EP0368949A1 - Nouveaux composes d'antibiotiques - Google Patents

Nouveaux composes d'antibiotiques

Info

Publication number
EP0368949A1
EP0368949A1 EP89903509A EP89903509A EP0368949A1 EP 0368949 A1 EP0368949 A1 EP 0368949A1 EP 89903509 A EP89903509 A EP 89903509A EP 89903509 A EP89903509 A EP 89903509A EP 0368949 A1 EP0368949 A1 EP 0368949A1
Authority
EP
European Patent Office
Prior art keywords
compound
ncib
formula
culture
column
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Withdrawn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
EP89903509A
Other languages
German (de)
English (en)
Inventor
Medha Athalye
Anna Louisa Elson
Martin Leonard Gilpin
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.)
Beecham Group PLC
Original Assignee
Beecham Group PLC
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 GB888803031A external-priority patent/GB8803031D0/en
Priority claimed from GB888822512A external-priority patent/GB8822512D0/en
Priority claimed from GB888829591A external-priority patent/GB8829591D0/en
Application filed by Beecham Group PLC filed Critical Beecham Group PLC
Publication of EP0368949A1 publication Critical patent/EP0368949A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
    • C07K9/006—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure
    • C07K9/008—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure directly attached to a hetero atom of the saccharide radical, e.g. actaplanin, avoparcin, ristomycin, vancomycin
    • 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; 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
    • 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
    • C12R2001/365—Nocardia

Definitions

  • the present invention relates to a novel antibacterially active material obtainable from a microorganism, to a process for its production, and to its pharmaceutical use.
  • microorganisms A large number of microorganisms have been isolated from nature and certain of those microorganisms have been found to produce various metabolites, which can be isolated and some of which have useful antibacterial activity.
  • One such metabolite is a substance which has been designated MM 47761. It is believed to be a novel glycopeptide compound and it has been found to have useful antibacterial activity.
  • the present invention accordingly provides the novel substance MM 47761, and pharmaceutically acceptable derivatives thereof, such as pharmaceutically acceptable acid addition salts.
  • the present invention also provides a process for the production of the substance MM 47761 which comprises cultivating an MM 47761-producing microorganism and subsequently isolating MM 47761 or a derivative thereof from the culture.
  • the present invention furthermore provides a process for the preparation of the substance MM 47761 which comprises separating MM 47761 or a derivative thereof from a solution of MM 47761 in admixture with other antibacterially active substances and/or inactive substances by adsorption onto an affinity resin.
  • the substance MM 47761 has the following characteristics:
  • MM 47761 may be obtained by the cultivation of an MM 47761 producing microorganism and the recovery of Mm 47761 or a derivative thereof from the culture.
  • 'cultivation' means the deliberate aerobic growth of an organism in the presence of assimilable sources of carbon, nitrogen, sulphur and mineral salts. Such aerobic growth may take place in a solid or semi-solid nutritive medium, or in a liquid medium in which the nutrients are dissolved or suspended.
  • the cultivation may take place on an aerobic surface or by submerged culture.
  • the nutritive medium may be composed of complex nutrients or may be chemically defined. It has been found that suitable microorganisms for use in the cultivation process according to the invention include bacterial strains belonging to the order Actinomycetales that are capable of elaborating
  • mutant strain which arises spontaneously or through the effect of an external agent whether that agent is applied deliberately or otherwise.
  • Suitable methods of producing mutant strains including those outlined by H.I. Adler in 'Techniques for the Development of Microorganisms' in 'Radiation and Radioisotopes for Industrial Microorganisms', Proceedings of a Symposium, Vienna, 1973, page 241, International Atomic Energy Authority, and these include:
  • Ionizing radiation e.g. X-rays and ⁇ -rays
  • u.v. light u.v. light plus a photosensitizing agents (e.g. 8-methoxypsoralen), nitrous acid, hydroxylamine, pyrimidine base analogues (e.g. 5-bromouracil), acridines, alkylating agents (e.g. mustard gas, ethyl-methane sulphonate), hydrogen peroxide, phenols, formaldehyde, heat, and
  • a photosensitizing agents e.g. 8-methoxypsoralen
  • nitrous acid hydroxylamine
  • pyrimidine base analogues e.g. 5-bromouracil
  • acridines alkylating agents (e.g. mustard gas, ethyl-methane sulphonate), hydrogen peroxide, phenols, formaldehyde, heat, and
  • Actinomycete sp. NCIB 12608 is believed to be a previously unreported strain in the species amvcolatopsis orientalis and therefore also forms a part of the present invention, particularly in biologically pure form. It has been deposited at the
  • the fermentation medium for cultivating NCIB 12608 suitably contains sources of assimilable carbon and assimilable nitrogen together with inorganic salts.
  • suitable sources of nitrogen include yeast extract, soyabean flour, meat extract, cottonseed, flour, malt, distillers dried solubles, amino acids, protein hydrolysates and ammonium and nitrate nitrogen.
  • Suitable carbon sources include glucose, lactose, maltose, starch and glycerol.
  • the culture medium also includes alkali metal ions (for example, sodium), halogen ions (for example, chloride), and alkaline earth metal ions (for example calcium and magnesium), as well as trace elements such as iron and cobalt.
  • the cultivation may suitably be effected at a temperature of about 20 to 35°C , advantageously 20 to 30°C, and the culture may suitably be harvested up to 7 days, advantageously about 3 to 5 days, after the initiation of fermentation in order to give an optimum yield of MM 47761.
  • the desired MM 47761 or a derivative thereof may then be isolated from the culture medium and worked up and purified using conventional techniques for glycopeptide compounds. All such isolation and purification procedures may conveniently be effected at cool to ambient temperature, for example at a temperature within the range of from 4 to 30°C, conveniently from
  • the desired product is generally obtained predominantly from the culture filtrate, and it is therefore convenient for the first isolation step to involve removal of solid material from the fermentation broth by, for example, filtration or centrifugation, to give a clarified culture filtrate.
  • the desired compound may readily be identified in a routine manner by testing for antibacterial activity and/or by monitoring the h.p.l.c. retention time.
  • the separation procedure may include a high-performance liquid chromatography step, preferably as the last step. Elution may be effected using aqueous NaH 2 PO 4 /acetonitrile.
  • MM 47761 and its derivatives may be crystalline or non-crystalline and, if crystalline, may optionally be hydrated or solvated.
  • Culture NCIB 12608 has also been found to produce a further glycopeptide antibiotic which has been designated MM49721 and has the characteristics set out hereinbelow in the Examples.
  • MM 49721 and its derivatives may be crystalline or non-crystalline and, if crystalline, may optionally be hydrated or solvated.
  • MM 47761 and MM 49721 are believed to be the compounds of formula (I):
  • R is chlorine (MM 47761) or hydrogen (MM 49721).
  • a further aspect of the invention provides a process for the preparation of the pseudoaglycone of MM 47761 or MM 49721, that is, a compound of formula (II):
  • R is as defined above, which process comprises acid catalysed hydrolysis of MM 47761 or MM 49721.
  • the hydrolysis is typically carried out at elevated temperature, for example in refluxing 5M hydrochloric acid for about 5 minutes.
  • the compounds according to the invention are suitably provided in substantially pure form, for example at least 50% pure, suitable at least 60% pure, advantageously at least 75% pure, preferably at least 85% pure, more preferably at least 95% pure, especially at least 98% pure, all percentages being calculated as weight/weight.
  • An impure or less pure form of a compound according to the invention may, for example, be used in the preparation of a more pure form of the same compound or of a related compound (for example a corresponding derivative) suitable for pharmaceutical use.
  • the compounds of the invention have antibacterial properties and are useful for the treatment of bacterial infections in animals, especially mammals, including humans, in particular humans and domesticated animals (including farm animals).
  • the compounds may be used for the treatment of infections caused by a wide range of organisms including, for example, those mentioned herein.
  • the present invention provides a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable derivative thereof together with a pharmaceutically acceptable carrier or excipient.
  • the present invention also provides a method of treating bacterial infections in animals, especially in humans and in domesticated mammals, which comprises administering a compound of the invention or a pharmaceutically acceptable derivative thereof, or a composition according to the invention, to a patient in need thereof.
  • the compounds and compositions according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other antibiotics.
  • compositions according to the invention may be formulated for administration by any route, for example oral, topical or parenteral.
  • the compositions may, for example, be made up in the form of tablets, capsules, powders, granules, lozenges, creams, syrups, or liquid preparations, for example solutions or suspensions, which may be formulated for oral use or in sterile form for parenteral administration by injection or infusion.
  • Tablets and capsules for oral administration may be in unit dosage form, and may contain conventional excipients including, for example, binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; and pharmaceutically acceptable wetting agents, for example sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or another suitable vehicle before use.
  • Such liquid preparations may contain conventional additives, including, for example, suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate or acacia;.
  • non-aqueous vehicles which may include edible oils
  • edible oils for example almond oil, oily esters (for example glycerine), propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and, if desired, conventional flavouring and colour agents.
  • compositions according to the invention intended for topical administration may, for example, be in the form of ointments, creams, lotions, eye ointments, eye drops, ear drops, impregnated dressings, and aerosols, and may contain appropriate conventional additives, including, for example, preservatives, solvents to assist drug penetration, and emollients in ointments and creams.
  • Such topical formulations may also contain compatible conventional carriers, for example cream or ointment bases, and ethanol or oleyl alcohol for lotions.
  • Such carriers may constitute from about 1% to about 98% by weight of the formulation; more usually they will constitute up to about 80% by weight of the formulation.
  • compositions according to the invention may be formulated as suppositories, which may contain conventional suppository bases, for example cocoa-butter or other glycerides.
  • compositions according to the invention intended for parenteral administration may conveniently be in fluid unit dosage forms, which may be prepared utilizing the compound and a sterile vehicle, water being preferred.
  • the compound depending on the vehicle and concentration used, may be either suspended or dissolved in the vehicle.
  • the compound may be dissolved in water for injection and filter-sterilised before being filled into a suitable vial or ampoule, which is then sealed.
  • conventional additives including, for example, localanaesthetics, preservatives, and buffering agents can be dissolved in the vehicle.
  • the composition may be frozen after being filled into the vial, and the water removed under vacuum; the resulting dry lyophilized powder may then be sealed in the vial and a accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions may be prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration.
  • the compound may instead be sterilised by exposure to ethylene oxide before being suspended in the sterile vehicle.
  • a surfactant or wetting agent is included in such suspensions in order to facilitate uniform distribution of the compound.
  • a compound or composition according to the invention may suitable be administered to the patient in an antibacterially effective amount.
  • a composition according to the invention may suitably contain from 0.1% by weight, preferably from 10 to 60% by weight, of a compound according io the invention (based on the total weight of the composition), depending on the method of administration.
  • the compounds according to the invention may suitably be administered to the patient at a daily dosage of from 1.0 to 50 mg/kg of body weight.
  • a daily dosage of from 1.0 to 50 mg/kg of body weight For an adult human (of approximately 70 kg body weight), from 50 to 3000 mg, for example about 1500 mg, of a compound according to the invention may be administered daily.
  • the dosage for adult humans is from 5 to 20 mg/kg per day. Higher or lower dosages may, however, be used in accordance with normal clinical practice.
  • each unit dose may suitably comprise from 25 to 1000 mg, preferable from 50 to 500 mg, of a compound according to the invention.
  • Culture NCIB 12608 was grown for 7 days at 26°C on a solid agar slant in a McCartney bottle.
  • the agar medium had the following composition:
  • a spore suspension was prepared by adding 10ml of sterilised water containing 0.005% Triton X 100 to a McCartney bottle agar culture of NCIB 12608, followed by sonication of the suspension for 1 minute. 1ml of this suspension was added to a flask of seed stage medium [Triton X 100 was obtained from B.D.H Chemicals Ltd., Poole, Dorset].
  • the seed stage fermentation was carried out in a 500ml conical flask containing 100ml of seed stage medium.
  • the seed stage medium contained: Constituent Amount (g/l)
  • the stock trace element solution contained:
  • the medium was adjusted to pH7.3 before sterilisation at 117°C for 15 minutes.
  • soya bean flour was Arkasoy 50 supplied by the British Arkady Co. Ltd., Old Trafford, Manchester]. Incubation was carried out for 72 hours at 26°C and 240r.p.m. on a gyratory shaker.
  • glycopeptide, MM 47761 was isolated from the clarified broth by adsorption onto D-alanyl-D-alaninesepharose affinity resin.
  • the affinity adsorbent was prepared from D-alanyl-D-alanine immobilised on Activated CH-Sepharose 4B [6-Aminohexanoic acid-activated-sepharose-4B was obtained from Sigma Chemical Co., Poole, Dorset].
  • the clarified broth (2400ml) prepared as described in a) was stirred for 1 hour with D-alanyl-D-alaninesepharose affinity resin (30ml wet volume) .
  • the mixture was filtered onto a glass scinter funnel and the filtrate discarded.
  • the affinity resin was washed with distilled water (100ml) and filtered as before.
  • the resin was washed twice more with distilled water.
  • the glycopeptide was eluted from the affinity resin by stirring with 0.1M ammonia containing 50% acetonitrile (50ml) for 15min.
  • the mixture was filtered and the filtrate evaporated under reduced pressure to dryness, to yield a cream solid.
  • the solid was re-suspended in water (50ml) and the glycopeptide adsorbed once more onto D-alanyl-D-alanine-sepharose affinity resin (30ml wet volume).
  • the resin was washed with water and the glycopeptide eluted with 0.1M ammonia containing 50% acetonitrile as previously described.
  • the eluant was evaporated to dryness to yield 195mg of substantially pure MM 47761.
  • the agar medium had the following composition:
  • the medium was adjusted to pH 7.0 before sterilisation in an autoclave at 121°C for 15 minutes.
  • the flasks were then incubated on a gyratory shaking table at 240r.p.m. for 48 hours at 28°C.
  • the fermenter was stirred by an agitator fitted with three vaned-disc impellers at 50r.p.m. and supplied with sterile air at
  • Clarified broth (310L) from example 2a was applied to a 12L Amberlite IRA 458 anion-exchange column, (Cl- form) at a flow rate of lLmin -1 .
  • Clarified broth (310L) from example 2a was applied to a 12L Amberlite IRA 458 anion-exchange column, (Cl- form) at a flow rate of lLmin -1 .
  • the column was washed with 20L of deionised water.
  • the percolate and water wash were combined, adjusted to pH 7.0 and loaded onto a 6.9L column of Diaion HP20 at a flow rate of 600ml.min -1 .
  • the column was washed with 10L of deionised water and the percolate and water wash discarded.
  • the active material was eluted from the column with propan-1-ol/water, 40/60. 1 litre fractions were collected. Fractions with antibiotic activity (6-24) were bulked and evaporated in vacuo to 2.1L.
  • the HP20 column was further eluted with propan-1-ol/water, 50/50 containing 0.1M ammonia.
  • NaH 2 PO 4 was added to the concentrated solution (1.4L) to give a molarity of 0.005M and the pH adjusted to 6.7 with 5M NaOH.
  • the buffered solution was loaded onto a 0.8L CM Sephadex C25 column previously equilibrated in 0.005M NaH 2 PO 4 pH 6.6 at a flow rate of 30ml.min -1 .
  • the column was washed with 1L of 0.05M NaH 2 PO 4 pH 7.0 and eluted using an exponential gradient of 0.05M NaH 2 PO 4 pH 7.0 to 0.2M Na 2 HPO 4 pH 9.2 (1L mixing volume). After 500ml of eluate had passed, 20ml fractions were collected. Those fractions containing MM 47761 (41-180) were combined and adjusted to pH 7.0 with 5M
  • the solution (2.8L) was loaded onto a 1.3L column of HP20.
  • the column was washed with 3.4L of deionised water and eluted with 2.5L propan-1-ol/water, 50/50 containing 0.1M ammonia.
  • the eluate was evaporated in vacuo to 0.9L and the pH adjusted to 7.0 using 1M HCl.
  • the MM 47761 obtained from large scale fermentations of NCIB 12608, as described in Example 2, may contain residual amounts of MM 49721 and may be further purified using preparative HPLC.
  • MM 47761 containing approximately 5% MM 49721 was dissolved in 1ml of 0.1M NaH 2 PO 4 , pH 6.0.
  • Six aliquots of 100 or 150 ⁇ l (totalling 750 ⁇ l) were loaded onto a Dynamax 150-A preparative HPLC column, 10mm ⁇ 300mm, containing 12 ⁇ m particles of C 18 reverse phase silica. [Rainin Instrument Co., Woburn, MA, USA].
  • the column was eluted with 0.1M NaH 2 PO 4 pH 6.0 containing 7% acetonitrile at a flow rate of 6.0ml.min -1 .
  • the eluant was monitored at 210nm on a Waters Lambda-Max model 481 spectrophotometer, using a semi-preparative flow cell, (2.1mm path length).
  • the product obtained from large scale fermentations of culture NCIB 12608, as described in Example 2, may contain MM 49721.
  • the MM 49721 can be isolated using CM Sephadex C25 cation-exchange column chromatography.
  • Fractions 72-83 contained MM 49721
  • fractions 92-114 contained MM 47761.
  • Fractions containing MM 49721 were bulked, adjusted to pH 6.5 and treated with D-alanyl-D-alanine Sepharose affinity resin as described in previous examples. After elution from the affinity resin the product was freeze dried to yield 143 mg of substantially pure MM
  • Fermentation samples were monitored for antibiotic activity by bioassay on Staphylococcus aureus V573, using the conventional hole in plate method.
  • MM 47761 had a retention time of 6.0 minutes.
  • the solvent used was 0.1M NaH 2 PO 4 pH 7.5 containing 10% acetonitrile, and 0.005M sodium heptane sulphonate ion-pairing reagent, at a flow rate of 2ml/min; MM49721 had a retention time of 7.4 min.
  • the resulting solid was then dissolved in water (200ml) and the pH of the solution adjusted to 6.0 by addition of saturated sodium hydrogen carbonate solution.
  • D-Ala-D-Ala sepharose affinity resin 40-50ml settled resin
  • the resin was collected by filtration and washed with distilled water (100ml).
  • the glycopeptide was removed from the resin by suspension of the resin in 50% acetonitrile/50% 0.2M ammonium hydroxide solution (100ml).
  • N-hydroxysuccinimide ester of 6-aminohexanoic acid Sepharose 4B 60g was placed on a glass scinter and washed with ImM hydrochloric acid solution (2L) under suction. The wet cake was then added to a solution of D-alanyl-D-alanine (1.5g) in 0.1M sodium bicarbonate solution (60ml) and occasionally shaken over the next hour. The suspension was filtered under suction and the residue suspended in 0.1M tris
  • Hydrolysed whole-cells of the culture NCIB 12608 contained the meso isomer of diaminopimelic acid. Arabinose and Galactose were the major sugars present while ribose was detected in minor quantities. Mycolic acids were not present. These results indicate that culture NCIB 12608 has a cell-wall type IV with type A sugar pattern (Lechevalier et al, 1986). However, lack of mycolic acids places this culture firmly outside the genus Nocardia sensu stricto.
  • culture NCIB 12608 is identified as a strain of Amycolatopsis orientalis. Although NCIB 12608 differs from the type strain of Amycolatopsis orientalis (ATCC 19795) in some tests, the differences are relatively minor and thus, culture NCIB 12608 is identified as a new strain of the species Amycolatopsis orientalis.

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Virology (AREA)
  • Biophysics (AREA)
  • Biomedical Technology (AREA)
  • Microbiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • General Engineering & Computer Science (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

On produit des antibiotiques glycopeptidiques MM 47761 et MM 49721 de la formule (I), dans laquelle R représente le chlore ou l'hydrogène, au moyen du NCIB 12608, une souche de Amycolatopsis orientalis.
EP89903509A 1988-02-10 1989-02-09 Nouveaux composes d'antibiotiques Withdrawn EP0368949A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB888803031A GB8803031D0 (en) 1988-02-10 1988-02-10 Novel compound
GB8803031 1988-02-10
GB8822512 1988-09-26
GB888822512A GB8822512D0 (en) 1988-09-26 1988-09-26 Novel compound
GB8829591 1988-12-19
GB888829591A GB8829591D0 (en) 1988-12-19 1988-12-19 Novel compound

Publications (1)

Publication Number Publication Date
EP0368949A1 true EP0368949A1 (fr) 1990-05-23

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ID=27263781

Family Applications (1)

Application Number Title Priority Date Filing Date
EP89903509A Withdrawn EP0368949A1 (fr) 1988-02-10 1989-02-09 Nouveaux composes d'antibiotiques

Country Status (2)

Country Link
EP (1) EP0368949A1 (fr)
WO (1) WO1989007612A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0339982A1 (fr) * 1988-04-28 1989-11-02 Beecham Group Plc Composés antibiotiques
PT94638A (pt) * 1989-07-10 1991-03-20 Bristol Myers Squibb Co Processo para a preparacao do antibiotico bu-3889v com actividade antiviral e de composicoes farmaceuticas que o contem
PT836619E (pt) * 1995-07-05 2004-11-30 Aventis Bulk S P A Purificacao de antibioticos dalba-heptidicos por focagem isoelectrica

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4479897A (en) * 1983-04-27 1984-10-30 Eli Lilly And Company Actaplanin antibiotics
US4497802A (en) * 1983-10-21 1985-02-05 Eli Lilly And Company N-Acyl glycopeptide derivatives
US4552701A (en) * 1984-04-16 1985-11-12 Eli Lilly And Company Glycopeptide antibiotics and process of preparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8907612A1 *

Also Published As

Publication number Publication date
WO1989007612A1 (fr) 1989-08-24

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