MXPA99001491A - Derivatives of 11-acetyl-12,13 dioxabiciclo [8.2.1] tridecenone, procedure for its preparation, and medications containing these compounds - Google Patents

Abstract

The present invention relates to N-demethyl-N-isopropyl-erythromycin-A derivatives narrowed in the ring, with modified side chain, and with motility agonist properties that are gastrointestinally effective, as well as their preparation.

Description

Derivatives of 1 1 -acetyl-12,13-dioxabicyclo [8.2.1] tridecenone, process for its preparation, and drugs containing these compounds The present invention relates to novel compounds of (2R, 3S, 4S, 5R, 6R, 10R, 11R) -3- [(2,6-dideoxy-3-C-methyl-3-o-methyl-aL-ribohexopyranosyl ) -oxi] -5- [3,4,6-trideoxy-3-amino-β-D-xylohexopyranosyl) -oxy] -2,4,6,8,10-pentamethyl-11-acetyl-12, 13- N-substituted dioxabicyclo [8.2.1] tridec-8-en-l-one, with motilin agonist properties, and its salts by addition of acids, as well as pharmaceutical preparations containing these compounds and processes for the preparation of these compounds . The compounds according to the invention constitute N-demethyl-N-isopropyl derivatives of erythromycin A which are narrowed in the ring, with a modified side chain. The antibiotic erythromycin A has, as is known, along with its antibiotic effects also unwanted gastrointestinal side effects for antibiotics, among others a strong multiplication of contractile activity in the gastrointestinal region with seizures in the stomach and intestines, nausea, vomiting and diarrhea. There have been several attempts to modify erythromycin A in such a way that derivatives are obtained in which the antibiotic effect is practically no longer present, but an influencing effect on the motility of the gastrointestinal tract is retained. European Patent No. EP 0 550 895 discloses N-demethyl-N-isopropyl-erythromycin A derivatives narrowed in the ring, with active motilin agonist properties in the gastrointestinal tract. In addition, similar erythromycin derivatives narrowed in the ring are known from European Patent Application EP-A 382,472, which, however, have antibiotic effects. The present invention has established the mission to develop new derivatives of erythromycin A, narrowed in the ring and active orally, without antibiotic effect and with properties that favorably influence the motility of the gastrointestinal tract and with an improved profile of effects. It has finally been discovered that the new derivatives with N-desmethyl-N-isopropyl of erythromycin A, narrowed in the ring, whose side chain in position 11 of the cyclic fundamental framework had been modified by oxidation, are not active as antibiotics, but they have selective motilin agonist properties and stimulate the motility of the gastrointestinal tract in a favorable way and have effects that reinforce the tonicity of the lower sphincter of the esophagus and the tonicity of the stomach. Because of their effect profile, the substances according to the invention are suitable for the treatment of motility disorders in the gastrointestinal tract and in this context they are distinguished by a good compatibility and a good oral activity. The present invention therefore relates to novel compounds of (2R, 3S, 4S, 5R, 6R, 10R, 11R) -2, 4, 6, 8, 10-pentamethyl-11-acetyl-12, 13-dioxabicyclo [ 8.2.1] tridec-8-en-l-one of the general Formula I wherein R 1 signifies hydrogen or methyl and R 2 signifies hydrogen or lower alkanoyl, and their acid addition salts, stable and physiologically compatible. If in the compounds of Formula I a substituent means or contains lower alkyl, it may be branched or unbranched and possess from 1 to 4 carbon atoms. Especially the compounds of Formula I, in which R 1 signifies methyl, are favorable.

R2 preferably represents hydrogen. If R2 means lower alkanoyl, acetyl is preferred. The compounds of Formula I can be obtained, in a manner known per se, in a compound of general Formula II, wherein R 1x and R * 2 have the above meanings, transforming the 2 ', 3' -dihydroxy-pent-2'-yl chain located in position 11 of the cyclic fundamental network, by oxidative dissociation with a glycol, in an acetyl side chain, and if desired, in the compound obtained of Formula I, in which R 1 signifies hydrogen, introducing a methyl radical R, or in the compound obtained of Formula I, in which R 1 signifies methyl , separating the methyl radical R, and if desired transforming free compounds of the Formula I into their stable salts by addition of acids, or transforming the salts by the addition of acids into the free compounds of the Formula I. The oxidative dissociation with a glycol of the side chain 2 ', 3' -dihydroxy-pent-2'-yl in position 11 of the cyclic fundamental framework of compounds of Formula II can be carried out with appropriate oxidizing agents, such as lead tetraacetate, in the The solvents used are solvents suitable for this purpose: apolar or weakly polar solvents such as benzene, toluene or xylene are suitable as solvents, and the reaction can be carried out at temperatures between 0 ° C and 40 ° C, preferably at ambient emperature. The compounds obtained of Formula I, in which R 1 signifies hydrogen, can be subsequently alkylated in a manner known per se to form the corresponding N-methylated compounds. The alkylation can be carried out in a manner known per se by reaction with a methyl halide or as reductive alkylation by reaction with formaldehyde under reducing conditions, and can be carried out, for example, in the presence of a reducing agent, for example a compound borohydride complex such as sodium cyano-borohydride, sodium triacetoxy borohydride or sodium borohydride. If desired, the alkylation can also be carried out by reaction with a methyl halide, especially methyl iodide, or with a methyl sulfonic acid ester. Suitably, the alkylation is carried out in an organic solvent which is inert under the reaction conditions. For reductive alkylation, cyclic ethers such as tetrahydrofuran (= THF) or dioxane, aromatic hydrocarbons such as toluene, or also lower alcohols are suitable as solvents. The alkylation can be carried out at temperatures between room temperature and the boiling temperature of the solvent. When carrying out the alkylation with a methyl derivative, for example a methyl halide such as methyl iodide, it is conveniently worked in the presence of a base such as, for example, an alkali metal carbonate or a tertiary organic amine. Starting from the compounds of Formula I, in which R 1 is methyl, the methyl radical R can be subsequently removed if desired. The demethylation can be carried out in a manner known per se by treating the compound with a halogen, especially iodine and / or bromine, in an inert solvent and in the presence of an appropriate base. Suitable bases are, for example, alkali metal alcoholates, alkali metal hydroxides and alkali metal salts of weak organic acids. The compounds of Formula I can be isolated from the reaction mixture and purified in a manner known per se. The acid addition salts can be converted in the customary manner to the free bases and these, if desired, can be converted in a known manner into pharmacologically compatible acid addition salts. In order to avoid secondary reactions of hydrolysis, it is convenient to use, for the formation of salts, only equivalent amounts of acids. Suitable salts for the addition of pharmacologically acceptable acids of the compounds of the formula I are, for example, their salts with inorganic acids, for example carbonic acid, hydrohalic acids, especially hydrochloric acid, or with organic acids, for example mono- or lower aliphatic di-carboxylic acids, such as maleic acid, fumaric acid, lactic acid, tartaric acid or acetic acid. The starting compounds of Formula II, wherein R2 means hydrogen, are known from EP-B 0.550.895, and can be prepared according to the procedures described therein. The starting compounds of the formula II, in which R means lower alkanoyl, can be prepared by reacting in a known manner compounds of the formula II, in which R2 means hydrogen, with carboxylic acids of the general formula III, R3-COOH III wherein R3 means lower alkyl, or derivatives capable of reacting with these acids. As the reactants capable of reacting of acids of Formula III, anhydrides of acids and acid halides, optionally mixed, are involved. Thus, for example, chlorides or bromides of the acids of Formula III or mixed esters of the acids of Formula III can be used with organic sulfonic acids, for example with lower alkane sulphonic acids optionally substituted with halogen, such as methanesulfonic acid or trifluoromethanesulfonic acid, or with aromatic sulfonic acids such as, for example, benzenesulfonic acids or with benzenesulfonic acids which are substituted with lower alkyl or halogen, eg toluenesulfonic acids or bromobenzenesulfonic acids. The reaction can be carried out as an acylation in an organic solvent which is inert under the reaction conditions at temperatures between -20 ° C and room temperature. Suitable solvents are di-lower alkyl ketones, for example acetone, halogenated hydrocarbons such as dichloromethane, aromatic hydrocarbons such as benzene or toluene, or cyclic ethers such as THF or dioxane, or mixtures of these solvents. The acylation can be carried out conveniently, especially when, as the acylating agent, an anhydride or a mixed anhydride of the acids of the Formula III is used with a suifonic acid, in the presence of an acid-binding reagent. Suitable acid-binding agents are, for example, inorganic bases such as alkali metal carbonates, for example potassium carbonate, or organic bases soluble in the reaction mixture, such as tertiary nitrogen bases, for example tere. lower alkyl-amines and pyridines, such as, for example, triethyl-amine, tripropyl-amine, N-methyl-morpholine, pyridine, 4-dimethylaminopyridine, 4-diethylamino-pyridine or 4-pyrrolidino-pyridine. If desired, in a compound obtained from Formula II, in which R 1 signifies hydrogen, a methyl radical R 1 can be introduced, or in a compound obtained from Formula II, in which R 1 signifies methyl, the methyl radical can be separated R1 Such methylations or demethylations can be carried out in a manner known per se, for example under the conditions described for the introduction or separation of a methyl group in the compounds of the formula I. The novel compounds of the formula I and their salts by addition of physiologically compatible acids possess interesting pharmacological properties, especially motilin agonist properties, which stimulate especially the motility of the gastrointestinal tract. In this context, they are distinguished by a favorable profile of effects with surprisingly good oral activity. These compounds are free of antibiotic effects and have a high selective affinity for motilin receptors, whereas in the active dose ranges of motilin agonist mode they do not show any practically relevant affinity with other receptors in the gastrointestinal tract, such as adrenaline receptors. , acetylcholine, histamine, dopamine or serotonin. The compounds exhibit surprisingly good compatibility with the liver, which makes them suitable for applications for extended periods of time. In order to guarantee a regulated digestion of the ingested nutrition, in the healthy state the autonomic nervous system and the hormones of the gastrointestinal tract cooperate in order to generate a regulated contractile activity of the gastrointestinal tract, not only directly after the ingestion of nutrition but also also when the gastrointestinal tract is empty. Motilin is a known gastrointestinal peptide hormone, which stimulates the motility of the gastrointestinal tract and induces a coordinated motility throughout the gastrointestinal tract in a fasted state as well as after ingestion of nutrition. The compounds of Formula I manifest physiological effects of the type of motilin, by becoming active as agonists for motilin receptors. Thus, the compounds of Formula I manifest pronounced stimulating effects in the gastrointestinal region and in the lower sphincter of the esophagus. They produce especially an acceleration of the emptying of the stomach, an increase of the tonicity of the stomach and a long-lasting increase of the tonicity at rest of the sphincter of the esophagus. Because of its profile of effects of the motilin type, the substances are suitable for the treatment of morbid conditions that are linked to motility disorders in the gastrointestinal tract and / or to the reflux of the food porridge from the stomach to the esophagus. Thus, the compounds of Formula I are indicated, for example, in cases of gastroparesis of the most different origins, disorders of stomach tonicity, disorders of stomach emptying and gastroesophageal reflux, dyspepsia and motility disorders after surgical operations. . The active properties on the gastrointestinal tract exhibited by the compounds of Formula I can be tested in classical pharmacological test methods in vi tro and in vivo.

Description of the test methods 1. Determination of the binding capacity of the test substances to motilin receptors The affinity of the compounds of Formula I to motilin receptors is measured in vi tro with a fraction of a tissue homogenate material from the antrum of rabbits. The dislodgment of radioactive labeled iodine motilin is determined from the union between motilin and receptors, carried out by the test substances. The binding studies to receptors were carried out according to a modification of the method of Borman et al. (Regulatory Peptides 15. (1986), 143-153). For the preparation of motilin labeled with iodine, motilin is enzymatically oxidized using lactoperoxidase, in a manner known per se, eg analogously to the method described by Bloom et al. (Scand. J. Gastroenterol. 1976) 47-52). In order to obtain the fraction of a homogenized tissue material, which is used in the test, from the antrum of a rabbit, the antrum released from mucous membranes is crushed and homogenized with a homogenizer for 15 seconds, at a rate of 1,500 revolutions per minute, in a 10-fold volume of a cold homogenization buffer solution (50 mM Tris-HCl buffer, 250 mM sucrose, 25 mM KCl, 10 mM MgCl 2, pH 7.4) with addition of inhibitors (1 mM iodoacetamide, 1 μM pepstatin, 0.1 mM methylsulfonyl fluoride, 0.1 g / 1 trypsin inhibitor and 0.25 g / 1 bacitracin) The homogenate is then centrifuged for 15 minutes at 1,000 xg, the The residue obtained is washed four times with a solution n buffer homogenizing and finally resuspended in a 0.9% sodium chloride (volume corre- sponding in 5 times the amount by weight of the antrum). The fraction of tissue, which has thus been obtained, which is designated as "crude membrane preparation", is used for the test. For the fixation experiment, 200 μl of the crude membrane fraction (0.5-1 mg of protein) are incubated in 200 μl of a buffer solution A (50 mM Tris-HCl buffer, 20 μM of albumin) at 30 ° C for 60 min. 1.5% bovine serum (= Bovine Serum Albumin, BSA), 10 mM MgCl2, pH 8.0), diluted with 100 μl of iodinated motilin in buffer solution B (10 mM Tris-HCl buffer, 1% BSA) , pH 8) (final concentration 50 pM). The reaction is stopped by the addition of 3.2 ml of the cold buffer solution B and the fixed and non-fixed motilin are separated from each other by centrifugation (1,000 x g, for 15 minutes). The residue obtained as sediment after centrifugation is washed with buffer solution B and counted in a gamma particle counter. Eviction studies are carried out by adding increasing amounts of the substance to be tested to the incubation medium. As solutions of the test substance, aqueous solutions were used which had been prepared by suitable dilution of original solutions of water 60 x 10"4 molar.The test substances hardly soluble in water are first dissolved in 60% ethanol and this solution diluted with an amount of water such that in the solution to be tested the ethanol concentration does not exceed 1.6% by volume.From the measurement data obtained, the concentration of the CI5Q of the respective test substance is determined as the concentration 50% inhibition of the specific binding of the iodinated motilin to the motilin receptors.From this value, the corresponding pIC50 value is calculated In accordance with the foregoing method, the substances of Examples 1 and 2 were determined for the substances pCI50 values indicated in the following Table 1. The numbers of Examples indicated refer to the Preparation Examples described below.

Table 1 2. In vivo determination of the influence of substances on stomach tonicity Stomach tonicity plays an important role during emptying of the stomach. An increased stomach tone contributes to an accelerated emptying of the stomach. The influence of substances on stomach tonicity is determined in Beagle dogs with the help of a barostat, which is attached to a bag of synthetic material located inside the dog's stomach and which makes it possible to measure the volume or pressure in the dog's stomach. The stomach volume at constant pressure in the stomach or stomach pressure at a constant volume in the stomach are determined with the barostat. In the case of increasing the stomach tonicity, a decreased volume of the stomach is checked at a certain pressure and an increased pressure at a certain volume. In the test model used for the investigation of the increase in stomach tonicity that is produced by the substances, the modification of the volume of the stomach at constant pressure which is caused by the substances is measured.The stomach of the animals tested is measured. it relaxes by ingestion of lipids, that is to say the stomach tonicity decreases, with which the volume of the stomach increases correspondingly As a measure of the effect of increase of the stomach tonicity that the substances present, the reduction of the stomach volume increased by% is measured in%. the lipid intake that is established after ingestion of these substances by the new increase in stomach tonicity T a on of a nr 'is Ho l PH OG? TII 1 m; -p-? i fÉiQl-? p > n É- > -! 1- < - »mnHp l n p test, administered in the well-compatible dose of 2.15 μmol / kg i.d. (intraduodenally), a reduction in 59.5% of the stomach volume that has been increased after lipid intake. Oral administration of the above-mentioned test substance in the same dose of 2.15 μmol / kg produced an unusually pronounced reduction in stomach volume, the relaxation of stomach volume, induced by lipids, being practically prevented. These findings can be assessed as clear indications of a particularly high bioavailability, especially high orally, of the substances according to the invention. 3. In vivo determination of the influence of the substances on resting tonicity of the lower sphincter of the esophagus This determination is carried out in awake and fasted male Beagle dogs, to which, before the beginning of the test, esophageal fistulas and duodenal cannulas were placed. The pressure of the lower sphincter of the esophagus is measured by means of a perfused catheter system with lateral orifice, which is connected with a hand-held receiver and a recorder. The catheter is guided through the esophageal fistula to the stomach and then manually withdrawn slowly (traction manometry through). When passing the part of the catheter with the lateral orifice through the high pressure zone of the lower sphincter of the esophagus a peak is recorded. From this peak, the pressure in mm of Hg is determined. In this way, the basal sphincter pressure of the esophagus is first determined as a control value. The test substance is then orally applied and after 15 min the pressure in the lower sphincter of the esophagus is measured at 2 minute intervals for a period of 60 minutes. The increase in pressure is calculated after taking the test substance, compared to the predetermined basal pressure. In this test, the basal tonicity of the esophageal sphincter increased by 143% by a dose of 2.15 μmol / kg of the substance of Example 1. This effect persisted throughout the duration of the trial, 60 min. Because of their effects on the gastrointestinal tract, the compounds of Formula I are suitable in gas-troenterology as medicaments for higher mammalian animals, especially humans, for the prophylaxis and treatment of motility disorders of the gastrointestinal tract. The doses to be used may be individually diverse and vary naturally depending on the type of condition to be treated and the manner of application. For example, parenteral formulations will generally contain less active substance than oral preparations. In general, however, for applications to higher mammalian animals, especially humans, drug forms with an active substance content of 1 to 100 mg per individual dose are suitable. As medicaments, the compounds of Formula I can be contained together with conventional pharmaceutical adjuvants in galenical preparations such as, for example, tablets, capsules, suppositories or solutions. These galenic preparations can be produced according to methods known per se, using conventional solid carrier materials, such as, for example, lactose, starch or talc or liquid diluting agents, such as, for example, water, fatty oils or liquid paraffins and by using conventional pharmaceutically acceptable adjuvants, for example tablet disintegrating agents, solubilizers or preservatives.

The following Examples should explain the invention in greater detail, but do not limit the extension in any way.

Example 1: (2R, 3S, 4S, 5R, 6R, 10R, 11R) -3- [(2,6-Dideoxy-3-C-methyl-3-o-methyl-aL-ribohexopyranosyl) -oxi] -5- [3 , 4,6-trideoxy-3 - (N-methyl-N-isopropyl-amino) -β-D-xylohexopyranosyl) -oxi] -2,4,6,8,10-pentamethyl-11-acetyl-12, 13 -dioxabicyclo [8.2.1] -tridec-8-en-l-one (compound of Formula I, R1 = methyl, R2 = hydrogen) A) 100 g of [2R (2 'R, 3' R), 3S, 4S, 5R, 6R, 10R, 11R] -11- (2 ', 3'-dihydroxy-pent-2'-yl) -3 - [(2,6-dideoxy-3-C-methyl-3-0-methyl-aL-ribohexopyranosyl) -oxy] -5- [3,4,6-trideoxy-3- (N-methyl-N-isopropyl -amino) -β-D-xylohexopyranosyl) -oxy] -2, 4, 6, 8, 10 -pentamet il-12, 13-dioxabicyclo- [8.2.1] tridec-8-en-l-one (= compound of Formula II, R1 = methyl, R2 = hydrogen) were dissolved under a nitrogen atmosphere in 2500 ml of toluene. To this preload was added 100.0 g of lead tetraacetate. and the resulting suspension was stirred for 5 hours at room temperature. The reaction mixture was then washed consecutively with a saturated solution of sodium hydrogencarbonate and then with water as frequently as needed until the washing water reacted neutrally. The organic phase was dried over sodium sulfate and concentrated by evaporation under reduced pressure. Chromatography of the remaining residue on silica gel (eluent: methyl-tert-butyl-ether = MTBE) provided 81, 9 g of the title compound as a white powder, e.g. F. = 198 - 200 ° C, ppooddeerr: optical rotary r I 20 -24.6 '(c = 1.0 in CH2C12) B) 1.1 g of the compound obtained above were dissolved in 1 ml of acetonitrile. To this preload, 0.17 g of malonic acid was added, and it was heated to 60-70 ° C. After dissolution of the solid constituents, 10 ml of MTBE was added, and it was heated to boiling for 5 minutes while cooling to reflux. Then 10 ml of MTBE was added again and the mixture was allowed to cool with stirring at room temperature. The precipitated crystals were separated by filtration with respect to the solution, washed twice, each time with 10 ml of MTBE, and dried under vacuum at 60 ° C. 1.2 g of the monomalonate of the title compound were obtained, melting range: 115.6-174, 6 ° C (not clear).

Example 2 (2R, 3S, 4S, 5R, 6R, 10R, 11R) -3- [(2,6-Dideoxy-3-C-methyl-3-o-methyl-aL-ribohexopyranosyl) -oxi] -5- [3 , 4,6-trideoxy-2-O-acetyl-3- (N-methyl-1-N-isopropyl-amino) -β-D-xylohexo-pyrranosyl) -oxi] -2,4,6,8, 10- pentamethyl-11-acetyl-12, 13-dioxa-bicyclo [8.2.1] tridec-8-en-l-one (compound of Formula I, R1 = methyl, R2 = acetyl) A) 210.0 g of the starting compound of Example 1 (= compound of Formula II, R1 = methyl, R2 = hydrogen) were dissolved under a nitrogen atmosphere in 2.4 1 of acetone and mixed with 85.8 g. g of potassium carbonate. To this preload 63.4 g of acetic acid anhydride was added and the obtained suspension was stirred at room temperature for 20 hours. Then, the reaction mixture was poured onto a mixture of 2400 g of ice and 1000 ml of water and stirred for 30 minutes. The aqueous phase was extracted three times with ethyl acetate, the organic phases were combined and the excess solvent was concentrated by evaporation in a vacuum. Recrystallization from the crude product obtained in n-pentane afforded 200 g of [2R (2 'R, 3' R), 3S, 4S, 5R, 6R, 10R, 11R] -11- (2 ', 3' - dihydroxy-pent-2'-yl) -3- [(2,6-dideoxy-3-C-methyl-3-0-methyl-a; -L-ribohexopyranosyl) -oxy] -5- [3,4, 6- tridesoxy-2-0-acetyl-3- (N-methyl-N-isopropyl-amino) -β-D-xylohexopyranosyl) -oxy] -2,4,6,8,10-pentamethyl-12, 13- dioxabicyclo [8.2.1] -tridec-8-en-l-one (= compound of Formula II-, R1 = methyl, R2 = acetyl) P. f. = 128-130 ° C.

B) 10.1 g of the product obtained above were reacted in the manner described in Example 1 with 9.1 g of lead tetraacetate. 6.0 g of the title compound were obtained as white solid material, e.g. F. = 164 ° C, optical rotary power [I heard] 2D ° = -23.2 ° (c = 1.0 in CH2C12).

Example I: Capsules containing (2R, 3S, 4S, 5R, 6R, 10R, 11R) -3- [(2,6-dideoxy-3-C-methyl-3-0-methyl-aL-ribohexopyranosyl) -oxi] -5 - [3, 4, 6-trideoxy-3- (N-methyl-N-isopropyl-amino) -β-D-xylohexopyranosyl) -oxy] -2,4,6,8, 10-pentamethyl-11-acetyl- 12, 13-dioxabicyclo [8.2.1] tridec-8-en-l-one: Capsules containing the active substance were prepared using the following adjuvant and constituent substances per capsule: (2R, 3S, 4S, 5R, 6R, 10R, 11R) -3- [(2,6-dideoxy-3-C-methyl-3-0-methyl-aL-ribohexopyranosyl) -oxy] -5- [3 , 4,6-trideoxy-3- (N-methyl-N-isopropyl-amino) -β-D-xylohexopyranosyl) -oxy] -2,4,6,8,10-pentamethyl-11-acetyl-12, 13 -dioxabicyclo [8.2.1] - tridec-8-en-l-one 20 mg Corn starch 60 mg Lactose 301 mg Ethyl acetate (= -AE) is.

The active substance, corn starch and lactose were made with the aid of AE to form a homogenous paste mixture. The pulp was crumbled and the resulting granulate was placed on an appropriate sheet and dried at 45 ° C for solvent removal. The dried granules were passed through a shredder and mixed with the following additional adjuvants in a mixer: Talc 5 mg Magnesium stearate 5 mg Corn starch 9 mg and then it was packed in capsules with a capacity of 400 mg (= capsule size 0).

Claims (5)

1. - Compounds of (2R, 3S, 4S, 5R, 6R, 10R, 11R) -2, 4, 6, 8, 10-pentamethyl-11-acetyl-12, 13-dioxabicyclo [8.2.1] tridec-8-en -l-one of the general formula I wherein R 1 signifies hydrogen or methyl and R 2 signifies hydrogen or lower alkanoyl, and their salts by addition of physiologically compatible acids.

2. Compounds according to claim 1, wherein R1 means methyl.

3. Compounds according to one of the preceding claims, wherein R2 means hydrogen.

4. Medicaments, which contain a pharmacologically effective amount of a compound according to claim 1 and pharmaceutical adjuvants and / or vehicle substances.

5. Process for the preparation of compounds of (2R, 3S, 4S, 5R, 6R, 10R, 11R) -2,4,6,8, 10 -pentamethyl-11-acetyl-12, 13-dioxabicyclo [8.2. 1] tridec-8-en-l-one of the general Formula I wherein R 1 signifies hydrogen or methyl and R 2 signifies hydrogen or lower alkanoyl, and their salts by the addition of physiologically compatible acids, characterized in that in a compound of the general Formula II, wherein R1 and R2 have the above meanings, the 2 ', 3'-dihydroxy-pent-2'-yl side chain at position 11 of the cyclic backbone is transformed by oxidative cleavage with a glycol on an acetyl side chain and at If desired, in the compound obtained of Formula I, in which R 1 signifies hydrogen, a methyl radical R 1 is introduced, or in the obtained compound of Formula I, in which R 1 signifies methyl, the methyl radical R 1 is separated, and if desired free compounds of Formula I are transformed into their salts by the addition of acids, or the salts by addition of acids are transformed into the free compounds of Formula I. -COOH