SK285313B6 - 11-Acetyl-12,13-dioxabicyclo[8.2.1]-tridecenones derivatives, process for making them and pharmaceutical compositions containing them - Google Patents

Abstract

Ring-contracted N-desmethyl-N-isopropyl-erythromycin-A derivatives having a modified side chain and gastrointestinally effective motilin-agonistic properties, the preparation thereof and pharmaceutical compositions containing them are described.

Description

Technical field

The present invention relates to novel derivatives of (2R, 3S, 4S, 5R, 6R, 10R, 11R) -3 - [(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl) oxy ] -5- [3,4,6-trideoxy-3-amino - [1-D-xylohexopyranosyl] oxy] -2,4,6,8,10-pentamethyl-11-acetyl-12,13-dioxabicyclo [ 8.2.1] tridec-8-en-1-one, substituted on a nitrogen atom, with motilin-agonist properties and their stable and physiologically acceptable acid addition salts, as well as medicaments containing these compounds. The derivatives of the invention are cyclically reduced N-desmethyl- N -isopropyl derivatives of erythromycin A with a modified side chain.

BACKGROUND OF THE INVENTION

As is known, the antibiotic erythromycin A has, in addition to its antibiotic effects, undesirable gastrointestinal side effects for antibiotics, inter alia a strong increase in contraction activity in the gastrointestinal tract area, nausea, vomiting and exaggeration.

There have been several attempts to modify erythromycin A to obtain derivatives in which there is practically no antibiotic effect, but an effect affecting the motility of the gastrointestinal tract is maintained. EP-A-0 550 895 discloses ring-reduced Ndesmethyl-N-isopropyl-erythromycin A derivatives with gastrointestinal potentiating motilin agonist properties.

Further, ring-erythromycin-like derivatives of erythromycin are known from patent application EP-A 382 472 but have antibiotic effects.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide novel orally active erythromycin A derivatives with reduced ring sizes without antibiotic effect and properties with an improved profile, favorably affecting the motility of the gastrointestinal tract.

It has been found that the novel A-desmethyl-A-isopropyl derivatives of erythromycin A with reduced rings whose side chain has been modified by oxidation at position 11 of the cyclic backbone are not antibiotic active but have selective motilin agonist properties and favorably stimulate gastrointestinal tract motility and exert enhancing effects on the lower esophageal sphincter tone and on the stomach tone.

Because of their effective profile, the compounds according to the invention are suitable for the treatment of motility disorders in the gastrointestinal tract and are characterized by good tolerability and good oral efficacy.

The present invention therefore relates to novel derivatives 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-1-one of formula (1)

where

R ¹ is hydrogen or methyl,

R ² is hydrogen or lower alkanoyl containing from 1 to 4 carbon atoms, and the stable and physiologically acceptable acid addition salts.

Particularly suitable are compounds of formula (I) wherein R ¹ is methyl.

R ² is preferably hydrogen. When R ² is lower alkanoyl, acetyl is preferred.

The compounds of formula (I) may be prepared by a known method in a compound of formula (II),

wherein R ¹ and R ² are as defined herein, convert the 2 ', 3'-dihydroxypent-2-yl side chain at position 11 of the cyclic backbone by oxidative glycol cleavage to the acetyl side chain and optionally to obtain the compound of formula (I) obtained. wherein R ¹ is hydrogen, a methyl radical is introduced or is cleaved from the compound of formula (I), wherein R ¹ is methyl, the methyl radical is cleaved, and optionally the free compounds of formula (I) are converted to their stable and physiologically acceptable addition salts with with acids or their stable and physiologically acceptable acid addition salts are converted into the free compounds of formula (I).

Oxidative glycol cleavage of the 2 ', 3'-dihydroxypent-2-yl side chain at position 11 of the cyclic backbone of compounds of formula (II) may be accomplished by suitable oxidizing agents, e.g. lead acetate in suitable solvents such as non-polar or weakly polar solvents such as benzene, toluene or xylene. The reaction may be carried out at temperatures between 0 ° C and 40 ° C, preferably at room temperature.

The obtained compounds of formula (I), wherein R ¹ is hydrogen, can be additionally alkylated in a known manner to the corresponding N-methyl compounds in a known manner. The alkylation may be carried out in a known manner by reaction with a methyl halide or as a reductive alkylation by reaction with formaldehyde under reducing conditions and may be carried out, for example, in the presence of a reducing agent, for example a complex borohydride compound such as

Is sodium cyanoborohydride, sodium triacetoxyborohydride or sodium borohydride. Alternatively, the alkylation may also be carried out by reaction with a methyl halide, in particular methyl iodide or methylsulfonic acid ester. Suitably, the alkylation can be carried out under reaction conditions in an inert solvent. Suitable solvents for reductive alkylation are cyclic ethers such as tetrahydrofuran (= THF) or dioxane, aromatic hydrocarbons such as toluene or lower alcohols. The alkylation can take place 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 conveniently carried out in the presence of a base such as an alkali metal carbonate or a tertiary organic amine.

From the compounds of formula (I) wherein R ¹ is methyl, the methyl radical may be additionally cleaved. The demethylation may be carried out in a known manner by treatment with halogen, in particular iodine or bromine, in an inert solvent in the presence of a suitable base. Suitable bases are, for example, alkali metal alcoholates and alkali metal salts of weak organic acids.

The compounds of formula (I) can be isolated and purified from the reaction mixture in a known manner. The acid addition salts may be converted into the free bases in a known manner and, if desired, they may be converted in a known manner into stable and physiologically acceptable acid addition salts. To avoid hydrolysis reactions, it is expedient to use only an equivalent amount of acids for salt formation.

Suitable stable and physiologically acceptable acid addition salts of the compounds of formula (I) are, for example, their inorganic acid salts, e.g. with carbonic acid, hydrohalic acids, especially hydrochloric acid or organic acids, for example aliphatic mono- or dicarboxylic acids, such as maleic, fumaric, lactic, tartaric or acetic acids.

The starting compounds of formula (II) wherein R ² is hydrogen are known from patent application EP-B 0550 895 and can be prepared by the process described herein.

The starting compounds of formula (II) wherein R ² is lower alkanoyl can be prepared by reacting compounds of formula (11) wherein R ² is hydrogen in a known manner with carboxylic acids of formula (III)

R ² -COOH (III) wherein R ³ is lower alkyl or with reactive derivatives of these acids.

Suitable acid derivatives of the formula (III) are, in particular, possible mixed anhydrides and acid halides. For example, acid chlorides or bromides of formula (III) may be used with organic sulfonic acids, for example, optionally lower alkanesulfonic acids, halogen substituted, such as methanesulfonic acid or trifluoromethanesulfonic acid, or benzenesulfonic acids substituted with lower alkyl or halogen, for example toluenesulfonic acid. . The reaction may be carried out as acylation under reaction conditions in an inert organic solvent at temperatures between -20 ° C and room temperature. Suitable solvents are lower dialkyl ketones, for example acetone, halogenated hydrocarbons such as dichloromethane or aromatic hydrocarbons such as benzene or toluene, or cyclic ethers such as THF or dioxane, or mixtures of these solvents.

Acylation may conveniently be used, in particular, when an anhydride or a mixed anhydride of the acid of formula (III) with a sulfonic acid in the presence of acidifying agents is used as the acylating agent. Suitable acidifying agents are, for example, inorganic bases such as alkali metal carbonates such as potassium carbonate or organic bases soluble in the reaction mixture as tertiary nitrogen bases, for example tertiary lower alkyl amines, pyridines such as triethylamine, tripropylamine, Λ'-methylmorpholine, pyridine, 4-dimethylaminopyridine, 4-diethylaminopyridine or 4-pyrrolidinopyridine.

Optionally, a methyl radical R ¹ may be introduced into the compound of formula (II) wherein R ¹ is hydrogen or the methyl radical may be cleaved from the compound of formula (II) wherein R ¹ is methyl. These methylations or demethylations may be carried out in a manner known per se, under the conditions described, for example, for introducing a methyl group into or cleaving it from derivatives of formula (I).

The novel derivatives of formula (I) and their stable physiologically acceptable acid addition salts have interesting pharmacological properties, in particular motilin agonist properties, which stimulate motility of the gastrointestinal tract. They have a favorable effect profile with good oral efficiency. They are devoid of antibiotic effects and have a high selective affinity for motilin receptors, while exhibiting virtually no relevant affinity for other receptors in the gastrointestinal tract, such as adrenaline, acetylcholine, histamine, dopamine or serotonin receptors in the agonist-effective motilin dose range. Surprisingly, the compounds have good liver compatibility and are therefore suitable for use over an extended period of time.

In order to ensure the controlled digestion of food intake, the autonomous nervous system and hormones of the gastrointestinal tract act in a healthy state, not only directly after ingestion of the food, but also when the gastrointestinal tract is empty. Motilin is a known gastrointestinal peptide hormone that stimulates the motility of the gastrointestinal tract and induces coordinated motility throughout the gastrointestinal tract in the fasted state as well as after ingestion of food.

The compounds of formula (I) exhibit the physiological effects of motilin by becoming effective as agonists for motilin receptors. The compounds of formula (I) thus exhibit excellent stimulating effects in the digestive tract and in the lower esophageal sphincter. In particular, they cause an acceleration of gastric emptying, an increase in gastric tone and a prolonged increase in the tone of the esophageal sphincter tone. Due to their effective motilin profile, the substances are suitable for the treatment of disease states that are associated with motility disorders in the gastrointestinal tract or returning a slurry of food from the stomach to the esophagus. The compounds of formula (I) are recommended, for example, in gastroparitis of various origins, gastric tone disorders, gastric emptying disorders and gastroesophageal reflux disorders, dyspesia and postoperative motility disorders.

DETAILED DESCRIPTION OF THE INVENTION

The gastrointestinal efficacy of the compounds of formula (I) can be demonstrated by pharmacological test methods in both the test tube and the living body:

Description of test methods.

1. Determination of the ability of test substances to bind motilin receptors.

The affinity of the compounds of formula (I) for motilin receptors is assayed in a tube fraction of tissue homogenate from the prepyrolithic portion of the rabbit stomach. Displacement, by radioactive iodine-labeled motilin, from motilin-receptor binding by test substances is determined.

Receptor binding studies are performed according to a modification of the method of Borman et al. (Regulators of Peptide 15 (1986), 143-153). For the preparation of iodine 125-labeled motilin, motilin is enzymatically iodinated in a known manner, e.g. analogous to the method described by Bloom et al. (Scand. J. Gastroenterol. 11 (1986) 47-52), using lactoperoxidase.

To obtain the tissue homogenate from the prepyrolytic portion of the rabbit stomach used in the assay, the mucosa-free prepyrolytic portion of the stomach is crushed and homogenized in a 10-fold volume of cold homogenization buffer (50 mM tris-HCl buffer, 250 mM sucrose, 25 mM KCl, 10 mM). mM _MgCl2, pH 7.4) with the addition of inhibitors (1 mM iodoacetamide, 1 .mu.M pepstatin, 0.1 mM methylsulfonyl fluoride, 0.1 g / 1 of trypsin inhibitor, 0.25 g / 1 of bacitracin) with a homogenizer at 15 s 1500 rpm. The homogenate is centrifuged for 15 minutes at 1000 g, the residue is washed four times with homogenizing buffer and finally resuspended in 0.9% sodium chloride solution (in a volume corresponding to five times the mass of the prepyrolytic portion of the stomach). The tissue fraction thus obtained, referred to as the "raw membrane preparation", is used for the assay.

For the binding assay, 200 µl of crude membrane fraction (0.5-1 mg protein) is incubated in 400 µl of Buffer A (500 mM Tris-HCl buffer, 1.5% BSA, 10 mM MgCl ₂ , pH 8.0). 100 µl of iodinated motilin in buffer B (10 mM tris-HCl buffer, 1% BSA, pH 8), diluted to (final concentration of 50 µM), 60 min. at 30 ° C. The reaction is stopped by addition of 3.2 ml of cold buffer B and bound and unbound motilin is separated by centrifugation (1000 g, 15 minutes) and measured in a gamma counter. Mucosal studies are performed by adding an increasing amount of the substance to be measured to the incubation medium. Aqueous solutions are prepared as test solutions of the substances and are prepared by appropriate dilution of 60 χ 10 ^-4 molar suitable stock solutions. Test substances which are sparingly soluble in water are initially dissolved in 60% ethanol, and this solution is diluted with an amount of water such that the concentration of ethanol in the solution to be tested does not exceed 1.6% by volume. From the obtained measurement data is determined as the _IC50 concentration of each test substance which causes 50% inhibition of specific binding of the iodinated motilin to the motilin receptors. The corresponding pIC ₅ value is then calculated from this. According to the previous method, the values given in Table 1 were determined for the substances of Examples 1 and 2. The given example numbers refer to the examples described in the following.

Table 1

Example # PIC ₅₀ 1 8.01 2 7.75

Determination of the effect of substances on the stomach tone in the living body.

Stomach tone plays an important role in gastric emptying. Increased gastric tone contributes to its accelerated emptying.

The effect of substances on the stomach tone is determined on the beagle stomach tone by means of a barostat, which is connected to a plastic bag in the dog's stomach and allows measurement of the dog's stomach volume and pressure. The barostat is used to determine the stomach volume at a constant stomach pressure or the stomach pressure at a constant volume. With an increased gastric tone, a reduced gastric volume and an increased pressure at a certain volume are determined at a certain pressure. In the model used to test substances causing gastric tone increase, the gastric change caused by the substances is measured at constant pressure. The stomach of the test animal is relaxed by lipid uptake, i. j. the stomach tone drops, thereby increasing the stomach volume accordingly. As a measure of the increasing effect of substances on the gastric tone, the resulting reduction in gastric volume, increased by the addition of lipid upon ingestion, is measured in% by the gastric tone increase again.

In this test model, the compound of Example 1 showed a well-acceptable dose of 2.15 pmol / kg, provided i. d., a decrease in stomach volume of 59.5% after lipid addition. Oral administration of the aforementioned substance at the same dose of 2.15 pmol / kg caused an unusually significant decrease in gastric content, whilst the induced relaxation of gastric volume was completely prevented by the lipid. These findings can be evaluated as significant indications for the high, especially high oral bioavailability of the substances of the invention.

Determination of the impact of substances in the living body on the tone of the lower esophageal sphincter at rest.

This determination is performed on fasted beagle fasted dogs that were inserted into the esophagus and a fine tube into the duodenum prior to the start of the fistula experiment. The lower esophageal sphincter pressure is measured using a perfused catheter system with a side orifice that is connected to a pressure transducer and recording device. The catheter is passed through the esophagus fistula into the stomach and then slowly withdrawn manually (= transit manometry). When the part of the catheter with the side opening is pressed through the high pressure zone of the lower esophageal sphincter, the peak is registered. The pressure in mm Hg is then determined from this peak.

In this way, a control value of the initial pressure of the esophageal sphincter is first determined. Subsequently, the test substance is applied and after 15 minutes the pressure on the lower esophageal sphincter is measured at 2 minute intervals for 60 minutes. The increase in post-dose pressure of the test substance is calculated as compared to the baseline pressure.

In this test, the baseline tone of the esophageal sphincter was increased by a dose of 2.15 pmol / kg of the substance of Example 1 by 143%. This effect was maintained for a total test time of 60 minutes.

Because of their effects in the gastrointestinal tract, the compounds of formula (I) are useful in gastroenterology as medicaments for larger mammals, particularly humans, for the prophylaxis and treatment of motility disorders in the gastrointestinal tract.

The doses to be used may vary individually and may naturally vary according to the type of condition to be treated and the forms of administration. For example, parenteral formulations will generally contain less active ingredient than oral preparations. In general, however, dosage forms containing from 1 to 100 mg per unit dose are suitable for administration to higher mammals, especially humans.

As therapeutic agents, compounds of formula (I) may be included with conventional pharmaceutical agents in galenic formulations, such as e.g. tablets, capsules, suppositories or solutions. These galenic formulations may be made according to known methods using conventional solid carriers such as e.g. milk sugar, starch and talc or liquid diluents such as e.g. water, liquid fats or liquid paraffins and using pharmaceuticals

These are known excipients, for example, tablet disintegrators, dissolution aids or preservatives.

The following examples are intended to illustrate the invention in more detail, but the scope thereof is not limited in any way.

Example 1 [2R, 3S, 4S, 5R, 6R, 10R, 11R] -3 - [(2,6-Dideoxy-3-C-methyl-3-O-methyl-α-ribohexopyranosyl) -oxy] -5 - [(3,4,6-trideoxy-3- (A / N-methyl-7V-isopropylamino) -3-D-xylo-hexopyranosyl) -oxy] -2,4,6,8,10-pentamethyl-11-acetyl-12 13-dioxabicyclo [8.2.1] tridec-8-en-1-one (compound of formula (I), R ^{1 =} methyl, R ² = hydrogen)

100 g of [2R (2'R, 3'R), 3S, 4S, 5R, 6R, 10R, 11R] -1- (2 ', 3'-dihydroxypent-2'-yl) -3 - [(2, 6-dideoxy-3-C-methyl-3-O-methyl-.alpha.-L-ribohexopyranosyl) oxy] -5- [3,4,6-trideoxy-3- (N-methyl- / V-isopropylamino) -pD- xylohexopyranosyl) oxy] 2,4,6,8,10-pentamethyl-12,13-dioxabicyclo [8.2.1] tridec-8-en-1-one (compound of formula (II), R ¹ = methyl, R ² = hydrogen) was dissolved in 2500 ml of toluene under nitrogen. To this was added 100 g of lead acetate and the resulting suspension was stirred for 5 hours at room temperature. Subsequently, the reaction mixture was washed in this sequence with saturated sodium bicarbonate solution and then so often washed with water until the wash water was neutral. The organic phase was dried over sodium sulfate and evaporated under reduced pressure. Chromatography of the residue on silica gel (eluent, methyl tert-butyl ether = MTBE) gave 81.9 g of the title compound as a white powder, melting point = 198 ° C to 200 ° C, optical rotation [α] _D = -24.6 ° (c = 1.0 in CH ₂ Cl ₂ ).

1.1 g of the obtained compound was dissolved in 1 ml of acetonitrile. To this was added 0.17 g of malonic acid and heated to 60 ° C-70 ° C. After dissolution of the solids, 10 mL of MTBE was added and refluxed for 5 minutes. Subsequently, 10 ml of MTBE was added again and the mixture was allowed to cool to room temperature while stirring. The precipitated crystals were filtered off, washed twice with 10 ml MTBE and dried at 60 ° C under vacuum. 1.2 g of the title compound monomalonate were obtained, m.p. 115.6 ° C - 174 ° C (fuzzy).

Example 2 (2R, 3S, 4S, 5R, 6R, 10R, 11R) -3 - [(2,6-Dideoxy-3-C-methyl-3-O-methyl-α-ribohexopyranosyl) oxy] -5 - [(3,4,6-trideoxy-2-O-acetyl-3- (N-methyl-N-isopropylamino) -β-D-xylohexopyranosyl) 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 = acetyl)

210 g of the starting compound of Example 1 (compound of formula (II), R ¹ = methyl, R ² = H) were dissolved under nitrogen in 2.4 1 of acetone and treated with 85.8 g of potassium carbonate. To this was added 63.4 g of acetic anhydride and the resulting suspension was stirred for 20 hours at room temperature. Subsequently, the reaction mixture was quenched with 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 phase was concentrated and the excess solvent was evaporated in vacuo. Recrystallization of the crude product obtained from n-pentane yielded 200 g of [2R (2'R, 3'R), 3S, 4S, 5R, 6R, 10R, 11RJ-11- (2 ', 3'-dihydroxypent-2). '-yl) -3 - [(2,6-dideoxy-3-C-methyl-3-O-methyl-.alpha.-L-ribohcxopyranozyl) oxy] -5- [3,4,6-tri deoxy-2-O-acetyl -3- (N-methyl-N-isopropylamino-β-D-xylohexopyranosyljoxy) 2,4,6,8,10-pentamethyl-12,13-dioxabicyclo [8.2.1] tridec-8

-en-1-one (compound of formula (II), R ¹ = methyl, R ² = acetyl), mp 128 ° C -130 ° C.

10.1 g of the product obtained above were reacted with 9.1 g of lead acetate as described in Example 1. 6.0 g of the title compound were obtained as a white solid, melting point = 164 ° C, optical rotation [α] _D 20 = -23.2 ° (c = 1.0 in CH ₂ Cl ₂ ).

Example I

Capsules containing (2R, 3S, 4S, 5R, 6R, 10R, 11R) -3 - [(2,6-dideoxy-3-C-methyl-3-O-methyl-α-ribohexopyranosyl) oxy] -5- ((3,4,6-trideoxy-N-3- (N-methyl-N-isopropylamino) -β-D-xylohexopyranosyl) oxy) -2,4,6,8,10-pentamethyl-11-acetyl-12, 13-dioxabicyclo [8.2.1] tridec-8-en-1-one.

Capsules containing the active ingredient were made using the following excipients and ingredients per capsule: (2R, 3S, 4S, 5R, 6R, 1R, 11R) -3 - [(2,6-dideoxy-3 -C-) methyl-3-O-methyl-α-L-ribohexopyranosyl) oxy] -5 - [(3,4,6-trideoxy-3- (N-methyl-AM-propylamino) -PD-xylohexopyranosyl) oxy] -2,4,6 8,10-pentamethyl-11-acetyl-12,13-dioxabicyclo [8.2.1] tridec-8-en-1-one 20 mg corn starch 60 mg milk sugar 301 mg ethyl acetate (= EE) qs

The active ingredient, corn starch and milk sugar were processed to a homogeneous pasty mixture by EE. The paste was ground and the resulting granulate was placed on a suitable sheet and dried at 45 ° C to remove the solvent. The dry granulate was introduced into a crusher and mixed with the following excipients in a homogenizer.

talc 5mg magnesium stearate 5mg corn starch 9mg and then filled into capsules containing 400 mg (= capsule size 0).

Claims (5)

1. Derivatives of (2R, 3S, 4S, 5R, 6R, 10R, 1R) -2,4,6,8,10-pentamethyl-11-acetyl-12,13-dioxabicyclo [8.2.1] class-8 -en-1-one of formula (I) (I) wherein R ¹ is hydrogen or methyl, R ² is hydrogen or lower alkanoyl containing from 1 to 4 carbon atoms, and the stable and physiologically compatible acid addition salts. Derivatives according to claim 1, wherein R ¹ is methyl. Derivatives according to any one of claims 1 or 2, wherein R ² is hydrogen. 4. A medicament comprising a pharmacologically effective amount of a derivative according to claim 1 and conventional pharmaceutical excipients and carriers. 5. A process for the preparation of (2R, 3S, 4S, 5R, 6R, 10R, 1R) -2,4,6,8,10-pentamethyl-11-acetyl-12,13-dioxabicyclo [8.2. 1] tridec-8-en-1-one of general formula (I), (1), wherein R ¹ is hydrogen or methyl, R ² is hydrogen or alkanoyl having 1 to 4 carbon atoms, and the stable and physiologically compatible acid addition salts, characterized in that in the compound of formula (II) wherein R ¹ and R ² are as defined in Claim 1, converting the 2 ', 3'-dihydroxypent-2'-yl side chain at the 11-position of the cyclic backbone by oxidative glycol cleavage to the acetyl side chain, and optionally introducing a methyl moiety into the obtained compound of formula (I) wherein R ¹ is hydrogen or the resulting compound of formula (I) wherein R ¹ is methyl, the methyl radical is cleaved, and optionally the free compounds of formula (I) are converted into their stable and physiologically tolerable acid addition salts or their stable and physiologically tolerable addition salts the acid salts are converted to the free compounds of formula (I).