MXPA01004147A - Bile-acid substituted phenyl alkenoyl guanidines, method for the production thereof, use thereof as medicaments or diagnostic agents and medicaments that contain them - Google Patents

Abstract

The invention relates to substituted phenyl alkenoyl guanidines, the pharmaceutically acceptable salts thereof, and physiolgically functional derivatives. Compounds of formula (I) are disclosed, wherein the radicals have the meanings thus cited. Also disclosed are the physiologically acceptable salts thereof, physiologically functional derivatives and methods for the production thereof. The inventive compounds are, for instance, suitable for use as medicaments for the prophylaxis or treatment of gall stones.

Description

FENIL ALQUENOIL GUANIDINAS SUBSTITUTED WITH BILIARY ACID, PROCESS FOR PREPARATION, USE AS MEDICINES OR DIAGNOSIS AND MEDICATIONS CONTAINING THEM The invention relates to substituted phenyl alkenoyl guanidines and their pharmaceutically tolerable salts and physiologically functional derivatives. Apart from a number of factors, the formation of gallstones is determined essentially by the composition of the bile, in particular by the concentration and proportion of cholesterol, phospholipids and bile salts. The prerequisite for the formation of cholesterol gallstones is the presence of bile that is supersaturated in cholesterol (Ref Carey, MC and Small, D.M. (1978) "The physical chemistry of cholesterol solubility in bile. gallstone formation and dissolution in man ", (The chemical physics of the solubility of cholesterol in bile, Relation with the formation of gallstones and dissolution in humans), J. Clin.Invest 61: 998-1026). Until now, the gallstones have primarily been removed surgically, so that there is a great therapeutic need for medicinal dissolution of gallstones and for the prevention of gallstone formation. The invention is based on the object of making available compounds which are capable of preventing the formation of gallstones by preventing over saturation of the bile with cholesterol or by retarding the formation of cholesterol crystals from saturated bile. The invention therefore relates to compounds of the formula I where TI and T2 independently of each other are: or hydrogen, where TI and T2 can not simultaneously be hydrogen; z is R (A), R (B), R (C), R (D) independently of each other are hydrogen, F, Cl, Br, I, CN, OH, NH2, -alkyl with 1 to 8 carbon atoms, - O-alkyl having 1 to 8 carbon atoms, wherein the alkyl radicals may be substituted one or more times by F; C3-C8-cycloalkyl, phenyl, benzyl, NHR (7), NR (7) R (8), O-alkenyl with 3 to 6 carbon atoms, O-cycloalkyl with 3 to 8 carbon atoms, OR - phenyl, 0-benzyl, wherein the phenyl nucleus can be substituted up to 3 times by F, Cl, CF 3, methyl, methoxy, NR (9) R (10); R (7), R (8) independently of each other are hydrogen, -alkyl having 1 to 8 carbon atoms, wherein the alkyl radical may be substituted one or more times by F, cycloalkyl with 3 to 8 carbon atoms, alkenyl with 3 to 6 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, phenyl, benzyl, wherein the phenyl nucleus may be substituted up to 3 times by F, Cl, CF 3, methyl, methoxy, NR (9) R (10) ); or R (7), R (8) together form a chain of 4 or 5 methylene groups of which a CH2 group can be replaced by oxygen, sulfur, NH, N-CH3 or N-benzyl; R (9), R (10) independently of each other are hydrogen, alkyl with 1 to 4 carbon atoms, perfluoroalkyl with 1 to 4 carbon atoms; x is zero, 1 or 2; and is zero, 1 or 2; R (E), R (F) independently of each other are hydrogen, F, Cl, Br, I, CN, alkyl having 1 to 8 carbon atoms, O-alkyl having 1 to 8 carbon atoms, wherein the alkyl radical can be substituted one or more times by F, cycloalkyl with 3 to 8 carbon atoms. carbon, -O-alkenyl with 3 to 6 carbon atoms, O-cycloalkyl with 3 to 8 carbon atoms, O-phenyl, O-benzyl, wherein the phenyl nucleus may be substituted up to 3 times by F, Cl, CF3 , methyl, methoxy, NR (9) R (10); R (l), R (2), R (3) independently of each other are hydrogen, F, Cl, Br, I, CN, -alkyl with 1 to 8 carbon atoms, -O-alkyl with 1 to 8 carbon atoms, wherein the alkyl radicals may be substituted one or more times by F, - (C = 0) -N = C (NH2) 2, - (SO0_2) -alkyl with 1 to 8 carbon atoms, - (S02) -NR (7) R (8), -O-alkylenephenyl with 0 to 8 carbon atoms carbon, -alkylphenyl with 0 to 8 carbon atoms, wherein the phenyl nuclei can be substituted up to three times by F, Cl, CF 3, methyl, methoxy, -alkylene with 0 to 8 carbon atoms-NR (9) R ( 10); L is -O-, -NR (47) -, -alkylene with 1 to 8 carbon atoms, -alkenylene with 1 to 8 carbon atoms-, -alkynylene with 1 to 8 carbon atoms-, -COO-, - CO-NR (47) -, -S02-NR (47) -, -O- (CH2) n-0-, -NR (47) - (CH2) n-0-, - R (48) -CO- (CH2) n-0-, -CO-NR (48) - (CH1) n-0-, -O-CO- (CH2) n-0-, -S02-NR (48) - (CH2) n -0-, -NR (48) -C0-CH2-CH2-C0-NR (48) - (CH2) n-0-, -NR (48) -CO-CH = CH-CO-NR (48) - (CH2) n-0-, -NR (48) -S02- (CH2) n-0-; R (47) is hydrogen, -alkyl with 1 to 8 carbon atoms, R (48) -C0-, phenyl, benzyl; R (48) is hydrogen, alkyl having 1 to 8 carbon atoms, phenyl and benzyl, wherein the phenyl nucleus may be substituted up to three times by F, Cl, CF3, methyl, methoxy; n is 1 to 8; R (40) to R (45) independently of one another are hydrogen -OR (50), -SR (50), NHR (50), -NR (50) 2, -O- (CO) -R (50), -S- (CO) -R (50), -NH- (CO) -R (50), -O-PO- (OR (50)) -OR (50), -O- (S02) -OR ( 50), -R (50), a link to L; or R (40) and R (41), R (42) and R (43), R (44) and R (45) in each case together form the oxygen of a carbonyl group; where always only one of the radicals R (40) to R (45) have the meaning of a link to L; K is -OR (50), -NHR (50), -NR (50) 2, -HN-CH2-CH2-C02H, -HN-CH2-CH2-S03H, -NH- CH2 -COOH, -N (CH3) CH2C02H, -HN-CH (R46) C02H, -OKa, wherein Ka is a cation, such as for example a metal ion an alkaline or alkali metal or a quaternary ammonium ion; R (46) is hydrogen, alkyl having 1 to 4 carbon atoms, benzyl, -CH2-0H, H3CSCH2CH2-, H02CCH2-, H02CCH2CH2-; R (50) is hydrogen, alkyl having 1 to 4 carbon atoms, phenyl or benzyl, wherein the phenyl nucleus may be substituted up to three times by F, Cl, CF3, methyl, methoxy; and their pharmaceutically tolerable salts and physiologically functional derivatives. Preferred compounds of the formula I are those where TI and T2 independently of each other are: or hydrogen, where TI and T2 can not simultaneously be hydrogen; L-z is R (E) is hydrogen, F, Cl, CN, alkyl having 1 to 4 carbon atoms, -O-alkyl having 1 to 4 carbon atoms, wherein the alkyl radicals can be substituted one or more times by F, cycloalkyl with 3 to 6 carbon atoms, alkenyl with 3 to 8 carbon atoms, O-cycloalkyl with 3 to 6 carbon atoms, O-phenyl, O-benzyl, wherein the phenyl nucleus may be substituted up to three times by F, Cl, CF 3, methyl, methoxy, NR (9) R (10); R (9), R (10) independently of each other are hydrogen, CH3, CF3; R (l), R (2), R (3) independently of each other are hydrogen, F, Cl, CN, -S02-C 1-4 -alkyl, -S02-N (C 1-4 -alkyl) 2, -S02-NH-alkyl having 1 to 4 carbon atoms, -S02-NH2, -S02-alkyl with 1 to 4 carbon atoms, -alkyl with 1 to 4 carbon atoms, -O-alkyl having 1 to 4 carbon atoms, wherein the alkyl radicals can be substituted one or more times by F, -O-alkylenephenyl with 0 to 4 carbon atoms, -alkylenephenyl with 0 to 4 carbon atoms, wherein the phenyl nuclei may be substituted up to three times by F, Cl, CF3, methyl, methoxy; L is -O-, -NR (47) -, -alkylene with 1 to 4 carbon atoms, -alkenylene with 1 to 4 carbon atoms, -alkynylene with 1 to 4 carbon atoms, -COO-, -CO- NR (47) -, -S02-NR (47) -, -O- (CH2) r? -0-, -NR (47) - (CH2) n-0-, -NR (48) -CO- ( CH2) n-0-, -CO-NR (48) - (CH2) n-0-, -S02-NR (48) - (CH2) n-0-; R (47) is hydrogen, alkyl having 1 to 4 carbon atoms, R (48) -C0-, phenyl, benzyl; R (48) is hydrogen, alkyl having 1 to 4 carbon atoms, phenyl and benzyl, wherein the phenyl nucleus may be substituted up to three times by F, Cl, CF3, methyl, methoxy; n is 1 to 4; R (41), R (42), R (45) independently of each other are hydrogen, -OR (50), NHR (50), -NR (50) 2, -O- (CO) -R (50), -NH- (CO) -R (50); R (50) is hydrogen, alkyl having 1 to 4 carbon atoms, phenyl or benzyl, wherein the phenyl nucleus may be substituted up to three times by F, Cl, CF3, methyl, methoxy; K is -OR (50), -NHR (50), -NR (50) 2, -HN-CH2-CH2-C02H, -HN-CH2-CH2-S03H, -NH-CH2-COOH, -N (CH3 CH2C02H, -OKa, wherein Ka is a cation, such as for example an alkali metal or alkaline earth metal ion or a quaternary ammonium ion; and their pharmaceutically tolerable salts and physiologically functional derivatives. Particularly preferred compounds of the formula I are those where TI and T2 independently of each other are or hydrogen where TI and T2 can not simultaneously be hydrogen; and L-z is R (41) R (E) is hydrogen, F, Cl, CN, alkyl having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, -O-alkyl having 1 to 4 carbon atoms, CF3, -OCF3; R (l), R (2) independently of each other are hydrogen, F, Cl, CN, -S02-CH3, S02NH2-, -alkyl having 1 to 4 carbon atoms, -O-alkyl having 1 to 4 carbon atoms, wherein the alkyl radicals can be substituted one or more times by F; -O-alkylenephenyl with 0 to 4 carbon atoms, -alkylenephenyl with 0 to 4 carbon atoms, wherein the phenyl nuclei can be substituted up to three times by F, Cl, CF3, methyl, methoxy; R (3) is hydrogen; L is -0-, -NR (47) -, -CH2-CH2-, CH = CH-, - (C C) -, -COO-, -CO-NR (47) -, -S02-NR (47) -, -O- (CH2) n-0-, -NR (47) - (CH2) n-0-, -NR ( 48) -CO- (CH2) n-0-, -CO-NR (48) - (CH2) n-0-, -S02-NR (48) - (CH2) n-0-; R (47) is hydrogen, alkyl having 1 to 4 carbon atoms, R (48) -C0-, phenyl, benzyl; R (48) is hydrogen, alkyl having 1 to 4 carbon atoms, phenyl and benzyl, wherein the phenyl nucleus may be substituted up to three times by F, Cl, CF3, methyl, methoxy; n is 1 to 4; R (41) is hydrogen, -OH; K is -OR (50), -NHR (50), -NR (50) 2, -HN-CH2-CH2-C02H, -HN-CH2-CH2-S03H, -NH-CH2-COOH, -N (CH3 CH2C02H, -OKa, wherein Ka is a cation, such as for example an alkali metal or alkaline earth metal ion or a quaternary ammonium ion; R (50) is hydrogen, alkyl having 1 to 4 carbon atoms, phenyl or benzyl, wherein the phenyl nucleus may be substituted up to three times by F, Cl, CF3, methyl, methoxy; and its pharmaceutically tolerable salts. Very particularly preferred compounds of formula I are those having the structure where TI and T2 independently of each other are or hydrogen, where TI and T2 can not simultaneously be hydrogen; L-z is L is -NH-CH2-CH2-0-; R (E) is hydrogen, alkyl with 1 to 4 carbon; R (l), R (2) independently of each other are hydrogen, F, Cl, CN, -S02-CH3, -alkyl having 1 to 4 carbon atoms, -O-alkyl having 1 to 4 carbon atoms, wherein the alkyl radicals may be substituted one or more times by F; and its pharmaceutically tolerable salts. "*" in the above formulas marks the point of linking TI or T2 to the phenyl ring of formula I. If the compounds of formula I contain one or more centers of asymmetry, these may have either the S or R configuration. The compounds can be present as optical isomers, as diastéreomers, as racemates or as mixtures thereof. The double-bond geometry of the compounds of formula I can already be E or Z. The compounds can be present in the mixture as double-bond isomers. The expression "when the alkyl radical may be substituted one or more times by F" also includes perfluorinated alkyl radicals. The alkyl radicals designated can already be straight or branched chain. The term "physiologically functional derivative" as used herein indicates any physiologically tolerable derivative of a compound of formula I according to the invention, for example an ester which upon administration to a mammal, such as a human, is capable (directly or indirectly ) of forming a compound of formula I, or its active metabolite. The physiologically functional derivatives also include pro-drugs of the compounds according to the invention. These pro-drugs can be metabolized in vivo to a compound according to the invention. These pro-drugs themselves can be active or inactive. The compounds according to the invention can also be present in various polymorphic forms, for example as amorphous and polymorphic crystalline forms. All polymorphic forms of the compounds according to the invention are included within the scope of the invention and are also a further aspect of the invention. Next, all references to "compound (s)" according to formula (I) refer to (a) compound (s) of formula (I) as described above and its salts, solvates and physiologically functional derivatives as described here. The amount of a compound according to formula (I) that is necessary in order to achieve the desired biological effect depends on a number of factors, for example the specific compound selected, the intended use, the manner of administration and the condition patient's clinic Pharmaceutical compositions according to the invention are those which are suitable for oral and oral administration (for example sublingual), although the most convenient administration form in each individual case depends on the nature and severity of the condition to be treated and the type of compound according to formula (I) used in each case. Coated formulations and coated delayed release formulations are also included within the scope of the invention. Enteric and acid resistant formulations are preferred. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate. Suitable pharmaceutical compounds for oral administration can be present in separate units, such as for example capsules, wafers or tablets, which in each case contain 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 compositions can be prepared by any convenient pharmaceutical method which includes a step in which the active compound and the excipient (which may consist of one or more additional constituents) are brought into contact. In general, the compositions are prepared by a uniform and homogeneous mixing of the active compound with a suitable excipient, a tablet for example, can be prepared by compressing or shaping a powder or granules of the compound, if appropriate with one or more additional constituents. Pressed tablets may be produced by tabletting the compound in free flowing form, such as for example a powder or granules, if appropriate in admixture with a binder, lubricant, inert diluent and / or (an amount of) dispersing agent (s). (s) / active voltage (in a convenient machine). Conformed tablets can be produced by configuring the powdered wetted compound with an inert liquid diluent in a convenient machine. Pharmaceutical compositions which are suitable for per-oral (sublingual) administration include troches, which contains a compound according to formula (I) with a flavoring, usually sucrose and gum arabic or tragacanth and lozenges including the compound in an inert base such like gelatin and glycerol or sucrose and gum arabic. The invention further relates to a process for the preparation of a compound of the formula (I), which comprises reacting a compound of the formula II where TI and T2, R (l), R (2) and R (3) have the meanings indicated above and G is a functionality that can be replaced by Lz, with a compound ALz in a manner known to the person skilled in the specialty, GA is removed and a compound of formula I results. The functionality G of the compound having formula II may for example have the meaning of bromine or iodine. By catalysis of Pd (0), the desired C-C bond can then be obtained in a known manner.

The acetylene bile acid derivatives of the formula III are prepared from convenient bile acid ketones. For this, lithium acetylide is added to the keto bile acids analogously to known processes (U.S. Patent No. 5,641,767). The compounds of the formula I and their pharmaceutically tolerable salts and physiologically functional derivatives are distinguished by a favorable influence on the composition of bile and prevent the formation of stones by preventing the supersaturation of the bile with cholesterol or by retarding the formation of crystals of supersaturated bile cholesterol. The compounds can be used by themselves or in combination with lipid-lowering active compounds. The compounds are particularly suitable for prophylaxis and for the treatment of stones. The compounds of the formula (I) according to the invention pass the hepatobiliary system and therefore act on these tissues. In this way, the water absorption of the vesicle is inhibited by inhibiting the apical NHE antibody of subtype III of the vesicle epithelium, which results in diluted bile. The biological test of the compounds according to the invention is carried out in determining the inhibition of the sodium / proton exchanger sub-type 3. 1. Test Description For the determination of the IC50 values for the inhibition of NHE-3 protein human (expressed in LAP1 cell line) the intracellular pH recovery (pHi after acidification is determined, which starts in functional NHE even under bicarbonate-free conditions.) For this, the pHi is determined using the pH-sensitive fluorescent dye BCECF ( Calbiochem, precursor BCECF-AM is used.) The cells were first loaded with BCECF The BCECF fluorescence is determined in a fluorescence ratio spectrometer (Photon Technology International, South Brunswick, NJ, USA) at excitation wavelengths of 505 and 440 nm and an emission wavelength of 535 nm and converts to pHi by calibration curves.The cells have already been incubated in NH buffer 4C1 (pH 7.4) during BCECF loading (NH4C1 buffer: 115mM NaCl, 20mM NH4C1, 5mM KCl, 1mM CaCl2, 1mM, 20mM MgSO4 Hepes, 5mM glucose, 1mg / ml BSA; a pH of 7.4 is established using 1 M NaOH). Intracellular acidification is induced by addition of 975 μl of an NH4C1-free buffer to 25 μl aliquots of cells incubated in NH4C1 buffer. The subsequent rate of pH recovery is recorded for three minutes. For the calculation of the inhibitory potency of the substances tested, the cells were first investigated in buffers where a full pH recovery was carried out or there was no recovery of pH. For full recovery of pH (100%) the cells were incubated in buffer containing Na + (133.8 mM NaCl, 4.7 mM KCl, 1.25 mM CaCl2, 1.25 mM MgCl2 / 0.97 mM Na2HP04, 0.23 mM NaH2P04, 5 mM Hepes, 5 mM glucose, a pH of 7.0 is established using 1 M NaOH). For determination of the 0% value, the cells were incubated in a free Na + buffer (133.8 mM choline chloride, 4.7 mM KCl, 1.25 mM CaCl2, 1.25 mM MgCl2, 0.97 mM K2HPO4, _0.23 mM KH2P04, 5 mM Hepes , 5 mM glucose, a pH of 7.0 is established using 1 M NaOH). The substances to be tested were prepared in the buffer containing Na +. The recovery of the intracellular pH at each tested concentration of a substance is expressed in percent of the maximum recovery. The IC50 value of the respective substance is calculated from percentage values of the pH recovery using the SigmaPlot program (Version 3.0, Jandel Scientific, USA). Results: Example 1: IC50 = 1.7 μM / I The following examples serve to illustrate the invention in greater detail, without restriction to products and modalities described in the examples. List of abbreviations MeOH methanol LAH lithium aluminum hydride DMF N, N-dimethylformamide The impact of electrons Cl chemical ionization RT ambient temperature EA ethyl acetate (EtOAc) p.f. melting point HEP n-heptane DME dimethoxyethane ES electron spray FAB rapid bombardment of atoms CH2C12 - dichloromethane THF tetrahydrofuran eq. equivalent General process for the coupling of substituted aryl halides and substituted terminal acetylenes: The aryl halide (1 eq) is introduced into DMF or together with an auxiliary base (4 eq) such as for example triethylamine and a Pd catalyst, such as example slowly and if necessary, the previous amount of catalyst is added again. In the course of this, the reaction temperature may exceed RT and reach about 100 C; typically 60 C. The crude product can be precipitated by the addition of ethyl acetate and filtered. Subsequent salt formation is achieved by the addition of acid in acetone. Example 1: D i ac t t a t of acid 4 -. { 3β- [3,4-Bis (3-guanidine-2-methyl-3-oxopropenyl) phenylethynyl] -3,7a, 12 -trihydroxy-10β, 13β-] - f enant en-17-yl} pentanoic, yellowish solid, m.p. 250 C (dec), MS: M + + H (FAB) = 880.

Preparation of intermediaries 1 and 2: Intermediary 1: 3ß-acetylenic acid Synthesis route: a) Methyl 3, 7, 12-triacetilcolato 90 g of methyl cholate and 3.0 g of dimethylaminopyridine are dissolved in 500 ml of pyridine, and the solution is treated with 500 ml of acetic anhydride and stirred overnight at room temperature. ambient. It is emptied on ice-water and extracted with ethyl acetate (3x). Drying (MgSO4) and evaporation of the organic phase resulted in 92 g of methyl 3, 7, 12-triacetylcolate, MS: M + + Li (FAB) = 555. b) Methyl 7, 12-diacetylcolate 150 ml of acetic anhydride were added slowly by drops at 5 ° C to 1.5 1 of methanol. After minutes, 92 g of methyl 3, 7, 12-triacetylcolate are added and the mixture is stirred at room temperature for one hour. It was emptied on ice water and extracted with ethyl acetate (3x). The organic phase is washed with 1N Na 2 CO 3 solution, dried using MgSO 4 and evaporated. 85 g of the crude product are obtained, MS: M + + Li (FAB) = 513. c) Methyl 3-keto-7, 12-diacetylcolate 85 g (168 mmol) of methyl 7, 12-diacetylcolate, 183. 7 g of pyridinium chlorochromate and 175 g of molecular sieves were stirred at room temperature for 2 h in 2.5 1 dichloromethane. The mixture is poured into 7 1 diethyl ether and the solids are removed by filtration. The solvent is evaporated and the residue is dissolved in ethyl acetate. After chromatography on a Florisil column, 59.6 g of the product is obtained in MS: M + + Li (FAB) = 511. d) Methyl 3β-acetylene-7, 12-diacetylcolate Acetylene is passed in 750 ml of absolute tetrahydrofuran at -55 ° C for 25 minutes under argon. 145 ml of 15% n-butyllithium in hexane were added dropwise to this solution and stirred for 10 minutes. 45 g (89 mmol) of methyl 3-keto-7,12-diacetylcolate were then added and the mixture was stirred at -40 ° C for 1.5 h. For processing, 500 ml of saturated aqueous ammonium chloride solution are added and the mixture is extracted with (3x), and the organic phase is dried over MgSO 4 and evaporated. The residue is chromatographed on silica gel (n-heptane / ethyl acetate 1: 1). 35.3 g of the product is obtained, MS: M '+ Li (FAB) = 537. e) 3-acetylene-cyclic acid 35.2 g (66 mmol) of the product of d) are dissolved in 11 ml of methanol, treated with 300 ml of 2N sodium hydroxide solution and heated under reflux for 25 h. The solvent is evaporated, the residue is dissolved in water and the solution is acidified to pH using 2N hydrochloric acid. The precipitate is filtered off and washed with water until neutral. Drying of the residue gave 14.6 g of the product, MS: M + + Li (FAB) = 439. Intermediate 2: 1, 2-Bis [3- (guanidine of E-2-methylpropenoic acid)] -4-bromo-benzene dihydrochloride Synthesis route a) 4-Bromo-1, 2-phthalyl alcohol from dimethyl 4-bromophthalate according to standard methods (for example reduction with LAH), colorless oil; MS (Cl): M + + H = 217. b) 4-Bromo-l, 2-phthalaldehyde of 2a) for example, by oxidation of Swern under standard conditions, amorphous solid MS (Cl): M1 + H = 213. c) 4-B r o mole, 2-d i [3 - (e t i l E-2-methylpropenoate)] benzene by deprotonation of 1 eq. of triethyl 2-phosphonopropionate with 1 eq. of n-butyl lithium in hexane at 0 ° C and subsequent reaction at RT with 0.5 eq. of 4-bromo-1,2-phthalaldehyde 2b). After complete reaction of the dialdehyde, the mixture is worked up with water and extracted three times by stirring with toluene. After drying the combined organic phases over magnesium sulfate, the solvent is removed in vacuo and the residual crude product is separated by chromatography on silica gel using EA / HEP mixtures as eluent, colorless oil; MS (Cl): M + + H = 381. d) 4-B romo-l, 2-di [3- (E-2-methylpro-enoic acid)] benzene from 2c) by hydrolysis according to a standard method (sodium hydroxide in methanol), colorless amorphous solid , MS (ES): M + + H = 325. e) 1,2-Bís dihydrochloride [3 guanidide 3- (E-2-methylpropenoic acid)] -4-bromobenzene 2d) according to the general variant, colorless solid; p.f. 240 ° C; MS (FAB): M + + H = 407. f) D i a c e t t o d e a c i d o 4 -. { 3 ß - [3, 4-B i s (3-guani dina-2-me t i l-3 -o x i p r o p e n i l) f e n t i n i l] 3, 7, 12a-trihydroxy-10β, 13β-dimethylhexadecahydrocyclopen ta [a] phenanthren-17-yl} 2-pentanoic acid) and 3β-acetylenyolic acid by coupling Pd (0) according to the general process in DMF at 60 ° C in the course of 2 h. Example 2: B e n c i l 4 -. { 3 ß - [3,4-bis (3-guanidino-2-methyl-3-oxopropenyl) phenylethynyl] -3a, the., 12a-trihydroxy-10β, 13β-dimethylhexadecahydrocyclopen ta [a] phen-antren-17-il } pentanoate, yellow solid mp 155 ° C, MS: M + + H (ES) = 849. 3ß-acetylenycolate. Example 3: Bencil 4-. { 3β- [4- (3-guanidine-3-oxopropenyl) phenylethynyl] -3 O O, 7a, 12 -trihydroxy-10β, 13β-dimethylhexadeca hydrocyclopenta [a] f enantren-17-yl} pentanoate, yellowish solid p.f. 189 ° C, MS: M * + H (FAB) = 710. Synthesis according to the general process using guanidide of 4-bromo-cinnamic acid and benzyl 3ß-ace ilencolate. Example 4: Methyl 4-. { 3β- [4- (3-guanidino-3-oxopropenyl) phenylethynyl] -3Ci, 7a, 12 -trihydroxy-10β, 13β-dimethylhexadecahydrocyclopenta [a] phenanthren-17-yl} pentanoate, yellowish solid, m.p. 60 ° C, MS: M + + H (FAB) = 718.

Synthesis analogous to the general process by the guanidide reaction of 4-bromo-cinnamic acid and benzyl 3β-acetylenycolate. Example 5 A cido (4 - { 3 ß - [3,4-Bis (3-guanidine-2-methyl-3-oxopropenyl) phenylethynyl] -3 a, 7 a, 1 2-trihydroxy-1 0 β, 1 3 ß -dimethylhexadecahydrocyclopenta [a] phen-antren-17-yl.} pentane a) Methyl [4- (3β-etinyl-3a, 7or, 12a -trihydroxy-10β, 13β-dimethylhexa-decahydrocyclopenta [ a] phenanthren-17-yl) pentanoylamino] acetate 530 mg of 3-acetylenyl acid (intermediary le) and 510 μl of triethyl-amine are dissolved in 30 ml of THF and 175 ml of ethyl chloroformate are added dropwise at 0 ° C . The mixture is stirred at 0 ° C for 15 minutes, then a solution of 340 mg of glycine methyl ester hydrochloride in 10 ml of DMF is added dropwise and the mixture is stirred at RT for 4 hours. It is diluted with 200 ml of EA and washed twice 50 ml of 5% aqueous NaHS04 solution each time. Dry over MgSO4 and remove the solvent in vacuo. The residue is recovered in 100 ml of EA and washed three times with my solution • saturated aqueous Na2CO3 each time. Dry over MgSO4 and remove the solvent in vacuo. Chromatography on silica gel using EA / MeOH 10: 1 and subsequently a second time with EA, results in 280 mg of a colorless foam. R £ (EA) = 0.37 MS (FAB): 518 (M + H) + b) Acid [4- (3-β-ethynyl-3, 7a, 12a -trihydroxy-lOβ, 13β-dimethylhexadeca-hydrocyclopenta [a] phenanthren -17-yl) -pentanoylamino] acetic acid 270 mg of methyl [4 - (3-β-etinyl-3, 7a, 12a-trihydroxy-10β, 13β-dimethyl-hexadecahydrocyclopenta [a] f enantren-17-yl) pentanoylamino] acetate and 630 μl of a 1N aqueous NaOH solution are dissolved in 5 ml of ethanol and allowed to stand at RT for 16 hours. The solvent is removed in vacuo, the residue is recovered using 50 ml of a saturated aqueous NaH2P04 solution and the mixture is extracted three times with 50 ml of EA each time. Dry over MgSO4 and remove the solvent in vacuo. 230 mg of an amorphous solid are obtained. Rf (acetone / water 10: 1) = 0.25 MS (FAB): 502 (M + 2Li) + c) Acid (4- { 3ß- [3,4-Bis (3-guanidine-2-methyl-3 -oxo-propenyl) phenylethynyl] -3a, 7, 12oi -trihydroxy-O-β, 1 3-β-dimethylhexadeca-hydrocyclopenta [a] f e-antren-17-yl.} pentanoylamino) acetic 230 mg of [4 - (3β-ethynyl-3a, 7 OI, 12a-trihydroxy-10β, 13β -dimethexadeca- idro-cyclopenta [a] f enantren-17-yl) -pentanoylamino] acetic acid and 183 mgde N-. { 3 - [4-bromo-2- (3-guanidine-2-methyl-3-oxopropenyl) phenyl] -2-methylacryloyl} guanidine are reacted at 60 ° C in the course of 3 h by coupling Pd (0) according to the general process. After preparative HPLC on C18 LiChrosorb using acetonitrile / water 2: 4 + 0.1% acetic acid + 0.1% ammonium acetate 70 mg of an amorphous solid, are obtained. Rf (n-butanol / glacial acetic acid / water 3: 1: 1) = 0.33 MS (ES): 816 (M + H) * Example 6: 4- Acid. { 3- [2-Fluoro-4- (3-guanidine-2-methyl-3-oxopropenyl) phenylethynyl] -3,7,12-trihydroxy-10,13-dimethylhexadecahydrocyclopenta [a] phenanthren-17-yl} pentanoic a) Butyl 3 - (4-bromo-3-fluorophenyl) -2-methylacrylate 2 g of l-bromo-2-fluoro-4-iodobenzene and 1.1 ml of diisopropylethylamine are dissolved in 20 ml of dimethylacetamide (anhydrous) and a slight Argon stream is passed through the solution for 5 minutes. 1.4 ml of butyl acrylate and 10 mg of 2,6-di-t-butyl-4-methylphenol are then added and the mixture is heated to 100 ° C. Finally, 4 ml more of dimethylacetamide is degassed by means of a stream of argon and 80 mg of trans -bis- (β-acetate) bis [o- (di-o-tolifosfino) benzyl] -dipaladium (Tetrahedron Lett, 1996, 37 (36 ), 6535-6538) are suspended. This suspension is added to the mixture of the other reagents and stirred at 140 ° C for 90 minutes. The mixture is then diluted with 200 ml of EA, and washed twice with 100 ml of water and each time and once with 100 ml of saturated aqueous NaCl solution. Dry over MgSO4 and remove the solvent in vacuo. Chromatography on silica gel produces 230 mg of a colorless oil. Rf (EA / HEP) = 0.27 MS (DC1): 315 (M + H) + b) Butyl 3 -. { 4- [17- (3-carboxy-1-met i lpropi 1) -3,7,12-trihydroxy-1,1,13-di-methylhexadecahydrocyclopenta [a] phenanthren-3-ethynyl] -3-fluoro- phenyl } -2-methylacrylate 64 mg of bis (triphenylphosphine) palladium (II) chloride, 17 mg of Cul, 0.5 ml of triethylamine and 230 mg of butyl 3- (4-bromo-3-fluorophenyl) -2-methyl-acrylate Dissolve in 10 ml of anhydrous DMF and a solution of 395 mg of 3d-acetylenynic acid in 10 ml of anhydrous DMF are added dropwise in the course of one hour. The mixture is stirred at 60 ° C for one hour and a solution of 395 mg of 3d-acetylenyolic acid in 10 ml of anhydrous DMF are slowly added dropwise at 60 ° C. The mixture is stirred at 60 ° C for a further 2 hours, then 64 mg of bis (triphenylphosphine) palladium (II) chloride and 17 mg of Cul are added further and the mixture is again stirred at 60 ° C for 2 hours. Finally 80 mg more of 3D-acetylencholic acid [lacuna] and the mixture is stirred at 60 ° C for 2 hours. The solvent is removed in vacuo, the residue is taken up in 100 ml of a 5% aqueous NaHS04 solution and the mixture is extracted three times with 100 ml of EA each time. Dry over Na2SO4 and remove the solvent in vacuo. Chromatography on silica gel using EA / MeOH 5: 1, produces 90 mg of a wax-like substance. Rf (EA / MeOH 5: 1) = 0.56 MS (FAB): 667 (M + H) + c) Á c i d o 4 -. { 3 - [2-fl úor-4 - (3-guanidine-2-methyl-3-oxopropenyl) -phenylethynyl] -3,7,12-rihydroxy-10, 13 -dimethylhexadecahydrocyclopenta [a] f en-antren-17 -il} pentanoic 73 mg of guanidine hydrochloride and 71 mg of potassium t-butoxide are dissolved in 2 ml of anhydrous DMF and the solution is stirred at RT for 30 minutes. This suspension is injected in 85 mg butyl 3 - . 3 - . { 4 - [1 7 - (3-carboxy-1-methypropyl) -3,7,1-trihydroxy-10, 13 -dimethyl-hexadecanediocyclopenta [a] f enantren-3-ethynyl] -3-f luoro-phenyl } -2-methyl acrylate and the mixture is stirred at 100 ° C for 5 hours. After cooling, 10 ml of water are added, the mixture is adjusted to pH = 4 using aqueous HCl solution and extracted three times using 10 ml of EA each time. Dry over MgSO4 and remove the solvent in vacuo. Chromatography on silica gel using acetone / water 10: 1 yields 15.5 g of an amorphous solid. R £ (acetone / water 10: 1) = 0.19 MS (ES): 652 (M + H) + Example 7: Acid 4 - (3 -. {2 - [2, 6 - D ifl ú or - 4 - (3-guanidine-2-methyl-3-oxopropenyl) phenylamino] -ethoxy.) - 7,1, -dihydroxy-10,13-dimethylhexadecahydrocyclopenta [a] - a) 4- (3-. {2- [2,6-Difluoro-4- (3-guanidine-2-methyl-3-oxo-propenyl) phenylamino] -ethoxy} -7, 12-dihydroxy-10 acid , 13-dimethylhexadecahydrocyclopenta [a] phen-antren-17-yl) pentanoic acid 100 g of cholic acid are dissolved in 500 ml of pyridine and 23.1 ml of mesyl chloride are added dropwise at 0 ° C for a period of 30 minutes. The mixture is stirred at RT for three hours, then it is drained at 0 ° C over a solution of 400 ml of H2SO4 in 3 l of water and extracted 4 times with 750 ml of EA each time. Dry over Na2SO4 and remove the solvent in vacuo. The residue is crystallized using diisopropyl ether and 117.1 g are obtained; p.f. 121 ° C (with decomposition). R £ (EA / HEP / acetic acid 5: 5: 1) = 0.31 MS (FAB): 487 (M + H) + b) 4- [7,12-dihydroxy-3- (2-hydroxyethoxy) -10, Methyl 13-dimethyl-hexa-decahydrocyclopenta [a] phenanthren-17-yl] pentanoate 116 g of 4- (7,1, 12-dihydroxy-3-methanesulfonyloxy-10, 13 -dimethylhexadecahydrocyclopenta [a] phenanthren-17-yl) pentanoic and 130 ml of triethylamine are dissolved in 650 ml of glycol and the mixture is stirred at 100 ° C for 3 hours and at 115 ° C for 7.5 hours. The reaction mixture is poured into a solution of 400 ml of H2SO4 in 3 l of water at 0 ° C and extracted 7 times with 750 ml of EA each time. Dry over Na2SO4 and the solvent is removed in vacuo. The intermediary INT is obtained. 130 ml of acetyl chloride are added dropwise to 900 ml of methanol at 0 ° C. A solution of INT in 400 mi [lacuna] is then added and the mixture is shaken RT for 6 hours. Allow it to stand at RT for 60 hours, then empty over 2.6 1 of water and extract 8 times with 500 ml of diisopropyl ether (DIP) each time. The organic phase is then washed 6 more times with 600 ml of a semi-saturated aqueous solution of NaHCO 3 each time. Dry over Na2SO4 and remove the solvent in vacuo. Chromatography on silica gel using EA, results in 32 g of a resinous solid. Rf (EA) = 0.19 MS (FAB): 467 (M + H) + c) M e t i 1 4 -. { 3 - [2 - (1, 3-d i or x or -1,3-dihydroisoindol-2-yl) ethoxy] -7, 12-di-hydroxy-10,13-dimethylhexadecahydrocyclopenta [a] f enantren-17-yl} pentanoate. 1 . 5 g d e m e t i l 4- [7,12-dihydroxy-3- (2-hydroxyethoxy) -10,13 -dimethylhexadecahydrocyclopenta [a] phenanthren-17-yl] pentanoate, 950 mg of triphenylphosphine and 550 mg of phthalimide are heated to 45.degree. ° C in 26 ml of THF and 1.14 ml of diethyl azodicarboxylate are added dropwise at this temperature. The reaction mixture is stirred at 45 ° C for 2 hours, then it is drained in 200 ml of a semi-concentrated aqueous solution of NaHCO 3 and extracted 3 times with 200 ml of EA each time. The organic phase is dried over Na 2 SO 4 and the solvent is removed in vacuo.

Chromatography on silica gel using t-butyl methyl ether (MTB) yields 1.76 g of a viscous oil. Rf (EA) = 0.60 MS (FAB): 602 (M + Li) + d) Methyl 4- [3- (2-aminoethoxy) -7, 12-dihydroxy-10, 13 -dimethylhexadeca-hydrocyclopenta [a] f enantren - 17 -yl] pentanoate 1.7 g of methyl 4-. { 3- [2- (1, 3-dioxo-1,3-dihydroisoindol-2-yl) ethoxy] -7, 12-dihydroxy-10, 13-dimethylhexadecahydrocyclopenta [a] phenanthren-17-yl} pentanoate and 0.52 ml of hydrazine hydrate (80%) are dissolved in 14 ml of methanol and the solution is refluxed for three hours. It is then cooled to 40 ° C and the reaction mixture is treated with 8.7 ml of an aqueous 2N HCl solution. It is stirred at 40 ° C for 30 minutes, then the volatile constituents are removed in vacuo. Chromatography on silica gel using acetone / water 10: 1 yields 540 mg of resinous solid. Rf (acetone / water 10: 1) = 0.06 MS (FAB): 466 (M + H) + e) 4- [3- (2-Aminoethoxy) -7,12-dihydroxy-10, 13 -dimethylhexadecahydro- Cyclopenta [a] -fenanthren-17-yl] pentanoic acid 3 g of methyl 4- [3 - (2-aminoethoxy) -7,12-dihydroxy-10,13-dimethylhexadeca-hydrocyclopenta [a] phenanthren-17-yl] - pentanoate and 310 mg of NaOH are stirred at RT for 24 hours in 5 ml of water and 30 ml of methanol. The solvents are removed in vacuo, the residue is recovered with 200 ml of water and adjusted to pH = 7-7.5 using aqueous HCl solution. The mixture is stirred for one hour and the product is then separated by filtration. 1.6 g of a pale yellow crystalline solid are obtained. P.f. 185-195 ° C.

R f (CH 2 Cl 2 / MeOH / acetic acid / water 32: 8: 1: 1) = 0.18 MS (ES): 452 (M + H) + f) Ethyl 2-methyl-3- (3, 4, 5-trifluorophenyl) 4.3 ml acrylate of triethyl 2-phosphonopropionate are dissolved in 30 ml of anhydrous THF and 12.5 ml of a 1.6 N solution of n-butyl lithium in hexane are added dropwise at 0 ° C. The mixture is stirred at RT for 15 minutes and a solution of 3.2 g of 3,4,5-trifluorobenzaldehyde in 8 ml of anhydrous THF is then added dropwise. The mixture is stirred at RT for 1 hour and allowed to stand at RT for 16 hours. The reaction mixture is diluted with 300 ml of water, 30 ml of saturated aqueous Na 2 CO 3 solution are added and extracted three times with 100 ml of EA each time. Dry over Na2SO4 and then remove the solvent in vacuo. Chromatography on silica gel using EA / HEP 1: 8 yields 3.8 g of colorless crystals; p.f 54 ° C. R £ (EA / HEP 1: 8) = 0.35 MS (DCl): 245 (M + H) + g) Ethyl 3- (4-. {2- [17- (3-carboxy-1-methylpro-il) -7,12-dihydroxy-10, 13-di-methyl exadeca-hydrocyclopenta [a] phenanthren-3-yloxy] ethylamino] -3,5-difluorophenyl) -2-methacrylate 600 mg of 4- [3- (2-aminoethoxy) -7,12-dihydroxy-10,13-dimethylhexadeca-hydrocyclopenta [a] -phenanthren-17-yl] pentanoic acid, 390 mg of ethyl 2-methyl-3- (3,4,5-trifluorophenyl) ) acrylate and 828 mg of K2C03, are stirred at 130 ° C for 2.5 hours in 10 ml of dimethylacetamide. The reaction mixture is diluted with 400 ml of CH2C12 after cooling and washed with 400 ml of a 5% aqueous NaHS04 solution. Dry over MgSO4 and remove the solvent in vacuo. Chromatography on silica gel using CH2Cl2 / MeOH 10: 1 yields 155 mg of a colorless oil. Rf (CH 2 Cl 2 / MeOH 10: 1) = 0.27 MS (ES): 676 (M + H) + i) 4- (3. {2- [2,6-Difluoro-4- (3-guanidine-) acid 2-methyl-3-oxo-propenyl) phenyl-amino] ethoxy] -7, 12-dihydroxy-10, 13-dimethylhexadecahydrocyclo-penta [a] phenanthren-17-yl) pentanoic 130 mg of guanidine hydrochloride and 125 mg of Potassium t-butoxide is stirred at RT for 30 minutes in 1 ml of anhydrous DMF. A solution of 150 mg of ethyl 3- (4-. {2- [17- (3-carboxy-l-methylpropyl) -7, 12-dihydroxy-10, 13 -dimethexadexahydrocyclopenta [a] phenanthren-3-yloxyl) ] ethyl-amino} -3,5-difluorophenyl) -2-methacrylate in 1 ml of anhydrous DMF is then added and stirred at 110-115 ° C for 6 hours. The reaction mixture is then poured into 100 ml of water, adjusted to pH = 6 using aqueous HCl solution and the product is separated by filtration. Dry with thin vacuum and 8.0 mg of an amorphous solid are obtained. Rf (CH2Cl2 / MeOH / acetic acid / water 32: 8: 1: 1) - 0.21 MS (ES): 689 (M + H) +.

Claims (10)

1. CLAIMS 1. - A compound of the formula I where Ti and T2 independently of each other are: or hydrogen, where TI and T2 can not simultaneously be hydrogen; z is
2. R (A), R (B), R (C), R (D) independently of each other are hydrogen, F, Cl, Br, I, CN, OH, NH2, -alkyl with 1 to 8 carbon atoms, - O-alkyl having 1 to 8 carbon atoms, wherein the alkyl radicals may be substituted one or more times by F; C3-C8-cycloalkyl, phenyl, benzyl, NHR (7), NR (7) R (8), O-alkenyl with 3 to 6 carbon atoms, O-cycloalkyl with 3 to 8 carbon atoms, OR phenyl, O-benzyl, wherein the phenyl nucleus can be substituted up to 3 times by F, Cl, CF 3, methyl, methoxy, NR (9) R (10); R (7), R (8) independently of each other are hydrogen, -alkyl having 1 to 8 carbon atoms, wherein the alkyl radical may be substituted one or more times by F, cycloalkyl with 3 to 8 carbon atoms, alkenyl with 3 to 6 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, phenyl, benzyl, wherein the phenyl nucleus can be substituted up to 3 times by F, Cl, CF3, methyl, methoxy, NR (9) R (10) ); or R (7), R (8) together form a chain of 4 or 5 methylene groups of which a CH2 group can be replaced by oxygen, sulfur, NH, N-CH or N-benzyl; R (9), R (10) independently of one another are hydrogen, alkyl having 1 to 4 carbon atoms, perfluoroalkyl having 1 to 4 carbon atoms; x is zero, 1 or 2; and is zero, 1 or 2; R (E), R (F) independently of one another are hydrogen, F, Cl, Br, I, CN, alkyl having 1 to 8 carbon atoms, O-alkyl having 1 to 8 carbon atoms, wherein the alkyl radical it can be substituted one or more times by F, cycloalkyl with 3 to 8 carbon atoms, -O-alkenyl with 3 to 6 carbon atoms, O-cycloalkyl with 3 to 8 carbon atoms, O-phenyl, O-benzyl, wherein the phenyl nucleus may be substituted up to 3 times by F, Cl, CF3, methyl, methoxy, NR (9) R (10); R (l), R (2), R (3) independently are hydrogen, F, Cl, Br, I, CN, -alkyl with 1 to 8 carbon atoms, -O-alkyl with 1 to 8 carbon atoms, carbon, wherein the alkyl radicals may be substituted one or more times by F, - (C = 0) -N = C (NH2), - (SOQ_2) -alkyl with 1 to 8 carbon atoms, - (S02) - NR (7) R (8), -O-alkylenephenyl with 0 to 8 carbon atoms, -alkylenephenyl with 0 to 8 carbon atoms, wherein the phenyl nucleus may be substituted up to three times by F, Cl, CF3, methyl , methoxy, -alkylene with 0 to 8 carbon atoms-NR (9) R (10); R (50) is hydrogen, alkyl having 1 to 4 carbon atoms, phenyl or benzyl, wherein the phenyl nucleus may be substituted up to three times by F, Cl, CF3, methyl, methoxy; and its pharmaceutically tolerable salts. 2. - Compound of the formula I according to claim 1, wherein TI and T2 independently of each other are: or hydrogen, where TI and T2 can not simultaneously be hydrogen; L-z is
3. R (E) is hydrogen, F, Cl, CN, alkyl having 1 to 4 carbon atoms, -O-alkyl having 1 to 4 carbon atoms, wherein the alkyl radicals can be substituted one or more times by F, cycloalkyl with 3 to 6 carbon atoms, alkenyl with 3 to 8 carbon atoms, O-cycloalkyl with 3 to 6 carbon atoms, O-phenyl, O-benzyl, wherein the phenyl nucleus may be substituted up to three times by F, Cl, CF 3, methyl, methoxy, NR (9) R (10); R (9), R (10) independently of each other are hydrogen, CH 3, CF 3; R (l), R (2), R (3) independently of each other are hydrogen, F, Cl, CN, -S02-alkyl having 1 to 4 carbon atoms, -S02-N (alkyl having 1 to 4 carbon atoms) carbon) 2, -S02-NH-alkyl having 1 to 4 carbon atoms, -S02-NH2, -S02-alkyl having 1 to 4 carbon atoms, -alkyl having 1 to 4 carbon atoms, -O-alkyl having 1 to 4 carbon atoms, wherein the alkyl radicals can be substituted one or more times by F, -O-alkylenephenyl with 0 to 4 carbon atoms, -alkylenephenyl with 0 to 4 carbon atoms, wherein the phenyl nuclei can be be replaced up to three times by F, Cl, CF3, methyl, methoxy; L is -0-, -NR (47) -, -alkylene with 1 to 4 carbon atoms, -alkenylene with 1 to 4 carbon atoms, -alkynylene with 1 to 4 carbon atoms, -COO-, -C0- NR (47) -, -S02-NR (47) -, -O- (CH2) r, -0-, -NR (47) - (CH2) n-0-, -NR (48) -CO- ( CH2) n-0-, -CO-NR (48) - (CH2) n-0-, -S02-NR (48) - (CH2) n-0-; R (47) is hydrogen, alkyl having 1 to 4 carbon atoms, R (48) -CO-, phenyl, benzyl; R (48) is hydrogen, alkyl having 1 to 4 carbon atoms, phenyl and benzyl, wherein the phenyl nucleus may be substituted up to three times by F, Cl, CF3, methyl, methoxy; n is 1 to 4; R (41), R (42), R (45) independently of each other are hydrogen, -OR (50), NHR (50), -NR (50) 2, -O- (CO) -R (50), -NH- (CO) -R (50); R (50) is hydrogen, alkyl having 1 to 4 carbon atoms, phenyl or benzyl, wherein the phenyl nucleus may be substituted up to three times by F, Cl, CF3, methyl, methoxy; K is -OR (50), -NHR (50), -NR (50) 2, -HN-CH2-CH2-C02H, -HN-CH2-CH2-S03H, -NH-CH2-COOH, -N (CH3 CH: C02H, -OKa, wherein Ka is a cation, such as, for example, an alkali metal or alkaline earth metal ion or a quaternary ammonium ion; or its pharmaceutically tolerable salts. 3. Compound of the formula I according to claims 1 or 2, characterized in that TI and T2 independently of each other are: or hydrogen, where TI and T2 can not simultaneously be hydrogenated; and L-z is
4. R (41) R (E) is hydrogen, F, Cl, CN, alkyl having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, -O-alkyl having 1 to 4 carbon atoms, CF3, - OCF3; R (l), R (2) independently are hydrogen, F, Cl, CN, -S02-CH3, -alkyl with 1 to 4 carbon atoms, -O-alkyl with 1 to 4 carbon atoms, wherein the alkyl radicals may be substituted one or more times by F; -O-alkylenephenyl with 0 to 4 carbon atoms, -alkylene with 0 to 4 carbon atoms; R (48) is hydrogen, alkyl having 1 to 4 carbon atoms, phenyl and benzyl, wherein the phenyl nucleus may be substituted up to three times by F, Cl, CF3, methyl, methoxy; n is 1 to 4; R (41) is hydrogen, -OH; K is -OR (50), -NHR (50), -NR (50) 2, -HN-CH2-CH2-C02H, -HN-CH2-CH2-S03H, -NH-CH2-C00H, -N (CH3 CH2C02H, -OKa, wherein Ka is a cation, such as, for example, an alkali metal or alkaline earth metal ion or a quaternary ammonium ion; R (50) is hydrogen, alkyl having 1 to 4 carbon atoms, phenyl or benzyl, wherein the phenyl nucleus may be substituted up to three times by F, Cl, CF3, methyl, methoxy; and its pharmaceutically tolerable salts. 4. Compound of formula I according to one or more of claims 1 to 3, characterized in that formula I has the structure wherein TI and T2 independently of each other, are or hydrogen, where TI and T2 can not simultaneously be hydrogen; L-z is
5. L is -C? C-, -NH-CH2-CH2-0-; R (E) is hydrogen, alkyl with 1 to 4 carbon; R (l), R (2) independently are hydrogen, F, Cl, CN, -S02-CH3, -alkyl with 1 to 4 carbon atoms, -O-alkyl with 1 to 4 carbon atoms, wherein the alkyl radicals may be substituted one or more times by F; and its pharmaceutically tolerable salts. 5. - A pharmaceutical product comprising one or more of the compounds according to one or more of claims 1 to 4.
6. 6. - A pharmaceutical product comprising one or more of the compounds according to one or more of the claims 1 to 4, and one or more active compounds for lipid reduction.
7. 7. - Compound according to one or more of claims 1 to 4, for use as a medicament for the prophylaxis or treatment of gallstones.
8. 8. Compound according to one or more of claims 1 to 4, in combination with at least one additional lipid-reducing active compound as a medicament for the treatment of gallstones.
9. 9. - Process for the production of a pharmaceutical product comprising one or more of the compounds according to one or more of claims 1 to 4, which comprises mixing the active compound with a pharmaceutically convenient excipient and carrying this mixture in a form suitable for administration.
10. 10. The use of compounds according to one or more of claims 1 to 4, for the production of a medicament for the prophylaxis or treatment of gallstones.