MXPA97003546A

MXPA97003546A - Benzotiazepinas hipolipidemi

Info

Publication number: MXPA97003546A
Application number: MXPA/A/1997/003546A
Authority: MX
Inventors: Edward Brieaddy Lawrence; Louis Handlon Anthony; Lewis Hodgson Gordon Jr
Original assignee: Wellcom Foundation The Limited
Priority date: 1994-11-17
Filing date: 1997-05-14
Publication date: 1997-08-01

Abstract

The present invention relates to the compounds of the formula (I) characterized in that R1 and R2 are the same or different and each is an alkyl of 1 to 6 carbon atoms optionally substituted by one or more groups selected from hydroxy, halogen, alkyl from 1 to 6 carbon atoms, alkoxy from 1 to 6 carbon atoms, R4 is an aryl group of 6 to 14 carbon atoms or a heteroaryl group of 3 to 13 carbon atoms each substituted with one to eight substituents, R5a, R5b, R5c and R5d each represents atoms or groups which are the same or different and each is hydrogen, halogen, cyano, R8-acetyl, OR8, alkyl of 1 to 6 carbon atoms optionally substituted by one or more groups selected from hydroxy, halogen, alkyl from 1 to 6 carbon atoms, alkoxy from 1 to 6 carbon atoms, R6 and R7 are the same or different and each is hydrogen, alkyl of 1 to 6 carbon atoms optionally substituted, or R6 and R7 together with the carbon atom to which it is Together they form a spiro-cycloalkyl group of 3 to 6 carbon atoms, X is CH 2, C = O, C = S, or C = NR 8, wherein R 8 is as defined above, R 12 and R 15 are the same or different and each one is selected from hydrogen or alkyl from 1 to 8 carbon atoms, and 1 is an integer from 0-2, and salts, solvates or physiologically functional derivatives thereof

Description

HYPOLIPIDEMIC BENZOTIAZEPINES Field of the Invention The present invention relates to novel hypolipidemic compounds, with novel processes and intermediates for their preparation, with pharmaceutical compositions containing them and with their use in medicine, particularly in the prophylaxis and treatment of hyperlipidermal conditions and associated conditions, like arteriosclerosis. Background of the Invention Hyperlipidemic conditions are often associated with high concentrations of low density lipoprotein cholesterol in the plasma. Such concentrations can be reduced by decreasing the absorption of bile acids that occur from the intestine. One method by which this can be achieved is to inhibit the superior absorption system of bile acid in the terminal of the ileum. Such inhibition stimulates the conversion of cholesterol to bile acid by the liver and the resulting increase in cholesterol demand produces a corresponding increase in the effort to clear LDL cholesterol from blood plasma or serum. A novel class of heterocyclic compounds has been identified as reducing the concentrations of LDL cholesterol in plasma or serum and consequently they are particularly useful as hypolipidemic agents. Due to the decrease in the concentrations of cholesterol and cholesterol ester in the plasma, the compounds of the present invention retard the development of arteriosclerotic lesions and reduce the incidence of events related to coronary heart diseases. The latter are defined as cardiac events associated with increased concentrations of cholesterol and cholesterol ester in plasma or serum.

Ref. 24549 International Patent Application No. PCT / GB / 9300328 describes the 1,4-benzothiazepine compounds, which have hypolipidemic activity. A group of original 1,5-benzothiazepine substituted compounds have now been discovered, which also have hypolipidemic activity Description of the invention. Accordingly, the present invention provides compounds of the formula (I), wherein R 1 and R 2 are the same or different and each is an optionally substituted C 3 -C 6 cycloalkyl alkyl, or R 1 and R 2 together with the carbon atom, to which they are attached, form a spiro-cycloalkyl group C3-6 optionally substituted group; R4 is a C6-? 4 aryl group, or a C3-3 heteroaryl group each optionally substituted with one to eight substituents, which are the same or different and are selected from the halogens, hydroxy, nitro, C? Alkoxy? 6-phenyl, C6.6 alkoxy, optionally substituted C6 alkyl, S (0) nR8, SO2NR8R9, CO2R8, O (CH2CH2O) nR8, OSO2R8, O (CH2) pSO3R8, O (CH2) PNR9R10 and O ( CH2) PN + R9R10R11 wherein, from R8 to R11 are the same or different and are independently selected from hydrogen or optionally substituted C1-6 alkyl, and wherein p is an integer of 1-4 and n is an integer of 0-3; R5a R5b R5c and Rsd each represent atoms or groups, which are the same or different and each is hydrogen, halogen, cyano, R8-acetyl, OR8, optionally substituted Ci -6 alkyl, COR8, CH (OH) R8, S (O) nR8, SO2NR8R9, P (O) (OR8) 2, OCOR8, OCF3, OCN, SCN, NHCN, CH2OR8, CHO, (CH2) PCN, CONR9R10, (CH2) PCO2R8, (CH2) PNR9R10, CO2R8 ', NHCOCF3, NHSO2R8, OCH2OR8, OCH = CHR8, O (CH2CH2O) nR8, OSO2R8, O (CH2) PSO3R8, O (CH2) PNR9R10 and O (CH2) PN + R9R10R11 where, from R8 to R11, n and p, are as they are defined and characterized above; or R5a and R5b, R5b and R5c, or R5c and R5d together with the ring to which they are linked, form a cyclic group -O (CR9R10) mO- wherein R9 and R10 are defined and characterized above, and m is 1 or 2; R6 and R7 are the same or different and each is hydrogen, optionally substituted C? -6 alkyl, C3-C6 cycloalkyl, or R6 and R7 together with the carbon atom to which they are attached, form a spiro-cycloalkyl C3 group -6 optionally substituted. X is CH2, C = O, C = S, or C = NR8 where R8 was previously characterized; and I is an integer of 0-2, and salts, solvates or physiologically functional derivatives thereof. Conveniently R1 is an alkyl group d.e. Preferably R1 is methyl, ethyl, or n-propyl, and more preferably R1 is ethyl. Conveniently R2 is a C? 6 alkyl group. Preferably R2 is methyl, ethyl, or n-propyl, and more preferably R2 is ethyl or n-butyl. Conveniently R is a phenyl group optionally substituted with one to five, preferably one or two substitutes, which are the same or different and are each selected from halogens, hydroxy, nitro, C6-6 alkoxy -phenyl, C6 alkoxy- 6, optionally substituted C? -6 alkyl, S (O) nR8, CO2R8, O (CH2CH2O) nR8, OSO2R8, 0 (CH2) PSO3R8, O (CH2) PNR9R10 and O (CH2) PN + R9R10R11, preferably halogen, hydroxy, nitro, phenyl C? .6 alkoxy, C? -6 alkoxy, alkyl C ? -6 substituted opiconally. R 4 is preferably phenyl optionally substituted at the 3-position and / or 4 by a halogen, hydroxy, methyl, ethyl, methoxy, ethyl, trifluoromethyl, hydroxy, carboxy or O (CH 2) 3 SO H. The best thing is that R 4 was a unsubstituted phenyl or phenyl substituted at the 3 and / or 4 positions with halogen, hydroxy or C? .6 alkoxy, for example, methoxy or ethoxy. Conveniently R5a 'R5b' R5c and R5d are the same or different and are, each hydrogen, C? 4 alkoxy, halogen, hydroxy or CM alkyl, optionally substituted by fluorine. Preferably R5a, R5b, R5c and R5d are the same or different and are each hydrogen, methyl, methoxy, hydroxy, methyl trifluoride or halogen. More preferably, R5a and R5d are hydrogens and R5b and R5c are the same or different and each is hydrogen, C? -alkoxy, hydroxy, halogen or C? -4 alkyl, optionally substituted by fluorine. It is best that R5a and R5b are hydrogens and R5b and R5c are the same or different and each is hydrogen, methyl methoxy, hydroxy, trifluoride methyl or halogen. Conveniently R6 and R7 are the same or different and each is hydrogen or a C6-C6 alkyl group, for example, methyl or ethyl. The best thing is that R6 and R7 are both hydrogens. Conveniently X in CH2 or C = 0 Conveniently, from R9 to R11 are the same or different and each is hydrogen or methyl. Conveniently I is 0 or 2, and preferably is 2. When 1 or more of R1, R2, R4 or R11 is a substituted C? .6 group or comprises a C? -6 alkyl group, the substitutes may be the same or different, and each is selected from the hydroxy, halogen, alkyl C? .6l C? .6 alkoxy, COR12, nitrile, CO2R12, SO3R12, NR13R14, N + R13R14R15, where, from R12 to R15 are the same or different and each is selected from hydrogen or C? .6 alkyl, preferably methyl.

The preferred additional compounds of formula (I) are: (±) -3-n-Butyl-3-ethyl-2,3-dihydro-5-phenyl-1, 5-benzothiazepin-4-one (±) -3 -n-Butyl-3-ethyl-2,3-dihydro-5-phenyl, 5-benzothiazepin-4-one-l, l-dioxide (±) -3-n-Butyl-3-ethyl-2, 3,4,5-tetrahydro-5-phenyl-1, 5-benzothiazepine; (±) -3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1, 5-benzothiazepine-1, l-dioxide (±.}. -3-n-Butyl -2-isobutyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1, 5-benzothiazepine-1,1-dioxide 3,3-Diethyl-2,3-dihydro-5-phene-1,5-benzothiazepin-4-one; 3, 3-Diethyl-2,3-dihydro-5-phene-l.5-benzothiazepin-4-one-l, I-dioxide 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl -l, 5-benzothiazepine; 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1, 5-benzothiazepine-1, l-dioxide; 3,3-Dimethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one; 3,3-Dimethyl-2,3-dihydro-5-phenyl-1, 5-benzothiazepin-4-one-l, l-dioxide; 3,3-Dimethyl-2,3,4,5-tetrahydro-5-phenyl-1, 5-benzothiazepine; 3,3-Dimethyl-2,3,4,5-tetrahydro-5-phenyl-l, 5-benzothiazepine-1, l-dioxide; (±) -3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide; 3,3-Dietl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide; (±) -3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide; (±) -3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1, 5-benzothiazepin-8-ol-1,1-dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-8-ol-1,1-dioxide; (±) -3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1, 5-benzothiazepin-8-ol-1,1-dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,5-benzothiazepin-8-ol-1,1-dioxide; (±) -7-bromo-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide; 7-bromo-3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide; (±) -3-n-Butii-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1, 5-benzothiazepin-7,8-diol-1,1-dioxide; 3, 3-Diethyl-2, 3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-7,8-diol-1,1-dioxide; (±) -3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1-monoxide; 3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1, 5-benzothiazepine-1 -monoxide; (±) -3-n-Butyl-3-ethyl-2, 3, 4, 5-tetrahydro-5-phenyl-1, 5-benzothiazepin-8-ol-1-monoxide; 3,3-Diethyl 2,3,4,5-tetrahydro-5-phenyl-l, 5-benzothiazepin-8-ol-l-monoxide, (±) -3-n-Butyl-3-ethyl-2,3 -dihydro-8-methoxy-5-phenyl-1,5-benzothiazepin-4-one; (±) -3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine; (±) -3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine; 1, 1-dioxide; (±) -3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-hydroxy-5-phenyl-1,5-benzothiazepine; 1,1-dioxide; (±) -7-Bromo-3-n-butyl-3-ethyl-2,3-dihydro-8-methoxy-5-phenyl-1, 5-benzothiazepin-4-one; (±) -7-Bromo-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide; (±) -7-Bromo-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-8-ol-1,1-dioxide; (±) -3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,5-benzothiazepin-8-ol-1,1-dioxide; (±) -3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide; (±) -3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-7,8-diol 1,1-dioxide; (±) -7-Bromo-3-n-butyl-3-ethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one; (±) -3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide; and, (±) -3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-7-ol-1,1-dioxide; Particularly preferred compounds include: (±) -3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,5-benzothiazepin-8-ol 1, 1- dioxide y, (±) -3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-hydroxy-5-phenyl-1, 5-benzothiazepine-1, 1-dioxide The pharmaceutically accepted salts are recommended for medical applications because of their high aqueous solubility relative to their origin, i.e., basic compounds. Said salts must clearly have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition acid salts of the compounds of the present invention include those derived from inorganic acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulfuric and sulfuric acids; and organic acids, such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic, tartaric and trifluoroacetic. The chloride salt is particularly preferred for medical purposes. Convenient pharmaceutically acceptable salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, and alkaline earth salts, such as magnesium and calcium salts. Salts that do not have a pharmaceutically acceptable anion are, within the scope of the invention, useful intermediates for the preparation or purification of pharmaceutically acceptable salts and / or for non-therapeutic use, for example, in in vitro applications. Any reference to "the compound (s) of the formula (I)", "compounds of the present invention", "compounds related to the invention", etc., refer to the compound (s) of the formula (I) as described above, together with their respective salts, solvates and their physiologically functional derivatives, as defined herein. The term "physiologically functional derivatives" as used herein, is to refer to any physiologically acceptable derivative of a compound of the present invention, for example, an ester, which upon administration to a mammal, such as a human, is capable of providing (directly or indirectly) such a compound and, therefore, an active metabolite thereof. A complementary aspect of the present invention are the prodrugs of the compounds of the invention. Such prodrugs can be metabolized in vivo to give a compound according to the invention. These prodigies may or may not be active in their own right. The compounds of the present invention can also exist in different polymorphic forms, for example, in the crystalline and amorphous forms. All polymorphs of the compounds of the present invention fall within the scope thereof and, therefore, are a complementary aspect of the invention itself.

The term "alkyl" is used herein to refer, unless otherwise stated, to a monovalent or branched-chain radical. Likewise, the terms "cycloalkyl" and "spiro-cycloalkyl" refer, unless otherwise stated, to bivalent radicals cycle or spiro-cycle respectively. The term "alkoxy" refers to a monovalent line or branched chain radical attached to a molecular part of origin through an oxygen atom. The term "aryl" refers to a monovalent, mono-, bi-, tri-cyclic aromatic ring. The term "heteroaryl" refers to a monovalent, monovalent, or tri-cyclic aromatic ring containing one or more heteroatoms (e.g., nitrogen, oxygen, sulfur). The term "phenylalkoxy" refers to a monovalent phenyl group bonded to a divalent C 1-6 alkylene group which, in turn, is attached to a molecular part of origin through an oxygen atom. The term "halogen" refers to fluorine, chlorine, bromine or iodine. The compounds of the formula (I) exist in forms wherein the carbon centers -C (R1) (R2) - and -C (R6) (R7) - can be malleable. The present inventincludes within its scope each possible substantially free optical isomer, i.e. as well as associat with less than 5%, of any other isomer (s), and mixtures of one or more optical isomers in any proport including ceramic mixtures. In those cases where the absolute stereochemistry of centra -C (R1) (R2) - and -C (R6) (R7) - has not been determined, the compounds of the inventare defined in terms of the relative posit of the substitutes of R1 / R2 and R6R7. Thus, in those compounds where the principal of the substitutes, i.e. the higher mass substitute, together with the previous substitute are located both on the same side of the thiazepine ring, here they are referred to as "cis", and those compounds in which the principal of the substitutes is located on the opposite side with Regarding the previous substitute, here they are referred to as "trans". For a competent person it will be evident that each of the two "cis" and "trans" compounds of the inventcan exist in two enantiomeric forms, which are individually designated "(+) -" or "(-) -" according to the directof rotatof the plane of the polarized light when it passed through a sample of the compound The cis or trans compounds of the invent in which the individual enantiomers have not been resolved are referred to for this occasusing the prefix "(+ -) - "With respect to the complementary aspects of the invent there are also provided: (a) The compounds of the formula (I) and the pharmaceutically acceptable salts, solvates and corresponding physiological functl derivatives, for use as therapeutic agents, particularly in the prophylaxis and treatment of clinical condit, for which an inhibitor of the absorptof bile acid is indicated, for example, of a hyperlipidemic conditand, in diseases associated with it, such as arteriosclerosis; (b) Pharmaceutical composit containing a compound of the formula (I), or some of its pharmaceutically acceptable salts, solvates or physiologically functl derivatives, at least one pharmaceutically acceptable carrier and optlly, one or more physiologically active agents; (c) The use of any compound of the formula (I) or of any pharmaceutically acceptable salt, solvate or corresponding physiologically functl derivative, in the manufacture of a medicament for the prophylaxis or treatment of a certain clinical condit for which an inhibitor of the bile acid absorptis indicated, for example, a hyperlipidemic conditand the diseases associated with it, such as arteriosclerosis; (d) A method for inhibiting the absorptof bile acids from the intestine of a mammal, such as a human, which consists of administering an effective amount of a compound of the formula (I), of any pharmaceutically acceptable salt , solvate or a corresponding physiologically functl derivative, which inhibits the absorptof bile acid into the mammal; (e) A method for reducing the concentrations of LDL cholesterol of blood plasma or serum in a mammal such as a human, which consists in the administration of an effective amount of a compound of the formula (I), or pharmaceutically acceptable salt, solvate or a corresponding physiologically functional derivative, which is cholesterol lowering for the mammal; (f) A method of reducing the concentrations of cholesterol and cholesterol ester in the blood plasma or serum of a mammal, such as a human, which consists of administering an effective amount of a compound of the formula (I) ), or of any pharmaceutically acceptable salt, solvate or a corresponding physiologically functional derivative, which reduces the cholesterol and the cholesterol ester in the mammal; (g) A method for increasing the fecal excretion of bile acids in a mammal, such as a human, which consists in the administration of an effective amount of a compound of the formula (I), or of any pharmaceutically acceptable salt, solvate or a corresponding physiologically functional derivative, which increases the fecal excretion of bile acids in the mammal; (h) A method for the prophylaxis or treatment of a certain clinical condition in a mammal, such as a human for whom an inhibitor of bile acid absorption is indicated, for example in a hyperlipidemic condition and associated diseases, as is arteriosclerosis, which consists in the administration of a therapeutically effective amount of a compound of the formula (I), or of any pharmaceutically acceptable salt, solvate or a corresponding physiologically functional derivative, to the mammal; (i) A method for reducing the incidence of coronary heart diseases and related events in a mammal, such as a human, which consists of administering an effective amount of a compound of the formula (I) , or of some. pharmaceutically acceptable salt, solvate or a corresponding physiologically functional derivative, which reduces coronary heart diseases and related events in mammals; (j) A method for reducing the concentration of cholesterol in the blood plasma or in the serum of a mammal, such as a human, which consists of administering an effective amount of a compound of the formula (I) which is cholesterol reducer; (k) The processes for the preparation of the compounds of the formula (I) (including salts, solvates and corresponding physiologically functional derivatives as defined herein); (I) Novel chemical intermediates in the preparation of the compounds of the formula (I); and (m) The compounds of synthetic examples 1-27 as will be shown later, herein.

The amount of the compound of the formula (I) that is required to carry out the biological effect will obviously depend on the number of factors, for example, of the specific compound chosen, the use for which it is required, the form of administration, and the clinical condition of the recipient. In general, a daily dose is in the range of 0.001 mg. up to 100 mg. (typically from 0.01 mg to 50 mg.) per day, per kilogram in weight; for example, 0.01-10 mg / kg. /day. Thus, orally administrable unit dose formulations, such as tablets or capsules, may contain, for example, 0.1 to 100 mg, typically 0.1 to 10 mg, and preferably 0.1 to 5 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 conditions, the compounds of the formula (I) can be used as the compound p-se, but are preferably presented with an acceptable carrier in the form of a pharmaceutical composition. The carrier must be, of course, acceptable in the sense of being compatible with the other ingredients of the composition and should not be deadly to the recipient. The carrier can be solid or liquid, or both, and is preferably formulated with the composition of a unit dose, for example, a tablet, which can contain from 0.05% to 95% by weight of the active compound. Other pharmacologically active substances can also be presented including other compounds of the formula (I). The pharmaceutical compositions of the invention can be prepared by any of the well known pharmaceutical techniques which essentially consist in the addition and mixing of the components. Pharmaceutical compositions corresponding to the present invention include those which are convenient by oral, rectal, local, buccal (eg sublingual) and different routes to the digestive tract (eg subcutaneous, intramuscular, intradermal, intravenous), although the most convenient route , in any given case, depends on the nature and severity of the condition being treated, and on the nature of the particular compound of the formula (I) that is being used. The enteric layer and the release formations controlled by the enteric layer also fall within the scope of the invention. The recommended enteric layers include cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl cellulose phthalate and the anionic polymers of methacrylic acid and methyl methacrylic acid ester. Enteric coatings and controlled release enteric coatings include tablets and capsules. The pharmaceutical compositions recommended for oral administration can be presented in discrete units, such as capsules, tablets, pills or tablets, each containing a predetermined amount of a compound of formula (I), which is in the form of powders or granules, or as a liquid solution or suspension that can be aqueous or non-aqueous; either as an oil-in-water emulsion or a water-in-oil emulsion. As already indicated, such compositions can be prepared by any recommended pharmaceutical method, which include the step of bringing the active compound and the carrier into an association (which may constitute one or more crository ingredients). In general, the compositions are prepared by addition and intimate and uniform mixing of the active compound with the liquid carrier or finely divided solid carrier, or both; and then, if necessary, shape the product. For example, a tablet can be prepared by compression and molding a powder or granules of the compound, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the compound in its free-flowing form, in a recommendable machine, such as powder or granules optionally mixed with a linker, lubricant, inert diluent and / or with surface-active agents. . The molded tablets can be made by molding, in a recommended machine, the pulverized compound moistened with an inert liquid diluent. Controlled release tablets can be prepared in a similar manner, and with the addition of, for example, hydroxypropylmethyl cellulose. Enteric coated tablets can be prepared by coating the tablets with an enteric polymer such as cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl cellulose phthalate and the anionic polymers of methacrylic acid of methacrylic methylester ( Eudragit L). Except for Eudragit L, these polymers must also include 10% (of the weight of the amount of polymer used) of a plasticizer to prevent the membrane from fracturing during application or storage. Recommended plasticizers include diethyl phthalate, tributyl cirtrate and triacetin.

Controlled release enteric coated tablets can be prepared by coating the controlled release tablets with an enteric polymer, such as cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl cellulose phthalate and the anionic polymers of metracrylic acid. and methacrylic acid methyl ester (Eudragit L). Except for Eudragit L, these polymers must also include 10% (by weight of the amount of polymer used) of a plasticizer to prevent the membrane from fracturing during application or storage. Recommended plasticizers include diethyl phthalate, tributyl citrate and triacetin. Capsules can be prepared by adding and mixing a compound of formula (I) with, for example, magnesium stearate, pregelatinized starch, sodium starch glycolate, and / or magnesium stearate, and filling the hard gelatine capsules with two parts with the resulting mixture. Controlled release capsule compositions can be prepared by the addition and mixing of a compound of formula (I), with for example microcrystalline cellulose and / or lactose, and extruded with an extruder and then spherical shaped and Dry the extruded product. The dried pills are coated with a controlled release membrane, which can be, for example, ethyl cellulose, and are filled into two-part hard gelatin capsules. Enteric capsule compositions can be prepared by the addition and mixing of a compound of formula (I) with, for example, microcrystalline cellulose and / or lactose, and extruded with an extruder and then spherically shaped and dried. Extruded product. 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 recommended by buccal (sublingual) administration include tablets containing a compound of formula (I), on a flavor basis, regularly sucrose and acacia or tragacanth, and tablets containing the compound in an inert base, which it can be gelatin and glycerin or sucrose and acacia. Recommended pharmaceutical compositions by way of administration external to the digestive tract, conveniently contain sterile aqueous preparations of a compound of the formula (I), preferably isotonic with the blood of the designated receptor. These preparations are preferably administered intravenously, although administration can also be effected by subcutaneous, intramuscular or intradermal injection. Said preparations can be conveniently carried out by adding and mixing the compound with water and integrating the resulting sterile and isotonic solution with the blood. The corresponding injectable compositions will generally contain from 0.1 to 5% w / w of the active compound. Recommended pharmaceutical compositions by rectal administration are presented as unit dose suppositories. These can be prepared by the addition and mixing of a compound of formula (I) with one or more conventional solid carriers, for example, cocoa butter, and then the resulting mixture is shaped. Transdermal administration is also possible. Pharmaceutical compositions recommended by transdermal administration route may be presented as discrete patches that are adapted to remain in contact with the epidermis of the recipient for a prolonged period of time. Said patches should preferably contain the active compound in an aqueous solution, dissolved and / or dispersed in an optionally regulated adhesive, or be dispersed in a polymer. A recommended concentration of the active compound is around 1% to 35%, preferably around 3% to 15%. As a particular possibility, the active compound can be delivered from the patch by means of electrotransport or iontophoresis, for example, as described in Pharmaceutical Research, 3 (6), 318 (1986) The compounds of formula (I) can be prepared by conventional methods known to a skilled person or analogously by the processes described in the art. For example, the compounds of formula (I) wherein I is 0, R6 and R7 are Hydrogens and X is CH2, can be prepared by the reduction of the carbonyl group of a compound of formula (II).

Where R1, R2 and R5, a 'b C | d defined above, using for example, a reducing agent such as Aluminum Hydride (AIH3), diisobutylaluminum hydride (DIBAL) or Boron Hydride (BH3) in a convenient organic solvent, such as THF. The compounds of formula II, defined above, are novel and constitute a complementary aspect of the present invention. The compounds of formula (II) can be prepared by a reaction of compounds of formula III.

Where R1, R2 and R5, a 'b' c 'd defined above, with an appropriate R4-Z in the presence of a base, for example potassium carbonate (K2CO3) and optionally in the presence of a catalyst, for example copper iodide (Cul), where R 4 is defined above, and Z is a convenient leaving group, for example, halogens. The R4'Z compounds are commercially available or can be prepared by methods well known or readily available to those skilled in the art. The compounds of the formula III already characterized and defined above are original and constitute a further aspect of the present invention. The compounds of the formula (III) can be prepared by cyclization of the compounds of the formula (IV).

Where R1, R2 and R5, a 'bl c' d are already characterized and defined above, by reactions with an acid, for example an organic acid such as a ticosic acid, preferably at a temperature carried, for example, 225 ° C. The compounds of the formula (IV) can be prepared by reactions of the compounds of the formula (V) with compounds of the formula (Va).

(Goes) Where R1, R2 and R5a 'b' c 'd are already characterized and defined above and Z is a convenient leaving group, for example halogen, in the presence of an organic base, for example triethylamine or pyrrolidine. The compounds of formula (V) and (Va) are commercially available or can be prepared by methods well known or readily available to those skilled in the art. The compounds of the formula (I) wherein I in 1 or 2, can be prepared from the corresponding compound of the formula (I), wherein I is 0 by oxidation of the thio part with a suitable oxidizing agent, for example, peroxide of hydrogen, organic peroxy acid, Oxano < R) (potassium peroxymonosulfate) or osmium tetroxide (OSO4). The compounds of the formula (I), wherein R6 and / or R7 are different from hydrogen can be prepared by treating the corresponding compound of the formula (I) wherein I is 1 or 2 and R6 and R7 are hydrogen with a base, for example lithium n-butyl, followed by a reaction with the appropriate R6-Z or R7-Z, wherein R6 and R7 have already been characterized above and are other than hydrogen and Z is a suitable leaving group as has already been characterized above. Alternatively, the compounds of the formula (III) can be prepared from compounds of the formula (VI) Where R1, R2 and R5a 'b? c 'd already characterized and defined above by reaction with an acid, for example polyphosphoric acid at an elevated temperature of, for example, 120 ° C.

The compounds of the formula (Vi) can be prepared from compounds of the formula (VII). where R1, R2 and 5a b c d? already characterized and defined above, by reaction with hydroxylamine (H2NOH). The compounds of the formula (VII) can be prepared by cyclizing compounds of the formula (VIII) where R1, R2 and R5a '' c 'd, already characterized and defined above, in the presence of an acid, for example sulfuric acid (H2SO4) The compounds of the formula (VIII) can be prepared by the reaction compounds of the formula ( IX).

(DO wherein R5a 'b c d' already characterized and defined above, with compounds of the formula (VI), analogous to the preparation of compounds of the formula (IV) described above.

The compounds of formula (IX) are commercially available or can be prepared by methods well known or readily available to those skilled in the art. Alternatively, the compounds of the formula (II) can be prepared by cyclizing compounds of the formula (X). wherein R1, R2, R4 and R5 -aa, bD ,, cc ,, da, 'already characterized and defined above in the presence of an organic acid, for example, ticosic acid. The compounds of the formula (X) can be prepared from compounds of the formula (XI). wherein R 4 and R 5a b c d 'characterized and defined above, with compounds of the formula (Va) analogous to the preparation of compounds of the formula (IV) described above. The compounds of the formula (XI) can be prepared by methods well known or readily available to those skilled in the art, for example by the methods set forth by H. Gilman and J. Dietrich, J. Am Chem. Soc. 80 380- 383 (1958) which is incorporated here in its entirety.

The components of the formula (I) wherein X is C = O can be prepared following the method for the preparation of compounds of the formula (II) described above. The compounds of the formula (I) wherein X is C = S can be prepared from the corresponding compounds of the formula (I) wherein X is C = O by conversion of the C = O part, for example with the Lawessons reagent (2.4 bi (4-methoxyphenyl) -1,3-dithia 2,4-diphosphtane-2,4-disulfide). The compound of the formula (I) substantially free of other optical isomers can be obtained either by chiral synthesis, for example, by the use of the appropriate chiral initiation matepals, such as a chiral compound of the formula (Va), or by resolution of the products obtained from a non-chiral synthesis, for example, by chiral hplc, enzymatic resolution, or by classical resolution with chiral acids. An optional conversion of the compounds of the formula (I) or a compound of the formula (I) including a basic substitute, to a corresponding acid addition of yeses can be affected by the reaction of a solution of the appropriate acid, for example, one of those mentioned above. An optional conversion of a compound of the formula (I) including a substitute acid to a corresponding basic salt can be affected by reaction with a solution of the appropriate base, for example, sodium hydroxide. The optional conversion of a physiologically functional derivative, such as an ester, can be obtained 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 from the literature to those skilled in the art, for example, by alkylation of a hydroxy group.

For a better understanding of the invention the following examples are shown as an illustration and should not be construed in any way as limiting the scope of the invention.

General procedures The proton magnetic resonance spectrum was recorded at 300 MHz. Mass spectra were recorded under atmospheric chemical ionization pressure (APCI) conditions in an LSMS instrument or were developed by Oneida Research Services Inc. under chemical ionization (Cl) conditions using methane as the reactive gas. The elemental analysis was developed by Atlantic Microlab Inc. All reactions were developed under a nitrogen atmosphere. The TLC plates were 60 plates of Whatman MK6F silica gel and were visualized under a UV lamp. The column chromatography was developed with silica gel 60 EM (230-400 mesh). The reagents were obtained by Aldrich Chemical Co. unless otherwise noted and used without further purification. The solvents were Aldrich anhydrous grades. Example 1 Preparation of (±) -3-n-Butyl-3-ethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one (a) (±) -2 - ((tert-butyldimethyl-silicoxy) ) methyl-ethyl-hexanol To a suspension of 60% NaOH (7.5 g 187.2 mmol) in 400 ml THF, 2-n-butyl-2-ethyl-1,3-propanediol (30.0 g, 187.2 mmol) was added in 3 portions. ) was stirred for 45 min to the resulting gum was added tertbutyl dimethyl silyl chloride (28.2 g, 187.2 mmol) and stirred for 2 hours.The solvent was evaporated and the residue was partitioned between water and ether. was washed with a solution of bicarbonate and brine and concentrated, column chromatography (5% ethyl acetate / petroleum ether) gave the title compound as a colorless oil (50.12 g, 182.6 mmol, 98%). (DMSO-d6) d 4.19 (t, 1 H); 3.29 (s, 2H); 3.13 (d, 2H); 1.15 (m, 8H); 0.84 (s, 9H); 0.83 (t, 3H); 0.73 (t, 3H); -0.01 (s, 6H). MS Da / e = 275 (MH +). Calculated for C? 5H34O2Si: C, 65.63; H, 12.48. Found: C, 65.87; H, 12.47. (b) (±) -2-Ethyl-2 (Hydroxymethyl) -hexanoic acid To a solution of the product from example 1 (a) (4.43 g, 16.0 mmol) in 16 ml CCI4, 16 ml of CH3CN and 24 ml of H20 was added NalO4 (13.69 g, 64 mmol) and RuCI3 (0.16 g, 0.8 mmol) and mixed for 16 hr. The mixture was concentrated and the solvents evaporated. The residue was partitioned between H2O and CH2CH2. The aqueous phase was extracted 3 times with CH2Cl2, dried, concentrated. The residue was dissolved in 3 ml. THF, IM tetrabutylammonium fluoride in THF (1.75 ml, 1.75 mmol) was added and the solution was stirred for 1 hour. The solvent was evaporated and the resulting oil was divided between H20 and CH2CH2. The aqueous phase was extracted three times with CH2CH2? dried, concentrated. Column chromatography (95%, CH2Cl2 / 4% MeOH / 0.5% H2O / 0.5% acetic acid) gave the product compound as an oil 2.26 g (13.0 mmol, 81%). 1 H NMR (DMSO-de) d 11.95 (br s, 1 H); 4.74 (br s, 1 H); 3.42 (s, 2H); 1.53-1.03 (m, 8H); 0.84 (t, 3H); 0.73 (t, 3H). MS Da / e = 175 (MH +) and 129 (M-CO2H). Calculated for C9H1803: C, 62.04; H, 10.41. Found: C, 61.94; H, 10.44. (c) (±) -2- (bromemetyl) -2-ethyl hexanoic acid A solution of the product of Example 1 (b) (2-30 g, 13.2 mmol) in 48% Hbr (40 ml.) was Reflowed for 20 hrs. After entering Temp. The solution was transferred to a separatory funnel, extracted 3 times with ethyl acetate, dried over Na 2 SO 4 and concentrated. After pumping in high vacuum to remove traces of HBr obtaining the title compound (2.46 g, 10.4 mmol, 79%). 1 H NMR (DMSO-d 6) d 3.60 (s, 2H); 1.62-1.04 (m, 8H); 0.85 (t, 3H); 0.75 (t, 3H). MS Da / e = 157 (M-Br), 237 (M), 238, 239 (M + 2). Calculated for C9H1702Br: C, 45.59; H, 7.23, Br, 33.70. Found: C, 46.27; H, 7.17, Br, 32.94. (d) (±) -2- (((2-Aminophenyl) thio) methyl) -2 -hetilexanoic acid To a solution of the product of Example 1 (c) (0.52 g, 2.19 mmol) in THF (4 ml) was added 2 aminothiophenol (0.41 g, 3.29 mmol, recently distilled) and pyrolidine (or trethylamine 3.29 mmol) and stirred for 48 h. The reaction mixture was transferred to a separatory funnel and divided between H2O and CHCl3. The aqueous layer was extracted 3 times with CHCl3, column chromatography (30% ethyl acetate in petroleum ether) to give the title compound (0.5g, 1.78 mmol, 81%) 1H NMR (DMS0-d6) d 12.40 (br, s 1 H); 7.25 (d, 1 H); 7.00 (t, 1 H); 6.67 (d, 1 H), 6.48 (t, 1 H); 5.23 (br, s, 2H); 2.91 (s, 2H); 1.66-0.99 (m, 8H); 0.77 (t, 3H); 0.67 (t, 3H) MS Da / e = 282 (MH +), 264 (M-H2O), 236 (M-CO2H). Calculated for C.5H23NSO2 x (0.8 EtOAc): C, 62.12; H, 8.42; N, 3.98; S, 9.11. Found: C, 62.41; H, 8.28; N, 33.83, S, 8.91. (e) (±) -3-n-butyl-3-ethyl-2,3-dihydro-1,5-benzothiazepin-4-one A solution of the product of Example 1 (d) (0.66 g, 2.35 mmol) and toluenesulfonic acid (0.15 g, 0 79 mmol) in tetradecane (30 ml) was refluxed for 3 hours. After cooling to Temp. The reaction mixture was charged directly to a column of silica and the product extracted with 10% ethyl acetate / petroleum ether giving the title compound (0.44 g, 167 mmol, 71%) .PF = 90.0 ° C 1 H NMR (DMSO-de) & 9.71 (s, 1 H); 7.39 (d, 1 H); 7.23 (t, 1 H); 7.10 (d, 1 H); 6.95 (t, 1 H); 2.92 (s, 2H); 1.72-1.20 (m, 4H); 1.15 (m 4H); 0.78 (m, 6H). MS Da / e = 264 (MH +;. Calculated for C15H2? NSO: C, 68.40; H, 8.04; N, 5.32; S, 12.17. Found: C, 68.25; H, 8.11; N, 5.29, S, 12.09. (f) (±) -3-h-butyl-3-et? -1-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one To a solution of the product of Example 1 (e) (4.07 gr. , 15.45 mmol) in phenyl iodide (17 mL, 154 mmol) was added copper iodide (0.28 g, 1.5 mmol) and potassium carbonate (2.13 g, 15.45 mmol), and the mixture was refluxed for 16 h. of the reaction was allowed to cool and was charged directly to a silica column and extracted with 5% ethyl acetate / petroleum ether to give a title compound (5.14 g, 15.14 mmol, 98% yield) MP = 159.4 ° C .1H NMR (DMSO-d6) &7.67-6.86 (m, 9H); 3.1 1 (s, 2H); 1.58-1.13 (m, 8H); 0.77 (m, 6H). MS Da / e = 340 (MH +) Calculated for C? 2 H25NSO: C, 74.30; H, 7.42; N, 4.13; S, 9.44 Found C, 74.11; H, 7.49; N, 4.03, S, 9.36. Example 2. Preparation of (±) -3-n-butyl-3-ethyl-2,3-dihydro-5-phenyl-1, 5-benzothiazepin-4-one-1.1 dioxide To a solution of the compound of Example 1 ( f) (0.95 g, 2.8 mmol) in trifluoroacetic acid (9.5 ml) at 0 ° C was added 30% hydrogen peroxide (1.60 g, 14 mmol) and mixed for 16 hr. The solution was neutralized with a sodium carbonate solution and the product was extracted 3 times with ethyl acetate. The organic extracts were dried (Na2SO4), concentrated and the resulting oil loaded onto a silica column. The product was extracted with 20% ethyl acetate / petroleum ether giving the title compound as a white powder (0.96 g, 2.58 mmol 92%). P.F .. = 57.6 ° C. 1 H NMR (DMSO-d 6) d 7.94- 7.06 (m, 9H); 3.73 (s, 2H); 1.72 - 0.98 (m, 8H); 0.77 (m, 6H). MS Da / e = 372 (M H +). Calculated for C2? H25 NSO3: C, 67.90; H, 6.78; N, 3.77; S, 8.63. Found: C, 67.61; H, 6.92; N, 3.62; S, 8.57. Example 3 Preparation of (+) - 3-n-butyl-3-ethyl-2.2.3.4.5-tetrahydro-5-phenyl-1,5-benzothiazepine. To a solution of AIH3 (44 mmol, generated in situ of H2SO4, 22 mmol, and LiAIH4, 44 mmol) in 44 ml of diethyl ether, was added the compound of Example 1 (f) (5.0 g, 14.60 mmol) in 40 mL THF at 0o C. The reaction mixture was allowed to warm to Temp. Amb. For 2 hr. and was stirred to T.A. for 15 hr. After time, TLC (20% ethyl acetate / petroleum ether) showed complete reaction. The reaction vessel was cooled to 0 ° C and the excess AIH3 was quenched by adding 30 drops of H 2 O / THF (1: 2) followed by 5 ml 1 M NaOH. The mixture was transferred to a separatory funnel and extracted 3 times with ether. The ether extracts were combined, dried, concentrated and column chromatographed (petroleum ether) to give the title compound (4.74 g, 14.55 mmol, 99%). 1 H NMR (DMSO-dβ) d 7.26-6.69 (m, 9H); 3.67 (br s, 2H); 2.78 (m, 2H); 1.21 - 1.05 (m, 8H); 0.71 (m, 6H). MS Da / e = 325 (M +), 326 (MH +). Calculated for C21 H27 NS: C, 77.49; H, 8.36; N, 430, S, 9.85. Found: C, 77.51; H, 8.40; N, 4.31; S, 9.73. Example 4. Preparation of (±) -3-n-butyl-3-ethyl-2,3A5-tetrahydro-5-phenyl-1.5-benzothiazepine -1,1-dioxide. To a solution of the compound of Example 3 (4.73 g, 14.53 mmol) in 100 ml of THF and 23 ml of tert-butanol was added N-methyl-morpholine oxide N (5.1 g, 43.6 mmol) and osmium tetroxide (0.8 mmol, 2.5% weight in 2-methyl-2-propanol). The mixture was stirred at Temp. Amb. For 16 hr. At which point 50 ml of Na HCO3 was added to neutralize any acid, the mixture was transferred to a separatory funnel and extracted 3 times with ethyl acetate. The organic layers were washed with sodium hyposulfite and brine, dried (Na 2 SO) and concentrated. Column chromatography (10% ethyl acetate / petroleum ether) yielded the title compound (4.76 g, 13.3 mmol, 92% yield). ? NMR (DMSO-d6) d 7.87-6.81 (m, 9H); 3.72 (m, 2H); 3.33 (s, 2H); 1 55 - 0.97 (m, 8H); 0.69 (m, 6H). MS Da / e = 358 (MH +).

Calculated for C2? H27 NSO2: C, 70.55; H, 7.61; N, 3.92; S, 8.97. Found: C, 70.37; H, 7.59; N, 3.84; S, 9.07. Example 5. Preparation of (±) -3-n-butyl-2-isobutyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-1,1-dioxide. To a solution of the compound of Example 4 (0.565 g, 1.58 mmol) in 10 mL of THF was added n-butyl lithium (2.5 M in THF, 1.74 mmol) at -78 ° C. This was stirred for 20 min at -78 ° C after which iodo-2-methyl propane drops (1.3 M in THF, 6.32 mmol) were added at -78 ° C. The reaction mixture was bro to 0 ° C and stirred for 16 h. The excess base was quenched by adding brine (10 ml) and the product was extracted with ether (3 x 20 ml). The ether extract was dried, concentrated and the residue applied to a column of silica gel. The product was extracted with 10% ethyl acetate / petroleum ether giving a yellow oil (0.48 g, 1.16 mmol, 74%). 1 H NMR (DMSO-d 6) d 7.89-6.80 (m, 9H); 3.30 (br m, 2H); 3.09 (br s, 1 H); 1.88-0-63 (m, 23H). MS Da / e = 414 (MH +), 436 (M + Na). Calculated for C25 H35 NSO2: C, 72.60; H, 8.53; N, 3.39; S, 7.75. Found: C, 72.39; H, 8.56; N, 3.27; S, 7.88. Example 6. Preparation of 3,3-diethyl-2,3-dihydro-5-phenyl-1,5-benzotrazepin-4-one. (a) 2 - ((tert-butyl dimethyl silyl) oxy) methyl-2-ethyl butanol. The title compound was prepared from 2,2-diethyl-1,3-propanediol according to the procedure of Example 1 (a). 1 H NMR (DMSO-d 6) d 4.20 (t, 1 H); 3.29 (s, 2H); 3.14 (d, 2H); 1.13 (q, 4H); 0.84 (s, 9H); 0.73 (t, 6H); 0.73 (t, 3H); -0.01 (s, 6H). MS Da / e = 247 (MH +). Calculated for C13 H30 O2 Si: C, 63.35; H, 12.26. Found C, 63.27; H, 12.25. • (b) 2-ethyl-2- (disoxymethyl, -butyric acid.

The title compound was prepared from the product of Example 6 (a) (41.28 g, 189 mmol) using the procedure for Example 1 (b) yielding (24.4 g, 167 mmol, 88%) H NMR DMSO-d6) d 3.42 (s, 2H); 1.89 (s, 1 H); 1.44 (q, 4H); 0.73 (t, 6H). MS Da / e = 147 (MH +). Calculated for C7 H14 O3 x 0.3 (AcOH): C, 55.39; H, 9.33. Found: C, 55.38; H, 9.17. (c) 2- (bromomethyl) -2-ethyl-butyric acid. The title compound was prepared from the product of Example 6 (b) (22.2 g, 151 mmol) according to the procedure indicated for Example 1 (c). After removing the HBr in vacuo, 10B was obtained (19.8 g, 94.7 mmol, 63%). 1 H NMR (DMSO-dβ) d 3.60 (s, 2H); 1.58 (q, 4H); 0.75 (t, 3H). MS Da / e = 209 (M), 211 (M + 2). Calculated for C7 H13 O2 Br: C, 40.21; H, 6.27; Br, 38.21. Found: C, 40.92; H, 6.38; Br, 37.17. (d) 2 - (((2-aminophenyl) thio) methyl) -2-ethyl butyric acid. The title compound was prepared from the compound of Example 6 (c) (19.7 g, 94 mmol) according to the procedure of Example 1 (d). Column chromatography gave the product (9.77 g, 40 mmol, 43%). 1 H NMR (DMSO-d 6) d 7.24 (d, 1 H); 7.00 (t, 1 H); 6.69 (d, 1 H); 6.49 (t, 1 H); 2.91 (s, 2H); 1.60 (q, 4H); 0.68 (t, 3H). MS Da / e = 254 (MH +). Calculated for Ci3 H19 NSO2: C, 61.62; H, 7.57; N, 5.52; S, 12.65. Found: C, 61.34; H, 7.62; N, 5.33; S, 12.40. (e) 3,3-Diethyl-2,3-dihydro-1,5-benzothiazepine-4-one. The title compound was prepared by thermal ring closure of the product of Example 6 (d) (9.7 g, 38 mmol) as indicated in Example 1 (e). Column chromatography (50% ethyl acetate / petroleum ether) gives the title compound (6.22 g, 26.4 mmol, 70% yield). 1 H NMR (DMSO-d 6) d 9.73 (s, 1 H); 7.40 (d, 1 H); 7.23 (t, 1 H); 7.10 (d, 1 H); 6.97 (t, 1 H); 2.92 (s, 2H); 1.71 -1 1.48 (m, 4H); 0.76 (m, 6H). MS Da / e = 236 (MH +). Calculated for Ci3 H17 NSO: C, 66.34; H, 7.28; N, 5.95; S, 13.67. Found: C, 66.34; H, 7.37; N, 5.96; S, 13.58. (f) 3,3-Diethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepine-4-one. N-phenylation of the compound of Example 6 (e) (5.40 g, 23 mmol) was carried out following the procedure of Example 1 (f) to yield the title compound after column chromatography (7.04 g, 22.6 mmol, 99 % yield) MP = 86.4 ° C 1 H NMR (DMSO-d 6) d 7.66-6.87 (m, 9H); 3.09 (s, 2H); 1.45 (m, 4H); 0.76 (m, 6H), MS Da / e = 312 (MH +). Calculated for C? 9H2? NSO: C, 73.21; H, 6.79; N, 4.49, S, 10.29 Found: C, 73.36; H, 6.90; N, 4.49; S, 10.42. Example 7 Preparation of 3,3-diethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepine-4-one 1,1-dioxide The oxidation of the compound of Example 6 (f) (2.00 g, 6.4 mmol) for Sulfone was carried out by the procedure indicated for Example 2. Column chromatography (50% ethyl acetate / petroleum ether) gave the title product (1.92 g, 5.59 mmol, 88% yield). P.F .. = 163.0-165.6 ° C. 1HNMR (DMSO-d6) d 7.94-7.07 (m, 9H); 3.72 (S, 2H); 1.80-1 22 (br m, 4H); 0.76 (m, 6H). MS Da / e = 344 (MH +), 366 (M + Na +); Calculated by C? 9H21NSO3: C, 66.44; H, 6.16 N, 4.07; S, 9.33. Found C, 66.22; H, 6.21; N, 4.06, S, 9.42. Example 8 Preparation of 3 3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine. The reduction of the compound of Example 6 (f) (2.43 g, 7.80 mmol) was carried out by the procedure indicated for Example 3. Column chromatography (20% ethyl acetate / petroleum ether) gave the title product (2.01 gr, 6.76 mmol, 87% yield). 1 H NMR (DMSO-d 6) d 7.29-6.71 (m, 9H); 3.65 (br s, 2H); 2.77 (s, 2H); 1.36-1.15 (m, 4H); 0 67 (m, 6H). MS Da / e = 298 (MH +). Calculated for d9H23NS: C, 76.71; H, 7.79 N, 4.70; S, 10.77. Found C, 76.64; H, 7.82; N, 4.69; S, 10.72. Example 9 Preparation of 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1, 5-benzothiazepine-1, 1-dioxide. Oxidation of the compound of Example 8 (0.53 g, 1.80 mmol) was carried out by the procedure indicated for Example 4. Column chromatography (50% ethyl acetate / petroleum ether) gave the title product as a yellow solid ( 0.55 g, 1.67 mmol, 93% yield) MP = 128.0-130.2 ° C 1HNMR (DMSO-d6) d 7.88-6.84 (m, 9H); 3.73 (br s, 2H); 3.32 (s, 2H); 1.55-1.30 (m, 4H); 0.68 (m, 6H) MS da / e = 330 9 (MH +), 352 (M + Na +). Calculated for C? 9H23NSO2: C, 69.27; H, 7.04; N, 4.25; S, 9.73. Found: C, 69.06; H, 7.16; N, 4.16; S, 9.56. Example 10 Preparation of 3,3-Dimethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepine-4-one. (a) Bromopivalic acid The title compound was prepared from hydroxypivalic acid (TCI America, 50.0 g, 423 mmol) using the procedure for Example 1 (c). After removing the HBr under high vacuum the product was obtained (66.42 g, 367 mmol, 87%) 1 H NMR (DMSO-d6) d 12.3 (br s); 3.57 (s, 2H); 1.19 (s, 6H). MS Da / e = 181 (M), 183 (M + 2). Calculated for C5H902Br: C, 33.17; H, 5.01; Br, 44.13. Found C, 34.07; H, 5.08; Br, 42.45. (b) 2 - (((2-aminophenyl, thio) methyl) -2-methylpropionic acid Bromopivalic acid (Example 10 (a)) (59.4 g, 328 mmol) was reacted with 2-aminothiophenol (41 g, 328 mmol freshly distilled)) according to the procedure of Example 1 (d). Column chromatography afforded the title compound (52.3 g, 232 mmol, 71%) 1 H NMR (DMSO-d6) d 12.44 (br s, 1 H); 7.22 (d, 1 H); 6.99 (t, 1 H); 6.63 (d, 1 H); 6.47 (t, 1 H); 5.27 (br s, 2H); 2.88 (s, 2H); 1.14 (s, 6H). MS Da / e = 226 (MH +), 208 (M-H20), 180 (M-C02). Calculated for CnH15NSO2: C, 58.64; H, 6.71; N, 6.22; S, 14.23. Found: C, 58.41; H, 6.78; N, 6.13; S, 14.29 (c) 3,3-dimethyl-2,3-dihydro-1,5-benzothiazepine -4 (5H) -one.

The title compound was prepared by thermal ring closure of the compound of Example 10 (b) (33.4 g, 148 mmol) as indicated for Example 1 (e). Column chromatography (25% ethyl acetate / petroleum ether) gave the product (25.39 g, 122 mmol, 83% yield) P.F .. = 112.6 ° C. 1 H NMR (DMSO-d 6) d 9.71 (s, 1 H); 7.40 (d, 1 H); 7.23 (t, 1 H); 7.11 (d, 1 H); 6.96 (t, 1 H); 2.95 (s, 2H); 1.18 (s, 6H). MS Da / e = 208 (MH +). Calculated for Cu H13 NSO: C, 63.74; H, 6.32; N, 6.76; S, 15.47. Found: C, 63.94; H, 6.37; N, 6.56; S, 15.28. (d) 3,3-Dimethyl-2,3 Dehydro-5-phenyl-1,5-benzothiazepine-4-one. N-phenylation of the compound of Example 10 © (22.0 g 106 ml) was carried out Following the procedure described for example (f) to produce after column chromatography, the title compound (28.69 g, 101 mmol, 96% yield) MP = 103.8 C 1 H NMR (DMSO-d 6) d 7.68-6.88 (m, 9H); 3.19 (s, 2H); 1.05 (s, 6H); MS Da / e = 284. (MH +), 306 (M + Na +). Calculated for C17H17NSO: C, 72.05; H, 6.05; 4.94; S.11.31. Found: C.71.85; H.6.13; N, 4.85; S, 11.26.

Example 11 Preparation of 3.3 -Dimethyl-2,3-dehydro-5-phenyl-1,5-benzothiazepine-4-amino-1,1-dioxide. Oxidation of the compound of Example 10 (d) (8.69 g, 30.7 mmol) was carried out following the procedure for Example 2 to give, after column chromatography and with oven drying, a white powder as the product (8.80 g). , 27.9 mmol, 91% yield) PF = 140.8 ° C. 1 H NMR (DMSO- dβ) d 7.95-7.04 (m, 9H); 3.81 (s, 2H); 1.10 (s, 6H). MS Da / e = 316 (MH +), 338 (M + Na +). Calculated for C? 7H? 7NSO3 x (0.5 H2O): C, 62.94; H, 5.59; N.4.32; S, 9.88. Found: C, 62.98; H.5.28; N, 4.26; S, 9.68. Example 12 Preparation of 3,3-Dimethyl-2,3,4,5-tetrahydro-5-phenyl-1, 5-benzothiazepine The reduction of the component of Example 11 (8.88 g, 30.7 mmol) was carried out following the procedure for Example 3 to give the product, after column chromatography (5% ethyl acetate / petroleum ether), as a yellow oil (8.02g, 29.77 mmol, 96% yield) 1H NMR (DMSO-d6) d 7.44-6.68 ( m, 9H); 3.31"(br s, 2H); 2.65 (s, 2H); 0.93 (s, 6H) MS Da / e = 270 (MH +), Calculated for Ci7H19NS: C, 75.79; H, 7.11; N 5.20; S, 11.90; Found: C.75.82; H, 7.06; N.5.28; S, 11.86. Example 13 Preparation of 2,3,4,5 Tetrahydro-3,3-dimieti-5-phenyl-1,5-benzothiazepine-1, 1-dioxide Oxidation of the compound of Example 12 (5.66 g, 21.01 mmol) was carried out following the procedure for Example 4 to give, after column chromatography (20% ethyl acetate / petroleum ether) a white powder (5.56 g). , 18.45 mmol, 88% yield) MP = 168.0-168.6 ° C.1H NMR (DMSO-d6) d 7.92-.6.83 (m, 9H); 3.66 (br s, 2H); 3.33 (s, 2H); 1.03 (s, 6H). MS Da / e = 302 (MH +), 324 (M + Na +).

Calculated for C? 7H? 9NSO2: C, 67.75; H, 6.35; N 4.65; S, 10.65. Found: C, 67.85; H, 6.44; N, 4.68; S, 10.71. Example 14 Alternative preparation of (±) -3-n-butyl-3-ethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepine-4-one. (a) 2 Anilinobenzenethiol This was prepared according to the procedure of H. Gilman and J. Dretrch, J.

American Chemical Society 80 (1958) pp. 380-383. To a solution of phenothiazine (10.0 g, 50.2 mmol) in 50 ml. THF were added lithium lamellae (2.0 g, 288 mmol) for 45 min. This mixture was stirred for one hour after that the solution was pipetted, separating it from the unreacted lithium and partitioned between ether and water in a separatory funnel. The product was extracted with NaoH, 4N. The ether layer produced unreacted phenothiazine (4.02g, 20mmol, 40%). The aqueous base layer was neutralized to pH4 and extracted 3 times with ether. The ether layer was dried, concentrated and the residue chromatographed (5% ethyl acetate / petroleum ether) to give the title compound (5.49, 27.3 mmol, 55% yield). 1 H NMR (DMSO-de) d 7.65-6.74 (m, 9H). MS Da / e = 202 (MH +). Calculated for C? 2 H NS: C, 71.61; H, 5.51; N, 6.96; S, 15.93. Found: C, 71.66; H, 5.46; N, 6.92; S, 15.90. (b) (+) -2 - (((Anilinophenyl) thio) methyl) -2-ethylhexanoic acid. This was prepared by reacting the compound of Example 14 (a) (3.06 g, 15.2 mmol) with the compound of Example 1 (c) (3.50 g, 15.0 mmol) according to the procedure used to prepare in Example 1 (d) ). Column chromatography (50% ethyl acetate / petroleum ether gave the title compound (3.70 g, 10.4 mmol, 70%) 1H NMR (DMSO-d6) d 12.48 (br s, IH): 7.46-6.83 (m, 9H); 3.01 (S, 2H); 1.55-1.03 (m, 8H); 0.73 (m, 6H) MS Da / e = 358 (MH +). Calculated for C2? H27NSO2: C, 70.55; H, 7.61; N, 3.91; S, 8.96, Found: C, 70.61; H, 7.62; N.3.85; S, 8.88. (C) (±) -3-n-Butyl-3-ethyl-2,3 dihydro- 5-phenyl-1.5-benzothiazepine-4-one The ring closure of the compound of example 14 (b) (0.59 g, 1.65 mmol) was carried out using the procedure of example 1 (e) to give the title compound (0.17). g, 0.51 mmol, 31% yield) 1 H NMR (DMSO-d 6) is identical to the product of Example 1 (f) described above Example 15. Preparation of (±) -3-n-butyl-3-ethyl-2, 3-Hydro-8-methoxy-5-phenyl-1,5-benzothiazepine-4-one. a) 2-amino-5-methoxythiophenol A solution of 2-amino-6-methoxybenzothiazole (36 g 200 mmol, Aldrich Chemical Co.) and 400 ml. of an aqueous solution of 30% potassium hydroxide was refluxed for 16 h. The dark solution was cooled to 0 ° C and neutralized to pH 6 with a 50% acetic acid solution and stirred for one hour. The resulting precipitate was filtered and the product collected on the filter paper and dried (25.29 g, 81% yield). 1 H NMR (DMSO-d 6) d 6.91-6.44 (m, 3H) 5.90 (br s, 2H), 3.52 (s, 3H). Ms Da / e = 154 (M-H) b) (±) -3-n-butyl-3-eti I-2,3-dihydro-8-methoxy-1,5-benzothiazepine-4 (5H) -one. To a solution of the compound of Example 1 (c) (25.1 g, 105.8 mmol) in 150 mL of dimethyl formamide was added to the compound of Example 15 (a) (13.7 g, 88.2 mmol) and 13 mL. of triethylamine. The mixture was stirred overnight and then transferred to a separatory funnel with 200 ml of water. The pH was adjusted to 4 with 0.1 N HCl and the product was extracted with 6 x 50 ml. diethyl ether. The ether extracts were removed, dried and the solvent evaporated to a viscous oil. To this was added 200 ml of tetradecane and 825 mg of p-toluenesulfonic acid and the mixture refluxed for 1.5 h. The reaction mixture was cooled and charged onto a column of silica gel and the product extracted with 20% ethyl acetate / petroleum ether (15.15 g, 59% yield). MP = 100.4 °. 1 H NMR (DMSO-d 6) d 9.51 (s, 1 H); 7.96 -6.81 (m, 3H); 3.70 (s, 3H); 2.94 (S, 2H) 1.71-1.39 (m, 4H); 1.19-1 -13 (m, 4H); 0.79 (t, 3H); 0.74 (t, 3H). MS Da / e = 294 (MH +). Calculated for C16 H23 NSO2: C, 65.49; H, 7.90; N, 4.77; S, 10.93. Found: C, 65.39; H, 7.94; N, 4.80; S, 10.85. c) (±) -3-n-Butyl 3-ethyl-2-3-dihydro-8-methoxy-5-phenyl-1,5-benzothiazepine-4-one. The compound of example 15 (b) (11.0 g, 37.5 mmol) was reacted with phenyl iodide, using the procedure described for example 1 (f) to give the product (13.07 g 94% yield) H NMR (DMSO-dβ). ) d 7.54-6.79 (m, 8H); 3.75 (s, 3H); 3. 11 (s, 2H); 1.51-1 -13 (m, 8H); 0.77 (m, 6H). MS Da / e = 370 (MH +). Calculated for C22 H27 NSO2 x 0.75 H2O: C, 68.99; H 7.50 N, 3.66; S, 8.35. C, 68.95 was found; H, 714; N, 3.63; S, 8.25 Example 16. Preparation of (±) -3- n -butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine. The compound of example 15 (c) (2.25 g, 6.10 mmol) was reacted with Al H3 using the procedure described for example 3 to give the product (1.95 g, 90% yield). 1 H NMR (DMSO-d 6) d 7.1 1 - 6.65 (m, 8H) 3.70 (s, 3H); 3.51 (br s, 2H); 2.66 (s, 2H); 1.40-1.10 (m, 8H); 0.72 (m, 6H) MS Da / e = 356 (MH +).

Calculated for C22 H29 NSO: C, 74.32; H, 8.22; N, 3.94; S, 9.02. Found C, 74. twenty; H, 8.16; N, 3.88; S, 8.95. Example 17. Preparation of (±) 3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide The compound of Example 16 (1.52 4.28 mmol) was oxidized to the sulfone in analogy to the procedure described for Example 4 giving the product (1.61 g 97% yield) 1 H NMR (DMSO-d6) d 7.35-6.79 (m, 8H) 3.80 (s 3H ); 3.65 (br s, 2H); 3. 26 (s 2H); 1.51-1.02 (m, 8H); 0.73 (m 6H) Ms Da / e = 388 (MH +). Calculated for C22 H29 NSO3: C, 68.18; H.7.54; N, 3.61; S, 8.27. Found C, 68.13; H, 7.59; N, 3. 57; S, 8.21.

Example 18. Preparation of (±) -3-n-butyl-3-etl-2,3,4,5-tetrahydro-8-hydroxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide To a bromide mixture Aluminum (1 M in CH2 Cl2 16 mmol) and ethanediol (7.4 ml 100 mmol) at 0 ° C was added the compound of Example 17 (0.78 g 2.01 mmol) in 30 mL CH2 Cl2. The mixture was stirred for one hour at 0 ° C and then 25 ml of water was added and the product extracted with 3 x 20 ml CH 2 Cl 2. The organic layer was dried and the solvents evaporated. The residue was applied to a column of silica gel and the product extracted with 35% ethyl acetate / petroleum ether (0.74 g, 98%) 1 H NMR (DMSO-d6) d 10.00 (s, 1 H) 7.28 - 6.74 (m 8H) 3.6 (br s, 2H); 3.21 (s 2H); 1.55 - 1.02 (m, 8H); 0.73 (m, 6H); MS Da / e = 374 (M H +). Calculated for C21 H27 NSO3 x 0.4 H2O: C, 66.25; H, 7.36; N, 3.68; S, 8.42. Found: C, 66.12; H, 7.37; N, 3.61; S, 8.30. Example 19 Preparation of (±) -7-bromo-3-n-butyl-3-ethyl-2,3-dihydro-8-methoxy-5-phenyl-1,5-benzothiazepine-4-one. (a) (+) - 7-bromo-3-n-butyl-3-ethyl-2,3-dihydro-8-methoxy-1,5-benzothiazepine-4 (5H) -one. To a solution of the compound of Example 15 (c) (5.59 g, 19.05 mmol) in methylene chloride (120 ml) at 0 ° C was added N-bromo succinimide (6.78 g, 38.10 mmol) and stirred for 30 min. The reaction mixture was washed once with water and the organic layer was dried, concentrated and the residue loaded on a column of silica gel. The product was extracted with 10% ethyl acetate / petroleum ether (6.60, 93% yield). P.F. = 102 ° C. 1H NMR (DMSO-d6). d 9.60 (s 1 H); 7.31 (s, 1 H); 7.09 (s, 1 H); 3.80 (s, 3H); 2.91 (S, 2H); 1.71-1.39 (m 4H) 1.19-1.13 (m, 4H); 0.80 (t, 3H); 0.75 (t, 3H) Ms Da / e = 372, 374 (MH +). Calculated for Cie H22 Br NSO2: C.51.62; H, 5.96; N, 3.76; S, 8.61; Found: C, 51.33; H, 5.87; N, 3.65; S, 8.44. b) (±) -7-bromo-3-n-butyl-3-ethyl-2,3-dihydro-8-methoxy-5-phenyl-1,5-benzothiazepine-4-one. To a solution of the compound of Example 19 (a) (6.60 g 17.7 mmol) in bromobenzene (35 ml) was added copper bromide (500 mg) and potassium carbonate (2.5 g) and the mixture was refluxed for 20 hours. The reaction mixture was loaded onto a column of silica gel and the product extracted with 10% ethyl acetate / petroleum ether (5.05 g, 64% yield) MP = 131.0-132.8 ° 1 H NMR (DMSO-dβ) d 7.40 - 7.05 (m 7H); 3.88 (s 3H); 3.14 (s, 2H); 1.55 - 1.03 (m, 8H); 0.77 (m, 6H). MS Da / e = 448, 450 (M H +) calculated for C22 H26 Br N SO2 x 0.3 H2O: C, 58.23; H, 5.91; N, 3.09; Br, 17.61. Found: C, 58.25; H, 5.96; N, 3.05; Br, 17.56. Example 20. Preparation of (±) -7-bromo-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine 1.1-dioxide. To a solution of Al H3 (29 mmol, generated in situ from H2 SO4 15.5 mmol and Li Al H4 (29 mmol) in 29 mL diethyl ether was added the compound of Example 19 (b) (4.38 g, 9.77 mmol ) in 15 ml THF at 0 ° C. The reaction mixture was allowed to warm at room temperature for 2 h and was stirred at room temp for 15 h, after which time TLC (20% ethyl acetate / petroleum ether) showed complete reaction The reaction of the flask was cooled to 0 aC and the excess of Al H3 was quenched by adding 25 ml of H2O / THF (1: 2) dripping followed by 5 ml of 1 M NaOH. transferred to a separatory funnel and extracted 3 times with ether.The ether extract was combined, dried, concentrated and column chromatographed (5% ethyl acetate / petroleum ether) The fractions containing product were rotary evaporated and the resulting oil was dissolved in 50 ml of tetrahydrofuran and t-butanol, and osmium tetroxide (2.5% by weight) was added to this solution. methyl 2 propanol, 5.1 ml) and N-methylmorpholine N-oxide (2.7 g, 22.9 mmol), and the mixture was stirred at Temp. Amb. For 18 hours and at this point 50 ml were added. NaHCo3 to neutralize any acid, the mixture was transferred to a separating funnel extracted 3 times with ethyl acetate. The organic layers were washed with brine, dried (Na2SO4) and concentrated. Column chromatography (10% ethyl acetate / petroleum ether) gave the product (3.41 g, 7.30 mmol, 75% yield), P.F .. = 107.5 - 110.0 ° C. 1 H NMR (DMSO-d 6) d 7.42-6.81 (m, 7H); 3.90 (s, 3H); 3.65 (s, 2H); 3.31 (s, 2H); 1.51 - 0.97 (m, 8H); 0.71 (m, 6H). MS Da / e = 466, 468 (MH +). Calculated for C22 H28 Br N SO3: C, 56.65; H, 6.05; N, 3.00; S, 6.87; Found: C, 56.80; H, 6.19; N 3.01; S, 6.80. Example 21 Preparation (±) -7-Bromo-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-phenyl-1,5-benzothiazepine-8-ol 1.1 dioxide The compound of Example 20 (3.19 g, 6.84 mmol) was dimethylated using the procedure for Example 18 to give the product (2.48 g, 77% yield) MP = 182.5 - 183.6 ° C. 1 H NMR (DMSO-d 6) d 10.87 (br s, 1 H) 7.46-6.82 (m, 7H); 3.62 (br s, 2H); 3.25 (s, 2H); 1.49-1.02 (m, 8H); 0.71 (m, 6H). MS Da / e = 452, 454 (MH +). Calculated for C21 H26 Br N SO3: C, 55.75; H, 5.79; N, 3.10; S, 7.09. Found: C, 55.79; H, 5.93; N 3.15; S, 7.17. Example 22 Preparation of (+) 3-n-butyl-3-etiñ-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,5-benzothiazepine -8-ol 1.1-dioxide To the compound of example 21 (0.50 g, 1.10 mmol) in ethyl acetate (2.0 ml) and sodium methoxide (10 ml, 25% by weight) was added copper (I) bromide (57 mg) and the mixture was refluxed for 2 h. The reaction mixture was neutralized with 1 N HCl, and extracted with ether 3 x 15 ml. The ether extracts were dried and concentrated and the residue was applied to a column of silica gel. The product was extracted with 20% ethyl acetate / petroleum ether (0.44 g, 99% yield). 1 H NMR (DMSO-d 6) d 9.69 (s, 1 H); 7.26-6.52 (m, 7H); 3.60 (s, 5H); 1.53-1.02 (m, 8H); 0.71 (m, 6H). MS Da / e = 404 (MH +). Calculated for C22 H29 N SO4: C, 65.48; H, 7.24; N, 3.47; S.7.94. Found: C, 65.41; H, 7.26; N 3.53; S, 8.02. Example 23 Preparation of (±) 3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,5-benzothiazepine 1.1-dioxide The compound of Example 20 (2.62 g) , 5.62 mmol) was treated with sodium methoxide using the procedure for example 22 to give the product (1.95 g, 83% yield). 1 H NMR (DMSO-d 6) d 7.30 (s, 1 H); 7.21-6.79 (m, 5H); 6.52 (s, 1 H); 3.80 (s, 3H); 3.62 (br s, 2H); 3.59 (s, 3H); 3.20 (s, 2H); 1.53-0.98 (m, 8H); 0.73 (m, 6H). MS Da / e = 418 (M H +). Calculated for C23 H31SO4; C, 66.16; H, 7.48; N, 3.35; S, 7.68. Found: C, 66.10; H, 7.50; N, 3.42; S, 7.74. Example 24 Preparation of (±) 3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-7,8-diol 1.1-dioxide Al sodium hydride (60% , 0.19 g, 4.79 mmol) in dimethylformamide (20 ml) was added ethanediol (0.35 ml, 4.79 mmol) and the compound of example 23 (0.50 g, 1.19 mmol). The reaction mixture was refluxed for 3 hours, then 25 ml. of saturated ammonium acetate (aq) was added, the pH adjusted to 7 and extracted with ethyl acetate 3x10 ml. The organic phase was dried, concentrated and applied to a column of silica gel. The product was extracted with 50% ethyl acetate / petroleum ether (0.40 g, 86% yield). 1 H NMR (DMSO-d 6) d 9.79 (br, 2H); 7.23 (s, 1 H); 7.19-6.76 (m 5H); 6.37 (s, 1 H); 3.58 (br s, 2H); 3.11 (s, 2H); 1.50-0.98 (m, 8H); 0.72 (m, 6H). MS Da / e = 390 (M H +). Calculated for C2? H27 NSO X0.5 H2O: C, 63.29; H, 7.08; N, 3.51; S, 8.05. Found: C, 63.47; H, 7.21; N, 3.36; S, 7.92. Example 25 Preparation of (±) -7-Bromo-3-n-butyl-3-ethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepine-4-one (a) (±) -7-Bromo-3-n-butyl-3-ethyl-2,3-dihydro-1-5-benzothiazepine-4 (5H) -one To a solution of the compound of Example 1 (e) ( 8.28g, 31.1 mmol) in acetic acid (30 mL) at Temp. Amb. Bromine was added dropwise (1.75 ml, 34.2 mmol) and stirred for 18 hrs. The reaction mixture was washed once with water, extracted 2x20 ml. with ether, and the organic phase was dried, concentrated and the residue charged to a silica gel column. The product was extracted with 50% ethyl acetate / petroleum ether (9.23 g, 87% yield) P.F. = 104.4 ° C. 1 H NMR (DMSO-d 6) d 9.81 (s, 1 H); 7.58 (s, 1 H); 7.42 (d, 1 H); 7.04 (d, 1 H); 2.96 (S, 2H); 1.73-1.40 (m, 4H); 1.19-1.15 (m, 4H); 0.80 (t, 3H); 0.76 (t, 3H); MS Da / e = 342, 344 (M H +). Calculated for C15 H20 BrNSO: C, 53.63; H.5.89; N, 4.09; S, 9.37. Found: C, 52.76; H, 5.93; N, 4.17; S, 9.21 (b) (±) -7-Bromo-3-n-butyl-3-ethyl-2,3-dihydro-5-phenyl-1,5-benzaothiazepine-4-one To the compound of example 25 (a) ( 8.8 g, 23.61 mmol) was reacted with phenyl iodide according to the procedure used in Example 1 (f) to give a product (8.96 g, 91% yield) which is a 3: 1 ratio of Bromo-7 to Yodide -7, which can be converted completely to Bromo 7 by the treatment with LiBr (10 eq) and copper bromide (I) (10 mol%) in reflux DMF (18 h). 1 H NMR (DMSO-d 6) d 7.84 (d, 1 H); 7.52 (dd, 1 H) 7.37-7.03 (m, 5H); 6.84 (d, 1 H); 3.15 (S, 2H); 1.57-1.13 (m 8H); 0.77 (m, 6H). MS Da / e = 418.420 (M H +). Calculated for C2. H24 BrNSO: C, 60.29; H, 5.78; N, 3.35; Br, 19.10. Found: C, 60.56; H, 5.83; N, 3.25; Br, 18.83. Example 26 Preparation of (±) -3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,5-benzothiazepine 1,1-dioxide To the compound of Example 25 (b) (7.71 g, 18.4 mmol) was reacted with AIH3 using the procedure described for Example 3 supplying an oil that was treated directly with OsO4 according to the procedure for Example 4. The resulting sulfone was treated with sodium methoxide according to Example 22 giving the product (67% of total yield for the three steps). 1 H NMR (DMSO-d 6) d 7.35-6.79 (m, 8H); 3.79 (s, 3H); 3.62 (br s, 2H); 3.26 (s, 2H); 1.53-1.00 (m, 8H); 0.73 (m, 6H). MS Da / e = 388 (M H +). Calculated for C22 H29 NSO3: C, 68.18; H, 7.54; N, 3.61; S, 8.27. Found: C, 67.89; H, 7.65; N, 3.42; S, 8.20. Example 27 Preparation of (±) -3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-7-ol 1.1-dioxide The compound of example 26 (1.05g , 2.71 mmol) was treated with aluminum bromide and ethanetiol according to the procedure for Example 18 to give the title product (0.90 g, 89%) 1 H NMR (DMSO-d 6) d 9.99 (s, 1 H); 7.27-6.74 (m 8H); 3.61 (br s, 2H); 3.20 (s, 2H); 1.50-1.00 (m, 8H); 0.73 (m, 6H). MS Da / e = 374 (M H +). Calculated for C21 H27 NSO3 x 0.25 H2O: C, 66.73; H, 7.33; N, 3.71; S, 8.48. Found: C, 66.67; H, 7.32; N, 3.67; S, 8.49. Biological assay In vivo inhibition of bile acid reabsorption In male Sparque-Dawley rats, weighing 220-260 gms, they were pigeonholed in individual cages and ate normal feed. The rats were orally dosed (1 ml / 100 gm body weight) with test compounds, as a suspension in 0.5% methylcellulose at 9:00 a.m. and at 3:30 p.m. During two days. The control group received 0.5% methylcellulose. Two hours after the morning dose of the second day, they were given, orally to the rats, a piezca (1.3 nmol) of 23.25-75 Se-homocyclic taurine acid (75SeHCAT) in 1.0 ml. saline 75SeHCAT, a synthetic range emission analogous to bile acid, which is absorbed by the active inducer system of iliac bile acid, similar to taurocholic acid, has been used clinically as a measure of the absorption of iliac bile acid. Stools are collected by 24 Hrs. following the administration of 75SeHCAT. The fecal content of 75SeHCAT was determined using a Packar Autogamma 5000 Series Gamma counter. The% inhibition of bile acid reabsorption is calculated as follows: 75 Sc eHCATtotal - 7 '53SeHCAT excreted from the treaty 1 minus 100 =% inhibition 75SeHCAT total - 75SeHCAT excreted from control The percentage of inhibition of the reabsorption of bile acid in the rat using 75SeHCAT, for the compounds of examples 2, 4, 7 and 9, with a concentration of 10 mg. / kg. it was 7, 36, 20 and 29% respectively. In the same test the compounds of examples 18, 22, 23 and 27 with a concentration of 1 mg / kg. they had a percentage of the inhibition of bile acid reabsorption of between 50 and 65%.

Claims

CLAIMS: The compounds of the formula (I) characterized in that R1 and R2 are the same or different and each is a C6-6 alkyl, optionally substituted C3-6 cycloalkyl, or R1 and R2 together with the carbon atom, to which they are attached, form a spiro cycloalkyl group C3.6? Pcnally substituted; R 4 is a Cβ-14 group, or a C 3 -. 3 heteroanil group each optionally substituted with one to eight substituents, which are the same or different and are selected from the halogens, hydroxy, nitro, C 1-6 alkoxy - phenyl, C6.6 alkoxy, optionally substituted C6.6 alkyl, S (0) nR8, SO2NR8R9 CO2R8, O (CH2CH2O) nR8, OSO2R8, O (CH2) pSO3R8, O (CH2) pNR9R10 and O (CH2) PN + R9R10R11 wherein, from R8 to R11 are the same or different and are independently selected from hydrogen or optionally substituted C1-6 alkyl, and wherein p is an integer of 1-4 and n is an integer of 0-3; R5a, R5b, R5c and R5d each represent atoms or groups, which are the same or different and each is hydrogen, halogen, cyano, R8-acetyl, OR8, optionally substituted C. -6 alkyl, COR8, CH (OH) R8, S (O) nR8, SO2NR8R9, P (0) (OR8) 2, OCOR8, OCF3, OCN, SCN, HCN, CH2OR8, CHO, (CH2) PCN, CONR9R10, (CH2) PCO2R8, (CH2) PNR9R10, CO2R8 ', NHCOCF3, NHSO2R8, OCH2OR8, OCH = CHR8, O (CH2CH2O) nR8, OSO2R8, O (CH2) PSO3R8, O ( CH2) PNR9R10 and O (CH2) PN + R9R10R11 wherein, from R8 to R11, n and p, are as defined and characterized above; or R5a and R5b, R5 and R5c, or R5c and R5d together with the ring to which they are attached, form a cyclic group -O (CR9R10) mO- wherein R9 and R10 are defined and characterized above, and m is 1 or 2; R6 and R7 are the same or different and each is hydrogen, optionally substituted C1-6 alkyl, C3-6 cycloalkyl, or R6 and R7 together with the carbon atom to which they are attached form a spiro-cycloalkyl C3 group. 6 optionally substituted. X is CH2, C = 0, C = S, or C = NR8 where R8 was previously characterized; and I is an integer of 0-2, and salts, solvates or physiologically functional derivatives thereof. 2) A compound of formula (1) according to claim 1, characterized in that R1 is methyl or ethyl; R 2 is methyl, ethyl or n-butyl; R4 is phenyl; R5a and R5d are hydrogens; R5b and R5c are the same or different and each is hydrogen, methyl, methoxy, hydroxy, trifluoromethyl or halogen; R6 and R7 are the same or different and each is hydrogen, methyl, ethyl or n-butyl; X is CH2 or C = O; I is 2; or a salt, solvate or a physiologically functional derivative thereof. 3) A compound of formula (I) selected from the group consisting of: (±) -3-n-Butii-3-ethyl-2,3-dihydro-5-phenyl-l, 5-benzothiazepin-4-one (± ) -3-n-Butyl-3-ethyl-2,3-dihydro-5-phene-l, 5-benzothiazepin-4-one-l, l-dioxide; (±) -3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1, 5-benzothiazepine; (±) -3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1, 5-benzothiazepine-1, l-dioxide (+.} - 3-n-Butyl -2-isobutyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1, 5-benzothiazepine-1, 1-dioxide 3,3-Diethyl-2,3-dihydro-5-phenylis l.5-benzothiazepin-4-one; 3,3-Diethyl-2,3-dhydro-5-phenyl-l, 5-benzothiazepin-4-one-l, 3,3-Diethyl I-dioxide -2,3,4,5-tetrahydro-5-phenyl-1, 5-benzothiazepine; 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1, 5-benzothiazepine-1 , l-dioxide, 3,3-Dimethyl-2,3-dihydro-5-phenyl-1, 5-benzothiazepin-4-one; 3,3-Dimethyl-2,3-dihydro-5-phenol-1 , 5-benzothiazepin-4-one-l, I-dioxide, 3,3-Dimethyl-2,3,4,5-tetrahydro-5-phenyl-1, 5-benzothiazepine, 3,3-Dimethyl-2,3 , 4,5-tetrahydro-5-phenyl-l, 5-benzothiazepine-1, l-dioxide; (±) -3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8 -dimethoxy-5-phenyl-1, 5-benzothiazepine-1, 1-dioxide, 3,3-diethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1, 5-benzothiazepine -1, 1-dioxide; (±) -3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1, 1-dioxide 3.3-Diet il-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide; (±) -3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1, 5-benzothiazepin-8-ol-1,1-dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-8-ol-1,1-dioxide; (±) -3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1, 5-benzothiazepin-8-ol-1,1-dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,5-benzothiazepin-8-ol-1,1-dioxide; (±) -7- bromo -3- n -Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide; 7-bromo-3,3-Dietl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide; (±) -3-n-Butii-3-etl-2,3,4,5-tetrahydro-5-phenyl-1, 5-benzothiazepin-7,8-diol-1,1-dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-7,8-diol-1,1-dioxide; (±) -3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1-monoxide; 3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1, 5-benzothiazepine-1 -monoxide; (±) -3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1, 5-benzothiazepin-8-ol-1-monoxide; 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-l, 5-benzothiazepin-8-ol-l-monoxide, (±) -3-n-Butyl-3-ethyl-2,3-dihydro-8-methoxy-5-phenyl-1,5-benzothiazepin-4-one; (±) -3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine; (±) -3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine: 1,1-dioxide; (±) -3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-hydroxy-5-phenyl-1,5-benzothiazepine; 1,1-dioxide; (±) -7-Bromo-3-n-butyl-3-ethyl-2,3-dihydro-8-methoxy-5-phenyl-1, 5-benzothiazepin-4-one; (±) -7-Bromo-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide; (±) -7-Bromo-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-8-ol-1,1-dioxide; (±) -3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,5-benzothiazepin-8-ol-1,1-dioxide; (±) -3-p-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide; (±) -3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-7,8-diol-1-, dioxide; (±) -7-Bromo-3-p-butyl-3-ethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one; (±) -3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,5-benzothiazepine-1, 1-dioxide; and, (±) -3-n-butyl-3-et? l-2, 3,4, 5-tetrahydro-5-phenyl-1, 5-benzothiazepin-7-ol-1,1-dioxide; 4) A compound of formula (I) selected from: (±) -3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,5-benzothiazepin- 8-ol 1, 1- dioxide; and, (±) -3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-hydroxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide or a salt , solvate, or a physiologically functional derivative thereof. 5) A method of treating the clinical condition of a mammal, for which the inhibitor of the superior absorption of bile acid is indicated, the method is characterized in that it comprises administering to a mammal an amount effective for the inhibition of the absorption of the bile acid of a compound of formula (I) corresponding to any one of claims 1 to 4, or of a pharmaceutically acceptable salt, solvate, or of some physiologically functional derivative thereof. 6) A method of treating a hyperlipidemic condition in a mammal, characterized in that it comprises administering to the mammal an effective amount of a hyperlipidemic treatment of a compound of formula (I) corresponding to any of claims 1 to 4, or of a pharmaceutically acceptable salt, solvate or a physiologically functional derivative thereof. The method of claim 6, characterized in that the hyperlipidemic condition is arteriosclerosis. A compound of the formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, solvate, or a physiologically functional derivative thereof, for use in medicine. A compound of the formula (I) according to any one of claims 1 to 4 or of a pharmaceutically acceptable salt, solvate, or a physiologically functional derivative thereof, for use in the prophylaxis or treatment of a condition hyperlipidemic 0) A compound of the formula (I) corresponding to any one of claims 1 to 4 or of a pharmaceutically acceptable salt, solvate, or a physiologically functional derivative thereof, for use in the manufacture of a medicament for the treatment of the hyperlipidemic condition. 1) A pharmaceutical composition, characterized in that it comprises a compound of formula (I) corresponding to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate, or a physiologically functional derivative thereof, at least one carrier pharmaceutically acceptable and, optionally, ono or other more physiologically active agents.
2) A process for the manufacture of a compound of formula (I) according to any of claims 1 to 5, or a salt, solvate or a physiologically functional derivative thereof, characterized in that it includes, either: (a) ) reaction of a compound of the formula (III) wherein R1, R2 and R5a b c d 'are characterized and defined above, with the appropriate R4-Z, wherein R4 is characterized and defined above, and Z is a suitable leaving group, or (b) cyclization of the compound of the formula (X) where R1, R2 and R) 55aa, bo, cg, da, already characterized and defined above, and then: (i) where I needs to be 1 or 2, oxidation of the thio part; and / or (ii) where X needs to be C = S, conversion of part C = O; and / or (iii) where X needs to be CH2, reduction of part C = O; and / or (ii) where R6 and / or R7 need to be other than hydrogen, reacting with the appropriate compound of the formula R6-Z and / or R7-Z wherein R6, R7 and Z are as already characterized and defined above and / or (iv) the optional conversion of the resulting compounds of the formula (I) to a salt, solvate or a physiologically functional derivative of extos, and / or (v) an optional resolution of any optical isomer thereof. compounds of formula (I)