MXPA01002783A - Propanolamine derivatives substituted with heterocyclic compounds, methods for their production, pharmaceutical compositions containing said compounds and the use thereof - Google Patents

Abstract

The invention relates to substituted propanolamine derivatives and their pharmaceutically acceptable salts and functional derivatives. The invention describes compounds of formula (I), wherein the radicals have the meanings thus cited, as well as their physiologically acceptable salts, physiologically functional derivatives and methods for the production thereof. The compounds are suitable as, for example, hypolipidemic agents.

Description

DERIVATIVES OF PROPANOLAMINE SUBSTITUTED WITH HETEROCYCLIC COMPOUNDS, METHODS FOR ITS PRODUCTION, PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOUNDS AND ITS EMPLOYMENT Description Propanolamine derivatives substituted by heterocyclic radicals, processes for their preparation, pharmaceutical compositions comprising these compounds and their use. The invention relates to substituted propanolamine derivatives and pharmaceutically tolerated salts and their physiologically functional derivatives. Various classes of active compounds for the treatment of adiposity and alterations in lipid metabolism have already been described: "polymeric adsorbents, such as, for example, cholestyramine" benzothiazepines (WO 93/16055) »dimeros and conjugates of bile acids (patent EP 0 489 423) and "the amides of 4-amino-2-ureido-pyrimidine-5-carboxylic acid (patent EP 0 557 879).

The invention is based on the object of providing more compounds that exhibit a therapeutically valuable hypolipidemic action. Therefore, the invention relates to compounds of the formula I: which is: phenyl, pyridyl, thienyl, furyl, pyrimidyl, indolyl, thiazolyl, imidazolyl, coumarinyl, phthalimidyl, quinolyl, piperazinyl, tetrazolyl, triazolyl, oxazolyl, isoxazolyl, isothiazolyl or its thieno-, pyridino- or benzofused derivatives, it is possible that the aromatic or heteroaromatic radical is mono- or di-substituted by fluorine, chlorine, bromine, iodine, OH, CF3, -N02 CN, alkoxy (Ci-Cß), alkyl (Ci-Cß) NH2, -NH-R " -N (R9) R10, CHO, -COOH, -COOR11, - (C = 0) -R12, alkyl (Ci-Ce) -OH, alkyl (C? -C6) (-OH) -phenyl, alkyl (C) -C6) -CF3, alkyl (C6C6) -N02, alkyl (C6C6) -CN, alkyl (C6C6) -NH2, alkyl (C6C6) -NH-R9, alkyl (C? -C6) -N (R) R, (C? -C6) alkyl-CHO, (C? -C6) alkyl -COOH, (C? -C6) alkyl -COOR11, alkyl- (C = 0) ) -R12, -O-alkyl (d-Ce) -OH, -O-alkyl (Ci-Cß) -FC3, -O-alkyl (C? -C6) -N02, -O-alkyl (C? -C6) ) -CN, -O-alkyl (C? -C6) -NH2, -O-alkyl (C? -C6) -NH-R9, -0-10 alkyl (C? -C6) -N (R9) R10, -O-alkyl (C? -C6) -CHO, -0- (C? -C6) -COOH, -O-alkyl (CL-C6) -COOR11, -0- alkyl (C? -C6) - ( C = 0) -R12, -N-S03H, -S02-CH3 or -0- alkyl (Ci-Cß) -O-alkyl (Ci-Cß) -phenyl where one or more of the hydrogens in the alkyl radicals can be replaced by fluorine; D is phenyl, pyridyl, thienyl, furyl, pyrimidyl, indolyl, thiazolyl, imidazolyl, coumarinyl, phthalimidyl, quinolyl, piperazinyl, tetrazolyl, -triazolyl, oxazolyl, isoxazolyl, isothiazolyl or 4, 5, 6, 7-tetrahydrobenzisoxazole or its thieno-, pyridino- or benzo-fused derivatives, it being possible for the aromatic or heteroaromatic radical to be mono- or di-substituted by fluorine, chlorine , bromine, iodine, OH, CF3, -N02, CN, alkoxy (C? ~ C8), alkyl (Ci- C). NH2, -NH-R9, -N (R9) R10, CHO, -COOH, -COOR11, - (C = 0) -R12, alkyl (C? -C6) -OH, alkyl (C? -C6) (- OH) - phenyl, alkyl (C? -C6) -CF3, alkyl (C? -C6) -N02, alkyl (C? -C6) -CN, alkyl (C? -C6) -NH2, alkyl (C? ~ C6) -NH-R9, alkyl (C? -C6) -N (R9) R10, alkyl (C? -C6) -CHO, alkyl (C? -C6) -COOH, alkyl (C? -C6) -COOR11 , alkyl- (C = 0) -R12, -O-alkyl (C? -C6) -OH, -0-alkyl (C? -C6) -CF3, -O-alkyl (C? -C6) -N02, -0- alkyl (C? -C6) -CN, -O-alkyl (C? -C6) -NH2, -0- alkyl (C? -C6) -NH-R9, -O-alkyl (C? -C6) ) -N (R9) R10, -0- alkyl? (C? -C6) -CHO, -O-alkyl (C? -C6) -COOH, -0- alkyl (C? -C6) -COOR11, -O -alkyl (C? -C6) - (C = 0) -R12, -N-S03H, -S02-CH3, (C0-C6) alkyl-pyridyl, -0- (C? -C6) -0-alkyl (C? -C6) -phenyl or alkyl (Cr.C.sub.S) -phenyl, wherein the phenyl radicals can be substituted up to two times by F, Cl, CF.sub.3, 0CF3, alkyl (C? -C6) or -O-alkyl ( C? -C6) and where one or more of the hydrogens in the alkyl radicals can be replaced by fluorine; with the proviso that C and D do not have the following meanings simultaneously: C = phenyl and D = phenyl, C = phenyl and D = pyridyl, C = pyridyl and D = phenyl, C = pyridyl and de = pyridyl; R1, R2, R3, R4, independently of each other, are hydrogen, fluorine, chlorine, bromine, iodine, OH, CF3, -N02, CN, alkoxy (Ci-Cß), alkyl (Ci-Cß) • NH2, -NH -R " -N (R9) R10, CHO, -COOH, -COOR11, - (C = 0) -R .1L2, alkyl (C? -C6) -OH, alkyl (QL-C6) (-OH) -phenyl, alkyl (C? -C6) -CF3, alkyl (C? -C6) -N02, alkyl (Ci- C6) -CN, alkyl (C? -C5) -NH2 / alkyl (C? -C6) -NH-R9 , alkyl (C? -C6) -N (R9) R10, alkyl (C? -C6) -CHO, alkyl (C? -C6) -COOH, alkyl (C? -C6) -COOR11, alkyl only) -R12, -O-alkyl (C? -C6) -OH, -O-alkyl (C? -C6) -FC3 / -O-alkyl (C? -C6) -N02, -O-alkyl (d-Ce) -CN , -O-alkyl (C? -C6) -NH2, -O-alkyl (C? -C6) -NH-R9, -0- (C1-C6) alkyl -N (R9) R10, -O-alkyl ( C? -C6) -CHO, -0-Alkyl-CeJ-COOH, -O-alkyl (C? -C6) -COOR11, -0- alkyl (C? -C6) - (C = 0) -R12, - N-S03H, -S02-CH3, or -0-alkyl (C? -C3) -O-alkyl (C? -C6) -phenyl, wherein one or more of the hydrogens in the alkyl radicals can be replaced by fluorine; R9 to R, independently of one another, are hydrogen or alkyl (C? -C6); and their pharmaceutically tolerated salts and their physiologically functional derivatives.

Preferred compounds of formula I are those in which one or more radicals have or have the following meanings: C is phenyl, pyridyl, thienyl, furyl, pyrimidyl, indolyl, thiazolyl, imidazolyl, coumarinyl, phthalimidyl, quinolyl, piperazinyl, tetrazolyl, triazolyl, oxazolyl, isoxazolyl, isothiazolyl or its benzo-molten derivatives, it being possible for the aromatic or heteroaromatic radical to be mono- or di-substituted by fluorine, chlorine, bromine, iodine, OH, CF3, -N02 / CN, alkoxy (C? C8), alkyl (Ci- C8), cycloalkyl (C3-C6), NH2 > CHO, -COOH or OCF3; D is phenyl, pyridyl, thienyl, furyl, pyrimidyl, indolyl, thiazolyl, imidazolyl, coumarinyl, phthalimidyl, quinolyl, piperazinyl, tetrazolyl, triazolyl, oxazolyl, isoxazolyl, isothiazolyl or their benzo-molten derivatives, where possible that the aromatic or heteroaromatic radical is mono- or di-substituted by fluorine, chlorine, bromine, iodine, OH, CF3, -N02, CN, alkoxy (Cj.-C8), alkyl (Ci- C8), cycloalkyl (C3- C6), NH2, CHO, -COOH or OCF3; with the proviso that C and D do not simultaneously have the following meanings: C = phenyl and D = phenyl, C = phenyl and D = pyridyl, C = pyridyl and D = phenyl, C = pyridyl and de = pyridyl; R1, R2, R3, R4, independently of one another, are hydrogen, fluorine, chlorine, bromine, iodine, OH, CF3, OCF3, -N02, CN, (C? -C8) alkoxy, (C? -C8) alkyl. NH2, -NH-R9, -N (R9) R10, CHO, -COOH, -COOR11, - (C = 0) -R12, in which one or more hydrogens in the alkyl radicals can be replaced by fluorine; R9 to R12, independently of one another, are hydrogen or (C? -C8) alkyl. and their pharmaceutically tolerated salts and their physiologically functional derivatives.

Particularly preferred compounds of the formula I are those in which one or more radicals have or have the following meanings: C is phenyl, pyridyl, thienyl, pyrimidyl, indolyl, thiazolyl, quinolyl, oxazolyl or isoxazolyl, it being possible for the aromatic or heteroaromatic radical to be mono- or disubstituted by fluorine, chlorine, bromine, or (Ci- C8) alkyl; D is phenyl, pyridyl, thienyl, pyrimidyl, indolyl, thiazolyl, quinolyl, imidazolyl, triazolyl, oxazolyl or isoxazolyl, it being possible for the aromatic or heteroaromatic radical to be mono- or di-substituted by fluorine, chlorine, bromine, or alkyl (C ? -C8); with the proviso that C and D do not simultaneously have the following meanings: C = phenyl and D = phenyl, C = phenyl and D = pyridyl, C = pyridyl and D = phenyl, C = pyridyl and de = pyridyl; R1, R2, R3, R4, independently of one another, are hydrogen, fluorine, chlorine, bromine, iodo, OH, CF3, 0CF3, -N02, CN, alkoxy (Ci-Cs), alkyl (C? -8), cycloalkyl (C3-C6), NH2, -NH-R9, -N (R9) R10, CHO, -COOH, -COOR11 or - (C = 0) -R12, in which one or more hydrogens in the alkyl radicals can be replaced by fluorine; R9 to Ri2 / independently of each other, are hydrogen or alkyl (C? -Cβ); and its pharmaceutically tolerated salts.

The term "alkyl" is understood to mean straight or branched chain hydrocarbons. The invention also relates to a process for the preparation of the compounds of the formula I, which comprises the following reaction scheme: Process A Scheme 1 R isomers Compounds of type IV are obtained by the reaction of the o-, m-, or p-substituted imines, type II, with the ketone III. The reaction can be carried out, for example, by mixing the two compounds by volume, without solvent, and then heating the mixture, or in a suitable solvent, such as ethanol, tetrahydrofuran (THF), toluene, diglyme or tetradecane, temperatures from 20 to 150 ° C.

The keto compounds, of type IV, are reduced to hydroxy compounds of type V, with NaBH 4 or another suitable reducing agent, in a suitable solvent, such as, for example, methanol, THF or THF / water, at temperatures between - 30 ° C and + 40 ° C. During the reduction, up to four mixtures of isomers (racemates) are obtained as the reaction products. The various racemates can be separated from each other by fractional crystallization or by silica gel chromatography. The racemic compounds of type V, thus obtained, can also be separated into their enantiomers. The division of the racemates of V into the type VII enantiomers can be carried out by chromatography under a chiral column material or by processes known from the literature, using the optically active auxiliary reagents (see J. Org. Chem. , 1979, 4891). Due to their superior solubility in water, compared to the starting or base compounds, the salts, pharmaceutically tolerated, are particularly suitable for medical applications. These salts must have an anion or cation, pharmaceutically tolerated. Addition salts with suitable, pharmaceutically tolerated acids of the compounds according to the invention are the salts of inorganic acids, such as hydrochloric acid and the acid Bromhydric, phosphoric, metaphosphoric, nitric, sulfonic and sulfuric acids, and organic acids, such as, for example, acetic acid and benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic acids , maleic, malic, methanesulfonic, succinic, p-toluenesulfonic, tartaric and trifluoroacetic. For medical purposes, the chlorine salt is to be used particularly in preferred form. Some suitable, pharmaceutically tolerated, basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Salts with an anion, which are not tolerated pharmaceutically, also belong to the present invention, as beneficial intermediates for the preparation or purification of pharmaceutically tolerated salts and / or for non-therapeutic use, for example, in in vitro applications. . The term "physiologically functional derivative", used herein, designates any physiologically tolerated derivative of a compound of formula I, according to the invention, for example an ester, which, when administered to a mammal, such as , for example, man is capable of forming (directly or indirectly) a compound of formula I or its active metabolite. Physiologically functional derivatives also include prodrugs of the compounds according to the invention. These prodrugs can be metabolized in vivo to give a compound, according to the invention. These prodrugs can be active by themselves or inactive. The compounds, according to the invention, can also exist in various polymorphic forms, for example as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds, according to the invention, belong to the context of the invention and are a further aspect of the invention. In the following text, all references to "compounds, according to the formula (I) ", refer to the compounds of the formula (I), as described above, and their physiologically functional salts, solvates and derivatives, as described herein: The amount of a compound, according to the formula (I), necessary to achieve the desired biological effect, depends on a number of factors, for example, the specific compound selected, the intended use, the mode of administration and the clinical condition of the patient. Daily dose is in the range of 0.3 to 100 mg (typically from 3 to 50 mg) per day per kilogram of body weight, for example from 3 to 10 mg / kg / day. An intravenous dose may be, for example, in the range of 0.3 to 1.0 mg / kg, which may suitably be administered as an infusion of 10 ng to 100 ng per kilogram per minute. Suitable infusion solutions for this purpose may comprise, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg per milliliter, individual doses may comprise, for example, from 1 mg to 10 g of the active compound. Ampoules for injections may contain, for example, 1 mg to 100 mg, and single dose formulations, which can be administered orally, such as, for example, tablets or capsules, may comprise, for example, 1.0 to 1000 mg , typically from 10 to 600 mg. In the case of pharmaceutically tolerated salts, the aforementioned weight data refer to the weight of the benzothiazepia ion, derived from the salt. For the prophylaxis or treatment of the aforementioned states, the compounds, according to the formula (I), can be used by themselves as the compound, but they are preferably present in the form of a pharmaceutical composition with a tolerated excipient . This excipient must, of course, be tolerated, in the sense that it is compatible with the other constituents of the composition and does not harm the patient's health The excipient may be a solid or liquid or both, and is preferably formulated with the compound as a single dose, for example as a tablet, which may comprise 0.05 to 95% by weight of the active compound. Likewise, pharmaceutically active substances may also be present, which include the further compounds according to formula (I). The pharmaceutical compositions, according to the invention, can be prepared by one of the known pharmaceutical methods, which substantially comprise mixing the constituents with pharmacologically tolerated excipients and / or auxiliaries. The pharmaceutical compositions, according to the invention, are those which are suitable for oral, rectal, topical, oral (for example sublingual) and parenteral (for example subcutaneous, intramuscular, intradermal or intravenous) administration, although the most The appropriate administration in each individual case depends on the nature and severity of the condition to be treated and on the nature of the particular compound, according to the formula (I) used. The coated formulations and the sustained release coated formulations also belong to the context of the invention. The formulations that are resistant to acids and juices gastric are preferred. Suitable coatings that are resistant to gastric juices include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, and anionic polymers of methacrylic acid and methyl methacrylate. Pharmaceutical compounds suitable for oral administration may exist in separate units, such as, for example, capsules, tablets or lozenges, each of which comprises a certain amount of the compound, according to 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. As already mentioned, these formulations can be prepared by any suitable pharmaceutical method, which comprises a step in which the active compound and the excipient (which can comprise one or more additional constituents) are brought into contact. In general, the compositions are prepared by uniform and homogeneous mixing of the active compound with a liquid and / or a finely divided solid excipient, after which the product is formed, if necessary. Thus, for example, a tablet can be prepared by pressing or forming a powder or granules of the compound, optionally with one or more additional constituents. The pressed tablets can be prepared by their formation in free flowing form, such as, for example, a powder or granules, optionally in admixture with a binder, lubricant, inert diluent and / or one (or more) surface tension / dispersion agents in a suitable machine. The shaped tablets can be prepared by shaping the powdery compound, which has been moistened with an inert liquid diluent, in a suitable machine. Pharmaceutical compositions which are suitable for per-oral (sublingual) administration include sucking tablets, comprising a compound of formula (I), with a flavor substance, usually sucrose, and gum arabic or tragacanth, and Pills comprising the compound in an inert base, such as gelatin, and glycerol or sucrose and gum arabic. Pharmaceutical compositions suitable for parenteral administration preferably include sterile aqueous formulations of a compound, according to formula (I), which are preferably isotonic with the blood of the intended recipient. These formulations are preferably administered in an intravenous form, although administration can also take place subcutaneously, intramuscularly or intradermally, as an injection. These formulations they can be prepared preferably by mixing the compound with water and making the resulting solution sterile and isotonic with the blood. Injectable compositions, according to the invention, generally comprise from 0.1 to 5% by weight of the active compound. Pharmaceutical compositions suitable for rectal administration are preferably in the form of individual dose suppositories. They can be prepared by mixing a compound, according to formula (I), with one or more conventional solid excipients, for example, cocoa butter, and shaping the formed mixture. Pharmaceutical compositions suitable for topical application to the skin, are preferably in the form of an ointment, cream, lotion, paste, spray, aerosol or oil. Petroleum jelly, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances may be used as excipients. The active compound, in general, is present in a concentration of 0.1 to 15% by weight of the composition, for example 0.5 to 2%. A transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal applications may be in the form of individual patches, which are suitable for close contact for prolonged period with the epidermis of the patient. These patches suitably comprise the active compound in an aqueous solution, optionally regulated, dissolved and / or dispersed in an adhesion promoter or dispersed in a polymer. A suitable concentration of the active compound is about 1 to 35%, preferably about 3 to 15%. As a particular possibility, the active compound can be released by electro-transport or iontophoresis, as described, for example, in Pharamceutical Research, 2 (6): 318 (1986). The invention relates to compounds of the formula I in the form of their racemates, racemic mixtures and pure enantiomers, and to their diastereomers and mixtures thereof. The alkyl, alkenyl and alkynyl radicals in the substituents R1, R1 ', R2, R3 and R4 can be straight chain or branched. The compounds of the formula I and their pharmaceutically tolerated salts and their physiologically functional derivatives are distinguished by their favorable actions in the lipid metabolism. The compounds e may be used by themselves or in combination with additional active compounds that decrease lipids. The compounds are suitable for the prophylaxis and, in particular, for the treatment of disorders in the lipid metabolism. In particular, hyperlipidemia. The compounds of formula I are also suitable for influencing the serum cholesterol level and for the prevention and treatment of arteriosclerotic symptoms. The following findings demonstrate the pharmacological activity of the compounds, according to the invention. The biological tests of the compounds, according to the invention, were carried out by determining the inhibition of the admission of [3H] -taurocholates, in the vesicles of the limiting membrane of the ileocecal tail of rabbits. The inhibition test was carried out as follows: 1. Preparation of the vesicles of the tail boundary membrane from the ileum of rabbits Vesicles of the tail boundary membrane of intestinal small intestinal cells, were prepared by the so-called Mg2 + precipitation method. New Zeland male rabbits (2 to 2.5 kg body weight) were sacrificed by an intravenous injection of 0.5 ml of T61®, an aqueous solution of 2.5 mg of tetracaine-HCl, 100 mg of embutramide and 25 mg of mebezonium iodide. The small intestine was removed and filled with a physiological saline solution cooled with ice. Terminal 7/10 of Small intestine (measured in the oral-rectal direction, ie, the terminal ileum, which contains the active Na + -dependent bile acid transport system) was used for the preparation of the membrane vesicles of the tail boundary. The intestines were frozen in bags under nitrogen at -80 ° C. For the preparation of the membrane vesicles, the frozen intestines were melted at 30 ° C in a water bath. The mucosa was detached and suspended in 60 ml of a 12 mM Tris-HCl regulator, cooled with ice (pH of 7.1) / 300 mM of mannitol, 5 mM of EGTA / 1 O mg / l of phenylethylsulfonyl-fluoride / 1 mg / l of the soybean trypsin inhibitor (32 U / mg / 0.5 mg / l bovine lung trypsin inhibitor (193 U / mg / 1 bacitracin) After dilution to 300 ml with chilled distilled water with ice, the mixture was homogenized with an Ultraturrax device (IKA Werk Staufen, Germany, rod 18) for 3 minutes at 75% of maximum power, while cooling with ice. After the addition of 3 ml of a MgCl2 IT solution (final concentration, 10 mM), the mixture was allowed to stand for exactly 1 minute at 0 ° C. The cell membranes were added by the addition of Mg2 + and precipitated, with the exception of the boundary membranes of the tail. After centrifugation for 15 minutes at 300 x g (5000 rpm, SS-34 rotor), the precipitate was discarded and the supernatant, which Contains the boundary membranes of the tail, centrifuged at 48,000 x g (20,000 rpm, SS-34 rotor) for 30 minutes. The supernatant was discarded and the precipitate was rehomogenized in 60 ml of the 12 mM Tris / HCl buffer (pH 7.1) / 60 mM mannitol, 5 mM 5EGTA with a Potter Elvejhem homogenizer (Braun, Melsungen, 900 rpm, run 10). After the addition of 0.1 ml of a MgCl2 IM solution, and an incubation time of 15 minutes at 0 ° C, the mixture was centrifuged again at 30000 x g for 15 minutes. The supernatant was centrifuged again at 48,000 xg (20,000 rpm, SS-34 rotor) for 30 minutes. The precipitate was taken in 30 ml of the 10 mM Tris / Hepes buffer (pH 7.4) / 300 mM mannitol and resuspended by 20 strokes e a Potter Elvejhem homogenizer at 1000 rpm. After centrifugation at 48,000 x g (20,000 rpm, SS-34 rotor) for 30 minutes, the precipitate was taken in 0.5-2 ml of the Tris / Hepes buffer (pH 7.4) / 280 mM mannitol (final concentration 20 mg / ml) and resuspended with the help of a tuberculin syringe with a 27 gauge needle. The vesicles were used for transport investigations directly, after the preparation, or were stored in 4 mg portions in liquid nitrogen at -196 ° C. 2. Inhibition of the admission of Na + -dependent 3 [H] -taurocholate in vesicles of the limb of the tail of the ileum. The admission of substrates into the vesicles of the boundary membrane of the tail, described above, was determined by means of the so-called membrane filtration technique. 10 μl of the vesicle suspension (100 μg of protein) were pipetted onto the wall of a polystyrene incubation tube (11 x 70 mm) containing the incubation medium with the corresponding ligatures (90 μl). The incubation medium comprised 0.75 μl = 0.75 μCi of 3 [H (G)] -taurocholate (specific activity: 2: 1 Ci / mmol) / 0.5 μl of 10 mM taurocholate /8.75 μl of the sodium transport regulator (10 mM) of Tris / Hepes (pH 7.4) / 100 mM mannitol / 100 mM NaCl) (Na-TB) or 8.75 μl of the potassium transport buffer (10 mM Tris / Hepes (pH 7.4) / 100 mM mannitol / 100 mM KCl) (KTB) and 80 μl of the solution of the inhibitor in question, dissolved in the Na-T or KT regulator, depending on the experiment. The incubation medium was filtered through a polyvinylidene fluoride membrane filter (SYHV LO 4NS, 0.45 μm f 4 mm, Millipore, Eschborn, Germany). The transport measurement was started by mixing the vesicles with the medium of incubation. The concentration of the taurocholate in the incubation lot was 50 uM. After the desired incubation time (usually 1 minute), transport was stopped by the addition of 1 ml of an ice-cold stop solution (10 mM Tris / Hepes, (pH 7.4) / 150 mM KCl). The formed mixture was sucked immediately onto the cellulose nitrate membrane filter (ME 25, 0.45 μm, diameter 25 mm, Schleicher &; Schuell, Dassuell, Germany) under a vacuum of 25 to 35 mbar. The filter was rinsed with 5 ml of an ice-cold stop solution. To measure the admission of the radiolabelled taurocholate, the membrane filter was dissolved with 4 ml of the Quickszint 361 scintillator (Zinsser Analytik GmbH, - Frankfurt, Germany) and the radioactivity was measured by the measurement of scintillation of the liquid in a measuring device TriCarb 2500 (Canberra, Packad GMBH, Frankfurt, Germany).

The measured values were obtained as dpm (decompositions per minute), after calibration of the apparatus, with the help of standard samples and after correction of any chemiluminescence present. The control values were determined each in Na-T-B and K-T-B. The difference between admission in Na-t-B and K-T-B gave the transport content dependent on Na +. The IC50 Na + designated the inhibitor concentration to which the transport content dependent on Na + was inhibited by 5D%, based on the control. The pharmacological data comprise a series of tests in which the interaction of the compounds, according to the invention, with the intestinal bile acid transport system in the terminal small intestine, was investigated. The results are summarized in Table 1. Table 1 shows the measured values (biological test) of the inhibition of the [3H] -taurocholate admission in the vesicles of the borderline membrane of the ileum of rabbits. The quotients of the IC5o Na values of the reference substance such as taurokenedeoxycholate (TCDC) and of the particular test substance were reported. The following examples serve to illustrate the invention in greater detail, without limitation thereof for the products and modalities described in the examples. ro n The compounds shown in Table 1 are diastereomers that are in the form of racemates. In the Isomer column, the relative polarity of a particular diastereomer is indicated, the greater number correlates with a low value of Rf.

It can be seen from the table that the compounds of formula I show a good action that lowers lipids The preparation of some examples is described in detail below, and the other compounds of the formula I (see Table 1) were obtained analogously, from the corresponding starting compounds: Example A 38 ml of 15   n-butyllithium; in n-hexane, 5.6 g (0.06 mol) of picoline in 50 ml of absolute tetrahydrofuran was added dropwise at -60 ° C. The mixture was warmed to room temperature and cooled again to -60 ° C. Slowly, in drops, 8.5 g of 5-ethylthiophene-2-carboxylic acid (0.05 mol) in 15 ml of tetrahydrofuran was added, and the mixture was then warmed to room temperature and stirred for an additional hour. After the addition of 300 ml of water and neutralization by means of an aqueous solution of citric acid, 20%, the mixture was extracted with 100 ml of methylene chloride (3x) and the organic phases were dried with Na2SO4 and evaporated under reduced pressure. After chromatography on silica gel with n-heptane / ethyl acetate, as the phase mobile, 2.6 g (24% of theory) of the reaction product was obtained, in the form of a pale yellow oil. C12H11NOS (217.3) MS 218. 2 M + H + 51 ml (0.5 mol) of benzaldehyde, 47 g (0.5 mol) of 2-aminopyridine and 1 g of p-toluenesulfonic acid were dissolved in 400 ml of toluene and the solution was heated under reflux for 3 hours, using a separator. Water. The solution was cooled and the organic phase was washed twice with an aqueous saturated solution of NaHCO 3 and twice with 100 ml of water, each. It was then dried by Na 2 SO and concentrated under reduced pressure. The crude product obtained, as an oil, was distilled under an oil pump vacuum. Yield: 73.8 g (81% of theory) of the product Boiling point Q.z 125 ° C C? 2H? 2N2 (192.2) MS 183.3 M + H + (Mixture of two diastereomers) 2.6 g (12 mmol) of ketone, from Example la, and 2.2 g (12 mmol) of imine, of Example Ib, were dissolved in 50 mol of ethanol. After a few minutes, a colorless solid began to precipitate. To bring the reaction to completion, the mixture was stirred at room temperature for 48 hours. After cooling, the precipitate was separated by filtration, with suction, and recrystallized from ethanol. Yield: 3.45 g (72% of theory) of the product Melting point: 160 ° C (Preparation of the four possible diastereomers, see Examples 27 to 30 in Table 1) 3.4 g (8.5 ^ mmoles) of the keto compound of Example le, were dissolved in a mixture of 350 ml of methylene chloride, 25 ml of methanol and 8 ml of water, 2.4 g of sodium borohydride were added and the mixture was stirred at room temperature for 5 hours. The solution was then extracted twice with 150 ml of water and the organic phase was dried with Na 2 SO and evaporated. The residue was chromatographed on silica gel (n-heptane / ethyl acetate, 1: 1). Four compounds, each racemic, were obtained with colorless crystalline products. First fraction: 1.1 g (32%) of highly non-polar racemate (Example 27); Rf (ethyl acetate / n-heptane = 1/1): 0.37 Melting point: 115 ° C C24H23N30S (401.5) MS (FAB) 402.2 M + H + Second fraction: 0.32 g (9%) of non-polar racemate (Example 28) Rf (ethyl acetate / n-heptane = 1/1): 0.30 Melting point: 134 ° C C24H23N3OS (401.5) MS (FAB) 402.2 M + H + Third fraction: 0.54 g (16%) moderately polar racemate (Example 20) Rf (ethyl acetate / n-heptane = 1/1): 0.22 Melting point: 183 ° C C24H23N3OS (401.5) MS (FAB) 402.2 M + H + Fourth fraction: 0.38 g (11%) racemate polar (Example 30) Rf (ethyl acetate / n-heptane = 1/1): 0.16 Melting point: 169 ° C C24H23N3OS (401.5) MS (FAB) 402.2 M + H +

Claims (14)

1. CLAIMS 1. A compound of the formula I wherein C is phenyl, pyridyl, thienyl furyl, pyrimidyl, indolyl, thiazolyl, imidazolyl, coumarinyl, phthalimidyl, quinolyl, piperazinyl, tetrazolyl, triazolyl, oxazolyl, isoxazolyl, isothiazolyl or its thieno-, pyridino- or benzo-molten derivatives, it being possible for the aromatic or heteroaromatic radical to be mono- or di-substituted by fluorine, chlorine, bromine, iodine, OH, CF3, -N02, CN, (C? -C8) alkoxy, alkyl (C? -C8 NH2, - NH-R " -N (R9) R10, CHO, -COOH, -COOR11, (C = 0) -R12, alkyl (C? -C6) -OH, alkyl (C? -C6) (-OH) -phenyl, alkyl (C) -C6) -CF3, alkyl (C6C6) -N02 / alkyl (C6C6) -CN, alkyl (C6C6) -NH2, alkyl (Ci-Cg) -NH-R9, alkyl (C? - £ 6) -N (R9") R10, alkyl (C? -C6) -CHO, alkyl (C? -C6) -COOH, alkyl (C? -C6) -COOR11, alkyl only) -R12 , -O-alkyl (C? -C6) -OH, -O-alkyl (C? -C6) -FC3, -O-alkyl (C? -C6) -N02, -O-alkyl (C? -C6) -CN, -O-alkyl (C? -C6) -NH2, -O-alkyl (C? -C6) -NH-R9, -O- alkyl (C? -C6) -N (R9) R10, -O -alkyl (C? -C6) -CHO, -0- alkyl (C? -C6) -COOH, -O-alkyl (C? -C6) -COOR11, -0- alkyl? (C? -C6) - ( C = 0) -R12, -N-S03H, -S02-CH3 or -0- alkyl (C? -C6) -O-alkyl (.Ci-Cßl-phenyl, where one or More of the hydrogens in the alkyl radicals can be replaced by fluorine; D is phenyl, pyridyl, thienyl, furyl, pyrimidyl, indolyl, thiazolyl, imidazolyl, coumarinyl, 15 phthalimidyl, quinolyl, piperazinyl, tetrazolyl, triazolyl, oxazolyl, isoxazolyl, isothiazolyl or 4, 5, 6, 7-tetrahydrobenzisoxazole or its thieno-, pyridino- or benzo-fused derivatives, it being possible for the aromatic or heteroaromatic radical to be 20 mono- or di-substituted by fluorine, chlorine, bromine, iodine, OH, CF3, -N02, CN, alkoxy (C? -C8), alkyl (Ci- C?). NH2, -NH-R9, -N (R9) R10, CHO, -COOH, -COOR11, - (C = 0) -R12, alkyl (C? -C6) -OH, alkyl (C? -C6) (- 0H) - phenyl, alkyl (C? -C6) -CF3, alkyl (C? -C6) -N02, alkyl (d-Ce) -CN, alkyl (C? -C6) -NH2, alkyl (OL-C6) -NH-R9, alkyl (C? -C6) -N (R9) R10, alkyl (C? -C6) ) - CHO, alkyl (C? -C6) -COOH, alkyl (QL-C6) -COOR11, alkyl- (C = 0) -R12, -O-alkyl (C? -C6) -OH, -0-alkyl (C? -C6) -CF3, -O-alkyl (C? -C6) -N02 -0- alkyl (C? -C6) -CN, -O-alkyl (C? -C6) -NH2, -0- alkyl (C? -C6) -NH-R9, -O-alkyl (C? -C6) -N (R9) R10, -O-alkyl (C? -C6) -CHO, -O-alkyl (C? - C6) -COOH, -O- (C? -C6) alkyl -COOR11, -O-alkyl (C? -C6) - (C = 0) -R12, -N-SO3H, -S02-CH3 / alkyl (C0) -C6) -pyridyl, -0- alkyl (C? -C6) -0-alkyl (C? -C6) -phenyl or alkyl (Co. Ce) -phenyl, wherein the phenyl radicals can be substituted up to twice by F , Cl, CF3, 0CF3, alkyl (C? -C6) or -O-alkyl (C? -C6) and where one or more of the hydrogens in the alkyl radicals can be replaced by fluorine; with the proviso that C and D do not have the following meanings simultaneously: C = phenyl and D = phenyl, C = phenyl and D = pyridyl, C = pyridyl and D = phenyl, C = pyridyl and de = pyridyl; R1, R2, R3, R4, independently of each other, are hydrogen, fluorine, chlorine, bromine, iodine, OH, CF3, -N02 / CN, alkoxy (Ci-Ca) alkyl (C? -C8 NH2, -NH-Ry -N (R9_) R10, CHO, -COOH, -COOR11, (C = 0) -R12, alkyl (C? -C6) -OH, alkyl (C? -C6) (-OH) -phenyl, alkyl (C) -C6) -CF3, alkyl (C? -C6) -N02 alkyl (Ci- C6) -CN, alkyl (C? -C6) -NH2, alkyl (C? -C6) -NH-R9, alkyl (C -C6) -N (R9) R10, alkyl (C? -C6) -CHO, alkyl (C? -C6) -COOH, alkyl (C? -C6) -COOR11, alkyl- (C = 0) -R12 , -O-alkyl (C? -C6) -OH, -O-alkyl (Cj.-C6) -FC3 / -O-alkyl (Ci-C6) -N02 / -O-alkyl (C? -C6) - CN, -O-alkyl (CA-C6) -NH2, -O-alkyl (C? -C6) -NH-R9, -0- alkyl (C? -C6) -N (R9) R10, -O-alkyl (C? -C6) -CHO, -0- alkyl (C? -C6) -COOH, -O-alkyl (C? -C6) -COOR11, -0- alkyl (C? -C6) - (C = 0 ) -R12, -N-S03H, -S02-CH3, or -0- alkyl (Ci-Cß) -O-alkyl (Ci-Cß) -phenyl, where one or more of the hydrogens in the alkyl radicals can be replaced by fluorine; R9 to R12, independently of each other, are hydrogen or alkyl (C6C6); and their pharmaceutically tolerated salts and their physiologically functional derivatives.
2. 2. A compound of formula I, as claimed in claim 1, in which C is phenyl, pyridyl, furyl thienyl, pyrimidyl, indolyl, thiazolyl, imidazolyl, coumarinyl, phthalimidyl, quinolyl, piperazinyl, tetrazolyl, triazolyl, oxazolyl, isoxazolyl, isothiazolyl or their derivatives benzo-fused, it being possible for the aromatic or heteroaromatic radical is mono- or di-substituted by fluorine, chlorine, bromine, iodine, OH, CF3, -N02, CN, alkoxy (C? -C8), alkyl (C? ~ Cß) / cycloalkyl (C3-C6), NH2, CHO , -COOH or OCF3; D is phenyl, pyridyl, furyl thienyl, pyrimidyl, indolyl, thiazolyl, imidazolyl, coumarinyl, phthalimidyl, quinolyl, piperazinyl, tetrazolyl, triazolyl, oxazolyl, isoxazolyl, isothiazolyl or their derivatives benzo-fused, it being possible for the aromatic or heteroaromatic radical is mono- or di-substituted by fluorine, chlorine, bromine, iodine, OH, CF3, -N02, CN, (C? -C8) alkoxy, (Ci- C8) alkyl, (C3-C6) cycloalkyl, NH2, CHO, -COOH or 0CF3; with the proviso that C and D do not have the following meanings simultaneously: C = phenyl and D = phenyl, C = phenyl and D = pyridyl, C = pyridyl and D = phenyl, C = pyridyl and de = pyridyl; R1, R2, R3, R4, independently of each other, are hydrogen, fluorine, chlorine, bromine, iodine, OH, CF3, OCF3, -N02, CN, (C? -C8) alkoxy, (Ci-C?) Alkyl. NH2, -NH-R9, -N (R9) R10, CHO, -COOH, -COOR11, - (C = 0) -R12, in which one or more hydrogens in the alkyl radicals can be replaced by fluorine; E9 to R12, independently of each other, are hydrogen or alkyl (C? ~ C8). and their pharmaceutically tolerated t salts and their physiologically functional derivatives.
3. 3. A compound of formula I, as claimed in claims 1 or 2, in which: C is phenyl, pyridyl, thienyl, pyrimidyl, indolyl, thiazolyl, quinolyl, oxazolyl or isoxazolyl, it being possible for the aromatic or heteroaromatic radical to be monosubstituted or disubstituted by fluorine, chlorine, bromine, or alkyl (Ci- C8); D is phenyl, pyridyl, thienyl, pyrimidyl, indolyl, thiazolyl, quinolyl, imidazolyl, triazolyl, oxazolyl or isoxazolyl, it being possible for the aromatic or heteroaromatic radical to be monosubstituted or disubstituted by fluorine, chlorine, bromine, or alkyl (C ? ~ C8); with. the condition that C and D do not simultaneously have the following meanings: C = phenyl and D = phenyl, C = phenyl and D = pyridyl, C = pyridyl and D = phenyl, C = pyridyl and D = pyridyl; R1, R2, R3, R4, independently of one another are hydrogen, fluorine, chlorine, bromine, iodine, OH, CF3, OCF3, -N02 / CN, alkoxy (Ci-SCs) alkyl (OL-CS), cycloalkyl (C3 -C6), NH2 / -NH-R9, -N (R9) R10, CHO, -COOH, -COOR11 or - (C = 0) -R12, in which one or more hydrogens in the alkyl radicals can be replaced by fluorine; R9 to R2, independently of each other, are hydrogen or alkyl (Ci-Ca); and its pharmaceutically tolerated salts.
4. 4. A pharmaceutical composition, comprising one or more of the compounds, as claimed in one or more of claims 1 to 3.
5. 5. A pharmaceutical composition, comprising one or more of the compounds, as claimed in one or more of claims 1 to 3, and one or more active compounds that lower lipids.
6. 6. A compound, as claimed in one or more of claims 1 to 3, for use as a medicament for the prophylaxis or treatment of alterations in lipid metabolism.
7. A compound, as claimed in one or more of claims 1 to 3, for use as a medicament for the treatment of hyperlipidemia. 8-.
8. A compound, as claimed in one or more of claims 1 to 3, for use as a medicament for the prophylaxis or treatment of arteriosclerotic symptoms.
9. A compound, as claimed in one or more of claims 1 to 3, in combination with at least one more active compound, which lowers lipids, for use as a medicament for the prophylaxis or treatment of disorders in the lipid metabolism.
10. 10. A compound, as claimed in one or more of claims 1 to 3, in combination with at least one active compound more than decreasing lipids, as a medicament for the treatment of hyperlipidemia. .
11. 11. A compound, as claimed in one or more of claims 1 to 3, in combination with at least one active compound further lowering the lipids, for use as a medicament for the prophylaxis or treatment of arteriosclerotic symptoms.
12. 12. A process for the preparation of a pharmaceutical composition, which comprises one or more of the compounds, as claimed in one or more of claims 1 to 3, this process comprises mixing the active compound with a suitable pharmaceutically excipient and carrying This mixture in a form suitable for administration.
13. 13. The use of a compound, as claimed in one or more of claims 1 to 3, for the preparation of a medicament for the prophylaxis or treatment of alterations in lipid metabolism.
14. 14. The use of a compound, as claimed in one or more of claims 1 to 3, for the preparation of a medicament for the treatment of hyperlipidemia. SUMMARY OF THE INVENTION The invention relates to substituted propanolamine derivatives and their pharmaceutically tolerated salts and physiologically functional derivatives. Compounds of the formula I are described: I wherein the radicals have the given meanings, and their physiologically tolerated salts and physiologically functional derivatives, as well as processes for their preparation. The compounds are suitable, for example, as hypolipidemic agents.