Hypolipidemic 1,4-benzothiazepine-1,1-dioxides and methods for their production

 

(57) Abstract:

The invention relates to new 1,4-benzothiazepine-1,1-dioxides of the formula (I), where R1is non-branched C1-6alkyl group, R2is non-branched C1-6alkyl group, R3is hydrogen, R4represents phenyl, R5R6and R8selected from hydrogen, R7represents a group of formula (Ia) and (IB), where the hydroxy-group may be substituted by acetyl, R16represents-COOH, -CH2-OH, -CH2-O-acetyl-Sooma, R9and R10the same or different and each represents hydrogen or C1-6alkyl group, X represents-O-, or its salt, solvate and physiologically acceptable derivatives. Also disclosed is the compound of formula (V) and methods for producing these compounds. Compounds according to the invention show an activity of inhibiting the absorption of bile acids and can be used as an active ingredient of a medicinal product for the prevention or treatment hyperlipidemics States. 6 C. and 3 h.p. f-crystals, 1 PL.

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The present invention relates to a new lipid-lowering compounds, to methods of their polycrystalline in medicine, especially for the prevention and treatment hyperlipidemics States, such as atherosclerosis.

Gipolipidemicheskie condition often associated with elevated concentrations of plasma low density lipoprotein (LDL) cholesterol and very low density lipoprotein lipoproteins (VLDL) cholesterol. Such concentrations can be reduced by reducing the absorption of bile acids in the intestine. One way to achieve this is by inhibition of active absorption of bile acids in the final ileum. This inhibition stimulates the conversion of cholesterol to bile acids by the liver, resulting in increased demand for cholesterol, and, in turn, leads to a corresponding increase in the speed of removing LDL and lonp cholesterol from plasma or serum.

Discovered a new class of heterocyclic compounds that reduce the concentration of LDL and lonp cholesterol in plasma or serum, and therefore, particularly useful as hypolipidemic agents. Reducing the concentration of cholesterol and of ester cholesterol in plasma, the compounds of the present invention inhibit the formation of atherosclerotic plaques, and reduce the likelihood of manifestations, svisheniki concentrations of cholesterol and of ester cholesterol in plasma or serum.

For the purposes of the present description gipolipidemicheskoe condition is defined as any condition in which the total concentration of cholesterol (LDL+lonp) in serum or plasma exceeds 240 mg/DL (6/21 mmol/l) (J/Amer.Med.Assn./ 256, 20, 2849-2858 (1986)).

In international patent application W96/05188 disclosed compounds of the formula (0):

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The authors have discovered a group of compounds, which have a higher lipid-lowering activity in vivo than the compounds disclosed in international patent application WO 96/05188. These compounds differ in the definition of the group R7.

Accordingly, the present invention proposed the compounds of formula (I):

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where R1is non-branched C1-6alkyl group;

R2is non-branched C1-6alkyl group;

R3represents hydrogen or a group OR11where R11represents hydrogen, optionally substituted C1-6alkyl or C1-6alkylcarboxylic group;

R4represents pyridine or optionally substituted phenyl;

R5, R6and R8the same or different and each is selected from hydrogen, halogen, cyano, R15-acetylide, OR15it is15, F3, OCN, SCN, NHCN, CH2OR15CHO, (CH2)pCN, CONR12R13, (CH2)pCO2R15, (CH2)pNR12R13, CO2R15,

NHCOCF3, NHS2R15, OCH2OR15, OCH=CHR15, (CH2CH2O)nR15, (CH2)pSO3R15,

O(CH2)pNR12R13and O(CH2)pN+R12R13R14where

p represents an integer from 1 to 4;

n represents an integer from 0 to 3;

R12, R13, R14and R15independently selected from hydrogen and optionally substituted C1-6of alkyl;

R7represents a group of the formula:

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or

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where the hydroxyl group may be substituted by acetyl, benzyl or -(C1-C6)-alkyl-R17< / BR>
where the alkyl group may be substituted by one or more of the hydroxyl groups;

R16represents-COOH, -CH2-OH, -CH2-O-acetyl, Sooma, -Cooet;

R17represents H, -OH, -NH2, -COOH or COOR18;

R18is (C1-C4)-alkyl or-NH-(C1-C4)-alkyl;

X represents-NH - or-O-; and

R9and R10the same purpose ground receiving stations derivatives.

If R4represents a substituted phenyl group can be from one to five, preferably one or two substituent, which are the same or different and each is selected from halogen, hydroxy, nitro, phenyl-C1-6alkoxy, C1-6alkoxy, optionally substituted C1-6of alkyl, S(O)nR15, CO2R15, (CH2CH2O)nR15, (CH2)pSO3R15, O(CH2)pNR12R13and(CH2)pN+R12R13R14where R12-R15, n and R have the previously indicated meanings.

Preferred variants of compounds of formula (I) include compounds of formulas (III), (IV) or (IVa):

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where R1-R10and X have the previously indicated meanings.

If one or more of R3-R6, R8or R11-R14substituted C1-6alkyl group, or C1-6alkyl group, the substituents may be the same or different and each selected from hydroxy, halogen, C1-6of alkyl, C1-6alkoxy, COR20, nitrile, CO2R20, SO3R20, NR21R22; N+R21R22R23where R20-R23the same or different, and each is drank, and preferably, R1represented ethyl. Convenient to R2was represented by methyl, ethyl, n-propyl, n-butyl or n-pentyl. Preferably, R2was n-butyl. Preferably, R5was hydrogen.

Conveniently, R7choose from:

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It is convenient to X was represented by-O-.

Convenient to R9and R10represented hydrogen, methyl or ethyl, hydrogen.

Preferably, R9and R10both were represented by hydrogen.

Convenient to R4was pyridyl or phenyl, optionally substituted, preferably at the 4 - and/or 3-position by halogen, stands, ethyl, methoxy, ethoxy, trifluoromethyl, hydroxy, carboxy, or(CH2)3SO3N. Preferably, R4represented unsubstituted phenyl.

In the compounds of the formula (III): convenient to have at least one, and preferably all of the R5, R6and R8was hydrogen. If R5, R6and R8other than hydrogen, then it is convenient to represent WITH1-4alkyl, optionally substituted by fluorine, WITH1-4alkoxy, halogen or hydroxy, it is most convenient - methyl, Pdobno, order two or three of R5, R6and R8was hydrogen, and the other would be WITH1-4alkyl, optionally substituted by fluorine, WITH1-4alkoxy, halogen or hydroxy, the most convenient, methyl, methoxy, hydroxy, trifluoromethyl or chloro and preferably methoxy.

In the compounds of the formula (IV): convenient to have at least one, and preferably all of the R5, R6and R8was hydrogen. If R5, R6and R8other than hydrogen, then it is convenient to represent WITH1-4alkyl, optionally substituted by fluorine, WITH1-4alkoxy, halogen or hydroxy, it is most convenient to represent methyl, methoxy, hydroxy, trifluoromethyl or chlorine, and preferably methoxy. Most preferably, R1was n-butyl, R2represented ethyl, R3, R5, R6, R8, R9and R10represented hydrogen, R4represented phenyl, and R7was:

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Pharmaceutically acceptable salts are best suited for medical purposes, because of their higher water solubility compared to the original, i.e. the main compounds. Such salts are, obviously, must be pharmaceutically acceptable anyone include salt, derived from inorganic acids such as hydrochloric, Hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic, and sulfuric acid and such organic acids as acetic, benzolsulfonat, benzoic, citric, econsultancy, fumaric, gluconic, glycolic, sotynova, lactic, lactobionic, maleic, malonic, methansulfonate, amber, pair-toluensulfonate, wine and triperoxonane acid. For medical purposes the most suitable chlorides. Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts, such as salts of sodium and potassium, salts of alkaline earth metals such as magnesium salt and calcium.

Salts containing pharmaceutically unacceptable anion, fall within the scope of the present invention, and suitable as a convenient intermediates for obtaining or purification of pharmaceutically acceptable salts and/or for use in therapeutic applications, for example in applications in vitro.

The term "physiologically functional derivative" in the sense used here, refers to any physiologically acceptable derivative of the compound of the present invention, for example to svenne) this compound or its active metabolite.

Another aspect of the present invention are proletarienne forms of the compounds of the present invention. Such prodrugs as a result of metabolism in vivo can give the compounds of the present invention. Such prodrugs can be active or inactive by themselves.

Compounds of the present invention can exist in different polymorphic forms, such as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the present invention fall within the scope of the present invention and constitute an additional aspect.

The term "alkyl" in the sense used here, unless otherwise specified, refers to a monovalent branched or unbranched chain of the radical. Similarly, the term "alkoxy" refers to a monovalent branched or unbranched chain of the radical, attached to the main molecular fragment through an oxygen atom. The term "funeralcare" refers to a monovalent phenyl group, attached to a divalent C1-6alkalinous group, which itself is attached to the main molecular fragment through an oxygen atom.

The compounds of formula (I) semestinya includes within its scope each of the possible optical isomers in almost pure, i.e., containing less than 5% of any other optical isomers (isomers), form, and mixtures of one or more of the optical isomers in any proportion, including racemic mixtures.

For the purposes of the present description the absolute chirality of the above carbon centres are given in the order of-C(R1)(R2), then CHR4-.

In cases where the absolute stereochemistry of the-C(R1) and CHR4is not defined, the compounds of the present invention is defined in terms of the relative provisions of the R1/R2and H/R4substituents, and thus, those compounds in which the most massive of R1and R2substituents, i.e., a Deputy with the greater weight, and the substituent R4both are located on one side diazepinones rings, in this context referred to as "CIS", and those compounds in which the more massive of the substituents R1and R2located on opposite sides of the ring, referred to as "TRANS", and they are preferred. Professionals should be obvious that as the "CIS" and "TRANS" compounds of the present invention can exist in two enantiomeric forms, which are individually designated as "( + ) " or "( - ) " in accordance with the direction vrusho of the invention, in which the individual enantiomers have not been separated here indicate using prefix "(+)-".

In accordance with the following aspects of the present invention is also suggested:

(a) the compounds of formula (I) and their pharmaceutically acceptable salt, solvate, and physiologically functional derivatives for use as therapeutic agents, particularly for the prevention and treatment of clinical conditions, which shows the inhibitor absorption of bile acids, such hyperlipidemics conditions as atherosclerosis.

(b) a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate or physiologically functional derivative with at least one pharmaceutically acceptable carriers and, optionally, one or more physiologically active agents;

(c) the use of the compounds of formula (I) or its pharmaceutically acceptable salt, MES or physiologically functional derivative in the manufacture of a medicine for the prevention or treatment of clinical conditions, which shows the inhibitor absorption of bile acids, such hyperlipidemias, for example person, which includes the introduction of an effective inhibiting the absorption of bile acids in the number of compounds of formula (I) or its pharmaceutically acceptable salt, MES or physiologically functional derivative, the mammal;

(e) a method of reducing concentrations in the blood plasma or serum LDL and lonp cholesterol in mammals, for example humans, which includes the introduction of effective cholesterol-number of the compounds of formula (I) or its pharmaceutically acceptable salt, MES or physiologically functional derivative to the mammal;

(f) a method of reducing the concentrations of cholesterol and of ester cholesterol in plasma or serum of such a mammal, such as man, which comprises the administration to a mammal effective to reduce the content of cholesterol or of ester cholesterol amounts of compounds of formula (I) or its pharmaceutically acceptable salt, MES or physiologically functional derivative;

(g) the method of increasing the fecal excretion of bile acids in a mammal, such as man, which includes the introduction of effectively increasing the fecal excretion of bile acids in the number soedinenie, the mammal;

(h) method of prevention or treatment of clinical conditions in mammals such as man, which shows the inhibitor absorption of bile acids, for example, hyperlipidemics conditions such as atherosclerosis, which includes the introduction of therapeutically effective amounts of compounds of formula (I) or its pharmaceutically acceptable salts of MES, or physiologically functional derivative to the mammal;

(i) a method of reducing the incidence of diseases associated with coronary heart disease in mammals such as man, which comprises introducing an effective amount for reducing the number of cases of diseases associated with coronary heart disease, the compounds of formula (I) or its pharmaceutically acceptable salt, MES or physiologically functional derivative;

(j) the method of reducing the concentration of cholesterol in the blood plasma or serum of a mammal, such as man, which comprises introducing an effective amount for reducing cholesterol, the compounds of formula (I);

(k) the means of obtaining compounds of formula (I) (including its salt, solvate and physiologically functional derivatives as herein defined); and

(1) the AK here disclosed.

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

The amount of the compounds of formula (I), which is necessary to achieve the desired biological effect will naturally depend on a number of factors, for example from specifically selected connection, intended use, method of administration and the clinical condition of the recipient. The daily dose is in the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day per kilogram of body weight, for example 3-10 mg/kg/day. The dose for intravenous administration can be, for example, in the range from 0.3 mg to 1.0 mg/kg, which can usually be introduced in the form of infusion with a speed of from 10 ng to 100 ng/kg per minute. Liquid for intravenous infusion for these purposes may include, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg per milliliter. A unit dosage may contain, for example, from 1 mg to 10 g of the active compound. Thus, ampoules for injection may contain, for example, from 1 mg to 100 mg as a single dose for oral administration such as tablets or capsules, may contain, How to weight benzodiazepinovogo ion, derived from salt.

For the prevention or treatment of the conditions listed above, the compounds of formula (I) can be used as themselves, but it is preferable to present them with an acceptable carrier in the form of pharmaceutical compositions. The media of course must be acceptable in the sense of compatibility with other ingredients of the composition and must not have a harmful influence on the recipient. The media can be both solid and liquid, or both, and is preferably prepared together with the connection in the form of a composition in a unit dose, for example in the form of a tablet, which may contain from 0.05% to 95% by weight of active compound. Can contain other pharmacologically active agents, including other compounds of formula (I). The pharmaceutical compositions of the present invention can be obtained by any of the well known techniques of pharmacy consisting essentially of mixing.

The pharmaceutical compositions of the present invention include compositions for oral, rectal, surface, buccal (e.g., under the tongue) and parenteral (e.g. subcutaneous, intramuscular, dermal or intravenous) administration, the treatment of disease, and from the nature of the specific compounds of formula (I), which intend to use. In the scope of the present invention also includes compositions with protivolodochnyi floor and protivolodochnyi coating for controlled selection. Preferred compositions, resistant to acids and gastric juice. Suitable protivolodochnye coatings include acetated cellulose, polyvinylacetate, phthalate of hydroxypropylmethylcellulose and anionic polymers of methacrylic acid and methyl ester of methacrylic acid.

Pharmaceutical compositions for oral administration may be present in such discrete singular form as capsules, lozenges or tablets, each containing a predetermined amount of the compounds of formula (I) in the form of a powder or granules; as solutions or suspensions in aqueous or non-aqueous liquid; or as emulsions water in oil or oil in water. As indicated, such compositions can be obtained by any known in the pharmaceutical method which includes a step of mixing the active compound and the carrier (which may contain one or more additional ingredients). Typically, such compositions have in result, or both, and then, if necessary, giving the product the desired shape. So, for example, tablets can be obtained by extruding or melting the powder or granules of the compound, optionally with one or more additional ingredients. Molded tablets can be obtained by extruding in a suitable device, the connection in freely presuposes the form of, for example, in the form of powder or granules, optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent (agents). Fused tablets can be obtained, melting in the respective device, the powdered compound moistened inert liquid diluent.

Pharmaceutical compositions suitable for buccal (under the tongue) administration include the compound of formula (I) in the flavor basis, usually sucrose, the resin of acacia or tragakant, and lozenges containing compound in such an inert basis as gelatin and glycerin or sucrose and acacia.

Pharmaceutical compositions for parenteral administration typically comprise sterile aqueous preparations of the compounds of formula (I) preferably is isotonic with the blood of the intended recipient. These drugs are preferably of Wadi. Such drugs are usually prepared by mixing the compound with water, sterilizing the resulting solution and adding it isotonicity with blood. Injectisome compositions of the present invention usually contain from 0.1 to 5% weight/weight of the active compounds.

Pharmaceutical compositions suitable for rectal injection preferably present in the form of a single dose suppositories. They can be obtained by mixing the compound of formula (I) with one or more conventional solid carriers, for example cocoa butter, and then shaping the resulting mixture.

Pharmaceutical compositions suitable for surface application to the skin preferably take the form of ointments, creams, lotions, pastes, sprays, aerosols or oils. The media that can be used include vaseline, lanoline, polyethylene glycols, alcohols and combinations of two or more of them. The active compound is typically present in concentrations of from 0.1 to 15% (weight/weight) of the composition, for example from 0.5 to 2%.

It is also possible transdermal administration. Pharmaceutical compositions suitable for transdermal administration, can be in the form of discrete patches adapted to remain in close contact with the disease is Obedinenie and optional superyoung, aqueous solution, dissolved and/or dispersed in an adhesive or dispersed in the polymer. Suitable concentrations of the active compounds comprise an amount from about 1% to 35%, preferably from about 3% to 15%. In particular, the active compound may be delivered from the patch by using electrotransport or iontophoresis, for example, by the method described in Pharmaceutical Research, 2(6), 318 (1986).

Compounds of the present invention can be obtained by conventional means, known in the art or by processes analogous to published.

For example, the compounds of formula (I) can be obtained by a method that includes:

a) acylation of compounds of formula (II):

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a standard way (for example, using N,N-carbonyldiimidazole) X-H group, or

a) alkylation of compounds of formula (II) standard methods for the X-H group, or

a) glycosylation or glucuronidation of compounds of formula (II)- X-H group, especially using imidatly way, and

b) removing the protective groups, in particular with hydroxy - and amino-functional groups, for example acetyl through hydrolysis, and benzyl - via hydrogenolysis.

The compounds of formula (II) can be obtained by way of the isomers, can be obtained either by using chiral synthesis, for example using an appropriate source of chiral material (materials), such as aziridine, or sharing products derived from achiral synthesis, for example using chiral HPLC or by using the classical separation of chiral acids.

The optional conversion of the compounds of formula (I) or compounds of formula (I) containing the main Deputy, the corresponding salt of the accession acid can be accomplished by the reaction with a solution of the appropriate acid, for example, one of these earlier. The optional conversion of the compounds of formula (I) containing acidic Deputy, in the corresponding basic salt can be performed when interacting with the solution of the corresponding base, for example sodium hydroxide. Optional transformation into such functional derivative, as the ester can be carried out by methods known in the art or are available from the chemical literature.

In addition, the compounds of formula (I) can be converted into other compounds of formula (I) standard methods known in the art, or are available from the literature, for example by alkylation of Oia with the connection 11 WO 96/05188.

For evidence of higher lipid-lowering activity of the compounds of the present invention conducted tests with three genetically modified cell lines. They were derived the well-known cell line Chinese hamster ovary" (SNS) (cells Chinese hamster ovary), which is due to the built-in expression plasmids additionally produces sodium-dependent transporters for bile acids. The first cell line (CHO/pPIBAT8) in this case represents the conveyor ileum rabbit (RIBAT), second (CHO/pHIBAT8) conveyor ileum person (HIBAT), and the third (SNO/L5) hepatic Transporter man. All plasmids based on the standard plasmid pCDNAlneo, which, as important elements contains a cytomegalovirus promoter for the permanent expression of heterologous genes, and the gene for the development of resistance of cells to the substance G418.

The source material for obtaining plasmids for RIBAT-producing cell line (pRIBAT8) was total RNA terminal ileum of the pig. From it using RT-PCR procedure (reaction reverse transcriptase followed by polymerase chain reaction) using oligonucleotide

5'-gtcagaccagaagcttgggcttctgcagac-3'

and

5'1 pair of bases adjacent to the 5', and 31, a pair of bases adjacent to the 3'-untranslated segment. This plot flank, arseplay sites for restriction enzymes Hind3 (5'- end) and Xbal (3'-end). The obtained cDNA and DNA plasmids pcDNAlneo process using two restriction enzymes and the resulting fragments combine with ligase to obtain the expression plasmid pRIBAT8.

Plasmid for HIBAT-producing cell line (pHIBAT8) receive similar pRIBAT8. In this case, total RNA terminal ileum person and oligonucleotides

5'-taaaagttggatccggtagaagtaaacg-3'

and

5'-tctgttttgtcctctagatgtctacttttc-3'

serve as the source material. In addition to the full protein-coding section HIBAT obtained cDNA also contains 97 base pairs at the 5'-adjacent and 5 base pairs at the 3'-adjacent noncoding area. This plot flank, arseplay sites for restriction enzymes BamHl (5'-end) and Xbal (3'-end). The obtained cDNA and DNA plasmids pcDNAlneo process using the two restriction enzymes and the resulting fragments combine with ligase to obtain the expression plasmid pRIBAT8.

Commercially available cDNA gene Bank obtained from human liver, is the initial materialmay chain reaction) using oligonucleotide

5'-ggagtggtcttccactggatcccaggaggatggagg-3'

and

5'-ccagaatccaggccacctctagaagggctaggctgt-3',

synthesize cDNA, which contains the complete protein-coding block H Wat, and 7 base pairs adjacent to the 5'- and 6 base pairs adjacent to the 3'-untranslated segment. This plot flank, arseplay sites for restriction enzymes VMN (5'-end) and Xbal (3'-end). The obtained cDNA and DNA plasmids pcDNAlneo process using two restriction enzymes and the resulting fragments are combined using ligase to obtain the expression plasmid pHLBAT5.

To obtain a genetically modified cell lines, Cho cells transfection using DNA from pRIBAT8, pHIBAT8 or pHLBAT5, and cells that develop resistance to the selected substance G418 selective additionally cultivate, adding the substance to the cell's environment. Cells CHO/pRIBAT8, CHO/pHIBAT8 and CHO/pHLBAT5 further isolated from the number of G418-resistant cells, and cultivate pure clonal lines. Tool, which is used for subsequent selection in this case is a fluorescent derivative of a bile acid (3-NBD-NCT; N-[7-(4-nitrobenzo-2-oxa-1, 3-diazole)] -3-amino-7a, 12A-dihydroxyfuran-24 oil)-2'-aminoethanesulfonic. Cells with intact t is scantime. Therefore, it becomes easy to differentiate from cells without intact transporters bile acids using a fluorescent microscope.

All three cell lines efficiently transported radioactivedecay human beings need it to acid from the extracellular environment into the cell. This process is sodium-dependent. In contrast, Cho cells without intact transporters bile acids only absorb only a very small number of human beings need it to acid. Based on this, the characterization of the test compounds by the method of the present invention is as follows: cell type CHO/pRIBAT8, CHO/pHIBAT8 or CHO/pHLBAT5 simultaneously exhibit in the cultural cups radioactivedecay human beings need it to acid, and measure the test substance and the absorption by the cells of the radioactive material. The concentration of the test substance change systematically from Cup to Cup, keeping constant all other parameters. To prepare them for the experiment, cells in the usual manner cultured in medium (minimal essential medium (MEM); 1% MEM solution, nonessential amino acids, 10% fetal calf serum; 400 g/ml G418) in culture flasks; if necessary, removed from their environment with pomoshyu in the environment. Shortly before reaching confluently cells the medium was removed and the contents in each Cup washed twice with 1.5 ml PBS (Dulbecco phosphate superyoung saline). After removal of the wash solution in each Cup add 1 ml of a certain concentration of a test compound in PBS, and incubated at 21oC for 30 minutes. This pre-incubated solution then replace the test solution containing |24-14C|-human beings need it to acid at a concentration of 4.3 M and a specific radioactivity 7400Bq/ml, but in all other respects have the same volume and composition, as preincubation solution. Cells exhibiting a test solution at the 21oC for 30 minutes and then washed 5 times with 1.5 ml PBS per Cup. For the implementation of the lysis of the cells, 1 ml of an aqueous solution containing 0.1 mol/l NaOH and 0.1% (weight/volume) SDS was added to each Cup, which is incubated for 30 minutes at 21oWith and thoroughly RUB.

And, finally, the contents of each Cup mixed with 10 ml of commercially available scintillation solution, and determine the radioactivity retained by the cells by using a device that measures the scintillation.

Results related to transport, the magnitude of the value in those cases if measurements were carried out without inhibition test substance. Half maximal inhibition values (IC50) get any of the graphics or arithmetically:

Example 3

IC50(RIBAT): 70 nm = 0,07 μm

Example 11 WO 96/05188

IC50(RIBAT): 4 μm

A similar study of the influence of the same substances on the transport of cell line CHO/pHIBAT8 shows that in this case, the corresponding IC50values vary approximately in the same order of magnitude. In contrast, the IC50the value defined for the cell line CHO/pHLBAT5 was several orders of magnitude higher. This shows that the compounds of the present invention can provide comparative effect on ontologique sodium-dependent transporters for bile acids of various kinds, and, in contrast, the effect on analogichnye conveyors other organs is much less.

For a better understanding of the invention provides the following example to illustrate (for example, N,N-carbonyl diimidazol), and it should not be construed as in any way limiting the scope of invention.

Example 1

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To a solution of 2.9 g of methyl 2,3,4-tri-O-acetylglucosamine in 100 ml of dry dichloro the R is stirred for 10 minutes. Then add 730 mg of potassium carbonate.

After 30 minutes stirring at room temperature the mixture is filtered through a small layer of silicon dioxide, elwira ether. The obtained filtrate was concentrated in vacuo to obtain the crude product in the form of a solid pale yellow color (3.7 g). 1.0 g of this product was dissolved in 15 ml of dry dichloromethane and added to a solution of Phenol (1) (TRANS-racemate) in 30 ml of dry dichloromethane. After cooling to -10oWith the type of 0.32 ml F3t2and after 30 minutes at -10oC, the resulting mixture is stirred for 20 hours at room temperature. Then the reaction mixture was diluted with dichloromethane and washed with aqueous sodium bicarbonate solution and brine. The combined organic phases are dried over sodium sulfate and evaporated in vacuum. The crude product is purified chromatographically on silica gel (n-heptane/ethyl acetate 2:1) to obtain 625 mg of the compound of example 1 Rf=0,17 (n-heptane/ethyl acetate 1:1).

C34H43NO12S (689): MS (fast atom bombardment, 3-NBA):690(M+H+).

Example 2

Example 3

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To a solution of 900 mg of the compound of example 1 in 45 ml of methanol is added 15 ml of 1N. NaOH. After 4 hours at comnational to pH 3 using 2n. HCl and evaporated to dryness. In the chromatographic processing on silica gel (CH2Cl2/MeOH/ 33% aq. NH3=30:10:3) get 2 factions.

1 faction: example 2, Rf= 0,85 (CH2CL2/Meon/33% aq. NH3=30:10:3) (spray ionization electrons) (C27H35NO8S (531): MS(ESI):532 (M+H+)

2 fraction: example 3, Rf= 0,52 (CH2CL2/Meon/33% aq. NH3, 30:10:3) (C27H35NO9S (549):MS (fast atom bombardment, 3-NBA) 550(M+H+)

Example 4

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The compound of example 4 receive by way of example, 1 Rf=0,20 (n-heptane/ethyl acetate 1:1)

C35H45NO12S (703) Mass spectrum (ei spray of electrons): 704(M+H+)

Example 5

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The compound of example 5 receive by way of example 2

Rf=0,20 (CH2C12/Meon/33% aq. NH3, 60:10:3)

C27H37NO8S (535): Mass spectrum (fast atom bombardment 3-NBA): 536 (M+H+)d

1. 1,4-benzothiazepine-1,1-dioxide of the formula (I)

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where R1is non-branched C1-6alkyl group;

R2is non-branched C1-6alkyl group;

R3represents hydrogen;

R4represents phenyl;

R/BR>< / BR>
where the hydroxy-group may be substituted by acetyl;

R16represents-COOH, -CH2-OH, -CH2-O-acetyl-Sooma;

R9and R10the same or different and each represents hydrogen or C1-6alkyl group;

X represents-O-;

or its salt, solvate and physiologically functional derivatives.

2. Connection on p. 1 of formula (III)

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where R1-R10and X are specified in paragraph 1.

3. Connection on p. 1, which have the formula (IVa)

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where R1-R10and X are specified in paragraph 1.

4. The compound according to any one of paragraphs. 1-3, where R7chosen from compounds of formulas

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5. 1,4-benzothiazepine-1,1-dioxide of the formula (V)

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6. The compound according to any one of paragraphs. 1-5 or its pharmaceutically acceptable salt, MES or physiologically functional derivative as the active ingredient of the medicinal product for the prevention or treatment of a clinical condition in which shows the inhibitor absorption of bile acids.

7. A method of obtaining a compound according to any one of paragraphs. 1-5 and its salts, solvate and physiologically functional derivatives, characterized in that it includes the s protective groups, especially, when hydroxyl and amidofunctional groups.

8. A method of obtaining a compound according to any one of paragraphs. 1-5 and its salts, solvate and physiologically functional derivatives, characterized in that it includes a) alkylation of compounds of formula II standard methods in X-H group and (b) removing the protective groups, especially hydroxyl and amino functional groups.

9. A method of obtaining a compound according to any one of paragraphs. 1-5 and its salts, solvate and physiologically functional derivatives, characterized in that it includes a) glycosylation or glucuronidation of compounds of formula II-X-H group and (b) removing the protective groups, especially hydroxyl and amino functional groups.

 

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