EP0871639A1 - Orthosomycines nouvelles provenant de micromonospora carbonacea - Google Patents

Orthosomycines nouvelles provenant de micromonospora carbonacea

Info

Publication number
EP0871639A1
EP0871639A1 EP96936106A EP96936106A EP0871639A1 EP 0871639 A1 EP0871639 A1 EP 0871639A1 EP 96936106 A EP96936106 A EP 96936106A EP 96936106 A EP96936106 A EP 96936106A EP 0871639 A1 EP0871639 A1 EP 0871639A1
Authority
EP
European Patent Office
Prior art keywords
compound
compounds
pharmaceutically acceptable
acceptable salt
complex
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Withdrawn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
EP96936106A
Other languages
German (de)
English (en)
Inventor
Ronald A. Mierzwa
Min Chu
John K. Jenkins
Mahesh G. Patel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Sharp and Dohme Corp
Original Assignee
Schering Corp
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 US08/604,692 external-priority patent/US5780442A/en
Application filed by Schering Corp filed Critical Schering Corp
Publication of EP0871639A1 publication Critical patent/EP0871639A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • C07H19/01—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen
    • 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
    • A61P31/04—Antibacterial agents

Definitions

  • the invention relates to novel antibacterial compounds A, B, C, D, E, F, G, H and J, and their preparation, and to compositions containing such compounds.
  • This Invention also relates to a fermentation broth of the microorganism Micromonospora Carbonac ⁇ a var Africana , and the component parts thereof obtainable by cultivation of a pure culture of Micromonospora Carbonac ⁇ a var Africana .
  • the invention relates to the microorganism Micromonospora
  • Carbonaoaa var Africana Another aspect of the invention is directed to the antibiotic complex produced by cultivating a strain of Micromonospora Carbonac ⁇ a var Africana in a pH and temperature controlled aqueous nutrient medium having assimilable sources of carbon and nitrogen under oontrofed submerged aerobic conditions until a composition of matter having substantial antibiotic activity is produced.
  • a major component of the culture of the present invention is antibiotic 13-384, component 1, as disclosed in U.S.P.4,597,968, which is hereby incorporated by reference. (Another major component of the culture is the corresponding nitroso analog.)
  • the present invention claims other compounds of the culture as described below.
  • the present invention is also related to an antibiotic composition comprising a pharmaceutically acceptable carrier and an antibiotically effective amount of one or more compounds selected from the group consisting of compounds A, B, C, D, E, F, G, H and J.
  • the present invention is also related to a method of trea ⁇ ng a bacterial infection which comprises administering an antibiotically effective amount of one or more compounds selected from the group consisting of compounds A, B, C, D, E, F, G, H and J.
  • Figures 1, 2, 4, 5, 6, 7 and 8 are proton NMR spectra for Compounds A, B, E, F, G, H, and J, respectively.
  • Figure 3 is a proton NMR spectra for a mixture Compounds C and D.
  • the medium composition was as follows: beef extract (Difco) 3, Tryptone (Difco) 5, Cerelose (CPC, 2001) 1, potato dextrin (Avebe, WPD-650) 24, yeast extract (Universal, Tastone) 5, calcium carbonate (Pfizer, Albaglos) 1, and sficone defoamer (Union Carbide, SAG-471, 30% suspension) 0.3 mU
  • the flask was incubated 48 hours at 30°C with agitat ' ion (300 rpm, 1 inch stroke), and 30 L of the culture were transferred to 6)£ L flasks, each containing 500 mL of the same seed medium.
  • the 3 L culture was transferred into an inoculation fermenter containing 300 L of the same medium for an additional 24 hours of cultivation. Finally, the contents of the inoculation fermenter were transferred to a larger fermenter containing 10,000 L of production medium.
  • composition of the production medium was as follows: yeast extract 5, meat peptone (Marcor, type PS) 6, Cerelose 22, com steep powder (Marcor) 2, potato dextrin 60, boiled linseed oil (KJeenstrip) 4, calcium carbonate 4, cobalt chloride-6 H2O (Mallinckrodt) 0.002, silicone defoamer 0.5 mL/L
  • yeast extract 5 meat peptone (Marcor, type PS) 6
  • Cerelose 22 Cerelose 22
  • com steep powder Marcor
  • potato dextrin 60 boiled linseed oil
  • KJeenstrip boiled linseed oil
  • calcium carbonate 4 cobalt chloride-6 H2O (Mallinckrodt) 0.002
  • silicone defoamer 0.5 mL/L
  • the fermentation was conducted at 36°C for 120 to 140 hours under aeration and agitation maintaining the dissolved oxygen between 50 to 100% saturation.
  • the fermentation was carried out with 80-240 standard cubic feet per
  • the fermentation broth was cooled to about 25°C.
  • One half of the fermentation broth was transferred to a separate vessel, agitated and adjusted with 2 N NaOH to pH 10.5.
  • a 300 L XAD-7 resin (Rohm & Haas non functional acrylic ester polymeric adsorbent) was charged to the fermentation broth and agitated for 0.5 hours.
  • the pH was lowered to 9.25 and agitated for 3.5 hours.
  • the pH was further lowered to 7.00, and the resin was separated form the broth by screening. Tap water was used to wash the resin free from both broth and myoelia.
  • the second half of the fermentation broth was processed in the same way.
  • the antibiotic complex containing cuts were combined and extracted with 140 L of 0.1 M sodium phosphate monobasic, adjusted to pH 8 with sodium hydroxide, then with 2 x 60 L deionized water.
  • the ethyl acetate layer was vacuum concentrated at less than 30°C to one tenth the original volume (about 50 L) with azeotropic distillation of residual water.
  • the concentrate was precipitated into 100 L of heptane (2 volumes).
  • the precipitate was filtered and dried at about 25°C in a vacuum oven using a nitrogen bleed to give 5.2 to 5.5 kg of crude material (2.6 to 3.1 kg of antibiotic complex).
  • Fractions 5 to 11 which were enriched in the main antibiotic component were combined and vacuum concentrated to about 6 L at less than 30°C.
  • the main cut was isolated by adding the concentrate to 2 volumes of heptane with agitation.
  • the precipitate was filtered and dried in a vacuum oven at about 25°C with a nitrogen bleed to obtain 1.2 kg of product.
  • the head cut fractions 3 and 4 which were enriched in impurities were prcocessed in a simlar manner to obtain 0.4 kg of product.
  • the tail cut fractions 12 to 15 which were enriched in impurities, were prcocessed in a similar manner to obtain 0.2 kg of product.
  • the purification was accomplished in a two step chromatographic procedure. Both head (ID 33285-104-2) and tail cuts (ID 33285-104-1) obtained from initial purification were first chromatographed under medium pressure conditions with diol- bonded silica gel (40-63 ⁇ irregular media). The column was equilibrated with a ternary mixture of CH2CI2: Heptane: MeOH (60:40:2 v/v/v) at a flow rate of 30-50 mL min. with nitrogen gas. After sample application, 2.4 L-2.8 L of mobile phase was collected and discarded. The mobile phase was then adjusted and fractions collected based on diol column bed volume.
  • Complex 1 was further purified by dissolving 30-40 mg of the sample in 0.5 ml Cf ⁇ C ⁇ MeOH (96:4 v/v) and injecting on a semi-preparative PVA-Sil column (250 x 20 mm) equilibrated with CH 2 Cl2 ' lv1eOH (97.52.5 v/v). A flow rate of 12 mL/min yielded 5 mg of the desired material within a 12-14.2 minute elution time window. After four additional injections were made, a total of 24 mg of Compound A (>98% pure) was obtained.
  • the structures of the compounds were elucidated based on spectroscopic data analyses, including ultraviolet (UV). infrared (IR), Fast Atom Bombardment mass spectrometry (FAB-MS), proton and carbon-13 nuclear magnetic resonance ( 1 H and 13 C NMR) methods. These compounds were characterized as novel everninomicin related antibiotics. 3 C NMR data of two important ortho-esters are listed in Table 1. 1 H NMR spectral data of individual compounds are shown in FIGS 1-8, respectively.
  • the structure elucidation of Compound A was accomplished by analysis of mass and NMR spectroscopic data.
  • the FAB mass spectral data showed a 34 amu increase of molecular weight by comparison with the reference sample (13-384-component-1, everninomicin).
  • a trichloro containing molecular ion cluster was observed in the FAB mass spectrum. Both observations revealed the presence of a third chlorine atom in Compound A.
  • the attachment of this extra chlorine atom to the aromatic ester fragment on right side of the molecule was determined based on a secondary fragmentation analysis in comparison with the reference sample (13-384-component-1, everninomicin). (DIAGRAM 1).
  • Everninomicin is the antibiotic 13-384, component 1 , as disclosed in USP 4,597,968 The italicized, capital letters identify the rings in the compounds of the invention
  • the minor components were tested for activity based on an agar disk-diffusion protocol. Each component was dissolved at 1 mg mL in CH2CI2 : MeOH (95:5 v v) and a ten fold dilution made in the same vehicle. Twenty microliters of each concentration was transferred to an 8 mm standard paper disk and allowed to air dry for thirty minutes. Each set of disks were placed on agar seeded with Staphylococcus aureus at two pH's (7/8) and incubated overnight at 35°C. Zones of sizes of inhibition are given below as the diameter of the circle of inhibition and are given in millimeters. The results are tabulated below:
  • NT means not tested.
  • compositions comprising a pharmaceutically acceptable carrier and one or more compounds selected from the group consisting of A, B, C, D, E, F, G, H and J.
  • the antibiotics may be administered with any suitable pharmaceutical carrier and administered orally, parenterally or topically in a variety of formulations.
  • the antibiotics of this invention may be compounded in the form of tablets capsules, elixirs and the like. Tablets and capsules may contain such excipients as starch or lactose; liquid forms may contain coloring or flavoring agents.
  • Topical preparations may be in the form of creams, hydrophobic or hydrophilic ointments or aqueous, non-aqueous emulsion-type lotions. Typical carriers for such formulations are water, oils, greases, polyesters, and polyols.
  • Parenteral formulations, e.g. injectible dosage forms are usually liquids such as solutions or suspensions with typical carriers being distilled water or saline solution.
  • the dose to be administered in any particular dosage form will depend on various factors, such as the characteristics of the animal species being treated, the susceptibility of the infecting organism to the antibiotic, and the stage and severity of the infection. Generally, the dosage administered is from about 1.0 mg to about 25 mg kg of body weight per day, in divided dosages, the specified dosage being left to the discretion of the practitioner. In treating certain patients with the compounds of this invention, it is possible to include other pharmaceutically active ingredients in the dosage unit.
  • the microorganism used to obtain the compounds of this invention is a mutant strain of Micromonospora Carbonac ⁇ a var Africana as set forth in US Patent 4, 597, 68 which is hereby incorporated by reference.
  • the way in which this mutant strain is obtained is as set forth in this application.
  • the mutant strain of Micromonospora Carbonacea var Africana was prepared as set forth just below. Initially, parent strain SCC 1413 was subject to N-nHrosoguanidine (NTG) mutagenesis resulting in greater than a 90% kill of the culture. Fifteen hundred surviving isolates were examined for enhanced biological activity against S. aureus and E. coli.
  • Single colony isolates were germinated in test tubes containing 10 mL of germination media and shaken at 250 r.p.m. on a gyratory shaker at 30°C for 48 hours. Fermentation studies were initiated by transferring 2.5 mL of the seed to 250 mL Erlenmeyer flasks containing 50 mL of fermentation media and incubating at 30°C for 96 hours at 250 r.p.m. on a gyratory shaker. SCC 1631 was identified as an improved producer of the 13-384 complex on the basis of its improved bioactrvtty against £_ aureus and JE soli .
  • Strain SCC 1756 was isolated by NTG mutation of SCC1631 followed oy selection of the isolates on agar plates containing 150 ⁇ g/mL of everninomicin(complex of nitro and nitroso analogs). Strain SCC 2146 was obtained by NTG mutagenesis of SCC 1756. Except for isolating the NTG mutagenized strains of SCC 1631 on the high levels of everninomicin (complex of nitro and nitroso analogs), the protocols for both mutation studies were as previously described.
  • fermentation broths were extracted with ethyl acetate and the concentrates were chromatographed on Whatman LKGDF thin layer plates in a solvent system consisting of chloroform:methanol (9:1) followed by bioautography against I a_JJ_£ S and JE_£_2ll to confirm the production of all components of the antibiotic complex.
  • solvent system consisting of chloroform:methanol (9:1)
  • bioautography against I a_JJ_£ S and JE_£_2ll to confirm the production of all components of the antibiotic complex.
  • thin layer plates were examined by using the Shimadzu CS-930 TLC plate scanner and quantitating the higher producing extracts using HPLC.
  • Combined titers are defined as the sum of everninomicin nitro and nitroso analogs.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Communicable Diseases (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Saccharide Compounds (AREA)

Abstract

Des orthosomycines ont été isolées du bouillon de fermentation du microorganisme Micromonospora Carbonacea var Africana, désigné par SCC 2146. Ces composés sont des agents antibactériens. La présente invention concerne aussi des compositions et des procédés de traitement d'infections bactériennes.
EP96936106A 1995-10-10 1996-10-08 Orthosomycines nouvelles provenant de micromonospora carbonacea Withdrawn EP0871639A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US604692 1984-04-27
US501095P 1995-10-10 1995-10-10
US5010P 1995-10-10
US08/604,692 US5780442A (en) 1996-02-21 1996-02-21 Orthosomycins from micromonospora carbonacae
PCT/US1996/015750 WO1997013777A1 (fr) 1995-10-10 1996-10-08 Orthosomycines nouvelles provenant de micromonospora carbonacea

Publications (1)

Publication Number Publication Date
EP0871639A1 true EP0871639A1 (fr) 1998-10-21

Family

ID=26673786

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96936106A Withdrawn EP0871639A1 (fr) 1995-10-10 1996-10-08 Orthosomycines nouvelles provenant de micromonospora carbonacea

Country Status (7)

Country Link
EP (1) EP0871639A1 (fr)
JP (1) JP3199748B2 (fr)
AU (1) AU703452B2 (fr)
CA (1) CA2234164C (fr)
HU (1) HUP9902644A3 (fr)
NZ (1) NZ320971A (fr)
WO (1) WO1997013777A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5763600A (en) * 1997-04-18 1998-06-09 Schering Corporation Oligosaccharide antibiotics and process for preparation thereof
US6279219B1 (en) 1998-09-24 2001-08-28 Takahiro Engineering Works Ltd. Roller turret including rollers mounted on support portions of roller shafts, which are eccentric with respect to stud portions fixed in holes in turret body, and method of manufacturing the roller turret
US6861513B2 (en) 2000-01-12 2005-03-01 Schering Corporation Everninomicin biosynthetic genes
US20030143666A1 (en) * 2000-01-27 2003-07-31 Alfredo Staffa Genetic locus for everninomicin biosynthesis

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4597968A (en) * 1982-08-06 1986-07-01 Schering Corporation Antibiotic 13-384 complex from Micromonospora carbonacea var africana
US4622314A (en) * 1985-10-15 1986-11-11 Schering Corporation Substituted oligosaccharide antibiotics

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9713777A1 *

Also Published As

Publication number Publication date
WO1997013777A1 (fr) 1997-04-17
AU703452B2 (en) 1999-03-25
HUP9902644A2 (hu) 1999-11-29
JPH11507393A (ja) 1999-06-29
CA2234164C (fr) 2001-12-25
AU7383796A (en) 1997-04-30
HUP9902644A3 (en) 2000-10-30
JP3199748B2 (ja) 2001-08-20
CA2234164A1 (fr) 1997-04-17
NZ320971A (en) 1999-08-30

Similar Documents

Publication Publication Date Title
EP0315147B1 (fr) Antibiotiques, bénanomicines A et B et déxylosylbenanomicine B, leur fabrication et utilisation
US5250563A (en) Inhibitors of HIV protease
AU703452B2 (en) Novel orthosomycins from micromonospora carbonacea
US4597968A (en) Antibiotic 13-384 complex from Micromonospora carbonacea var africana
EP0116690A1 (fr) Composition antivirale contenant un indole-N-glycoside
US5780442A (en) Orthosomycins from micromonospora carbonacae
CA2012013C (fr) Antibiotique bmy-41339 antimoral
EP0420552B1 (fr) Antibiotique antifongique, sa préparation et son utilisation
EP0317292B1 (fr) Antibiotiques du groupe muréidomycine, leur préparation et leur emploi
EP0253413B1 (fr) Antibiotiques appelés "Mureidomycines A,B,C et D", leur procédé de préparation et leur emploi thérapeutique
EP0372986B1 (fr) Composé KS-505 et procédé de préparation
AU2016362540B2 (en) Antibiotic FIIRV 104/18 complex and the isolated individual factors thereof
AU648122B2 (en) Dynemicin C antitumor antibiotic
US4461831A (en) Antitumor agents albacarcins V and M
CA1338184C (fr) Antibiotique bu-386t antitumoral
AU5405294A (en) Antibiotic agents
US4123608A (en) Antibiotic compound
JPH05155888A (ja) 新規な抗生物質およびそれらの製造
JPS6317834B2 (fr)
US4956374A (en) Polysubstituted thiazolylpyridine carboxyamide antifungal antibiotic
JP2883708B2 (ja) 新規な抗かび性抗生物質デキシロシルベナノマイシンａならびにその製造法
WO2000014100A1 (fr) Derives de l'antibiotique nocathiacine prepares par biotransformation microbienne
MXPA98002749A (en) Orthosomicinas novedosas isolated from micromonospora cardona

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19980409

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU NL PT SE

AX Request for extension of the european patent

Free format text: LT PAYMENT 980409;LV PAYMENT 980409

17Q First examination report despatched

Effective date: 20000425

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20010613