United with bile acids derivatives propanolamine, drug

 

(57) Abstract:

The invention relates to substituted derivatives of propanolamine with bile acids of formula I and their pharmaceutically acceptable salts and physiologically functional derivatives, where GS is a group of the bile acid of the formula II, R1connection with X, HE, R2connection with X, HE, -O-(C1-C6)alkyl, -NH-(C2-C6)-alkyl-SO3N, -NH-(C1-C6)-alkyl-COOH, R1and R2at the same time does not mean the relationship with X, X -

l,m, n- 0,1; L - (C1-C6)-alkyl, AA1, AA2independently amino acid residue, may be one - or multi-substituted amino group. The compounds I are suitable as lipid. 2 N. and 7 C.p. f-crystals, 1 PL.

I

2. Ingibirovaniya the invention relates to substituted derivatives of propanolamine and their pharmaceutically acceptable salts and physiologically functional derivatives.

Already described several classes of biologically active substances for the treatment of obesity (diseases Dercum) and disorders of lipid metabolism:

polymeric adsorbents, such as, for example, cholestyramine,

- benzothiazepine (WO 93 is nowych acids (EP 0557879).

The task of the invention are compounds exhibiting therapeutically applicable lipid-lowering (lowering lipids in the blood) effect.

Thus, this invention relates to compounds of the formula I

where GS denotes a group of the bile acid formula

R1indicates communication with X, HE;

R2indicates communication with X, HE, O-(C1-C6)-alkyl, NH-(C2-C6)-alkyl-SO3H, N(CH3)-CH2-CH2-SO3H, NH(C1-C6)-alkyl-COOH, N (CH3)-(C1-C6)-alkyl-COOH;

provided that R1and R2not simultaneously have the following value

R1the relationship with X and

R2the relationship with X;

R3, R4denote independently from each other H, HE;

X denotes

or communication;

1, n, m independently from each other 0 or 1;

L represents (C1-C6)-alkyl, phenyl;

AA1, AA2independently of one another denote an amino acid residue or amino acid residue, which one - or multi-substituted aminoadenine group;

and their pharmaceutically in formula I, in which one or more residues have the following meaning:

GS denotes a group of the bile acid formula

R denotes a relation with X, HE;

R2indicates communication with X, HE, O-(C1-C6)-alkyl, NH-(C2-C6)- alkyl-SO3H, N(CH3)-CH2-CH2-SO3H, NH(C1-C6)-alkyl-COOH, N(CH3)-(C1-C6)-alkyl-COOH;

provided that R1and R2not simultaneously have the following value

R1the relationship with X and

R2the relationship with X;

X denotes

or communication;

1, m, n independently from each other 0 or 1;

L represents (C1-C6)-alkyl, phenyl;

AA1, AA2independently of one another denote an amino acid residue or amino acid residue, which one - or multi-substituted aminoadenine group;

and their pharmaceutically acceptable salts and physiologically functional derivatives.

Especially preferred are the compounds of formula 1, in which one or more residues have the following meaning:

GS denotes a group of the bile acid formula

provided that R1and R2not simultaneously have the following value

R1the relationship with X and

R2the relationship with X;

X denotes

or communication;

1, m, n independently from each other 0 or 1;

L represents (C1-C6)-alkyl;

AA1, AA2independently of one another denote an amino acid residue or amino acid residue, which one - or multi-substituted aminoadenine group;

and their pharmaceutically acceptable salts.

The term "alkyl" mean a linear or branched hydrocarbon chain.

Under amino acid" or "amino acid residues" mean stereoisomeric forms, i.e., D - or L-forms of the following compounds:

Abbreviations of the amino acids used according to the conventional method of notation (cf. Schroder, Lubke, The Peptides, Band I, New York 1965, Seiten XXII-XXIII; Houben-Weyl, Methods der Organischen Chemie, Band XV/1 und 2, Stuttgart 1974). Amino acid (D-Asp denotes the D-form of aspartic acid. Peptides are by their chemical nature of the inorganic salts of acids and hydrolysis rosegallery can be protected functional groups of the side chains of amino acid residues (see, for example, T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 2ndEdition, John Wiley and Sons, New York 1991). Preferred aminosidine groups are tertbutyloxycarbonyl (BOC), 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Z), 2-(3,5-acid)prop-2-yloxy-carbonyl (Ddz), methyl, tert-butyl, trityl, S-tert-butyl, tert-butylaminoethyl.

This invention relates further to methods of preparing compounds of formula 1, which are distinguished by the following reaction schemes (Schemes 1-4):

Compounds of type IV receive, exposing the o-, m - or p-substituted imine type II reaction with the ketone III. This reaction can be performed, for example, by mixing both compounds, without solvent and subsequent heating, or in a suitable solvent, such as ethanol, tetrahydrofuran (THF), toluene, diglyme or tetradecane, at temperatures from 20C to 150C.

Catasetinae type IV restore in a suitable solvent, such as, for example, methanol, THF or THF/water using NaBH4or other suitable reducing agent at temperatures between-30C and +40C to hydroxycodone type V. If the restore as the main reaction products are formed in most cases a mixture of two isomers (ramaya on silica gel. The nitro-group in compounds of type V can be recovered by known methods such as, for example, catalytic hydrogenation with Pd or Pd on coal and H2in methanol.

Thus obtained racemic compounds of type VI can be further separated into their enantiomers. The separation of racemates VI on the enantiomers of type VII can be carried out by chromatography over chiral column material or by using known literature methods with optically active auxiliary reagents (cf. J. Org. Chem. 44, 1979, 4891).

According to the scheme 2 aromatic amines of type VI or VII (a racemate or a pure enantiomer) can be converted to amino acid by known standard method combination of peptides derived VIII. As this method is suitable, for example, the combination of TOTU and triethylamine in DMF (see literature: G. Breipohl, W. Konig EP 0460446; W. Konig, G. Breipohl, P. Pokorny, M. Birkner in E. Girat and D. Andreu (Eds.) Peptides 1990, Escom, Leiden, 1991, 143-145). Remnants AA1and AA2have given for the formula I is. The amino group of amino acids provide a protective group, such as Fmoc, the carboxyl group is unprotected.

The amino acids with functional groups in the side chain, these groups avslag according to the invention.

To obtain the derivative VIII, the protective group of amino group otscheplaut, for example, in the case of Fmoc in a mixture of DMF and piperidine. Get dipeptide conjugates IX, if proceeding from compounds of type VIII repeat the sequence of reactions (a) combination of amino acids, (b) removal of the protective group.

Derivatives of bile acids of type X can be obtained from the esters of 3-aminoalkanoic acid by binding with alkyl or arylcarbamoyl acids or their derivatives, such as, for example, succinic anhydride, according to the known methods (for example, EP 0614908, EP 0489423). These compounds (X) is subjected to reaction with amino compounds of type VI, VII, VIII or IX according to the standard method combination of peptides. After the reaction combinations by saponification alkilani broadcasting group, part of the bile acids get connection type XI.

The amino compounds of type VI, VII, VIII or XI can be subjected to reaction with a carboxyl group of bile acids. It also finds application known method of combination of peptides, for example, of combination reaction in the presence of TOTU and triethylamine or dicyclohexylcarbodiimide, hydroxybenzotriazole and triethylamine in THF. According to these methods can be polycaste compared to the original or basic compounds are particularly suitable for medical applications. These salts must contain a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable additive salts of acid compounds of this invention are salts of inorganic acids such as hydrochloric acid, Hydrobromic acid, phosphoric, metaphosphoric, nitric, sulfonic, and sulfuric acids, and organic acids, such as, for example, acetic acid, benzolsulfonat, benzoic, citric, econsultancy, fumaric, gluconic, glycolic, sotynova, lactic, lactobionic, maleic, malic, methansulfonate, succinic, p-toluensulfonate, wine and triperoxonane acid. For medical purposes especially preferably used chloride salt. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), and salts of alkaline-earth metals (such as magnesium salts and calcium).

Salts with a pharmaceutically unacceptable anion is also included in the scope of this invention as useful intermediates for obtaining or purification of pharmaceutically acceptable salts and/or for use in non-therapeutic, for example, in in vitro applications.

iamlive derived compounds according to the invention of the formula I, for example ether, which when administered to a mammal, such as, for example, a person that (directly or indirectly) to form a compound of formula I or one of its active metabolites.

To physiologically functional derivatives are also prodrugs of the compounds of the present invention. Such prodrugs can be metabolised in vivo to the compounds of this invention. These prodrugs may themselves be or may not be active.

Compounds according to this invention may also exist in different polymorphic forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of this invention are included in the scope of this invention and are subject invention.

Hereinafter all references to "compound (compounds) according to the formula (I)" refers to the compound (compounds) of the formula (I) described above, and their salts, solvate and described physiologically functional derivatives.

The amount of the compounds of formula (I), which is required to achieve the desired biological effect depends on a number of factors, such as the selected specific connections, the estimated applied is about 100 mg (typically from 3 mg to 50 mg) per day per kilogram of body weight, for example 3-10 mg/kg/day. Intravenous dose is, for example, in the range from 0.3 mg to 1.0 mg/kg/day, which is appropriately in the form of infusion may be given from 10 ng to 100 ng per kilogram per minute. Suitable infusion solutions for these purposes may, for example, contain from 0.1 ng to 10 mg, typically from 1 ng to 10 mg per milliliter. Single dose can, for example, contain from 1 mg to 10 mg of active substance. Thus, ampoules for injection may contain, for example, from 1 mg to 100 mg, and oral input single ready-to-eat form, such as, for example, tablets or capsules may contain from 1.0 to 1000 mg, typically from 10 to 600 mg. In the case of pharmaceutically acceptable salts of the above weight data relate to the weight benzodiazepinovyh ion salts. For the prevention or therapy of the abovementioned conditions, the compounds of formula (I) can be used as individual compounds, but preferably they are acceptable carrier in the form of pharmaceutical compositions. The media, of course, must be acceptable, in the sense that it is compatible with other components of the composition and is not harmful to the health of patients. The carrier may be solid or liquid or both, and his goth 0.05% to 95% of active substance. Can also present additional pharmaceutically active substances, including additional compounds of formula (I). The pharmaceutical compositions according to this invention can be prepared in accordance with known pharmaceutical methods, which essentially consist in the fact that the components are mixed with pharmacologically acceptable carriers and/or auxiliary substances (additives).

The pharmaceutical compositions according to this invention are those compositions which are suitable for oral administration, rectal, local, peroral (for example sublingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable route of administration in each individual case depends on the type and severity of the subject to treatment status and the type are applied in each case the compounds of formula (I). In the scope of this invention are also prepared in the form of pills and repository shaped in the form of pellets (form slow-release depot-forms). The preferred forms are resistant to acids and gastric juices. Suitable resistant to gastric juice coating including the polymers of methacrylic acid and of methyl methacrylate and methacrylic acid.

Suitable pharmaceutical compounds for oral administration can be in the form of separate units such as, for example, capsules, capsules with wafers, tablets for sucking or tablets, which in each case contain a certain amount of the compounds of formula (I); as powders or granules; as solution or suspension in an aqueous or nonaqueous liquid; or as an emulsion of the type oil-in-water or water in oil. These compositions can be prepared, as mentioned above, in accordance with any suitable pharmaceutical method which includes a stage in which the active substance and the carrier (which may consist of one or more additional components) is brought into contact. In General, these compositions are prepared by uniform and homogeneous mixing of the active substance with a liquid and/or finely divided solid carrier, after which the product, if necessary, is formed. For example, a tablet may be made by compressing or molding a powder or granules of the compound, if necessary with one or more additional components. Molded tablets may be made by tabletting connection is wasysym, a softening agent, an inert diluent and/or one or more surface-active / dispersing agents, in a suitable apparatus. Molded tablets may be made by molding powdered hydrated inert liquid diluent compounds in a suitable apparatus.

Pharmaceutical compositions suitable for peroral (sublingual) administration include tablets for sucking, which contain the compound of formula (I) with a flavoring substance, normally sucrose and gum Arabic or Trianta, and lozenges, which contain the compound in an inert basis such as gelatin and glycerol or sucrose and gum Arabic.

Suitable pharmaceutical compositions for parenteral administration include preferably sterile aqueous compositions of the compounds of formula (I), which are preferably isotonic with the blood of the intended recipient. These compositions are preferably administered intravenously, although administration can also be carried out subcutaneously, intramuscularly or intradermally in the form of injections. These compositions can be preferably prepared by mixing the compound with water and sterilizing the resulting solution and giving him Sudanese.

Suitable pharmaceutical compositions for rectal injection preferably prepared in the form of candles with a single dose. They can be prepared by mixing the compounds of formula (I) with one or more conventional solid carriers, for example cocoa butter, and placing the resulting mixture in the form.

Suitable pharmaceutical compositions for local application on the skin exist in the form of ointment, cream, lotion, paste, spray, aerosol or oil. As the carrier can be used vaseline, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. The active ingredient is typically present in a concentration of from 0.1 to 15 wt.% composition, for example from 0.5 to 2%.

Possible is also the percutaneous introduction. Suitable pharmaceutical compositions for percutaneous applications can be separate patches that are suitable for prolonged close contact with the epidermis of the patient. These patches contain the active substance in buffered, if necessary, an aqueous solution, dissolved and/or dispersed in increasing the adhesion of the tool or dispersed in the polymer. A suitable concentration of the active substance composition is about, as, for example, described in Pharmaceutical Research, 2(6):318 (1986), may be released by electrotransport or iontophoresis.

This invention relates to compounds of formula I in the form of their racemates, racemic mixtures and pure enantiomers, their diastereomers and mixtures thereof.

The compounds of formula I and their pharmaceutically acceptable salts and physiologically functional derivatives differ favorable effect on lipid metabolism. These compounds can be used alone or in combination with additional active substances which lower the content of lipids in the blood. These compounds are suitable for the prophylaxis and, in particular, for treating disorders of lipid metabolism, in particular hyperlipidemia. The compounds of formula I are also suitable for impact on cholesterol levels in serum, as well as for the prevention and treatment arteriosclerotic phenomena.

These data confirm the pharmacological effectiveness described in this invention compounds.

Biological testing of the compounds of this invention was performed by examining the inhibition of the absorption of3H]-taurocholate in membrane vesicles brush kinnah vesicles to the brush border of the iliac glands of the rabbit.

Receipt of membrane vesicles to the brush border of intestinal cells of the small intestine was performed using the so-called method MD2+-precipitation. Male new Zealand rabbits (body weight 2-2 .5 kg) were killed by intravenous injection of 0.5 ml Kzt61®, an aqueous solution of 2.5 mg tetracaine-HCl, 100 mg embutramide and 25 mg mebezonium. The small intestine was removed and washed with chilled on ice physiological common salt solution. End 7/10 small intestine (measured in oral-rectal direction, i.e., terminal ileum, which contains active PA+-dependent transport of bile acids) was used to obtain the membrane of the brush border vesicles. Intestines were frozen in plastic bags under nitrogen at-80C. To obtain membrane vesicles frozen intestines were thawed at 30 ° C in a water bath. The mucosa was scraped and suspended in 60 ml ice mixture 12 mm Tris/Hcl-buffer (pH 7,1)/300 mm mannitol, 5 mm EGTA/10 mg/l phenylmethylsulfonyl/1 mg/l of trypsin inhibitor derived from soy (32 U/mg)/0.5 mg/l of trypsin inhibitor obtained from bovine lung (193 U/mg) 5 mg/l bacitracin. After dilution to 300 ml chilled on ice, distilled water, homogenizing the addition of 3 ml of 1 M solution MDS2(final concentration 10 mm) was kept exactly 1 minute at 0C. By adding MD2+the cell membrane was aggregated and precipitated with the exception of the brush border membranes. After a 15-minute centrifugation at 3000g (5000 rpm, rotor SS-34) the precipitate was discarded and the supernatant, which contains the brush border membrane, centrifuged for 30 minutes at 48000g (20000 rpm, rotor SS-34). The supernatant was discarded, the precipitate re-homogenized in 60 ml of a mixture of 12 mm Tris/model HC1 buffer (pH 7,1)/60 mm mannitol, 5 mm EGTA using a homogenizer Potter Elvejhem (Braun, Melsungen, 900 rpm, 10 cycles). After adding 0.1 ml of a solution of MgCl2and a 15-minute incubation period at 0C centrifuged for 15 minutes at 3000g. The supernatant was centrifuged again for 30 minutes at 48000g (20000 rpm, rotor SS-34). The precipitate was placed in 30 ml of a mixture of 10 mm Tris/s buffer (pH 7.4)/300 mm mannitol and re-homogeneous suspended by 20 cycles in the homogenizer Potter Elvejhem at 1000 Rev/min After 30 minutes centrifugation at 48000g (20000 rpm, rotor SS-34) the sediment was placed in 0/5-2 ml of a mixture of Tris/s buffer (pH 7.4)/280 mm mannitol (final concentration 20 mg/ml) and resuspendable using a tuberculin syringe with needle 27 Gauge. Vesicles or used C is E.

2. Inhibition of uptake of [3N]-taurocholate in membrane vesicles to the brush border of the ileum.

The absorption of the substrates in the above-described membrane of the brush border vesicles was determined using the so-called method of membrane filtration. 10 μl of the suspension of vesicles (100 μg protein) was pietravalle in the form of droplets on the wall of polystyrene incubation tubes (1170 mm), which contained the incubation medium with the appropriate ligands (90 μl). This incubation medium contains 0.75 ál=0,75 µci of [3H(G)]-taurocholate (specific activity: 2,1 CI/mmol)/0,5 ál of 10 mm taurocholate/8,75 ál buffer for transport of sodium (10 mm Tris/Hepes (pH 7.4)/100 mm mannitol/100 mm NaCl (Na-T-B) or is 8.75 μl of buffer for transport of potassium (10 mm Tris/Hepes (pH 7.4)/100 mm mannitol/100 mm KCl) (K-T-B) and 80 μl of a solution of the corresponding inhibitor, depending on the experiment, dissolved in Na-T-buffer or K-T-buffer. This incubation medium was filtered through a PVDF membrane filter (SYHV LO 4NS, 0.45 μm, 4 mm diameter, Millipore, Eschborn/ Germany). By mixing vesicles with the incubation medium was started measuring transport. Concentration taurocholate in the initial incubation mixture was 50 μm. After gelatelno the target (10 mm Tris/Hepes (pH 7.4)/150 mm KCl). The resulting mixture was immediately sucked out under vacuum 25-35 mbar through a membrane filter of cellulose nitrate (ME 25, 0.45 μm, 25 mm diameter, Schleicher (Schuell, Dassel, Germany). The filter was washed in 5 ml ice stop solution.

To measure the uptake of radioactively labeled taurocholate this membrane filter suspended with 4 ml of scintillator Quickszint 361 (Zinsser Analytik GmbH, Frankfurt, Deutschland) and radioactivity was measured in a measuring device TriCarb 2500 (Canberra Packard GmbH, Frankfurt, Deutschland). Measured values after calibration with standard samples and after adjusting for possible present chemiluminescence was received in the form of u/min (disintegrations per minute).

The benchmarks were determined in each case in Na-T-B and T-B. the difference between the absorption in the Na-T-B and K-T-B gave Na+-sensitive traffic. The concentration of inhibitor at which PA+-dependent share of transport inhibited by 50% over the control, denoted as IC50Na+.

Pharmacological data includes a series of tests, which examined the interaction of the compounds of this invention with intestinal transport of bile acids in the terminal small intestine. The results privatenet in membrane vesicles to the brush border of the ileum of rabbits. Given the relationship IC50Na-indicators of comparative substances in the form of taurochenodeoxycholate (TCDC) and the test in each case the matter.

The following examples in more detail to explain the invention without limiting the invention described in these examples, the products and options for implementation.

Example 1

A.

To 50 g (0.54 mol) of picoline in 770 ml of tetrahydrofuran was added dropwise at-55C 366 ml of 15% n-utility in n-hexane. Was heated to room temperature and again cooled to-55C. Was slowly added dropwise 77 g of N,N-dimethylbenzamide (0.52 mol) in 570 ml of tetrahydrofuran, and then heated to room temperature and stirred for 1 hour. After you add 550 ml of 1 N. hydrochloric acid were extracted with ethyl acetate (3x), the organic phase was dried MgSO4, and was evaporated. By distillation of the residue was obtained and 47.5 g (47%) of product. Boiling point 134-S/0,28 mbar.

b.

to 20.0 g (0.13 mol) b-nitrobenzaldehyde, 12.5 g (0.13 mol) of 2-aminopyridine and 0.3 g of p-toluensulfonate acid in 150 ml of toluene was heated for 2.5 hours under reflux. The solution was cooled, the resulting precipitate was aspirated and dried.

C.

12.0 g (61 mmol) of ketone from example la and 15.0 g (66 mmol) of imine of example 1b was heated for 45 minutes on the steam bath. The reaction mixture was dissolved in ethanol by heating. After cooling, the precipitate was aspirated and recrystallized from ethanol.

Yield: 11.8 g (46%) of the product

C25H20N403(424,2) MS (FAB) 425 M+H+

d.

8.0 g (18,8 mmol) catasetinae from example 1C was dissolved in 300 ml of a mixture of tetrahydrofuran/water 10:1, connected with of 4.67 g of sodium borohydride and stirred at room temperature for 2 hours. Then, the solution was evaporated, the residue was combined with 100 ml of 2 N. hydrochloric acid and heated on the steam bath until complete dissolution. After cooling, brought to pH 4 N. NaOH solution and was extracted with ethyl acetate (2x). The organic phase was dried MgSO4and was evaporated. The residue was chromatographically on silica gel (heptane/ethyl acetate 1:1). Received two racemic compounds in the quality of the product.

1st fraction: 3,9 g (48%) nonpolar racemate (example 1 (d/1)

WITH25H22N403(TO 426.2) MS (FAB) 427 M+N+

2nd fraction: 2.5 g (31%) of the polar racemate (example 1 (d/2)

2at room temperature. The catalyst was filtered and the solution was evaporated. The residue was chromatographically through silica gel (n-heptane/ethyl acetate 7:13).

Output: 1/9 g (82%) of product

WITH25H24N40 (396,22) MS (FAB) 397 M+N+

f.

(+)-enantiomer (example 1 (f/2)

100 mg of the racemic compound of example 1E was separated using preparative WIH the enantiomers. Separation was carried out using CSP column-Chiralpak (Fa. Daicel, Dusseldorf) with a mixture n/a hexane/ethanol 4:1.

As the first fraction was obtained 40 mg (-)-enantiomer (example 1 f/1), as the 2nd fraction was obtained 40 mg (+)-enantiomer (example 1 (f/2).

g.

4.0 g (10.1 mmol) of the amino compounds from example 1E (nonpolar racemate), 4,85 g (10.3 mmol) of N-Fmoc-D-Lys(BOC)HE 4/0 g (12.2 mmol) of TOTU and 2.7 ml of triethylamine were dissolved in 300 ml of dimethylformamide and stirred for 2 hours at room temperature. The reaction mixture was poured into water and was extracted with ethyl acetate (2x). The organic phase was dried (gS4) and was evaporated. The residue was dissolved in 150 ml of a mixture of dimethylformamide/piperidine 2:1 for removal of Fmoc group and paramashiva the s phase was dried (MgSO4) and was evaporated. Chromatography on silica gel (dichloromethane/methanol 9:1) were obtained 4.0 g (63,5%) of product.

C36H44N604(624,3) MS (FAB) 625 M+N+

h.

5.0 g (up 11,86 mmol) methyl ester 3-aminobolic acid (European patent application EP 0614908), 1.3 g (13 mmol) of succinic anhydride and 16.5 ml of triethylamine was dissolved in 75 ml of tetrahydrofuran and stirred for 1 hour at room temperature. The solution was evaporated. The residue was dissolved in water, acidified with hydrochloric acid, was extracted with ethyl acetate (3x).

The organic phase was dried (MgSO4) and was evaporated.

Yield: 5.8 g (94%)

C29H47NO7(521,3) MS (FAB) 528 M+Li+.

i.

4.0 g (6.4 mmol) of the compound from example 1g, of 3.45 g (6.6 mmol) derived bile acid from example 1h, 1.2 ml of triethylamine, 2.16 g (16 mmol) of hydroxybenzotriazole and 2,56 g dicyclohexylcarbodiimide (12.4 mmol) was dissolved in 250 ml of tetrahydrofuran and 5 hours was stirred at room temperature. The mixture was evaporated, the residue was dissolved in ethyl acetate and washed with a solution Panso3. The organic phase was dried (gS4) and was evaporated. Chromatography on silica gel (dichloromethane/methanol 19:1 then 9:1) recip="ptx2">

3.1 g (a 2.75 mmol) of the methyl ester from example li was dissolved in 200 ml of ethanol was combined with 31 ml of 1 n NaOH solution and stirred for 5 hours at room temperature. The mixture was evaporated, the residue was dissolved in water and connected with a saturated solution of NaH2PO4. Were extracted with ethyl acetate (2x), the organic phase was dried over MgSO4and was evaporated. The crude product was chromatographically on silica gel (dichloromethane/methanol 4:1).

Yield: 2.25 g (73%)

C64H87N7O10(1113,7) MS (FAB) 1120,7 M+Li+

k.

1.5 g (1.35 mmol) of the compound from example lj and 0.81 ml of triethylamine were combined at 0C with of 0.48 ml of ethyl ether chloro-formic acid and was stirred for 10 minutes. After this was added 0.6 g of taurine dissolved in 30 ml of 0.1 n NaOH solution, and was stirred for 24 hours at room temperature. The mixture was evaporated, the residue was dissolved in a small amount of water and poured in a saturated solution of Na2HPO4. This mixture was extracted with ethyl acetate (3x), the organic phase was dried MgSO4and was evaporated. After chromatography on silica gel (dichloromethane/methanol 4:1, then methanol) received 0,98 g (60%) of the taurine conjugate.

WITH66H92N4and was evaporated. After chromatography on silica gel (ethyl acetate/n-heptane 7:3) was received of 3.85 g (85%) of product.

This Fmo-protected intermediate product (3.6 g) was dissolved in 110 ml of a mixture of piperidine/DMF 1:10 and was stirred for 1 hour at room temperature. The mixture was evaporated and chromatographically on silica gel (dichloromethane/methanol 19:1 then 9:1).

Yield: 1.8 g (72/5%)

WITH30H31N502(493,2) MS (FAB) 494 M+H+

b.

1.7 g (3,44 mmol) of the compound from example 2A was mixed with 1.4 g (3.61 mmol) Finoc-L-phenylalanine, 1.9 grams (5,80 mmol) of TOTU and 1.0 ml of triethylamine in 150 ml of DMF for 4 hours at room temperature. The reaction mixture was evaporated and the residue was chromatographically on silica gel (ethyl acetate/n-heptane 4:1). Received two fractions:

1st fraction: 1.28 g (43%) non-polar diastereoisomer (example 1 b/1)

WITH54H50N6ABOUT5(862,4) MS (FAB) 863,4 M+N+

2nd fraction: 0 +

C.

0.8 g (0,93 mmol) of the compound from example 2 (b/2 was dissolved in 33 ml of a mixture of DMF/piperidine 10:1 and stirred for 1 hour at room temperature. After evaporation the residue was chromatographically on silica gel (dichloromethane/methanol 19:1 then 9:1).

Yield: 0.35 g (59%)

WITH39H40N6ABOUT3(640,3) MS (FAB) 641,3 M+H+

d.

0.5 g (0.78 mmol) of the compound from example 2C, 0.45 g (0.86 mmol) derived bile acids from the sample lh was subjected to reaction as described in example li. Received 0,38 g (43%) of product.

WITH68H85N7ABOUT9(1143,6) MS (FAB) 1144,6 M+N+

E.

0.31 g (0.27 mmol) of the methyl ester from example 1d was dissolved in 30 ml of ethanol was combined with 3.0 ml of 1 n NaOH solution and stirred 12 hours at room temperature. The reaction mixture was evaporated, and the residue was chromatographically on silica gel (dichloromethane/methanol 4:1).

Yield: 220 mg (72%)

C67H83N7O9 (1129,6) MS (FAB) 1130,6 M+H+

Example 3

0.3 g (0.78 mmol) of 3-(4-AMINOPHENYL)-1-phenyl-2-pyridin-2-yl-3-(pyridine-2-ylamino)propan-1-ol (receipt similar to the example le), 0.34 g (0.83 mmol) of waterline was stirred in 50 ml of tetrahydrofuran for 2 days at room temperature. After completion of the reaction, the solids were filtered off. The solution was evaporated, and the residue was chromatographically on silica gel (dichloromethane/methanol 9:1 and 17:3). Was obtained 0.33 g (55%) of product.

C49H62N4O5(786,5) MS (FAB) 787,5 M+H+

Using appropriate starting compounds similar to examples 1-3 were given examples 4-14.

Example 4

C49H62N4O5(787,1) MS (FAB) 788,1 M+H+

Example 5 (non-polar diastereoisomer)

C53H67N5O7(886,2) MS (FAB) 887,2 M+H+

Example 6

C54H69N5O7(900,2) MS (FAB) 901,2 M+H+

Example 7 (polar diastereoisomer)

C53H67N5O7(886,2) MS (FAB) 887,2 M+H+

Example 8

C53H67N5O7(886,2) MS (FAB) 887,2 M+H+

Example 9

C60H81N7O8(1028,4) MS (FAB) 1029,4 M+H+

Example 10

C59H79N7O8(1014,3) MS (FAB) 1015,3 M+H+

Example 11

C67H83N7O9(1130,5) MS (FAB) 103+

Example 13

C68H85N7O9(1144,5) MS (FAB) 1145,5 M+H+

Example 14

C66H90N8O11(1171,5) MS (FAB) 1172,5 M+H+.

1. The compounds of formula I

where GS denotes a group of the bile acid formula

R1indicates communication with X, HE;

R2indicates communication with X, HE, O-(C1-C6)-alkyl, NH-(C2-C6)-alkyl-SO3N, NH-(C1-C6)-alkyl-COOH;

provided that R1and R2not simultaneously have the following meanings: R1the relationship with X and R2the relationship with X;

X denotes

or communication;

l, m, n independently of one another denote 0 or 1;

L represents (C1-C6)-alkyl;

AA1, AA2independently of one another denote an amino acid residue or amino acid residue, which one - or multi-substituted aminoadenine group, and their pharmaceutically acceptable salts.

2. Drug containing one or more compounds on p. 1 for the prevention or treatment of lipid disorders, hyperlipidemia, or arterio will win one or more active substances, reduces the content of lipids in the blood.

4. Connection on p. 1 as a drug for prevention or treatment of lipid metabolism disorders.

5. Connection on p. 1 as a drug for the treatment of hyperlipidemia.

6. Connection on p. 1 as a drug for prevention or treatment arteriosclerotic phenomena.

7. Drug under item 3 as a means for prevention or treatment of lipid metabolism disorders.

8. Drug under item 3 as a means for the treatment of hyperlipidemia.

9. Drug under item 3 as a means for prevention or treatment arteriosclerotic phenomena.

 

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