Substituted bile acids phenylalaninamide, drug

 

(57) Abstract:

The invention relates to substituted phenylalkylamines, their pharmaceutically acceptable salts and physiologically functional derivatives. The described compounds of formula Ia

where T1 and T2 independently

and T1 and T2 simultaneously cannot be N

L-z means

L-CC-, -NH-CH2-CH2-O-; R(E) - H, (C1-C4)alkyl, R(1), R(2) - H, F, Cl, CN, -SO2-CH3, (C1-C4)alkyl, -O-(C1-C4)alkyl, and their physiologically acceptable salts, physiologically functional derivatives and the way they are received. These compounds are suitable, for example, as pharmaceuticals for the prevention or treatment of gallstones. 2 S. and 2 C.p. f-crystals.

This invention relates to substituted phenylalkylamines and their pharmaceutically acceptable salts and physiologically functional derivatives.

The formation of bile concrements) is determined, along with a number of factors, essentially the composition of bile, in particular the concentration and ratio of cholesterol, phospholipids and bile salts. A prerequisite for the formation of try of cholesterol in bile. Relationship to gallstone formation and dissolution in man. J. Clin. Invest., 61:998-1026).

Gallstones are still mostly removed surgically, so there is a great therapeutic need in the medical dissolution of gallstones and in the prevention of gallstone formation.

The task of the invention are compounds that can prevent the formation of gallstones, preventing saturation of bile with cholesterol or slowing the formation of cholesterol crystals from supersaturated bile.

Thus, the invention relates to compounds of the formula I

where T1 and T2 independently represent

or hydrogen, and T1 and T2 cannot simultaneously be hydrogen;

z denotes

R(A) R(B) R(C) R(D) independently denote hydrogen, F, Cl, Br, I, CN, OH, NH2, -(C1-C8) alkyl, -O-(C1-C8) alkyl, where the alkyl residues can be single or multi-substituted by F, (C3-C8)cycloalkyl, phenyl, benzyl, other(7), NR(7)R(8), O-(C3-C6)alkenyl, O-(C3-C6) cycloalkyl, O-phenyl, O-benzyl, and phenyl nucleus may be substituted up to three times F, Cl, CF3, stands, methoxy, NR(9)R(10);

R shall be one or multi-substituted by F, (C3-C8) cycloalkyl, (C3-C6) alkenyl, (C3-C8) cycloalkyl, phenyl, benzyl, and phenyl nucleus may be substituted up to three times F, Cl, CF3, stands, methoxy, NR(9)R(10), or

R(7) R(8) together form a chain of 4 or 5 methylene groups, of which one CH2-group may be replaced by oxygen, sulfur, NH, N-CH3or N-benzyl;

R(9) R(10) independently of one another denote hydrogen, (C1-C4) alkyl, (C1-C4) perfluoroalkyl;

x is zero, 1 or 2;

y is zero, 1 or 2;

R(E) R(F) independently of one another denote hydrogen, F, Cl, Br, I, CN, (C1-C8) alkyl, (C1-C8) alkyl, where the alkyl residue may be single or multi-substituted by F, (C3-C8) cycloalkyl, O-(C3-C6) alkenyl, O-(C3-C8) cycloalkyl, O-phenyl, O-benzyl, and phenyl nucleus may be substituted up to three times F, Cl, CF3, stands, methoxy, NR(9)R(10);

R(1), R(2), R(3) independently of one another denote hydrogen, F, Cl, Br, I, CN, -(C1-C8) alkyl, -O-(C1-C8) alkyl, where the alkyl residues can be single - or multi-substituted by F, -(C=O)-N=C(NH2)2, -(SO0-2)-(C1-C8) Ala the RA can be substituted up to three times F, Cl, CF3, stands, methoxy, -(C0-C8) alkylene-NR(9)R(10);

L represents-O-, -NR(47)-, -(C1-C8) alkylene-, -(C1-C8)albaniles-, -(C1-C8)akinyan-, -COO-, -CO-NR(47)-, -SO2-NR(47)-, -O-(CH2)n-O-, -NR (47)-(CH2) n-O-, -NR(48)-CO-(CH2)n-O-, -CO-NR(48)-(CH2)n-O-, -O-CO-(CH2)n-O-, -SO2-NR (48) -(CH2)n-O-, -NR (48)-CO-CH2-CH2-CO-NR (48) -(CH2)n-O-, -NR (48) -CO-CH=CH-CO-NR (48)-(CH2)n-O-, -NR (48)-SO2-(CH2)n-O-;

R(47) denotes hydrogen, (C1-C8) alkyl, R(48)-CO-, phenyl, benzyl;

R(48) denotes hydrogen, (C1-C8) alkyl, phenyl and benzyl, with the phenyl nucleus may be substituted up to three times F, CL, CF3, stands, methoxy;

n is 1-8;

R(40)-R(45) independently of one another denote hydrogen, -OR(50), SR(50), other(50), -NR(50)2-O-(CO)-R(50), -S-(CO)-R(50), -NH-(CO)-R(50), -O-PO(OR(50))-OR(50), -O-(SO2)-OR(50), -R(50), the relationship with L or

R(40) R(41) R(42) R(43), R(44) and R(45) is formed in each case together with the oxygen of the carbonyl group, and there is always exactly one of the residues R(40)-R(45) indicates communication with L;

It means-OR(50), -other(50), -NR(50)2, -NH-CH2-CH2-CO2H-N-CH2-CH2-SO3N, -NH-CH2-COOH, -N (what does alkaline-earth metal or a Quaternary ammonium ion;

R(46) denotes hydrogen, C1-C4-alkyl, benzyl, -CH2HE, H3S2CH2- BUT2CLO2- BUT2CLO2CH2-;

R(50) denotes hydrogen, (C1-C4) alkyl, phenyl or benzyl, with the phenyl nucleus may be substituted up to three times F, CL, CF3, stands, methoxy;

and their pharmaceutically acceptable salts and physiologically functional derivatives.

Preferred are the compounds of formula I

where T1 and T2 independently represent

or hydrogen, and T1 and T2 cannot simultaneously be hydrogen;

L-z denotes

R(E) denotes hydrogen, F, Cl, CN, (C1-C4) alkyl, -O-(C1-C4) alkyl, and alkyl residues can be single - or multi-substituted by F, (C3-C6) cycloalkyl, (C3-C6)alkenyl, O-(C3-C6) cycloalkyl, O-phenyl, O-benzyl, and phenyl nucleus may be substituted up to three times F, Cl, CF3, stands, methoxy, NR(9)R(10);

R(9) R(10) independently of one another denote hydrogen, CH3, CF3;

R(1), R(2), R(3) independently of one another denote hydrogen, F, Cl, CN, -SO2-(C-NH2, -SO2-(C1-C4) alkyl, -(C1-C4) alkyl, -O-(C1-C4) alkyl, and alkyl residues can be single - or multi-substituted by F, -O-(C0-C4) alkalinity -(C0-C4) alkylester, and the phenyl nucleus can be substituted up to three times F, Cl, CF3, stands, methoxy;

L represents-O-, -NR(47)-, -(C1-C4) alkylene-, -(C1-C4)albaniles-,

-(C1-C4)akinyan-, -COO-, -CO-NR(47)-, -SO2-NR(47)-, -O-(CH2)n-O-, -NR (47)-(CH2)n-O-, -NR(48)-CO-(CH2)n-O-, -CO-NR(48)-(CH2)n-O-, -SO2-NR(48)-(CH2)n-O-;

R(47) denotes hydrogen, (C1-C4) alkyl, R(48)-CO-, phenyl, benzyl;

R(48) denotes hydrogen, (C1-C4) alkyl, phenyl and benzyl, with the phenyl nucleus may be substituted up to three times F, CL, CF3, stands, methoxy;

n is 1-4;

R(41) R(42), R(45) independently of one another denote hydrogen, -OR(50), other(50), -NR(50)2, -O-(CO)-R(50), -NH-(CO)-R(50);

R(50) denotes hydrogen, (C1-C4) alkyl, phenyl or benzyl, with the phenyl nucleus may be substituted up to three times F, C1, CF3, stands, methoxy;

It means-OR(50), -other(50), -NR(50)2, -NH-C IS, -Oka, and Ka denotes a cation, such as, for example, an ion of an alkaline or alkaline-earth metal or a Quaternary ammonium ion;

and their pharmaceutically acceptable salts and physiologically functional derivatives.

Especially preferred are the compounds of formula I

where T1 and T2 independently represent

or hydrogen, and T1 and T2 cannot simultaneously be hydrogen;

L-z denotes

R(E) denotes hydrogen, F, Cl, CN, (C1-C4) alkyl, -O-(C1-C4) alkyl, CF3, -F3;

R(1), R(2) independently of one another denote hydrogen, F, CL, CN, -SO2-CH3, SO2NH2, -(C1-C4) alkyl, -O-(C1-C4) alkyl, and alkyl residues can be single - or multi-substituted by F, -O-(C0-C4) alkalinity -(C0-C4) alkylester, and the phenyl nucleus can be substituted up to three times F, C1, CF3, stands, methoxy;

R(3) represents hydrogen;

L represents-O-, NR(47), -CH2-CH2- CH=CH-, -(SS)-, -COO -,- CO-NR(47), -SO2-NR(47)-, -O-(CH2)n-O-, -NR(47)-(CH2)n-O-, -NR(48)-CO-(CH2)n-O-, -CO-NR (48) -(CH2)n the sludge, benzyl;

R(48) denotes hydrogen, (C1-C4) alkyl, phenyl and benzyl, with the phenyl nucleus may be substituted up to three times F, C1, CF3, stands, methoxy;

n is 1-4;

R(41) denotes hydrogen, -HE;

It means-OR(50), -other(50), -NR(50)2, -NH-CH2-CH2-CO2H, -NH-CH2-CH2-SO3N, -NH-CH2-COOH, -N(CH3)CH2CO2N-Oka, and Ka denotes a cation, such as, for example, an ion of an alkaline or alkaline-earth metal or a Quaternary ammonium ion;

R(50) denotes hydrogen, (C1-C4) alkyl, phenyl or benzyl, with the phenyl nucleus may be substituted up to three times F, CL, CF3, stands, methoxy;

and their pharmaceutically acceptable salts.

Especially preferred are the compounds of formula I with the structure Ia

where T1 and T2 independently represent

or hydrogen, and T1 and T2 cannot simultaneously be hydrogen;

L-z denotes

L denotes-SS-, -NH-CH2-CH2-O-;

R(E) denotes hydrogen, (C1-C4) alkyl;

R(1), R(2) independently of one another denote hydrogen, F, C1, CN, -SO2-CH3that is about replaced by F;

and their pharmaceutically acceptable salts.

* Notes in the above formulas, the connection point T1 or T2 to the phenyl ring of formula I.

If the compounds of formula I contain one or more centers of asymmetry, they can be configured as S and R. These compounds can exist as optical isomers, diastereomers, racemates or mixtures thereof.

The geometry of the double bond of the compounds of this invention can be either E or Z. the Compounds can exist in mixture in the form of isomers on double bond.

The expression “alkyl residue may be single - or multi-substituted by F, is also perforated alkyl residues.

These alkyl residues may be the remnants of both the linear and branched chain.

Pharmaceutically acceptable salts on the basis of their higher solubility compared to the parent compounds or basic compounds are particularly suitable for medical purposes. These salts must be pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid additive salts of the compounds of this invention ablauts what I nitric, sulfonic, and sulfuric acids, and organic acids, such as, for example, acetic acid, benzolsulfonat acid, benzoic, citric, econsultancy, fumaric, gluconic, glycolic, setinova, lactic, lactobionic, maleic, malic, methansulfonate, succinic, p-toluensulfonate, wine and triperoxonane acid. For medical purposes especially preferred is a chlorine-containing salt. Suitable pharmaceutically acceptable basic additive 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).

Used herein, the term “physiologically functional derivative” refers to any physiologically tolerated derivative of a compound of this invention of formula I, for example an ester, 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 referred to as prodrugs of the considered compounds. Such prodrugs can be metabolised in vivo in seeding of the invention may also exist in different polymorphic forms, for example, in amorphous or crystalline polymorphic forms. All polymorphous forms of the compounds of this invention are included in the scope of the invention and constitute the object of the present invention.

In the further description, all references to "compound (compound in accordance with formula (I)" refers to the compound (compounds) of the formula (I) described above, and their salts, solvate and 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 specific compounds, intended use, method of administration and the clinical condition of patients.

In General, the daily dose is in the range from 0.1 to 100 mg (typically from 0.1 to 50 mg) per day per kilogram of body weight, such as 0.1-10 mg/kg per day. Tablets or capsules may contain, for example, from 0.01 to 100 mg, typically from 0.02 to 50 mg. In the case of pharmaceutically acceptable salts of the above weight data relate to the weight produced from salt ions aminopropanol. For the prevention or treatment of the aforementioned conditions the compounds of formula (I) can be applied individually in the form of connections, but predpochtitelen to 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 is prepared with the compound in the form of a single dose, for example, in the form of a tablet, which may contain from 0.05 to 95 wt.% the active substance. May be other pharmaceutically active substances, including additional compounds of formula (I). The pharmaceutical compositions of this invention can be prepared according to known pharmaceutical methods, which essentially consist in the fact that the components are mixed with pharmacologically acceptable carriers and auxiliary substances (additives).

Pharmaceutically acceptable compositions of the present invention is a composition suitable for oral administration through the mouth or oral (for example, sublingual) administration, although the most suitable route of administration in each individual case depend on the type and severity of the subject to treatment status and the type used in each case, the compounds of formula (I). Index composition and index form prolonged action are also in the frame of the top is going resistant to gastric juice coating include acetate-phthalate cellulose, the polyvinyl acetate-phthalate, hydroxypropylmethylcellulose and anionic polymers of methacrylic acid and methyl methacrylate.

Suitable pharmaceutical compounds for oral administration can be in the form of separate units such as, for example, capsules, capsules with wafers, sucking tablets or pills, which in each case contain a certain amount of the compounds of formula (I); as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquid or in the form of emulsions of the type oil-in-water" or type "water in oil". These compositions can be prepared, as already mentioned, according to any suitable pharmaceutical methods, which include the stage at which the active substance and the carrier (which may consist of one or more additional components) is brought into contact. In General, the compositions are prepared uniform and homogeneous mixing of the active substance with a liquid and/or finely divided solid carrier, after which the product, if required, is formed. For example, a tablet may be prepared by compressing or molding a powder or granulate, if necessary with one or more updat is but a fluid form, such as, for example, a powder or granules, if necessary mixed with a binder, a softening agent, an inert diluent and/or one (several) of surface-active substances suitable for tabletting machine. Molded tablets may be prepared by molding a powder, moistened with an inert liquid diluents connection suitable for this machine.

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

This invention relates further to a method for obtaining compounds of formula I, characterized in that the compound of formula II

where T1, T2, R(1), R(2) and R(3) have the above values and G denotes exchanged with L-z functional group known to a person skilled manner is subjected to reaction with compound A-L-z, while GA is split off and formed the compound of formula (I).

Funcc then be achieved in a known manner desired binding-With-regard.

Acetyltyrosine bile acids of the formula (III) is obtained from the appropriate ketones bile acids. For this acetylide lithium type similar to a known method (U.S. patent 5641767) to cetorelli acids.

The compounds of formula (I) and their pharmaceutically acceptable salts and physiologically functional derivatives differ favorable effect on the composition of bile and prevent the formation of gallstones, preventing saturation of bile with cholesterol or slowing the formation of cholesterol crystals from supersaturated bile. These compounds can be used individually or in combination with active substances that lower lipids in the blood. These compounds are suitable, in particular, for the prevention and treatment of gallstones.

The compounds of this invention of formula (I) are in the hepatobiliary system and therefore act on these fabrics. Thus inhibited the absorption of water from the gall bladder inhibition of apical NHE-antiporta subtype 3 of the epithelium of the gallbladder, resulting in a diluted liquid bile.

Biological testing of the compounds of this invention were carried out by determining the inhibition of the three is B> for inhibition of NHE-3 protein human (expressed cell line LAP1) was determined by the recovery of pH (pHiafter acidification, which occurs in the case of functionally capable NHE also in the absence of bicarbonate. For this pHidetermined using the pH-sensitive fluorescent dye BCECF (Calbiochem, applied predecessor BCECF-AM). Cells were first loaded with BCECF. The BCECF fluorescence was determined by spectrometer Fluorescence Ratio Spectrometr" (Proton Technology International, South Brunswick, N. J., USA) is an excitatory wavelengths of 505 and 440 nm and the wavelength of emission of 535 nm and using the calibration curves were converted into pHi. Cells were incubated already when loading BCECF in NH4C1-buffer (pH 7.4) (NH4Cl-buffer: 115 mm NaCl, 20 mm NH4Cl, 5 mm KCl, 1 mm CaCl2, 1 mm MgSO4, 20 mm Hepes, 5 mm glucose, 1 mg/ml BSA; pH adjusted to 7.4 using 1 M NaOH). Intracellular acidification induced by adding 975 µl containing NH4Cl buffer to the aliquot 25 ál inkubiruemykh in NH4CL-buffer cells. The subsequent rate of recovery of pH were recorded for 3 minutes. To calculate the inhibitory capacity of tested substances, the cells were first examined in the buffers, in which there was a complete recovery SUP>-containing buffer (133,8 mm NaCl, of 4.7 mm KCl, 1.25 mm CaCl2, 1.25 mm MgCl2, 0,97 mm Na2HPO4, 0.23 mm NaH2PO4, 5 mm s, 5 mm glucose, pH was brought to 7.0 with 1 M NaOH). To determine 0%-indicator cells were incubated in buffer without PA+(133,8 mm choline chloride, a 4.7 mm KCl, 1.25 mm CaCl2, 1.25 mm MgCl2, 0,97 mm K2HPO4, 0.23 mm KN2RHO4, 5 mm s, 5 mm glucose, pH was brought to 7.0 with 1 M NaOH). Analyte tested in PA+-containing buffer.

Recovery of intracellular pH at each tested concentration of a substance expressed in percent of maximum recovery. From the percentages of recovery of pH using the program SigmaPlot (Version 3.0, Jandel Scientific, USA) was calculated IC50each test substance.

Results

Example 1: IC50= - 1.7 mm/l

The following examples serve for a more detailed explanation of the invention without limiting the invention described in the examples of products and forms of implementation.

List of abbreviations:

Meon - methanol

LAH - sociallyengaged

DMF - N,N-dimethylformamide

EI is electron impact

CI - x is CCA melting

NER - n-heptane

DME - dimethoxyethan

ES - elektrorazpredelenie

FAB is the bombardment of accelerated atoms

CH2Cl2- dichloromethane

THF-tetrahydrofuran

EQ. equivalent

A common way combinations of aryl halides and substituted end acetylenes.

Aryl halides (1 EQ.) put together with the supporting base (4 equiv.) such as, for example, triethylamine and Pd-katalysatoren, such as, for example, palladiumtechnological (3 mol.%) in DMF. For 0.5-3 hours slowly add the derivative of acetylene and if necessary add more time above the amount of the catalyst. The reaction temperature may exceed CT and approximately 100C, it is usually equal to about 60C. The crude product may be precipitated by ethyl acetate and filtered. Subsequent salt formation is achieved by adding acid in acetone.

Example 1.

The diacetate 4-{3-[3,4-bis-(3-guanidino-2-methyl-3-oxopropyl)phenylethynyl]-3,7,12-trihydroxy-10,13-dimethyldichlorosilane[a]phenanthrene-17-yl}pentanol acid, yellow solid, so pl. C (decomposition).

MS:

M+

The synthesis.

a) Methyl ether 3,7,12-triacetylcellulose acid

90 g of methyl ester holeva acid and 3.0 g of dimethylaminopyridine was dissolved in 500 ml of pyridine, mixed with 500 ml of acetic anhydride and stirred overnight at room temperature. The mixture was poured into ice water and was extracted with ethyl acetate (3x). Drying (gSO4) and evaporation of the organic phase allocate 92 g of methyl ester 3,7,12-triacetylcellulose acid.

MS: M++N (FAB)=555.

b) Methyl ester of 7,12-diacetylene acid

When 5S 150 ml of acetic anhydride was slowly added dropwise to 1.5 l of methanol. After 15 min was added 92 g of methyl ester 3,7,12-triacetylcellulose acid and stirred for 1 hour at room temperature. The mixture was poured into ice water and was extracted with ethyl acetate (3x). The organic phase is washed with 1 N. solution PA2CO3, dried MgSO4and was evaporated. Received 85 g of the crude product.

MS: M++Li (FAB)=513.

c) Methyl ester of 3-keto-7,12-diacetylene acid

85 g (168 mmol) of methyl ester of 1,12-diacetylene acid, 183,7 g chloroformiate pyridinium and 175 g of molecular sieves were stirred in 2.5 l di obyvali. The solvent is evaporated and the residue was dissolved in ethyl acetate. After chromatography over Florisil column got to 59.6 g of the product.

MS: M++Li (FAB)=511.

d) Methyl ester of 3-acetylene-7,12-diacetylene acid

In 750 ml of absolute tetrahydrofuran at-55C in the atmosphere of argon for 25 min was injected acetylene. To this solution was added dropwise 145 ml of 15% n-utility in hexane and stirred for 10 minutes Then added 45 g (89 mmol) of methyl ester of 3-keto-7,12-diacetylene acid and stirred 1.5 hours at-40C. Processing was added 500 ml of a saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate (3x), the organic phase was dried over MgSO4and was evaporated. The residue was chromatographically on silica gel (n-heptane/ethyl acetate, 1:1). Got to 35.3 g of the product, MS: M++Li (FAB) =537.

e) 3-Acetylecholine acid

35.2 g (66 mmol) of the product from (d) was dissolved in 1 l of methanol was combined with 300 ml of 2 n sodium hydroxide solution and boiled under reflux for 25 hours. The solvent is evaporated, the residue was dissolved in water and acidified 2 N. hydrochloric acid to pH 2. The precipitate was filtered and washed with water until neutral. Drying of the residue gave 14.6 g of product, MS: M+<-bromine benzol

Synthesis:

a) 4-bromo-1,2-diol phthalic received from dimethyl 4-promptlabel acid according to standard methods (e.g., the restoration LAH), colorless oil, MS: M++H (FAB)=217;

b) 4-bromo-1,2-phthaldialdehyde was obtained from 2A) through, for example, Swern oxidation under standard conditions, amorphous solid, MS: M++H (FAB)=213;

c) 4-bromo-1,2-di-[3-(ethyl ester of S-2-methylpropenoic acid)]benzene was obtained by deprotonation of 1 EQ. teeterboro ether 2-phosphonopropionic acid with 1 EQ. n-utility in hexane at 0 C followed by reaction at room temperature with 0.5 EQ. 4-bromo-1,2-phthaldialdehyde 2b). After full use of MDA were treated with water and was extracted three times by shaking with toluene. After drying the combined organic phases over magnesium sulfate the solvent was removed in vacuo and the remaining crude product is chromatographically separated on silica gel with mixtures HER/NER (ethyl acetate/n-heptane as eluent, colorless oil, MS: M++N (FAB)=381;

d) 4-bromo-1,2-di-[3-(E-2-methylpropanoate acid)]benzene was obtained from 2C) by saponification according to the standard method (sodium hydroxide in methanol is ispropanol acid)]-4-bromine benzol were obtained from 2d) according to the General option, colourless solid, so pl. S, MS: M++N (FAB)=407;

f) diacetate 4-{3-[3,4-bis-(3-guanidino-2-methyl-3-oxopropyl)phenylethynyl]-3,7,12-trihydroxy-10,13-dimethyldichlorosilane[a]phenanthrene-17-yl}pentanol acid was obtained from 2F) and 3-acetylindole acids by Pd(0)-combinations according to the General method in DMF at 60C for 2 hours.

Example 2.

Benzyl ether of 4-{3-[3,4-bis-(3-guanidino-2-methyl-3-oxopropyl)phenylethynyl]-3,7,12-trihydroxy-10,13-dimethyldichlorosilane[a]phenanthrene-17-yl}pentanol acid, yellow solid, so pl. S, MS: M++H (ES)=849.

The synthesis was performed analogously to example 1 using benzyl ester 3-acetylindole acid.

Example 3.

Benzyl ether 4-{3-[4-(3-guanidino-3-oxopropyl)phenylethynyl]-3,7,12-trihydroxy-10,13-dimethyldichlorosilane[a]phenanthrene-17-yl}pentanol acid

yellowish solid substance, so pl. S, MS: M++H (FAB)=710.

The synthesis was similar to the General method using benzyl ether of guanidine 4-bromcresol acid benzyl ester 3-acetylindole acid.

Example 4.

Methyl EF is Ren-17-yl}pentanol acid, yellowish solid substance, so pl. 60C, MS: M++H (FAB)=718.

The synthesis was similar to the General method by reaction of guanidine 4-bromcresol acid benzyl ester 3-acetylindole acid.

Example 5.

(4-{3-[3,4-bis-(3-Guanidino-2-methyl-3-oxopropyl)phenylethynyl]-3,7,12-trihydroxy-10,13-dimethyldichlorosilane[a]phenanthrene-17-yl}pentanediamine)acetic acid

a) Methyl ester [4-(3-ethinyl-3,7,12-trihydroxy-10,13-dimethyldichlorosilane[a]phenanthrene-17-yl}pentanediamine)acetic acid

530 mg of 3-acetylindole acid (intermediate 1) and 510 μl of triethylamine dissolved in 30 ml of THF and added dropwise at 0C 175 μl of ethyl ether of Harborview acid. Stirred for 15 min at 0C, then add dropwise a solution of 340 mg of methyl ester hydrochloride of glycine in 10 ml of DMF and stirred for 4 h at room temperature. Diluted with 200 ml ethyl acetate and washed twice with 50 ml in each case 5% aqueous solution of NaHSO4. Dried over gSO4and the solvent is removed in vacuum. The residue is placed in 100 ml ethyl acetate and washed three times in 50 ml in each case saturated aqueous solution of Na

Rf(EE) = 0,37, MS (FAB) =518 (M+N)+.

b) [4-(3-Ethinyl-3,7,12-trihydroxy-10,13-dimethyldichlorosilane [a]phenanthrene-17-yl}pentanediamine)acetic acid

270 mg of methyl ester [4-(3-ethinyl-3,7,12-trihydroxy-10,13-dimethyldichlorosilane[a]phenanthrene-17-yl}pentanediamine)acetic acid and 630 μl of 1 N. aqueous solution of NaOH dissolved in 5 ml ethanol and incubated for 16 h at room temperature. The solvent is removed in vacuum, the residue is placed in 50 ml of a saturated aqueous solution of NaH2PO4and thrice extracted with 50 ml of ethyl acetate in each case. Dried over gSO4and the solvent is removed in vacuum. Obtain 230 mg of an amorphous solid.

Rf(acetone/water, 10:1) = 0,25, MS(FAB): 502 (M+2Li)+.

with) (4-{3-[3,4-bis-(3-Guanidino-2-methyl-3-oxopropyl)phenylethynyl]-3,7,12-trihydroxy-10,13-dimethyldichlorosilane[a]phenanthrene-17-yl}pentanediamine)acetic acid

230 mg of [4-(3-ethinyl-3,7,12-trihydroxy-10,13-dimethyldichlorosilane[a]phenanthrene-17-yl}pentanediamine)acetic acid and 183 mg of N-{3-[4-bromo-2-(3-guanidino-2-methyl-3-oxopropyl)phenyl]-2-methylacrylic}guanidine p is preparative HPLC through LiChrosorb C18 with a mixture of acetonitrile/water, 2:4, + 0,1% acetic acid + 0.1% ammonium acetate receive 70 mg of an amorphous solid.

Rf(n-butanol/acetic acid/water, 3:1:1) = 0,33, MS (ES): 816 (M+H)+.

Example 6.

4-{3-[2-Fluoro-4-(3-guanidino-2-methyl-3-oxopropyl)phenylethynyl]-3,7,12-trihydroxy-10,13-dimethyldichlorosilane[a]phenanthrene-17-yl}pentane acid

a) Butyl ether 3-(4-bromo-3-forfinal)-2-methylacrylate acid

2 g of 1-bromo-2-fluoro-4-iodobenzoyl and 1.1 ml of diisopropylethylamine dissolved in 20 ml of dimethylacetamide (anhydrous) and 5 min bubbled light current of argon through the solution. Then added to 1.4 ml of butyl ester of acrylic acid and 10 mg of 2,6-di-tert-butyl-4-METHYLPHENOL and heated to 100C. Finally Tegaserod following 4 ml of dimethylacetamide using a current of argon and suspended in 80 mg of TRANS-bis(-acetato)bis[o-tolylphosphino)benzyl]diplegia (Tetrahedron Lett., 1996, 37(36), 6535-6538). This suspension is added to a mixture of the remaining components of the reaction and stirred for 90 min at 140 ° C. The mixture is then diluted with 200 ml of HER, washed with 2 times 100 ml of water and 1 time with 100 ml saturated aqueous NaCl. Dried over gS4and the solvent is removed in vacuum. Chromatography on silica gel get 230 mg bescot propyl)-3,7,12-trihydroxy-10,13-dimethyldichlorosilane[a]phenanthrene-3-ylethynyl]-3-forfinal}-2-methylacrylate acid

64 mg of bis(triphenylphosphine)palladium(II)chloride (17 mg CuI, 0.5 ml of triethylamine, and 230 mg butyl ether 3-(4-bromo-3-forfinal)-2-methylacrylate acid dissolved in 10 ml of anhydrous DMF and added dropwise at 60C for one hour a solution of 395 mg 3 acetylecholine acid in 10 ml of anhydrous DMF. Stirred for 1 hour at 60C and then slowly added dropwise a solution of 395 mg-acetylecholine acid in 10 ml of anhydrous DMF at 60C. Stirred for 2 hours at 60C, then again added 64 mg of bis(triphenylphosphine)palladium(II)chloride and 17 mg / Cul and again stirred for 2 hours at 60C. Finally, add 80 mg of 3-acetylindole acid and stirred for 2 hours at 60C. The solvent is removed in vacuum, the residue is placed in 100 ml of 5% aqueous NaHSO4and 3 times extracted with 100 ml in each case. Dried over Na2SO4and the solvent is removed in vacuum. Chromatography on silica gel with a mixture of HER/Meon, 5:1, receive 90 mg of a waxy substance.

Rf(EE/MeOH, 5:1) = 0,56, MS (FAB): 667 (M+N)+.

c) 4-{3-[2-fluoro-4-(3-Guanidino-2-methyl-3-oxopropyl)phenylethynyl]-3,7,12-trihydroxy-10,13-dimethyldichlorosilane[a]phenanthrene-17-yl}pentane acid

73 mg of the hydrochloride gwenie. This suspension is applied by spraying 85 mg butyl ester 3-{4-[17-(3-carboxy-1-methylpropyl)-3,7,12-trihydroxy-10,13-dimethyldichlorosilane[a]phenanthrene-3-ylethynyl]-3-forfinal}-2-methylacrylate acid and stirred for 5 hours at 100C. After cooling, add 10 ml of water, adjusted pH to 4 with an aqueous solution of HCl and extracted three times with 10 ml every time. Dried over gSO4and the solvent is removed in vacuum. Chromatography on silica gel with a mixture of acetone/water, 10:1, gain of 15.5 mg of an amorphous solid.

Rf(acetone/water, 10:1) = 0,19, MS (ES): 652 (M+N)+.

Example 7.

4-(3-{2-[2,6-Debtor-4-(3-guanidino-2-methyl-3-oxopropyl)phenylamino]ethoxy)-7,12-dihydroxy-10,13-dimethyldichlorosilane[a]phenanthrene-17-yl}pentane acid

a) 4-(7,12-Dihydroxy-3-methanesulfonate-10,13-dimethyldichlorosilane[a]phenanthrene-17-yl)pentane acid

100 g holeva acid are dissolved in 500 ml of pyridine and at 0C is added dropwise during 30 min of 23.1 ml methylchloride. Stirred for 3 hours at room temperature, then poured on a solution of 400 ml of H2SO4in 3 l of water and extracted 4 times with 750 ml of IT every time. Dried over Na2SO4and dissolve the P CLASS="ptx2">

Rf(HER/NER/acetic acid, 5:5:1)=0,31, MS (FAB): 487 (M+H)+.

b) Methyl ester of 4-[7,12-dihydroxy-3-(2-hydroxyethoxy)-10,13-dimethyldichlorosilane[a]phenanthrene-17-yl]pentanol acid

116 g of 4-(7,12-dihydroxy-3-methanesulfonate-10,13-dimethyldichlorosilane[a]phenanthrene-17-yl)pentanol acid and 130 ml of triethylamine are dissolved in 650 ml of glycol and stirred for 3 hours at 100C, and 7.5 hours when 115S. The reaction mixture is poured at 0C to a solution of 400 ml of N2SO4in 3 l of water and extracted 7 times with 750 ml of IT every time. Dried over Na2SO4and the solvent is removed in vacuum. Receive the intermediate product ZWP.

Add at 130 0C ml acetylchloride to 900 ml of methanol. Then add a solution ZWP 400 ml) and stirred for 6 hours at room temperature. Stand for 60 hours at room temperature, then poured 2.6 l of water and extracted 8 times with 500 ml of diisopropyl ether (DIP). Then the organic phase is still 6 times washed with 600 ml each time polysystem aqueous solution Panso3. Dried over Na2SO4and the solvent is removed in vacuum. Chromatography on silica gel with ethyl acetate to obtain 32 g of a resinous solid.

Rf (EExi-10,13-dimethyldichlorosilane[a]phenanthrene-17-yl}pentanol acid

1.5 g of methyl ester 4-[7,12-dihydroxy-3-(2-hydroxyethoxy)-10,13-dimethyldichlorosilane[a] phenanthrene-17-yl]pentanol acid, 950 mg of triphenylphosphine and 550 mg phthalimide heated in 26 ml of THF to 45C and at this temperature is added dropwise to 1.14 ml diethyl ester of azodicarboxylic acid. Stirred for 2 hours at 45C, then the reaction mixture is poured into 200 ml policecontributing aqueous solution of NaHCO3and thrice extracted with 200 ml. Dried over Na2SO4and the solvent is removed in vacuum. Chromatography on silica gel with tert-butylmethylamine ether (MTB) gain of 1.76 g of viscous oil.

Rf(EE) = 0,60, MS (FAB): 602 (M+Li)+.

d) Methyl ester of 4-[3-(2-aminoethoxy)-7,12-dihydroxy-10,13-dimethyldichlorosilane[a]phenanthrene-17-yl]pentanol acid

1.7 g of methyl ether 4-{3-[2-(1,3-dioxo-1,3-dihydroindol-2-yl)ethoxy]-7,12-dihydroxy-10,13-dimethyldichlorosilane[a] phenanthrene-17-yl]pentanol acid, and also of 0.52 ml of hydrazine hydrate is added (80%) are dissolved in 14 ml of methanol and 3 h refluxed. Then cooled to 40C and the reaction mixture is combined with 8,7 ml 2 N. aqueous HCl. Stirred further at 40 ° C, then remove the volatile components in vacuo. tx2">

Rf(acetone/water, 10:1) = 0,06, MS (FAB): 466 (M+H)+.

e) 4-[3-(2-Aminoethoxy)-7,12-dihydroxy-10,13-dimethyldichlorosilane[a]phenanthrene-17-yl]pentane acid

3 g of methyl ester 4-[3-(2-aminoethoxy)-7,12-dihydroxy-10,13-dimethyldichlorosilane[a]phenanthrene-17-yl]pentanol acid and 310 mg of NaOH are stirred in 5 ml of water and 30 ml of methanol for 24 hours at room temperature. The solvents are removed in vacuo, the residue is placed in 200 ml of water and adjusted pH to 7-7,5 aqueous solution of HCl. Stirred for 1 hour and then the product is filtered. Obtain 1.6 g of pale yellow crystalline solid, so pl. 185-C.

Rf(CH2C12/Meon/acetic acid/water, 32:8:1:1) = 0,18, MS (ES): 452 (M+H)+.

(f) Ethyl ester of 2-methyl-3-(3,4,5-tryptophanyl)acrylic acid

the 4.3 ml teeterboro ether 2-phosphonopropionic acid are dissolved in 30 ml anhydrous THF and added dropwise at From 12.5 ml of a 1.6 n solution of n-utility in hexane. 15 min, stirred at room temperature and then added dropwise a solution of 3.2 g of 3,4,5-triftorbyenzola aldehyde in 8 ml of anhydrous THF. One hour and stirred at room temperature and left to stand at room temperature for 16 hours. for extracted with 100 ml. Dried over Na2SO4and the solvent is removed. Chromatography on silica gel with a mixture of HER/NER, 1:8, obtain 3.8 g of colorless crystals, so pl. S.

Rf(HER/NER, 1:8) = 0,35, MS (DCI): 245 (M+N)+.

d) Ethyl ester 3-(4-{2-[17-(3-carboxy-1-methylpropyl)-7,12-dihydroxy-10,13-dimethyldichlorosilane[a]phenanthrene-3-yloxy]ethylamino}-3,5-differenl)-2-methylacrylate acid

600 mg of 4-[3-(2-aminoethoxy)-7,12-dihydroxy-10,13-dimethyldichlorosilane[a]phenanthrene-17-yl]pentanol acid, 390 mg of ethyl ester of 2-methyl-3-(3,4,5-tryptophanyl)acrylic acid and 828 mg2CO3stirred in 10 ml of dimethylacetamide 2.5 hours at 130C. The reaction mixture after cooling, diluted with 400 ml of CH2C12and washed with 400 ml of 5% solution of NaHSO4. Dried over MgSO4and the solvent is removed in vacuum. Chromatography on silica gel with a mixture of CH2Cl2/MeOH, 10:1, obtain 155 mg of a colorless oil.

Rf (CH2Cl2/MeOH, 10:1) = 0,27, MS (ES): 676 (M+N)+.

i) 4-(3-{2-[2,6-Debtor-4-(3-guanidino-2-methyl-3-oxopropyl)phenylamino]ethoxy)-7,12-dihydroxy-10,13-dimethyldichlorosilane[a]phenanthrene-17-yl)pentane acid

130 g of guanidine hydrochloride and 125 g of potassium the g ethyl ester 3-(4-{2-[17-(3-carboxy-1-methylpropyl)-7,12-dihydroxy-10,13-dimethyldichlorosilane[a]phenanthrene-3-yloxy]ethylamino}-3,5-differenl)-2-methylacrylate acid in 1 ml of anhydrous DMF and stirred for 6 hours at 110-115S. The reaction mixture is then poured on 100 ml of water, adjusted pH to 6 with an aqueous solution of HCl and the product is filtered. In a small vacuum dried, yielding 8.0 mg of an amorphous solid.

Rf(CH2C12/Meon/acetic acid/water, 32:8:1:1) = 0,21, MS (ES): 689 (M+N)+.

1. The compounds of formula Ia

where T1and T2independently of one another denote

or hydrogen, with T1and T2cannot simultaneously be hydrogen;

L-z denotes

L denotes-SS-, -NH-CH2-CH2-O-;

R(E) denotes hydrogen, (C1-C4)alkyl;

R1, R2 independently of one another denote hydrogen, F, Cl, CN, -SO2-CH3, -(C1-C4)alkyl, -O-(C1-C4)alkyl, and alkyl residues can be single or multi-substituted by F,

and their pharmaceutically acceptable salts.

2. Drug containing one or more compounds on p. 1 for the prevention or treatment of gallstones.

3. Drug under item 2, characterized in that it additionally contains one or more reduces the content of lipids in the blood active washes gallstones.

 

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