MXPA98001992A - 1,4-benzotiazepin-1, 1-dioxidos hipolipemian - Google Patents

Abstract

The present invention relates to novel lipid-lowering compounds, to their processes and new intermediates for their preparation, to pharmaceutical compositions containing them and to their use in medicine, particularly in the prophylaxis and treatment of hyperlipidaemic conditions, such as atherosclerosis. Compounds of the formula (I): wherein R1 to R10 and X are as defined

Description

1, 4-Benzothiazepin-1, 1-lipid-lowering dioxides The present invention relates to novel lipid-lowering compounds, to processes and new intermediates for their preparation, to pharmaceutical compositions containing them and to their use in medicine, particularly in the prophylaxis and treatment of hyperlipidaemic conditions, such as atherosclerosis. Hyperlipidemic states are frequently associated with high plasma concentrations of low density lipoprotein cholesterol (LDL) and very low density lipoprotein cholesterol (VLDL). These concentrations can be reduced by decreasing the absorption of bile acids from the intestine. One method by which this can be achieved is by inhibiting the active absorption system of bile acids in the terminal ileum. Said inhibition stimulates the conversion by the liver of the cholesterol into bile acid and the resulting increase in the demand for cholesterol produces a corresponding increase in the rate of elimination of the LDL and VLDL cholesterol from the plasma or blood serum. Currently, a new class of heterocyclic compounds has been identified that reduce plasma or serum cholesterol concentrations of LDL and VLDL and are consequently particularly useful as lipid-lowering agents. By decreasing the concentrations of cholesterol and cholesterol ester in the plasma, the compounds of the present invention retard the accumulation of atherosclerotic lesions and reduce the incidence of episodes related to coronary heart diseases. These are defined as cardiac events associated with higher concentrations of cholesterol and cholesterol ester in plasma or serum. For the purposes of this specification, a hyperiipemic state is defined as any state in which the total cholesterol concentration (LDL + VLDL) in plasma or serum is greater than 240 mg / dL (6.21 mmol / L) (J Amer. Med. Assn. 256, 20, 2849-2858 (1986)).

International patent application No. WO 96/05188 describes compounds of formula (0) The inventors of the present invention have now discovered a group of compounds that have greater lipid-lowering activity in vivo than those specifically described in the international patent application No. WO 96/05188. The compounds differ in the definition of the R7 group. Accordingly, the present invention provides compounds of the formula (I): wherein R1 is a straight chain C1_alkyl group; R2 is a straight chain C ^ alkyl group; R is hydrogen or an OR11 group in which R11 is hydrogen, an optionally substituted C ^ or C alqu alkylcarbonyl group; R is pyridyl or optionally substituted phenyl; R5, R6 and F are the same or different and each is selected from hydrogen, halogen, cyano, R15-acetyl, OR15, optionally substituted C ^ g alkyl, COR15, CH (OH) R15, S (O) nR15, P (O) (OR15) 2, OCOR15, OCF3, OCN, SCN, NHCN, CH2OR15, CHO, (CH2) pCN, CONR12R13, (CH2) pCO2R15, (CH2) pNR12R13, CO2R15, NHCOCF3, NHS02R15, OCH2OR15, OCH = CHR15 , 0 (CH2CH2O) nR15, O (CH2) pS03R15, O (CH2) pNR12R13 and 0 (CH2) pN + R12R13R14 where P is an integer of 1-4, n is an integer of 0-3 and R 12 R 13, R 14 and R 15 are independently selected from hydrogen and optionally substituted C 1 alkyl; R 'is a group of the formula wherein the hydroxyl groups may be substituted with acetyl or benzyl, or -20-alkyl (CrC6) -R 17 wherein the alkyl group may be substituted with one or more hydroxyl groups; R 16 is -COOH-CH 2 -OH; -CH2-0-acetyl, -COOMe, -COOEt; R 17 is H, -OH, -NH 2, -COOH or COOR 18; R 18 is alkyl (CrC 4) or -NH-alkyl (C C 4); X is -NH- or -O-; and R9 and R10 are the same or different and each is hydrogen or C, _g alkyl; 30 and its salts, solvates and physiologically functional derivatives.

When R 4 is a substituted phenyl group, it may have from one to five, preferably one or two identical or different substituents and each selected from halogen, hydroxy, nitro, phenyl-C 1 alkoxy, C 1 alkoxy, C 1 alkyl, ^ optionally substituted, S (0) nR15, C02R15, 0 (CH2CH20) nR15, 0 (CH2) pS03R15, 0 (CH2) pNR12R13 and 0 (CH2) N + R12R13R14, wherein R12 to R15, n and p are as they are defined above. Preferred embodiments of the compounds of formula (I) include compounds of formula (III), (IV) or (IVa) ) in which R1 to R10 and X are as defined above. When one or more of R 3 to R 6, R 8 or R 11 to F 4 is a substituted C 1 ___ alkyl group, or comprises a C 1 alkyl group, the substituents may be the same or different and each is selected from hydroxy, halogen , C ^ alkyl, C ^ alkoxy, COR20, nitrile, C02R2 °, S03R2 °, NR21R22, N + R21R22R23, in which R20 to R23 are the same or different and each is selected from hydrogen or C1_alkyl. Suitably R1 is methyl, ethyl or n-propyl and preferably R1 is ethyl. Suitably R2 is methyl, ethyl, n-propyl, n-butyl or n-pentyl. Preferably R2 is n-butyl. Preferably R5 is hydrogen. Suitably R7 is selected from Suitably X is -O-. Suitably R9 and R10 are hydrogen, methyl or ethyl, hydrogen Preferably R9 and R10 are both hydrogen. - Suitably R 4 is pyridyl or optionally substituted phenyl, preferably in the 4 and / or 3 position with halogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, hydroxy, carboxy or O (CH 2) 3 SO 3 H. Preferably R 4 is unsubstituted phenyl. In the compounds of the formula (III): suitably at least one, and preferably all, of R5, R6 and R8 are hydrogen. When R5, R6 and R8 are other than hydrogen they are suitably C alquilo alquilo alkyl optionally substituted with fluorine, C alco-4 alco alkoxy, halogen or hydroxy, more suitably methyl, methoxy, hydroxy, trifluoromethyl or chloro and preferably methoxy. In the compounds of the formula (IV): suitably two or three of R5, R6 and ff are hydrogen, the others being C1-4alkyl optionally substituted with fluorine, C4alkoxy, halogen or hydroxy and more suitably methyl, methoxy , hydroxy, trifluoromethyl or chloro and preferably methoxy.

In the compounds of formula (IVa): suitably at least one, and preferably all, of R5, R6 and R8 are hydrogen. When R 5, R 6 and R 8 are other than hydrogen, they are suitably C 1 4 alkyl optionally substituted with fluorine, C 1 alkoxy, halogen or hydroxy, more suitably methyl, methoxy, hydroxy, trifluoromethyl or chloro and preferably methoxy. More preferably, R1 is n-butyl, R2 is ethyl, R3, R5, R6, R8, R9 and R10 are hydrogen, R4 is phenyl and R7 is The pharmaceutically acceptable salts are particularly suitable for medical applications due to their greater aqueous solubility in relation to the precursor compounds, ie basic. Said salts must clearly have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention include those derived from inorganic acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic and sulfuric acids, and from organic acids, such as acetic acids, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic, tartaric and trifluoroacetic. For medical purposes, the chloride salt is particularly preferred. Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, and alkaline earth metal salts, such as magnesium and calcium salts. Salts having a non-pharmaceutically acceptable anion are within the scope of the invention as intermediates useful for the preparation or purification of pharmaceutically acceptable salts and / or for use in non-therapeutic applications, for example in vitro.

The term "physiologically functional derivative" as used herein refers to any physiologically acceptable derivative of a compound of the present invention, for example, an ester, which by administration to a mammal, such as a human being, is capable of to provide (directly or indirectly) said compound or one of its active metabolites. A further aspect of the present invention is constituted by the prodrugs of the compounds of the invention. Said prodrugs can be metabolized in vivo to a compound according to the invention. These prodrugs can themselves be or not be active. i o The compounds of the present invention can also exist in different polymorphic forms, for example, amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the present invention are within the scope of the invention and are one of its additional aspects. The term "alkyl" as used herein refers, unless otherwise indicated, to a monovalent straight or branched chain radical. Likewise, the term "alkoxy" refers to a straight or branched chain monovalent radical linked to the parent molecular moiety through an oxygen atom. The term "phenylalkoxy" refers to a pivalent or monovalent group bonded to a divalent C1-6 alkylene group which in turn is linked to the parent molecular moiety through an oxygen atom.The compounds of formula (I) exist in wherein the carbon centers -C (R1) (R2) - and -CHR4- are / are chiral The present invention includes within its scope each possible optical isomer Substantially free, ie associated with less than 5%, of any other optical isomer (s), and mixtures of one or more optical isomers in any proportions, including racemic mixtures. For the purposes of this specification, the absolute chiralities of the aforementioned carbon centers are given in the order -C (R1) (R2), and continuation -CHR4-.

In cases where the absolute stereochemistry in -C (R) (R2) -, and -CHR4- has not been determined, the compounds of the invention are defined as a function of the relative positions of the substituents R1 / R2 and H / R4. Thus the compounds in which the most voluminous of the substituents R1 and R2, ie the substituent of higher mass, and the substituent R4 are both located on the same side of the thiazepine ring are referred to herein as "cis" and the compounds in which the most voluminous of the substituents R1 and R2 is located on opposite sides of the ring are termed "trans" and are preferred. It will be apparent to the experts that both the "cis" and "trans" compounds of the invention may each exist in two enantiomeric forms that are referred to individually "(+) -" or "(-) -" in accordance with the direction rotation of a plane of polarized light when it passes through a sample of the compound. The cis or trans compounds of the invention in which the individual enantiomers have not been resolved are referred to herein using the prefix "(+) -". According to further aspects of the invention, there are also provided: (a) compounds of formula (I) and their pharmaceutically acceptable salts, solvates and physiologically functional derivatives, for use as therapeutic agents, particularly in the prophylaxis and treatment of clinical conditions for which an acid absorption inhibitor is indicated biliary, for example a hyperlipidaemic state, such as atherosclerosis; (b) pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, at least one pharmaceutically acceptable excipient and, optionally, one or more other physiologically active agents; (C) the use of a compound of formula (I) or of one of its pharmaceutically acceptable salts, solvates or physiologically functional derivatives in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition for which it is indicated an inhibitor of bile acid absorption, for example a hyperlipidemic state, such as atherosclerosis; (d) a method for inhibiting the absorption of bile acids from the intestine of a mammal, such as a human, which comprises administering to the mammal an effective amount inhibiting the absorption of bile acids of a compound of formula (I) or one of its pharmaceutically acceptable salts, solvates or physiologically functional derivatives; (e) a method for reducing blood plasma or serum cholesterol concentrations of LDL and VLDL in a mammal, such as a human, which comprises administering to the mammal an effective cholesterol reducing amount of a compound of formula (I) or of one of its pharmaceutically acceptable salts, solvates or physiologically functional derivatives; (f) a method for reducing the cholesterol and cholesterol ester concentrations in the plasma or blood serum of a mammal, such as a human, which comprises administering to the mammal an effective amount reducing cholesterol and cholesterol ester of a compound of formula (I) or one of its pharmaceutically acceptable salts, solvates or physiologically functional derivatives; (g) a method for increasing the fecal excretion of bile acids in a mammal, such as a human, which comprises administering to the mammal an amount effective to increase the fecal excretion of bile acids of a compound of formula (I) or of one of its pharmaceutically acceptable salts, solvates or physiologically functional derivatives; (h) a method for the prophylaxis or treatment of a clinical condition in a mammal, such as a human being, for which a bile acid absorption inhibitor is indicated, for example, a hyperlipidemic state, such as atherosclerosis, which comprises administering to the mammal a therapeutically effective amount of a compound of the formula (I) or one of its pharmaceutically acceptable salts, solvates or physiologically functional derivatives; (i) a method for reducing the incidence of episodes related to coronary heart disease in a mammal, such as a human being, which comprises administering an effective reducing amount of coronary heart disease-related episodes of a compound of formula (I) or of one of its pharmaceutically acceptable salts, solvates or physiologically-functional derivatives; Q) a method for reducing the concentration of cholesterol in the plasma or blood serum of a mammal, such as a human being, which comprises administering an effective cholesterol reducing amount of a compound of formula (I); (k) processes for the preparation of compounds of formula (I) (including their salts, solvates and physiologically functional derivatives defined herein); Y (I) new intermediate chemical compounds in the preparation of the compounds of formula (I); (m) the compounds of synthesis example 1 to 5 described below.

Hereinafter all references to "compound (s) of formula (I)" refer to compound (s) of formula (I) as described above together with their salts, solvates and physiologically functional derivatives defined herein . The amount of a compound of formula (I) that is required to achieve the desired biological effect will, of course, depend on several factors, for example, the specific compound chosen, the intended use of it, the mode of administration and the condition clinical of the receiver. In general, a daily dose is in the range of 0.3 mg to 100 mg (typically 3 mg to 50 mg) per day per kilogram of weight, eg, 3-10 mg / kg / day. An intravenous dose can, for example, be in the range of 0.3 mg to 1.0 mg / kg, which can conveniently be administered as an infusion of 10 ng to 100 ng per kilogram per minute. Infusion fluids suitable for this purpose may contain, for example, 0.1 ng to 10 mg, typically 1 ng to 10 mg, per milliliter. The unit doses 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 and orally administrable unit dose formulations, such as tablets or capsules, may contain, for example, from 1.0 to 1000 mg, typically from 10 to 1000 mg. 600 mg. In the case of pharmaceutically acceptable salts, the weights indicated above refer to the weight of the benzothiazepine ion derived from the salt. For the prophylaxis or treatment of the aforementioned states, the compounds of formula (I) can be used as the compound per se, but are preferably presented with an acceptable excipient in the form of a pharmaceutical composition. Naturally, the excipient should be acceptable in the sense of being compatible with the other ingredients of the composition and should not be detrimental to the recipient. The excipient may be solid or liquid, or both, and is preferably formulated with the compound as a unit dose composition, for example, a tablet, which may contain from 0.05% to 95% by weight of the active compound. Other pharmacologically active substances, including other compounds of formula (I), may also be present. The pharmaceutical compositions of the invention can be prepared by any of the well known pharmacy techniques consisting essentially of mixing the components. The pharmaceutical compositions according to the present invention include those suitable for oral administration, rectal, topical, buccal (for example, sublingual) and parenteral (for example, subcutaneous, intramuscular, intradermal or intravenous), although the most appropriate route in any given case will depend on the nature and severity of the condition to be treated and on the nature of the particular compound of formula (I) to be employed. Enteric coated and enteric coated controlled release formulations are also within the scope of the invention. Formulations resistant to acids and gastric juices are preferred. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methacrylic acid methyl ester. Pharmaceutical compositions suitable for oral administration can be presented in individual units, such as capsules, stamps, troches or tablets, each containing a predetermined amount of a compound of formula (I); as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil type emulsion. As indicated, said compositions may be prepared by any suitable pharmacy method, which includes the operation of associating the active compound and the excipient (which may be constituted by one or more accessory ingredients). In general, the compositions are prepared by uniformly and intimately admixing the active compound with a liquid carrier or finely divided solid, or both, and then, if necessary, shaping the product. For example, a tablet or tablet can be prepared by compressing or molding a powder or granules of the compound, optionally with one or more accessory ingredients. The tablets can be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binding agent (s), lubricant, inert diluent and / or surfactant / dispersant. The molded tablets can be prepared by molding, in a suitable machine, the powder compound moistened with an inert liquid diluent. Pharmaceutical compositions suitable for buccal (sub-lingual) administration include troches comprising a compound of formula (I) in a flavored base, generally sucrose and gum arabic or tragacanth, and lozenges comprising the compound in an inert base, such as gelatin and glycerin or sucrose and gum arabic. Pharmaceutical compositions suitable for parenteral administration conveniently comprise sterile aqueous preparations of a compound of formula (I), preferably isotonic with the blood of the desired receptor. These preparations are preferably administered intravenously, although administration can also be effected by means of subcutaneous, intramuscular or intradermal injection. Said preparations can be conveniently prepared by mixing the compound with water and making the solution sterile and isotonic with the blood. resulting. Injectable compositions according to the invention will generally contain from 0.1 to 5% w / w of the active compound. Pharmaceutical compositions suitable for rectal administration are preferably presented as suppositories in unit doses. They can be prepared by mixing a compound of formula (I) with one or more conventional solid excipients, for example, cocoa butter, and then shaping the resulting mixture. Pharmaceutical compositions suitable for topical application to the skin preferably take the form of balsam, cream, lotion, paste, spray, aerosol or oil. The excipients that can be used include petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of them. The active compound is generally present at a concentration of 0.1 to 15% w / w of the composition, for example, from 0.5 to 2%. Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal administration may be present as individual patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Said patches suitably contain the active compound in an aqueous solution optionally buffered, dissolved and / or dispersed in an adhesive, or dispersed in a polymer. A suitable concentration of the active compound is from about 1% to 35%, preferably about 3% to 15%. As a particular possibility, the active compound can be released from the patch by electrotransport or iontophoresis, for example, as described in Pharmaceutical Research, 2 (6), 318 (1986). The compounds of the invention can be prepared by conventional methods known to those skilled in the art or analogously to methods described in the art. For example, the compounds of the formula (I) can be prepared by a process comprising: a) acylating a compound of the formula (II) by procedures of the standard type (for example with N, N-carbonyl-diimidazole) in the group -XH or a) to alkylate a compound of formula (II) by procedures of the standard type in the -XH group or to) glycosylate or glucuronidate a compound of formula (II) in the group -XH, especially using the imidate method and b) cleaving the protecting groups, especially the hydroxyl and amino functional groups, for example acetyl by hydrolysis and benzyl by hydrogenolysis. The compounds of formula (II) can be prepared according to the method of preparation described in WO 96/05188. The compounds of formula (I), substantially free of other optical isomers, can be obtained either by chiral synthesis, for example, by the use of the appropriate chiral starting material (s), such as aziridine, or by resolution of the products obtained by achiral synthesis, for example by chiral HPLC or by classical resolution with chiral acids. The optional conversion of a compound of formula (I), or a compound of formula (I) comprising a basic substituent, into a corresponding acid addition salt can be effected by reaction with a solution of the appropriate acid, for example, one of the aforementioned. The optional conversion of a compound of formula (I) comprising an acidic substituent into a salt with the corresponding base can be effected by reaction with a solution of the appropriate base, for example sodium hydroxide. Optional conversion to a physiologically functional derivative, such as an ester, can be carried out by methods known to those skilled in the art or obtainable in the chemical literature. In addition, the compounds of formula (I) can be converted to different compounds of formula (I) by typical methods known or available in the literature by those skilled in the art, for example by alkylation of a hydroxy group. Comparison of lipid-lowering activity of the compounds according to the invention with compound number 11 of WO 96/05188: In order to provide the highest lipid-lowering activity of the compounds according to the invention, tests were carried out by means of three cell lines genetically modified. They came from the line of cells of "Chinese hamster ovary" (CHO) generally known, which due to having uninformed expression plasmids additionally produced bile acid transporters dependent on sodium. The first cell line (CHO / pRIBAT8) was in this case the rabbit ileum transporter (RIBAT), the second (CHO / pHIBAT8) the human ileum transporter (HIBAT) and the third (CHO / pHLBAT5) the hepatic transporter of human beings. All the plasmids were based on the neo standard pCDNAI plasmid, which as important elements has a cytomegaloviral promoter for the permanent expression of heterologous genes and a gene for the production of resistance of the cells against the substance G418. The starting material for the production of the plasmid for the RIBAT producer cell line (pRIBATd) was total RNA from the terminal ileum of the rabbit. From it by means of an RT-PCR procedure (reverse transcriptase reaction, followed by a polymerase chain reaction) with the help of the oligonucleotides 5'-GTCAGACCAGAAGCTTGGGCTTCTGCAGAC-3r and 5'-ATCTTAATAATATTCTAGACAG IIIII CTTTG-3 ' a cDNA containing the coding region of the total protein of the RIBAT was synthesized, and also 41 base pairs adjacent to 5 'and 31 base pairs in the untranslated region adjacent to 3'. This region was flanked by cleavage sites for the restriction enzymes Hind3 (at the 5 'end) and Xbal (at the 3' end). The obtained cDNA and the pcDNAl neo plasmid DNA were digested using the two restriction enzymes mentioned and the resulting fragments were ligated by means of ligase to give the expression plasmid pRIBATd. The plasmid for the HIBAT producing cell line (pHIBAT8) was similarly prepared to pRIBATd. In this case, the total RNA of the human terminal ileum and the oligonucleotides S'-TAAAAGTTGGATCCGGTAGAAGTAAACG-S 'and 5, -TCTGTTTTGTCCTCTAGATGTCTACTTTTC-3, served as starting material. In addition to the coding region of the total protein of HIBAT, the resulting cDNA also contained 97 base pairs adjacent to 5 'and 5 base pairs in the untranslated region adjacent to 3'. This region was flanked by the cleavage sites for the restriction enzymes BamHl (at the 5 'end) and Xbal (at the 3' end). The obtained cDNA and the pcDNAl neo plasmid DNA were digested using the two restriction enzymes mentioned and the resulting fragments were ligated by means of ligase to give the expression plasmid pRIBATd. A commercially available cDNA gene library prepared from the human liver served as the starting material for the plasmid for the preparation of the HLBAT producer cell line (pHLBAT5). From it by means of a PCR procedure (polymerase chain reaction) with the help of the oligonucleotides S'-GGAGTGGTCTTCCACTGGATCCCAGGAGGATGGAGG-S 'and 5'-CCAGAATCCAGGCCACCTCTAGAAGGGCTAGGCTGT-3', a cDNA containing the coding region of the DNA was synthesized. the total HLBAT protein, and also 7 base pairs adjacent to 5 'and 6 base pairs in the untranslated region adjacent to 3'. This region was flanked by cleavage sites for the restriction enzymes BamHl (at the 5 'end) and Xbal (at the 3' end). The obtained cDNA and the pcDNAI neo plasmid DNA were digested using the two restriction enzymes mentioned and the resulting fragments were ligated by means of ligase to give the expression plasmid pHLBAT5. For the preparation of genetically modified cell lines, CHO cells were transfected with pRIBATd DNA, pHIBATd or pHLBATd and cells that developed resistance to selection substance G418 were further selectively cultured by addition of the substances to the cell medium. The CHO / pRIBATd, CHO / pHIBATd and CHO / pHLBAT5 cells were then isolated from the amount of G41 d resistant cells and the pure clonal lines were cultured. The tool used to follow the isolation process was in this case a fluorescent derivative of bile acids (3ß-NBD-NCT; N- [7- (4-nitrobenzo-2-oxa-1,3-diazol)] - 3β-amino-7a, 12a-dihydroxy-5β-colan-24-oil) -2'-aminoethanesulfonate). Cells with intact bile acid transporters rapidly absorbed this substance from the cell medium and as a result became fluorescent. They could thereby easily differentiate themselves from the cells without intact bile acid transporters with the aid of a fluorescence microscope. The three cell lines efficiently transported radiolabelled taurocholic acid from the extracellular medium into the cell. This procedure depended on sodium. In contrast to this, CHO cells without intact bile acid transporters only absorbed very small amounts of taurocholic acid. Based on this knowledge, a characterization of the test substances according to the invention was carried out as follows: cells of the CHO / pRIBATd, CHO / pHIBAT8 or CHO / pHLBAT5 type were simultaneously exposed in culture plates to radiolabeled taurocholic acid and a substance and the absorption by the cells of the radioactive material was measured. The concentrations of the test substance of the present invention were systematically varied from one plate to another and the other parameters were kept constant. To prepare them for the experiment, the cells were routinely cultured in a medium (minimal essential medium (MEM), 1% solution in non-essential amino acids of MEM, 10% fetal calf serum, 400 g / ml G418) In culture flasks, if necessary, they were separated from their environment by means of trypsin, inoculated in diluted form into culture plates (diameter: 3.5 cm) and further cultivated in the medium. Shortly before reaching the cell confluence, the medium was removed from the cells and the contents of each plate was washed twice with 1.5 ml of PBS (Dulbecco's phosphate buffered saline). After removing the wash solution, 1 ml of defined concentration of the test substance in PBS was added to each plate and then incubated at 21 ° C for 30 minutes. This preincubation solution was then replaced by a test solution containing [24-14C] -taurocholic acid at a concentration of 4.3 M and a specific radioactivity of 7400 Bq / ml, but which also had the same volume and same composition as the solution before incubation. The cells were exposed to the test solution at 21 ° C for 30 minutes and then washed five times with 1.5 ml of PBS per plate. To lyse the cells, 1 ml of an aqueous solution containing 0.1 mol / l NaOH and 0.1% (w / v) SDS was added to each plate, which was incubated for 30 minutes at 21 ° C and It was crushed. Finally, the content of each plate was mixed with 10 ml of a commercially available scintillation solution and the radioactivity absorbed by the cells was determined with the aid of a scintillation measuring device. To determine the transport results, the radioactivity values were not directly represented, but their percentage of relation to a control value in the event that such measurement had been made without inhibiting the test substance. From here, the values of maximum inhibition of the half (Cl50) were obtained graphically or arithmetically: Example 3 Cl50 (RIBAT) 70 nM = 0.07 μM Example 11 of WO 96/05188 Cl50 (RIBAT) 4 μM An analogous investigation of the effect of the same substances on the transport of the CHO / pHIBAT8 cell line showed that in that case the corresponding Cl50 value varied approximately within the same order of magnitude. In contrast, the Cl50 value determined with the CHO / pHLBAT5 cell line was several powers greater than 10. This shows that the compounds according to the invention can exert a comparable effect on sodium-dependent bile acid orthologous transporters of various species and, in contrast, the effect on the paralogical transporters of other organs can be much smaller. For a better understanding of the invention, the following example is given as an illustration (eg with N, N-carbonyl-diimidazole) and is not to be understood as limiting the scope of the invention.Example 1 To a solution of 2.9 g of methyl-2,3,4-tri-0-acetyl glucuronate in 100 ml of anhydrous dichloromethane at room temperature under argon was added 4.6 ml of trichloroacetonitrile and the solution was stirred for 10 minutes. minutes Then 730 mg of potassium carbonate was added. After 30 min of stirring at room temperature, the mixture was filtered through a small piece of silica, eluting with ether. The filtrate was concentrated in vacuo to give the crude product as a pale yellow solid (3.7 g). 1.0 g of this product was dissolved in 15 ml of anhydrous dichloromethane and added to a solution of Phenol I (transracemate) in 30 ml of anhydrous dichloromethane. After cooling to 10 ° C, then 0.32 ml of BF3.ET20 was added and after 30 minutes at -10 ° C the mixture was stirred at room temperature for 20 hours. The mixture was then diluted with dichloromethane and washed with aqueous sodium bicarbonate and brine. The combined organic phases were dried over Na2SO4 and evaporated in solvent vacuum. The crude product was purified by chromatography on silica gel, (n-heptane / ethyl acetate, 2: 1), to obtain 625 mg of example 1.. Rf = 0.17 (n-heptane / ethyl acetate 1: 1) C34H43NO12S (689): MS (FAB, 3-NBA): 690 (M + H +).

- - Example 2 Example 3 To a solution of 900 mg of Example 1 in 45 ml of methanol was added 15 ml of 1 N NaOH. After 4 hours at room temperature 150 ml of H20 was added and the organic solvent was evaporated in vacuo. The aqueous solution was adjusted to a pH of 3 with 2N HCl and evaporated until dry. Chromatography on silica gel (CH2Cl2 / MeOH / 33% aqueous NH3, 30: 10: 3) yielded two fractions.

Fraction 1: Example 2, Rf = 0.85 (CH2Cl2 / MeOH / 33% aqueous NH3, 30: 10: 3). C27H33N08S (531): MS (ESI): 532 (M + H +) Fraction 2: Example 3, Rf = 0.52 (CH2Cl2 / MeOH / 33% aqueous NH3, 30: 10: 3). (C27H35NO9S (549): MS (FAB, 3-NBA): 550 (IVI + H +) Example 4 Example 4 was obtained analogously to example 1. Rf = 0.20 (n-heptane / ethyl acetate 1: 1). C35H45NO12S (703): MS (ESI): 704 (M + H +) Example 5 Example 5 was obtained analogously to example 2. Rf = O.20 (CH2Cl2 / MeOH / 33% aqueous NH3, 60: 10: 3).

C27H37N08S (535): MS (FAB, 3-NBA): 536 (M + H +).

NMR data of Example 3 Chemical shifts in MeOHd4 at 300 K

Claims (13)

1. CLAIMS 1.- A compound of the formula (I) wherein R is a straight chain C ^ alkyl group; is a straight chain C ^ alkyl group; R is hydrogen or an OR11 group in which R11 is hydrogen, an optionally substituted C C ^, C o alkylcarbonyl group; R is pyridyl or optionally substituted phenyl; R5, R6 and F? they are the same or different and each is selected from hydrogen, halogen, cyano, R15-acetyl, OR15, optionally substituted C1- alkyl, COR15, CH (OH) R15, S (O) nR15, P (O) (OR15) 2, OCOR15, OCF3, OCN, SCN, NHCN, CH2OR15, CHO, (CH2) pCN, CONR12R13, (CH2) pCO2R15, (CH2) pNR12R13, CO2R > 1'5 °, NHCOCF3, NHSO2R 1'5 °, OCH2OR > 15 OCH = CHR15, O (CH2CH2O) nR15, O (CH2) pSO3R15, O (CH2) pNR12R13 and O (CH2) pN + R12R13R14 where it is an integer of 1-4, n is an integer of 0- 3 and R12, R13, R14 and R15 are independently selected from hydrogen and optionally substituted C, ^ alkyl; R7 is a group of the formula in which the hydroxyl groups may be substituted with acetyl or benzyl, or -alkyl (Cr6) -R17 wherein the alkyl group may be substituted with one or more hydroxyl groups; R 16 is -COOH or -CH 2 -OH; -CH2-0-acetyl, -COOMe or -COOEt; R17 is H, -OH, -NH2, -COOH or COOR18; R 18 is alkyl (CrC 4) or -NH-alkyl (CrC 4); is -NH- or -O-; and R and R are the same or different and each is hydrogen or C1_alkyl; and its salts, solvates and physiologically functional derivatives.
2. 2. The compounds according to claim 1, having the formula (III) wherein R1 to R and X are as defined in claim 1.
3. 3. The compounds according to claim 1, which have the formula (IV): wherein R1 to R and X are as defined in claim 1.
4. 4. The compounds according to claim 1 having the formula (IVa) wherein R1 to R10 and X are as defined in claim 1.
5. 5. A compound according to any of claims 1 to 4, wherein R7 is selected from fifteen twenty 25 30 and X is -0- 6.- A compound of the formula 7 '.- A pharmaceutical composition comprising one or more compounds according to any of claims 1 to 6. 8.- A pharmaceutical composition resistant to acids and gastric juices, comprising one or more compounds according to any of the claims 1 to 6. 9. A method for treating a clinical condition in a mammal for which a bile acid absorption inhibitor is indicated, which comprises administering to a mammal an effective amount inhibiting the absorption of bile acid in accordance with any one of claims 1 to 6. 10. A method for treating a hyperlipidaemic state in a mammal, comprising administering to the mammal, an effective amount for hyperlipidemiant treatment of a compound according to any of claims 1 to 6. The method of claim 10, wherein the hyperlipidaemic state is atherosclerosis. 12. The use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition for the that an inhibitor of biliary absorption is indicated. 13. A method for the preparation of a compound according to any one of claims 1 to 6, and its salts, solvates or physiologically functional derivatives, comprising a) acylating a compound of formula II by procedures of the standard type in the group -XH or a) to alkylate a compound of formula II by procedures of the standard type in the group -XH or to) glycosylate or glucuronidate a compound of formula II in the group -XH, and b) to cleave the protective groups , especially the hydroxyl and amino functional groups.