HK1038594A - Mumbaistatin, a process for its production and its use as a pharmaceutical - Google Patents

Description

Mumbaistatin, preparation method and application thereof as medicament

The present invention relates to a compound called Mumbaistatin (Mumbaistatin) obtained by culturing the microorganism HIL-008003(DSM 11641), and its pharmaceutically acceptable salts and derivatives. Mumbaistatin is a glucose-6-phosphate translocase inhibitor and can be used to treat diabetes. The invention also relates to a process for the preparation of Mumbaistatin, to the microorganism HIL-008003(DSM 11641), to the use of Mumbaistatin and its pharmaceutically acceptable salts and derivatives as a medicament, especially in the treatment of diabetes, and to pharmaceutical compositions comprising Mumbaistatin or its pharmaceutically acceptable salts or derivatives.

An increase in hepatic glucose output rate is a common feature of diabetes. Particularly for non-insulin dependent diabetes mellitus (NIDDM), there is a strong correlation between fasting plasma glucose levels and hepatic glucose output. The 2 pathways for glucose production in the liver are gluconeogenesis and glycogenolysis. The final steps of both pathways are catalyzed by microsomal glucose-6-phosphatase, a key enzyme in the homeostatic regulation of blood glucose levels. It is known that the level of this enzyme is also increased in experimental and pathological diabetes. Thus, interfering with the enzyme system should reduce hepatic glucose production.

Liver glucose-6-phosphatase is a multicomponent system comprising at least 3 functional activities: glucose-6-phosphate translocase (T1), glucose-6-phosphate phosphohydrolase and phosphate/pyrophosphate translocase (T2). Glucose-6-phosphate translocase facilitates transport of glucose-6-phosphate into the lumen of the Endoplasmic Reticulum (ER). Phosphohydrolase, whose active site is located on the luminal surface of the ER, hydrolyzes glucose-6-phosphate and releases glucose and phosphate into the lumen. Although phosphate/pyrophosphate translocase promotes phosphate efflux, the exact mechanism of glucose efflux is still unclear.

The high substrate specificity of glucose-6-phosphate translocase makes it a potential target for drug intervention in the treatment of diabetes. Thus, among the physiologically produced sugar phosphates, only glucose-6-phosphate is transported by the translocase. In contrast, phosphatases are non-specific and are known to hydrolyze a variety of organophosphates.

A series of nonspecific inhibitors of glucose-6-phosphatase have been described in the literature, for example phloridzin (J.biol.chem.)242, 1955-containing 1960(1967)), 5 ' -dithiobis-2-nitrobenzoic acid (Biochem.Biophys.Res.Commun.)48, 694-containing 699(1972)), 2 ' -diisothiocyanatostilbene and 2-isocyanato-2 ' -acetoxystilbene (J.Biol.chem.)255, 1113-containing 1119 (1980)). The earliest inhibitors of the glucose-6-phosphatase system which could be used therapeutically were proposed in European patent applications EP-A-587087 and EP-A-587088. Kodastatin (kodaistins) A, B, C and D, described in international patent application PCT/EP 98/02247, were the earliest inhibitors of glucose-6-phosphate translocase from microbial sources.

It has now been found that a new compound called Mumbaistatin with high glucose-6-phosphate translocase inhibitory activity is obtainable from different microbial sources. The invention therefore relates to a compound called Mumbaistatin of formula C₂₈H₂₀O₁₂Characterised by any one or more of its physicochemical and spectroscopic characteristics as set out in any of the following, e.g. in FIG. 9¹H NMR spectrum of which¹H NMR spectroscopic data, in FIG. 10¹³Described in C NMR spectra¹³C NMR spectroscopic data, the invention also relates to pharmaceutically acceptable salts and derivatives of the compounds, such as esters, ethers and obvious chemical equivalents, including all stereoisomeric and tautomeric forms.

Mumbaistatin has a new structure not reported so far, and belongs to quinone compounds. Chemical abstracts literature searches using the molecular formula of Mumbaistatin as a search key indicate that Mumbaistatin is a novel compound. None of the other compounds represented the structural features of Mumbaistatin.

Mumbaistatin is obtained by culturing microorganisms called HIL-008003 or Y-9645974 (hereinafter HIL-008003). The microorganism used for the preparation of Mumbaistatin was isolated from soil samples collected from Hiranyakeshi riverbed near Amboli, Maharashtra, India. The microorganism HIL-008003 has been identified as Streptomyces litmocidini (Streptomyces litmocidini). The German Collection of Microorganisms and Cell Cultures (DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH), Mascheroder Weg 1b, D-38124, Braunschweig, Germany have stored the microorganism on 7, 4 days 1997 and are given the accession number DSM 11641.

Thus, the present invention also provides a process for the preparation of a novel compound, designated Mumbaistatin, and pharmaceutically acceptable salts and derivatives thereof, from Streptomyces HIL-008003, its mutants and variants. The method comprises cultivating HIL-008003, a mutant or variant thereof, under aerobic conditions in a nutrient medium containing one or more carbon sources and one or more nitrogen sources, and optionally nutrient inorganic salts and/or trace elements, and then isolating the compound and purifying it in a conventional manner.

The nutrient medium preferably contains a carbon source, a nitrogen source and nutrient inorganic salts and optionally trace elements. The carbon source is, for example, starch, glucose, sucrose, dextrin, fructose, molasses, glycerol, lactose or galactose, preferably glucose. Nitrogen sources are, for example, soybean meal, peanut meal, yeast extract, beef extract, peptone, tryptone, malt extract, corn steep liquor, gelatin or casamino acids, preferably soybean meal and corn steep liquor. The nutritive inorganic salts and trace elements are, for example, disodium hydrogenphosphate, dipotassium hydrogenphosphate, sodium chloride, cobalt chloride, calcium carbonate, potassium nitrate, ammonium sulfate or magnesium sulfate, preferably cobalt chloride and calcium carbonate.

The culture of HIL-008003 is usually carried out at 25-30 ℃ and pH 6.0-8.0. Preferably, HIL-008003 is cultured at 27 ℃ (± 1 ℃) and at pH 7.0.

To obtain the hair of Mumbaistatin, HIL-008003, of the present invention in optimal yieldThe fermentation is preferably carried out for about 40 to 70 hours. It is particularly preferred to ferment under submerged conditions, for example in shake flasks and laboratory fermentors, for about 40 to 48 hours. If desired, can be used in fermenters^Desmophen (polypropylene oxide) as an antifoaming agent. The progress of the fermentation and the formation of Mumbaistatin can be detected by the following methods: improvements were made according to the method described in Methods in Enzymology 174,58-67(1989), using colorimetric analysis in microtiter plates at room temperature, untreated and used^Inhibition of glucose-6-phosphate translocase activity was determined in rat liver microsomes disrupted by Triton X-100. In the resulting broth culture, Mumbaistatin is mainly present in the culture filtrate, and therefore Mumbaistatin can be recovered as such: recovering by extracting the culture filtrate with water-immiscible solvent such as ethyl acetate, dichloromethane, chloroform and butanol at pH 5-8, or by using^Diaion HP-20(Mitsubishi Chemical Industries Limited,Japan)、^Amberlite XAD (Rohm and Haas Industries, U.S. A.), or activated carbon by hydrophobic interaction chromatography, or by ion exchange chromatography at pH 5-8. Preferably, by^Diaion HP-20 is adsorbed and the compound is then desorbed using an eluent such as water, methanol, acetone, acetonitrile, n-propanol, isopropanol or mixtures thereof. The active eluate was concentrated and freeze-dried to obtain a crude product.

The resulting crude product can be further purified using any of the following techniques: normal phase chromatography using alumina or silica gel as stationary phase, eluent such as ethyl acetate, chloroform, methanol or mixtures thereof; reversed phase chromatography using as the stationary phase a reversed phase silica gel such as dimethyloctadecylsilyl silica gel known as RP-18, or dimethyloctylsilyl silica gel known as RP-8, eluting agents such as water, buffers such as phosphate buffer, acetate buffer, citrate buffer (pH 2-8), and organic solvents such as methanol, acetonitrile, acetone, tetrahydrofuran or mixtures of these solvents; gel permeation chromatography in a solvent such as methanol, chlorineUsing resins such as chloroform, acetone, ethyl acetate, or mixtures of these solvents^Sephadex LH-20(Pharmacia Chemical Industries,Sweden)、TSKgel^Toyopearl HW-40F (TosoHaas, Tosoh Corporation, Japan), or in water^Sephadex G-10 and G-25; countercurrent chromatography using a two-phase elution system consisting of 2 or more solvents such as water, methanol, ethanol, isopropanol, n-propanol, tetrahydrofuran, acetone, acetonitrile, dichloromethane, chloroform, ethyl acetate, petroleum ether, benzene and toluene. These techniques may be used repeatedly, or different techniques may be used in combination. Preferably, the method is first to use^Toyopearl chromatography followed by reversed phase modified silica gel (RP-18) chromatography.

The compound Mumbaistatin may be converted to its pharmaceutically acceptable salts and derivatives, such as esters and ethers, and other obvious chemical equivalents, all of which are within the scope of the present invention. The invention also includes all salts and derivatives of Mumbaistatin which are not suitable per se for use as a medicament, but which are useful for the preparation of pharmaceutically acceptable salts and derivatives. The present invention includes Mumbaistatin and all salts and derivatives thereof which exist in all their stereoisomers and tautomeric forms. Salts and derivatives of Mumbaistatin may be prepared by standard methods known to those skilled in the art. Salts such as sodium and potassium salts may be prepared, for example, by treating a Mumbaistatin with a suitable sodium or potassium base. Esters can be prepared, for example, by reacting a carboxylic acid with a mubaistatin in the presence of a reagent such as Dicyclohexylcarbodiimide (DCC), or by treating the mubaistatin with an acylating agent such as an acid chloride. Other methods for preparing esters are described in the literature, for example, J.March, Advanced Organic Synthesis,4th Edition, John Wiley & Sons, 1992.

Esters of Mumbaistatin within the scope of the present invention include molecular lactones, i.e., lactones. Compounds to be mentioned in particular as subject of the invention are the compound designated L970860 and its pharmaceutically acceptable salts and derivatives, including all stereoisomeric and tautomeric forms thereof. Compound L970860 was obtained by treatment of Mumbaistatin with trifluoroacetic acidA lactone. The molecular formula is C₂₈H₁₈O₁₁Characterised by one or more of the following physicochemical and spectral characteristics, e.g. as in FIG. 7¹H NMR spectrum of which¹H NMR spectroscopic data, in FIG. 8¹³Described in C NMR spectra¹³C NMR spectrum data. The lactonization of Mumbaistatin to L970860 can be used to isolate or purify Mumbaistatin.

Ethers can be prepared, for example, by reacting a Mumbaistatin with an alkylating agent under basic conditions. Other methods for preparing ethers are described in the literature, for example, Advanced Organic Synthesis,4th Edition, J.March, John Wiley & Sons, 1992.

Mumbaistatin potently inhibits microsomal glucose-6-phosphate translocase in rat liver. The results of the pharmacological tests are given below. Thus Mumbaistatin and its pharmaceutically acceptable salts and derivatives may be used as a pharmaceutically active ingredient, especially in the treatment of diabetes, more generally in the treatment or prevention of conditions caused by or associated with increased glucose-6-phosphate translocase activity, or in the treatment or prevention of conditions in which decreased glucose-6-phosphate translocase activity is intended. Mumbaistatin and its pharmaceutically acceptable salts and derivatives can be administered to animals, preferably mammals, especially humans, as a medicament alone, in a mixture with each other, and in the form of a pharmaceutical composition capable of enteral or parenteral administration. The invention therefore also relates to a Mumbaistatin and pharmaceutically acceptable salts and derivatives thereof for use as a medicament, and the use of Mumbaistatin and pharmaceutically acceptable salts and derivatives thereof for the preparation of a medicament for reducing the activity of glucose-6-phosphate translocase, in particular for the treatment of diabetes. The invention also relates to a pharmaceutical composition comprising an effective amount of Mumbaistatin and/or one or more pharmaceutically acceptable salts and/or derivatives thereof and a pharmaceutically acceptable carrier.

Mumbaistatin may be administered orally, intramuscularly, intravenously, or by other routes of administration. Pharmaceutical compositions containing mubaistatin or a pharmaceutically acceptable salt or derivative thereof, individually or in combination, can be prepared by: one or more compounds are mixed with one or more pharmaceutically acceptable excipients and/or adjuvants, such as fillers, emulsifiers, lubricants, flavoring agents, colorants or buffer substances, according to standard methods, and the resulting mixture is converted into a suitable pharmaceutical dosage form, such as a tablet, coated tablet, capsule or suspension or solution suitable for enteral or parenteral administration.

Examples of adjuvants and/or excipients which may be mentioned are starch, tragacanth, lactose, talc, agar, polyethylene glycol, ethanol and water. Suitable and preferred parenteral formulations are suspensions or solutions in water. The active substance itself may also be administered in a suitable dosage form, e.g. in capsules, without the use of carriers or diluents. The pharmaceutical composition comprising Mumbaistatin or a pharmaceutically acceptable salt or derivative thereof may further comprise other pharmaceutically active ingredients.

In general, the galenic form and the method of administration and the dosage range applicable in a particular case depend on the species of animal to be treated and on the state of the respective disorder or disease and can be optimized by methods known in the art.

In addition to their use as pharmaceutically active agents and as intermediates in the preparation of derivatives, Mumbaistatin and its pharmaceutically acceptable salts and derivatives are also useful as diagnostic aids, e.g., in vitro diagnostics, and for research purposes in biochemical studies where inhibition of glucose-6-phosphate translocase is required.

The following examples are illustrative of the present invention and are not intended to limit the scope of the invention. Abbreviations: MeOH with methanol; DMSO dimethyl sulfoxide; TFA trifluoroacetic acid

Example 1 isolation of HIL-008003 from soil (a) composition of nutrient isolation medium: corn starch: 10.0g casein: 1.0g of peptone: 1.0g yeast extract: 1.0gK₂HPO₄: 0.5g of agar powder: 13.0g demineralized water: 1.0 liter pH: 7.5(b) soilSheeting and separating

10g of soil collected from the Hiranyakeshi river bed near Amboli, Maharashtra, India was added to 90ml of sterilized demineralized water in a 250ml conical flask, which was shaken on a rotary shaker for 2 hours (220 rpm). Then the soil suspension is diluted in 10 steps to 10-5. From the final dilution, 1ml of the suspension was taken, placed in the center of a sterile glass Petri plate (diameter 15cm), and then about 50ml of the above-mentioned isolation medium supplemented with 25. mu.g/ml of amphotericin B as an antifungal agent was poured thereinto. The medium was cooled to 45 ℃ before pouring and the plates were vortexed thoroughly. The mixture of soil suspension and medium was settled and incubated at 28 ℃ (+ -1 ℃) for 7 days. The Petri plates were observed periodically, and the microorganism HIL-008003(Y-9645974) was isolated from the growing microorganisms.

Example 2 maintenance of culture HIL-008003 was maintained in a medium having the following composition: malt extract: 10.0g yeast extract: 4.0g of glucose: 4.0g of agar powder: 13.0g demineralized water: 1.0 liter pH: 7.0

After the above components were sufficiently dissolved by heating, they were dispensed into test tubes and then sterilized at 121 ℃ for 20 minutes. The test tube was then cooled and solidified in an inclined state. In the growth of HIL-008003, the agar slant was streaked by wire looping and incubated at 28 ℃ (+ -1 ℃) until good growth was observed. Well-grown cultures were stored in a refrigerator at 8 ℃.

Example 3 fermentation of the composition of HIL-008003 seed medium in shake flasks: glucose: 15.0g soybean meal: 15.0g of corn steep liquor: 5.0g NaCl: 5.0g of CaCO₃: 2.0g demineralized water: 1.0 liter pH: 7.0

The above seed medium was dispensed in an amount of 80ml into 500ml Erlenmeyer flasks and autoclaved at 121 ℃ for 20 minutes. The Erlenmeyer flasks were cooled to room temperature, and then each flask was dosed with the well-grown culture of example 2 above as a pileus amountFlasks were inoculated and shaken on a rotary shaker at 240rpm at 27 ℃ (± 1 ℃) for 72 hours to produce seed cultures. Composition of production medium: glucose: 20.0g soybean meal: 10.0g of CaCO₃: 0.2g of cobalt chloride: 0.001g of demineralized water: 1.0 liter pH: 7.0

The production medium was dispensed in an amount of 60ml in 500ml Erlenmeyer flasks and autoclaved at 121 ℃ for 20 minutes. The Erlenmeyer flask was cooled to room temperature and then inoculated with the seed culture described above (1% v/v). Fermentation was carried out on a rotary shaker at 240rpm at 27 ℃ (+ -1 ℃) for 40-48 hours.

Production of Mumbaistatin was monitored by measuring inhibition of glucose-6-phosphate translocase. After harvesting, the culture broth was centrifuged and Mumbaistatin was isolated from the culture filtrate and purified as described in example 5.

Example 4 fermentation of HIL-008003 in a fermentor step 1: preparation of seed cultures in Shake flasks

The seed medium of example 3 was dispensed in an amount of 160 ml into a 1 liter Erlenmeyer flask and autoclaved for 20 minutes. Seed medium was grown in these flasks as described in example 3. Step 2: preparation of seed cultures in fermentors

80 l of seed medium as described in example 3 in a 100 l Marubishi fermenter were sterilized in situ for 45 minutes at 121 ℃. Cooled to 27 ℃. + -. 1 ℃ and inoculated with 4.5 liters of the above seed culture. The fermentation was carried out with the following parameters: temperature: stirring at 27 ℃ (± 0.5 ℃): air exchange at 80 rpm: 50lmp harvest time: 24-hour step 3: large-scale fermentation

Will contain 150ml of antifoam^Desmophen (polypropylene oxide), 700 liters of production medium as described in example 3 in a 1000 liter Marubishi fermenter were sterilized in situ at 121 ℃ for 45 minutes. Cooled to 27 ℃. + -. 1 ℃ and inoculated with 75 liters of the seed culture of step 2. The fermentation was carried out with the following parameters: temperature: stirring at 27 ℃ (± 0.5 ℃): aeration at 50 rpm: at harvest time of 450lmpThe method comprises the following steps: 40-44 hours

The production of this compound was monitored by measuring the inhibition of glucose-6-phosphate translocase. When the fermentation is stopped, the pH of the culture broth is 6.0-7.0. After harvesting, the culture broth was centrifuged and the glucose-6-phosphate translocase inhibitor Mumbaistatin was isolated from the culture filtrate as described in example 5.

Example 5 isolation and purification of Mumbaistatin

About 1000 liters of culture broth were harvested and separated from the mycelium (12kg) by centrifugation. The desired compound Mumbaistatin was found to be present predominantly in the culture filtrate. The culture filtrate (730 liters) was filtered^Diaion HP-20 (28L, 3 ~ 4% v/v) column. The column was washed thoroughly with demineralized water (250 l) and then eluted with a MeOH/water gradient. Thus elution was with 10% MeOH (120L) and 40% MeOH (300L). Each collected fraction was 15 liters. The active eluates obtained with 40% MeOH (15X 16 l) were combined, concentrated under 10-100mmHg at 35 ℃ under reduced pressure and freeze-dried to give 240g of active crude which exhibited the IC₅₀5. mu.g/ml.

The crude product (240g) was passed through a second HP-20 column. The column was washed thoroughly with demineralized water (150 l) and then eluted with a MeOH/water gradient. Thus elution was with 20% MeOH (80L) and 40% MeOH (100L). The collected fractions were 10 liters and 2 liters, respectively. The active eluates (2X 30L) obtained with 40% MeOH were combined, concentrated under 10-100mmHg at 35 ℃ under reduced pressure, lyophilized to give 20g of enriched material showing the IC₅₀At 1. mu.g/ml.

Purifying the enriched material thus obtained by two successive gel permeation chromatographies using^Sephadex LH-20, using different ratios of matrix to gel. The above-mentioned enrichment material was passed through a 4cm X120 cm glass column packed in 4 batches (5 g each)^Sephadex LH-20 (1.5L). The mobile phase was water and the flow rate was maintained at 2.5 ml/min. Each collected fraction was 25 ml. By using^Lichrocart HPLC of a 100 RP-18(250 mm. times.4 mm) column monitored the active eluate using a gradient elution (20 min.) with 0.1% aqueous TFA-CH 3CN at a flow rate of 1 ml/min and monitoring at 270 nm. Combining the active eluates containing the desired components, concentrating under reduced pressure at 35 deg.C under 10-100mm Hg, and freeze drying to obtain 1g of highly enriched material with IC₅₀Is 0.1-0.3 μ g/ml.

The above materials were passed in 2 batches (500 mg each) through a plug in a glass column (2.5 cm. times.110 cm)^Sephadex LH-20 for further purification. The mobile phase was water, and the flow rate was maintained at 0.5 ml/min. Each collected fraction was 6 ml. Fractions were combined according to HPLC (using conditions described above). The active fractions containing the desired compound were combined, concentrated under reduced pressure at 35 ℃ under 10-100mm Hg pressure, and lyophilized to give 160mg of a semi-pure compound, IC₅₀It was 0.06. mu.g/ml.

Finally, by using^Preparative HPLC on a Eurosphere 100C 18,10 μ (250 × 16mm) column purified the semi-pure material using a gradient elution (30 min) from 5% methanol/water to 40% methanol/water. The flow rate was maintained at 6 ml/min and monitored at 270nm to obtain pure Mumbaistatin (70 mg).

Mumbaistatin gives poor quality¹H NMR and¹³c NMR spectrum. Thus, the characteristics of the compound Mumbaistatin according to the invention were mainly determined based on the spectroscopic analysis of the lactone L970860 obtained by treating Mumbaistatin with TFA according to the method described in example 6.

EXAMPLE 6 preparation of lactone L970860

To 70mg of Mumbaistatin in methanol (5ml) was added 0.1% TFA (50ml) and the reaction mixture was heated at 50 ℃ for 1 hour. The mixture is then evaporated to dryness under reduced pressure at 35 ℃ under a pressure of 10-100 mmHg. By using^Preparative HPLC purification of the resulting reaction product on a Eurosphere 100, C18, 10. mu. column (250X 16mm) using 30% CH₃CN/0.1％TFA-80％CH₃Gradient elution (20 min) with CN/0.1% TFA at a flow rate of 6 ml/min and monitoring at 270nm gavePure L970860(55mg) was obtained.

The physicochemical and spectral characteristics of Mumbaistatin and lactone L970860 are summarized in Table 1. Figures 2, 3 and 5-10 show spectral data for the compounds of the present invention. FIGS. 1 and 4 show HPLC chromatograms. The contents of each figure are shown in table 1. TABLE 1

Mumbaistatin L970860 appearance properties: red brown solid solubility: methanol and DMSO in methanol and DMSO melting point: more than 250 deg.C (decomposition temp) > 250 deg.C (decomposition temp. [ alpha ])]_D: -50.0 ° (c0.024, MeOH) -45.0 ° (c0.024, MeOH) high pressure liquid phase retention time: 10.83 minute retention time: 13.08 min chromatography (HPLC): FIG. 1 the ESI-MS: 547(M-H)^- 529(M-H)^-(electrospray ionization mass spectrometry) molecular formula: c₂₈H₂₀O₁₂ C₂₈H₁₈O₁₁UV: FIG. 2 accompanying FIG. 5IR (KBr): FIG. 3 FIG. 6¹H NMR: FIG. 9 FIG. 7

(600MHz,D4-MeOH,27℃) (300MHz,D₆-DMSO)¹³C NMR: FIG. 10 FIG. 8

(150MHz,D₄-MeOH,27℃) (75MHz,D₆-DMSO) pharmacological characterization of Mumbaistatin and lactone L970860

Mumbaistatin with an IC of about 25nM₅₀Strongly inhibit microsomal glucose-6-phosphate translocase in rat liver. In contrast, Mumbaistatin has an IC of about > 100 μ M in microparticles disrupted with detergent₅₀Inhibits phosphatases, which indicates that Mumbaistatin is highly specific for translocase. Furthermore, Mumbaistatin does not affect the activity of the phosphate/pyrophosphate translocase. Mumbaistatin is a reversible, competitive inhibitor of glucose-6-phosphate translocase.

The effect of Mumbaistatin on glucose output was also evaluated in isolated rat hepatocytes. Mumbaistatin inhibits both fructose-induced gluconeogenesis and glucagon-induced glycogenolysis, and in both of these inhibitions, its IC₅₀The values were about 0.3. mu.M and about 0.6. mu.M, respectively.

L970860 IC at about 1.8. mu.M₅₀Inhibit microsomal glucose-6-phosphate translocase in rat liver.

Claims (9)

1. Mumbaistatin, a compound of formula C and pharmaceutically acceptable salts and derivatives thereof, in all stereoisomeric and tautomeric forms₂₈H₂₀O₁₂Characterized in that it¹H NMR spectra (FIG. 9) and¹³c NMR spectrum (FIG. 10).

2. Obtained by the process described below, in all its stereoisomers and tautomeric forms, of formula C₂₈H₂₀O₁₂The compound MumbaistatinAnd pharmaceutically acceptable salts and derivatives thereof: streptomyces species HIL-008003(DSM 11641) is cultured under aerobic conditions in a nutrient medium containing carbon and nitrogen sources and then isolated and purified by conventional methods.

3. Lactone L980860 in all its stereoisomers and tautomers and its pharmaceutically acceptable salts and derivatives, having the formula C₂₈H₁₈O₁₁Characterized in that it¹H NMR spectra (FIG. 7) and¹³c NMR spectrum (FIG. 8).

4. A process for the preparation of Mumbaistatin or a salt or derivative thereof according to any one of claims 1-3, comprising culturing the microorganism streptomyces HIL-008003(DSM 11641) under aerobic conditions in a nutrient medium containing a carbon source and a nitrogen source, followed by isolation and purification by conventional methods.

5. Streptomyces HIL-008003(DSM 11641).

6. Mumbaistatin according to any one of claims 1-3 or a pharmaceutically acceptable salt or derivative thereof for use as a medicament.

7. A pharmaceutical composition comprising an effective amount of the mubaistatin of any of claims 1-3, or a pharmaceutically acceptable salt or derivative thereof, and a pharmaceutically acceptable carrier.

8. Mumbaistatin according to any one of claims 1-3 or a pharmaceutically acceptable salt or derivative thereof for use as a glucose-6-phosphate translocase inhibitor.

9. Mumbaistatin or a pharmaceutically acceptable salt or derivative thereof according to any one of claims 1-3 for use in the treatment of diabetes.