Title of Invention

CYCLIPOSTINS, A METHOD FOR THEIR PRODUCTION AND THE USE OF THE SAME

Abstract

The invention relates to compounds of the general formula (I), wherein R?1¿, R?2¿, E, X¿1?, X¿2? and X¿3? have the definitions in this application, obtained by the cultivation of the $i(Streptomyces) species HAG 004107 (DSM 13381) and to the physiologically compatible salts and chemical equivalents of said compounds. The invention also relates to a method for producing the cyclipostins and their physiologically compatible salts and chemical equivalents as medicaments, in particular as inhibitors of lipases, and to pharmaceutical preparations containing cyclipostin or a physiologically compatible salt or equivalent thereof.

Full Text

Description Cyclipostins, process for their preparation and use thereof. The invention relates to novel compounds, called cyclipostins, obtainable by culturing Streptomycin species HAG 004107 (DSM 13381), and their physiologically tolerable salts and chemical equivalents. The invention furthermore relates to a process for the preparation of the cyclipostins, the microorganism HAG 004107 (DSM 13381), the use of the cyclipostins and their physiologically tolerable salts and chemical equivalents as pharmaceuticals, in particular as inhibitors of lipases, and pharmaceutical preparations which contain cyclipostin or a physiologically tolerable salt or equivalent thereof A disease which can be treated particularly advantageously with lipase inhibitors is the sugar disease diabetes mellitus. Diabetes mellitus is a condition which is characterized by increased blood sugar concentrations on account of chronic metabolic disorders. The metabolic disorders are based on an insulin deficiency or reduced insulin action. The lacking insulin action leads to defective utilization by the body cells of the glucose absorbed in the blood. On account of this and owing to neogenesis of glucose from proteins (gluconeogenesis) there is a rise in the blood glucose level. Moreover, in the case of decreased insulin action in the fatty tissue the insulin-antagonistic hormones, such as glucagon, lead to increased lipolysis and thus to raised fatty acid concentrations in the blood. Ketoacidosis occurs, i.e. the increased formation of ketone bodies (acetic acid, (3-hydroxybutyric acid, acetone). Under acute conditions, the extent of the biochemical dysregulation is life-threatening and leads, untreated, to diabetic coma and finally to rapid death. Diabetes belongs to the most frequent chronic metabolic disorders of man and it is estimated that up to more than 3% of the population have a diabetic or prediabetic disposition and are thus acutely threatened. There is therefore a great need for agents for the treatment or cure of diabetes mellitus. Diabetes is treated by insulin administration and in adult-onset diabetes, the so-called no insulin-dependent (NIDDM) or type II diabetes, sulfonylureas are first administered. The principle of action of the sulfonylureas is a proliferation of the secretion of insulin of the B-cells in the pancreas in order thus to compensate for the hormone deficiency or the insulin resistance. On progression of the condition, however, insulin also has to be employed. The action of insulin can be summarized in the following way. This peptide hormone lowers the concentration of the glucose in the blood and leads to an increase in anabolic processes and simultaneously to an inhibition of catabolic processes: It increases the glucose transport in the body cells, It increases the glycogen formation in the liver and in the muscles, It inhibits lipolysis, It increases the absorption of fatty acids into the fatty tissue and It increases the absorption of amino acids into the body cells and protein synthesis. One of the strongest effects of insulin is the inhibition of lipolysis. In the case of type II diabetics, this regulation of lipolysis is no longer effective and an increased level of free fatty acids in the blood occurs. Free fatty acids in the blood stimulate the gluconeogenesis in the liver and decrease the utilization of glucose in the skeletal muscles. Lipolysis, that is the release of fatty acids by the so-called hormone-sensitive lipase (HSL), which is found in the fat cells and is inhibited by insulin by a phosphorylation cascade, is controlled. Inhibitors, that is inhibitors of HSL, would therefore be desirable which stimulate the action of insulin and are able to lower the blood lipid level. Such agents are suitable for the treatment of type II diabetics to control the lipid metabolism, but applications would also be possible in other storage disorders. For these reasons, novel inhibitors of HSL and other lipases are urgently needed and therefore sought. It has surprisingly been found that the microorganism strain Streptomycin species HAG 004107, DSM 13381, is able to form highly active novel lipase inhibitors which inhibit the hormone-sensitive lipase even in very low concentrations. The novel natural compounds are organophosphates which consist of a double ring system (bicycle) and a substituted carbon chain and specifically inhibit the lipases. The ring structure has been described for the first time - only with a methyl group instead of the carbon chain - as an acetylcholine esterase inhibitor, CGA 134 736, by R. Neumann & H. H. Peter in Experiential, Volume 43, pages 1235-1237, 1987 and later the same compound, designated as cyclophostin, by T. Kuroki et al. in J. Antibiotics, 46, 1315-1318, 1993. This structurally related compound has no selective lipase-inhibiting properties. The previously known substances have disadvantages which are manifested In an unsatisfactory level of action, high toxicity and/or undesirable side effects. The present invention therefore relates to compounds of the formula I 1.14 -S-Ca-Ce-aikenyi, in which alkenes is linear or branched, 1.15 halogen in which the substituents 1.1 to 1.15 can also be additionally substituted, 2. - [-aryl-(CH2)n]m, in which [-aryl-(CH2)n]m is unsubstituted or mono- or disubstituted as described in 1.1 to 1.15 and n and m independently of one another are integers zero, 1, 2 or 3; 1. alkyl, in which alkyl is unsubstituted or mono- or disubstituted as described in 1.1 to 1.15, 2. -alkenyl, in which alkenyl is unsubstituted or mono- or disubstituted as described in 1.1 to 1.15, or 3. C2-C6-alkynyl, in which alkynes is unsubstituted or mono- or disubstituted as described in 1.1 to 1.15, E is a phosphorus (P) or sulfur (S) atom, Xi, X2 and X3 independently of one another are 1. -0-, 2. -NH-, 3. -N=. 4. -S-, or 5. -CH2-, and –CHR in all their stereochemical forms and mixtures of these forms in any ratio, and their physiologically tolerable salts and chemical equivalents. R^ preferably has a chain length of 6 to 24 carbon atoms, very preferably of 10 to 18 carbon atoms. The chain can be saturated, e.g. -alkyl, in which alkyl can be linear or branched, or unsaturated, e.g. -alkenyl or -alkynyl, in which alkenyl or alkynyl is linear or branched. Rib can be unsubstituted or identically or differently mono- or disubstituted by groups 1.1 to 1.15, as described above. The substitutents on the carbon atoms 8' to 16' are preferred and the positions 10' to 14' are particularly preferred. The substituents 1.1 to 1.15 can also be additionally substituted by one or more groups selected from: alcohol, baldheaded, acetyl, metal, ether, carboxyl, ester, amino, nitrile, nitro, oxime, oxime ether and halogen. A carboxylic carbon chain having 2 to 30 carbon atoms is a chain consisting of 2 to 30 carbon atoms with one or more, preferably with one, with two or with three ring systems, which preferably in each case consist of 4, 5, 6 or 7 carbon atoms. The rings can be mono-, di- or tricyclic, preferably monocyclic, and be positioned at the beginning, in the center and/or at the end of the carbon chain. The carbocycles can be aliphatic or of aromatic nature. Examples are: substituted biphenyl’s or alkylbenzenes. A heterocyclic carbon chain having 2 to 30 carbon atoms is a chain consisting of 2 to 30 carbon atoms having one or more, preferably having one to three, ring systems in which at least one carbon atom is replaced by heteroatoms, such as O, S or N. These rings can be mono-, di- or tricyclic, preferably monocyclic, and can be positioned at the beginning, in the center and/or at the end of the carbon chain. They can preferably be 4-, 5-, 6- or 7-membered rings, which are aliphatic or of aromatic nature. Examples are: alkyl piperidines, which are substituted or unsubstituted. Aryl is an aromatic ring or ring system having 6 to 14, preferably 6 to 10, carbon atoms, such as optionally substituted alkylphenol or alkylnaphthol. Halogen is chloride, bromide, fluoride or pseudohaiides, such as cyanide (nitrile). - is a straight-chain or branched alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl, i-propyl, tert-butyl and hexyi. On its own the ring system contains two asymmetrically substituted atoms, the carbon atoms 3 and the phosphorus atom. Both atoms can be present in the R or in the S configuration. It has surprisingly been found that the strain Streptomyces species HAG 004107, DSM 13381, is able in each case to form a number of stereoisomer of the compounds of the formula I, that is the strain synthesizes compounds in which the atoms C3 and P independently of one another can assume the R or the S configuration. Isomers having the spatial form on carbon(3) in the R configuration and on phosphorus in the S configuration occur in increased amount in cultures of the Sfrepfomyces species HAG 004107, DSM 13381. Formula I A: In addition, however, cyclipostins having other configurations, such as (R,R), (S,S) or (S,R) are also formed, which surprisingly also have considerable lipase-inhibitory actions. The compound of the formula I or of a physiologically tolerable salt or chemical equivalent thereof is reparable by fermenting the microorganism Streptomyces species HAG 004107, DSM 13381, or one of its variants or mutants under suitable conditions in a culture medium until one or more compounds of the formula I accumulate in the culture medium and then isolating them from the culture medium and optionally converting them into chemical equivalents and physiologically tolerable salts. The cyclipostins according to the invention can be produced by Actinomycetales species, preferably by Streptomyces species HAG 004107, DSM 13381. Streptomyces species HAG 004107, DSM 13381 has an ivory-colored mycelium (RAL 1014) and is characterized by the conidiophores characteristic of streptomycetes. An isolate has been deposited in the Deutsche Sampling von Mikroorganismen und Zellkulturen GmbH, Masquerader Wag IB, D 38124 Germany, according to the rules of the Budapest Convention on March 16, 2000 under the following number: Sfrepfomyces species HAG 004107, DSM 13381. Instead of the strain Streptomyces species HAG 004107, DSM 13381, it is also possible to employ its mutants and variants which synthesize one or more compounds of the cyclipostins according to the invention. Such mutants can be produced in a manner known per se by physical means, for example irradiation, such as with ultraviolet or X-rays, or chemical mutagens, such as ethyl methanesulfonate (EMS), 2-hydroxy-4-methoxy-benzophenone (MOB) or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). The invention thus relates to a process for the preparation of the compound of the formula I or a physiologically tolerable salt thereof, characterized in that it comprises fermenting the microorganism Streptomyces species HAG 004107, DSM 13381, or one of its variants or mutants under suitable conditions in a culture medium until one or more compounds of the formula I accumulate in the culture medium and then isolating them from the culture medium and optionally converting them into chemical equivalents and physiologically tolerable salts. Preferably, the strain Streptomyces species HAG 004107, DSM 13381, its mutants and/or variants is fermented in a nutrient solution (also called a culture medium) with a carbon and nitrogen source and the customary inorganic salts until the novel cyclipostins accumulate in the culture medium, then these cyclophostin are isolated from the culture medium and optionally separated into the individual active components. The fermentation is preferably carried out under aerobic conditions; it proceeds particularly well at a temperature between 18 and 35°C and at a pH between 6 and 8. The process according to the invention can be employed for fermentation on the laboratory scale (milliliter to liter range) and for the industrial scale (cubic meter scale). All percentages relate, if not stated otherwise, to the weight. Mixing ratios in the case of liquids relate to the volume, if no other details are given. Suitable preferred carbon sources for aerobic fermentation are assailable carbohydrates and sugar alcohols, such as glucose, lactose, sucrose or D-mannitol, and carbohydrate-containing natural products, such as oat flakes, soybean flour and malt extract. Possible nitrogen-containing nutrients are: amino acids, peptides and proteins, and their degradation products, such as peptones or krypton’s, furthermore meat extracts, yeast extracts, ground seeds, for example of corn, wheat, beans, Soya beans or the cotton plant, distillation residues of alcohol production, meat meals or yeast extracts, but also ammonium salts and nitrates. Inorganic salts which the nutrient solution can contain are, for example, chlorides, carbonates, sulfates or phosphates of the alkali metals or alkaline earth metals, iron, zinc, cobalt and manganese. The formation of the cyclipostins of the formula II to XV A according to the invention proceed particularly well in a culture medium which contains approximately 0.1 to 5%, preferably 0.3 to 3% of oat flakes and trace elements. The details in percent are in each case based on the weight of the entire culture medium. The preferred formation of the cyclipostins of the formula VIII to XV A can be particularly readily carried out in nutrient solutions which contain approximately 0.1 to 5%, preferably 0.3 to 2%, of glycerol and 0.2 to 5%, preferably 0.5 to 3%, of soya bean meal and 0.05 to 1.0 g/l, preferably 0.1 to 1.0 g/l, of sodium chloride. In the culture medium, Streptomyces species HAG 004107, DSM 13381, forms a mixture of cyclipostins. Depending on the composition of the culture medium, the quantitative amount of one or more of the cyclipostins according to the invention can vary. Moreover, it is possible by means of the media composition to control the synthesis of individual cyclipostins such that one or alternatively more of the cyclipostins is not prepared at all or is prepared in an amount below the detection limit of the microorganism. The culture preferably contains a detectable cyclipostin. The cyclipostins A or P or P 2 are preferably formed. In addition to the cyclipostins A to T2 (compounds of the formula II to XV A), further related compounds are formed in the culture medium of Streptomyces species HAG 004107, DSM 13381, which differ from the compounds shown in the formulae II to XV A by modified radicals R^ and R^. In smaller amounts, cyclipostins have been detected which have a truncated or further branched radical R\ Oxidation (hydroxylation) products of these secondary components are also detectable in cultures of Streptomyces HAG 004107, DSM 13381. The culturing of the microorganism is carried out aerobically, i.e., for example, submerse with shaking or stirring in shake flasks or fermenters, if appropriate with introduction of air or oxygen. It can be carried out in a temperature range from approximately 18 to 35°C, preferably at approximately 25 to 32°C, in particular at 26 to 30*^0. The pH range should be between 6 and 8, preferably between 6.5 and 7.8. The microorganism is cultured under these conditions, in general, for a period of 24 to 300 hours, preferably 30 to 90 hours. Advantageously, culturing is carried out in a number of stages, i.e. first one or more precultures is/are prepared in a liquid culture medium, which is then inoculated into the actual production medium, the main culture, for example in the volume ratio 1:10. The preculture is obtained, for example, by inoculating a mycelium into a nutrient solution and allowing it to grow for approximately 36 to 120 hours, preferably 48 to 96 hours. The mycelium can be obtained, for example, by allowing the strain to grow for approximately 3 to 40 days, preferably 4 to 10 days, on a solid or liquid nutrient medium, for example malt/yeast/agar or oat flakes/agar. The course of fermentation can be monitored by means of the pH of the cultures or of the mycelium volume, and by chromatographic methods, such as thin-layer chromatography or high-pressure liquid chromatography or testing the biological activity. The cyclipostins according to the invention are present in the mycelium and to a smaller part also in the culture filtrate. The isolation process described below serves for the purification of the cyclipostins according to the invention, preferably for the purification of the cyclipostins A and P. The isolation and/or purification of the cyclipostins according to the invention from the culture medium is carried out according to known methods taking into account the chemical, physical and biological properties of the natural substances. For the testing of the cyclipostin concentration in the culture medium or in the individual isolation stages, thin-layer chromatography, for example on silica gel using ethylene chloride/ethyl acetate or chloroform/methanol mixtures (e.g. in the quantitative ratio 98:1) as eluent or HPLC can be used. The detection in the case of thin-layer chromatographic separation can be carried out, for example, by means of color reagents such as molybdatophosphoric acid or I2 vapor, the amount of the substance formed expediently being compared with a calibration solution. For the isolation of the cyclipostins according to the invention, the mycelium is first separated off from the culture medium according to the customary processes and the cyclipostins are then extracted from the cell mass using an organic solvent which is optionally miscible with water. The organic solvent phase contains the cyclipostins according to the invention; they are optionally concentrated in vacuo and further purified as described below. The culture filtrate is optionally combined with the concentrate of the mycelium extract and extracted with a suitable water-immiscible organic solvent, for example with n-butanol or ethyl acetate. The organic phase subsequently separated off is optionally concentrated in vacuo and dissolved in 1/30 of the original volume of water/methanol. The further purification of one or more of the cyclipostins according to the invention is carried out by chromatography on suitable materials, preferably, for example, on molecular sieves, on normal-phase supports, such as silica gel, alumina, on ion exchangers or on adsorbed resins or on reverse phases (reversed phase, RP). The cyclipostins are separated with the aid of these chromatographic processes. The chromatography of the cyclipostins is carried out using organic solvents or using mixtures of aqueous and organic solutions. Mixtures of aqueous or organic solutions are understood as meaning all water-miscible organic solvents, preferably methanol, propane! and acetonitrile, in a concentration of 10 to 100% of solvent, preferably 60 to 90% of solvent, or alternatively all buffered aqueous solutions which are miscible with organic solvents. The buffers to be used are the same as indicated above. The separation of the cyclipostins on the basis of their differing polarity is carried out with the aid of reversed phase chromatography, for example on an MCI® (adsorber resin from Mitsubishi, Japan) or Ambulate XAD® (TOSOHAAS), on further hydrophobic materials, such as on RP-8 or RP-18 phases. Moreover, the separation can be carried out with the aid of normal-phase chromatography, for example on silica gel, alumina and the like. The chromatography of the cyclipostins is carried out using buffered or acidified aqueous solutions or mixtures of aqueous solutions with alcohols or other, water-miscible organic solvents. The organic solvent used is preferably propane and acetonitrile. Buffered or acidified aqueous solutions are understood as meaning, for example, water, phosphate buffer, ammonium acetate, citrate buffer in a concentration of 1 mM to 0.5 M, and formic acid, acetic acid, trifluoroacetic acid or all commercially available acids known to the person skilled in the art, preferably in a concentration of 0.01 to 3%, in particular 0.1%. Chromatography is carried out using a gradient which begins with 100% aqueous buffer and ends with 100% solvent; preferably a linear gradient of 50 to 100% 2-propanol or acetonitrile is run. Alternatively, gel chromatography or chromatography on hydrophobic phases can also be carried out. Gel chromatography is carried out on polyacrylamide or mixed polymer gels, such as Biogel-P 2® (Biorad), Fractogel TSK HW 40® (Merck, Germany or Tosco Haas, USA) or on Sephadex® (Pharmacia, Uppsala, Sweden). The sequence of the abovementioned chromatographies is reversible. A further, very effective purification step for cyclipostins is crystallization. The cyclipostins crystallized from solutions in organic solvents and from mixtures of water with organic solvents. The crystallization is carried out in a manner known per se, for example by concentrating or cooling saturated cyclipostin solutions. The cyclipostins according to the invention are stable in the solid or liquid state and in solutions in the pH range between 4 and 8, in particular 5 and 7, and can thus be incorporated into customary pharmaceutical preparations. The invention further comprises obvious chemical equivalents of the compounds of the formula I which have a slight chemical difference, i.e. have the same activity or can be converted into the compound according to the invention under mild conditions. The equivalents mentioned include, for example, esters and ethers, and oxidation, reduction and hydrogenation products of the compounds according to the invention. Esters, and ether derivatives, oxidation hydrogenation and reduction products can be prepared according to processes described in the literature, e.g. in "Advanced Organic Synthesis, 4^^ Edition, J. March, John Wiley & Sons., 1992. The present invention includes all stereoisomeric forms of the compounds of the formula I to XV A. Asymmetric centers contained in the compounds of the formula I to XV A can all independently of one another have the S configuration or the R configuration. The invention includes ail possible enantiomers and diastereomers, as well as mixtures of two or more stereoisomeric forms, for example mixtures of enantiomers and/or diastereomer, in all ratios. The invention thus relates to enantiomers in enantiomericaliy pure form, both as rotatory and as dextrorotatory antipodes, R and S configurations, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. In the presence of cis/trans isomerism, the invention relates both to the cis form and the trans from and mixtures of these forms in all ratios. On account of their valuable pharmacological properties, the compounds according to the invention are suitable for use as pharmaceuticals in human and/or veterinary medicine. They inhibit lipases and have properties favorable for the treatment of metabolic disorders which have their cause in the disturbance of the lipid metabolism. The compounds of the formula I according to the invention have a surprising inhibitory action on the hormone-sensitive lipase, HSL, an aliosteric enzyme in adipocytes, which is inhibited by insulin and is responsible for the breakdown of fats in fat cells and thus for the transfer of fat constituents into the blood stream. Inhibition of this enzyme thus corresponds to an insulin-like action of the compounds according to the invention, which finally leads to a decrease in free fatty acids in the blood and in blood sugar. They can thus be employed in dysfunctions of the metabolism such as in noninsulin-dependent diabetes mellitus, in the diabetic syndrome and in direct damage to the pancreas. The invention thus relates to pharmaceutical preparations which contain one or more of the cyclipostins according to the invention and/or chemical equivalents thereof. Use as a mixture with suitable excipients or carrier material is preferred. Carrier materials which can be employed in humans are all pharmacologically tolerable carrier materials and/or excipients. The invention furthermore relates to a process for the preparation of a pharmaceutical according to the invention, which is characterized in that it comprises bringing at least one of the compounds according to the invention into a suitable administration form using a pharmaceutieally suitable and physiologically tolerable carrier and, if appropriate, further suitable active compounds, additives or excipients. The pharmaceuticals according to the invention are in general administered orally, locally or parenteraliy, but rectal administration is in principle also possible. Suitable solid or liquid pharmaceutical preparation forms are, for example, granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, aerosols, drops or injectable solutions in ampule form, and preparations having protracted release of active compound, in whose preparation vehicles and additives and/or excipients such as disintegrants, coating agents, swelling agents, glidants or lubricants, flavorings, sweeteners or solubilizers are customarily used. Frequently used vehicles or excipients which may be mentioned are, for example, magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactoprotein, gelatin, starch, vitamins, cellulose and its derivatives, animal or vegetable oils, polyethylene glycols and solvents, such as sterile water, alcohols, glycerol and polyhydric alcohols. If appropriate, the dose units can be microencapsulated for oral administration in order to delay release or to extend it over a longer period, such as by coating or embedding the active compound in particle form in suitable polymers, waxes or the like. Preferably, the pharmaceutical preparations are prepared and administered in dose units, each unit containing as active constituent a specific dose of one or more compounds of the cyciipostins according to the invention and/or chemical derivatives thereof. In the case of solid dose units such as tablets, capsules and suppositories, this dose can be up to approximately 200 mg, but preferably approximately 0.1 to 100 mg, and in the case of injection solutions in ampule form up to approximately 200 mg, but preferably approximately 0.1 to 100 mg, per day. The daily dose to be administered is dependent on the bodyweight, age, sex and condition of the mammal. Under certain circumstances, however, higher or lower daily doses may also be appropriate. The administration of the daily dose can be carried out either by single administration in the form of an individual dose unit or else in a number of smaller dose units or by repeated administration of subdivided doses at specific intervals. The invention also relates to pharmaceutical preparations which contain one or more of the cyclipostins according to the invention and/or chemical derivatives thereof. Use as a mixture with suitable excipients or carrier material is preferred. In the case of humans, the carrier material used can be all pharmacologically tolerable carrier materials and/or excipients. The action of the compounds of the formula I according to the invention was tested on the following enzyme test system: Enzyme preparation; Preparation of the partially purified HSL: Isolated rat lipocytes are obtained from epididymal fatty tissue of nontreated male rats (Wistar, 220-250 g) by collagenase treatment according to published procedures (e.g. S. Nilsson et al., Anal. Biochem. 158, 1986, 399-407; G. Fredriksonetal., J. Biol. Chem. 256,1981,6311 -6320; H. Tornquist et a!., J. Biol. Chem. 251, 1976, 813-819). The lipocytes from 10 rats are washed three times by flotation with 50 ml of homogenization buffer in each case (25 ml Tris/HCI, pH 7.4, 0.25 M sucrose, 1 mM EDTA, 1 mM DTT, 10//g/ml of leupeptin, 10/yg/ml of antipain, 20/7g/ml of pepstatin) and finally taken up in 10 ml of homogenization buffer. The lipocytes are homogenized in a Teflon-in-glass homogenizer (Braun-Melsungen) by means of 10 strokes at 1500 rpm and 15°C. The homogenisate is centrifuged (Sorvall SM24 tubes, 5000 rpm, 10 min, 4°C). The lower layer between the overlying fatty layer and the pellet is removed and the centrifugation is repeated. The lower layer resulting from this is centrifuged again (Sorvall SM24 tubes, 20000 rpm, 45 min, 4°C). The lower layer is removed and treated with 1 g of heparin-sepharose (Pharmacia-Biotech, CL-6B, washed 5 x with 25 mM Tris/HCI, pH 7.4, 150 mM NaCI). After incubation for 60 min at 4°C (shake at intervals of 15 min), the batch is centrifuged (Sorvall SM24 tubes, 3000 rpm, 10 min, 4°C). The supernatant is brought to pH 5.2 by addition of acetic acid and incubated at 4°C for 30 min. The precipitates are collected by centrifugation (Sorvall SS34, 12 000 rpm, 10 min, 4°C) and suspended in 2.5 ml of 20 mM Tris/HCI, pH 7.0, 1 mM EDTA, 65 mM NaCI, 13% of sucrose, 1 mM DTT, 10/yg/ml of leupeptin/pepstatin/antipain. The suspension is dialyzed overnight at 4°C against 25 mM Tris/HCI, pH 7.4, 50% of glycerol, 1 mM DTT, 10//g/ml of leupeptin, pepstatin, antipain and then applied to a hydroxyappetite column (0.1 g per 1 ml of suspension, equilibrated with 10 mM potassium phosphate, pH 7.0, 30% of glycerol, 1 mM DTT). The column is washed with four volumes of equilibration buffer at a flow rate of 20 to 30 ml/h. The HSL is eluted with a volume of equilibration buffer which contains 0.5 M potassium phosphate, then dialyzed (see above) and concentrated 5 to 10 times by ultrafiltration (Amicon Diaflo PM 10 Filter) at 4°C. The partially purified HSL can be stored at -70*'C for 4 to 6 weeks. Assay: For the preparation of the substrates, 25-50/iCi of [^Hjtrioleoylglycerol (in toluene), 6.8/;Mol of unlabeled trioleoylglycerol and 0.6 mg of phospholipid (phosphatidyichoiine/phosphatidyiinositol 3:1 w/v) are mixed, dried by means of N2 and then taken up in 2 ml of 0.1 M KPj (pH 7.0) by ultrasonic treatment (Branson 250, microtips, setting 1-2, 2 x 1 min at a Imin interval). After addition of 1 ml of KPj and fresh ultrasonic treatment (4 x 30 sec on ice at 30 sec intervals), 1 ml of 20% BSA (bovine serum albumin) (in KPj) is added (final concentration of trioleoylglycerol at 1.7 mM). For the reaction, 100//I of substrate solution are pipetted into 100 pi of HSL solution (HSL prepared as above, diluted in 20 mM KPj, pH 7.0, 1 mM EDTA, 1 mM DTT, 0.02% BSA, 20 /jg/ml of pepstatin, 10 //g/ml of leupeptin) and incubated at 37°C for 30 min. After addition of 3.25 ml of methanol/chloroform/heptane (10:9:7) and of 1.05 ml 0.1 M KaCOs, 0.1 M boric acid (pH 10.5), the batch is mixed well and finally centrifuged (800 x g, 20 min). After phase separation, one equivalent of the upper phase (1 ml) is removed and the radioactivity is determined by liquid scintillation measurement. Evaluation: Substances are customarily tested in four independent batches. The inhibition of the enzymatic activity of the HSL by a test substance is determined by the comparison with a noninhibited control reaction. The calculation of the IC50 value is carried out by means of an inhibitory curve using at least 10 concentrations of the test substance. For the analysis of the data, the GRAPHIT software package, Elsevier- BIOSOFT, is used. In this test, the compound showed the following action: The cyclipostins A, P, P2 and R inhibit the lipolysis in rat adipocytes with IC50 = - 0.2 //M and they inhibit the human hormone-sensitive lipase (HSL) with trioleylglycerol as substrate: IC50 = - 0.07 to 0.5//M. With NBD (4-chloro-7-nitrobenzO'2-oxa-1,3-diazole) as a substrate, the HSL from rats is inhibited in concentrations from 4 nM to 10 nM. The cyclipostins inhibit both the hormone-sensitive lipase (HSL), and the monoacylglycerol lipase of the rat extract in submicromolar concentrations. The invention is illustrated further in the following examples. Percentages relate to the weight. Mixing ratios in the case of liquids relate to the volume, if no other details have been given. Examples Example 1 Preparation of a glycerol culture of Streptomyces species HAG 004107, DSM 13381. 100 ml of nutrient solution (malt extract 2.0%, yeast extract 0.2%, glucose 1.0% (NH4)2HP04 0.05%, pH 6.0) in a sterile 300 ml Erienmeyer flask are inoculated with the strain Streptomyces species HAG 004107, DSM 13381, and incubated on a rotating shaker at 28°C and 180 rpm for 7 days. 1.5 ml of this culture are then diluted with 1.5 ml of 99% strength glycerol and stored at -20°C. Example 2 Preparation of a preculture in the Erienmeyer flask of Streptomyces species HAG 004107, DSM 13381, A sterile 300 ml Erienmeyer flask containing 100 ml of the following nutrient solution: 15 g/l of glucose, 15 g/l of soybean flour, 5 g/l of cornsteep, 2 g/l of CaCOs and 5 g/l of NaCI is inoculated with a culture grown on a slant tube (same nutrient solution, but with 2% agar) or with 1 ml of a glycerol culture (see Example 1) and incubated at 180 rpm and 28'C on a shaker. A 48 to 96-hour-old submerse culture (inoculation amount about 10%) of the same nutrient solution suffices for the inoculation of 10 and 200 I fermenters. Example 3 Preparation in Erienmeyer flasks of a culture of Streptomyces species HAG 004107, DSM 13381. Sterile 300 ml Erienmeyer flasks containing 100 ml of the following nutrient solution: 20 g/l of oat flakes for dogs 2.5 ml of trace element solution are inoculated with a 10% Inoculation amount of the preculture (Example 2) and incubated at 180 rpm and 28°C on a shaker. The culture can be used after two days for obtaining the cyclipostins or for inoculating fermenters. The trace element solution has the following composition: 3 g/l of CaCl2 x 2H2O 1 g/l of Fe(lll) citrate; 0.2 g/l of MnS04 x H2O; 0.1 g/lofZnCIa; 0.025 g/l of CUSO4 x 5H2O, 0.02 g/l of Na tetraborate 0.004 g/l of C0CI2 x 6H2O 0.01 g/l of Na molybdate. Example 4 Preparation of the cyclipostins of the formulae II to IX. A 200 I fermenter is operated with 90 liters of nutrient solution under the following conditions: Nutrient medium: 20 g/l of oat flakes in water; 2.5 ml/I of trace element. pH 7.8 (before sterilization) The nutrient solution is heat-sterilized for 30 minutes and, after cooling, 5% of the volume is inoculated with inoculation material obtained according to Example 3. Trace element solution: 3 g/l of CaCIa x 2H2O 1 g/l of Fe(lll) citrate; 0.2 g/l of MnS04 x H2O; 0.1 g/lofZnCl2; 0.025 g/l of CUSO4 X 5H2O, 0.02 g/l of Na tetraborate 0.004 g/l of C0CI2 X 6H2O 0.01 g/l of Na molybdate. Process time: 72 hours Incubation temperature: 28'C Stirrer speed: 90 rpm Aeration: 6 m^ of air per hour, The fermentation is carried out without addition of antifoam. The production maximum is achieved after about 40 to 76 hours. Example 5 Preparation of the cyclipostins X to XV A. A 200 I fermenter is operated under the following conditions with a filling of 100 I: Nutrient medium: 5 g/l of glucose; 20 g/l of glycerol; 20 g/l of soybean flour; 5 g/l of yeast extract; 3 g/l of NaCI; 2.5 ml/I of trace element solution pH 7.0 (before sterilization) Process time: 72 hours, Incubation temperature: 27°C, Stirrer speed: 65 rpm, Aeration: 6 m^ of air per hour. The fermentation is carried out without addition of agents for suppressing foam formation. The production maximum is achieved after about 48 hours. Example 6 Isolation of the cyclipostin mixture from the culture solution of Streptomyces species HAG 004107, DSM 13381. After completion of the fermentation of Streptomyces species HAG 004107, DSM 13381,100 liters of culture broth from the fermenter, obtained according to Example 4, are filtered with addition of about 2% filter aid (e.g. Celite®) and the cell mass (10 liters) is extracted with 40 liters of methanol. The active compound-containing, methanolic solution is freed from the mycelium by filtration and concentrated in vacuo. The concentrate is applied to a prepared, 7 liter ©MCI GEL, CHP20P column. Elution is carried out using a gradient of water to propan-2-ol. The column flow (20 liters per hour) is collected in fractions (10 liters each) and the fractions containing cyclipostins (19 to 21) are in each case concentrated in vacuo. The fractions are investigated by means of HPLC (see Example 7). Fraction 19 comprises the cyclipostin A to E and their isomers, fraction 20 cyclipostin F and isomers thereof, fraction 21 the inhibitors cyclipostin N, P, P 2, Q, R, S and T and their isomers. Example 7 HPLC analysis of the cyclipostins. The high-pressure liquid chromatographic (HPLC) analysis of the cyclipostins is carried out in an HP 1100® unit with YMC Pack Pro CI 8® columns [AS-303, 250 x 4.6 mm, S-5//m, 120 A°]. The flow is 1 ml/minute, the column temperature 40°C. A gradient of 0.05% trifluoroacetic acid to acetonitrile is used. 100% acetonitrile is achieved as eluent after 11 minutes and the column is then constantly (isocratically) eluted further with this solvent. Detection is carried out by measuring the ultraviolet absorption at 210 nm. Using this procedure, the cyclipostins have the following retention times: Cyclipostin A 12.7 minutes, Cyclipostin A 2 12.6 minutes, Cyclipostin F 13.2 minutes, Cyclipostin N 15.9 minutes, Cyclipostin P 17.7 minutes, Cyclipostin P 2 17.3 minutes, Cyclipostin Q 18.3 minutes, Cyclipostin R 16.7 minutes, Cyclipostin R2 16.4 minutes, Cyclipostin S 18.5 minutes, Cyclipostin T 19.1 minutes and Cyclipostin T2 18.7 minutes. Example 8 Preparation of pure cyclipostin A and A 2. Fraction 19, obtained according to Example 6, is concentrated in vacuo and 1 g of the concentrate, dissolved in water/methanol (1:1), is applied to a Nucieoprep 100-5 Ci8 AB® column (21 x 250mm). Elution is carried out using a gradient of 50% acetonitrile in 0.01% trifluoroacetic acid to 100% acetonitrile. The flow is 50 ml/minute. The column flow is checked by the measurement of the light absorption at 210 nm and by testing the lipase-inhibiting properties. Fractions of 60 ml each are taken. Cyclipostin A is found in fractions 34 and 35, and cyclipostin A 2 in fractions 41 to 44. These fractions are in each case combined, concentrated in vacuo and separated successively on an SP 250/10 Nucleosil 100-5 CIS HD® column. The gradient chosen was 50% to 66% acetonitrile in 0.01% trifluoroacetic acid and the pH of the solutions was adjusted to 4.0 with a drop of ammoniumhydroxide solution. The fractions which contained pure compounds were in each case combined and freeze-dried. They afforded 5.4 mg of pure cyclipostin A as a waxy substance and 3 mg of cyclipostin A 2 as an oil. Example 9 Characterization of cyclipostin A. Appearance: neutral, colorless, waxy substance soluble in oxygen-containing organic solvents, but only slightly soluble in water and petroleum ether. UV maximum: 228 nm in methanol. IR bands: 1752 and 1671 cm'By high-resolution FAB mass spectrometry using a nitrobenzyl alcohol/LiCI matrix, the following molecular weight is found: 467.2757 amu, correspond to the empirical formula for cyclipostinin A-Li of C23H4i07PLi, From this, an empirical formula for cyclipostin A of C23H41O7P results, molecular weight: 460. By electron spray mass spectrometry, in the positive ionization mode (ESI, positive) a peak at 461 amu, corresponding to (M + H)'*' is found; moreover the characteristic peak at 221 amu, corresponding to CyHioOeP. In the ESI negative mode, 459 amu (M - H)", 337 amu (C16H34O5P) and 219 amu (CyHsOeP) are found. For the determination of the position of the alcohol group, derivatization with N-methyl-N-trimethylsilyltrifluoroacetamide is carried out and the sample is investigated using elecron ionization mass spectrometry. The trimethylsilyl derivative results: Example 10 Characterization of cyclipostin B, Cyclipostin B is isolated as described in Example 8 for cyclipostin A by multiple repetition of the chromatographic steps and characterized as in Example 9. Appearance: neutral, colorless, waxy substance soluble in oxygen-containing organic solvents, but only slightly soluble in water and petroleum ether. UV maximum: 228 nm in methanol. By electron spray mass spectrometry, in the positive ionization mode (ESI, positive) a peak at 461 amu, corresponding to (M + H)"^ is found; moreover the characteristic peak at 221 amu, corresponding to CyHioOeP. In the ESI negative mode, 459 amu (M " H)', 337 amu (C16H34O5P) and 219 amu (CyHsOeP) are found. For the determination of the position of the alcohol group, derivatization is carried out using N-methyl-N-trimethylsilyltrifluoroacetamide and the sample is investigated by electron ionization mass spectrometry. The trimethylsilyl derivative results of mass 554 amu: The position of the silylated hydroxy! group is indicated by the intensive ions at 511 amu (a-cleavage) and 145 amu (a-cleavage). Empirical formula of cyclipostin B: C23H41O7P, molecular weight: 460. Example 11 Characterization of cyclipostin C. Cyclipostin C is isolated as described in Example 8 for cyclipostin A by multiple repetition of the chromatographic steps and characterized as in Example 9. Appearance: neutral, colorless, waxy substance soluble in oxygen-containing organic solvents, but only slightly soluble in water and petroleum ether. UV maximum: 228 nm in methanol. By electron spray mass spectrometry, in the positive ionization mode (ESI, positive) a peak at 461 amu, corresponding to (M + H)"^ is found; moreover the characteristic peak at 221 amu, corresponding to CyHioOeP. In the ESI negative mode, 459 amu (M - H)", 337 amu (C16H34O5P) and 219 amu (CyHeOeP) are found. For the determination of the position of the alcohol group, derivatization is carried out using N-methyl-N-trimethylsilyltrifluoroacetamide and the sample is investigated by electron ionization mass spectrometry. The trimethylsilyl derivative results of mass 554 amu: The position of the silylated hydroxyl group is indicated by the intensive ions at 525 amu (a-cleavage) and 131 amu (a-cleavage). Empirical formula of cyclipostin C: C23H41O7P, molecular weight: 460. Example 12 Characterization of cyclipostin F. Fraction 20, obtained according to Example 6, is separated as described in Example 8 and the cyclipostin F is isolated by multiple repetition of the chromatographic steps and characterized as in Example 9. Reaction time: 13.2 minutes. Appearance: neutral, colorless, waxy substance soluble in oxygen-containing organic solvents, but only slightly soluble in water and petroleum ether. UV maximum: 228 nm in methanol. By electron spray mass spectrometry, in the positive ionization mode (ESI, positive) a peak at 459 amu, corresponding to (M + H)"^ is found; moreover the characteristic peak at 221 amu, corresponding to CyHioOeP. In the ESI negative mode, 457.6 amu (M - H)", 336 amu (C16H32O5P) and 219 amu (CyHaOeP) are found. Empirical formula of cyclipostin F: C23H39O7P, molecular weight: 458. Example 13 Characterization of cyclipostin P. Fraction 21, obtained according to Examples 5 and 6, is separated as described in Example 8 and cyclipostin P is isolated by multiple repetition of the chromatographic steps (210 mg) and characterized as in Example 9. Cyclipostin P was crystallized by dissolving the 210 mg in 3 ml of propan-2-ol and 13 ml of acetonitrile and addition of 8 ml of water. After filtering off and washing with cold acetonitrile, a final weight of 135 mg of cyclipostin was obtained, m.p. 58-59°C. Retention time: 17.7 minutes. Appearance: neutral, colorless, waxy substance soluble in oxygen-containing organic solvents, but only slightly soluble in water and petroleum ether. UV maximum: 228 nm in methanol. IR bands: 2917, 2852, 1753, 1671, 1471, 1214, 996 and 832 cm'By high-resolution FAB mass spectrometry using a nitrobenzylalcohol matrix, the following molecular weight is found: 445.2717 amu, correspond to (M+H)"^ for cyclipostinin P of C23H42O6P. From this, an empirical formula for cyclipostin P of C23H41O6P results, molecular weight: 444. By electron spray mass spectrometry, in the positive ionization mode (ESI, positive) a peak at 445 amu, corresponding to (M + H)"^ is found; moreover the characteristic peak at 221 amu, corresponding to CyHioOeP. In the ESI negative mode, 443 amu (M - H)', 321 amu (C16H34O4P) and 219 amu (CyHgOeP) are found. Retention time: 17.1 minutes. Appearance: neutral, colorless, oily substance soluble in oxygen-containing organic solvents, but only slightly soluble in water and petroleum ether. UV maximum: 228 nm in methanol. By high-resolution FAB mass spectrometry using a nitrobenzylalcohol matrix, the following molecular weight is found: 445.2721 amu, correspond to (M + H)*^ for cyciipostin P of C23H42O6P. From this, an empirical formula for cyclipostin P 2 of C23H41O6P results, molecular weight: 444. By electron spray mass spectrometry, in the positive ionization mode (ESI, positive) a peak at 445 amu, corresponding to (M + H)^ is found; moreover the characteristic peak at 221 amu, corresponding to CrHioOeP. In the ESI negative mode, 443 amu (M - H)", 321 amu (C16H34O4P) and 219 amu (CrHaOeP) are found. Example 15 Obtainment and characterization of cyclipostin N. Fraction 21, obtained according to Examples 5 and 6, is separated as described in Example 8 and cyclipostin N is isolated by multiple repetition of the chromatographic steps (2 mg) and characterized as in Example 9. Retention time: 15.9 minutes. Appearance: neutral, colorless, oily substance soluble in oxygen-containing organic solvents, but only slightly soluble in water and petroleum ether. UV maximum: 228 nm in methanol. By high-resolution mass spectrometry [lacuna] FAB conditions, a quasi-molecular ion (M + H) at 417.2405 was observed corresponding to an empirical formula of C21H38O6P (theory: 417.2406). Characteristic fragment in the ESI^ mode: 221 amu. Example 16 Obtainment and characterization of cyclipostin R. Fraction 21, obtained according to Examples 5 and 6, is separated as described in Example 8 and cyclipostin R is isolated by multiple repetition of the chromatographic steps (8 mg) and characterized as in Example 9. Retention time: 16.7 minutes. Appearance: neutral, colorless, crystalline substance soluble in oxygen-containing organic solvents, but only slightly soluble in water and petroleum ether. UV maximum: 228 nm in methanol. By high-resolution mass spectrometry [lacuna] FAB conditions, a quasi-molecular ion (M + H) at 431.2561 was observed corresponding to an empirical formula of C22H40O6P (theory: 431.2562). Characteristic fragment in the ESI"^ mode: 221 amu. Example 17 Obtainment and characterization of cyclipostin R2. Fraction 21, obtained according to Examples 5 and 6, is separated as described in Example 8 and cyclipostin R2 is isolated by multiple repetition of the chromatographic steps (8 mg) and characterized as in Example 9. Retention time: 16.4 minutes. Appearance: neutral, colorless, oily substance soluble in oxygen-containing organic solvents, but only slightly soluble in water and petroleum ether. UV maximum: 228 nm in methanol. By high-resolution mass spectrometry [lacuna] FAB conditions, a quasi-molecular ion (M + H) at 431.2564 was observed corresponding to an empirical formula of C22H40O6P (theory: 431.2562). Characteristic fragment in the ESr mode: 221 amu. Example 18 Obtainment and characterization of cyclipostin S. Fraction 21, obtained according to Examples 5 and 6, is separated as described in Example 8 and cyclipostin S is isolated by multiple repetition of the chromatographic steps (0.7 mg) and characterized as in Example 9. Retention time: 18,5 minutes. Appearance: neutral, colorless, solid substance soluble in oxygen-containing organic solvents, but only slightly soluble in water and petroleum ether. UV maximum: 228 nm in methanol. By high-resolution mass spectrometry [lacuna] FAB conditions, a quasi-molecular ion (M + H) at 459.2883 was observed corresponding to an empirical formula of C24H44O6P (theory: 459.2575). Characteristic fragment in the ESr mode: 235 amu. Example 19 Obtainment and characterization of cyclipostin T. Fraction 21, obtained according to Examples 5 and 6, is separated as described in Example 8 and cyclipostin T is isolated by multiple repetition of the chromatographic steps (5 mg) and characterized as in Example 9. Retention time: 19.1 minutes. Appearance: neutral, colorless, solid substance soluble in oxygen-containing organic solvents, but only slightly soluble in water and petroleum ether. UV maximum: 228 nm in methanol. By high-resolution mass spectrometry [lacuna] FAB conditions, a quasi-molecular ion (M + H) at 473.3030 was observed corresponding to an empirical formula of C25H46O6P (theory: 473.3032). Characteristic fragment in the ESr mode: 249 amu. Example 20 Obtainment and characterization of cyciipostin T2 Fraction 21, obtained according to Examples 5 and 6, is separated as described in Example 8 and cyciipostin T2 is isolated by multiple repetition of the chromatographic steps (4 mg) and characterized as in Example 9. Retention time: 18.7 minutes. Appearance: neutral, colorless, solid substance soluble in oxygen-containing organic solvents, but only slightly soluble in water and petroleum ether. UV maximum: 228 nm in methanol. By high-resolution mass spectrometry [lacuna] FAB conditions, a quasi-molecular ion (M + H) at 473.3035 was observed corresponding to an empirical formula of C25H446O6P (theory: 473.3032). Characteristic fragment in the ESr mode: 249 amu. Example 21 Inhibition of the hormone-sensitive lipase (HSL). The hormone-sensitive lipase from rats is inhibited in the following concentrations (IC50) using trioleylglycerol as a substrate: Cyclipostin A: 20 nM, Cyclipostin N: 450 nM, Cyclipostin P: 30 nM, Cyclipostin P2: 40 nM, Cyclipostin R: 10 nM, Cyclipostin R2; 220 nM, Cyclipostin S: 20 nM, Cyclipostin T: 200 nM, Cyclipostin 12: 60 nM. Patent claims: 1. A compound of the formula I in which R^ is 1. a carbon chain having 2 to 30 carbon atoms, which can be straight-chain, branched, saturated or unsaturated, carob- or heterocyclic and in which the carbon chain is optionally mono- or disubstituted by: 1.1 -OH, 1.2 =0, 1.3 - in which alkyl is linear or branched, 1.4 - , in which alkenyl is linear or branched, 1.5 - alkyl, in which alkyl is linear or branched, 1.6 - , 1.7 1.8 1.9 - -alkyl, in which alkyl is linear or branched, 1.10 -NH- -alkenyl, in which alkenyl is linear or branched, 1.11 -NH2, 1.12 =S, 1.13 -S- , in which alkyl is linear or branched, or 1.14 -S- alkenyl, in which alkenyl is linear or branched, 1.15 halogen, in which the substituents 1.1 to 1.15 can also be additionally substituted, 2.0 - [-aryl-{CH2)n]m, in which [-aryKCH2)n]m is unsubstituted or mono- or disubstituted as described in 1.1 to 1.15 and n and m independently of one another are integers zero, 1, 2 or 3; -alkyl, in which alkyl is unsubstituted or mono- or disubstituted as described in 1.1 to 1.15, 2.0 -alkenyl, in which alkenyl is unsubstituted or mono- or disubstituted as described in 1.1 to 1.15, or, 3.0 -alkynyl, in which alkynyl is unsubstituted or mono- or disubstituted as described in 1.1 to 1.15, E is a phosphorus (P) or sulfur (S) atom, Xi, X2 and X3 independently of one another are 1.0 -0-, 2.0 -NH-, 3.0 -N=, 4.0 -S-, or 5.0 -CH2-, and –CHR in all its stereo chemical forms and mixtures of these forms in any ratio, or its physiologically tolerable salts and chemical equivalents, 2. A compound of the formula I or a physiologically tolerable salt thereof as claimed in claim 1, characterized in that R^ is a carbon chain having 10 to 18 carbon atoms, which can be straight-chain, branched, saturated or unsaturated, cargo- or heterocyclic, in which the carbon chain is unsubstituted or mono- or disubstituted as described in 1.1 to 1.15. 3. A compound of the formula 1 or a physiologically tolerable salt thereof as claimed in claim 1 or 2, characterized in that R^ is 1 .0 -(CH2)15CH3 , 2.0 -(CH2)i3CH(CH3)2, 3.0 -(CH2)iiCH(OH)(CH2)3CH3, 4.0 -(CH2)iiCH(OH)CH2CH(CH3)2, 5.0 -(CH2)i2CH(OH)(CH2)2CH3, 6.0 -(CH2)i3CH(OH)CH2CH3, 7.0 -(CH2)i4CH(OH)CH3, 8.0 -(CH2)i5CH2(OH), 9.0 -(CH2)i6CH3, 10.0 -(CH2)i3C=OCH2CH3 11.0 -{CH2)i2C=OCH2CH2CH3 12.0 -(CH2)iiC=OCH2CH2CH2CH3 13.0 -(CH2)i3CH3 14.0 -(CH2)iiCH(CH3)2 15.0 -(CH2)i4CH3 or 16.0 -(CH2)i2CH(CH3)2. 4. A compound of the formula I or a physiologically tolerable salt thereof as claimed in claim 1, 2 or 3, characterized in that 5. A compound of the formula I or a physiologically tolerable salt thereof as claimed in claim 4, characterized in that R^ is -CH3, -CH2CH3 or -CH2CH2CH3. 6. A compound of the formula I or a physiologically tolerable salt thereof as claimed in one or more of claims 1 to 5, reparable by fermenting the microorganism Streptomycin species HAG 004107, DSM 13381, or one of its variants or mutants under suitable conditions in a culture medium until one or more compounds of the formula I accumulate in the culture medium and then isolating them from the culture medium and optionally converting them into chemical equivalents or physiologically tolerable salts. 7. A process for the preparation of a compound of the formula I or a physiologically tolerable salt thereof as claimed in one or more of claims 1-6, characterized in that it comprises fermenting the microorganism Streptomycin species HAG 004107, DSM 13381, or one of its variants or mutants under suitable conditions in a culture medium until one or more compounds of the formula I accumulates in the culture medium and then isolating them from the culture medium and optionally converting them into chemical equivalents or physiologically tolerable salts. 8. The process as claimed in claim 7, characterized in that the fermentation is carried out under aerobic conditions at a temperature between 18 and 35°C and at a pH between 6 and 8. 9. A compound of the formula I or a physiologically tolerable salt thereof as claimed in one or more of claims 1-6 for use as a pharmaceutical. 10. A compound of the formula I or a physiologically tolerable salt thereof as claimed in one or more of claims 1-6 for use as a pharmaceutical for the inhibition of lipases. 11. A compound of the formula I or a physiologically tolerable salt thereof as claimed in one or more of claims 1-6 for use as an antidiabetic. 12. A pharmaceutical preparation which contains at least one compound of the formula I or a physiologically tolerable salt thereof as claimed in one or more of claims 1-6. 13. A process for the production of pharmaceutical preparations as claimed in claim 12, characterized in that it comprises bringing at least one compound of the formula I or a tolerable salt thereof as claimed in one or more of claims 1-6 into a suitable administration form using suitable recipients and/or vehicles. 14. Streptomyces species HAG 004107, DSM 13381. 15. A pharmaceutical preparation substantially as herein described and exemplify .

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