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WO1997013777A1 - Orthosomycines nouvelles provenant de micromonospora carbonacea - Google Patents

Orthosomycines nouvelles provenant de micromonospora carbonacea Download PDF

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Publication number
WO1997013777A1
WO1997013777A1 PCT/US1996/015750 US9615750W WO9713777A1 WO 1997013777 A1 WO1997013777 A1 WO 1997013777A1 US 9615750 W US9615750 W US 9615750W WO 9713777 A1 WO9713777 A1 WO 9713777A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
compounds
acceptable salt
complex
Prior art date
Application number
PCT/US1996/015750
Other languages
English (en)
Inventor
Ronald A. Mierzwa
Min Chu
John K. Jenkins
Mahesh G. Patel
Original Assignee
Schering Corporation
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 Corporation filed Critical Schering Corporation
Priority to NZ320971A priority Critical patent/NZ320971A/xx
Priority to AU73837/96A priority patent/AU703452B2/en
Priority to EP96936106A priority patent/EP0871639A1/fr
Priority to KR1019980702634A priority patent/KR100313651B1/ko
Priority to CA002234164A priority patent/CA2234164C/fr
Publication of WO1997013777A1 publication Critical patent/WO1997013777A1/fr

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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 Carbonacea var Africana , and the component parts thereof obtainable by cultivation of a pure culture of Micromonospora Carbonacea 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 Carbonacea 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. DESCRIPTION OF THE FIGURES
  • Figures 1, 2, 4, 5, 6, 7 and 8 are proton NMR spectra for
  • 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 mL/L
  • the flask was incubated 48 hours at 30°C with agitation (300 rpm, 1 inch stroke), and 30 mL of the culture were transferred to 6 ⁇ 2 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 (Kleenstrip) 4, calcium carbonate 4, cobalt chloride-6 H 2 O (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
  • Ca carbonate 4 calcium carbonate
  • cobalt chloride-6 H 2 O (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 minute air flow for about 120-130 hours.
  • 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 mycelia.
  • 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 ⁇ 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
  • 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.
  • Compound F (9.5 mg) were obtained. However, the first component (2.4 mg) was identified as a mixture of two compounds, Compound C and Compound D, based on analysis of spectroscopic data.
  • 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. 13 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.
  • DIAGRAM 2 structures of other compounds were also elucidated and are illustrated in DIAGRAM 2.
  • Compound C and H are shown in DIAGRAM 3.
  • Compound J was characterized as a relatively small disaccharide linked to a bicyclic aromatic ester moiety through an orthoester functionality as shown DIAGRAM 4 below.
  • the minor components were tested for activity based on an agar disk-diffusion protocol. Each component was dissolved at 1 mg/mL in CH 2 CI 2 : 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.
  • the nearly equivalent potency of Compound A with everninomicin was further documented on a four fold dilution.
  • This invention may be carried out using pharmaceutically
  • 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.
  • the microorganism used to obtain the compounds of this invention is a mutant strain of Micromonospora Carbonacea var Africana as set forth in US Patent 4, 597, 968 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-nitrosoguanidine (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.
  • NMG N-nitrosoguanidine
  • 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 S. aureus and E. coli .
  • 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 S. aureus and E. coli to confirm the production of all components of the antibiotic complex.
  • a solvent system consisting of chloroform:methanol (9:1) followed by bioautography against S. aureus and E. coli 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.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Communicable Diseases (AREA)
  • Medicinal Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biotechnology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (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.
PCT/US1996/015750 1995-10-10 1996-10-08 Orthosomycines nouvelles provenant de micromonospora carbonacea WO1997013777A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
NZ320971A NZ320971A (en) 1995-10-10 1996-10-08 Orthosomycins from micromonospora carbonacea
AU73837/96A AU703452B2 (en) 1995-10-10 1996-10-08 Novel orthosomycins from micromonospora carbonacea
EP96936106A EP0871639A1 (fr) 1995-10-10 1996-10-08 Orthosomycines nouvelles provenant de micromonospora carbonacea
KR1019980702634A KR100313651B1 (ko) 1995-10-10 1996-10-08 미크로모노스포라카르보나세아로부터의신규한오르토소마이신
CA002234164A CA2234164C (fr) 1995-10-10 1996-10-08 Orthosomycines nouvelles provenant de micromonospora carbonacea

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US501095P 1995-10-10 1995-10-10
US60/005,010 1995-10-10
US08/604,692 US5780442A (en) 1996-02-21 1996-02-21 Orthosomycins from micromonospora carbonacae
US08/604,692 1996-02-21

Publications (1)

Publication Number Publication Date
WO1997013777A1 true WO1997013777A1 (fr) 1997-04-17

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/015750 WO1997013777A1 (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)

Cited By (3)

* 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
WO2001055180A3 (fr) * 2000-01-27 2002-01-10 Ecopia Biosciences Inc Locus genetique pour la biosynthese d'everninomicine
WO2001051639A3 (fr) * 2000-01-12 2002-02-28 Schering Corp Gènes biosynthétiques d'éverninomicine

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Citations (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

Patent Citations (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
GANGULY A.K. ET AL: "The structure of new oligosaccharide antibiotics, 12-384 components 1 and 5", HETEROCYCLES, vol. 28, no. 1, 1989, AMSTERDAM NL, pages 83 - 88, XP000614822 *

Cited By (7)

* 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
WO2001051639A3 (fr) * 2000-01-12 2002-02-28 Schering Corp Gènes biosynthétiques d'éverninomicine
US6861513B2 (en) 2000-01-12 2005-03-01 Schering Corporation Everninomicin biosynthetic genes
US7229813B2 (en) 2000-01-12 2007-06-12 Schering Corporation Everninomicin biosynthetic proteins
US7790411B2 (en) 2000-01-12 2010-09-07 Schering Corporation Everninomicin biosynthetic genes
US7947480B2 (en) 2000-01-12 2011-05-24 Schering Corporation Everninomicin biosynthetic genes
WO2001055180A3 (fr) * 2000-01-27 2002-01-10 Ecopia Biosciences Inc Locus genetique pour la biosynthese d'everninomicine

Also Published As

Publication number Publication date
JP3199748B2 (ja) 2001-08-20
AU703452B2 (en) 1999-03-25
AU7383796A (en) 1997-04-30
HUP9902644A3 (en) 2000-10-30
NZ320971A (en) 1999-08-30
CA2234164A1 (fr) 1997-04-17
JPH11507393A (ja) 1999-06-29
HUP9902644A2 (hu) 1999-11-29
CA2234164C (fr) 2001-12-25
EP0871639A1 (fr) 1998-10-21

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