WO1999055896A1 - NOUVEL INHIBITEUR L 970885 DE GLUCOSE-6-PHOSPHATE TRANSLOCASE PROVENANT D'UN ACTINOMYCETE sp., SES DERIVES CHIMIQUES, SON PROCEDE DE PREPARATION ET SON UTILISATION COMME PRODUIT PHARMACEUTIQUE - Google Patents

NOUVEL INHIBITEUR L 970885 DE GLUCOSE-6-PHOSPHATE TRANSLOCASE PROVENANT D'UN ACTINOMYCETE sp., SES DERIVES CHIMIQUES, SON PROCEDE DE PREPARATION ET SON UTILISATION COMME PRODUIT PHARMACEUTIQUE Download PDF

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Publication number
WO1999055896A1
WO1999055896A1 PCT/EP1999/002671 EP9902671W WO9955896A1 WO 1999055896 A1 WO1999055896 A1 WO 1999055896A1 EP 9902671 W EP9902671 W EP 9902671W WO 9955896 A1 WO9955896 A1 WO 9955896A1
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Prior art keywords
compound
actinomycete
hil
culture
glucose
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PCT/EP1999/002671
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English (en)
Inventor
Keshavapura Hosamane Sreedhara Swamy
Nirogi Venkata Satya Ramakrishna
Erra Koteswara Satya Vijaya Kumar
Tulsidas Sitaram More
Rajendra Prakash Tanpure
Swati Dhananjay Tare
Prashant Venkatesh Shanbhag
Ravi Gajanan Bhat
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Aventis Pharma Deutschland Gmbh
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Application filed by Aventis Pharma Deutschland Gmbh filed Critical Aventis Pharma Deutschland Gmbh
Priority to AU59473/99A priority Critical patent/AU5947399A/en
Publication of WO1999055896A1 publication Critical patent/WO1999055896A1/fr

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    • 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
    • C12P15/00—Preparation of compounds containing at least three condensed carbocyclic rings
    • 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
    • C12P1/00—Preparation of compounds or compositions, not provided for in groups C12P3/00 - C12P39/00, by using microorganisms or enzymes
    • C12P1/06—Preparation of compounds or compositions, not provided for in groups C12P3/00 - C12P39/00, by using microorganisms or enzymes by using actinomycetales
    • 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
    • C12R2001/04—Actinomyces

Definitions

  • This invention relates to a new compound L 970885 obtainable from an Actinomycete sp. (culture number HIL-000337), a process for their peparation, and their use in the manufacture of medicaments.
  • Increased rate of hepatic glucose output is a general feature of diabetes mellitus.
  • NIDDM non- insulin dependent diabetes mellitus
  • the two pathways by which glucose is produced in the liver are gluconeogenesis and glycogenolysis.
  • the terminal steps of both pathways is catalysed by the microsomal glucose-6-phosphatase, a key enzyme in the homeostatic regulation of blood glucose levels.
  • the level of this enzyme has also been known to be elevated in both experimental and pathological conditions of diabetes. Interference with this enzyme system should, therefore, result in a reduced hepatic glucose production.
  • Hepatic glucose-6-phosphatase is a multicomponent system comprised of atleast three functional activities: a glucose-6-phosphate translocase (T1 ), a glucose-6-phosphate phosphohydrolase and a phosphate/pyrophosphate translocase (T2).
  • the glucose-6- phosphate translocase facilitates transport of glucose-6-phosphate into the lumen of the endoplasmic reticulum (ER).
  • ER endoplasmic reticulum
  • the phoshohydrolase with its active site situated on the lumenal surface of the ER, hydrolyses glucose-6-phosphate and releases glucose and phosphate into the lumen. While the efflux of phosphate is facilitated by the phosphate/pyrophosphate translocase, the exact mechanism of glucose efflux is still not clear.
  • glucose-6-phosphate translocase The high degree of substrate specificity of glucose-6-phosphate translocase makes this a potential target for pharmacological intervention in the treatment of diabetes mellitus.
  • glucose-6-phosphate 2 only glucose-6-phosphate 2
  • the phosphatase is non-specific and is known to hydrolyse a variety of organic phosphate esters.
  • Kodaistatin A Indian Patent Application No. 69/BOM/97 dt. Feb. 4, 1997; EP Appl. No. 97106453.0 dt. April 18, 1997] and Kodaistatins B-D [Indian Patent Application No. 562/BOM/97 dt. Sept. 26, 1997] are the first glucose-6-phosphate translocase inhibitors from microbial sources.
  • L 970885 a compound with the molecular formular C 28 H ⁇ On (L 970885) obtainable from from an Actinomycete sp (culture number HIL-000337).
  • L 970885 may be described as a glucose-6- phosphate translocase inhibitor.
  • L 970885 has a hitherto unreported new structure belonging to anthraquinone class of compounds.
  • a chemical abstract literature search using search keys of the molecular formula established L 970885 to be a new compound. No other compound represented the structural features of L 970885.
  • the microorganism, culture number HIL-000337 used for the production of L970885 was isolated from a soil sample collected from Rahne Fall, Madhya Pradesh, India.
  • the microorganism HIL-000337 belongs to the order of Actinomycetales and has been deposited with the German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany with an accession number DSM No. 11992.
  • Another object of the present invention is to provide a process for the production of a new compound named L 970885 from culture number HIL-000337, 3
  • the said process comprises cultivation of culture HIL- 000337, its mutants and variants, under aerobic conditions in a nutrient medium containing sources of carbon and nitrogen, nutrient inorganic salts followed by isolation and purification of the said compound from the culture filtrate.
  • compositions containing the compound L 970885 or chemical derivatives thereof together with a pharmaceutically tolerated auxiliary and/or excipient the use of the compound L 970885 or chemical derivatives thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diabetes mellitus and the Actinomycete sp. culture number HIL-000337 (DSM 11992) and ist mutants and/or variants.
  • the nutrient medium contains sources of carbon, nitrogen and inorganic salts.
  • the carbon sources are, for example, starch, glucose, surcose, dextrin, fructose, molasses, glycerol, lactose or galactose, preferably glucose.
  • the sources of nitrogen are soyabean meal, peanut meal, yeast extract, beef extract, peptone, tryptone, malt extract, corn steep liquor, gelatin or casamino acids, preferably soyabean meal and corn steep liquor.
  • the nutrient inorganic salts are sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, calcium chloride, calcium carbonate, potassium nitrate, ammonium sulphate or magnesium sulphate, preferably cobalt chloride and calcium carbonate.
  • Cultivation of culture No. HIL-000337 may be carried out at temperatures between 25-30°C and pH between 6.0 and 8.0.
  • culture No. HIL-000337 is cultivated at 27°C (+ 1 °C) and pH 7.0.
  • the fermentation is preferably carried out for 40 to 70 hours when an optimal yield of L 970885 of the present invention is obtained. It is particularly preferred to carry out the fermentation for 60-70 hours under submerged conditions in shake flasks and 43-48 hours in laboratory fermenters. if desired, Desmophen ® (Polypropylene oxide) may be used as an antifoam agent in the fermenters. The progress of fermentation and formation of L 970885 can be detected by measuring the inhibition 4
  • L 970885 is present only in the culture filtrate Thus, it can be recovered by extraction of the culture filtrate with a water immiscible solvent such as ethyl acetate, dichloromethane, chloroform or butanol at pH 5-8 or by hydrophobic interaction chromatography using polymeric resins such as "Diaion HP-
  • the crude material can be further purified by using any of the following techniques normal phase chromatography (using alumina or silica gel as stationary phase and eluents such as ethyl acetate, chloroform, methanol or combinations thereof), reverse phase chromatography (using reverse phase silica gel like dimethyl- octadecylsilylsilica gel, also called RP-18 or dimethyloctylsilylsilica gel also called RP-8 as stationary phase and eluents such as water, buffers viz phosphate, acetate, citrate (pH 2-8) and organic solvents such as methanol, acetonit ⁇ le or acetone, or combinations of these solvents), gel permeation chromatography using resins such as "Sephadex LH-20 ® " (Pharmacia Chemical Industries, Sweden), TSKgel Toyopearl HW-40F (TosoHaas, Tosoh Corporation, Japan) in solvents such as methanol,
  • L 970885 can be administered orally, intramuscularly or intravenously.
  • Pharmaceuticals which contain L 970885 or in combinations as the active substance is subject of the present invention also. They can be prepared by mixing the active compound with one or more pharmacologically tolerated auxiliaries and/or excipients such as, for example, fillers, emulsifiers, lubricants, masking flavours, colorants or buffer substances, and converted into a suitable pharmaceutical form such as, for example, tablets, coated tablets, capsules, granules, powders, emulsions, suspensions or solutions suitable for parenteral administration.
  • auxiliaries and/or excipients such as, for example, fillers, emulsifiers, lubricants, masking flavours, colorants or buffer substances
  • auxiliaries and/or excipients which may be mentioned are tragacanth, lactose, talc, agar-agar, polyglycols, ethanol and water. Suitable and preferred for parenteral administration are suspension or solutions in water. It is also possible to administer the active substances as such, without vehicles or diluents, in a suitable form, for example, in capsules.
  • the dosage of the active compound L 970885 to be administered and the frequency of administration depend on the potency of the active compound and additionally on the nature and severity of the disease to be treated and on the sex, age, weight and individual responsiveness of the mammal to be treated.
  • the daily dose of the compound L 970885 in a human patient of about 75 kg weight is at least 1 mg to at most 500 mg, preferably from about 10 mg to 250 mg, it being possible, according to requirement, in several doses per day, and also, where appropriate, to be lower or higher.
  • the compound L 970885 may be converted into its pharmaceutically acceptable salts and derivatives like esters and ethers. Salts like sodium may be prepared by treating the active compound L 970885 with the corresponding bases. Esters may be prepared by reacting the compound L 970885 with carboxylic acids in the presence of reagents such as dicyclohexylcarbodiimide (DCC) or by treating the compound with acylating agents such as acid chlorides. Other methods of preparation of esters are given in literature [Advanced Organic Synthesis, 4th Edition, J. March, John Wiley & Sons, 1992]. 6
  • DCC dicyclohexylcarbodiimide
  • Ethers may be prepared from L 970885 by reaction with alkylating agents under basic conditions. Other methods of preparation of ethers are given [Advanced Organic Synthesis, 4th Edition, J. March, John Wiley & Sons, 1992].
  • Yeast extract 1.0 g
  • Agar powder 13.0 g
  • Demineralized water 1.0 litre pH: 7.5
  • Example 2 The medium was cooled to 45°C before pouring and the plate swirled thoroughly. The mixture of soil suspension and medium was allowed to settle and incubated at 30°C (+ 1°C) for 7 days. The petri plate was periodically observed and the culture No. HIL-000337 was isolated from amongst the growing microorganisms.
  • Example 2 The medium was cooled to 45°C before pouring and the plate swirled thoroughly. The mixture of soil suspension and medium was allowed to settle and incubated at 30°C (+ 1°C) for 7 days. The petri plate was periodically observed and the culture No. HIL-000337 was isolated from amongst the growing microorganisms.
  • Example 2 The medium was cooled to 45°C before pouring and the plate swirled thoroughly. The mixture of soil suspension and medium was allowed to settle and incubated at 30°C (+ 1°C) for 7 days. The petri plate was periodically observed and the culture No. HIL-000337 was isolated from amongst the growing microorganisms.
  • Example 2
  • Yeast extract 4.0 g
  • Agar powder 13.0 g
  • Demineralized water 1.0 litre pH: 7.0
  • test tubes After dissolving the above mentioned ingredients throughly by heating, it was distributed in test tubes and then sterilized at 121°C for 20 minutes. The test tubes were then cooled and allowed to solidify in a slanting position. The agar slants were streaked with the growth of the culture No. HIL-000337 by a wire loop and incubated at 28°C (+ 1°C) until a good growth was observed. The well grown cultures were stored in the refrigerator at 8°C.
  • composition of seed medium :
  • Soyabean meal 15.0 g
  • Demineralized water 1.0 litre pH: 7.0
  • the above seed medium was distributed in 80 ml amounts in 500 ml Erienmeyer- flasks and autoclaved at 121° C for 20 minutes.
  • the flasks were cooled to room temperature and each flask was then inoculated with a loopful of the above mentioned well grown culture of Example 2 and shaken on a rotary shaker for 72 hours at 240 rpm at 27°C (+ 1°C) to give seed culture.
  • Soyabean meal 10.0 g
  • Demineralized water 1.0 litre pH: 7.0
  • the production medium was distributed in 60 ml amounts in 500 ml Erienmeyer flasks and autoclaved at 121°C for 20 minutes. The flasks were cooled to room temperature and then inoculated with the above mentioned seed culture (1 % v/v). The fermentation was carried out on a rotary shaker at 240 rpm and at a temperature of 27°C (+ 1°C) for 66 hours.
  • L 970885 was monitored by measuring the inhibition of glucose-6- phosphate translocase. After harvesting, the culture broth was centrifuged and L 970885 was isolated from the culture filtrate and purified as described in Example 5.
  • Example 3 The seed medium of Example 3 was distributed in 150 ml amounts in 1 L Erienmeyer flasks and autoclaved for 20 minutes. The seed culture was grown in these flasks as described in Example 3. Stage 2 : Preparation of seed culture in fermenter
  • the production of the compound was monitored by measuring the inhibition of glucose-6-phosphate translocase.
  • the pH of the culture broth was 6.0-7.0.
  • the culture broth was centrifuged after harvesting and the glucose-6-phosphate translocase inhibitor L 970885 was isolated from the culture filtrate as described below in Example 5. 10
  • the active eluates (4 x 10 litres), obtained with 50% methanol in water were combined, concentrated under reduced pressure of 10-100 mm of Hg at 35 °C and lyophillized to yield the crude active material (160 g) showing an IC 50 of 29 ⁇ g/ml.
  • the crude material was again passed through a Diaion HP-20 (2.5 litres) column.
  • the column was washed thorougly with demineralized water (10 litres) and then eluted with 50% methanol in water.
  • the fractions were collected in one litre size.
  • the active eluates were combined and concentrated under reduced pressure of 10- 100mm of Hg at 35 °C and lyophillized to obtain enriched material (40 g) having an ICso ⁇ f 20 ⁇ g/ml.
  • the above material was purified by passing through Sephadex LH-20 (2 litres) packed in glass column using demineralized water as the mobile phase. The flow rate was maintained at 1 ml/minute. The fractions were collected in 25 ml. size. The active fractions were pooled, concentrated under reduced pressure of 10-100mm of Hg at 35 °C and lyophillized to obtain further enriched material (1.4 g) material having an IC 5 o of 18 ⁇ g/ml.
  • the above material was further purified by passing through another Sephadex LH- 20 (800 ml) packed in glass column using demineralized water as the mobile phase. The flow rate was maintained at 0.8 ml/minute. The fractions were collected in 15 ml size. The active fractions were combined, concentrated under reduced pressure of 10-100 mm of Hg at 35 °C and lyophillized to obtain semipure material (200 mg) having an IC 50 of 15 ⁇ g/ml. 1 1
  • the semipure material, thus obtained, was finally purified by preparative HPLC using LichroCART RP-18 column (250 x 10 mm).
  • the mobile phase was 25% acetonit le in 0.1 % trifluroacetic acid at a flow rate of 6 ml/min and detection at 210 nm.
  • the pure compound, thus obtained, was 15 mg with an IC 50 of 18 ⁇ M.
  • the purity of the compound L 970885 was checked by HPLC (High Pressure Liquid Chromatography) on a LiChrocart (250 mm x 4 mm) RP Select B (5 ⁇ ) column using a gradient of 0.1 % aqueous orthophosphahc acid (pH 2.5) to CH 3 CN in 20 min at a flow rate of 1 ml/min and UV detection at 280 nm
  • L 970885 inhibits potently the activity of rat liver microsomal glucose-6-phosphate translocase with an IC50 of about 18 ⁇ M.
  • the microorganism identified under I above was accompanied by
  • microorganism identified under I above was received by this International Depositary Authority on (date of original deposit) and a request to convert the original deposit to a deposit under the Budapest Treaty was received by it on (date of receipt of request for conversion)

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Abstract

La présente invention concerne un nouvel inhibiteur L 970885 de glucose-6-phosphate translocase produit par un Actinomycète sp. (numéro de culture HIL-000337) lors de sa fermentation; son procédé de préparation; des dérivés chimiques provenant du composé L 970885; l'utilisation du composé L 970885 et de ses dérivés et des substances pharmacologiques actives comme médicaments, notamment pour le traitement du diabète sucré. L'invention concerne également un Actinomycète sp. HIL-000337 (DSM 11992) destiné à la production du composé mentionné ci-dessus L 970885.
PCT/EP1999/002671 1998-04-27 1999-04-21 NOUVEL INHIBITEUR L 970885 DE GLUCOSE-6-PHOSPHATE TRANSLOCASE PROVENANT D'UN ACTINOMYCETE sp., SES DERIVES CHIMIQUES, SON PROCEDE DE PREPARATION ET SON UTILISATION COMME PRODUIT PHARMACEUTIQUE WO1999055896A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU59473/99A AU5947399A (en) 1998-04-27 1999-04-21 A new glucose-6-phosphate translocase inhibitor L 970885 from an actinomycete SP., and chemical derivatives thereof, a process for the preparation and theirv use as pharmaceuticals

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP98107631 1998-04-27
EP98107631.8 1998-04-27

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WO1999055896A1 true WO1999055896A1 (fr) 1999-11-04

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8008324B2 (en) 2000-07-28 2011-08-30 Aeterna Zentaris Gmbh Indole derivatives and their use as medicament

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
HEMMERLE H ET AL: "Chlorogenic acid and synthetic chlorogenic acid derivatives: Novel inhibitors of hepatic glucose-6-phosphate translocase", JOURNAL OF MEDICINAL CHEMISTRY, vol. 40, no. 2, 17 January 1997 (1997-01-17), pages 137 145, XP002078904, ISSN: 0022-2623 *
JACKSON M ET AL.: "Altromycins, novel pluramycin-like antibiotics I. Taxonomy of the producing organism, fermentation and antibacterial activity", THE JOURNAL OF ANTIBIOTICS, vol. 43, no. 3, March 1990 (1990-03-01), pages 223 - 228, XP002113417 *
KOYAMA K & NATORI S: "Further characterization of seven bis (naphto-gamma-pyrone) congeners of ustilaginoidins, coloring matters of Claviceps virens (Ustilago virens)", CHEMICAL AND PHARMACEUTICAL BULLETIN, vol. 36, no. 1, 1 January 1988 (1988-01-01), pages 146 - 152, XP002078903, ISSN: 0009-2363 *
MUKHOPADHYAY T ET AL: "2-Demethylazalomycins F4a and F5a, two new antifungal metabolites from Actinomycete sp. HIL-Y-9120362", JOURNAL OF ANTIBIOTICS., vol. 48, no. 11, November 1995 (1995-11-01), JAPAN ANTIBIOTICS RESEARCH ASSOCIATION. TOKYO., JP, pages 1350 - 1352, XP002113418, ISSN: 0021-8820 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8008324B2 (en) 2000-07-28 2011-08-30 Aeterna Zentaris Gmbh Indole derivatives and their use as medicament

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