MXPA01003207A - Propanolamine derivatives linked with bile acid used for treating disorders of the lipid metabolism - Google Patents

Abstract

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

Description

PROPANOLAMINE DERIVATIVES LINKED TO BILIS ACIDS FOR THE TREATMENT OF DISTURBANCES IN LIPID METABOLISM The invention relates to substituted propanolamine derivatives and pharmaceutically tolerated salts and physiologically functional derivatives thereof. Various classes of active compound have already been described for the treatment of adiposity and disturbances in lipid metabolism - polyrheric adsorbers such as for example, cholestyramine-benzothiacepmas (WO 93/16055) 1C) - bile acid dimers and conjugates (EP 0 489 423) - 4-am? no-2-ure? do-p? r? m? dm- 5 -carboxamias (EP 0 556 879) The invention was based on the object of providing additional compounds that exhibit a therapeutically valuable hypolipidomic action The invention, therefore, relates to compounds of formula 1 . _ where GS is a group of bile acid of the formula Rl is a bond to X, OH, R2 is a bond to X OH, O- (Ct-C6) -alqu i lo NH-? C2-Cb) -alkyl-S03H, N (CH, j -CH2- CH2-SO, H NHÍ C, -C6 j -al? Ui lo-COOH N (CH3) - (Cl-C,) -alkyl -COOH. with the proviso that R1 and P2 do not have the following meaning R1 and a bond to X and R2 a bond to X, R3, R4 independently of each other are H OH 0 X is - -AA, - X f-AA2 -L- -N | H 1 c a bond l, m, n independently of one another are 0 or 1 L is alkyl- (C? -Cb), phenyl AA?, AA2 independently of one another are an amino acid radical or an amino acid radical which is mono or polysubstituted by an amino acid protecting group, and pharmaceutically tolerated salts and physiologically functional derivatives thereof The preferred compounds of formula 1 are those in which one or more radicals has the following meaning GS in group of bile acid from the tormul- R1 a bond to X OH, R2 a bond to X, OH, O- (d-Cb) -alkyl, NH- (C2-C6) -alkyl-S03H, N (CH,) -CH2-CH2-S03H , NH- (Cj-C-alkyl-COOH, N (CH3) - (-Cβ) -alkyl 1 -COOH, with the proviso that R1 and R2 do not simultaneously have the following meaning R1 a bond to X and R2 a link to X, X or a bond 1, m, n independently of one another, 0 or 1, L alkyl- (C? -C6), phenyl AAi, AA2 independently of each other, an amino acid radical or an amino acid radical that is mono- or polysubstituted by a protecting group of amino acids and pharmaceutically tolerated salts and physiologically functional derivatives thereof Particularly preferred compounds of formula 1 are those in which one or more radicals has the following meaning GS a group of acid of bile of the formula R1 a bond to X OH R2 a bond to X, QH. 0- (C, -Cb) -alkyl. NH- (C2-Cb) -alkyl-S3H. NH- (d-d) -alkyl 1 -COOH. with the proviso that R1 and R2 do not simultaneously have the following meaning. R1 a link to X and R2 a link to X or a bond, 1, n independently of one another 0 or 1 L ali lo- i C? -C6) 'AA,. AA2 independently of one another are an amino acid radical or an amino acid radical which is mono- or polysubstituted by an amino acid protecting group, and pharmaceutically tolerated salts thereof. The term "alkyl" is understood to mean branched hydrocarbon chains or straight chain c, The term amino acids or amino acid radicals means the stereoisomeric forms, ie, D- or L- forms of the following compounds alanine glycine proline cistern histidine glutamine Q aspartic acid isoleucine arginma glutamic acid lysine serine phenylalanine leucma threonine triptofan methyna valine tyrosma asparagma ] _C | 2-ammoadipic acid 2-ammonium-2-butbutic acid 2-amynaadipic acid 3-ammonium-sobutypic acid-2-alanine acid 2-ammop-methyl acid 2-ammobutyric acid 2 , 4-d? Apunobutyr? Co acid 4-am? Nobutyr? Co desraosma or piperidic acid 2, 2-d? Am? Nop? Mél? Co acid 6-ammocapro? Co acid 2,3-d? Ammoprop? On 2-ammoheptane acid co-N-ethylglycine 2- (2-t-eml) -gl? c? na 3- (2-t? in? l) -alamine peni cylamine N-rnetylglycine 5 N-ethylaparagine N -methyloleucine hydroxymethyl 6-N-methylamine to hydroxylamine N-metilvane 3-hydroxy proline 4-hydroxy proline norleucine 5 isosmosm orni tubula allo-isoleucine acid 11-am? noundecano? co The amino acids abbreviated in accordance with the usual customary nomenclature (cf Schroeder, L? Bke Peptides Volume 1, New York 1965, pages Q XXII-XXIII Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry] Volume XV / 1 and 2 Stuttgart 1974) The amino acid D-Asp is the D-form of aspartic acid The peptides are acidic amides of their chemical nature and dissociate into amino acids - | _5 during hydrolysis The term amino acid protecting groups is to be understood as meaning appropriate groups with which the functional groups of the side chains of the amino acid radicals are protected (see for example TW Green, PGM Wuts Protective Groups in Organic Synthesis, 2nd Edition, John Wiley and Sons, New York 1991) Preferred amino acid protecting groups are t-butyloxycarbonyl (BOC) 5 9-fluorenylmethoxycarbonyl (Fmoc) benzyloxycarbonyl (Z), 2- (3 , 5-d? Methox? Phenyl) prop-2-? loxi carbon ilo (Ddz), methyl. t-butyl, triethyl and S-t-butyl t-butyl-laminocarbon The invention is further related to processes for the preparation of compounds of formula 1 which proceed in accordance with the following reaction equations (equations 1 to 4) Equation 1 racematc 1 racomate splming onanliomer Type IV compounds are obtained by reacting o-m- or -substituted types II with ketone III. The reaction can be carried out for example by mixing the two compounds by volume without a solvent and then heating, or in a suitable solvent, such as ethanol, tetrahydrofuran (THF), toluene, diglyme or tetradecane, at temperatures of 20aC to 150SC Keto compounds of type IV are reduced to hydroxy compounds of type V with NaBH "or other appropriate reducing agent in a suitable solvent , such as for example methane THF or THF / water at temperatures between -30aC and + 40aC Two mixtures of isomer (racemates) are usually obtained as the main product in the reduction The various racemates can be separated from each other by fractional crystallization or chromatography of silica gel The nitro group in compounds of type V can be reduced by known processes, such as for example catalytic hydrogenation with Pd or Pd-en- carbon and H2 in methanol Racemic compounds of type VI obtained d? in this way they can be further separated into their enanomers. The division of VI racemate into enantiomers of type VII can be carried out by chromatography on chiral column material or by means of methods known from the literature using optically active auxiliary reagents (cf J Org. Chem 44 1979 4891) Equation 2 VI or Vil 1 FmocAAOH 2 doprotoction According to equation 2, the aromatic amines of type VI or VII (race ato or pure enanomer) can be reacted with an amino acid by known conventional peptide coupling processes to provide VIII derivatives. An appropriate process, for example, is to copulate with TOTU and triethylamine in DMF (for the literature see G Breipohl W omg EP 0460446. W Konig G Ereipohl P Pokorny M Birkner in E. Giral and D Anareu eEcs) Peptides 1990, Escom. Leiden, 1991 143-145) Radicals AAi and AA? they have the meaning provided under formula 1 The amino function of the amino acid ST provides with a protecting group for example Fmoc and the carboxylic acid Lico is unprotected In amino acids with functional groups in the side chain, these are protected accordingly, either temporarily during the synthesis or to remain in the compounds according to the invention to bring the amino function protecting group to the derivative VIII is for example divided in the case of Fmoc in a mixture of DMF and piperidma The conjugates of dipeptide IX they are obtained if starting the compounds of type VIII the reaction sequence (a) which couples an amino acid and (b) deprotection is repeated Equation 3 1 coupling reaction 2. hydrolysis The bile acid derivatives of type X can be prepared from the acid ester of 3-am? No-b? 1 is linking with alkyl arylcarboxylic acids or derivatives thereof such as for example succinic anhydride by known processes (for example EP 0614908 EP 0489423) Compounds (X) are reacted with arninc compounds of type VI, VII VIII or IX by conventional peptide coupling processes. After the coupling reaction, compounds of type XI are obtained by hydrolysis of the alkyl ester function of part of the acid of bile Ecuac ón 4 Amino compounds of type VI, VII, VIII or XI can be reacted with the carboxylic acid function of bile acids. The known coupling processes of polypeptide are also used here, for example. copulating in the presence of TOTU and triet i lamina or with dicyclohexy Icarbodi imide hydroxybenzotriazole and triethylamine in THF. Compounds of type XII can be obtained by this process. Due to their superior solubility in water compared to the starting or base compounds, the pharmaceutically tolerated salts are particularly suitable for moderate applications. These salts should have a pharmaceutically tolerated anion or cation. The pharmaceutically tolerated acid addition salts of the according to the invention are salts of inorganic acids, such as hydrochloric, or hydrobromic, phosphoric, metaphosphobic, nitric, sulphonic and sulfuric acid, and of organic acids, such as, for example, acetic or benzenesulonic acid, benzoic acid, citric acid, etansul phonic, fumaric, gluconic, glycolic, isotonic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic. p-toluenesulfonic, tartaric, and tri-furanoic acid. The chlorine salt is particularly preferably used for modest purposes. The appropriate 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 magnesium salts). calcium). Salts with an anion that is not pharmaceutically tolerated are also included within the scope of the invention as beneficial intermediates for the preparation or purification of pharmaceutically tolerated salts and / or for use in non-therapeutic applications for example, in in vitro applications. "physiologically functional derivative" used herein denotes any physiologically tolerated derivative of a compound of formula 1 d? according to the invention, for example an ester which, during administration to a mammal, such as for example, humans, is capable of forming (directly or indirectly) a compound of formula 1 or an active metabolite thereof Physiologically derived functional products also include prodrugs of the compounds according to the invention. These prodrugs can be ^ Metabolize in vivo a compound in accordance with the invention These prodrugs may or may not be active themselves. The compounds according to the invention may also be in various polymorphic forms, for example as amorphous or crystalline polymorphic forms. All polymorphic forms of the compounds according to the invention are included within the scope of the invention and are a further aspect of the invention. All references to "compound (s) according to formula (1)" below are related to compound (s) of the formula (1) as described above, and its salts, solvates and physiologically functional derivatives as described herein The amount of a compound according to the formula (1) which is necessary to achieve the effect The desired biological function depends on a number of factors, for example, the specific compounds selected, the intended use, the mode of administration and the clinical condition of the the patient In general, the daily dose is on the scale of 0 3 mg to 100 mg (typically 3 mg to 50 mg) per day per kilogram of body weight for example 3-10 mg / kg / day An intravenous dose, for example it may be on the scale from 0 3 mg to 10 mg / kg which can be appropriately administered as an infusion of 10 ng to 100 ng per kilogram per minute. The appropriate infusion solutions for this purpose may comprise, for example, 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 The ampules for injections in this manner may contain, for example from 1 mg to 100 mg and individual dose formulations for oral administration such as for example tablets or capsules may contain, for example from 10 to 1000 mg, typically from 10 to 600 mg. In the case of pharmaceutically tolerated salts , the weight data mentioned above are related to the weight of the benzothiazepma ion derived from the salt. For prophylaxis or treatment of the above-mentioned conditions the compounds according to the formula (1) can be used as the compound but preferably they are in the Form of a pharmaceutical composition with a tolerated excipient The excipient should of course be tolerated in the sense that it is compatible with the other constituents of the composition and is not harmful to the health of the patient. The excipient can be a solid or a liquid or both. , and preferably is formulated with the compound as a single dose for example as a tablet which can comprise from 0 to 95% by weight of the active compound Additional pharmaceutically active substances can also be present including additional compounds according to formula (1). The pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods comprising essentially 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 peroral (for example sublingual) and parenteral (e.g. subcutaneous, intramuscular, mdermic or intravenous) administration even though the most appropriate mode of administration in each individual case it depends on the nature and severity of the condition to be treated and on the nature of the particular compound in accordance with the formula (1 j used) The coated formulations and sustained release formulations coated Also included within the scope of the invention Formulations that are resistant to acid and gastric play are preferred. Suitable coatings that are resistant to gastric juice include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, and polymers. ammonia of methacrylic acid and methyl methacrylate The pharmaceutical compounds suitable for oral administration can be in the form of separate units such as for example capsules on chewable tablets or tablets each of which comprises a certain amount of the compound according to the formula (1) , 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 compositions can be formulated by any suitable pharmaceutical method comprising a step in the than the active compound and the excipient (which ede comprising one or more additional constituents) are brought into contact. The compositions are generally prepared by uniform and homogeneous mixing of the active compound with a liquid and / or finely divided solid carrier, after which the product is configured if required. For example, a tablet can be prepared by pressing or stirring a powder or granules of compound optionally with one or more additional constituents. The pressed tablets can be prepared by tabletting the compound in the free-flowing form, such as for example a powder or granules. , optionally mixed with an inert diluent lubricating binder and / or one (or more) surfactants / dispersants, in an appropriate machine. The shaped tablets can be prepared by shaping the powdered compound that has been moistened with an inert liquid diluent in an appropriate machine. Pharmaceutical compositions that are suitable for administration n peroral (sublingual j include lozenges which comprise a compound according to formula (Ij with a substance sabopzante, usually sucrose, and gum arabic or tragacanth, and lozenges, 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 (1), which are preferably isotonic with the blood of the intended recipient. These formulations are preferably administered intravenously, even when the administration can also occur subcutaneously intramuscularly intramuscularly or intradermally, as an injection. These formulations can be prepared by example, by mixing the compound with water and making the resulting solution sterile and isotonic with blood. The injectable compositions according to the invention generally comprise from 0 to 5% by weight of the active compound. The pharmaceutical compositions suitable for rectal administration are of preferential a of the form of single-dose suppositories These can be prepared by mixing a compound according to formula (1) with one or more conventional solid excipients, for example cocoa butter, and introducing the formed mixture into a mold. The pharmaceutical compositions Suitable for topical application to the skin are preferably in the form of an ointment, cream lotion, paste, spray, aerosol or oil. The excipients that may be used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances The active compound is generally present in a concentration of 0 1 to 15% by weight of the composition for example 0 to 2% Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal applications can be in the form of individual patches that They are suitable for long-term close contact with the epidermis of the patient. These parch is appropriately comprise the active compound in an optionally buffered aqueous solution, dissolved and / or dispersed in an adhesion promoter or dispersed in a polymer. An appropriate concentration of active compound is about 1% to 35%, preferably about 3% to 15%. As a particular possibility, the active compound can be released by electrotransport or iontophoresis, as described, for example, in Pharmaceutical Research, 2 (6) 318 (1986). The invention relates to compounds of formula 1 in the form of their racemates racemic mixtures and pure enanomers and their diastereomers and mixtures thereof Compounds of formula 1 and pharmaceutically tolerated salts and physiologically functional derivatives thereof are distinguished by favorable actions on lipid metabolism. Compounds can be employed by themselves or in combination with additional active lipid reduction compounds The compounds They are suitable for prophylaxis and, in particular for treatment of disturbances in lipid metabolism, in particular hyperlipidemia. Compounds of formula 1 are also suitable for influencing serum cholesterol levels and for prevention and treatment of artepoesclerotic symptoms. The following findings demonstrate the pharmacological activity of the compounds according to the invention The biological test of the compounds according to the invention was carried out by determining the inhibition of [3H] -taurocholate admission in brush border membrane vesicles of the ileum of rabbits Inhibition test was carried out as follows 1 Preparation of brush border membrane vesicles from the ileum of rabbits The preparation of brush border membrane vesicles from intestinal small intestinal cells was carried out by the method of precipitation called Mg2t Rabbits m New Zealand anthocyanins (2 to 2 5 kg body weight) were sacrificed by intravenous injection of 0 5 ml of T61lR) an aqueous solution of 2 5 mg tetracaine HCl 100 m embutramide and 25 mg mebezonium iodide The small intestine it was separated and rinsed with ice physiological saline solution The 7/10 terminal of the small intestine (measured in the oral-rectal direction) ie the terminal ileus, which contains the b + acid-dependent Na + transport system) was used for the preparation of the brush-edge membrane vesicles The intestines were frozen at -80 ° C in plastic bags under nitrogen For the preparation of the membrane vesicles the frozen intestines were thawed at 30 C in a water bath The mucosa was scraped and suspended in 60 ml of 12 mM Tris / HCl buffer (pH 7 l = / 300 mM mannitol, 5 mM EGTA / 10 mg / l of femylmethylsulfonyl fluoride / 1 mg / l of soybean bean trypsin inhibitor (32 U / mg) / 0 5 mg / l of bovine lung trypsin inhibitor 19193 U / mg) 5 mg / l of bacitracma After from the dilution to 300 ml with ice distilled water the mixture was made with an Ultraturrax (rod 18- IKA Werk Staufen Germany) at 75% of the maximum for 3 minutes, while it was cooled with ice After the addition of 3 ml of MgCl2 solution to the IM (final concentration of 10 mM), the mixture was left to rest ra 0CC for exactly 1 minute By adding Mg2 +, the ce cell membranes are aggregated, and precipitated with the exception of the brush edge membranes after centrifugation at 3000 xg (5000 rpm, SS-34 rotor) for 15 minutes , the precipitate was discarded and the supernatant containing the brush border membrane, was centrifuged at 48,000 xg (20,000 rpm, SS-34 rotor) for 30 minutes. The supernatant was discarded and the precipitate was rehomogenized in 60 ml of buffer 12. mM Tris / HCl (pH 7.1) / 60 mM of tol, 5 mM EGTA with a Potter lvejhem homogenizer (Braun, Melsungen, 900 rpm, 10 runs) After the addition of 0 1 ml of 1M solution of MgCl 2 and a Incubation time of 15 minutes at 0 ° C the ST mixture was centrifuged again at 3000 xg for 15 minutes. The supernatant was then centrifuged again at 48,000 xg (20,000 rpm SS-34 rotor) for 30 minutes. The precipitate was taken in 30 ml of buffer. 10 mM Tris / Hepes (pH 7 4) / 300 mM of mannitol and homogeneously resuspended by 20 runs in a Potter Elvejhem homogenizer at 1000 rpm After centrifugation at 38,000 xg (20,000 rpm, SS-34 rotor) for 30 minutes, the precipitate was absorbed in 0 to 2 ml of Tris buffer / Hepes (pH 7 4) / 280 M mannitol (final concentration 20 mg / ml) and was resuspended with the help of a tuberculin syringe with a 27-gauge needle. The vesicles were used directly for transport studies after preparation. or were stored at -196eC in 4 mg portions in liquid nitrogen. 2. Inhibition of the admission of [__] Na + -dependent taurocholate in brush border membrane vesicles of the ileum The admission of substrates in the above-described brush border membrane vesicles was determined by means of the technique called membrane filtration. lOul of the vesicle suspension (100 ug of protein) were pipetted as drops towards the wall of a polystyrene incubation tube / ll x 70 mm), which contained the incubation medium with the corresponding ligands (90 ul). incubation medium comprised 0 75 ul = 0 75 uCi [3H (G)] -taurocholate (specific activity 2 1 Ci / mmol) / 0 5 ul of 10 mM taurocholate / 8.75 ul of sodium transport buffer (10 mM Tris / Hepes (pH 7 4) / 100 mM of mam tol / 100 mM of Ncl) (Na-TB) or 8 75 ul of potassium transport buffer (10 mM Tris / Hepes (pH 7 4) / 100 M of mamtol / 100 mM KCl), (KT-Bj and 80 ul of the inhibitor solution in question, dissolved in a buffer of Na-T ot KT amp, depending on the experiment The incubation medium was filtered through a lead polyvinyl fluoride membrane filter (SYHV LO 4NS 0 45 um, 4 mm OR Millipore, Eschborn, Germany) The transport measurement was started by mixing the vesicles with the incubation medium The concentration of 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 ice-cold stop solution (10 mM Tps / Hepes) (pH 7 41/150 mM KCl) The formed mixture was immediately removed by suction filtration under a vacuum of 25 to 35 mbar on a cellulose nitrate membrane filter (MEE 25)., 0 45 um, 25 mm diameter, Schleicher &; Schuell Dassell Alema al The filter was rinsed with 5 ml of frozen stop solution To measure the admission of the radioactively labeled taurocholate, the membrane filter was dissolved with 4 ml of the Quickszmg 361 scintillator (Zmsser Analytik GmbH, Frankfurt, Germany) and the radioactivity was measured by measurement is liquid scintillation in a TriCarb 2500 measuring device (Canberra Packard 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 in each case in Na-T-B and K-T-B. The difference between the admission in Na-T-B and K-T-B provided the Na + -dependent transport content. That concentration of inhibitor at which the Na + -dependent transport content was inhibited by 50% - based on the control - was designated the IC50 Na +. The pharmacological data comprises a series of tests in which the interaction of the compounds according to the invention with the acid transport system of intestinal bile in the terminal small intestine were investigated. The results are summarized in Table 1 Table 1 shows measurement values of the inhibition of admission of [3H] -taurocholate in brush border membrane vesicles of ileum of rabbits The quotients of the values of IC5-- of the substance Reference materials such as tauroquendeoxycholate (TCDC) and the particular test substance are shown in Table 1 Compounds of Example Csotta-TCDC [umol) C50 -_- substanc? a [umol 1 3 1 51 1 k 1 59 2 d 0 56 2 e 1 96 4 0 50 7 0 15 8 0 91 9 2 02 10 1 63 11 1 96 12 2 58 13 0 56 14 1 52 The following examples serve to illustrate the invention in greater detail without limiting it to the products and embodiments described in the examples.

Example 1 366 ml of 15% strength n-butyllithium in n-hexane were added dropwise to 50 g (0.54 mol of picolma in 770 ml of tetrahydrofuran) at -55 ° C. The mixture was warmed to room temperature and cooled again to room temperature. -55 ° C 77 g of N-N-dimethylbenzamide (0.5-2 mole) in 570 ml of tetrahydrofuran were slowly added dropwise and the mixture was then warmed to room temperature and stirred for an additional hour after the addition of 550 nor of IN hydrochloric acid, the mixture was extracted with ethyl acetate (3x) and the organic phases were dried with MgSO, and evaporated. Distillation of the residue gave 47 g (47%) of product Boiling point 134-136aC / 0 23 mbar b. 0 g (0 13 mol) of o-nor robenzaldehyde 12 5 g (0 13 mol) of 2-aminopy pdna and 0 3 g of p-toluensulonic acid were heated under reflux in 150 ml of toluene for 2 hours. 5 hours, using a water separator The solution was cooled and the formed precipitate was filtered off with suction and dried. Yield 18 1 g (60%) of product Melting point 93-95sC C? 2HgN302 (227) MS (FAB) ) i 18 M + H * 12.0 g (61 mmol) of the ketone of Example 1 a and . 0 g (66 mmol) of the emulsion of Example 1 b were heated in a steam bath for 45 minutes. The reaction mixture was dissolved in ethanol, while it was quenched. After cooling, the precipitate was filtered off with suction and It was recrystallized from ethanol. Rend imi ent 11 8 g (46%) of product C25H20N < O3 (2 4 2 HS (FAB) 425 M + H * . 0 gi 18 8 mmol) of the sample compound was dissolved in 300 ml of tetrahydro tur anion water 10 1 4 67 g of sodium borohydride were added and the mixture was stirred at room temperature for 2 hours The solution was then evaporated 100 ml of 2N hydrochloric acid were added to the residue and the mixture was heated in a steam bath until everything had dissolved. After cooling the solution was made basic with NaOH solution and extracted with ethyl acetate ( 2x) The organic phases were dried with MgSO 4 and evaporated. The residue was chromatographed on silica gel and heptane / ethyl acetate 1 lj. Two racemic compounds were obtained as the product fraction 3 9 g (48%) of racemate not polar (Example 1 d / 1) C25H22N < 03 (426 2) MS (FAB) 427 M + H4 2a Fraction 2 5 g (31%) polar racemate (Example 1 d / 2) C2SH22N403 1426 2) MS (FAB ) 427 M + H ' 2 g (5.86 mmol) of the polar n racemate of Example 1 d / 1 were dissolved in 300 ml of methanol, approximately 20 mg of 10% Pd / C were added and hydrogenation was carried out under an atmosphere of H2 at room temperature. The catalyst was separated by filtration and 1-solution was evaporated. The residue was chromatographed on silica gel (n-heptane / ethyl acetate 7 13) Yield 1 9 g (82%) of product C25H2, N, 0 '396 22 j MS i FAB j 397 M + H '(+) -ananmer (Example 1 f / 2) 100 mg of the racemic compound of Example 1 and ST were separated into the enanomers by HPLC in preparation The separation was carried out on a CSO-Chiralpak column (Daicel, Dusseldorf) with 4: 1 n-hexane / ethanol. 40 mg of the (-) - enanomer (Example 1 f / l) was obtained as the first fraction and 40 mg of the (+) - enanomer (Example 1 f / 2) was obtained as the second fraction 9- 4 0 g (10 1 mmol) of the ammo compound of Example le (non-polar racemate), 4 85 g (10 3 mmol) of N-Fmoc-D-Lyx (BOC) OH 4 0 g (12 2 mmol) of TOTL and 2 7 ml d? Triethylamine was dissolved in 300 ml of dimethyl formamide and the solution was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate (2 x). The organic phases were dried (MgSO.l and evaporated). The residue was dissolved in 150 ml of dimeti-formamide / piperidine 2 1 to separate the Fmoc group and the stir-ST solution at room temperature for 1 hour. Poured into water and extracted with ethyl acetate (3 x) The organic phases dried (MgSO) and evaporated. Chromatography on silica gel (methylene chloride / methanol 9 1) yielded 4.0 g (63.5%) of product C36H4, NbO, (624 3) M5 (FAB) 625 M + H * .0 g (11 86 mmol) of 3beta-ammocolic acid methyl ester (European Patent Application EP 0614908) 13 g (13 mmol of succinic anhydride and 16 ml of triethylamine were dissolved in 75 ml of t? The residue was dissolved in water and the solution was acidified with hydrochloric acid and extracted with ethyl acetate (3 x). The organic phases were dried (MgSO 4) and the solution was stirred at room temperature for 1 hour. «) And evaporated Yield 5 8 g (94%) C2 <, H < 7N07 (521 3) MS (FAB) 528 M * Ll * 4.0 g (6.4 mmol) of the compound of Example 1 g 3.45 g (6 6 mmolj of the bile acid derivative of Example 1 h 1 2 ml of triethylamine 2 16 g '16 mmol) of hydroxybenzotpazoi and 2 56 g of di The hydroxylcarbodimide (12 4 mmolj) was dissolved in 250 ml of tetrahydro turan and the solution was stirred at room temperature for 5 hours. The mixture was evaporated and the residue was dissolved in ethyl acetate and the solution was washed with NaHCO 3 solution. The organic extracts were dried (MgSO,) and evaporated. Chromatography on silica gel (methylene chloride / methanol 19 1 then 9 1) gave 3 1 g (43%) of product C6SHß, N7O10 f 1127 7) MS (FAB) 1134 7 M + Ll * 3 1 g (2.75 mmol) of the methyl ester of Example 1 i were dissolved in 200 ml of ethanol 31 ml of NaOH solution were added and the mixture was stirred at room temperature for 5 hours. The mixture was evaporated and the residue was evaporated. dissolved in water was added NaH2PO solution < saturated The mixture was extracted with ethyl acetate (2 x) and the organic phases were dried over MgSO 4 and evaporated The crude product was chromatographed on silica gel (methylene chloride / methanol 4 1) Yield 2 25 g (73%) ) C64Hß 7? 10 (1 1 1 3 7) MS Í FAB) 1 1 2 0 7 M + L i * 0 48 g of ethyl chloroformate were added to 1 5 g (1 35 mmol 1 of the compound of Example i / 0 81 ml of triethylamine at 0 ° C and the mixture was stirred for 10 minutes. Then 0.6 g of taurine dissolved in 30 ml was added. ml of 0 1 N NaOH solution and the mixture was stirred at room temperature for 24 hours. The mixture was evaporated, the residue was dissolved in a little water and the solution was poured into saturated NaHjPO solution. The mixture was extracted with ethyl acetate. Ethyl (3x) and the organic phases were dried with MgSO, and evaporated. After chromatography on silica gel (methylene chloride / methanol 4 1, then methanol) 0 9 g (60%) of taurine conjugate were obtained C66H, 2Nß012S (1270 7) MS (FAB) 1243 6 M + Na * Example 2 5 gf 31 mmol) of the ammo compound of Example 1 e (non-polar racemate), 2 2 g (6 52 mm lj of Fmoc-L-proline, 2 5 g (762 mmol) of TOTU and 1 7 ml of triet The film was dissolved in 100 ml of dimethyl formamide and the solution was stirred at room temperature for 3 hours. The reaction mixture was evaporated in half, water was added and the mixture was extracted with ethyl acetate (3 x). The organic phases were dried over MgSO, and evaporated. After chromatography on silica gel (ethyl acetate / neptan 7 3), 35 g of 5% product were obtained. This intermediate product protected with Fmoc (3.6 g) was obtained. dissolved in 110 ml of pipepdine / DMF 1 10 and the solution was stirred at room temperature for 1 hour The mixture was evaporated and the residue was chromatographed on silica gel (methylene chloride / ethanol 19 1 then 9: 1) Performance 1 8 g (72 5%) C3oH31N50? (4 9 3 2) MS (FAB) 4 9 4 M + H * Example 2 b / 1 Example 2 b / 2 1 7 g (3.44 mmol) of compound d ^ l Example _ were stirred with 1 4 g (3 61 mmol) of Fmoc-L-femlala na 1 9 g 15 80 mmol) of TOTU and 10 ml of triethylamine in 150 ml of DMF at room temperature for 4 hours The reaction mixture was evaporated and the residue was chromatographed on silica gel (ethyl acetate, n-heptane 4 1). Two fractions were obtained. fraction 1 28 g (43%) of non polar polar diastereomer (Example 2 b / 1) Cs «HSoKA (862 4) MS (FAB) 863 4 M + H * 2a fraction 0 82 g (28%) of diather polar (Example 2 b / 1) C5 H5oN605 (86 2 4) MS (FAB) 8 6 2 4 M + H * 0 8 g (0.93 mmol) of the compound of Example 2 b / 2 were dissolved in 33 ml of DMF / piper id 10.1 and the mixture was stirred at room temperature for 1 hour. After evaporation, the residue was chromatographed on silica gel. silica (methylene chloride / methanol 19 1. then 9: 1) Yield 0 35 g (59%). C39H < oNb? 3 (640 3) MS (FAB) 641 3 M + H * d.

O 5 g (O 78 mmol) of the compound of Example 2 c and 0 45 g (0 86 mmol) of the bile acid derivative of Example 1 h were reacted by the process described for Example 1 i 0 38 g ( 43%) of product C6? H85N709 11143 6) MS (FAB) 1144 6 M + H * 0 31 gl 0 27 mmol) of the methyl ester dex Example 1 d were dissolved in 30 ml of ethanol, 3 ml of 1N NaOH solution was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was evaporated and the residue is chromatographed on silica gel (methylene chloride / methanol 4 1). Yield 220 mg (72%) CMHUNJO, (1129 6) MS (FAB) 1130 6 M + H * Example 0 3 g (0 78 mmol) of 3- (4-ammofe 1) -1- pheny 1-2-p? R? D? N-2-? L-3- (p? R? D? N-2 -? lam? no) -propan-l-ol (preparation analogously to Example le), 0 34 g (0 83 mmolj of ursocholic acid or 34 g (2 52 mmol i ae hydroxybenzotriazole or 41 g (2 mmol) of Dichlohexylcarbodumide and 15 ml of triethylaniline were stirred in 50 ml of tetrahydrofuran at room temperature for 2 days. When the reaction was complete, the solids were filtered off. The solution was evaporated and the residue chromatographed on silica gel. methylene / methanol 9 1 then 17 3) 0 33 g (55%) of product C49H62N405 (786 51 MS (FAB) 787 5 M + H * were obtained. Examples 4 to 14 were obtained from rranera analogous to Examples 1 to 3, starting from the corresponding starting compounds Example 4 d ^ N (787 1) MS (FAB) 788.1 M + H * Non-polar diastereomeric example C53H67N, 07, 8 & 6 MS.'FAB) 887 2 M + H * Example Cs4H6, N07 (900 2) MSiFABl 901 2 M + H * C53H - 507 (886 2) MS (FAB) 887 2 M + H * C53H67N507 (886 2) MS (FAB) 887.2 M + H * Example CsoHßiNjOß (1028 4) MS (FAB) 1029 4 M + H * Example 10 C59H79N70B (1014.3) MS (FAB) 1015.3 M + H * E j a lo 11 d7H83 70c) (1130.g) MS (FAB) 1031.5 M + H * Example C64Hß7N, 0, c 11114 4) MS (FAB) 1115 4 M + H * Example 13 CsßHßsNjO, [1144 5) MS (FAB) 1145 5 M t-H * Example 14 CßsH? ONßO ,, (1171.5) MS (FAB) 1172 5 M + H *

Claims (1)

1. CLAIMS A compound of formula 1 where GS is a group of bile acid of the formula. R1 is a bond to X OH, R2 is a bond to X OH, O- (dd) -al qui lo Mh- (C2-d) -alkyl-S03H, Ni CH3) -CH, -CH, -S03H , NH- C C, -Ce) -a lchi 1-CCOH N (CH3) - (C, -Cβ) -a 1 qu 11 -COOH - so ¬ with the proviso that R1 and R2 do not simultaneously have the following meaning R1 a bond to X and R2 a bond to X, R3, R < independently of one another are H OH, or a bond, 1, m, n alkyl- (C? -C6). phenyl, AAi, AA2 independently of one another are an amino acid radical or an amino acid radical which is mono or polysubstituted by an amino acid protecting group, and pharmaceutically acceptable salts and physiologically functional derivatives thereof 2 - A compound of the formula 1 in accordance with claim 1 wherein GS is a bile acid group of the formula R1 is a bond to X, OH, R2 is a bond to X, OH, O- (dd) -alkyl, NH- (C2-C6) -alkyl-SO3H, N (CH3) -CH2-CH2-S03H, NH- (dd) -alkyl-COOH; N (CH3) - (d-C6) -alkyl-COOH, with the proviso that R1 and R2 do not simultaneously have the following meaning R1 a bond to X and R2 a bond to X; P 0 X is (-AAH, AA2J- -L-u N- or a bond, 1, m, n independently of one another are 0 or 1 L is alkyl- (d-C6), femlo, AAi, AA2 independently one on the other are a radical amino acid or an amino acid radical which is mono- or polysubstituted by an amino acid protecting group, and pharmaceutically tolerated salts and physiologically functional derivatives thereof 3 - A compound of formula 1 according to claim 1 or 2, where GS is a group of bile acid of the formula R1 is a bond to X, OH: R2 is a bond to X, OH, O- (C, -C6) -alkyl, NH- (C2-d) -alkyl-S03H, NH-> C, -C6 ) -alk 1 -COOH: with the proviso that R 'and R2 do not simultaneously have the following meaning R1 a bond to X and R2 a bond to X:. or a link: 1, m. n independently of one another are 0 or 1; L Alkyl of (dd) AAL AA2 independently of one another is an amino acid radical or an amino acid radical which is mono- or polysubstituted by an amino acid protecting group: and pharmaceutically tolerated salts thereof 4 - A pharmaceutical product comprising one or more than the compounds according to one or more of claims 1 to 3 - A pharmaceutical product comprising one or more of the compounds according to one or more of claims 1 to 3 and one or more lipid-lowering active compounds 6 - A compound according to one or more of claims 1 to 3 for use as a pharmaceutical for the prophylaxis or treatment of disturbances in lipid metabolism 7 - A compound according to one or more of claims 1 to 3, for used as a pharmaceutical for the treatment of hyperlipidemia 8 - A compound according to one or more of claims 1 to 3 for use as a pharmacist for the prophylaxis or treatment of arteriosclerotic symptoms 9 - A compound according to one or more of claims 1 to 3, in combination with at least one additional lipid-reducing active compound for use as a pharmaceutical for prophylaxis or treatment of disturbances in lipid metabolism 10 - A compound according to one or more of claims 1 to 3, in combination with at least one additional lipid-reducing active compound as a pharmaceutical for treatment of hyperlipidemia 11 - A compound in accordance with a or more of claims 1 to 3, in combination with at least one additional lipid-reducing active compound as a pharmaceutical for the prophylaxis or treatment of arteriosclerotic symptoms. 12 - A process for the preparation of a pharmaceutical comprising one or more of the compounds according to one or more of claims 1 to 3Jt. , which comprises mixing the active compound with a pharmaceutically acceptable excipient and bringing this mixture to an appropriate form for administration. The use of a compound according to one or more of claims 1 to 3, for the preparation of a pharmaceutical for the prophylaxis or treatment of disturbances in lipid metabolism 14 - The use of a compound according to one or more of claims 1 to 3 for the preparation of a pharmaceutical for treatment of hyperlipide ia.