MXPA01009941A - 1,4-benzothiazepine-1,1-dioxide derivatives substituted by sugar radicals, methods for the production thereof, medicaments containing these compounds and the use thereof - Google Patents

Abstract

The invention relates to substituted 1,4-benzothiazepine-1,1-dioxide derivatives and to the acid addition salts thereof. The invention discloses 1,4-benzothiazepine-1,1-dioxide derivatives of formula (I), wherein R1, R2, R3 and Z have the cited descriptions, the physiologically compatible salts thereof and physiologically functional derivatives, as well as methods for producing the same. The compounds are suited for use, e.g. as hypolipidemic agents.

Description

DERIVATIVES OF 1, -BENZOTIAZEPIN-1, 1-DIOXIDE REPLACED BY SUGAR RADICALS, METHODS FOR THE PRODUCTION OF SAME, DRUGS CONTAINING THESE COMPOUNDS AND USE THEREOF The invention relates to 1, 4-benzothiazepin-1, 1-dioxide substituted derivatives, their physiologically tolerable salts and physiologically functional derivatives. The 1,4-benzothiazepine-1, 1-dioxide derivatives and their use for the treatment of hyperlipidemia and also of arteriosclerosis and hypercholesterolemia have already been described [see PCT Application No. PCT / GB 95/01884, Publication No. WO 96/05188]. The invention is based on the object of making available additional compounds which have a therapeutically valuable hypolipidemic action. Particularly, the object is to find novel compounds that cause a greater excretion of bile acid, a smaller dosage, compared to the compounds described in the prior art. Accordingly, the invention relates to compounds of the formula I wherein R1 is methyl, ethyl, propyl, butyl; R2 is H, OH; R3 is a sugar residue, a sugar residue, a sugar residue, a sugar residue, a sugar residue, a sugar residue, a sugar residue, or a tetra sugar residue is optionally monosubstituted or polysubstituted by a sugar protecting group; Z is - (C = 0) r, -alkyl C0-C? 5, - (C = 0) - C: alkyl, - C:; - NH-, (C = 0) n-C0-C alkyl? 6-0-, - (C = 0) n-C? -C? Alkyl 6- (C = 0) m, a covalent bond; n is 0 or 1; m is 0 or 1; and their pharmaceutically tolerable salts and physiologically functional derivatives. Preferred compounds of the formula I are the compounds in which one or more radical (s) have or have the following meaning: R 1 is ethyl, propyl, butyl; R2 is H, OH; R3 is a sugar residue, a sugar residue, the sugar residue or a sugar residue is optionally monosubstituted or polysubstituted by a sugar protecting group; Z is - (C = 0) n-Cn-C ?6alkyl, - (OO) n-C0-C alquiloalkyl; -NH-, (C = 0) n-C0-Calkyl; b-0-, - (C = 0) -alkyl C? -C? S- (C = 0) m, a covalent bond; n is 0 or 1; m is 0 or 1; and its pharmaceutically tolerable salts. Particularly preferred compounds of the formula I are the compounds in which one or more radical (s) have or have the following: U nificant: R 1 is ethyl, butyl; R2_en_H, OH; RJ is a sugar residue, the sugar residue is optionally monosubstituted or polysubstituted by a sugar protecting group; Z is - (OO) n-C0-C4 alkyl, a covalent bond; and its pharmaceutically tolerable salts. Taking into account their higher solubility compared to the initial or base compounds, the pharmaceutically tolerable salts are especially suitable for medical applications. These salts must have a pharmaceutically tolerable cation or anion. Suitable pharmaceutically tolerable acid addition salts of the compounds according to the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic and sulfuric acids, and also organic acids, such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isotonic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic, tartaric and trifluoroacetic acids. For medical purposes, the chlorine salt is used in a particularly preferred manner. Basic pharmaceutically tolerable salts are ammonium salts, alkali metal salts (such as, for example, salts of potassium and potassium) and alkaline earth metal salts (such as, for example, magnesium and calcium salts). Salts with a non-pharmaceutically tolerable anion are also included within the scope of the invention as intermediates useful for the preparation or purification of pharmaceutically tolerable salts and / or for their use in non-therapeutic applications., for example in vitro. The term "physiologically functional derivative" as used herein refers to any physiologically tolerable derivative of a compound according to the present invention, for example, an ester which, when administered to a mammal, such as, for example, to a human being, can (directly or indirectly) forming said compound or an active metabolite thereof. A further aspect of the present invention relates to prodrugs of the compounds according to the invention. Such prodrugs can be metabolized in zrivo to provide a conforming compound with the invention. These prodrugs can themselves be active or inactive. The compounds according to the present invention can also be present in various polymorphic forms, for example, as polymorphic, amorphous and crystalline forms. All polymorphic forms of the compounds according to the present invention are included within the scope of the invention and are a further aspect of the invention. In the following, all references to "compound (s)" according to formula (I) * refer to compound (s) of formula (I) in accordance with that described above, and to their salts, solvates and physiologically derivatives functional in accordance with what is described here. The amount of the compound according to formula (I) which is necessary in order to achieve the desired biological effect depends on numerous factors, for example, the specific compound selected, the intended use, the manner of administration and the clinical condition of the patient. In general, the daily dose is within a range of 0.1 mg to 100 mg (typically 0.1 mg and 50 mg) per day per kilogram of body weight, eg, 0.1 to 10 mg / kg / day. Tablets or capsules may contain, for example, 0.01 to 100 mg, typically 0.02 to 50 mg. In the case of pharmaceutically tolerable salts, the weight data antt. J mentioned refer to the weight of the benzothiazepine ion derived from the salt. For prophylaxis or therapy of the conditions mentioned above, the compounds according to formula (I) may be employed themselves as the compound, but are preferably present with a tolerable carrier in the form of a pharmaceutical composition. The vehicle must obviously be tolerable, in the sense that it is compatible with the other constituents of the composition and is not harmful to the patient's health. The vehicle can be a solid or a liquid or both and is preferably formulated with the compound as a single dose, for example, as a tablet, which can contain from 0.05% to 95% by weight of the active compound. Additional pharmaceutically active substances may also be present, including additional compounds according to formula (I). The pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods consisting essentially of the mixture of constituents with pharmaceutically tolerable carriers and / or excipients. Pharmaceutical compositions according to the present invention are compositions that are suitable for oral and peroral (eg, sublingual) administration, even if the most appropriate form of administration in each individual case depends on the nature and severity of the condition to be treated and of the type of compound according to formula (I) used in each case. Sugar-coated formulations and prolonged-release formulations, coated with sugar are also included in the scope of the invention. Formulations resistant to acids and enterics are preferred. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate. Pharmaceutical compounds suitable for oral administration may be present in separate units, as for example capsules, dragees, pills, or tablets, which in each case contain a certain amount of the compound according to the formula (I); as powders or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil in water or water in oil emulsion. These compositions can be prepared, in accordance with the above-mentioned, according to any suitable pharmaceutical method comprising a step in which the active compound and the vehicle (which can consist of one or more additional constituents) come into contact. In general, the compositions are prepared by uniform and homogeneous mixing of the active compound with a liquid and / or finely divided solid carrier, after which, if necessary, the product acquires a specific shape. Accordingly, for example, a tablet can be prepared by compressing or forming a powder or granules of the compound, if appropriate, with one or more additional constituents. Pressed tablets may be prepared by forming the compound in the form of a free-flowing tablet such as, for example, a powder or granules, where appropriate mixed with a binder, lubricant, inert diluent and / or a surfactant / dispersing agent or various surfactants / dispersing agents in a suitable machine .. Tablets formed can be prepared by forming the powder compound, moistened with an inert liquid diluent, in a suitable machine. Peroral administration (sublingual) include pellets containing a compound according to formula (I) with a flavoring, usually sucrose and gum arabic or tragacanth, and pellets comprising the compound in an inert base such as for example gelatin and glycerol or sucrose and gum arabic The invention also relates to both isomeric mixtures of the formula I and the pure stereoisomers of the formula I, and also to mixtures of diastereomers of the formula I and to the pure diastereomers. The separation of the mixtures is carried out chromatographically. Racemic and enantiomerically pure compounds of the formula I having the following structure are preferred: Sugar residues refer to compounds derived from aldoses and quetoses having from 3 to 7 carbon atoms, which may belong to the D or L series; they also include amino sugars, sugar alcohols or sugar acids.

Examples that may be mentioned are glucose, mannose, fructose, galactose, ribose, erythrose, glyceraldehyde, sedoheptulose, glucosamine, galactosamine, glucuronic acid, galacturonic acid, gluconic acid, galactonic acid, manonic acid, glucamine, 3-amino-1, 2- propandiol, glucaric acid and galactárico acid. Diazúcares are meant to refer to saccharides that contain two sugar units. Disaccharides, trisaccharides or tetrasaccharides are formed by the acetal bond of 2 or more sugars. The joints can be occur here in the form a or in the form ß. Examples that we can mention are lactose, maltose and cellobiose. If the sugar is substituted, the substitution is preferably carried out at the hydrogen atom of an OH group of the sugar. The following protecting groups are essentially suitable for the hydroxyl groups of the sugars: benzyl, acetyl, benzoyl, pivaloyl, trityl, tert-butyl-dimethylsilyl, benzylidene, cyclohexylidene or isopropylidene protecting groups. The compounds of the formula I and their pharmaceutically tolerable salts and physiologically functional derivatives are ideal pharmaceutical agents for the treatment of disorders of lipid metabolism, particularly hyperlipidemia. The compounds of the formula I are also suitable for influencing the serum cholesterol level and for preventing and treating arteriosclerotic symptoms. The compounds may also be optionally administered in combination with statins, such as, for example, simvastatin, fluvastatin, pravastatin, cerivastatin, lovastatin or atorvastin. The following findings confirm the pharmacological activity of the compounds according to the invention. The biological test of the compounds according to the invention was carried out by means of the perfusion test. This test investigates the action of the compounds according to the invention on the transport of bile acid in the ileum. The mixtures of diastereomers of the compounds were tested. The perfusion test was carried out as follows: Experimental fit Male Wistar rats (weight range: 250-350 g) were anesthetized with urethane (1.5 g / kg ip) and the bile duct was cannulated with a polyethylene tube . Eight cm from the ileocecal valve, an incision was made in the ileum and a silicone tube adapter was sewn. A second incision with implantation of a corresponding silicone adapter was made in the caecum. Silicone tubes were fastened on the adapter in order to perfuse the ileum in an orthograde and open (without recirculation) with perfusion buffer at a perfusion rate of 1 ml / min. The perfusion tubes were filled with perfusion buffer (137 mM NaCl, 0.9 mM CaCl2, 0.51 mM MgCl2, 8.1 mM Na2HP04, 2.7 mM KCl, 1.47 mM KH2P0) (pH 7.4), 1% (volume / volume) ethanol + 1 % DMSO. The perfusion buffer contained the test compounds in concentrations as indicated or the vehicle. The buffer was preheated to a temperature of 37 ° C. The perfusion buffer contained 3 mM taurocholic acid (TCA), which in turn was labeled with 1000 dpm / μl of JH TCA as a marker. Study design and evaluation of the results An experimental batch was selected which allowed the determination of the inhibition of bile acid transport in the individual animal. The bile was collected at intervals of 10 minutes for a period of 90 minutes (in the case of a subsequent washing phase to test the reversible nature for a period of up to 160 minutes.) Perfusion of the vehicle-containing buffer solution in a period of 40 minutes (pre-test substance) was followed by an infusion with perfusion buffer containing the test compound in the concentration to be tested (at 90 minutes) For the calculation of percentage inhibition by the compound of proof, the dpms (disintegrations per minute of 3H-TCA) in bile of 80-90 minutes (end of perfusion with the test substance) were related to the collection period of 30-40 minutes during the preliminary phase, when the Excretion of 3H-TCA in the control phase had reached its maximum and plateau. The ECso (= effective concentration 50) was calculated as the effective concentration between the inhibition values of different concentrations that inhibited the excretion of maximum bile acid by 50%. Results Table 1: Example Compounds perfusion of ileum EC50 (uM) 1 0.09 2 0.15 3 0.22 4 0.72 5 0.4 6 0.09 7 1.4 comparison example 1 9.8 From the measured data, it can be seen that the compounds of the formula I according to the invention have a better action by a factor of 7 to 100 in relation to the compounds described in the prior art. The following examples serve to illustrate the invention in greater detail, without restricting said invention to products and embodiments described in the examples. Example 1 C? H43N308S (593.74). MS (M + H) + = 594.3 Example 2 C29H43N3? 9S (609.74). MS (M + H) 610. 4 Example 3 C34H54N408S (678.89). MS (M + H) + = 6 ^ 9.4 Example 4 C4? H64N, 09S (777.03). MS (M + H) t = 777.6 Example 5 C31H4, N308S (621.79). MS (M + H) * = 622.4 Example 6 13a C31H4, N30-S (637.79). MS (M + H) '= 638.5 C3ßH58N40ßS (706.94). MS (M + H) '"707.6 Comparison example from WO 96/05188 (Example No. 20, 264W94 (Glaxo Wellcome)): Comparison Example 1 The examples were prepared as follows: Reaction scheme 1 Reaction scheme Reaction scheme 3 18 21a Synthesis of compound 2: 20 g (91.6 mmol) of 2,5-difluorobenzophenone 1 (Fluka) are dissolved in 400 ml of DMSO. 7.0 g (150 mmol) of lithium sulfide (Fluka) are added under an argon atmosphere. After three hours at a temperature of 120 ° C, the mixture is allowed to cool to room temperature. Stir with 200 ml of 2 M aqueous HCl and 500 ml of ethyl acetate. The organic phase is washed an additional two times with a NaCl solution, dried over MgSO4, filtered and concentrated. 24 g of crude product 2 are obtained in the form of a reddish oil. TLC (n-heptane / ethyl acetate 3: 1). R £ = 0.3, initial material 1 Rf = 0.4 C13H9F0S (232.28). MS (M + H) + = 233.1. Synthesis of compound 4: 7 g of crude product 2, 2.5 g (16 mmol) of dibutylaziridine 3 (R. Gauthier et al., J. Organomet, Chem. 140 (1977) 245-255) and 300 mg of p-acid toluenesulfonic are dissolved in 100 ml of lutidine. The reaction solution is boiled in a water separator for 3 hours. It is then concentrated and the residue is purified by flash chromatography. Yield 3.6 g (61%) of 4 in the form of a colorless oil. TLC (n-heptane / ethyl acetate 9: 1). Rf = 0.5 C23H? EFNS (369.55). MS (M + H) + = 370.3. Synthesis of compound 5: 3.6 g (9.7 mmol) of 4 and 6.0 g of NalOj are suspended., In 100 ml of acetonitrile, 50 ml of methylene chloride and 30 ml of water. After the addition of 200 mg RuCl3, the mixture is stirred vigorously at room temperature for 2 hours. The solution is diluted with 200 ml of ethyl acetate and washed twice with a NaCl solution. After drying in MgSO 4, it is concentrated and purified by flash chromatography. Yield: 3.47 g (89%) of 5 in the form of an amorphous solid. TLC (n-heptane / ethyl acetate 4: 1). Rf = 0.5, initial material 4_Rf = 0.6. C23H3FNO; S (401.55). MS (M + H) = 402.2. Synthesis of compound 6: 3.47 g (8.6 mmol) of 5 are dissolved in 24 ml of nitrating acid from 14 ml of HN03 and 10 ml of H2SO4). The temperature of the reaction is maintained at 20 ° C by cooling. After 30 minutes, the solution is poured into a mixture of 700 g of ice and 200 ml of ethyl acetate. The aqueous phase is separated and washed carefully with 150 ml of a saturated solution of NaHCO3. It is then dried in MgSO 4, concentrated and purified by flash chromatography. Yield: 3.0 g (78%) of 6 in the form of an amorphous solid. TLC (n-heptane / ethyl acetate 4: 1). R; = 0.4 C23H; -N204SF (446.54). MS (M + H) + = 447.2. Synthesis of compound 7: 3.0 g (6.7 mmol) of 6 are dissolved in 50 ml of 33% HNMe2 in ethanol (Flak, and the solution is stirred at a temperature of 50 ° C for 1 hour. environment and the resulting product is filtered Yield 2.86 g (90%) of 7, yellowish crystals, melting point 188 ° C. TLC (n-heptane / ethyl acetate 2: 1) Rf = 0.5, starting material 7 Rf = 0.6 C: H33N30; S (471.62). MS (M + H) + = 472.3. Synthesis dc1 • tax 8a / b as a mixture of enantiomers: 1.0 g (2.2 mmol) of 7 are suspended in 30 ml of toluene and 500 mg of platinum is added to activated carbon (10%). The mixture is hydrogenated in an autoclave with stirring for 30 minutes at a hydrogen pressure of 150 bar and at a temperature of 100 ° C. For the treatment, the mixture is filtered through silica gel, which is washed with 100 ml of methanol, the filtrate is concentrated and the residue is purified by flash chromatography. Yield 495 mg (48%) of 8a / b as an amorphous solid. TLC (n-heptane / ethyl acetate 1: 1). Rf = 0.3. C25H37 302S (443.65). MS (M + H) + = 444.3. Synthesis of compound lOa / b in the form of a mixture of diastereomers: 80 mg (0.18 mmol) of 8a / b and 100 mg (0.24 mmol) of penta-O-acetyl-D-gluconic acid (Org Synth. Vol. 5, 887) are dissolved in 4 ml of DMF (dimethylformamide). 100 mg (0.3 mmol) of TOTU (Fluka), 35 mg (0.24 mmol) of oxime (hydroxyiminocyanoacetate), and Fluka) and 0.1 ml (0.78 mmol) of NEM (4-ethylmorpholine) are added successively. After 1 hour at room temperature, the mixture is diluted with 20 ml of ethyl acetate and washed three times with water. The organic phase is dried over MgSO4, filtered and concentrated. The residue is purified by flash chromatography (ethyl acetate / n-heptane 2: 1) and 130 mg (86U of lOa / b as an amorphous solid is obtained. TLC (ethyl acetate / n-heptane 2: 1) .R: - = 0.3 The product lOa / b has the same retention as the initial material 8a / b, but is colored differently with 2M sulfuric acid C4? H57N30: 5S (131.97) MS (M + H) * = 832.6 Synthesis of compound lla / b in the form of a mixture of diastereomers: 130 mg (0.16 mmol) of lOa / b are dissolved in 5 ml of methanol, after the addition of 0.2 ml of a methoxide solution 1 M methanolic sodium, the mixture is allowed to stand at room temperature for 1 hour, then neutralized using a methanolic HCl solution and concentrated, the residue is purified by flash chromatography (methylene chloride / methanol / concentrated ammonia 30/10). / 3) and 78 mg (80%) of IOa / b is obtained in the form of an amorphous solid TLC (methylene chloride / methanol / concentrated ammonia 10/30/3) .Rf = 0.4. C31H4-N3O3S (621.80). MS (M + H) + = 622.4. Synthesis of compound 12a / b in the form of a mixture of diastereomers: 618 mg (0.74 mmol) of lOa / b are dissolved in 30 ml of methylene chloride and 385 mg (2.23 mmol) of 70% m-chloroperbenzoic acid (Fluka ) Add to. After 30 minutes at room temperature, the mixture is diluted with 100 ml of ethyl acetate and washed three times with a solution of NaHCO 3. After drying using MgSO4, the mixture is concentrated and 700 mg of are obtained. raw product This crude product is dissolved in 28 ml of a solution of TiC? / Acetonitrile 0.05 M. After the addition of 300 mg of solid Nal, the mixture is stirred for 15 minutes. For treatment, it is diluted with 150 ml of ethyl acetate and washed with 100 ml of a 2M sodium thiosulfate solution. The organic phase is dried over MgSO- and concentrated, and the residue is purified by flash chromatography. Yield 550 mg (87% in 2 steps) of 12a / b as an amorphous solid. TLC (n-heptane / ethyl acetate 2: 1). Rf = 0.3, initial material lOa / b Rf = 0.35. C4? H57N30: 4S (847.99). MS (M + H) + = 848.5. Synthesis of compound 13a / b in the form of a mixture of diastereomers: 550 mg (0.65 mmol) of 12a / b are dissolved in 20 ml of methanol. After the addition of 0.3 ml of a methanolic solution of 1 M sodium methoxide, the mixture is allowed to stand at room temperature for one hour. It is then neutralized using a methanolic HCl solution and concentrated. The residue is purified by flash chromatography (methylene chloride / methanol / concentrated ammonia 30/10/3) and 370 mg (89%) of 13a / b are obtained in the form of an amorphous solid. TLC (methylene chloride / methane / ammonia concentrate 30/10/3). Rf = 0.4. C3; H47N309S (637.80). MS (M + H) + = 638.4.

Synthesis of compound 15a / b in the form of a mixture of diastereomers: 719 mg / l.6 mmol) of 8a / b are dissolved in 30 ml of methylene chloride and 2 ml of triethylamine. 0.5 ml (3.7 mmol) of 14 is added dropwise to this solution and left to stand at room temperature for 15 minutes. The solution is then filtered through silica gel and washed with 100 ml of ethyl acetate. After concentration, the residue is purified by flash chromatography. Yield 950 mg (95%) of 15a / b as an amorphous solid. TLC (n-heptane / ethyl acetate 1: 1). Rf = 0.4. C3.H44BrN303S (606.67). MS (M + H) 1"= 607.3 Synthesis of compound 17a / b in the form of a mixture of diastereomers: 897 mg (1.47 mmol) of 15a / b are dissolved in 20 ml of DMF After the addition of 1.3 g (7.1 mmol) of 16 (glucamine, Fluka), the mixture is heated at a temperature of 80 ° C for two hours, then diluted with 50 ml of ethyl acetate and washed three times with water. MgSO 4, filtered and concentrated The residue is purified by flash chromatography (methylene chloride / methanol / concentrated ammonia 30/10/3) and obtained 700 mg (67%) of 17a / b as an amorphous solid. TLC (methylene chloride / methanol / ammonia concentrate 30/10/3). Rf = 0.4. C36H58N4O3S (706.95). MS (M + H) + = 707.4. Synthesis of compound 19: 8.0 g (18.8 mmol) of 9 (penta-O-acetyl-D-gluconoyl chloride, Org Synth, Vol 5.887) were added to a suspension of 8.0 g (40 mmol) of 18 (Fluka ) in 150 ml of anhydrous DMF. This suspension is stirred vigorously at room temperature for 20 hours. 500 ml of ethyl acetate and 200 ml of water are then added. The aqueous phase is extracted again with 250 ml of ethyl acetate. The combined organic phase is washed three times with a sodium chloride solution, dried over MgSO4, filtered and concentrated.

Yield 9.5 g (86%) of 19 in the form of a colorless oil. TLC (methylene chloride / methanol / ammonia concentrate 30/10/3). Rf = 0.8. C27H43NO? 3S (589.64). MS (M + H) + = 590.4. Synthesis of compound 21a / b in the form of a mixture of diastereomers: 200 mg (0.34 mmol) of 19.70 mg (0.17 mmol) of 20a / b (20a / b is prepared analogously to 8a / b by performing the sequence of reactions of reaction scheme 1 with 2-butyl-2-ethylaziridine (R. Gauthier et al., J. Organomet, Chem. 140 (197 '., 45-255) and 1, 240 mg of TOTU, 80 mg of oxime and 0.3 ml of NEM are reacted in 4 ml of DMF analogously to the procedure for compound lla / b After flash chromatography (methylene chloride / methanol / concentrated ammonia 30/5/1), 60 are obtained. mg (46%, in two stages) of 21a / b as an amorphous solid TLC (methylene chloride / methanol / concentrated ammonia 30/5/1) Rf - '.C40H64N4O9S (777.04) MS (M + HU = 777.8.

Claims (3)

1. CLAIMS 1. A compound of formula I, wherein R1 is methyl, ethyl, propyl, butyl; R2 is H, OH; R3 is a sugar residue, a sugar residue, a sugarsugar residue, a sugarsugar residue, a sugar residue, a sugar residue, a sugarsugar residue or a sugars protection group is optionally monosubstituted or polysubstituted by a sugar protection group; Z is - (C = 0) n-alkyl Co-C? 5, - (OO) r - C0-C alkyl? 6-NH-, - (C = 0) r, -alkyl Co-C: 6-0 -, - (OO) --always C: -C16- (OO) m / a covalent bond; n is 0 or 1; m is 0 or 1; or their pharmaceutically tolerable salts and physiologically functional derivatives.
2. A compound of the formula I according to claim 1, wherein one or more of the radicals has or has the following meaning: R 1 is ethyl, propyl, butyl; R2 is H, OH; R3 is a sugar residue, a sugar residue, the sugar residue or the sugar residue is optionally monosubstituted or polysubstituted by a sugar protection group; Z is - (OO) n-C0-C6alkyl- (C = 0) n-C0-C6alkyl-6-NH- .. - (C = 0) n-alkyl Co-C? E-0- , - (OO) n-alkyl? C? -C16- (OO) m, a covalent bond; n is 0 or 1; m is 0 or 1; or its pharmaceutically tolerable salts. A compound of the formula I according to claim 1 or according to claim 2, wherein one or more of the radicals has or has the following meaning: R 1 is ethyl, butyl; R2 is H, OH; R3 is a sugar residue, the sugar residue is optionally monosubstituted or polysubstituted by a sugar protection group; Z is - (OO) -C0-C4 alkyl, a covalent bond; or its pharmaceutically tolerable salts. A process for the preparation of compounds of the formula I according to claim 1 or 3 of claims 1 to 3, which comprises the reaction according to the following reaction scheme: of an amine of the formula II, wherein R1, R2 and R3 have the meanings indicated by the formula I, with removal of water to provide a compound of the formula I and convert optionalmer.i- the compound of the formula III obtained in a physiologically tolerable salt or a physiologically functional derivative. A pharmaceutical agent comprising one or more of the compounds according to claim 1 or claim
3. 3. A pharmaceutical agent comprising one or more of the compounds according to claim 1 or more of the claims. 1 to 3 and one or several statins. A compound as claimed in one or more of claims 1 to 3 for use as a drug for the treatment of disorders of lipid metabolism. A process for the production of a pharmaceutical agent comprising one or more of the compounds according to claim 1 or more of claims 1 to 3, which comprises mixing the active compound with a pharmaceutically acceptable carrier and transforming this mixture into a suitable form for its administration. The use of the compounds according to claim 1 in one or more of claims 1 to 3 for the production of a drug for the treatment of hyperlipidemia. FJ use of the compounds according to claim 1 in one or more of claims 1 to 3 for the production of a drug to influence the serum cholesterol level. The use of the compounds according to one or more of claims 1 to 3 for the production of a drug to prevent arteposclerotic symptoms.