DE10028193A1 - New bile acid conjugates with benzylamino substituted aromatic and heteroaromatic compounds useful for prevention and treatment of gall stones - Google Patents

Abstract

Conjugates of bile acids with benzylamino-substituted monocyclic and bicyclic aromatic and heteroaromatic compounds are new. The conjugates are compounds of formula (I) and their salts, solvates and physiologically functional derivatives (including esters and prodrugs): P'-L-G (I) G = group of formula (a): K' = OR7, NR7R8, NH-(CH2)2-CO2H, NH-(CH2)2-SO3H, NH-CH2-CO2H, N(CH3)-CH2-CO2H, NH-CH(R9)-CO2H; or OKa; Ka = cation; R7 and R8 = H, alkyl, Ph, or Ph-CH2; Ph = phenyl optionally substituted with 5 groups; R9 = alkyl, benzyl, CH2OH, (CH2)2-SCH3, CH2CO2H, or (CH2)2-CO2H; R1-R6 = H, OR10, SR10, NR10R13, OCOR10; SCOR10, NHCOR10, SO2OR10, R10, or a bond to L (one of R1-R6 is a bond to L); R10 and R13 = H, alkyl, Ph, or Ph-CH2; L = alkyl with CH2 group(s) optionally replaced by -CH=CH-, -CC-, -NR11-, -CO-, -O-, -SO2- and/or -S-; R11 = H, alkyl, COR12, phenyl, or benzyl; R12 = H, alkyl, Ph, or Ph-CH2; P' = group of formula (B1) or (B2); A, B', D' and E = N or CH; R16-R24 = H, F, Cl, Br, I, alkyl, fluoro-alkyl, CN, NO2, NR25R26, OR25, OCOR25, COR25, COOR25, CONR25R26, SO2R25, SO2OR25, or SO2NR25R26, or a bond to L (one of R16-R24 is a bond to L); and R25 and R26 = H, alkyl, fluoro-alkyl, phenyl, or benzyl. Independent claims are also included for: (A) the preparation of compounds (I); and (B) medicaments containing compounds (I) and optionally a lipid-lowering agent.

Description

The invention relates to substituted 4-benzylaminequinolines and their heteroanalogues, as well as their pharmaceutically acceptable salts and physiologically functional Derivatives.

The formation of gallstones becomes essential alongside a number of factors determined by the composition of the bile, in particular by the Concentration and the ratio of cholesterol, phospholipids and Bile salts. This is a prerequisite for the formation of cholesterol stones Presence of bile saturated with cholesterol (Lit. Carey, M.C. and Small, D.M. (1978) The physical chemistry of cholesterol solubility in bile. Relationship to gallstone formation and dissolution in man, J. Clin. Invest. 61: 998-1026).

Gallstones have mainly been surgically removed so far, making a large one therapeutic need for medicinal gallstone dissolution and Prevention of gallstone formation exists.

The invention had for its object to provide connections that are able to prevent the formation of gallstones by preventing the Prevent bile oversaturation with cholesterol or by preventing the formation of Delaying cholesterol crystals from oversaturated bile.

The invention includes compounds of formula I.

in what mean
G

K -OR (7), -NR (7) R (8), -HN-CH ₂ -CH ₂ -CO ₂ H, -HN-CH ₂ -CH ₂ -SO ₃ H, -NH- CH ₂ -CO ₂ H, -N (CH ₃ ) CH ₂ CO ₂ H, -HN-CHR (9) CO ₂ H, -OKa, where Ka is a cation, such as. B. an alkali or alkaline earth metal ion or a quaternary ammonium ion;
R (7), R (8) independently of one another are hydrogen, (C ₁ -C ₄ ) -alkyl, phenyl or benzyl, where the phenyl nucleus can be substituted up to 3 times with F, Cl, CF ₃ , methyl, methoxy;
R (9) (C ₁ -C ₄ ) alkyl, benzyl, -CH ₂ -OH, H ₃ CSCH ₂ CH ₂ -, HO ₂ CCH ₂ -, HO ₂ CCH ₂ CH ₂ -;
R (1) to R (6) independently of one another are hydrogen, -OR (10), -SR (10), -NR (10) R (13), -OCOR (10), -SCOR (10), -NHCOR ( 10), - OPO (OR (10)) ₂ , -OSO ₂ OR (10), -R (10), R (1) and R (2), R (3) and R (4), R (5 ) and R (6) each together form the oxygen of a carbonyl group, exactly one of the radicals R (1) to R (6) always meaning a bond to L;
R (10), R (13) independently of one another are hydrogen, (C ₁ -C ₄ ) -alkyl, phenyl or benzyl, where the phenyl nucleus can be substituted up to 3 times with F, Cl, CF ₃ , methyl, methoxy;
L (C ₁ -C ₁₅ ) alkyl, where one or more CH ₂ units are replaced by -CH = CH-, -C∼C-, -NR (11) -, -CO-, -O-, -SO ₂ - or -S- can be replaced;
R (11) hydrogen, (C ₁ -C ₈ ) alkyl, R (12) -CO-, phenyl, benzyl;
R (12) is hydrogen, (C ₁ -C ₈ ) -alkyl, phenyl and benzyl, where the phenyl nucleus can be substituted up to 3 times with F, Cl, CF ₃ , methyl, methoxy;
P

in what mean
AN or CH;
BN or CH;
DN or CH;
EN or CH;
R (16) to R (24) independently of one another are hydrogen, F, Cl, Br, I, (C ₁ -C ₄ ) -alkyl,
where the alkyl radicals can be substituted one or more times with fluorine, CN, NO ₂ , NR (25) R (26), OR (25), OCOR (25), COR (25), COOR (25), CONR (25 ) R (26), SO ₂ R (25), SO ₂ OR (25), SO ₂ NR (25) R (26),
where one of the radicals R (16) to R (24) always has the meaning of a bond to L;
R (25), R (26) independently of one another are hydrogen, (C ₁ -C ₄ ) -alkyl, where the alkyl radicals can be substituted one or more times by fluorine, phenyl and benzyl;
as well as their pharmaceutically acceptable salts and physiologically functional derivatives.

Compounds of the formula I in which one or more radicals have the following meaning are preferred
G

K -OR (7), -NR (7) R (8), -HN-CH ₂ -CH ₂ -CO ₂ H, -HN-CH ₂ -CH ₂ -SO ₃ H, -NH- CH ₂ -CO ₂ H, -N (CH ₃ ) CH ₂ CO ₂ H, -HN-CHR (9) CO ₂ H, -OKa, where Ka is a cation, such as. B. an alkali or alkaline earth metal ion or a quaternary ammonium ion;
R (7), R (8) independently of one another are hydrogen, (C ₁ -C ₄ ) -alkyl, phenyl or benzyl, where the phenyl nucleus can be substituted up to 3 times with F, Cl, CF ₃ , methyl, methoxy;
R (9) (C ₁ -C ₄ ) alkyl, benzyl, -CH ₂ -OH, H ₃ CSCH ₂ CH ₂ -, HO ₂ CCH ₂ -, HO ₂ CCH ₂ CH ₂ -;
R (1), R (3), R (5) independently of one another are hydrogen, -OR (10), NR (10) R (13), -OCOR (10), -NHCOR (10);
R (10), R (13) independently of one another are hydrogen, (C ₁ -C ₄ ) -alkyl, phenyl or benzyl, where the phenyl nucleus can be substituted up to 3 times with F, Cl, CF ₃ , methyl, methoxy;
L (C ₁ -C ₈ ) alkyl, where one or more CH ₂ units are replaced by -CH = CH-, -C∼C-, -NR (11) -, -CO-, -O- or -SO ₂ - can be replaced;
R (11) hydrogen, (C ₁ -C ₄ ) alkyl, R (12) -CO-, phenyl, benzyl;
R (12) is hydrogen, (C ₁ -C ₄ ) -alkyl, phenyl and benzyl, where the phenyl nucleus can be substituted up to 3 times with F, Cl, CF ₃ , methyl, methoxy;
P

AN or CH;
BN or CH;
R (16) to R (24) independently of one another are hydrogen, F, Cl, Br, (C ₁ -C ₄ ) -alkyl, where the alkyl radicals can be substituted one or more times by fluorine, NR (25) R (26) , OR (25), OCOR (25), COR (25), COOR (25), CONR (25) R (26), with one of the radicals R (16) to R (24) always meaning a bond to L. Has;
R (25), R (26) independently of one another are hydrogen, (C ₁ -C ₄ ) -alkyl, where the alkyl radicals can be substituted one or more times by fluorine, phenyl, benzyl;
as well as their pharmaceutically acceptable salts and physiologically functional derivatives.

Compounds of the formula I in which one or more radicals have the following meaning are particularly preferred
G

K -OR (7), -NR (7) R (8), -HN-CH ₂ -CH ₂ -CO ₂ H, -HN-CH ₂ -CH ₂ -SO ₃ H, -NH- CH ₂ -CO ₂ H, -N (CH ₃ ) CH ₂ CO ₂ H, -OKa, where Ka is a cation, such as. B. an alkali or alkaline earth metal ion or a quaternary ammonium ion;
R (7), R (8) independently of one another are hydrogen, (C ₁ -C ₄ ) -alkyl, phenyl or benzyl, where the phenyl nucleus can be substituted up to 3 times with F, Cl, CF ₃ , methyl, methoxy;
R (1) hydrogen, -OH;
L (C ₁ -C ₅ ) alkyl, where one or more CH ₂ units are replaced by -CH = CH-, -C∼C-, -NR (11) -, -CO-, -O- or -SO ₂ - can be replaced;
R (11) hydrogen, (C ₁ -C ₄ ) alkyl, R (12) -CO-, phenyl, benzyl;
R (12) is hydrogen, (C ₁ -C ₄ ) -alkyl, phenyl and benzyl, where the phenyl nucleus can be substituted up to 3 times with F, Cl, CF ₃ , methyl, methoxy;
P

R (16) to R (24) independently of one another are hydrogen, F, Cl, (C ₁ -C ₄ ) -alkyl, where the alkyl radicals can be substituted one or more times with fluorine, NR (25) R (26), OR (25), OCOR (25), COR (25), COOR (25), CONR (25) R (26), where always one of the radicals R (16) to R (24) has the meaning of a bond to L;
R (25), R (26) independently of one another are hydrogen, (C ₁ -C ₄ ) -alkyl, where the alkyl radicals can be substituted one or more times by fluorine, phenyl and benzyl;
and their pharmaceutically acceptable salts.

Compounds of formula I in which one or more radicals has or have the following meaning are very particularly preferred
G

R (1) hydrogen, -OH;
L (C ₁ -C ₅ ) alkyl, where one or more CH ₂ units are replaced by -CH = CH-, -C∼C-, -NR (11) -, -CO-, -O- or -SO ₂ - can be replaced;
P

where means
R (16) to R (24) independently of one another are hydrogen, F, Cl, (C ₁ -C ₄ ) -alkyl, where the alkyl radicals can be substituted one or more times with fluorine, NR (25) R (26), OR (25), OCOR (25), COR (25), COOR (25), CONR (25) R (26), where always one of the radicals R (16) to R (24) has the meaning of a bond to L;
R (25), R (26) independently of one another are hydrogen, (C ₁ -C ₄ ) -alkyl, where the alkyl radicals can be substituted one or more times by fluorine, phenyl and benzyl;
and their pharmaceutically acceptable salts.

If the compounds of the formula I contain one or more centers of asymmetry, see above both S and R can be configured. The connections can be made as optical isomers, as diastereomers, as racemates or as mixtures thereof are available.

The expression "where the alkyl radical can be substituted one or more times by F" also includes perfluorinated alkyl groups.

The alkyl radicals can be either straight-chain or branched.

Pharmaceutically acceptable salts are due to their higher water solubility compared to the original or basic connections, particularly suitable for medical applications. These salts must be pharmaceutically acceptable Have anion or cation. Suitable pharmaceutically acceptable Acid addition salts of the compounds according to the invention are salts inorganic acids, such as hydrochloric acid, hydrogen bromide, phosphorus, metaphosphorus, Nitric, sulfonic and sulfuric acid and organic acids, such as. B. Acetic acid, benzenesulfone, benzoin, lemon, ethanesulfone, fumarate, gluconium, Glycol, isethione, milk, lactobion, maleic, apple, methanesulfone, amber, p-toluenesulfone, Tartaric and trifluoroacetic acid. For medical purposes, in particularly preferably uses the chlorine salt. Suitable pharmaceutical compatible basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth salts (such as magnesium and calcium salts).

Salts with a non-pharmaceutically acceptable anion also belong in the Framework of the invention as useful intermediates for the manufacture or Purification of pharmaceutically acceptable salts and / or for use in non therapeutic, for example in vitro applications.

The term "physiologically functional derivative" as used herein means each physiologically compatible derivative of a compound of the formula according to the invention I, e.g. B. an ester which, when administered to a mammal, such as. B. the people is able to (directly or indirectly) a compound of formula I or an active To form metabolites thereof.

The physiologically functional derivatives also include prodrugs compounds of the invention. Such prodrugs can become one in vivo compound of the invention are metabolized. These prodrugs can be effective yourself or not.  

The compounds according to the invention can also be in various polymorphic Shapes exist, e.g. B. as amorphous and crystalline polymorphic forms. All Polymorphic forms of the compounds according to the invention belong in the The scope of the invention and are a further aspect of the invention.

In the following, all references refer to "compound (s) according to formula (I)" Compound (s) of the formula (I) as described above, and their salts, Solvates and physiologically functional derivatives as described herein.

The amount of a compound of formula (I) required to obtain the Achieving the desired biological effect depends on a number of Factors, e.g. B. the specific compound chosen, the intended one Use, route of administration and clinical condition of the patient.

The daily dose is generally in the range from 0.1 mg to 100 mg (typically from 0.1 mg to 50 mg) per day per kilogram of body weight, e.g. B. 0.1-10 mg / kg / day. Tablets or capsules, for example, can range from 0.01 to 100 mg, typically from 0.02 to 50 mg. In the case of pharmaceutically acceptable The above-mentioned weights refer to the weight of the salts Salt of the compound of formula I. For prophylaxis or therapy of the above States mentioned can the compounds according to formula (I) itself as Compound are used, but preferably they are with a compatible carrier in the form of a pharmaceutical composition. The Carrier must of course be compatible, in the sense that he with the others Components of the composition are compatible and not harmful to health is for the patient. The carrier can be a solid or a liquid or both and is preferably formulated with the compound as a single dose, for example as a tablet containing from 0.05% to 95% by weight of the active ingredient can. Other pharmaceutically active substances can also be present, including other compounds of formula (I). The invention Pharmaceutical compositions can be prepared according to one of the known Pharmaceutical methods are essentially manufactured in it exist that the ingredients with pharmacologically acceptable carrier and / or Auxiliaries are mixed.  

Pharmaceutical compositions according to the invention are those for oral and oral (e.g. sublingual) administration are suitable, although the most suitable method of administration in each individual case on the type and severity of the condition to be treated and the type of compound used according to formula (I). Also coated formulations and coated Slow release formulations are within the scope of the invention. Acidic and enteric formulations. Suitable enteric-coated Coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, Hydroxypropyl methyl cellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

Suitable pharmaceutical compounds for oral administration can be found in separate units, such as capsules, wafer capsules, Lozenges or tablets, each containing a certain amount of the compound according to formula (I); as powder 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 suitable pharmaceutical method that a Comprises step in which the active ingredient and the carrier (which consists of one or more additional components can be brought into contact. Generally the compositions are meant by uniform and homogeneous Mixing the active ingredient with a liquid and / or finely divided solid carrier manufactured, after which the product is molded if necessary. So can For example, a tablet can be made by using a powder or granulate Connection pressed or molded, optionally with one or more additional components. Pressed tablets can be made by tabletting the Free-flowing compound, such as a powder or granulate, optionally mixed with a binder, lubricant, inert thinner and / or one (more) surfactant / dispersant in one suitable machine. Shaped tablets can be shaped the powdered, moistened with an inert liquid diluent Connection to be made in a suitable machine.  

Pharmaceutical compositions for oral (sublingual) Administration suitable include lozenges that have a compound according to Contain formula (I) with a flavor, usually sucrose and Gum arabic or tragacanth, and pastilles that are compounded in an inert Include bases like gelatin and glycerin or sucrose and acacia.

The invention further relates to two processes for the preparation of the compounds of Formula I.

Process A) In a Pd (0) -catalyzed coupling reaction, a compound of the formula IIId in which X is z. B. Br or I means reacted with lid. The HX released in the process is captured using an auxiliary base (such as triethylamine or pyridine).

R1, R2, R3, R4, R5, K and P have the meaning given above. The acetylene Bile acid derivatives of the formula lid are made from suitable bile acid ketones produced. For this purpose, lithium acetylide is analogous to known processes (US 5,641,767) added to keto gallic acids.

Process B) carboxylic acids of the formula IIIe (R = OH) are in the presence of suitable coupling reagents such as. B. TOTU (Chemiker Zeitung, 98 (1974), 817), DCC / HOBt (J. Am. Chem. Soc., 77 (1955), 1067) or CMC / HOBt (J. Org. Chem., 21 (1956 ), 439), (see abbreviations) with compounds of formula IIe in a known manner, whereby an amide bond is formed. Likewise, the carboxamides I shown can be prepared by reacting activated carboxylic acid derivatives IIIe with compounds of the formula IIe in the presence of an auxiliary base (for example triethylamine or pyridine) in a manner known to those skilled in the art. As activated carboxylic acid derivatives are z. B. the corresponding chlorides (R = Cl), imidazolides (R = 1-imidazolyl; Angew. Chem. Int. Ed. Engl., 1 (1962), 351) or the mixed anhydrides with Cl-COOEt or tosyl chloride.

R1, R2, R3, R4, R5, K and P have the meaning given above. The 3-ethanolamine-bile acid building blocks of the formula IIe are known Method (Tetrahedron Lett., 34 (1993), 817).

The compounds of formula I and their pharmaceutically acceptable salts and Physiologically functional derivatives are characterized by a favorable influence the bile composition and prevent the formation of gallstones, by preventing the bile from becoming over-saturated with cholesterol, or by Delay the formation of cholesterol crystals from oversaturated bile. The Compounds can be used alone or in combination with lipid-lowering agents (see red list, chapter 58). The connections are suitable especially for prophylaxis and for the treatment of gallstones.

The compounds of formula (I) according to the invention enter the hepatobiliary System and therefore work in these tissues. So the water absorption is from the gallbladder by inhibiting the apical NHE antiport of subtype 3 of the Gallbladder epithelium inhibited, which results in a diluted bile.

The compounds according to the invention were tested biologically by Determination of the inhibition of the sodium / proton exchanger subtype 3.

1. Test description

In order to determine the residual activity of human NHE-3 protein (expressed in LAP1 cell line), the recovery of the intracellular pH (pH _i ) after acidification was determined, which begins with functional NHE even under bicarbonate-free conditions. For this purpose, the pH _{i was determined} using the pH-sensitive fluorescent dye BCECF (Calbiochem, the precursor BCECF-AM is used). The cells were initially loaded with BCECF. The BCECF fluorescence was determined in a "Ratio Fluorescence Spectrometer" (Photon Technology International, South Brunswick, NJ, USA) at excitation wavelengths of 505 and 440 nm and an emission wavelength of 535 nm and converted into pH _i using calibration curves. The cells were already incubated during the BCECF loading in NH ₄ Cl buffer (pH 7.4) (NH ₄ Cl buffer: 115 mM NaCl, 20 mM NH ₄ Cl, 5 mM KCl, 1 mM CaCl ₂ , 1 mM MgSO ₄ , 20 mM Hepes, 5 mM glucose, 1 mg / ml BSA; a pH of 7.4 is adjusted with 1 M NaOH). The intracellular acidification was induced by adding 975 μl of an NH ₄ Cl-free buffer (see below) to 25 μl aliquots of the cells incubated in NH ₄ Cl buffer. The subsequent rate of pH recovery was registered for 3 minutes. To calculate the inhibitory potency of the tested substances, the cells were first examined in buffers in which there was no or no pH recovery at all. For complete pH recovery (100%), the cells were incubated in Na ⁺ -containing buffer (133.8 mM NaCl, 4.7 mM KCl, 1.25 mM CaCl ₂ , 1.25 mM MgCl ₂ , 0.97 mM Na ₂ HPO ₄ , 0.23 mM NaH ₂ PO ₄ , 5 mM Hepes, 5 mM glucose, a pH of 7.0 is adjusted with 1 M NaOH). For the determination of the 0% value, the cells were incubated in a Na ⁺ -free buffer (133.8 mM choline chloride, 4.7 mM KCl, 1.25 mM CaCl ₂ , 1.25 mM MgCl ₂ , 0.97 mM K ₂ HPO ₄ , 0.23 mM KH ₂ PO ₄ , 5 mM Hepes, 5 mM glucose, a pH of 7.0 is adjusted with 1 M NaOH). The substances to be tested were prepared in the Na ⁺ -containing buffer. The recovery of intracellular pH at the tested concentration of a substance was expressed as a percentage of the maximum recovery.

Results

Example 1: residual activity of hNHE3 at 30 µM = 26%
Example 2: residual activity of hNHE3 at 30 µM = 33%
Example 3: residual activity of hNHE3 at 30 µM = 22%
Example 6: residual activity of hNHE3 at 30 µM = 39%
Example 11: residual activity of hNHE3 at 30 µM = 61%
Example 13: residual activity of hNHE3 at 30 µM = 40%
Example 14: Residual activity of hNHE3 at 30 µM = 52%
Example 15: residual activity of hNHE3 at 30 µM = 65%
Example 16: Residual activity of hNHE3 at 30 µM = 27%
Example 17: residual activity of hNHE3 at 30 µM = 36%
Example 18: residual activity of hNHE3 at 30 µM = 36%
Example 20: residual activity of hNHE3 at 30 µM = 56%
Example 23: residual activity of hNHE3 at 30 µM = 16%
Example 24: Residual activity of hNHE3 at 30 µM = 29%
Example 25: residual activity of hNHE3 at 30 µM = 18%
Example 26: residual activity of hNHE3 at 30 µM = 52%
Example 27: residual activity of hNHE3 at 30 µM = 54%
Example 28: residual activity of hNHE3 at 30 µM = 69%
Example 29: residual activity of hNHE3 at 30 µM = 61%
Example 30: residual activity of hNHE3 at 30 µM = 48%
Example 31: residual activity of hNHE3 at 30 µM = 69%

List of abbreviations

Me methyl LAH Lithium aluminum hydride DMF N, N-dimethylformamide El electron impact Cl Chemical ionization RT Room temperature EE Ethyl acetate mp Melting point HEP n-heptane DME Dimethoxyethane IT Electron spray FAB Fast atom bombing THF Tetrahydrofuran eq. equivalent to TOTU O - [(ethoxycarbonyl) cyanomethylene amino] -N, N, N ', N'-teramethyluronium terafluoroborate HOBt 1-hydroxy-benzotriazole CMC N-Cyclphexyl-N '- (2-morpholinoethyl) carbodiimide-methyl-ptoluenesulfonate DCC Dicyclohexylcarbodiimide

The following examples serve to explain the invention in more detail, without the same on products and embodiments described in the examples restrict.  

example 1

2-Methyl-3- (aceto-1-yl) -4- {4- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) hexadecahydro-cyclopenta [a] phenanthrene-3-yl) ethyn-2-yl] benzyl} amino quinoline

Presentation of the intermediate products

Intermediate 1

3β-acetylene-cholic acid

Synthetic route

• a) 3,7,12-triacetylcholic acid methyl ester
  90 g of methyl cholic acid and 3.0 g of dimethylaminopyridine were dissolved in 500 ml of pyridine, mixed with 500 ml of acetic anhydride and stirred overnight at room temperature. It was poured onto ice water and extracted with ethyl acetate (3x). Drying (MgSO ₄ ) and evaporation of the organic phase gave 92 g of methyl 3,7,12-triacetylcholic acid, MS (FAB): M ⁺ + Li = 555.
• b) 7,12-diacetylcholic acid methyl ester
  At 5 ° C 150 ml of acetic anhydride were slowly added dropwise in 1.5 l of methanol. After 15 minutes, 92 g of methyl 3,7,12-triacetylcholic acid were added and the mixture was stirred at room temperature for 1 h. It was poured onto ice water and extracted with ethyl acetate (3x). The organic phase was washed with 1N Na ₂ CO ₃ solution, dried with MgSO ₄ and evaporated. 85 g of crude product were obtained, MS (FAB): M ⁺ + Li = 513.
• c) 3-Keto-7,12-diacetylcholic acid methyl ester
  85 g (168 mmol) of 7,12-diacetylcholic acid methyl ester, 183.7 g of pyridinium chloro chromate and 175 g of molecular sieve were stirred in 2.5 l of dichloromethane at room temperature for 2 h. It was poured onto 7 l of diethyl ether and the solids were filtered off. The solvent was evaporated and the residue was dissolved in ethyl acetate. After chromatography on a Florisil column, 59.6 g of product were obtained, MS (FAB): M ⁺ + Li = 511.
• d) 3β-acetylene-7,12-diacetyl-cholic acid methyl ester
  In 750 ml abs. Tetrahydrofuran was introduced at -55 ° C under argon for 25 min acetylene. 145 ml of 15% n-butyllithium in hexane were added dropwise to this solution and stirring was continued for 10 min. 45 g (89 mmol) of 3-keto-7,12-diacetylcholic acid methyl ester were then added and the mixture was stirred at -40 ° C. for 1.5 h. For working up, 500 ml of saturated aqueous ammonium chloride solution were added and extracted with ethyl acetate (3x), the organic phase was dried over MgSO ₄ and evaporated. The residue was chromatographed on silica gel (n-heptane / ethyl acetate 1: 1). 35.3 g of product were obtained, MS (FAB): M ⁺ + Li = 537.
• e) 3β-acetylene-cholic acid
  35.2 g (66 mmol) of the product from d) were dissolved in 1 l of methanol, 300 ml of 2N sodium hydroxide solution were added and the mixture was heated under reflux for 25 h. The solvent was evaporated, the residue was dissolved in water and acidified to pH 2 with 2N hydrochloric acid. The precipitate was filtered off and washed neutral with water. Drying of the residue gave 14.6 g of product, MS (FAB): M ⁺ + Li = 439.

Intermediate 2

2-methyl-3- (aceto-1-yl) -4- (4-bromobenzyl) amino-quinoline

Synthetic route

• a) 2- (1-Methyl-3-oxo-but-1-enylamino) benzonitrile prepared according to standard methods from 2-aminobenzonitrile (Eur. Pat. Appl., C07D 215/42; J. Med. Chem., 31 ( 1988), 1278); yellow solid; Mp: 100 ° C; MS (Cl): M ⁺ + H = 201.
• b) 1- (4-Amino-2-methyl-quinolin-3-yl) ethanone can be started from 2- (1-methyl-3-oxo-but-1-enylamino) benzonitrile by cyclization with CuCl and K ₂ CO ₃ (J. Med. Chem., 31 (1988), 1278) or NaOMe-mediated (Eur. Pat. Appl., C07D 215/42) can be prepared by known processes; yellowish solid; MS (Cl): M ⁺ + H = 201.
• c) 1- (4- (4-Bromo-benzylamino-2-methyl-quinolin-3-yl) -ethanone
  In a two-phase system consisting of 75 ml CH ₂ Cl ₂ and 55 ml 50% NaOH, 1.8 g 1- (4-amino-2-methyl-quinolin-3-yl) -ethanone are mixed with 0.15 eq tetrabutylam monium hydrogen sulfate and 30 min at room temperature stirred vigorously. Then 1.1 eq of 4-bromobenzyl bromide are added and the mixture is stirred vigorously at room temperature for 4 to 5 h. For working up, the two phases are separated, the aqueous phase is extracted 2 × with CH ₂ Cl ₂ and the combined organic phases are washed 2 × with H ₂ O and dried with MgSO ₄ . The solvent is distilled off and the residue is purified on silica gel (300 g; CH ₂ Cl ₂ / MeOH 98: 2), the title compound being obtained as a colorless, glassy solid. MS (Es +): M ⁺ + H = 369.

General procedure for the Pd (0) -catalyzed coupling reaction

The bromoaryl compound (1.0 eq) and the bile acid acetylene block (1.5 eq) are placed in DMF / triethylamine (2: 1) and the solution degassed. After venting with argon, 0.1 eq Pd (PPh ₃ ) ₂ Cl ₂ and 0.1 eq Cul are added and the reaction solution is heated to 80 ° C. Depending on the course of the reaction, it is advisable to add further catalyst or to increase the temperature, which can reach up to 100 ° C. For working up, the solvent is removed and the crude product thus obtained is purified on silica gel using a CH ₂ Cl ₂ / MeOH mixture.

2-Methyl-3- (aceto-1-yl) -4- {4- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) hexadecahydro-cyclopenta [a] phenanthrene-3-yl) ethyn-2-yl] - benzyl} amino quinoline

After 21 hours at 100 ° C., the reaction according to the general procedure gives a yellow-orange solid, mp: 178 ° C. (dec.), MS (Es +): M ⁺ + H = 772.

Example 2

2-Methyl-3- (aceto-1-yl) -4- {4- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) hexadecahydro-cyclopenta [a] phenanthren-3-yl) eth-2-yl] benzyl} - amino-quinoline

The product from Example 1 obtained above is dissolved in ethanol / methanol 1: 1, Pd / C (10%) is added and the mixture is shaken under an H ₂ atmosphere until complete conversion is achieved. Filtering off the Pd catalyst and distilling off the solvent gives the hydrogenated product as a yellowish, crystalline solid. M.p .: 172 ° C (dec.); MS (Es +): M ⁺ + H = 726.

Example 3

2-Methyl-4-aminobenzyl-quinoline-3-carboxylic acid N- {2-O- [7α, 12α-dihydroxy-10β, 13β-dimethyl-17β- (methyl pentanoate-4-yl) hexadecahydro cyclopenta [a] phenanthrene -3β-yl]} - ethylamide

Presentation of the intermediate products

Intermediate 1

3β-O- (1-amino-et-2-yl) cholic acid methyl ester

The title compound can in a literature manner starting from cholic acid in six steps. (Tetrahedron Lett., 33 (1992), 195; Tetrahedron Lett., 34 (1993), 817).

Intermediate 2

4-benzylamino-2-methyl-quinoline-3-carboxylic acid

Synthetic route

• a) 4-Amino-2-methyl-quinoline-3-carboxylic acid methyl ester is prepared according to the procedure known to the person skilled in the art (Tetrahedron, 51 (1995), 12277). MS (Cl): M ⁺ + H = 217.
• b) 4-Benzylamino-2-methyl-quinoline-3-carboxylic acid methyl ester is synthesized according to the same method as for 1- (4- (4-bromo-benzylamino-2-methyl-quinolin-3-yl) - ethanone (Example 1, intermediate 2c) was described, starting from methyl 4-amino-2-methyl-quinoline-3-carboxylate and benzyl bromide. MS (Es +): M ⁺ + H = 307.
• c) 4-Benzylamino-2-methyl-quinoline-3-carboxylic acid is prepared by saponification of the methyl ester with KOH (5 eq) in ethanolic solution. After conversion is complete, the solvent is removed and the crude product is taken up in 2N NaOH. The aqueous solution is extracted with CH ₂ Cl ₂ , the phases are separated and the aqueous phase is neutralized with 2N HCl, the title compound precipitating. Filtering and drying gives a colorless solid. Mp: 190 ° C; MS (Cl): M ++ H = 293, M ⁺ -CO ₂ = 249.

2-methyl-4-aminobenzyl-quinoline-3-carboxylic acid N- {2-O- (7α, 12α-dihydroxy-10β, 13β- dimethyl-17β- (pentanoic acid methyl ester-4-yl) hexadecahydro- cyclopenta [α] phenanthren-3β-yl)} - ethylamide as trifluoroacetate

Intermediate 1 (1.0 eq) and intermediate 2 (1.0 eq) are placed in DMF, 1.0 eq HOBt are added and a solution of 1.1 eq CMC in DMF is added at 0 ° C. If necessary, additional CMC is added and / or the temperature is raised to 60 ° C. For working up, the solvent is removed, the residue is taken up in ethyl acetate and 2 × with sat. Washed NaHCO ₃ . The NaHCO ₃ phases are extracted once more with ethyl acetate and the combined organic extracts are washed twice with H ₂ O, dried with MgSO ₄ and evaporated. The crude product thus obtained was purified by preparative HPLC, the title compound being obtained as a slightly yellowish solid. Mp: 102 ° C; MS (Es +): M ⁺ + H = 741.

Example 4

2-Methyl-4-aminobenzyl-quinoline-3-carboxylic acid N- {2-O- [7α, 12α-dihydroxy-10β, 13β dimethyl-17ß- (pentanoic acid-4-yl) hexadecahydro-cyclopenta [a] phenanthrene -3ß-yl]} - ethylamide

The product from Example 3 is mixed with 5.0 eq KOH in a methanol / H ₂ O mixture and stirred at a temperature between room temperature and 50 ° C. If necessary, additional KOH is added until complete conversion is achieved. Then the solvent is removed, the residue is taken up in H ₂ O and neutralized with 1N HCl. The resulting precipitate is filtered off and dried, the product being obtained as a colorless solid. Mp: 143 ° C; MS (Es +): M ⁺ + H = 727.

Example 5

2-Methyl-4-aminobenzyl-quinoline-3-carboxylic acid-N- {2-O- [7α, 12α, dihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-N- (2-sulfonic acid) -ethylamide-4 -yl) -hexadecahydro cyclopenta [a] phenanthren-3β-yl]} - ethylamide as trifluoroacetate

85 mg of the product acid from Example 3 are abs in 5 ml. DMF solved. At 0 ° C a solution of 0.016 ml NEt ₃ in 1 ml abs. DMF added and 1.0 eq TOTU, dissolved in 2 ml abs. DMF added dropwise. After stirring for 1 h between 0 ° C. and room temperature, the solution thus obtained is added to a mixture of 1.0 eq taurine, 1 ml NEt ₃ , 2 ml H ₂ O and 2 ml DMF and stirring is continued. For working up, the reaction mixture is concentrated and purified by preparative HPLC, the title compound being obtained as a yellowish solid. Mp: 180 ° C; MS (Es +): M ⁺ + H = 834.

Example 6

2-Methyl-4- {4- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) - hexadecahydro-cyclopenta [a] phenthren-3-yl) - ethin-2-yl] -benzyl} -amino-quinoline-3-carboxylic acid methyl ester

Presentation of the intermediate products

Intermediate 1

3β-acetylene-cholic acid

see example 1

Intermediate 2

4- (4-Bromo-benzylamino) -2-methyl-quinoline-3-carboxylic acid methyl ester

Synthetic route

• a) 4-Amino-2-methyl-quinoline-3-carboxylic acid methyl ester can in the expert are known to be produced (Tetrahedron 51 (1995), 12277).  
• b) 4- (4-Bromo-benzylamino) -2-methyl-quinoline-3-carboxylic acid methyl ester synthesized according to the same procedure as for 1- (4- (4-bromo benzylamino-2-methyl-quinolin-3-yl) -ethanone (Example 1, intermediate 2c) has been described, starting from 4-amino-2-methyl-quinoline-3-carboxylic acid methyl ester and 4-bromobenzyl bromide. Mp: 89 ° C; MS (Es +): 385/387.

2-Methyl-4- {4- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) - hexadecahydro-cyclopenta [a] phenthren-3-yl) -ethin-2-yl] -benzyl} -amino-quinoline-3- Carboxylic acid methyl ester is according to the general procedure (see. Example 1, p. 19). Mp: 165 ° C; MS (FAB): 737.

Example 7

2-Methyl-4- {4- [1- (3α, 7α, 12α, trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) - hexadecahydro-cyclopenta [a] phenanthren-3-yl) - ethyn-2-yl] -benzyl} -amino-quinoline-3-carboxylic acid n-butyl ester

Presentation of the intermediate products

Intermediate 1

3β-acetylene-cholic acid

see example 1

Intermediate 2

4- (4-Bromo-benzylamino) -2-methyl-quinoline-3-carboxylic acid n-butyl ester

Synthetic route

• a) 4- (4-Bromo-benzylamino) -2-methyl-quinoline-3-carboxylic acid n-butyl ester 200 mg (1.0 eq) 4- (4-bromo-benzylamino) -2-methyl-quinoline-3-carboxylic acid methyl esters (see Example 5) are dissolved in an n-butanol / THF mixture and at room temperature. mixed with 2.5 eq NaH (55%) and stirred with exclusion of moisture for 2 h. For working up, the solvent is removed and the residue is taken up in CH ₂ Cl ₂ . H ₂ O is washed and the aqueous phase is extracted once more with CH ₂ Cl ₂ . The combined organic phases are saturated with sat. Washed NaHCO ₃ solution and dried with MgSO ₄ . Chromatography on silica gel (ethyl acetate / n-heptane 1: 1 → 4: 1) gives the product ester as a colorless solid. Mp: 116 ° C; MS (Es +): 427/429.

2-Methyl-4- {4- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) - hexadecahydro-cyclopenta [a] phenthren-3-yl) -ethin-2-yl] -benzyl} -amino-quinoline-3- carboxylic acid n-butyl ester is obtained according to the general procedure given (see Example 1) prepared. Mp: 70 ° C; MS (FAB): 779.

Example 8

2-Methyl-4- {4- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) - hexadecahydro-cyclopenta [a] phenthren-3-yl) - ethin-2-yl] -benzyl} -amino-quinoline-3-carboxylic acid isopropyl ester

Presentation of the intermediate products

Intermediate 1

3β-acetylene-cholic acid

see example 1

Intermediate 2

Isopropyl 4- (4-bromo-benzylamino) -2-methyl-quinoline-3-carboxylic acid

Synthetic route

• a) 4- (4-Bromo-benzylamino) -2-methyl-quinoline-3-carboxylic acid isopropyl ester analogous to 4- (4-bromo-benzylamino) -2-methyl-quinoline-3-carboxylic acid-n butyl ester (see Example 6) by transesterification of the corresponding methyl ester in an isopropanol I THF mixture, the title compound as colorless oil is obtained. MS (Es +): 413/415.

2-Methyl-4- {4- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) - hexadecahydro-cyclopenta [a] phenthren-3-yl) -ethin-2-yl] -benzyl} -amino-quinoline-3- Carboxylic acid isopropyl ester is according to the general procedure (s. Example 1, p. 19). Mp: 150 ° C; MS (FAB): 765.

Example 9

2-methyl-4-benzylamino-6- {2- [3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) hexadecahydro-cyclopenta [a] phenthren-3-yl] -ethin-1-yl} -quinoline 3-carboxylic acid methyl ester

Presentation of the intermediate products

Intermediate 1

3β-acetylene-cholic acid

see example 1

Intermediate 2

4- (4-Bromo-benzylamino) -2-methyl-quinoline-3-carboxylic acid isopropyl ester

Synthetic route

• a) 5-Bromo-2-amino-benzonitrile can be prepared in a manner known from the literature (Synlett, 1994, 450); MS (Cl): 197/199.
• b) 6-Bromo-4-amino-2-methyl-quinoline-3-carboxylic acid methyl ester can in the Those skilled in the art can be produced (Tetrahedron 51 (1995), 12277).
• c) 6-Bromo-4-benzylamino-2-methyl-quinoline-3-carboxylic acid methyl ester is after synthesized using the same method as for 1- (4- (4-bromo-benzylamino- 2-methyl-quino-3-yl) -ethanone (Example 1, intermediate 2c) was, starting from 6-bromo-4-amino-2-methyl-quinoline-3-carboxylic acid methyl ester and 4-bromobenzyl bromide. Mp: 89 ° C; MS (Es +): 385/387.

2-methyl-4-benzylamino-6- {2- [3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) -hexadecahydro-cyclopenta [a] phenthren-3-yl] -ethin-1-yl} -quinoline- 3-carboxylic acid methyl ester is prepared according to the general procedure (see Example 1) prepared. Mp: 223 ° C (dec.); MS (Es +): 737.

Example 10

2-Methl-4-benzylamino-6- {2- [3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β (pentanoic acid-4-yl) hexadecahydro-cyclopenta [a] phenthren-3-yl] - ethylen-1-yl} - methyl quinoline-3-carboxylate

The product described in Example 8 becomes analogous to that in Example 2 specified method hydrogenated, the target compound as a slightly yellow solid is obtained. Mp: <185 ° C (decomposition); MS (FAB): 741.

Example 11

2,5-Dimethyl-4- {4- [1- (3α, 7α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) hexadecahydro-cyclopenta [a] phenthren-3 -yl) -ethin-2-yl] -benzyl} -amino-quinoline-3-carboxylic acid methyl ester

Presentation of the intermediate products

Intermediate 1

3β-acetylene-cholic acid

see example 1

Intermediate 2

4- (4-Bromo-benzylamino) -2,5-dimethyl-quinoline-3-carboxylic acid methyl ester

Synthetic route

• a) 4-Amino-2,5-dimethyl-quinoline-3-carboxylic acid methyl ester can be analogous to Intermediate 2a, Example 6, prepared in a manner known to those skilled in the art (Tetrahedron 51 (1995), 12277).
• b) 4- (4-Bromo-benzylamino) -2,5-dimethyl-quinoline-3-carboxylic acid methyl ester synthesized according to the same procedure as for 1- (4- (4-bromo benzylamino-2-methyl-quinolin-3-yl) -ethanone (Example 1, intermediate 2c) has been described, starting from 4-amino-2,5-dimethyl-quinoline-3- carboxylic acid methyl ester and 4-bromobenzyl bromide. Mp: 150 ° C; MS (Cl +): 399/401.

2,5-Dimethyl-4- {4- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) hexadecahydro-cyclopenta [a] phenanthren-3-yl ) -ethin-2-yl] -benzyl) -amino-quinoline-3-carboxylic acid methyl ester is prepared according to the general procedure given (see Example 1). Mp: <155 ° C; MS (Es +): M ⁺ + H = 751.

Example 12

2,5-Dimethyl-4- {4- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) hexadecahydro-cyclopenta [a] phenanthren-3-yl ) -ethylen-2-yl] -benzyl) -amino-quinoline-3-carboxylic acid methyl ester

The product described in Example 11 is hydrogenated analogously to the method given in Example 2, the target compound being obtained as a slightly yellow solid. Mp: <180 ° C decomposition; MS (Es +): M ⁺ + H = 756.

Example 13

2-Methyl-3- (aceto-1-yl) -4- {3- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) hexadecahydro-cyclopenta [a] phenanthrene-3-yl) ethyn-2-yl] benzylamino-quinoline

Presentation of the intermediate products

Intermediate 1

3β-acetylene-cholic acid

see example 1

Intermediate 2

1- (4- (3-Bromobenzyl) amino-2-methyl-quinolin3-yl) ethanone

Synthetic route

• a) 1- (4-amino-2-methyl-quinolin-3-yl) ethanone can be analogous to intermediate 2a, Ex. 6, by tin-tetrachloride-mediated reaction of 2-aminobenzonitrile and Acetylacetone can be prepared in a manner known from the literature (Tetrahedron 51 (1995), 12277).
• b) 1- (4- (3-Bromobenzyl-) amino-2-methyl-quinolin3-yl) -ethanone is after the synthesized the same method as for 1- (4- (4-bromobenzyl) amino-2- methyl-quinolin-3-yl) -ethanone (Example 1, intermediate 2c) was, starting from 1- (4-amino-2-methyl-quinolin3-yl) -ethanone and 3-bromo benzyl bromide. Mp: 109 ° C; MS (Es +): 369/371.

2-Methyl-3- (aceto-1-yl) -4- {3- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) hexadecahydro-cyclopenta [a] phenanthren-3-yl) -ethin-2-yl] - benzylamino-quinofin is prepared by the general procedure given (see Example 1). Mp: <195 ° C decomposition; MS (Es +): M ⁺ + H = 721.

Example 14

2-Methyl-3- (aceto-1-yl) -4- {3- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) hexadecahydro-cyclopenta [a] phenanthren-3-yl) ethylene-2-yl] benzyl} amino-quinoline

The title compound is obtained by catalytic hydrogenation of the product described in Example 13, as described in Example 2. Mp: <170 ° C decomposition; MS (FAB +): M ⁺ = 725.

Example 15

2-Methyl-3- (aceto-1-yl) -4- {3- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-N-glycylamid-4-yl) -hexadecahydro-cyclopenta [a] phenanthrene-3-yl) - ethylene-2-yl] -benzyl} -amino-quinoline

Synthetic route

• a) 2-Methyl-3- (aceto-1-yl) -4- {3- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid (N-glycidylethyl ester) - amid-4-yl) hexadecahydro cyclopenta [a] phenanthrene-3-yl) ethylene-2-yl] benzyl} aminoquinoline.
  55 mg of the product prepared in Example 14 are abs in 5 ml. DMF submitted and at 0 ° C with 1 ml of a solution of 0.1 ml triethylamine in 10 ml abs. DMF offset. After adding 25 mg of TOTU, the mixture is stirred at 0 ° C. for 20 min and at room temperature for 30 min. This solution is added to a solution consisting of 11 mg of glycine ethyl ester hydrochloride in 2 ml of DMF, 2 ml of H ₂ O and 1 ml of tristylamine and stirred at room temperature until complete conversion is achieved. The solvent is distilled off and the residue is chromatographed on silica gel, giving 41 mg of the corresponding ethyl ester.
• b) 2-Methyl-3- (aceto-1-yl) -4- {3- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-N-glycylamide-4- yl) hexadecahydro-cyclopenta [a] phenanthrene-3-yl) ethylene-2-yl] benzyl} amino-quinoline.
  41 mg of the ethyl ester prepared are dissolved in 5 ml of methanol and a solution of 28 mg of KOH in 1.5 ml of H ₂ O is added dropwise at room temperature and the mixture is stirred at room temperature. After 2 hours, the solvent is removed, the residue is taken up in 5 ml of H ₂ O and the pH is adjusted to 5 with dilute HCl, whereupon the desired product precipitates. The precipitate is filtered off and dried in air. MS (Es +): M ⁺ + H: 782.

Example 16

2-Methyl-3- (aceto-1-yl) -4- {3- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-N- (2-sulfonic acid) - ethylamid-4-yl) hexadecahydro cyclopenta [a] phenanthren-3-yl) ethylene-2-yl] benzyl} aminoquinoline

55 mg of the product prepared in Example 14 are abs in 5 ml. DMF submitted and at 0 ° C with 1 ml of a solution of 0.1 ml triethylamine in 10 ml abs. DMF offset. After adding 25 mg of TOTU, the mixture is stirred at 0 ° C. for 20 min and at room temperature for 30 min. This solution is added to a solution consisting of 10 mg of taurine in 2 ml of DMF, 2 ml of H ₂ O and 1 ml of tristylamine and stirred at room temperature until complete conversion is achieved. The solvent is removed and the residue is chromatographed on silica gel, 36 mg of the title compound being obtained in the form of a slightly yellowish solid. MS (Es +): M ⁺ + H: 832.

Example 17

2-Methyl-3- (aceto-1-yl) -4- {2- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) hexadecahydro-cyclopenta [a] phenanthrene-3-yi) ethyn-2-yl] benzyl} amino quinoline

Presentation of the intermediate products

Intermediate 1

3ß-acetylene-cholic acid

see example 1

Intermediate 2

1- (4- (3-Bromobenzyl) amino-2-methyl-quinolin3-yl) ethanone

Synthetic route

• a) 4-Amino-2-methyl-quinolin-3-yl) -ethanone: s. Example 13, (Tetrahedron 51 (1995), 12277).
• b) 4- (2-Bromobenzyl-) amino-2-methyl-quinolin3-yl) -ethanone is used according to the same Process synthesized as already for 1- (4- (4-bromobenzyl) amino-2-methyl- quinolin-3-yl) -ethanone (Example 1, intermediate 2c) has been described, starting from 1- (4-amino-2-methyl-quinolin3-yl) -ethanone and 2-bromo benzyl bromide. Mp: 134 ° C; MS (Es +): 369/371.

2-Methyl-3- (aceto-1-yl) -4- {2- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) hexadecahydro-cyclopenta [a] phenanthren-3-yl) -ethin-2-yl] -benzyl} -amino-quinoline is prepared from the two intermediates by the general procedure given (see Example 1). MS (Es +): M ⁺ + H = 721.

Example 18

2-Methyl-3- (aceto-1-yl) -4- {2- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) hexadecahydro-cyclopenta [a] phenanthrene-3-yl) ethylene-2-yl] benzyl} amino quinoline

Hydrogenation of the product compound from Example 17 according to that in Example 2 The method listed provides the desired product in the form of an easy yellowish solid fabric. Mp: <165 ° C decomposition; MS (Es +): 725.

Example 19

4- [3β- (2- {4 - [(3-acetyl-2-methylquinolin-4-ylamino) methyl] benzoylamino) ethoxy) - 7α, 12α-dihydroxy-10β, 13β-dimethyl-hexadecahydrocyclopenta [a] methyl phenanthrene-17β-yl] pentanoate

Presentation of the intermediate products

Intermediate 1

3β-O- (1-amino-et-2-yl) cholic acid methyl ester

s. Example 3. (Tetrahedron Lett., 33 (1992), 195; Tetrahedron Lett., 34 (1993), 817).

Intermediate 2

4 - [(3-Acetyl-2-methyl-quinolin-4-ylamino) methyl] benzoic acid

Synthetic route

• a) 2-Methyl-3- (aceto-1-yl) -4- (4-bromobenzyl) amino-quinoline is in Example 1 as Intermediate 2 described.
• b) 4 - [(3-Acetyl-2-methyl-quinolin-4-ylamino) methyl] benzoic acid.
  370 mg of 2-methyl-3- (aceto-1-yl) -4- (4-bromobenzyl) aminoquinoline, 79 mg of triphenyl phosphine and 78 mg of calcium formate are dissolved in 4 ml of DMF and 4 ml of benzene. 9 mg of palladium acetate are added under a protective gas and the solution is heated to 120 ° C. under a CO atmosphere. After two hours, 58 mg of tetrakis triphenylphosphine-palladium are added and stirring is continued at 120 ° C. Stirring is continued at the specified temperature until there is no longer any increase in sales. Possibly. additional palladium catalyst is added. For working up, 2N NaOH is added and the mixture is extracted with dichloromethane. The organic phase is extracted once more with 2N NaOH and the combined aqueous phases are extracted with dichloromethane. The NaOH extracts are adjusted to a pH of 6 with 6N HCl and i. Vac. constricted. The residue is taken up in a little methanol. Insoluble salts are filtered off. The filtrate is concentrated and taken up in a little H ₂ O. The product is obtained as a yellow insoluble solid, which is suctioned off and dried in air. 81 mg of a yellow solid are obtained. Mp: <210 ° C decomposition; MS (Es +): 335.

4- [3β- (2- {4 - [(3-acetyl-2-methylquinolin-4-ylamino) methyl] benzoylamino) ethoxy) - 7α, 12α-dihydroxy-10β, 13β-dimethyl-hexadecahydrocyclopenta [a] methyl phenanthrene-17β yl] pentanoate.
67 mg of intermediate 2 are dissolved in 5 ml of DMF and 1 ml of a solution of 0.28 ml of triethylamine in 10 ml of DMF is added at 0.degree. After adding a solution of 66 mg TOTU in 2 ml DMF, 30 min at 0 ° C and a further 45 min at room temp. touched. This solution is added dropwise to a second solution of 93 mg of intermediate 1 in 2 ml of DMF and 1 ml of triethylamine and at room temperature. stirred until complete conversion is determined. For processing, i. Vac. concentrated and the residue taken up in ethyl acetate. The precipitate is filtered off and the filtrate is washed with NaHCO ₃ solution and with H ₂ O. The organic phase is separated off, dried with MgSO ₄ and freed from the solvent. The residue thus obtained is chromatographed on silica gel together with the separated precipitate, 71 mg of the product being obtained as a yellow-orange solid. Mp: <98 ° C decomposition; MS (Es +): 782.

Example 20

4- [3β- (2- {4 - [(3-acetyl-2-methylquinolin-4-ylamino) methyl] benzoylamino) ethoxy) - 7α, 12α-dihydroxy-10β, 13β-dimethyl-hexadecahydrocyclopenta [a] phenanthrene-17β yl] pentanoic acid

The ester obtained in Example 19 is analogous to that described in Example 4 Saponification implemented, the desired product as a colorless solid is obtained. Mp: <145 ° C decomposition; MS (Es +): 768.

Example 21

2-ethyl-4- {4- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) - hexadecahydro-cyclopenta [a] phenanthren-3-yl) - ethin-2-yl] -benzyl-amino-quinoline-3-carboxylic acid methyl ester

Presentation of the intermediate products

Intermediate 1

3β-acetylene-cholic acid

see example 1

Intermediate 2

4- (4-Bromo-benzylamino) -2-ethyl-quinoline-3-carboxylic acid methyl ester

Synthetic route

• a) 4-Amino-2-ethyl-quinoline-3-carboxylic acid methyl ester can in the expert are known to be produced (Tetrahedron 51 (1995), 12277).
• b) 4- (4-Bromo-benzylamino) -2-ethyl-quinoline-3-carboxylic acid methyl ester is after synthesized using the same method as for 1- (4- (4-bromo-benzylamino- 2-methyl-quinolin-3-yl) -ethanone (Example 1, intermediate 2c) was, starting from 4-amino-2-ethyl-quinoline-3-carboxylic acid methyl ester and 4-bromo-benzyl bromide. MS (Es +): 399/401.

2-Ethyl-4- {4- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) - hexadecahydro-cyclopenta [a] phenanthren-3-yl) -ethin-2-yl] -benzyl} -amino-quinolin-3- Carboxylic acid methyl ester is according to the general procedure (see. Example 1) prepared. Mp: <200 ° C; MS (FAB): 751.  

Example 22

2-ethyl-4- {4- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) - hexadecahydro-cyclopenta [a] phenanthren-3-yl) - ethylen-2-yl] -benzyl} -amino-quinoline-3-carboxylic acid methyl ester

The product described in Example 21 becomes analogous to that in Example 2 specified method hydrogenated, the target compound as a slightly yellow solid is obtained. Mp: <190 ° G (decomposition); MS (Es +): 755.

Example 23

2-Methyl-3- (aceto-1-yl) -4- {4- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) hexadecahydro-cyclopenta [a] phenanthrene-3-yl) ethyn-2-yl] - 3-fluoro-benzyl} amino-quinoline

Presentation of the intermediate products

Intermediate 1

3β-acetylene-cholic acid

see example 1

Intermediate 2

1- (4- (4-Bromo-3-fluoro-benzyl) amino-2-methyl-quinolin3-yl) ethanone

Synthetic route

• a) 1- (4-amino-2-methyl-quinolin-3-yl) ethanone; s. Example 13 (Tetrahedron 51 (1995), 12277).
• b) 1- (4- (4-Bromo-3-fluoro-benzyl) amino-2-methyl-quinolin3-yl) -ethanone is added synthesized using the same procedure as for 1- (4- (4-bromobenzyl) - amino-2-methyl-quinolin-3-yl) -ethanone (Example 1, intermediate 2c) was described, starting from 1- (4-amino-2-methyl-quinolin-3-yl) -ethanone and 4-bromo-3-fluoro-benzyl bromide. MS (Es +): 387/389.

2-Methyl-3- (aceto-1-yl) -4- {4- [1- (3α; 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) hexadecahydro-cyclopenta [a) phenanthrene-3-yl) ethyn-2-yl] - 3-fluoro-benzyl} amino-quinoline is made according to the general procedure given (see Example 1). MS (FAB): 739.

Example 24

2-Methyl-3- (aceto-1-yl) -4- {4- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) hexadecahydro-cyclopenta [a] phenanthrene-3-yl) ethylene-2-yl] - 3-fluoro-benzyl} amino-quinoline

The product described in Example 23 becomes analogous to that in Example 2 specified method hydrogenated, the target compound as a slightly yellow solid is obtained. MS (Es +): 744.

Example 25

2-Methyl-3- (aceto-1-yl) -4- {4- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) hexadecahydro-cyclopenta [a] phenanthrene-3-yl) ethyn-2-yl] - 3-chlorobenzyl} amino-quinoline

Presentation of the intermediate products

Intermediate 1

3β-acetylene-cholic acid

see example 1

Intermediate 2

1- (4- (4-Bromo-3-chlorobenzyl) amino-2-methyl-quinolin-3-yl) ethanone

Synthetic route

• a) 1- (4-amino-2-methyl-quinolin-3-yl) ethanone; s. Example 13 (Tetrahedron 51 (1995), 12277).
• b) 1- (4- (4-Bromo-3-chloro-benzyl) amino-2-methyl-quinolin-3-yl) -ethanone is added synthesized using the same procedure as for 1- (4- (4-bromobenzyl) - amino-2-methyl-quinolin-3-yl) ethanone (Example 1, intermediate 2c) was described, starting from 1- (4-amino-2-methyl-quinolin-3-yl) -ethanone and 4-bromo-3-chloro-benzyl bromide. MS (Es +): 403/405.

2-Methyl-3- (aceto-1-yl) -4- {4- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) hexadecahydro-cyclopenta [a] phenanthrene-3-yl) ethyn-2-yl] - 3-chloro-benzyl} amino-quinoline is made according to the general procedure given (see Example 1). MS (FAB): 755.  

Example 26

2-Methyl-3- (aceto-1-yl) -4- {4- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) hexadecahydro-cyclopenta [a] phenanthren-3-yl) -ethin-2-yl] - 2-fluoro-benzyl} amino-quinoline

Presentation of the intermediate products

Intermediate 1

3β-acetylene-cholic acid

see example 1

Intermediate 2

1- (4- (4-Bromo-2-fluoro-benzyl) amino-2-methyl-quinolin-3-yl) ethanone

Synthetic route

• a) 1- (4-amino-2-methyl-quinolin-3-yl) ethanone; s. Example 13 (Tetrahedron 51 (1995), 12277).
• b) 1- (4- (4-Bromo-2-fluoro-benzyl) amino-2-methyl-quinolin-3-yl) -ethanone is added synthesized using the same procedure as for 1- (4- (4-bromobenzyl) - amino-2-methyl-quinolin-3-yl) -ethanone (Example 1, intermediate 2c) was described, starting from 1- (4-amino-2-methyl-quinolin-3-yl) -ethanone and 4-bromo-2-fluoro-benzyl bromide. MS (Es +): 387/389.

2-Methyl-3- (aceto-1-yl) -4- {4- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) hexadecahydro-cyclopenta [a] phenanthrene-3-yl) ethyn-2-yl] - 2-fluoro-benzyl} amino-quinoline is made according to the general procedure given (see Example 1). MS (Es +): 739.

Example 27

2-Methyl-3- (aceto-1-yl) -4- {4- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) hexadecahydro-cyclopenta [a] phenanthrene-3-ylj-ethylene-2-yl] - 2-fluoro-benzyl} amino-quinoline

The product described in Example 26 becomes analogous to that in Example 2 specified method hydrogenated, the target compound as a slightly yellow solid is obtained. MS (Es +): 744.

Example 28

2-Methyl-3- (aceto-1-yl) -4- {4- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) hexadecahydro-cyclopenta [a] phenanthrene-3-yl) -ethin-2-yl] - 2-chlorobenzyl} amino-quinoline

Presentation of the intermediate products

Intermediate 1

3β-acetylene-cholic acid

see example 1

Intermediate 2

1- (4- (4-Bromo-2-chlorobenzyl) amino-2-methyl-quinolin-3-yl) ethanone

Synthetic route

• a) 1- (4-amino-2-methyl-quinolin-3-yl) ethanone; s. Example 13 (Tetrahedron 51 (1995), 12277).
• b) 1- (4- (4-Bromo-2-chloro-benzyl) amino-2-methyl-quinolin-3-yl) -ethanone is added synthesized using the same procedure as for 1- (4- (4-bromobenzyl) - amino-2-methyl-quinolin-3-yl) -ethanone (Example 1, intermediate 2c) was described, starting from 1- (4-amino-2-methyl-quinolin-3-yl) -ethanone and 4-bromo-2-chloro-benzyl bromide. MS (FAB +): 4031405.

2-Methyl-3- (aceto-1-yl) -4- {4- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) hexadecahydro-cyclopenta [a] phenanthrene-3-yl) ethyn-2-yl] - 2-chloro-benzyl} amino-quinoline is made according to the general procedure given (see Example 1). MS (FAB +): 756.

Example 29

2-Methyl-3- (aceto-1-yl) -4- {4- [1- (3α, 7α, 12 + α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) hexadecahydro -cyclopenta [a] phenanthrene-3-yl) -ethylene-2-yl] - 2-chloro-benzyl} -amino-quinoline

The product described in Example 28 becomes analogous to that in Example 2 specified method hydrogenated, the target compound as a slightly yellow solid is obtained. MS (Es +): 760.

Example 30

2,6-Dimethyl-3-acet-1-yl-4- {4- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) hexadecahydro-cyclopenta [a] phenanthrene-3-yl-) ethyn-2-yl] -benzyl} -aminopyridine

Presentation of the intermediate products

Intermediate 1

3β-acetylene-cholic acid

see example 1.

Intermediate 2

1- [4- (4-Bromo-benzylamino) -2,6-dimethyl-pyridin-3-yl] ethanone

Synthetic route

• a) 3-Acetyl-2,6-dimethyl-1H-pyridin-4-one can according to the method known from the literature can be produced (Chem. Pharm. Bull., 31, 1983, 4303).
• b) 1- (4-Chloro-2,6-dimethyl-pyridin-3-yl) -ethanone is known to the person skilled in the art Way synthesized (J. Heterocyclic Chem., 18, 1981, 603).
• c) 1- [4- (4-Bromobenzylamino) -2,6-dimethyl-pyridin-3-yl] ethanone 1.0 g of 1- (4-chloro-2,6-dimethyl-pyridin-3-yl) -ethanone is dissolved in 10 ml Dimethylacetamide dissolved and mixed with 1.5 equivalents of 4-bromo-benzylamine. The solution is heated to 140 to 150 ° C until no further increase in sales is noticeable. Possibly. another equivalent of 4-bromo-benzylamine can be added will. For working up the solvent i. Vac. distilled off and the Chromatograph the residue on silica gel, the title compound being yellow Oil is obtained. MS (Es +): 333/335.

2,6-dimethyl-3-acet-1-yl-4- {4- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) hexadecahydro-cyclopenta [a] phenanthrene-3-yl-) ethyn-2-yl] - benzyl) amino pyridine is prepared according to the general procedure (see Example 1) produced. MS (Es +): 685.

Example 31

2,6-Dimethyl-3-acet-1-yl-4- {4- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) hexadecahydro-cyclopenta [a] phenanthrene-3-yl-) ethylene-2-yl] -benzyl} -aminopyridine

The product obtained in Example 30 is after that described in Example 2 The process is hydrogenated, the title compound being obtained as a slightly yellowish solid becomes. MS (Es +): 689.

Example 32

2-Ethyl-6-methyl-5-acet-1-yl-4- {4- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) hexadecahydro -cyclopenta [a] phenanthrene-3-yl-) ethyn-2-yl] -benzyl} -aminopyridine

Presentation of the intermediate products

Intermediate 1

3β-acetylene-cholic acid

see example 1

Intermediate 2

1- (4- (4-Bromo-benzylamino) -2-ethyl-6-methyl-pyridin-5-yl] ethanone

Synthetic route

• a) 2,2-Dimethyl-5-propionyl- [1,3] dioxane-4,6-dione is known in the literature synthesized (J. Org. Chem., 43, 1978, 2087).
• b) 3-Acetyl-6-ethyl-2-methyl-1H-pyridin-4-one is based on that in Example 30 described method (Example 30; intermediate 2a) synthesized (Chem. Pharm. Bull., 31, 1983, 4303).
• c) 1- (4-Chloro-6-ethyl-2-methyl-pyridin-3-yl) -ethanone is analogous to Intermediate 2b, Example 30, prepared by the method known from the literature (J. Heterocyclic Chem., 18, 1981, 603).
• d) 1- [4- (4-Bromo-benzylamino) -2-ethyl-6-methyl-pyridin-5-yl] -ethanone is after the Instruction described in Example 30 (intermediate 2c), starting from 4- Chloro-2-ethyl-6-methyl-pyridine and 4-bromo-benzylamine. MS (Es +): 347/349.

2-ethyl-6-methyl-5-acet-1-yl-4- {4- [1- (3α, 7α, 12α-trihydroxy-10β, 13β-dimethyl-17β- (pentanoic acid-4-yl) hexadecahydro-cyclopenta [a] phenanthrene-3-yl-) ethyn-2-yl] - benzyl} -amino-pyridine is by the general method (see Example 1) produced. MS (Es +): 700.

Claims (10)

1. Compounds of formula I.
in what mean
G
K -OR (7), -NR (7) R (8), -HN-CH ₂ -CH ₂ -CO ₂ H, -HN-CH ₂ -CH ₂ -SO ₃ H, -NH- CH ₂ -CO ₂ H, -N (CH ₃ ) CH ₂ CO ₂ H, -HN-CHR (9) CO ₂ H, -OKa, where Ka is a cation, such as. B. an alkali or alkaline earth metal ion or a quaternary ammonium ion;
R (7), R (8) independently of one another are hydrogen, (C ₁ -C ₄ ) -alkyl, phenyl or benzyl, where the phenyl nucleus can be substituted up to 3 times with F, Cl, CF ₃ , methyl, methoxy;
R (9) (C ₁ -C ₄ ) alkyl, benzyl, -CH ₂ -OH, H ₃ CSCH ₂ CH ₂ -, HO ₂ CCH ₂ -, HO ₂ CCH ₂ CH ₂ -;
R (1) to R (6) independently of one another are hydrogen, -OR (10), -SR (10), -NR (10) R (13), -OCOR (10), -SCOR (10), -NHCOR ( 10), - OPO (OR (10)) ₂ , -OSO ₂ OR (10), -R (10), R (1) and R (2), R (3) and R (4), R (5 ) and R (6) each together form the oxygen of a carbonyl group, exactly one of the radicals R (1) to R (6) always meaning a bond to L;
R (10), R (13) independently of one another are hydrogen, (C ₁ -C ₄ ) -alkyl, phenyl or benzyl, where the phenyl nucleus can be substituted up to 3 times with F, Cl, CF ₃ , methyl, methoxy;
L (C ₁ -C ₁₅ ) alkyl, where one or more CH ₂ units are replaced by -CH = CH-, -C∼C-, -NR (11) -, -CO-, -O-, -SO ₂ - or -S- can be replaced;
R (11) hydrogen, (C ₁ -C ₈ ) alkyl, R (12) -CO-, phenyl, benzyl;
R (12) is hydrogen, (C ₁ -C ₈ ) -alkyl, phenyl and benzyl, where the phenyl nucleus can be up to 3 times substituted with F, Cl, CF ₃ , methyl, methoxy;
P
in what mean
AN or CH;
BN or CH;
DN or CH;
EN or CH;
R (16) to R (24) independently of one another are hydrogen, F, Cl, Br, I, (C ₁ -C ₄ ) -alkyl, where the alkyl radicals can be substituted one or more times by fluorine, CN, NO ₂ , NR (25) R (26), OR (25), OCOR (25), COR (25), COOR (25), CONR (25) R (26), SO ₂ R (25), SO ₂ OR (25) , SO ₂ NR (25) R (26), where always one of the radicals R (16) to R (24) has the meaning of a bond to L;
R (25), R (26) independently of one another are hydrogen, (C ₁ -C ₄ ) -alkyl, where the alkyl radicals can be substituted one or more times by fluorine, phenyl and benzyl;
and their pharmaceutically acceptable salts 2. Compounds of formula I, according to claim 1, characterized in that mean
G
K -OR (7), -NR (7) R (8), -HN-CH ₂ -CH ₂ -CO ₂ H, -HN-CH ₂ -CH ₂ -SO ₃ H, -NH- CH ₂ -CO ₂ H, -N (CH ₃ ) CH ₂ CO ₂ H, -HN-CHR (9) CO ₂ H, -OKa, where Ka is a cation, such as. B. an alkali or alkaline earth metal or a quaternary ammonium ion;
R (7), R (8) independently of one another are hydrogen, (C ₁ -C ₄ ) -alkyl, phenyl or benzyl, where the phenyl nucleus can be substituted up to 3 times with F, Cl, CF ₃ , methyl, methoxy;
R (9) (C ₁ -C ₄ ) alkyl, benzyl, -CH ₂ -OH, H ₃ CSCH ₂ CH ₂ -, HO ₂ CCH ₂ -, HO ₂ CCH ₂ CH ₂ -;
R (1), R (3), R (5) independently of one another are hydrogen, -OR (10), NR (10) R (13), -OCOR (10), -NHCOR (10);
R (10), R (13) independently of one another are hydrogen, (C ₁ -C ₄ ) -alkyl, phenyl or benzyl, where the phenyl nucleus can be substituted up to 3 times with F, Cl, CF ₃ , methyl, methoxy;
L (C ₁ -C ₈ ) alkyl, where one or more CH ₂ units are replaced by -CH = CH-, -C∼C-, -NR (11) -, -CO-, -O- or -SO ₂ - can be replaced;
R (11) hydrogen, (C ₁ -C ₄ ) alkyl, R (12) -CO-, phenyl, benzyl;
R (12) is hydrogen, (C ₁ -C ₄ ) -alkyl, phenyl and benzyl, where the phenyl nucleus can be substituted up to 3 times with F, Cl, CF ₃ , methyl, methoxy;
P
AN or CH;
BN or CH;
R (16) to R (24) independently of one another are hydrogen, F, Cl, Br, (C ₁ -C ₄ ) -alkyl, where the alkyl radicals can be substituted one or more times by fluorine, NR (25) R (26) , OR (25), OCOR (25), COR (25), COOR (25), CONR (25) R (26), with one of the radicals R (16) to R (24) always meaning a bond to L. Has;
R (25), R (26) independently of one another are hydrogen, (C ₁ -C ₄ ) -alkyl, where the alkyl radicals can be substituted one or more times by fluorine, phenyl, benzyl;
and their pharmaceutically acceptable salts. 3. Compounds of formula I, according to claim 1 or 2, characterized in that mean
G
K -OR (7), -NR (7) R (8), -HN-CH ₂ -CH ₂ -CO ₂ H, -HN-CH ₂ -CH ₂ -SO ₃ H, -NH- CH ₂ -CO ₂ H, -N (CH ₃ ) CH ₂ CO ₂ H, -OKa, where Ka is a cation, such as. B. an alkali or alkaline earth metal ion or a quaternary ammonium ion;
R (7), R (8) independently of one another are hydrogen, (C ₁ -C ₄ ) -alkyl, phenyl or benzyl, where the phenyl nucleus can be substituted up to 3 times with F, Cl, CF ₃ , methyl, methoxy;
R (1) hydrogen, -OH;
L (C ₁ -C ₅ ) alkyl, where one or more CH ₂ units are replaced by -CH = CH-, -C∼C-, -NR (11) -, -CO-, -O- or -SO ₂ - can be replaced;
R (11) hydrogen, (C ₁ -C ₄ ) alkyl, R (12) -CO-, phenyl, benzyl;
R (12) is hydrogen, (C ₁ -C ₄ ) -alkyl, phenyl and benzyl, where the phenyl nucleus can be substituted up to 3 times with F, Cl, CF ₃ , methyl, methoxy;
P
R (16) to R (24) independently of one another are hydrogen, F, Cl, (C ₁ -C ₄ ) -alkyl, where the alkyl radicals can be substituted one or more times with fluorine, NR (25) R (26), OR (25), OCOR (25), COR (25), COOR (25), CONR (25) R (26), where always one of the radicals R (16) to R (24) has the meaning of a bond to L;
R (25), R (26) independently of one another are hydrogen, (C ₁ -C ₄ ) -alkyl, where the alkyl radicals can be substituted one or more times by fluorine, phenyl and benzyl;
and their pharmaceutically acceptable salts. 4. Compounds of formula I, according to one or more of claims 1 to 3, characterized in that mean
G
R (1) hydrogen, -OH;
L (C ₁ -C ₅ ) alkyl, where one or more CH ₂ units are replaced by -CH = CH-, -C∼C-, -NR (11) -, -CO-, -O- or -SO ₂ - can be replaced;
P
where means
R (16) to R (24) independently of one another are hydrogen, F, Cl, (C ₁ -C ₄ ) -alkyl, where the alkyl radicals can be substituted one or more times with fluorine, NR (25) R (26), OR (25), OCOR (25), COR (25), COOR (25), CONR (25) R (26), where always one of the radicals R (16) to R (24) has the meaning of a bond to L;
R (25), R (26) independently of one another are hydrogen, (C ₁ -C ₄ ) -alkyl, where the alkyl radicals can be substituted one or more times by fluorine, phenyl and benzyl;
and their pharmaceutically acceptable salts. 5. Medicament containing one or more of the compounds according to one or more of claims 1 to 4. 6. Medicament containing one or more of the compounds according to one or more of claims 1 to 4 and one or more lipid-lowering Active ingredients. 7. A method for producing a medicament containing one or more of the compounds according to one or more of claims 1 to 4, characterized characterized in that the active ingredient with a pharmaceutically acceptable carrier is mixed and this mixture into a form suitable for administration brought. 8. Use of the compounds according to one or more of the claims 1 to 4 for the manufacture of a drug. 9. Use of the compounds according to one or more of the claims 1 to 4 for the manufacture of a medicament for the prophylaxis or treatment of Gallstones. 10. A process for the preparation of the compounds according to one or more of claims 1 to 4, characterized in that one according to the following formula
a compound of formula IId, in which K, R (1) and R (3) to R (6) have the meanings given for formula I, with a compound PX of formula IIId, in which P has the meaning given for formula I, for Brings reaction.