MXPA00011165A - Mumbaistatin, a process for its production and its use as a pharmaceutical - Google Patents

Abstract

The present invention relates to a compound named Mumbaistatin which is obtainable by cultivation of the microorganism HIL-008003 (DSM 11641), and to its pharmaceutically acceptable salts and derivatives. Mumbaistatin is a glucose-6-phosphate translocase inhibitor and can be used in the treatment of diabetes mellitus. The present invention further relates to a process for the production of Mumbaistatin, to the microorganism HIL-008003 (DSM 11641), to the use of Mumbaistatin and its pharmaceutically acceptable salts and derivatives as pharmaceuticals, in particular to their use in the treatment of diabetes mellitus, and to pharmaceutical compositions comprising Mumbaistatin or a pharmaceutically acceptable salt or derivative thereof.

Description

MUMBAISTATIN. A PROCESS FOR YOUR PRODUCTION AND YOUR EMPLOYMENT AS A PHARMACEUTICAL PRODUCT The present invention relates to a compound named Mumbaistatin, which can be obtained by culturing the microorganism HIL-008003 (DSM 11641), and its pharmaceutically acceptable salts and derivatives thereof. Mumbaistatin is an inhibitor of the translocase of glucose-6-phosphate and can be used in the treatment of diabetes mellitus. The present invention also relates to a process for the production of Mumbaistatin, to microorganisms HIL-008003 (DSM 11641), to the use of Mumbaistatin and its pharmaceutically acceptable salts and derivatives, as pharmaceutical products, in particular to its use in the treatment of diabetes mellitus, and pharmaceutical compositions comprising Mumbaistatin or a pharmaceutically acceptable salt or derivative thereof. The increased rate of hepatic glucose production is a general characteristic of diabetes mellitus. In particular, there is a strong correlation between fasting plasma glucose level in non-insulin-dependent diabetes mellitus (NIDDM) and hepatic glucose production. The two ways in which glucose is produced in the liver are the my • iiWítittÉtr gluconeogenesis and glycogenolysis. The terminal stages in both ways are catalyzed by glucose-6-microsomal phosphatase, a key enzyme in the homeostatic regulation of blood glucose levels. The level of this enzyme has also been known to rise in both the experimental and pathological conditions of diabetes. The interference with this enzyme system, therefore, should result in a reduced production of hepatic glucose. Glucose-6-phosphatase is a multi-component system comprised of at least three functional activities: a glucose-6-phosphate translocase (TI), a glucose-6-phosphate phosphohydrolase and a phosphate / pyrophosphate translocase (TI) . The translocase of glucose-6-phosphate facilitates the transport of glucose-6-phosphate in the lumen of the endoplasmic reticulum (ER). Phosphohydrolase, with its active site located on the lumenal surface of the ER, hydrolyzes glucose-6-phosphate and releases glucose and phosphate into the lumen. While the flow of phosphate is facilitated by the phosphate / pyrophosphate translocase, the exact mechanism of glucose flow is not yet clear. The high degree of substrate specificity of the glucose-6-phosphate translocase makes this a potential target for pharmacological intervention in the treatment of diabetes mellitus. So, among the phosphates . aafafcj. '. * - .. of sugar that occur physiologically, only glucose-6-phosphate is transported by the translocase. In contrast, phosphatase is not specific and it is known to hydrolyze a variety of organic phosphate esters. A series of non-specific glucose-6-phosphatase inhibitors have been described in the literature, for example phlorrhizin (J. Biol. Chem. 242, 1955-1960 (1967)), 5, 5'-dithio-bis- 2-nitrobenzoic acid (Biochem, Biophys, Common Res., 48, 694-699 (1972)), 2, 2'-diisocytiocyanato-stilbene and 2-isothiocyanato-2'-acetoxy-stilbene (J. Biol. Chem. 255, 1113-1119 (1980 = The first inhibitors, therapeutically usable, of the glucose-6-phosphatase system were proposed in the European patent applications EP-A-587 087 and EP-A-587 088. The Kodaistains A, B, C and D described in the international patent publication No. W098 / 47888, are the first inhibitors of the translocase of glucose-6-phosphate from microbial sources.It has now been found that from a different microbial source, a novel compound with High inhibitory activity of the glucose-6-phosphate translocase can be obtained, which has been named Mumbaistatin. an agent named Mumbaistatin, which has the molecular formula of C28H20O12, and which is characterized by one or more physical-chemical and spectral properties given below, such as its data NMR spectroscopies, illustrated in the NMR spectrum in FIG. 9 and their 13 C NMR spectroscopic data, illustrated in the 13 C NMR spectrum in FIG. 10, and their pharmaceutically acceptable salts and derivatives thereof, like esters, ethers and obvious chemical equivalents, which include all isomeric forms and all tautomeric forms. The Mumbaistatin has a novel structure, hitherto unreported, that belongs to the class of the quinone of the compounds. A research of the chemical extract literature that uses search keys of the molecular formula established that the Mumbaistatin is a novel compound. No other compound represents the structural characteristics of Mumbaistatin.

Zellkulturen GmbH), Mascheroder Weg IB, D-38124, Braunch eig, Germany and has been given accession number DSM 11641. Thus, the present invention also provides a process for the production of the novel compound named Mumbaistatin and its salts and derivatives pharmaceutically acceptable, of Streptomyces, species HIL-008003, its mutants and variants. This process comprises carrying out culture No. HIL-008003, its mutants or variants, under aerobic conditions, in a nutrient medium, containing one or more carbon sources, and one or more sources of nitrogen and, optionally, salts inorganic nutrients and / or trace elements, followed by isolation of the compound and its purification in a customary manner. The nutrient medium preferably contains carbon sources, nitrogen and inorganic nutrient salts and, optionally, trace elements. The carbon sources are, for example, starch, glucose, sucrose, dextnna, fructose, molasses, glycerol, lactose or galactose, preferably glucose. The sources of nitrogen are, for example, soy flour, peanut flour, yeast extract, beef extract, peptone, tryptone, malt extract, macerated corn liquor, gelatin or casamino acids, preferably the soy flour and macerated corn liquor.

The inorganic nutrient salts and the trace elements are, for example, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, cobalt chloride, calcium 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 temperatures between 25 and 30 ° C and at a pH between 6.0 and 8.0. Preferably, culture No. HIL-008003 is carried out at 27 ° C (± 1 ° C) and at a pH of 7.0. The fermentation of HIL-008003 is preferably carried out for 40 to 70 hours, when an optimum yield of the Mumbaistatin of the present invention is obtained. It is particularly preferred to carry out the fermentation for approximately 40 to 48 hours, under submerged conditions, for example, in agitator bottles, as well as in laboratory fermenters. If desired, ® Desmophen (polypropylene oxide) can be used as an antifoaming agent in the fermenters. The progress of fermentation and Mumbaistatin formation can be detected by measuring the inhibition of glucose-6-phosphate translocase activity in rat liver microsomes untreated and disturbed with Triton X-100, in microtiter plates, the room temperature, using a colorimetric assay, as described in Methods in Enzymology 174, 58-67 (1989), with some modifications. In the resulting culture broth, Mumbaistatin is present primarily in the culture filtrate and can thus be recovered by extraction of the culture filtrate with a water immiscible solvent, such as, for example, ethyl acetate, dichloromethane, chloroform or butanol, at a pH of 5 to 8, or by hydrophobic interaction chromatography. using polymeric resins, such as ®Diaion HP-20 (Mitsubishi Chemical Industries Limited, Japan), OAmberlite XAD (Rohm and Haas Industries, USA) or activated carbon or by ion exchange chromatography, at a pH of 5 to 8. The preferred method is adsorption on (SSDiaion HP-20, followed by desorption of the compound, using diluents, such as water , methanol, acetone, acetonitrile, n-propanol, isopropanol, or combinations thereof The concentration and lyophilization of the active eluate provides the crude compound The crude material can be further purified using any of the following techniques: by normal phase chromatography using alumina or silica gel as the stationary phase and diluents, such as ethyl acetate, chloroform, methanol or combinations thereof; by reverse phase chromatography, using the reverse phase silica gel, as the gel dimethyloctadecylsilylsilicate, also named RP-18, or dimethyloctyl silyl silica gel, also named RP-8, as the stationary phase, and diluents, such as water, regulators, such as phosphate, acetate, citrate (pH 2-8) , and organic solvents, such as methanol, acetonitop, acetone, tetrahydrofuran, or combinations of these solvents; by gel permeation chromatography, using resins, such as © Sephadex LH-20 (Pharmacia Chemical Industries, Sweden), TSKgel © Toypearl H -40F (TosoHaas, Toso Corporation, Japan) in solvents, such as methanol, chloroform acetone , ethyl acetate, or combinations of these solvents, or the © Sephadex G-10 and G-25 in water; or by countercurrent chromatography, using a biphasic diluent system, obtained from two or more solvents, such as water, methanol, ethanol, isopropanol, n-propanol, tetrahydrofuran, acetone, acetonitrile, methylene chloride, chloroform, ethyl acetate, petroleum ether, benzene and toluene. These techniques can be used repeatedly, or a combination of different techniques can be used. The preferred method is chromatography on © Toypearl, followed by reverse phase modified silica gel (RP-18). The Mumbaistatin compound can be converted into pharmaceutically acceptable salts and derivatives, such as esters and ethers and other obvious chemical equivalents, which ? . they are all covered by the present invention. The invention also covers all salts and derivatives of Mumbaistatin, which by themselves are not suitable for use as pharmaceuticals, but which can be used as intermediates in the preparation of pharmaceutically acceptable salts and derivatives. The invention covers Mumbaistatin and all its salts and derivatives in all its stereoisomeric and tautomeric forms. Salts and derivatives can be prepared by standard procedures known to those skilled in the material Salts, such as those of sodium and potassium, for example, can be prepared by treating Mumbaistatin with suitable bases of sodium or potassium. The esters can be prepared, for example, by the reaction of Mumbaistatin 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 the esters are given in the literature, for example, in J. March, Advanced Organic Synthesis, 4th Edition, John Wiley & Sons. 1992. Mumbaistatin esters, covered by the present invention, include intramolecular esters, ie, lactoses. A compound specifically mentioned as subject of the present invention is the compound which has been named L970860 and the pharmaceutically acceptable salts and derivatives thereof, in all its stereoisomeric and tautomeric forms, The compound L 970860 is a lactone obtainable by the treatment of Mumbaistatin with trifluoroacetic acid. It has the molecular formula C2ßH? ßOn, and is characterized by one or more of its physical-chemical and spectral properties given below, such as the spectroscopic data of the lH NMR illustrated in the spectrum of? NMR in Figure 7, and its spectroscopic data of 13C NMR, illustrated in the spectrum of l3C NMR in Figure 8. The lactonization of Mumbaistatin to give L970860 can be used in order to isolate or purify Mumbaistatin. The ethers can be prepared, for example, from treatment of diabetes mellitus, and, more generally, in the treatment or prophylaxis of conditions that are caused by, or associated with, an elevated activity of the glucose-6-phosphate translocase, or of conditions in which it is attempted to reduce the activity of the glucose-6-phosphate translocase. Mumbaistatin and its pharmacologically acceptable salts and derivatives can be administered to animals, preferably to mammals, and in particular to humans, as the pharmaceutical products themselves, in mixtures with others and in the form of pharmaceutical compositions, which allow enteral or parenteral administration. Therefore, the present invention also relates to Mumbaistatin and its pharmaceutically acceptable salts and derivatives, for use as pharmaceuticals and for the use of Mumbaistatin and its pharmaceutically acceptable salts and derivatives in the production of drugs to reduce the activity of the drug. glucose-6-phosphate tanslocase, in particular in the production of drugs for the treatment of diabetes mellitus. The present invention further relates to pharmaceutical compositions containing an effective amount of Mumbaistatin and / or one or more of its pharmaceutically acceptable salts and / or derivatives, together with a pharmaceutically acceptable carrier.

Mumbaistatin can be administered orally, intramuscularly, intravenously or by any other mode of administration. Pharmaceutical compositions containing Mumbaistatin or its pharmaceutically acceptable salts or derivatives, in single form or in combinations, can be prepared according to standard techniques, by mixing the compounds with one or more pharmaceutically acceptable excipients and / or auxiliaries, such such as, for example, fillers, emulsifiers, lubricants, agents that hide flavors, colorants or regulatory substances, and converting the mixture into a suitable pharmaceutical form, such as, for example, tablets, coated tablets, capsules or a suspension or solution suitable for Enteral or parenteral administration. Examples of auxiliaries and / or excipients, which may be mentioned, are starch, gum tragacanth, lactose, talc, agar-agar, polyglycols, ethanol and water.

As is customary, the galenic formulation and the method of administration, as well as the dosage, vary in an appropriate manner to specific cases, depending on the species to be treated and the status of the respective disease or condition, and can be optimize using methods known in the art. Apart from the use as pharmaceutically active ingredients and as intermediates in the production of derivatives, Mumbastatin and its salts and derivatives can also be used as adjuvants for diagnostic purposes, for example, in in vitro diagnostics, and for research purposes. in biochemical investigations in which an inhibition of the translocase of glucose-6-phosphate is convenient. The following examples are illustrative of the present invention, but not limiting of its scope. Abbreviations: MeOH, methanol; DMSO, dimethylsulfoxide, TFA, tpfluoroacetic acid. twenty ^^ - aS-í -'- ^^ - *., * Example 1 Isolation of soil culture HIL-008003 (a) Composition of nutrient isolation medium Corn starch 10.0 g Casein 1.0 g Peptone 1.0 g Yeast extract 1.0 g K2HP04 0.5 g agar powder 13.0 g 1.0 liter demineralised water pH 7.5 (b) Soil layer and insulation 10 g of soil collected from the bed of the Hiranysakeshi River, near Amboli, Maharashtra, India, were added to 90 ml of sterilized demineralized water, in a 250 ml Erlenmeyer flask, which was then shaken for 2 hours on a rotary shaker (220 rpm). The previous soil suspension was then serially diluted in stages, from 10 to 10 ~ 5. From the last dilution, 1 ml of the suspension was placed in the center of a sterile glass Petri dish (15 cm in diameter), in which then approximately 50 ml of the previous isolation medium, supplemented with 25 μg, were drained. / ml of amphotericin B, as an antifungal agent. The medium was cooled to 45 ° C, before emptying and the plate was completely rotated.

The mixture of soil suspension and medium was allowed to settle and incubated at 8 ° C (± 1 ° C) for 7 days. The petri dish was periodically observed and the culture of microorganisms No. HIL-008003 (culture No. Y-9645974) was isolated from the growing microorganisms.

Example 2 Culture Maintenance HIL-008003 Cultivation No. HIL-008003 was maintained in the following medium: Malt extract 10.0 g Yeast extract 4.0 g Glucose 4.0 g Agar powder 13.0 g Demineralized water 1 liter pH 7.0 After completely dissolving the ingredients, mentioned above, by heating, were distributed in test tubes and then sterilized at 121 ° C for 20 minutes. The test tubes were then cooled and allowed to solidify in an inclined position. The inclined agar tubes were marked with growth of culture No. HIL-008003 by a wire loop and incubated at 28 ° C (± 1 ° C) until good -frpíi '- tf ~ "~ - ° ~ * increase. The cultures grown in the cavities were stored in a refrigerator at 8 ° C.

EXAMPLE 3 Fermentation of the crop HIL-008003 in shaker flasks Composition of the planting medium: Glucose 15.0 g Soybean meal 15.0 g Macerated corn liquor 5.0 g NaCl 5.0 g CaC03 2.0 g Demineralized water 1.0 liter pH 7.0 The above planting medium was distributed in quantities of 80 ml in 500 ml Erlenmeyer flasks, and autoclaved at 121 ° C for 20 minutes. The flasks were cooled to room temperature and each flask was then inoculated with a complete cycle of the cavity growth culture, mentioned above, of Example 2, and stirred on a rotary shaker for 72 hours at 240 rpm and at 27 ° C ( ± 1 ° C) to give the sow crop.

Composition of the production medium: GBtt-5-f.-s. • sMßBl áS fekz. " . _aa £ a, Glucose 20.0 g Soy flour 10.0 g CaCO3 0.2 g Cobalt chloride 0.001 g Demineralized water 1 liter pH 7.0.

The production medium was distributed in quantities of 60 ml in 500 ml Erlenmeyer flasks and autoclaved at 121 ° C for 20 minutes. The flasks were cooled to room temperature and then inoculated with the aforementioned seed culture (1% volume / volume). The fermentation was carried out on a rotary shaker at 240 rpm, and at a temperature of 27 ° C (± 1 ° C) for 40 to 48 hours. The production of Mumbaistatin was monitored by measuring the inhibition of the translocase of glucose-6-phosphate. After harvesting, the culture broth was centrifuged and the Mumbaistatin was isolated from the culture filter and purified as described in Example 5.

Example 4 Fermentation of the crop HIL-008003 in fermenters Step 1: Preparation of the seed culture in vibration flasks. The culture medium of Example 3 was distributed in 160 ml quantities in 1 liter Erlenmeyer flasks and autoclaved for 20 minutes. The seed culture grew in these flasks, as described in Example 3. Step 2: Preparation of the seed culture in the fermentor 80 liters of the seed medium, as described in Example 3, in a Marubishi fermenter of 100 liters , they were sterilized in-house for 45 minutes at 121 ° C, cooled to 27 ° C ± 1 ° C and planted with 4.5 liters of the aforementioned seed culture. The fermentation was carried out with the following parameters: Temperature 27 ° C (± 0.5 ° C) Agitation 80 rpm Aeration 50 Ipm Harvest time 24 hours. a - * - .. **** * - .. ^ M ^ I? ÍHIÍ nrMM lllT -? P * Step 3: Large scale fermentation 700 liters of the production medium, as described in Example 3, in a 1000 liter Maruhishi fermenter, together with 150 ml of © Desmophen (polypropylene oxide), as an antifoaming agent, were sterilized In the case of 45 mininitos, at 121 ° C, they were cooled to 27 ° C ± 1 ° C and planted with 75 liters of the sowing crop from Stage 2. The fermentation was carried out with the following parameters: Temperature 27 ° C (± 0.5 ° C) Agitation 50 rpm Aeration 450 Ipm Harvest time 40-44 hours The production of the compound was monitored by measuring the inhibition of the translocase of glucose-6-phosphate. When the fermentation was discontinued, the pH of the culture broth was 5.0 to 7.0. This culture broth was centrifuged after harvesting and the Mumbaistatin, glucose-6-phosphate translocase inhibitor was isolated from the culture filtrate, as described below in Example 5.

Example 5 Isolation and Purification of Mumbaistatin Approximately 1000 liters of the culture broth were harvested and separated from the mycelium (12 kg) by centrifugation. The desired compound, Mumbaistatin, was found to be present primarily in the culture filtrate. This culture filtrate (730 liters) was passed through a column of © Diaion HP-20 (28 liters, 3-4 volume / volume). The column was washed thoroughly with water demineralized (250 liters) and then diluted with a MeOH step gradient in water. Thus, the dilution was made with 10% MeOH (120 liters) and 40% MeOH (300 liters). The fractions were collected in batches of 15 liters. The active eluates (15 x 16 liters) obtained with 40% MeOH were combined, concentrated under reduced pressure of 10 to 100 mm Hg at 35 ° C and lyophilized, to supply 240 g reduced pressure of 10-100 mm Hg at 35 ° C and lyophilized to deliver 20 g of enriched material, showing an IC5o of 1 μg / ml. The enriched material thus obtained was purified by two successive gel permeation chromatographies. Thus the above enriched material was separately passed in 4 batches of 5 g each, through © Sephadex LH-20 (1.5 liters), packed in a glass column of 4 cm x 120 cm. The mobile phase was water and the flow rate was maintained at 2.5 ml / min. The fractions were collected in a size of 25 ml. Active eluates were monitored by HPLC chromatography on a column of © Lichrocart 100 RP-18 (250 mm x 4 mm), using a gradient of 0.1% aqueous TFA to CH3CN in 20 min, at a flow rate of 1 ml / min and detection at 270 nm. Active eluates with the desired component were pooled and concentrated under reduced pressure of 10 to 100 mm Hg, at 35 ° C, and lyophilized to obtain 1 g of highly enriched material with an IC 50 of 0.1 to 0.3 μg / ml. The previous material was further processed in 2 batches of 500 mg each, passing through © Sephadex LG-20, packed in a glass column (2.5 x 110 cm). The mobile phase was water and the flow rate was maintained at 0.5 ml / min. The fractions were collected in a size of 6 ml. The fractions were grouped based on chromatography HPLC (with the aforementioned conditions). The active fractions with the desired compound were pooled, concentrated under reduced pressure of 10 to 100 mm Hg, at 35 ° C, and lyophilized to obtain 160 mg of a semi-pure compound, having an IC 50 of 0.06 μg / ml . Finally, the semi-pure material was purified by preparative HPLC chromatography on a column © Eurosphere 100 C 18, 10 μ (250 x 16 mm), using a gradient of 5% methanol in water, 40% methanol in water, in 30 minutes. The flow rate was maintained at 6 ml / min and the detection was 270 nm, to obtain Mumbaistatin (70 mg). Mumbaistatin gave poor quality of the NMR and 13C NMR spectra. The characterization of the main compound, Mumbaistatin, was therefore based primarily on the spectral analysis of lactone L970860, which was obtained by the treatment of Mumbaistatin with TFA, using the method described in Example 6.

Example 6 Preparation of lactone L970860 To 70 g of Mumbaistatin, dissolved in methanol (5 ml), 0.1% of TFA was added, and the reaction mixture was heated for 1 hour at 50 ° C. The mixture was then evaporated under reduced pressure of 10 to 100 mm Hg, at 35 ° C, until the dryness. The reaction product, thus obtained, was purified by preparative HPLC chromatography, on a column © Eurosphere 100, C18, 10μ (250 mm x 16 mm), using a gradient of 30% CH 3 CN in 0.1% 80% TFA % CH3CN in 0.1% TFA in 20 minutes, at a flow rate of 6 ml / minute and 270 nm detection to give pure L970860 (55 mg). The physical-chemical and spectral properties of Mumbaistatin and lactone L970860 are summarized in Table 1. The spectroscopic data of the compounds are given in Figures 2, 3 and 5 to 10 of the drawings. Figures 1 and 4 show the chromatograms of the HPLC. The contents of the individual drawings are indicated in Table 1. Table 1 Table 1 (Continued) Pharmacological Characterization of Mumbaistatin and Lactone L970860 Mumbaistatin potently inhibits the activity of the microsomal glucose-6-phosphate translocase of rat liver, with an IC50 of approximately 25 nM. In contrast, Mumbaistatin inhibits phosphatase activity in microsomes disrupted with detergents with an IC 50 of about > 100 μM, which indicates a high degree of specificity for the translocase. In addition, Mumbaistatin does not affect the activity of phosphate tanslocase / «* **. ».. - 111 -" rrriimia-fitilrTi pyrophosphate. Mumbaistatin is a reversible and competitive inhibitor of the glucose-6-phosphate translocase. Mumbaistatin was also evaluated in rat hepatocytes isolated in its effect on glucose production.

It inhibits both gluconeogenesis induced by fructose and glycogenolysis induced by glucagon, with IC50 values of approximately 0.3 uM and 0.6 μM, respectively. L970860 inhibits the activity of the microsomal glucose-6-phosphate translocase of rat liver, with an IC 50 of about 1.8 μM. - * - ~ - ~ «=" - - * --- "*" • -

Claims (9)

1. CLAIMS 1. Mumbaistatin, a compound of the molecular formula: C28H20O12, characterized by its H NMR spectrum (Figure 9) and its 13 C NMR spectrum (Figure 10) and its pharmaceutically acceptable salts and derivatives, in their stereoisomeric and tautomeric forms.
2. 2. Mumbaistatin, a compound of the molecular formula: C28H20O12, which can be obtained by culturing the microorganism species Streptomyces HIL-008003 (DSM 11641), under aerobic conditions, in a nutrient medium containing carbon and nitrogen sources , followed by isolation and purification, in a customary manner, and its pharmaceutically acceptable salts and derivatives, in all its stereoisomeric and tautomeric forms.
3. 3. The lactone, L970860, a compound of the molecular formula: CzßH? ßOu, cauterized by its 1 H NMR spectrum (Figure 7) and its 13 C NMR spectrum (Figure 8), and its pharmaceutically acceptable salts and derivatives, in all its stereoisomeric and tautomeric forms.
4. 4. A process for the production of Mumbaistatin, as claimed in claim 1 or claim 2, or lactone L970860, as claimed in claim 3, or an al or derivative of Mumbaistatm or lactone, comprising the culture of the species of Streptomyces microorganism HIL-008003 (DSM 11641), under aerobic conditions, in a nutrient medium, containing carbon and nitrogen sources, followed by isolation and purification of Mumbaistatin, in a customary manner and, optionally, converted to lactone L970860, or a salt or derivative of Mumbaistatin or lactone.
5. 5. Streptomyces species HIL-008003 (DSM 11641).
6. 6. The Mumbaistatin, as claimed in claim 1 or claim 2, or the lactone L970860, as claimed in claim 3, or a pharmaceutically acceptable salt or derivative of Mumbaistatin or lactone, for use as a pharmaceutical product.
7. A pharmaceutical composition, comprising an effective amount of Mumbaistatin, as claimed in claim 1 or claim 2, or lactone L970860, as claimed in claim 3, or a pharmaceutically acceptable salt or derivative of Mumbaistatin or the lactone, and a pharmaceutically acceptable carrier.
8. 8. Mumbaistatin, as claimed in claim 1 or claim 2, or lactone L970860, as claimed in claim 3, or a pharmaceutically acceptable salt or derivative of Mumbaistatin or lactone, for use as an inhibitor of the translocase of glucose-6-phosphate.
9. 9. Mumbaistatin, as claimed in claim 1 or claim 2, or lactone L970860, as claimed in claim 3, or a pharmaceutically acceptable derivative, or Mumbaistatin or lactone, for use in the treatment of diabetes mellitus.