WO1998024751A1 - Acides carboxyliques aliphatiques insatures (maracenines), procedes permettant de les preparer et agent antibacterien - Google Patents

Acides carboxyliques aliphatiques insatures (maracenines), procedes permettant de les preparer et agent antibacterien Download PDF

Info

Publication number
WO1998024751A1
WO1998024751A1 PCT/EP1997/006735 EP9706735W WO9824751A1 WO 1998024751 A1 WO1998024751 A1 WO 1998024751A1 EP 9706735 W EP9706735 W EP 9706735W WO 9824751 A1 WO9824751 A1 WO 9824751A1
Authority
WO
WIPO (PCT)
Prior art keywords
delta
trans
nmr
maracenin
methanol
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.)
Ceased
Application number
PCT/EP1997/006735
Other languages
German (de)
English (en)
Inventor
Hans Reichenbach
Gerhard Höfle
Bettina Böhlendorf
Martina Herrmann
Herbert Irschik
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.)
Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
Original Assignee
Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
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 Helmholtz Zentrum fuer Infektionsforschung HZI GmbH filed Critical Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
Publication of WO1998024751A1 publication Critical patent/WO1998024751A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/60—Unsaturated compounds containing ether groups, groups, groups, or groups the non-carboxylic part of the ether being unsaturated
    • 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
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/40—Preparation of oxygen-containing organic compounds containing a carboxyl group including Peroxycarboxylic acids

Definitions

  • the invention relates to unsaturated aliphatic carboxylic acids (maracenins), processes for their production and agents containing unsaturated aliphatic carboxylic acids (maracenins).
  • the invention relates to unsaturated aliphatic carboxylic acids (maracenins) of the general formula:
  • the invention further relates to an unsaturated aliphatic carboxylic acid (maracenin A ⁇ _) of the formula
  • the invention further relates to an unsaturated aliphatic carboxylic acid (maracenin A2) of the formula
  • delta 4 ' 5 -trans delta 11 ' 12 -trans, delta 14 '15 -cis, delta 17 ' 18 -cis and / or with the following parameters:
  • the invention further relates to an unsaturated aliphatic carboxylic acid (maracenin B ⁇ ) of the formula:
  • ny 3012 (m), 2964 (m), 2931 (m), 2875 (w), 2279 (m),
  • UV methanol
  • lamdam x log epsilon
  • the invention further relates to an unsaturated aliphatic carboxylic acid (maracenin B2) of the formula:
  • the invention further relates to an unsaturated aliphatic carboxylic acid of the formula (Maracenin C ⁇ ):
  • ny 3012 (w), 2925 (m), 285 (w), 1711 (s), 1654 (n), 1434 (m), 1412 (w), 1271 (m), 1215 (m), 1154 (s ), 1069 (w), 997 (m), 967 (m) and 924 (m) cm -1 , and
  • UV methanol
  • the invention further relates to an unsaturated aliphatic carboxylic acid (maracenin C) of the formula:
  • the invention further relates to an unsaturated aliphatic carboxylic acid (maracenin D j of the formula:
  • ny 3011 (m), 2963 (m), 2929 (m), 2873 (w), 2856 (w),
  • the invention further relates to an unsaturated aliphatic carboxylic acid (maracenin D2) of the formula:
  • the invention relates to a process for the production of unsaturated aliphatic carboxylic acids (maracenins), characterized in that
  • Sorangium cellulosum So ce 880 DSM 11252 in an aqueous medium containing carbon and nitrogen sources and mineral salts, aerobically cultivated in the presence of an adsorber resin,
  • the adsorber resin is optionally separated from the culture medium with the cells and extracted with methanol and then with acetone,
  • the invention further relates to a process for the production of unsaturated aliphatic carboxylic acids (maracenins), characterized in that
  • Sorangium cellulosum So ce 1128 DSM 11253 in an aqueous medium containing carbon and nitrogen sources and mineral salts, aerobically cultivated in the presence of an adsorber resin,
  • the adsorber resin is optionally separated from the culture medium with the cells and extracted with methanol and then with acetone,
  • Amberlite in particular Amberlite XAD-16, can be used as the adsorber resin in the process according to the invention.
  • step (d) You can also dry in step (d) with sodium sulfate.
  • Gel chromatography can also be carried out with Sephadex, in particular with Sephadex LH-20.
  • a further embodiment of the invention relates to an agent against bacteria, in particular mycobacteria and / or nocardia, containing an unsaturated aliphatic carboxylic acid (maracenin) according to the invention in addition to conventional auxiliaries and / or carriers.
  • an agent against bacteria in particular mycobacteria and / or nocardia
  • an unsaturated aliphatic carboxylic acid (maracenin) according to the invention in addition to conventional auxiliaries and / or carriers.
  • the agent according to the invention can be provided for the treatment of tuberculosis.
  • the vegetative cells are cylindrical rods with round ends, usually around 1 ⁇ m thick and 3 - 6 ⁇ m long. They appear dark in the phase contrast microscope. They move smoothly. On some nutrient media, the organism forms fruiting bodies in abundance. B. on filter paper over mineral salt agar. The fruiting bodies are dark red-brown cushions and consist of a more or less large number of sporangioles, spherical or polyhedral structures with a fixed wall, 20 to 30 ⁇ m in diameter, by flattening. In the sporangioles there are myxospores, rod-shaped permanent cells of a similar shape and size to the vegetative cells, but highly refractive and drying-resistant in the phase contrast microscope.
  • the organism grows on peptone agar, e.g. B. CY agar (Casitone, Difco, 0.3%; CaCl • H2O 0.1%; yeast extract, Difco, 0.1%; agar 1.5%; pH 7.2), however a carbohydrate, e.g. B. glucose or starch must be added.
  • the Carbohydrate can be used in a concentration of e.g. B. 0.1% can be added.
  • yeast agar e.g. B. VY / 2 agar (baker's yeast 0.5%, based on fresh weight; CaCl2 • 2H2O 0.1%; agar 1.5%; pH 7.2).
  • the strain quickly and vigorously breaks down chitin and starch.
  • So ce880 grows in liquid media partly clumped, partly in a homogeneous cell suspension, both in shake flasks (at e.g. 160 rpm) and in bioreactors (tested up to 100 liters). The cultivation takes place at 30 ° C under aerobic conditions.
  • Bioreactor with 100 1 content from Chemap (now Braun solutions), blade stirring system. Medium No. 3 (as above), additionally adsorber resin Amberlite XAD-16, 1%, v / v (Rohm and Haas, Darmstadt) and anti-foaming agent Tegosipon, 10 ml (Goldschmidt AG, Essen), but without HEPES.
  • the fermentor was inoculated with 4.8 l of preculture, which were grown in 6 x 2 l shake flasks with 800 ml of medium 3.
  • the strain forms the maracenins A and B during the fermentation.
  • Maracenin A was dissolved in methanol and applied to test sheets (6 mm in diameter) in amounts of 2 ⁇ g. These test sheets were placed on agar plates in which various test organisms were seeded in low cell density. These test plates were incubated at 30 ° C. After the test organisms had grown, the inhibitory zones were read off. The result is shown in the following table:
  • Botrytis cinerea 0 To determine the minimum inhibitory concentration, maracenin A and B in various concentrations were placed in test tubes containing a suspension of the test organisms in nutrient medium. The initial cell density was 10 cells / ml. The cultures were incubated with shaking at 30 ° C for 18 to 40 hours.
  • peptone from casein tryptically digested, Merck, 0.5%
  • Proteose Peptone Difco, 0.5%
  • Meat extract Oxoid, 0.1%
  • pH 7.0 pH 7.0
  • the minimum inhibitory concentration for L 929 mouse fibroblasts in cell cultures was 24 ⁇ g / ml for maracenin A and B. insulation
  • the precipitate (32 g) was separated by centrifugation.
  • the crude product remaining in solution (21 g) was fractionated by gel chromatography on Sephadex LH-20 with methanol as the eluent.
  • the fractions containing maracenins (1.4 g) were chromatographed on HD-SIL-18-20-60 (column: 929 x 90 mm, eluent: methanol / 0.05 mM ammonium acetate buffer 80/20, flow: 7 ml / min) - phated.
  • PC aluminum foils with silica gel 60 F 2 5 4 , layer thickness 0.2 mm, Merck art. 5554; Detection with vanillin / sulfuric acid spray reagent and heating to 120 ° C (-> violet red staining) mobile solvent: dichloromethane / acetone / methanol 85/10/5 Rf: 0.53
  • PC aluminum foils with silica gel 60 F25 4 , layer thickness 0.2 mm, Merck art. 5554; Detection with vanillin / sulfuric acid spray reagent and heating to 120 ° C (-> violet red staining) mobile solvent: dichloromethane / acetone / methanol 85/10/5 Rf: 0.51 HPLC: column: 2 x 125 mm, material: Nucleosil R 120-5C 18 ; Flow: 0.3 ml / min; Eluent: methanol / O .01 mM ammonium acetate buffer 75/25, UV detection: 220 nm Rt: 9.9 min
  • UV (methanol): lambda max (log epsilon) 205 nm (4.37).
  • the vegetative cells are cylindrical rods with round ends, usually around 1 ⁇ m thick and 3 - 6 ⁇ m long. They appear dark in the phase contrast microscope. They move smoothly. On some nutrient media, the organism forms fruiting bodies in abundance. B. on filter paper over mineral salt agar. The fruiting bodies are yellow-brown cushions and consist of a more or less large number of sporangioles, spherical or by mutually flattening polyhedral structures with a solid wall, 20 to 30 microns in diameter. In the sporangioles there are myxospores, rod-shaped permanent cells of a similar shape and size to the vegetative cells, but highly refractive and drying-resistant in the phase contrast microscope.
  • the organism grows on peptone agar, e.g. B. CY agar (Casitone, Pifco, 0.3%; CaCl 2 • 2H 2 0 0.1%; yeast extract, Pifco, 0.1%; agar 1.5%; pH 7.2), the however a carbohydrate, e.g. B. glucose or starch must be added.
  • the Carbohydrate can be used in a concentration of e.g. B. 0.1% can be added.
  • yeast agar e.g. B. VY / 2 agar (baker's yeast 0.5%, based on fresh weight; CaCl2 • H2O 0.1%; agar 1.5%; pH 7.2). Chitin breaks down quickly and vigorously per strain. So cell28 grows in liquid medium partly clumped, partly in a homogeneous cell suspension, both in shake flasks (at e.g. 160 rpm) and in bioreactors (tested up to 100 liters). Pie cultivation takes place at 30 ° C under aerobic conditions.
  • B. Medium No. 1 MP1 lm (peptone from casein, tryptically digested, Merck, 0.3%; CaCl 2 .2H 2 0 0.05%; MgS0 4 .7H 2 0 0.2%; pH 7.2 ), which is supplemented by a carbohydrate source, e.g. B. glucose, starch, cellulose, each 0.1%.
  • MP1 lm peptone from casein, tryptically digested, Merck, 0.3%
  • MgS0 4 .7H 2 0 0.2% pH 7.2
  • a carbohydrate source e.g. B. glucose, starch, cellulose, each 0.1%.
  • Inoculation was carried out by fermenter with 4.8 l of preculture, which were grown in 6 x 2 l shake flasks with 800 ml of medium 3 each. During the fermentation, a drop in pH below 6.9 was prevented by adding 5% KOH.
  • maracenins C and P are formed per strain.
  • various concentrations of maracenins C and P were placed in test tubes containing a suspension of the test organisms in nutrient medium.
  • the initial cell line was 10 5 cells / ml.
  • Pie cultures were incubated with shaking at 30 ° C for 18 to 40 hours.
  • peptone from casein tryptically digested, Merck, 0.5%
  • Proteose Peptone Pifco
  • Meat extract Oxoid, 0.1%
  • pH 7.0 pH 7.0
  • Test organism Minimum inhibitory concentration ( ⁇ g / ml
  • the minimum inhibitory concentration for L929 mouse fibroblasts in cell culture was 24 ⁇ g / ml for maracenin C and P. insulation
  • Precipitate (77 g) was separated by centrifugation.
  • the crude product remaining in solution (21 g) was fractionated by gel chromatography on Sephadex LH-20 with methanol as the eluent.
  • Fractions containing pie maracenine (1.7 g) were chromatographed on HP-SIL-18-20-60 (column: 929 ⁇ 90 mm, eluent: methanol / 0.05 mM ammonium acetate buffer 80/20, flow: 7 ml / min) .
  • the components were separated by preparative HPLC on Nucleosil 100-C18-7 (column: 250 x 16 mm, flow: 10 ml / min) with a mobile phase mixture of methanol and 0.05 mM ammonium acetate buffer in a ratio of 70/30.
  • PC aluminum foils with silica gel 60 F25 4 , layer thickness 0.2 mm, Merck art. 5554; Petition with vanillin / sulfuric acid spray reagent and heating to 120 ° C (-> violet red staining) mobile solvent: pichloromethane / acetone / methanol 85/10/5 (v / v / v) Rf_: 0.55
  • PC aluminum foils with silica gel 60 F25 4 , layer thickness 0.2 mm, Merck art. 5554; Detection with vanillin / sulfuric acid spray reagent and heating to 120 ° C (-> violet red staining) mobile solvent: dichloromethane / acetone / methanol 85/10/5 (v / v / v) Rf: 0.62 HPLC: column: 2 x 125 mm, material: Nucleosil R 120-5C 18 ; Flow:
  • UV (methanol): lambda max (log epsilon) 203 nm (4.16).

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

L'invention concerne des acides carboxyliques aliphatiques insaturés (maracénines) de la formule générale (I), dans laquelle, si x = 2, y = 1 et (a) désigne une liaison double, z = 0, R disparaît et (b) désigne une liaison triple ou z = 1, R désigne un atome et (b) désigne une liaison double ou, si x = 3, y = 2 et (a) désigne une liaison simple, z = 0, R disparaît et (b) désigne une liaison triple ou z = 1, R désigne un atome de Cl et (b) désigne une liaison double. Un autre mode de réalisation concerne un agent permettant de lutter contre les bactéries, en particulier contre des mycobactéries et/ou des bactéries du genre Nocardia, contenant une certaine quantité d'un acide carboxylique aliphatique insaturé (maracénine) selon l'invention en plus des substances porteuses ou auxiliaires habituelles. L'agent selon l'invention peut être destiné au traitement de la tuberculose.
PCT/EP1997/006735 1996-12-02 1997-12-02 Acides carboxyliques aliphatiques insatures (maracenines), procedes permettant de les preparer et agent antibacterien Ceased WO1998024751A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE1996149869 DE19649869A1 (de) 1996-12-02 1996-12-02 Ungesättigte aliphatische Carbonsäuren (Maracenine), Herstellungsverfahren und Mittel
DE19649869.4 1996-12-02

Publications (1)

Publication Number Publication Date
WO1998024751A1 true WO1998024751A1 (fr) 1998-06-11

Family

ID=7813351

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1997/006735 Ceased WO1998024751A1 (fr) 1996-12-02 1997-12-02 Acides carboxyliques aliphatiques insatures (maracenines), procedes permettant de les preparer et agent antibacterien

Country Status (2)

Country Link
DE (1) DE19649869A1 (fr)
WO (1) WO1998024751A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996011908A1 (fr) * 1994-10-13 1996-04-25 Peptide Technology Limited Acides gras polyinsatures modifies

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996011908A1 (fr) * 1994-10-13 1996-04-25 Peptide Technology Limited Acides gras polyinsatures modifies

Also Published As

Publication number Publication date
DE19649869A1 (de) 1998-06-04

Similar Documents

Publication Publication Date Title
DE69228239T2 (de) A 83543 Verbindungen und Verfahren zu ihrer Herstellung
DE60019898T2 (de) Mikrobielles verfahren zur herstellung von pravastatin
DE68928606T2 (de) Antiparasitäre Makrolid-Antibiotika
DE3036361A1 (de) Antibiotikum u-59 761, verfahren zu seiner gewinnung und isolierung sowie dabei verwendete biologisch reine kultur des mikroorganismus saccharopolyspora hirsuta, stamm 367 (nrrl 12045,dsm 1886)
DE3512194A1 (de) Ein neues ansamycin-antibiotikum, ein mikrobielles verfahren zu seiner herstellung und seine verwendung als arzneimittel
DE2445581C3 (de) Verfahren zur Herstellung von D-Gluconsäure-dlactam
WO1998024751A1 (fr) Acides carboxyliques aliphatiques insatures (maracenines), procedes permettant de les preparer et agent antibacterien
DE19630980B4 (de) Etnangien, Herstellung, Verwendung und Produktionsstamm sorangium cellulosum DSM 11 028
DE69218067T2 (de) Verfahren zur Herstellung von 3-deacylierten Derivaten eines 16-gliedrigen Macrolid-Antibiotikums, hierfür verwendeter Mikroorganismus, sowie neues Macrolid-Antibiotikum
DE3444184A1 (de) Antibiotikum em 5487
DE69823866T2 (de) Substanz ft-0554 und verfahren zu ihrer herstellung
CH620244A5 (en) Process for the microbiological preparation of a deacylpepsidin
DE69019591T2 (de) Phospholipase-A2-Inhibitor, Verfahren zu seiner Herstellung und diesen enthaltende pharmazeutische oder veterinäre Zusammensetzungen.
DE4410449C2 (de) Melithiazole A und B, Herstellungsverfahren, Mittel mit einem Gehalt an Melithiazol A und/oder B und Melittangium lichenicola DSM 9004 mit der Fähigkeit, Melithiazole A und B zu bilden
DE69013809T2 (de) Antibiotikum.
DE60006434T2 (de) Mikrobielle Umwandlung von 2-Methylquinoxalin
DE4211056C1 (en) Spiran heterocyclic deriv. for controlling fungi and bacteria uncontrollable - prepd. by fermenting Sorangium e.g. Polyangium cellulosum in medium contg. carbon and nitrogen sources and mineral salts in adsorber resin, and eluting
DE69206858T2 (de) Verbindung UCA1064-B
DE3881566T2 (de) Antitumor-derivate, verfahren zu ihrer herstellung und pharmazeutische zusammensetzungen, die sie enthalten.
DE69313931T2 (de) Polycyclische 31668P- und 31668U-Verbindungen, Verfahren zu ihrer Herstellung und ihre Verwendung als antibiotische oder antitumorale Arzneistoffe
DE2509337A1 (de) Verfahren zur herstellung von antibiotischen verbindungen des cephamycintyps
DE2510868C3 (de) Nanaomycin A und Verfahren zur Herstellung der Antibiorica Nanaomycin A und Nanaomycin B
EP0259778B1 (fr) Dérivé d'acide gentisine efficace antibiotiquement
DD202589A5 (de) Verfahren zur herstellung von narasin
DE19811540B4 (de) Apicularen A, Verfahren zu dessen Herstellung und cytostatisches Mittel mit Apicularen A

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): JP US

AL Designated countries for regional patents

Kind code of ref document: A1

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

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase