the known suppository bases by methods known in the art . Examples of such bases include cocoa butter , polyethylene glycols (carbowaxes) , polyethylene sorbitan monostearate , and mixtures of these with other compatible materials to modify the melting point or dissolution rate . These rectal suppositories can weigh from about 1 to 2.5 gm.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and animals , each unit containing a predetermined quantity of active material calculated to produce the desired pharmaceutical effect in association with the required pharmaceutical diluent , carrier or vehicle.
  • the specifications for the novel unit dosage forms of this invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular effect to be achieved and (b) the limitations inherent in the art of compounding such an active material for use in humans and animals , as disclosed in detail in this specification, these being features of the present invention.
  • suitable unit dosage forms in accord with this invention are tablets , capsules , pills , suppositories , powder packets , wafers , granules , cachets , teaspoonfuls , tablespoonfuls , dropperfuls , ampoules , vials , aerosols with metered discharges , segregated multiples of any of the foregoing, and other forms as herein described.
  • An effective quantity of antibiotic is employed in treatment .
  • the dosage of the specific compound for treatment depends on many factors that are well known to those skilled in the art . They include for example, the route of administration and the potency of the particular compound.
  • a dosage schedule for humans of from about 1 to 2 grams of compound in a single dose, administered parenterally or in the compositions of this invention, are effective for treating bacterial infections . More specifically, the single dose is about 2 grams of compound.
  • the oral and rectal dose is from about 1 to 2 grams in a single dose . More specifically, the single dose is about 2 grams of compound.
  • a soil stock of Streptomyces arginensis , NRRL-15941 is cultured on Hickney-Tresner Agar and stored at 4°C. Samples are homogenized i n water and replated on Hickney-Tresner Agar . After 7 days of incubation at 28° C , the growth is sufficient for a seed culture inoculum .
  • Seed cultures are grown in seed medi um (SSM.1 ) containing per liter of tap water: blackstrap molasses 5.8 g , Difco peptone 10 g, Difco yeast extract 4 g, dextrin 4 g, Liasparagine 0.2 g , COCI 2 .6H 2 O 1 mg; the medium is adj usted to pH 7.2 with KOH before sterilization .
  • the SSM.1 is dispensed into plain 500 ml wide-mouth Erlenmeyer flasks (capped with 2 milk filters) at 100 ml/ flask and autoclaved for 30 minutes at 121 °C , 15 psi .
  • Flasks are inoculated with homogenized agar plugs at a rate of .5-1 plug/ flask and shaken (250 rpra, 2.5" stroke ) for 3 days at 28°C .
  • the harvest pH is 8.3.
  • the seed cultures are fermented in media containing in amounts per liter of tap water: soybean meal 20 g , brewer' s yeast 2 g , Cerelose 20 g (added as 50%. solution after autoclaving) ; the medium is adj usted to pH 7.2 before sterilization .
  • the medium is dispensed, sterilized and shaken as described above.
  • the inoculation rate is 5 ml/1 00 ml of seed culture . Fermentation conditions are for 3 days at 28°C .
  • the beer is filtered using a f ilter aid as required and the soli d cake is washed in water in an amount one-tenth the volume of the filtrate filtered and added to the beer-filtrate which is saved.
  • a one liter column of IRC-50 (H+) is prepared and the filtrate mixture is adj usted to pH 8.5 using ammonium hydroxide .
  • the filtrate is passed through the column at a rate of 50-60 ml/minute and collected as a single fraction .
  • the antibiotic fraction is eluted off the IRC-50 column using 2N aqueous ammonium chloride collecting 2 liter-fractions and combining active fractions .
  • An 800 ml column of Amberlite XAD-4 is prepared.
  • the preceding ammonium chloride eluate is adj usted to a pH of 8.0 using ammonium hydroxide and passed over the column at a rate of 50-60 ml/ minute .
  • the column is washed with 3 liters of water .
  • the active fraction is elute d off by 5 elutions with methanol-water 70:30 w/v.
  • the 5 elutions of met hanol*1 water are concentrated to an aqueous solution , freeze- drie d and tested for activity.
  • the various filtrate or eluant solutions are bioassayed as previously described.
  • a typical assay is presented in Table 5.
  • the fractions from the IRC-50 column are being tested against M . luteus .
  • Final purification of 10381 a 1 is achieved by countercurrent distribution (CCD) .
  • Active fractions from an Amberlite XAD -4 column ar e dissolved in both phases of the solvent system consisting of 1-butanol/pH 7.0 phosphate buffer and distributed in an all-glass countercurrent distribution apparatus . After approximately 500 transfers , the bioactivity of the CCD-fractions is determined and the active fractions concentrated to an aqueous solution which is freeze-dried. The residue i s dissolved in water and pH adj usted to 8.
  • the aqueous solution is passed through a one liter column of Amberlite XAD-4 , and washed three times with three one-liter portions of water (wash 1 , 2 and 3) .
  • the column is then eluted with methanol-water ( 70 :30 v/v) .
  • the aqueous-methanolic fractions are assayed for antimicrobial activity (Table 6) .
  • Biologically -active fractions are combined , concentrated to an aqueous solution and freeze-dried to yield pure antibiotic 10381a 1 .
  • the physicochemical properties of 10381 a 1 are presented in Table 7.
  • the spectrum of 10381 a 1 ' s antimicrobial activity is presented in Table 10.
  • Antibiotic 10381 a 1 300 mg is dissolved in 10 ml of 1N methanolic hydrogen chloride .
  • the solution is clarified by f iltration over a sintered glass filter and mixed with 100 ml of acetone and 50 ml of ether .
  • the precipitated colorless material is isolated by filtratio n and dried.
  • Physicochemical data for 10381 a 1 hydrochloride are presented in Table 8.
  • Example 3 Antibiotic 10381 a 1 Methyl Ester Hydrochloride
  • Antibiotic 10381 a 1 500 mg is dissolved in 20 ml of 0.8 N methanoli c hydrogen chloride .
  • Inorganic salts S 184 very pale blue starch R 105 grayish greenish yellow
  • Amount Strength (zone of inhibition vs. M.luteus)
  • Solubility Soluble in water and lower alcohols. Insoluble in acetone, ethyl acetate, ether and chlorinated or saturated hydrocarbon solvents.
  • Liquid ratios are v/v; solid percentages are w/v.
  • Frequency Intensity Type Frequency Intensity Type
  • Frequency Intensity Type Frequency Intensity Type
  • Frequency Intensity Type Frequency Intensity Type
  • Frequency Intensity Type Frequency Intensity Type
  • Band Frequency Band frequencies in wavenumbers (CM -1 )
  • Frequency Intensity Type Frequency Intensity Type
  • Frequency Intensity Type Frequency Intensity Type
  • Band Frequency Band frequencies in wavenumbers (CM -1 )
  • Bacillus subtil is UC 564 0 Staphyloeoccus aureus UC 80 16h Staphylococcus aureus UC 3665 0 Micrococcus luteus UC 130 32 Micrococcus luteus UC 3383 32 Klebsiella pneumoniae UC 57 0 Escherichia coli UC 51 0 Salmonella schottmuelleri UC 126 0 Proteus vulgar is UC 93 0 Mycobacteri ⁇ n avium UC 159 17 Penici Ilium oxalicum UC 1268 36 Pseudomonas aeruginosa UC 95 0 Rhodopseudomonas UC 3238 33 sphaeroides Streptococcus pyogenes UC 152 25 Clostridium perfrigens UC 6509 18 Bacteroide ⁇ fragilis UC 651 3 21 *Staphylococcus aureus UC 6685 0 *Staphy

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  • Organic Chemistry (AREA)
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  • Biochemistry (AREA)
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  • Tropical Medicine & Parasitology (AREA)
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  • Food Science & Technology (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

L'antibiotique 10381A1, où R est de l'hydrogène, est un antibiotique contenant de la cytosine obtenu par culture de streptomyces arginensis dans un milieu aqueux puis par isolation. Des dérivés où R est un ester d'alkyl C1-C3 de l'antibiotique 10391a1 sont également décrits avec des sels pharmaceutiquement acceptables des formes natives et estérifiées. Les composés inhibent la croissance d'espèces choisies de levure, champignons et bactéries.
EP86902633A 1985-04-02 1986-03-31 Antibiotique 10381a 1? Withdrawn EP0217923A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US71891985A 1985-04-02 1985-04-02
US718919 1985-04-02

Publications (1)

Publication Number Publication Date
EP0217923A1 true EP0217923A1 (fr) 1987-04-15

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Family Applications (1)

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EP86902633A Withdrawn EP0217923A1 (fr) 1985-04-02 1986-03-31 Antibiotique 10381a 1?

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EP (1) EP0217923A1 (fr)
WO (1) WO1986005785A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5616320A (en) * 1985-04-02 1997-04-01 The Upjohn Company Use of antibiotics 10381b to promote growth
US5985274A (en) * 1985-04-02 1999-11-16 Pharmacia & Upjohn Company Antibiotic 10381A1 and process for the preparation of antibiotics 10381B
AU605495B2 (en) * 1986-07-03 1991-01-17 Pharmacia & Upjohn Company Process for the preparation of antibiotics 10381b
US6224864B1 (en) 1986-12-03 2001-05-01 Pharmacia & Upjohn Company Antibiotic 10381A, and process for the preparation of anitbiotics 10381B
TW380140B (en) * 1993-09-10 2000-01-21 Upjohn Co Antibiotics 10381v, w, x, y, z1, z2, pre-b and t

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8605785A1 *

Also Published As

Publication number Publication date
WO1986005785A1 (fr) 1986-10-09

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