IL128238A - 11-acetyl-12,13-dioxabicyclo [8.2.1] - tridecenone derivatives, processes for the preparation thereof and medicaments containing these compounds - Google Patents

Abstract

A (2R, 3S, 4S, 5R, 6R, 10R, 11R) - 2, 4, 6, 8, 10-pentamethyl-11- acetyl-12, 13-dioxabicyclo [8.2.1] - tridec- 8-en-1-one compound of the formula 2260 כ" ה באלול התשס" א - September 13, 2001 in which R1 denotes hydrogen or methyl, and R2 denotes hydrogen or lower alkanoyl, or a physiologically compatible acid addition salt thereof. They are for treatment of motility disturbances in the gastrointestinal tract.

Description

128238/2 Λ 1«31Λ Jl)i»D»il XttttWm pl&fft 0 3> ί1Λ ,}13-Η>1\5[1.2.8]-ϊ^7 3>.1«ρΐΝ -13,12- 11 JfllbW ll-Acetyl-12,13-dioxabicyclo[8.2.1]-tridecenone derivatives, processes for the preparation thereof and medicaments containing these compounds Solvay Pharmaceuticals GmbH C. 115308 ll-Acetyl-12 , 13 -dioxabicyclo [8.2.11 -tridecenone derivatives, processes for the preparation thereof and medicaments containing these compounds The present invention relates to novel N-substituted (2R, 3S,4S,5R, 6R, 10R, 11R) -3- [ (2 , 6-dideoxy-3-C-methyl-3-O-methyl-or-L-ribohexopyranosyl) -oxy] -5- [ (3,4,6-trideoxy-3-amino-3-D-xylohexopyranosyl) -oxy] -2,4,6,8, lO-pentamethyl-ll-acetyl-12 , 13-dioxabicyclo- [8.2.1] -tridec-8-en-l-one compounds with motilin-agonistic properties and to the acid addition salts thereof and also to pharmaceutical formulations containing these compounds and to processes for the preparation of these compounds. The compounds according to the invention are ring-contracted N-demethyl-N-isopropyl derivatives of erythromycin A with a modified side chain.

The antibiotic erythromycin A is known to have, in addition to its antibiotic effects, also gastrointestinal side effects which are undesirable for antibiotics, inter alia a great increase in the contraction activity in the gastrointestinal region with gastric and intestinal cramps, nausea, vomiting and diarrhoea.

There have been several attempts to modify erythromycin A so as to obtain derivatives in which the antibiotic effect is virtually no longer present, but an effect influencing the motility of the gastrointestinal tract is retained. European Patent No. 0 550 895 discloses ring-contracted N-demethyl-N-isopropyl-erythromycin A derivatives having gastrointestinally effective motilin-agonistic properties.

Furthermore, 'similar ring-contracted erythromycin derivatives are known from European Patent Application EP-A-382 472, but these have antibiotic effects.

IL 89996 discloses pharmaceutical compositions which comprise further similar ring-contracted erythromycin A derivatives as active ingredients. These compositions are useful in the treatment of gastrointestinal motility disorders.

The object of the present invention is to develop novel, orally-effective ring-contracted derivatives of erythromycin A without an antibiotic effect and with properties having a beneficial effect .on the motility of the gastrointestinal tract with an improved activity . profile..

It has now been found that the novel . ring-contracted N-demethyl-N-isopropyl derivatives of erythromycin A, the side chain of which in the 11 position of the cyclic parent structure has been modified by oxidation,, are not antibiotically effective, but have selectiv motilin-agonistic properties and stimulate the motility of the gastrointestinal tract in a beneficial way and show effects enhancing the tone of the lower' oesophagus sphincter and the tone of the stomach. ' Because of their activity profile, the substances according to the invention are suitable fo . the treatment of motility disturbances in the gastrointestinal tract and moreover are distinguished by good compatibility and good oral effectiveness.

The present invention therefore relates to "novel (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 compounds of the general formula I Furthermore, similar ring-contracted erythromycin derivatives are known from European Patent Application EP-A-382 472, but these have antibiotic effects.

The object of the present invention is to develop novel, orally-effective ring-contracted derivatives of erythromycin A without an antibiotic effect and with properties having a beneficial effect on the motility of the gastrointestinal tract with an improved activity profile.

It has now been found that the novel ring-contracted N-demethyl-N-isopropyl derivatives of erythromycin A, the side chain of which in the 11 position of the cyclic parent structure has been modified by oxidation, are not antibiotically effective, but have selective motilin-agonistic properties and stimulate the motility of the gastrointestinal tract in a beneficial way and show effects enhancing the tone of the lower oesophagus sphincter and the tone of the stomach.

Because of their activity profile, the substances according to the invention are suitable for the treatment of motility disturbances in the gastrointestinal tract and moreover are distinguished by good compatibility and good oral effectiveness.

The present invention therefore relates to novel (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 compounds of the general formula I 3 in which R1 denotes hydrogen or methyl, and R2 denotes hydrogen or lower alkanoyl, and the stable and physiologically compatible acid addition salts thereof.

If in compounds of Formula I one substituent is or contains lower alkyl, this may be branched or unbranched, and have 1 to 4 carbon atoms.

In particular, the compounds of Formula I in which R1 is methyl have proved beneficial.

R2 preferably stands for hydrogen. If R2 is lower alkanoyl, acetyl is preferred.

The compounds of Formula I can be obtained in that, in known manner, in a compound of the general formula II, in which R1 and R2 have the above meanings, the 2' ,3' -dihydroxypent-2 ' -yl side chain in the 11 position of the cyclic parent structure is converted by oxidative glycol cleavage into an acetyl side chain and, if desired, a methyl radical R1 is introduced into the resulting compound of Formula I in which R1 denotes hydrogen, or the methyl radical R1 is cleaved off in the resulting compound of Formula I in which R1 denotes methyl, and, if desired, free compounds of Formula I are converted into the stable acid addition salts thereof, or the acid addition salts are converted into the free compounds of Formula I .

The oxidative glycol cleavage of the 2 ', 3 ' -dihydroxypent-2 ' -yl side chain in the 11 position of the cyclic parent structure of compounds of Formula II can be performed using suitable oxidation agents such as lead tetraacetate in solvents suitable for this purpose.

Suitable solvents are non-polar or weakly polar solvents such as benzene, toluene or xylene. The reaction may be performed at temperatures between 0°C and 40°C, preferably at room temperature.

The resulting compounds of Formula I in which R1 denotes hydrogen can, if desired, subsequently be alkylated in known manner to give the corresponding N-methyl compounds. The alkylation can take place in known manner 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 of a complex borohydride compound such as sodium cyanoborohydride, sodium triacetoxyborohydride or sodium borohydride. If desired, the alkylation can also be carried out by reaction with a methyl halide, especially methyl iodide, or with a methylsulphonic acid ester. The alkylation is expediently carried out in an organic solvent which is inert under the reaction conditions. Suitable solvents for the reductive alkylation are cyclic ethers such as tetrahydrofuran (= THF) or dioxan, aromatic hydrocarbons such as toluene or alternatively lower alcohols. The alkylation can be carried out at temperatures between room temperature and the boiling point of the solvent. The alkylation with a methyl derivative, for example a methyl halide such as methyl iodide, is expediently carried out in the presence of a base such as, for example, an alkali metal carbonate or a tertiary organic amine.

The methyl radical R1 can, if desired, subsequently be cleaved off from the compounds of Formula I in which R1 denotes methyl . The demethylation can be effected in known manner by treating the compound with a halogen, in particular iodine and/or bromine, in an inert solvent in the presence of a suitable 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 known manner. Acid addition salts can be converted in conventional manner into the free bases, and the latter can, if desired, be converted in known manner into pharmacologically compatible acid addition salts. To avoid secondary hydrolysis reactions, it is expedient to use only equivalent amounts of acids for the salt formation.

Examples of suitable pharmacologically acceptable acid addition salts of the compounds of Formula I are the salts thereof with inorganic acids, for example carbonic acid, hydrohalic acids, especially hydrochloric acid, or with organic acids, for example lower aliphatic mono- or dicarboxylic acids such as maleic acid, fumaric acid, lactic acid, tartaric acid or acetic acid.

The starting compounds of Formula II in which R2 is hydrogen are known from EP-B 0 550 895, and can be prepared according to the processes described therein. The starting compounds of Formula II in which R2 is lower alkanoyl can be prepared by reacting compounds of Formula II in which R2 is hydrogen with carboxylic acids of the general formula III, R3-C00H III in which R3 is lower alkyl, or reactive derivatives of these acids, in known manner.

Suitable reactive derivatives of acids of Formula III are in particular optionally mixed acid anhydrides and acid halides. For example, acid chlorides or acid bromides of the acids of Formula III or mixed esters of the acids of Formula III with organic sulphonic acids, for example with lower alkanesulphonic acids optionally-substituted by halogen, such as methanesulphonic acid or trifluoromethanesulphonic acid, or with aromatic sulphonic acids such as benzenesulphonic acids or with benzenesulphonic acids substituted by lower alkyl or halogen, e.g. toluenesulphonic acids or bromobenzenesulphonic acids, can be used. The reaction may be performed 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 or aromatic hydrocarbons such as benzene or toluene or cyclic ethers such as THF or dioxan, or mixtures of these solvents.

The acylation can expediently be carried out in the presence of an acid-binding reagent, in particular if an anhydride or a mixed anhydride of the acids of Formula III with a sulphonic acid is used as acylation agent. 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 tert. lower alkylamines and pyridines, such as triethylamine, tripropylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, 4-diethylaminopyridine or -pyrrolidinopyridine .

If desired, a methyl radical R1 may be introduced into a resulting compound of Formula II in which R1 is hydrogen, or the methyl radical R1 in a resulting compound of Formula II in which R1 is methyl can be cleaved off. Such methylation or demethylation operations may be performed in known manner, for example under the conditions described for the 8 introduction or cleavage of a methyl group in the compounds of Formula I .

The novel compounds of Formula I and the physiologically compatible acid addition salts thereof have interesting pharmacological properties, especially motilin-agonistic properties stimulating the motility of the gastrointestinal tract. In this case, they are distinguished by a beneficial activity profile with surprisingly good oral effectiveness. They are free of antibiotic effects and have a high selective affinity for motilin receptors, whereas in dose ranges with motilin-agonistic effectiveness they show no practically relevant affinity for other receptors in the gastrointestinal tract such as adrenaline, acetylcholine, histamine, dopamine or serotonin receptors. The compounds have surprisingly good liver compatibility, which makes them suitable for applications over relatively long periods.

In order to ensure controlled digestion of the food consumed, in the healthy state, the autonomic nervous system and hormones in the gastrointestinal tract cooperate in order to generate a controlled contraction activity of the gastrointestinal tract not only immediately after intake of food but 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 the fasting state and after intake of food.

The compounds of Formula I show motilin-like physiological effects in that they act as agonists for motilin receptors. Thus, the compounds of Formula I show pronounced stimulating effects in the gastrointestinal region and at the lower oesophagus sphincter. In particular, they bring about an increased rate of gastric emptying, an increase in the stomach tone and a long-lasting increase in the resting tone of the oesophagus sphincter. Because of their motilin-like activity profile, the substances are suitable for the treatment of conditions which are associated with motility disturbances in the gastrointestinal tract and/or reflux of chyme from the stomach into the oesophagus. Thus, the compounds of Formula I are indicated, for example, for gastroparesis with a wide variety of causes, disturbances of the stomach tone, disturbances of gastric emptying and gastro-oesophageal reflux, dyspepsia and postoperative motility disturbances.

The gastrointestinally effective properties of the compounds of Formula I can be demonstrated in standard pharmacological test methods in vitro 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 for motilin receptors is measured in vitro on a fraction of a tissue homogenate from rabbit antrum. The displacement of radioactively labelled iodinated motilin from motilin receptor binding by the test substances is determined.

The receptor binding studies are carried out by a modification of the method of Borman et al . (Regulatory Peptides 15 (1986) , 143 - 153) . To prepare the 12Siodine-labelled motilin, motilin is iodinated enzymatically using lactoperoxidase in known manner, for example in analogy to the method described by Bloom et al. (Scand. J. Gastroenterol. JL1 (1976) 47 - 52).

To obtain the fraction of tissue homogenate used in the test from rabbit antrum, the antrum from which the mucosa have been removed is comminuted and homogenised in 10 times the volume of a cold homogenisation buffer solution (50 mM tris-HCl buffer, 250 mM sucrose, 25 mM KC1, 10 mM MgCl2, pH 7.4) with the addition of inhibitors (1 mM iodoacetamide, 1 μΜ pepstatin, 0.1 mM methylsulphonyl fluoride, 0.1 g/1 trypsin inhibitor, 0.25 g/1 bacitracin) with a homogeniser at 1500 revolutions per minute for 15 sec. The homogenate is then centrifuged at 1000 g for 15 minutes, the resulting residue is washed four times with homogenisation buffer solution and finally re-suspended in 0.9% strength sodium chloride solution (in a volume corresponding to 5 times the amount by weight of the antrum) . The tissue fraction obtained in this way, which is referred to as "crude membrane preparation", is used for the test.

For the binding test, 200 μΐ of the crude membrane fraction (0.5 - 1 mg of protein) in 400 μΐ of a buffer solution A (50 mM tris-HCl buffer, 1.5% bovine serum albumen (BSA) , 10 mM MgCl2, pH 8.0) are incubated with 100 μΐ of iodinated motilin diluted in buffer solution B (10 mM tris-HCl buffer, 1% BSA, pH 8) (final concentration 50 pM) at 30°C for 60 min. The reaction is stopped by adding 3.2 ml of cold buffer solution B, and bound and non-bound motilin are separated from one another by centrifugation (1000 g, 15 minutes) . The residue obtained as pellets after the centrifugation is washed with buffer solution B and counted in a gamma counter. The displacement studies are carried out by adding increasing amounts of the substance to be tested to the incubation medium. The test substance solutions used are aqueous solutions which are prepared by-suitable dilution of 60 x 10"4 molar aqueous stock solutions. Test substances which are sparingly soluble in water are initially dissolved in 60% strength ethanol, and this solution is diluted with sufficient water for the ethanol concentration in the solution to be tested not to exceed 1.6% by volume. The ICS0 of the particular test substance is determined from the resulting measured data as that concentration which brings about 50% inhibition of the specific binding of the iodinated motilin to the motilin receptors. From this the corresponding pIC50 value is calculated. The pIC50 values given in Table 1 below were determined for the substances of Examples 1 and 2 using the above method. The Example numbers quoted relate to the preparation examples described below.

Table 1 2. In vivo determination of the effect of the substances on the stomach tone.

The stomach tone plays an important role in gastric emptying. An increased stomach tone contributes to an increased rate of gastric emptying.

The influence of substances on the stomach tone is determined on beagles with the aid of a barostat which is connected to a plastic pouch in the stomach of the dog and permits measurement of volume or pressure in 12 the stomach of the dog. With the barostat, the stomach volume is determined at a constant pressure in the stomach or the stomach pressure is determined at a constant volume in the stomach. When the stomach tone increases, a reduced stomach volume is detected at a given pressure, and an increased pressure at a given volume. In the test model used to investigate the increase in stomach tone effected by the substances, the change in stomach volume caused by the substances is measured at constant pressure. The stomach of the test animals is relaxed by intake of lipids, i.e. the stomach tone decreases, which causes the stomach volume to increase correspondingly. The reduction in % of the stomach volume which has been increased by administration of lipids which occurs after intake of the substance due to a re-increase in stomach tone is measured as a measurement of the stomach tone-increasing effect of the substances.

The substance of Example 1 in this test model, administered i.d. in the readily compatible dose of 2.15 μπιοΐ/kg, showed a reduction in the stomach volume increased after lipid administration by 59.5%. Oral administration of the above test substance in the same dose of 2.15 μιηοΐ/kg caused an unusually marked reduction in the stomach volume, the lipid-induced relaxation of the stomach volume being practically completely hindered. These findings can be used as clear indications of a particularly high, in particular high oral, bioavailability of the substances according to the invention. 3. In vivo determination of the effect of the substances on the resting tone of the lower oesophagus sphincter. 13 This determination is carried out on male, conscious, fasting beagles which, before the start of the test, have each been provided with an oesophagus fistula and a duodenal cannula. The pressure of the lower oesophagus sphincter is measured by means of a perfused catheter system which has a lateral opening and which is connected to a pressure transducer and a recorder. The catheter is passed through the oesophagus fistula into the stomach and then slowly withdrawn manually (= pull-through manometry) . A peak is recorded when the catheter part with the lateral opening passes through the high-pressure zone of the lower oesophagus sphincter. The pressure in mm Hg is determined from this peak.

In this way, initially the basal pressure of the oesophagus sphincter is determined as control value. Subsequently, the test substance is administered orally and, after 15 min., the pressure at the lower oesophagus sphincter is measured at 2-minute intervals for a period of 60 min. The increase in the pressure after administration of test substance compared with the previously determined basal pressure is calculated.

In this test, the basal tone of the oesophagus sphincter was increased by 143% by oral administration of a dose of 0.464 μηιοΐ/kg of the substance of Example 1. This effect persisted throughout the entire 60 min. duration of the test .

Because of their effects in the gastrointestinal tract, the compounds of Formula I are suitable in gastroenterology as medicaments for larger mammals, especially humans, for the prophylaxis and treatment of motility disturbances in the gastrointestinal tract. 14 The doses to be used may differ between individuals and will naturally vary depending on the nature of the condition to be treated and the form of administration. For example, parenteral formulations will generally contain less active substance than oral preparations. However, in general medicament forms with an active substance content of 1 to 100 mg per single dose are suitable for administration to larger mammals, especially humans.

As medicinal agents, the compounds of Formula I may be contained with conventional pharmaceutical auxiliary substances in pharmaceutical formulations such as, for example, tablets, capsules, suppositories or solutions. These pharmaceutical formulations may be prepared by known methods using conventional solid vehicles such as, for example, lactose, starch or talcum, or liquid diluents such as, for example, water, fatty oils or liquid paraffins, and using customary pharmaceutical auxiliary substances, for example tablet disintegrants, solubilisers or preservatives.

The following examples are intended to explain the invention in greater detail but do not restrict its scope in any way.

Example 1: (2R,3S,4S, 5R, 6R, 10R, 11R] -3- [ (2 , 6-dideoxy-3-C-methyl-3-0-methyl-a-L-ribohexopyranosyl) -oxy] -5- [ (3,4,6-trideoxy-3- (N-methyl-N-isopropylamino) -β-Ό-xylo-hexopyranosyl) -oxy] -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 [2R(2'R,3'R) , 3S , 4S , 5R, 6R, 10R, 11R] -11- (2' ,3'- dihydroxypent-2 ' -yl) -3- [ (2 , 6-dideoxy-3-C-methyl-3- O-methyl-a-L-ribohexopyranosyl) -oxy] -5- [ (3,4, 6- trideoxy-3- (N-methyl-N-isopropylamino) -/3-D-xylo-hexopyranosyl ) -oxy] -2,4,6,8, 10 -pen amethyl -12,13-dioxabicyclo [8.2.1] -tridec-8-en-l-one (= compound of Formula II, R1 = methyl, R2 = hydrogen) was dissolved in 2500 ml toluene under a nitrogen atmosphere. 100.0 g lead tetraacetate was added to this receiving mixture, and the resulting suspension was stirred for 5 hours at room temperature. Then the reaction mixture was washed successively with saturated sodium hydrogen carbonate solution and then with water until the washing water reacted neutrally. The organic phase was dried over sodium sulphate and evaporated at reduced pressure. Chromatography of the remaining residue on silica gel (mobile solvent: methyl tert. butyl ether = MTBE) yielded 81.9 g of the title compound as a white powder, melting point - 198° - 200°C, optical rotation [a]£° = -24.6° (c = 1.0 in CH2C12) . 1.1 g of the compound obtained above was dissolved in 1 ml acetonitrile . 0.17 g malonic acid was added to this receiving mixture, and the mixture was heated to 60° - 70°C. Once the solid constituents had dissolved, 10 ml MTBE was added and the mixture was heated to boiling for 5 minutes with reflux cooling. Then another 10 ml MTBE was added, and the mixture was cooled to room temperature with stirring. The crystals produced were filtered off from the solution, washed twice with 10 ml MTBE each time, and were dried at 60 °C in a vacuum. 1.2 g of the monomalonate of the title compound were obtained, melting range: 115.6 - 174.6°C (indefinite).

Example 2 ; (2R,3S, 4S, 5R, 6R, 10R, 11R) -3- [ (2 , 6-dideoxy-3-C-methyl-3-O-methyl-a-L-ribohexopyranosyl) -oxy] -5- [ (3,4,6-trideoxy-2-0-acetyl-3- (N-methyl-N-isopropylamino) -β-Ό-xylohexopyranosyl) -oxy] -2,4,6,8, 10-pentamethyl-ll-acetyl- 12, 13-dioxabicyclo [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) was dissolved in 2.4 1 acetone under a nitrogen atmosphere and 85.8 g potassium carbonate was added thereto. 63.4 g acetic anhydride was added to this receiving mixture, and the resulting suspension was stirred for 20 hours at room temperature. Then the reaction mixture was poured on to a mixture of 2,400 g ice and 1,000 ml water and was stirred for 30 minutes. The aqueous phase was extracted three times with ethyl acetate, the organic phases were combined and the excess solvent was evaporated off in a vacuum.

Recrystallisation of the resulting crude product from n-pentane yielded 200 g [2R(2'R,3'R) ,3S,4S,5R,6R,10R, 11R] -11- (2' ,3'- dihydroxypent-2' -yl) -3- [ (2 , 6-dideoxy-3-C-methyl-3- 0-methyl-a-L-ribohexopyranosyl) -oxy] -5- [(3,4,6- trideoxy-2-0-acetyl-3- (N-methyl-N-isopropylamino) - /3-D-xylohexopyranosyl) -oxy] -2,4, 6,8, 10- pentamethyl-12, 13-dioxabicyclo [8.2.1] -tridec-8-en- 1-one (= compound of Formula II, R1 = methyl, R2 = acetyl) , melting point = 128° - 130°C.

B) 10.1 g of the product obtained above was reacted with 9.1 g lead tetraacetate in the manner described in Example 1. 6.0 g of the title compound was obtained as a white solid, melting 17 point = 16 °C, optical rotation [α]£° = -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- Q!-L-ribohexopyranosyl) -oxy] -5- [ (3,4, 6-trideoxy-3- (N-methyl-N-isopropylamino) -jS-D-xylohexopyranosyl) -oxy] -2 , 4 , 6, 8 , 10-pentamethyl-ll-acetyl-12 , 13-dioxabicyclo [8.2.1] -tridec-8-en-l-one : Capsules containing the active substance were produced using the following auxiliary substances and ingredients per capsule: (2R,3S,4S,5R,6R,10R,11R) -3- [ (2 , 6-dideoxy-3 -C-methyl-3-O-methyl-ar-L-ribohexopyranosyl) -oxy] -5- [ (3 , 4 , 6-trideoxy-3- (N-methyl-N-isopropylamino) -jS-D-xylohexopyranosyl) -oxy] -2,4,6,8, 10-pentamethyl-ll-acetyl-12 , 13-dioxabicyclo [8.2.1] -tridec-8-en-1-one 20 mg Corn starch 60 mg Lactose 301 mg Ethyl acetate (= EA) q.s.

The active substance, the corn starch and the lactose were processed to form a homogenous, pasty mixture using EA. The paste was comminuted, and the resulting granules were placed on a suitable metal sheet and dried at 45°C to remove the solvent. The dried granules were passed through a comminuting machine and mixed with the following additional auxiliary substances in a mixer: Talc 5 mg Magnesium stearate 5 mg Corn starch 9 mg 18 and then poured into 400 tng-capacity capsul (= capsule size 0) . 19

Claims (13)

1. A (2R/3Si4S,5R,6R,10R/llR) -2 , 4 , 6, 8 , 10-pentamethyl-ll-acetyl-12 , 13-dioxabicyclo [8.2.1] -tridec-8-en-l-one compound of the general formula I in which R1 denotes hydrogen or methyl, and R2 denotes hydrogen or lower alkanoyl, or a physiologically compatible acid addition salt thereof.

2. A compound according to Claim 1, in which R1 is methyl.

3. A compound according to any one of the above claims , in which R2 is hydrogen.

4. A pharmaceutical composition comprising a compound according to any one of Claims 1 to 3 and a carrier. 20

5. A process for the preparation of a (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 compound of the general formula I in which R1 denotes hydrogen or methyl, and R2 denotes hydrogen or lower alkanoyl, or a physiologically compatible acid addition salt thereof, characterised in that in a compound of the general formula II, 21 in which R1 and R2 have the above meanings, the 2 ' , 3 ' -dihydroxypent-2 ' -yl side chain in the 11 position of the cyclic parent structure is converted by oxidative glycol cleavage into an acetyl side chain and, if desired, a methyl radical R1 is introduced into the resulting compound of Formula. I in which R1 denotes hydrogen, or the methyl radical R1 is cleaved off in the resulting compound of Formula I in which R1 denotes methyl, and, if desired, a free compound of Formula I is converted into an acid addition salt thereof, or the acid addition salt is converted into the free compound of Formula I .

6. A compound according to any one of claims 1 to 3 for use as motilin agonist. ;

7. A compound according to any one of claims 1 to 3 for the prophylaxis and/or treatment of motility disturbances | in the gastrointestinal tract. ί ' f

8. Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for use as a motilin . ; agonist, sustantially as described in the specification.

9. Use of a compound according to any one of claims- 1 to 3 for the manufacture of a medicament for the prophylaxis and/or treatment of motility disturbances in the gastrointestinal tract, substantially as described in the specification. 128238/1 22

10. A composition according to claim 4 for use as a motilin agonist .

11. A composition according to claim 4 for the prophylaxis and/or treatment of motility disturbances in the gastrointestinal tract.

12. Use of a composition according to claim 4 for the manufacture of a medicament for use as a motilin agonist, substantially as described in the specification.

13. Use of a composition according to claim 4 for the manufacture of a medicament for prophylaxis and/or treatment of motility disturbances in the gastrointestinal tract, substantially as described in the specification. ror the Applicants REINHOLD COHN AND PARTNERS