MXPA00006639A - Hypolipidemic benzothiazepine compounds - Google Patents

Abstract

The invention is concerned with novel hypolipidemic compounds of formula (I), wherein R1 is H or methyl, and salts, solvates or physiologically functional derivatives thereof, with processes and novel intermediates for their preparation, pharmaceutical compositions containing them and with their use in medicine, particularly in the prophylaxis and treatment of hyperlipidermic conditions and associated diseases, such as atherosclerosis.

Description

HYPOOLIPIDEMIC COMPOUNDS OF BENZOTIAZEPINE Field of the Invention The present invention relates to novel hypolipidemic compounds, to processes and new intermediates for their preparation, to pharmaceutical compositions containing them and to their use in medicine, particularly in the treatment and prophylaxis of hyperlipidemic conditions and associated conditions such as atherosclerosis.

Background of the Invention Hyperlipidemic conditions are commonly associated with high plasma concentrations of low density lipoprotein (LDL) cholesterol. Such 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 admission system of bile acid in the terminal ileum. Such inhibition stimulates the conversion of cholesterol in REF .: 121431 bile acid by the liver and the resulting increase in demand for cholesterol produces a corresponding increase in the rate of clearance of LDL cholesterol from blood plasma or serum. The compounds of the present invention reduce the concentrations of cholesterol (LDL) in plasma or serum and consequently are particularly useful as hypolipidemic agents. By reducing cholesterol and cholesterol ester concentrations in plasma, the compounds of the present invention retard the accumulation of atherosclerotic lesions and reduce the incidence of events related to coronary heart disease. The latter are defined as associated cardiac events increased concentrations of cholesterol and cholesterol ester in plasma or serum. International Patent Application No. PCT / GB / 9300328 describes the 1,4-benzothiazepine compounds having hypolipidemic activity. International Patent Application No. PCT / GB95 / 02700 (published as WO / 9616051) describes the compounds of 1,5-benzothiazepine, which also has a hypolipidemic activity. A group of substituted 1, 5-benzothiazepine compounds have been found to have surprising hypolipidemic activity over those that have been specifically disclosed in the prior art.

Description of the Invention Accordingly, the present invention provides a compound of the formula (I) wherein R1 is H or methyl; or a salt, solvate or a physiologically functional derivative thereof. Preferably R1 is hydrogen.

Suitable compounds of the formula (I) are selected from: (+) -2, 3, 4, 5-Tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-hydroxy-1 , 5-benzothiazepine-1, 1-dioxide; (3S) -2, 3, 4, 5-Tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-hydroxy-l, 5-benzothiazepine-1, 1-dioxide; and (+ _) -2, 3, 4, 5-Tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-methoxy-l, 5-benzothiazepine-1, 1-dioxide; or a salt, solvate or a physiologically functional derivative thereof. The pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the compounds of origin, ie, basic compounds. Such salts must clearly have a pharmaceutically acceptable anion or cation. Suitably the 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 organic acids, such as, acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isotonic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic, tartaric, and trifluoroacetic acids. The chloride salt is particularly preferred for medical purposes. Suitably, pharmaceutically acceptable base salts include ammonium salts, alkali metal salts, such as magnesium and calcium salts. Salts without a 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 non-therapeutic uses, for example in in vi tro applications. Any reference to '"compound (s) of the formula (I)", "compounds of the present invention", "compounds according to the invention" etc., refer to compound (s) of formula (I) as described above or to its salts, solvate, or physiologically functional derivatives as defined herein. 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 when administered to a mammal, such as a human, is capable of provide (directly and indirectly) such compound or one of its metabolites. Such derivatives are clear to those skilled in the trade, without any experimentation, and with reference to the teaching of "Burger's Medicinal Chemistry And Drug Discovery, 5th Edition, Vol. 1: Principles And Practice, which is incorporated herein by reference. Physiologically functional derivatives that when administered to a mammal, such as a human, are capable of providing (directly and indirectly) a compound of the invention or an active metabolite, are commonly referred to as prodrugs, these prodrugs may or may not be Actives by themselves Suitably, the prodrugs of the present invention are formed in the Ri-position to give C? 6-ester or C? 6-alkoxy groups The active metabolites are those that can be generated in vi ve by the metabolism of the compounds of the present invention and include, for example, glucuronides The compounds of the present invention may also exist in different forms s polymorphic, for example, crystalline and amorphous polymorphic forms. All polymorphic forms of the compounds of the present invention are within the scope of the invention and are of a further aspect thereof. The compounds of the formula (I) are in forms in which the carbon center -C (Et) (n-Bu) is chiral. The present invention includes within its field each possible substantially free optical isomer, that is, as it is associated with less than 5% of any other optical isomer (s), and mixtures of one or more optical isomers. in any proportion, including racemic mixtures. The (S) -isomer is preferred. According to other aspects of the invention, there are also provided: (a) the compounds of the formula (I) and pharmaceutically acceptable salts, solvate, and physiologically functional derivatives thereof for use as therapeutic agents, particularly in the prophylaxis and treatment of clinical conditions for which an inhibitor of bile acid admission is indicated, for example, a hyperlipidemic condition and associated diseases such as atherosclerosis; (b) pharmaceutical compositions comprising a compound of the formula (I) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof and at least one pharmaceutically acceptable carrier and, optionally, one or more physiologically active agents; (c) the use of a compound of the formula (I), or a physiologically functional derivative thereof, pharmaceutically acceptable salt or solvate in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition for which an inhibitor of the bile acid admission is indicated, for example, a hyperlipidemic condition, and associated diseases 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 an effective amount of a bile acid absorption inhibitor of a pharmaceutically acceptable compound of formula (I) or a salt, solvate, or physiologically functional derivative thereof towards the mammal; (e) a method for reducing blood plasma or serum cholesterol concentrations of LDL in a mammal, such as a human, which comprises administering an effective amount of a cholesterol reducer of a compound of the formula (I) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, to the mammalG. ; (f) a method for reducing the concentrations of cholesterol and cholesterol ester in the blood plasma and serum of a mammal, such as a human, which is understood to administer an effective amount of a cholesterol reducer and cholesterol ester of a compound of the formula (I) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, to the mammal; (g) a method for increasing fecal excretion of bile acids in a mammal, such as a human, which comprises administering an effective amount of a compound to increase fecal excretion of bile acids of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, to the mammal; (h) a method for the prophylaxis or treatment of a clinical condition in a mammal, such as a human, for which an inhibitor of bile acid admission has been indicated, for example, in a hyperlipidemic condition, and in associated diseases such as atherosclerosis, which comprises administering a therapeutically effective amount of the compound of the formula (I) or its salt, solvate, or physiologically functional derivative thereof, to the mammal. (i) a method for reducing the incidence of events related to coronary diseases in a mammal, such as a human, which comprises administering an effective reducing amount of events related to coronary diseases, a compound of the formula (I) or its pharmaceutically acceptable, solvate, pharmaceutically acceptable salt or physiologically functional derivative of the (j) a method for reducing the concentration of cholesterol in the blood plasma or serum of a mammal, such as a human, which comprises administering an effective amount of a cholesterol-reducing compound of the formula (I); (k) processes for the preparation of compounds of the formula (I) (including salts, solvates, and physiologically functional derivatives as defined herein); and (1) new, chemical intermediates in the preparation of formula (I).

The compounds of the present invention can be co-administered with other physiologically active agents, including hypolipidemic agents such as bile acid separating agents, HMG-CoA reductase inhibitor derivatives (competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme- A reduccatase), for example statins, such as pravastatin, lovastatin, fluvastatin, or simvastatin The amount of a compound of the formula (I) that is required to achieve the desired biological effect will, of course, depend on a number of factors, for example, the specific compound chosen, the use for which it is proposed, the mode of administration, and the clinical status of the receiver. In general, a daily dose is in the range from 0.001 mg to 100 mg (typically from 0.01 mg to 50 mg) per day per kilogram of body weight, for example from 0.01-10 mg / kg / day. Thus all unit doses of orally administrable formulations, such as capsules or tablets, may contain, for example, from 0.1 to 100 mg, typically from 0.1 to 10 mg, preferably 0.1 to 5 mg. In the case of pharmaceutically acceptable salts, the weights indicated above refer to the benzothiazepine ion derived from the salt. For the prophylaxis or treatment of the conditions referred to above, the compounds of the formula (I) can be used as the compound per se, but are preferably presented with an acceptable carrier in the form of a pharmaceutical composition. The carrier should be clear, acceptable in the sense of being compatible with the other ingredients of the composition and should not be deleterious to the recipient. The carrier can be a solid or a liquid, or both, and is preferably formulated with the compound as a unit dose composition, for example, a tablet that can contain 0.05% -95% by weight of the active compound. Other pharmacologically active substances may also be present including other compounds of the formula (I). The pharmaceutical compositions of the invention can be prepared by any of the known pharmacy techniques, consisting essentially of the mixing of the components. When the compound of the formula (I) is used in combination with one or more physiologically active agents as described hereinbefore, the required amount of the other physiologically active agents to achieve the desired biological effect will also depend on a number of factors. The specific dose and dosing schedule will be determinable for those skilled in the trade. In general, the dose used will be the approved dose for medical use in humans. The pharmaceutical compositions according to the present invention include those suitable for oral, rectal, topical, buccal administration (for example, sublingual), and parenteral (for example, subcutaneous, intramuscular, intradermal, and intravenous) although the most appropriate route in any case will depend on the nature and severity of the condition to be treated or on the particular nature of the compound of the formulas (I) that are being used. Controlled release enteric coating formulations are also within the scope of the invention. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl phylate, and anvilic polymers of methacrylic acid and methacrylic acid methyl ester. The formulations of enteric coating and controlled release enteric coating include tablets and capsules. Pharmaceutical compositions suitable for oral administration may be presented in discrete units such as capsules, pills, lozenges, or tablets, each containing a predetermined amount of a compound of the formula (I); as a powder or granules: as a solution or suspension in an aqueous or non-aqueous liquid; or as an emulsion in oil or oil in water. As indicated, such compositions may be prepared under any acceptable pharmacy method including the step of bringing into association the active component and the carrier (which may constitute one or more accessory ingredients). In general, the compositions are prepared by uniformly and intimately mixing the active compound with a liquid or a finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet can be prepared by compressing or molding powder or granules of the compound, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the compound in free flowing form, such as powder or granules optionally mixed with a binder, with lubricating agents, inert diluents and surface dispersing / active agents. The molded tablets can be made by molding, in a suitable machine, the powder compound moistened with an inert diluent liquid. Controlled release tablets can be prepared in a similar manner and with the addition of for example, hydroxypropylmethylcellulose. Enteric coated tablets can be prepared by coating the tablets with an enteric polymer such as cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, or anionic polymers of methacrylic acid and methacrylic acid methyl ester (Eudragit L). Except for Eudragit L, these polymers must include 10% (by weight of the amount of polymer in use) of a plasticizer to prevent rupture of the membrane during application or storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin.

The controlled-release enteric coated tablets can be prepared by coating controlled release tablets with an enteric polymer such as cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, or anionic polymers of methacrylic acid and methacrylic acid methyl ester ( Eudragit L). Except for L, these polymers should also include 10% (by weight of the amount of polymer used) of a plasticizer to prevent membrane rupture during application or storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin. Capsules can be prepared by mixing a compound of the formula '(1) with, for example, magnesium stearate, pregelatinized starch, sodium starch glycolate, and / or magnesium stearate and filling two part gelatin capsules with the resulting mixture. Controlled release capsule compositions can be prepared by mixing the compound of formula (I) with, for example, microcrystalline cellulose and / or lactose, using an extruder, then spheronizing and drying the extrudate. The dry pills are coated with a controlling release membrane, for example, ethylcellulose, and filled into two-part hard gelatin capsules. The enteric capsule compositions can be prepared by mixing a compound of the formula (I) with, for example, microcrystalline cellulose. and / or lactose, extruding using an extruder, then spheronizing and drying the extrudate. The dried pills are coated with an enteric membrane, for example, cellulose acetate phthalate containing a plasticizer, for example, diethyl phthalate and filled into two-part hard gelatin capsules. Pharmaceutical compositions suitable for buccal (sublingual) administration include lozenges including a compound of the formula (I) in a flavored base, usually sucrose and gum arabic or tragacanth, and lozenges that incorporate 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 the formula (I), preferably isotonic with the blood of the recipient. These preparations are preferably administered intravenously, although administration can be effected by means of subcutaneous, intradermal and intramuscular injection. Such preparations can be conveniently prepared by mixing the compound with water and rendering the resulting sterile and isotonic solution with the blood. The 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 unit dose suppositories. These can be prepared by mixing a compound of the formula (I) with one or more of the conventional solid carriers, for example, cocoa butter, and then molding the resulting mixture.

Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the container for a prolonged period of time. Such patches suitably contain the active component in an aqueous solution optionally buffered, dissolved and / or dispersed in an adhesive or in a polymer. A suitable concentration of the active compound is from about 1% to 35%, preferably from about 3% to 15%. As a particular possibility, the active compound can be sent from electrotransport or iontophoresis, for example, as described in Pharmaceutical Research, 3 (6), 318 (1986). The compounds of the formula (I) can be prepared by conventional methods known to an experienced person, or in an analogous manner by processes described in the art. For example, compounds of the formula (I) wherein R 1 is H can be prepared from compounds of the formula (II) wherein Rla is an alkyl portion (for example, alkyl of 1 to 4 carbon atoms, suitably methyl), by dealkylation with a suitable agent, such as boron tribromide, in a suitable organic solvent, such as, for example, methylene. According to a second process (B), a compound of the formula (I) 'wherein R 1 is methyl, or a salt, solvate, or physiologically functional derivative thereof, can then be prepared from a compound of the formula (III) by oxidation of the sulfur group with, for example, a mixture of osmium tetroxide and N-methyl-morpholine-N-oxide. The compounds of the formula (II) or (III) can be prepared from compounds of the formula (IV), where Rla is defined above, by methods known in the art, particularly those described in W096 / 16051.

(IV) The compounds of the formula (IV) can be prepared by methods described in WO96 / 16051 or by reactive compounds of the formula (V) with compounds of the formula (Va) wherein Z is a suitable group to leave, for example, halo, first by reacting the compound of the formula (V) with a base, for example, aqueous potassium hydroxide at an elevated temperature, such as at 100 ° C. and then adding the compound of the formula (Va). The compounds of the formula (V) can be prepared from the compounds of the formula (VI) by reaction with ammonium thiocyanate and bromide in a suitable solvent such as acetic acid. The compounds of the formula (VI) are commercially available or can be prepared by methods known and available to those skilled in the art. The compounds of the formula (Va) can be prepared from compounds of the formula (VII) (VII) wherein R is a suitable hydroxy protecting group, for example, tert-butyldimethylsilyl, by oxidation of the compound of the formula (VII), with for example, sodium periodate and ruthenium trichloride in a suitable solvent such as carbon tetrachloride / acetonitrile / water . Subsequent to oxidation, the hydroxy protected by R 2 is deprotected and converted to the appropriate group Z by known methods, for example, with HBr. The compounds of the formula (VII) can be prepared from the corresponding diols by established methods known to those skilled in the art. The diols are commercially available or can be prepared by established methods or known to those skilled in the art. Compounds of the formula (I), substantially free of other optical isomers can be obtained by chiral synthesis, for example, by use of the appropriate chiral material (s) of initiation, such as chiral compound of formula (Va), or by resolution of the products obtained by chiral synthesis, for example, by chiral HPLC, enzymatic resolution, or by classical resolution with chiral acids. The optional conversion of a compound of the formula (I), or a compound of the formula (I) including a basic substitute, to an acid addition salt, can be effected by a reaction with a solution of the appropriate acid, for example, any of those mentioned above. The optional conversion of a compound of the formula (I), which comprises an acidic substitute to a corresponding base salt, can be effected by reaction with a solution of the appropriate base, for example, sodium hydroxide. The 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 from the chemical literature. In addition, the compounds of the formula (I) can be converted to different compounds of the formula (I) by standard methods known or available in the literature to those skilled in the art, for example, by methylation of a hydroxy group. For a better understanding of the invention, the following examples are given by way of illustration and should not be considered in any way as a limitation of the scope of the invention.

General Procedures: Proton magnetic resonance spectra were recorded at 300 MHz. Mass spectra were recorded under atmospheric pressure chemical ionization (APCI) conditions in an LCMS instrument or were performed by Oneida Research Services, Inc. under conditions of chemical ionization (Cl) using methane as the reactive gas. The elemental analyzes were performed by Atlantic Microlab, Inc. All reactions were carried out in a nitrogen atmosphere. The TLC plates were the Whatman MK6F silica gel plates 60 and were visualized under a UV lamp. The chromatography column was made with EM Science silica gel 60 (230-400 mesh). The reagents were obtained from Aldrich Chemical Co. unless otherwise indicated, and used without further purification. The solvents were anhydrous grade of Aldrich.

Example 1 Preparation of (3S) -2, 3, 4, 5-Tetra-idro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-methoxy-1, 5-benzothiazepine-1,1-dioxide and (3S) -2, 3, 4, 5-Tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-hydroxy-l, 5-benzothiazepine-1, 1-dioxide. (±) -2- ((Tert-Butyldimethylsilyl) oxy) methyl-ethyl- 'hexanol (1). To a suspension of 60% NaH (21.2 g) in 800 ml THF was added to three portions of 2-n-butyl-2-ethyl-l, 3-propanediol (85.0 g) and stirred for 1 h. The mixture was cooled to 0 ° C. To the resulting gum was added a solution of 1M of tert-butyldimethylsilyl chloride in THF (530 ml) and stirred overnight and allowing the solution to warm to RT (room temperature). The solvent was evaporated and the residue was partitioned between water (400 ml) and ether (300 ml). The ether layer was washed with a bicarbonate solution and concentrated brine. Column chromatography (5% ethyl acetate / petroleum ether) gave 1 as a colorless oil (142.6 g). MS Da / e = 275 (MH +) Caled for C? 5H3402 Si: C, 65.63; H, 12.48. Found: C, 65.87, H, 12.47. (+) -2- (Bromomethyl) -2-ethylhexanoic acid (2). To a solution of 1 (142.6 g) in 300 ml CC1, 300 ml CH3CN, and 450 ml H20 at 0 ° C was added Nal04 (283 g) and RuCl3 (2.0) and stirred for 20 h leaving the reaction mixture Warm to room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated by rotary evaporation. The residue was transferred to a separatory funnel and divided between H20 and CH2C12. The aqueous phase was extracted 3 times with CH2C12, dried and concentrated. The residue was taken up in 48% HBr (500 ml) and refluxed for 24 h. After cooling to room temperature the solution was transferred to a separatory funnel, extracted 3 times with ethyl ether, washed once with brine, dried over a 2 SO and concentrated. The product was purified by column chromatography on a silica gel washing the product with 20% ethyl acetate / petroleum ether to give 2 (IIIg). MS Da / e = 157 (M-Br), 237, 239 (M + 1). Caled for C H1702Br: C, 45.59; H, 7.23; Br, 33.70. Found: C, 46.27; H, 7.17; Br, 32.94. 2-amino-5-chloro-6-methoxybenzothiazole (4) To a solution of 3-chloro-p-anisidine (3.58.4 g) in acetic acid (400 ml) was added ammonium thiocyanate and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was cooled to 15 ° C in an ice bath. A solution of bromide (17.2 ml) in acetic acid (200 ml) was added to the reaction mixture for 10 minutes. After 10 minutes of stirring, the reaction mixture was then warmed to room temperature. Then it was stirred at room temperature for 3.5 hours, the reaction mixture was filtered and the solids were captured on filter paper. The solids were transferred to a flask and added to 200 ml in water. The suspension was vigorously stirred and 30 ml of 50% aqueous NaOH was added. The mixture was filtered by retaining the product on filter paper. The powder was dried under vacuum at 120 ° C to give 4 (51.Og) MS Da / e = 215 (M + 1). Caled for C8H7N2S0C1: C, 44.72; H, 3.29; N, 13.05; S, 14.93. Found: C, 44.63; H, 3.30; N, 12.96; S, 14.83. - Acid (+ _) -2 - (((2-Amino-4-chloro-5-methoxy-phenyl) thio) -methyl) -2-ethylhexanoic acid (5). To a suspension of 4 (20.0 g) in H20 (200 ml) was added KOH (100 g). The suspension was refluxed for 7 hours and allowed to cool to room temperature. To the dark solution was added 2 (33.2 g) in one portion. The reaction mixture was stirred for 18 hr at which point at this point the pH was adjusted to 4 with HCl. The mixture was transferred to a separatory funnel and extracted three times with ethyl acetate. The organic layer was dried and concentrated. The product was purified with silica gel column chromatography by washing the product with 10% ethyl acetate / petroleum ether to give 5 (30. Ig). MS Da / e = 368 (M + Na). (+ _) -2, 3-Dihydro-3-ethyl-3-butyl-5-H-7-chloro-8-methoxy-1,5-benzothiazepine-4-one (6). To a suspension of 5 (72.Og) in tetradecane (900 ml) was added toluene sulfonic acid (3.2 g). The mixture was heated to reflux temperature and refluxed for 15 minutes by pooling 4 ml H20 in a Dean-Stark trap. The solution was allowed to cool and transferred to a 1 liter Erlenmeyer flask which was allowed to stand for 18 h at 4 ° C. The tetradecane was decanted leaving solids that were recycled from the water / methanol. The mother liquors and the tetradecane solution were applied to a column of silica gel and the remaining product was washed with 20% ethyl acetate / petroleum ether. The material from the column was combined with the recrystallized material to give 6 (52.6 g). MS Da / e = (M + Na). Caled for C? 6l 122NS02C1 58.61; H, .76; N 4.27; S, 9. 78 Found: C, 58.70; H, 6.82; N, 4.23; S, 9.82. (3R) -2, 3, -Dihydro-3-ethyl-3-butyl-5-H-7-chloro-8-methoxy-1,5-genzothiazepine-4-one (7). Racemic 6 (50 g) was resolved on a CHIRALPAK ADMR 10 x 50 cm column eluting with 100% methanol at 25 ° C. The s isomer was washed first, and the r isomer was washed second. After concentrating the second peak, 7 was isolated (23.28 g, 99% ee). NMR XH (CDC13) d 7.82 (s, 1H), 7.03, (s, 1H), 6.99 (s, 1H), 3.88 (s, 3H), 2.95 (s, 2H), 1.85-1.45 (m, 4H) , 1.25 (m, 4H), 0.86 (m, 6H). (3R) -2, 3, -Dihydro-3-ethyl-3-butyl-5-phenyl-1-7-chloro-8-methoxy-1,5-benzothiazepine-4-one (8). To a solution of 7 (10.0 g) in iodobenzene (75 ml) was added copper iodide (I) (0.30 g) and potassium carbonate (4.23 g). The mixture was refluxed for 5.5 h and during that time it was allowed to cool to room temperature. The reaction mixture was loaded directly onto a column of silica gel. The iodobenzene was eluted with petroleum ether, and the product thereof was eluted with 15% ethyl acetate / petroleum ether to give 8 (10.9 g) MS Da / e = 404 (M + 1), 426 (M + Na). Caled for C22H26NS02C1 C, 65.41; H, 6.49; N, 3.47; S, 7.94. Found: C, 65.15; H, 6.59; N, 3.34; S, 7.72. (3S) -2, 3, 4, 5-Tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-methoxy-l, 5-benzothiazepine-1,1-dioxide (9). To a 1M solution of aluminum lithium hydride in ethyl ether (91.5 ml) was added dropwise to 0 ° C to a 7.2 M solution of sulfuric acid in THF (6.4 ml) and the mixture was stirred at 0 ° C for 1 h. To the mixture at 0 ° C was added 8 (10.9 g) in THF (75 ml). The reaction mixture was allowed to warm to room temperature and was stirred for 3.5 h at room temperature and at that point it was again cooled to 0 ° C and a 30% H20 solution. (v / v) in THF was added dropwise. A 1 N NaOH solution (15 ml) was added. The reaction mixture was filtered through a sintered glass funnel to remove the aluminum oxides. The filtrate was transferred to a separatory funnel and partitioned between water and ethyl ether. The aqueous layer was extracted three times with ether. The organic phase was dried (Na2SO4) and concentrated. The resulting oil was taken up in THF (175 ml). To the THF solution was added t-butanol (60 ml), N-methyl morpholine-N (10.7 g), and osmium tetraoxide (2.5 wt.% In t-butanol, 7.6 ml). The reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was transferred to a separatory funnel and partitioned between brine and ethyl acetate. The aqueous layer was extracted three times with acetyl acetate. The organic layer was dried, concentrated and the residue was applied to a column of silica gel. The product was eluted at 10% ethyl acetate / petroleum ether to give 9 (10.92 g). p.f. = 147.5 ° C. MS Da / e = 422 (M + 1), 444 (M + Na). Caled for C22H28NS03C1: C, 62.62; H, 6.69; N, 3.32; S, 7.60. Found: C, 62.53; H, 6.62; N, 3.32; S, 7.53. (3S) -2, 3, 4, 5-Tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-hydroxy-l, 5-benzothiazepine-1, 1-dioxide (Example 1) . To a solution of 9 (10.92 g) in methylene chloride (150 ml) at 0 ° C was added a solution of boron tribromide in methylene chloride in 1 M solution (36.3 ml). The reaction mixture was allowed to slowly warm to. Room temperature and stirred for 18 h and at this point it was allowed to cool again to 0 ° C and water (100 ml) was added dropwise. The mixture was transferred to a separatory funnel and extracted three times with methylene chloride. The organic extracts were dried, concentrated and the residue was applied to a column of silica gel. The product was eluted with 30% ethyl acetate / petroleum ether giving Example 1 (10.12 g).

P. F. = 179.6 - 180.2 ° C. MS Da / e = 406 (M-1, negative ion mode). Caled for C2? H26NS03Cl: C, 61.83; H, 6.42; N, 3. .43; S, 7.86. Found: C 61.76; H 6.47; N, 3.37; S, 7.76.

Biological Test (I) Inhibition of bile acid reabsorption Spraque-Dawley male rats (Charles River CD) weighing 220-260 gm were accommodated in individual cages and fed normal food. The rats were dosed by an oral probe (1 l / 100 gm body weight) with the test components in a suspension of 0.5% methylcellulose at 9:00 a.m. and 3:30 p.m. for two days. The control group received 0.5% methylcellulose. Two hours after the morning dose on day two, the rats were given. gave a trace amount (1.3 nmol) of 23.25-75Se- of homocyclic acid taurine (75SeHCAT) in 1.0 ml saline orally. 75SeHCAT, a synthetic analogue of bile acid gamma emitter. is absorbed by the active collection system of 'ilium bile, or taurocholic acid, has been used clinically as a measure of absorption of ilial bile acid. The faeces were collected during the 24 hours after the administration of 75SeHCAT. Fecal content of .75SeHCAT was determined using a Packard Auto-Gamma 5000 Series gamma counter. The% inhibition of bile acid reabsorption is calculated as follows: "Total SeHCAT - excreted 75SeHCAT of treated 1 minus X 100 =% inhibition 75 SeHCAT total - excreted 75SeHCAT control The percentage of inhibition of bile acid reabsorption in the rat using 75SeHCAT was used to determine ED30 (the dose required to give 30% inhibition of bile acid admission). 2, 3, 4, 5-Tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-hydroxy-l, 5-benzothiazepine-1, 1-dioxide (Example 1 of the present invention) , and the corresponding bromine compound, 2,3,4,5-tetrahydro-3-ethyl-3-butyl-1-5-phenyl-7-bromo-8-hydroxy-1,5-benzothiazepine-1,1-dioxide, (Example A as described in PCT / GB95 / 02700), were tested with each other in two series of experiments with 6 rats in each group (n = 12 in total).

ED30 (mg / kg) Example 1 0.04; Example A 0.17 (II) Percent of Cholesterol Decreasing in Rats Hypercholesterolemia was induced in male Sprague-Dawley rats (CD, Charles River thinking 200-300 g) by administration of a diet enriched in cholesterol and cholic acid. The diet was prepared from Wayne Laboratories Blocks, milled in food and mechanically mixed with cholesterol powder and cholic acid at a final concentration (by weight) of 1% and 0.5% respectively. Before administration of the diet, blood was taken under halothane anesthesia by cardiac puncture to determine lipid base levels. Serum was obtained for an analysis of total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), precipitable dextran cholesterol lipoprotein (VLDL + LDL). The rats were divided into groups so that each group had serum lipid base levels. Five days after the initial sampling of serum lipids the rats were fed ad lib with the diet enriched with cholic acid and cholesterol with which the administration of the compound began. The compound was administered by tube in a suspension in 0.5% methylcellulose (lml / 100 g body weight) b.i.d. at 9:00 a.m. and 3: 0 p.m. for 3 days and at 9:00 a.m. on day four. The control animals received 0.5% methylcellulose alone. The rats were bled four hours after the last dose for the determination of serum lipids. All blood samples were taken after a 4h fast. Serum TC concentrations were determined enzymatically using reagents obtained from Seragen Diagnostics (2). Serum HDL-C were determined after selective precipitation of VLDL and LDL with dextran sulfate and magnesium sulfate, with Seragen reagents (3). HDL-C were determined in the supernatant. VLDL + LDL cholesterol was determined as the difference between total and HDL-C. The following results were obtained for Example 4 and Example A, as defined below.

Dosage (mg / kg) 0.3. 0.1 0.03 Example 1 81% 56% 48% Example A 53% 17% 14% The results clearly demonstrate the unexpected improvement of the cholesterol-lowering properties of the compounds of the invention.

Examples of Pharmaceutical Composition In the following Examples, the active compound may be any compound of formula (I) and / or a pharmaceutically acceptable salt, solvate, or functional physiological derivative thereof.

(I) Compositions of the Tablet The following compositions A and B can be prepared by wet granulation of ingredients (a) to (c) and (a) to (d) with a povidone solution, followed by an addition of magnesium stearate and compression Composition A mg / Tablet mg / Tablet (a) Active ingredient 250 250 (b) Lactose B.P 210 26 (c) Starch glycolate 20 12 dry (d) Polidone B.P 15 (e) Magnesium stearate 5 500 300 Composition B mg / Tablet mg / Tablet (a) Active ingredient 250 250 (b) Lactose 150 150 (c) Avicel PH 101 60 26 (d) Starch glycolate 20 12 sodium (e) Polidone P.B 15 9 (f) Magnesium stearate 5 3 500 300 Composition C mg / Tablet Active ingredient 100 Lactose 200 Starch 50 Polidone 5 Magnesium stearate 4 359 The following compositions D and E can be prepared by direct compression of the mixed ingredients. The lactose used in composition E is of the direct compression type.

Composition D mg / Tablet Active ingredient 250 Magnesium stearate Pregelatinized starch NF1S 146 00 Composition E mg / Tablet Active ingredient 250 Magnesium stearate 5 Lactose 145 Avicel 100 500 Composition controlled release composition) mg / Tablet (a) Active ingredient 500 (b) Hydroxypropylmethylcellulose 112 Metocel K4M Premium (c) Lactose B.P 53 (d) Povidone B.P.C. 28 (e) Magnesium Stearate 7 700 The composition can be prepared by wet granulation of the ingredients (a) to (c) with a solution of. povidone, followed by the addition of magnesium stearate and compression.

Composition G (Enteric Coating Tablet) The tablets of Composition C with enteric coating can be prepared by coating the tablets with 25 mg / tablet of an enteric polymer such as cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, or anionic polymers of methacrylic acid and acid methylester. methacrylic (Eudragit L). Except for Eudragit L, these polymers should also include 10% (by weight of the amount of polymer in use) of a plasticizer to prevent rupture of the membrane during application or storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin.

Composition H (Tablets with Enteric Layer Controlled Release The enteric coating tablets of the Composition F can be prepared by coating the tablets with 50 mg / tablet of an enteric polymer such as cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, or anionic polymers of methacrylic acid and methylester of methacrylic acid (Eudragit L). Except for Eudragit L, these polymers should also include 10% (by weight of the amount of polymer in use) a plasticizer to prevent rupture of the membrane during application or storage. Suitable plastifiers include diethyl phthalate, tributyl citrate and triacetin.

(II) Composition of Capsule Composition A The capsules can be prepared by mixing the ingredients of Composition D mentioned above, and filling capsules in two parts of hard gelatin with the resulting mixture. Composition B (infra) can be prepared in a similar manner.

Composition B mg / capsule (a) Active ingredient 250 (b) Lactose B.P. 143 (c) Sodium starch glycolate (d) Magnesium stearate 2 420 Composition C mg / capsule Active ingredient 250 (b) Macrogol 4000 BP 350 600 The capsules can be prepared by melting the Macrogol 4000 BP, dispersing the active ingredient in the melt and filling hard gelatin capsules in two parts of this.Composition D mg / capsule Active Ingredient 250 Lecithin 100 Araquis Oil 100 450 Capsules can be prepared by dispersing the active ingredient in lecithin and arachis oil and filling soft gelatine capsules with the dispersion.

Composition E (Controlled Release Capsule) mg / capsule (a) Active Ingredient 250 (b) Cellulose Microcritalin 125 (c) Lactose BP 125 (d) Ethyl cellulose 13 513 The composition of the controlled release capsule can be prepared by extruding the mixed ingredients (a) to (c) using an extruder, then spheronizing and drying the extrudate. The dried tablets are covered with a release control membrane (d) and filled into two-part hard gelatin capsules.

Composition F (Enteric Capsule) mg / capsule (a) Active Ingredient 250 (b) Microcrystalline Cellulose ina 125 (c) Lactose BP 125 (d) Cellulose Acetate Phthalate 50 (e) Diethyl Phthalate 5 555 The composition of the enteric capsule can be prepared by extruding the mixed ingredients (a) to (c) using an extruder, then feronizing and drying the extrudate. The dried tablets are covered with an enteric membrane (d) containing a plasticiser (e) and filled into two-part hard gelatin capsules.

Composition G (Capsules with Enteric Coating of Controlled Release) The enteric capsules of Composition E can be prepared by coating the controlled release tablets with 50 mg / capsule an enteric polymer such as cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate, or anionic polymers of methacrylic acid and methyl ester of methacrylic acid (Eudragit L). Except for Eudragit L, these polymers must also include 10% (by weight of the amount of polymer used) of a plasticizer that prevents membrane rupture during application or storage.

Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin.

(III) Composition of Intravenous Injection Active Ingredient 0.200g Sterile phosphate buffer, free of pyrogens (pH 9.0) at 10 ml The active ingredient is dissolved in the majority of the phosphate buffer at 35-40 ° C, then it is given volume and filtered through a sterile micropore filter into 10 ml ampoules of sterile glass (Type 1) which are sealed with envelope seals and sterile plugs.

(IV) Composition of Intramuscular Injection Active Ingredient 0.20g Benzyl alcohol 0. lOg Glycofurol 75 1.45g Water for injection c.s for 3.00 ml The active ingredient is dissolved in glycofurol. The benzyl alcohol is then added and dissolved, and 3 ml of water is added. The mixture is then filtered through a sterile micropore filter and sealed in 3 ml glass ampoules (type 1).

(V) Syrup Composition Active Ingredient 0. 25g Sorbitol Solution 1. 50g Glycerol 1. OOg Sodium Benzoate 0. 005g Flavor 0.0125 ml Purified Water 5.0 ml The sodium benzoate is dissolved in a portion of the purified water and the sorbitol solution is added. The active ingredient is added and dissolved. The resulting solution is mixed with glycerol and then the required volume is given with the purified water.

(VI) Composition of Suppository mg / suppository Active Ingredient 250 Fat Dura, BP (Witepsol H15 1770 Dynamit NoBel) 2020 One-fifth of Witepsol H15 is melted in a bain-marie pan at 45 ° C maximum. The active ingredient is sifted through a 200 lm sieve and added to the melted base with mixing, using a Silverson with a cutting head, until a uniform dispersion is achieved. Maintaining the mixture at 45 ° C, the remaining Witepsol H15 is added to the suspension which is stirred to ensure a homogeneous mixture. The entire suspension is passed through a 250 lm stainless steel screen, and with constant movement, it is allowed to cool to 40 ° C. At a temperature of 38-40 ° C, 2.02 g aliquot of the mixture are filled into appropriate plastic molds, and the suppositories are allowed to cool to room temperature.

(VII) Composition Pesario mg / pesario Active Ingredient (631 m) 250 Anhydrous Dextrose 380 Potato Starch 363 E = Magnesium Tearate 7 1000 The ingredients mentioned above are mixed directly and the pessaries are prepared by compressing the resulting mixture.

(VIII) Transdermal Composition Active Ingredient 200 mg Alcohol USP 0.1 ml Hydroxyethyl cellulose The active ingredient and alcohol USP are gelatinized using hydroxymethyl cellulose and packaged in a transdermal device with a surface area of 10 cm2.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (11)

R E I V I N D I C A C I O N S

1. A compound of the formula (I) characterized in that R1 is H or methyl, or a salt, solvate or physiologically functional derivative thereof.

2. A compound of the formula (I), characterized in that it is selected from the group consisting of: (+) -2, 3, 4, 5-tetrahydro-3-ethyl-3-butyl-5-phenyl- 7-chloro-8-hydroxy-l, 5-benzothiazepine-1,1-dioxide; (3S) -2,3,4, 5-tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-hydroxy-l, 5-benzothiazepine-1, 1-dioxide, and (+) -2,3,4, 5-tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-methoxy-l, 5-benzothiazepine-1, 1-dioxide; or a salt, solvate or physiologically functional derivative thereof.

3. (+) -2, 3, 4, 5-tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-hydroxy-1,5-benzothiazepine-1, 1-dioxide; or a salt, solvate or physiologically functional derivative thereof.

4. (3S) -2,3,4, 5-tetrahydro-3-ethyl-3-butyl-5-phenyl-7-cioro-8-hydroxy-l, 5-benzothiazepine-1, 1-dioxide; or a salt, solvate or physiologically functional derivative thereof.

5. A method for treating a hyperlipidemic condition in a mammal, characterized in that it includes administering to the mammal an amount of the compound of the formula (I) for an effective hyperlipidemic treatment according to any of claims 1 to 4, or a pharmaceutically salt acceptable, solvate, or physiologically functional derivative thereof.

6. The method according to claim 5, characterized in that the hyperlipidemic condition is atherosclerosis.

7. A compound of the formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, for use in medicine.

A compound of the formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, for use in the prophylaxis or treatment of a hyperlipidemic condition.

9. A compound of the formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, for use in the manufacture of a medicament for the treatment of a hyperlipidemic A pharmaceutical composition, characterized in that it comprises a compound of the formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, at least one pharmaceutically acceptable carrier , and, optionally, one or more physiologically active agents.

11. A process for the manufacture of a compound of the formula (I) or a salt, solvate, or physiologically functional derivative thereof, characterized in that it comprises: (A) wherein R1 is H, the dealkylation of a compound of the formula (II) ) where Rla is an alkyl moiety; or wherein R1 is a methyl, oxidizing a compound of the formula (III)