CA2203921A1 - Hypolipidemic benzothiazepines - Google Patents

Abstract

The invention is concerned with novel hypolipidemic compounds of formula (I), 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 hyperlipidemic conditions, and associated diseases such as atherosclerosis.

Description

~YPOLIPIDEMIC BENZOT~IIAZEPINES

The present invention is concerned with new hypolipidemic compounds, with processes and novel intermediates for their preparation, with pharm~celltical compositions cont~ining them and with their use in medicine, particularly in the prophylaxis and treatment ofhyperlipidemic conditions and associated conditions such as atherosclerosis.

Hyperlipidemic conditions are often associated with elevated plasma concentrations of low density lipoplotein (LDL) cholesterol. Such concentrations can be reduced by decreasing the absorption of bile acids from the hlle~line. One method by which this may be achieved is to inhibit the bile acid active uptake system in the t~rrnin~l ileum. Such inhibition stimulates the conversion of cholesterol to bile acid by the liver and the resulting increase in demand for cholesterol produces a collesponding increase in the rate of clearance of LDL cholesterol from the blood plasma or serum.

A novel class of heterocyclic compounds has been identified which reduce the plasma or serum concentrations of LDL cholesterol and in consequence are particularly useful as hypolipidemic agents. By decreasing the concentrations of cholesterol and cholesterol ester in the plasma, the compounds of the present invention retard the build-up of atherosclerotic lesions and reduce the incidence of coronary heart disease-related events. The latter are defined as cardiac events associated with increased concentrations of cholesterol and cholesterol ester in the plasma or serum.

International Patent Application No. WO 93tl 6055 describes 1 ,4-benzothiazepinecompounds which have hypolipidemic activity. A group of novel substituted 1,5-benzothiazepine compounds has now been discovered which also have hypolipidemic activity.

Accordingly, the present invention provides compounds of the formula (I) 'O
R5d ~ )I 6 R5b~N~
R5a 1 4 AMENDED SHEET
IPEA/EP

wherein Rl and R2 are the same or difIe~e"t and each is optionally substit--ted Cl 6 alkyl, C3-6 cycloalkyl, or Rl and R2 together with the carbon atom to which they are att~ched form an optionally subs~ituted C3 6 spiro-cycloalkyl group;

R4 is a C6 14 aryl, or a C3 13 heteroaryl group each optionally substituted with one to eight substituents which are the sarne or different and are each selected from halogen, hydroxv, nitro, phenvl-C 1-6 alkoxy, C 1-6 alkoxy, optionally substituted C 1-6 alkyl, S(O)nR~, So2NR~R9, C02R8, O(CH tCH ~O)nR8, OS02R8, O(CH2)pS03R8, O(CH2)pNR9R10 and O(CH2)pN+R9R10R1 1 wherein R8 to R11 are the same or di~ren~
and are independently, selected from hydrogen or optionally substituted Cl 6 alkyl, and wherein p is an integer from 1-4 and n is an integer from 0-3;

R5a, R5b, R5C, and R5d each represent atoms or groups which are the same or di~erent and each is hydrogen~ halogen, cyano, R8-acetylide, oR8, optionally substituted C 1-6 alkyl, COR8, CH(OH)R8, S~O)nR8, SO~NR8R9, P(o)(OR8) ~, OCOR8, OCF3, OCN, SCN, NHCN, CH~OR8, CHO, (CH2)pCN, CoNR9R10, (CH2)pC02R8, (CH~)pNR9R10, C02R8, NHCOCF3, ~ISO ~R8, OCH ~OR8, OCH=CHR8, O(CH2CH20)nR8, OS02R8, O(CH2)pS03R8, O(CH2)pN~9R10 and O(CH2)pN+R9R10RIl wherein R8 to Rll, n, and p are as hereinbcrore defined; or R5a and RSb, R5b and RSC, or R5C and RSd together ~,vith the ring to which they are attached form a cyclic group -O(CR9R10)mo- wherein R9 and R10 are as hereinbefore defined and m is I or 2;

R6 and R7 are the sarne or di~elen~ and each is hydrogen, optionally substituted C 1-6 alkyl, C3-6 cycloalkyl, or R6 and R7 together with the carbon atom to which they are attached form an optionally substituted C3 6 spiro-cycloalkyl group;

X is CH2, C=O, C=S, or C=NR8 wherein R8 is as hereinbefore defined; andI is an integer from 0-2; and salts, solvates or a physiologically functional derivatives thereof.

Suitably Rl is a C1 6 alkyl group. Preferably R1 is methyl, ethyl or n-propyl and most preferably Rl is ethyl.

Suitably R2 is a C1 6 alkyl group. Preferably R2 is methyl, ethyl, n-propyl, n-butyl or n-pentyl and most preferably R2 is ethyl or n-butyl.

Suitably R4 is a phenyl group optionally substituted with one to five, preferably one or two, substituents which are the same or di~lent and are each selected from halogen, hydroxy, nitro, phenyl-C 1-6 alkoxy, C 1-6 alkoxy, optionally substituted C l -6 alkyl, S(O)nR8, C02R8, O(CH2CH20)nR8, OSO~R8, O(CH2)pS03R8, o(CH~)pNR9R l O and o(CH2)pN+R9R1OR11, preferably halogen, hydroxy, nitro, phenyl-Cl 6 alkoxy, Cl 6 alkoxy, or optionallv substituted Cl 6 alkyl. Preferably R4 is phenyl optionally substituted at the 3- and/or 4-position by halogen, hydroxy, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, hydro~, carboxy or O(CH2)3S03H. Most preferably R4 is unsubstituted phenyl or phenyl substituted at the 3- and/or 4-positions with halo~en, hydroxy or C l -6 alkoxy, for example, methoxv or ethoxy.

Suitably R5a, R5b, R5C, and R5d are the sarne or different and are each hydrogen, Cl 4 alkoxy, halogen, hvdroxv or Cl 4 alkyl optionally substituted by fluoro. Preferably R5a, R5b, R5C, and R5d ~re the same or different and are each hydro~en. methyl, methoxy, hydroxy, trifluoromethyl or halo More preferably R5a and R5d are hydro~en and R5b and R5c are the same or difI~le.ll and are each hydrogen, Cl 4 alkoxy, halogen hydroxy, or C 14 alkyl optionally substituted by fluoro. Most preferably R5a and R5d are hydro~en and R5b and R5c are the same or different and are each hydro_en, methyl, methoxy, hydroxy, trifluoromethyl or halo.

Suitably R6 and R7 are the same or different and are each hydrogen or a C 1-6 alkyl group, for example, methyl or ethyl. Most preferably, R6 and R7 are both hydrogen.

Suitably X is CH2 or C=O.

Suitably R9 to Rl 1 are the same or di~lel,l and are each hydrogen or methyl.

Suitably 1 is O or 2, and is preferably 2.

When one or more of Rl, R2, R4 to Rl I is a substituted C1 6 alkyl group, or comprises a C1-6 alkyl group the substituents may be the same or d,~e,enl and each is selected from hydroxy, halogen, Cl 6 alkyl, Cl 6 alkoxy, COR12, nitrile, C02R12, S03R12, NR13R14, N+R13R14R1S wherein R12 to R15 are the same or di~el~ and each is selected from hydrogen or C 1-6 alkyl preferably methyl.

Further pl efe~ d compounds of formula (I) are:
3-n-Butyl-3-ethyl-2,3-dihydro-5-phenyl- 1 ,5-benzothiazepin~-one;

3 -n-Butyl-3 -ethyl-2,3 -dihydro-5-phenyl- 1, 5-benzothiazepin-4-one- 1, 1 -dioxide;
( I )-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-S-phenyl-1,5-be~o~l~iazep;ne;
( l )-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-S-phenyl-1,5-benzothiazepine-1,1-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-phenyl- 1 ,5-benzothiazepin-4-one;
3,3-Diethvl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one l,l-dioxide;
3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl- 1 ,5-benzothiazepine;
3 ,3 -Diethyl-2,3 ,4, 5-tetrahydro-5-phenyl- 1, S-benzothiazepine- I, I -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- 1,1 -dioxide;
3,3-Dimethyl-2,3,4,5-tetrahydro-j-phenyl-1 ,5-benzothiazepine;
3,3-Dimethyl-2,3,4,5-tetrahydro-5-phenyl- 1 ,5-benzothiazepine- 1,1 -dioxide;
( I )-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-~-phenyl-1,5-benzothiazepine-1,1-dioxide;
3,3-Diethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,5-benzothiazepine-1, l-dioxide;
( I )-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl- 1 ,S-benzothiazepine- 1,1-dioxide;
3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-j-phenyl-1 ,S-benzothiazepine-l, l-dioxide;
( I )-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-8-ol-1, l-dioxide;
3 ,3-Diethyl-2,3 ,4, 5-tetrahydro-5-phenyl- 1, 5-benzothiazepin-8-ol- l, l -dioxide;
( l )-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-S-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-S-phenyl-l,S-benzothiazepine-1, 1-dioxide;
( I )-3-n-Butyl-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-benzothiazepin-7,8-diol-1,1-dioxide;
( I )-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-bel~zo~lliazepine-1-monoxide;
3, 3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothi~7epine-1-monoxide;
( I )-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-b~l~o~ e~.n-8-ol-1-monoxide;
3,3-Diethyl-2,3,4,5-tetrahydro-S-phenyl-1,5-benzothiazepin-8-ol-1-monoxide;
( I )-3-n-Butyl-3-ethyl-2,3-dihydro-8-methoxy-5-phenyl-1,5-bel~othiazepin-4-one;
( I )-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzo~hiazepine;

(+)-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-benzothia_epine-1,1-dioxide;
- (+)-7-Bromo-3-n-butyl-3-ethyl-2,3-dihydro-8-methoxy-5-phenyl-1,5-benzothia_epin-4-one;
(i)-7-Bromo-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothia_epine 1, l-dioxide;
(+)-7-Bromo-3-n-buty!-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,,,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 l,l-dioxide;
(+)-7-Bromo-3-n-butyl-3-ethyl-2,3-dihydro-5-phenyl- 1 ,5-benzothiazepin-4-one;
(+)-3-n-butyl-3-ethyl-~,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 ple~llc;d compounds include:
(+)-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.

Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent, i.e., basic, compounds. Such salts must clearly have a pharTn~ceutir~lly acceptable anion or cation. Suitable pharm~seutic~lly acceptable acid addition salts of the compounds of the present invention include those derived from inorganic acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulphonic and sulphuric acids, and organic acids, such as acetic, be~l7P,~ lphonic, benzoic, citric, eth~nPslllrhonic, fumaric, gluconic, glycollic, isothionic, lactic, lactobionic, maleic, malic, meth~n~slllrhonic~ sucrinic~ }~-toluenesulrhonic~ tartaric and trifluoroacetic acids. The chloride salt is particularly prefelled for medical purposes.
Suitable pharm~ceutically acceptable base salts include allllllol~i.lm salts, alkali metal salts, such as sodium and potassium salts, and alkaline earth salts, such as m~gn~Sillm and calcium salts.

WO 96/160Sl PCT/GB95/02700 Salts having a non-pharmaceutically acceptable anion are within the scope of the invention as useful interme~i~tes for the plc~ Lion or purification of pharmaceutically acceptable salts and/or for use in non-therapeutic, for example, in vitro, applications.

Any references to "compound(s) of formula (I)", "compounds of the present invention", "compounds according to the invention" etc., refer to compound(s) of formula (I) as described above toget~er with their salts, solvates and 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 exarnple, an ester, which upon administration to a m~mm~l, such as a human, is capable of providing (directly or indirectly) such a compound or an active metabolite thereof.

A further aspect of the present invention is prodrugs of the compounds of the invention.
Such prodrugs can be metabolised in vivo to give a compound according to the invention.
These prodrugs may or may not be active in their own right.

The compounds of the present invention can also exist in di~l~nL polymorphic forms, for example, amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the present invention are within the scope of the invention and are a further aspect thereof.

The term "alkyl" as used herein refers, umess otherwise stated, to a monovalent straight or bl~nched chain radical. Likewise, the terms "cycloalkyl" and "spiro-cycloalkyl" refer, unless otherwise stated, to a divalent cyclic or spiro-cyclic radical rcspe~Li~ely. The term "alkoxy"
refers to a monovalent straight or branched chain radical ~ ched to the parent molecular moiety through an oxygen atom. The term "aryl" refers to a monovalent mono-, bi- or tri-cyclic aromatic ring. The term "heteroa~ryl" refers to a monovalent mono-, bi- or tri-cyclic aromatic ring col~ ing one or more hete.odto,l,~(e.g., nitrogen, oxygen, sulfur). The term "phenylalkoxy" refers to a monovalent phenyl group att~ched to a divalent Cl 6 alkylene group which is itself att~rhed to the parent molecular moiety through an oxygen atom. The term "halo" refers to fluoro, chloro, bromo, or iodo.

The compounds of formula (I) exist in forms wherein the carbon centres -C(Rl)(R2)- and -C(R6)(R7)- can be chiral. The present invention inr.llldes within its scope each possible W O 96tl6051 PCT/GB95/02700 optical isomer subst~nti~lly free, i.e. as associated with less than 5%, of any other optical isomer(s), and mixtures of one or more optical isomers in any proportions, including racemic mixtures.

In those cases where the absolute stereochemistry at -C(Rl)(R2)- and -C(R6)(R7)- has not been determined, the compounds of the invention are defined in terrns of the relative positions of the Rl/R2 and R6R7 substituents. Thus, those compounds wherein the bulkier of the substituents, i.e. the substituent of higher mass are both located on the same side of the thiazepine ring are referred to herein as "cis", and those compounds in which the bulkier of the substituents are located on opposite sides of the ring are referred to as "trans." It will be evident to a skilled person that both "cis" and "trans" compounds of the invention can each exist in t~,vo enantiomeric forms which are individually designated "(+)-" or "(-)-"
according to the direction of rotation of a plane of polarised light when passed through a sample of the compound. Cis or trans compounds of the invention in which the individual enantiomers have not been resolved are referred to herein using the prefix "(t_)-~

According to further aspects ofthe invention, there are also provided:
(a) the compounds of formula (I) and pharmaceutically acceptable salts, solvates andphysiologically functional derivatives thereof for use as therapeutic agents, particularly in the prophylaxis and treatment of clinical conditions for which a bile acid uptake inhibitor is intlic~te~, for example, a hyperlipidemic condition, and associated ~ice~ces such as atherosclerosis;

(b) pharm~ceutical compositions comprising a compound of formula (I) or one of its pharm~ceutically acceptable salts, solvates, or physiologically functional derivatives, .
at least one pharmaceutically acceptable carrier and, optionally, one or more other physiologically active agents;

(c) the use of a compound of formula (I) or of a pharmaceutically acceptable salt, solvate, or physiolog,ically functional derivative thereof in the m~nf~ctl~re of a mediç~mPnt for the prophylaxis or treatment of a clinical condition for which a bile acid uptake inhibitor is in-lic~te~, for example, a hyperlipidemic condition, and associated ~ise~ses such as atherosclerosis;
.

(d) a method of inhibiting the absorption of bile acids from the intPstine of a m~mm~l, such as a human, which comprises ~tlministering an effective bile acid absorption inhibiting amount of a compound of formula (I) or of a pharm~cel.tic~lly acceptable salt, solvate, or physiologically functional derivative thereof to the m~mm~i (e) a method of reducing the blood plasma or serum concentrations of LDL cholesterol in a m~mm~l, such as a human, which comprises ~minist~ring an effective cholesterol reducing amount of a compound of formula (I) or of a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof to the m~mm~l;

(f) a method of reducing the concentrations of cholesterol and cholesterol ester in the blood plasma or serum of a m~mm~l such as a human, which comprises a~minicteringan effective cholesterol and cholesterol ester reducing amount of a compound of formula (I) or of a pharm~ceutically acceptable salt, solvate, or physiologically functional derivative thereof to the marnmal, (g) a method of increasing the fecal excretion of bile acids in a m~mm~l such as a human, which comprises a~minictering an effective bile acid fecal excretion increasing amount of a compound of formula (I) or of a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof to the m~mm~l;

(h) a method for the prophylaxis or ~-taLIl,tnL of a clinical condition in a m~mm~l, such as a human, for which a bile acid uptake inhibitor is in~ic~te~, for example, a hyperlipidemic condition~ and associated dice~ses such as atherosclerosis, whichcomprises a~minict~oring a therapeutically effective amount of a compound of theformula (I) or of a pharm~ceutically acceptable salt, solvate, or physiologically functional derivative thereofto the m~mm~l;

(i) a method of reducing the inri~onre of coronary heart disease-related events in a m~mm~l such as a human, which conl~"ises ~rlminictering an effective corona.y heart disease-related events reducing amount of a compound of formula (I) or of a pharm~ce~ltically acceptable salt, solvate, or physiologically functional derivative thereof;

~) a method of reducing the concentration of cholesterol in the blood plasma or serum of a m~mm~l, such as a human, which comprises a~minictering an effective cholesterol reducing amount of a compound of formula (I);

PCTI~b5SI'~27 (k) proceççes for the prep~ion of compounds of forrnula (I) (int,lll~in~ salts, solvates and physiologically functional derivatives thereof as defined herein);

(I) novel ch~mical interrne~ t~s in the preparation of compounds of forrnula (I); and (m) the compounds of synthetic Examples 1-27 as hereina~er disclosed.

The amount of a compound of forrnula (I) which is required to achieve the desired biological effect will, of course, depend on a number of factors, for exarnple, the specific compound chosen, the use for which it is intended, the mode of administration and the clinical condition of the recipient. In general, a daily dose is in the range of from 0.001mg to 100mg (typically from 0.01mg to 50mg~ per day per kilogram bodyweight, for example, 0.01-1Omg/kg/day. Thus, orally administrable unit dose forrnulations, such as tablets or capsules. may contain, for example, from 0.1 to 100mg, typically from 0.1 to 10mg, preferably 0.1 to 5mg. 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 conditions referred to above, the compounds of formula {I) can be used as the compound per se~ but are preferably presented with an acceptable carrier in the forrn of a pharmaceutical composition. The carrier must, of course, be acceptable in the sense of being compatible with the other ingredients of the composition and must 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, which can contain from 0.05% to 95% by weight of the active compound. Other pharmacologically active substances can also be present incllldinsg other compounds of formula (I). The pharm~ceutic~1 compositions of the invention can be prepared by any of the well known techniques of pharrnacy con~isLing essçnti~lly of admixing the components.

Pharm~ceutical compositions according to the present invention include those suitable for oral, rectal, topical, buccal (e.g. sub-lingual) and pa~ e.al (e.g. s1lbcut~n~ous, intr~ml.ccul~r, intradermal, or intravenous) ~minictration, although the most suitable route in any given case wiU depend on the nature and severity of the con-lition being treated and on the nature of the particular compound of formula (I) which is being used. Enteric-coated ~ and enteric-coated controlled release formulations are also within the scope of the invention. Suitable enteric coatinp~ include ce~ lose acetate phsh~l~te, polyvinylacetate phth~l~te, hyd,oi~y,uropylmethylcellulose phthalate and anionic polymers of methacrylic acid :U

and methacrylic acid methyl ester. Suitable enteric coated and enteric coated controlled release formulations include tablets and capsules.

ph~rm~ceutical compositions suitable for oral ~lmini~tration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each cont~ining a predetermined amount of a compound of forrnula (I); as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As indicated, such compositions can be ~ d by any suitable method of pharmacy which includes the step of bringing into association the active compound and the carrier (which can constitute one or more accessory ingredients). In general, the compositions are prepared by uniformly and intim~tely ~-lmixing the active compound with a liquid or finely divided solid carrier, or both, and then, if nece~ . y, shaping the product. For example, a tablet can be ~lc~cd by colllple;,~ g or moulding a powder or granules of the compound, optionally with one or more ~cces~io,y ingre~ient~ Collll~l ssed tablets can be plc~d by colll,~)rcssillg, in a suitable m~rhin~, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s).
Moulded tablets can be made by moulding, in a suitable m~hinP, the powdered compound moistened with an inert liquid diluent. Controlled release tablets can be plcpaled in 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 phth~l~te, polyvinyl~cet~te phth~l~te, hydroxypropylmethyl-cellulose phth~l~te, or anionic polymers of meth~crylic acid and methacrylic acid methyl ester (Eudragit LTM). Except for Eudragit L, these polymers should also include 10% (by weight of the quantity of polymer used) of a plasticizer to prevent membrane cracking during application or on storage. Suitable plasticizers include diethyl phth~l~te, tributyl citrate and triacetin.

Enteric-coated controlled release tablets can be ~ J~cd by coating controlled release tablets with an enteric polymer such as cellulose acetate phth~l~tP7 polyvinyl~ret~te phth~l~t~o7 hydroxypropylmethyl-cellulose phth~l~te or anionic polymers of methacrylic acid and methacrylic acid methyl ester(Eudragit L). Except for Eudragit L, thesepolymers should also include 10% (by weight of the quantity of polymer used) of a plasticizer to prevent membrane cracking during application or on storage. Suitable plasticizers include diethyl phth~l~te, tributyl citrate and triacetin.

AMENDED SHFET
IPEA/EP

Capsules can be plep~t:d by admixing a compound of formula (I) with, for example, "es;~lm stearate, preg~l~ntiniced starch, sodium starch glycollate, and/or m~gn~Cium stearate and filling two-part hard gelatin capsules with the resulting mixture.

Controlled release capsule compositions can be prepared by admixing a compound of formula (I) with, for example, microcrystalline cellulose and/or lactose, extruding using an extruder, then spheronising and drying the extrudate. The dried pellets are coated with a release controlling membrane, for example ethyl cellulose, and filled into two-part, hard gelatin capsules.

Enteric capsule compositions can be prepared by admixing a compound of formula (I) with, for exarnple, n~icrocrystalline cellulose and/or lactose, extruding using an extruder, then spheronising and drying the extrudate. The dried pellets are coated with an enteric membrane, for example cellulose acetate phthalate cons~ining a plasticizer, for example diethyl phth~l~te and filled into two-part, hard ~elatin capsules.

Pharmaceutical compositions suitable for buccal (sub-lingual) ~dministration include lozenges comprising a compound of formula (I) in a flavored base, usually sucrose and acacia or tr~g~c~nth, and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.

Pharm~elltical compositions suitable for parenteral adminictration conveniently comprise sterile aqueous preparations of a compound of formula (I), preferably isotonic with the blood of the intended recipient. These prepa, ~lions are preferably ~minict~red intravenously, although ~iminictration can also be effected by means of subcutaneous, intr~m~cc~ r, or intradermal injection. Such preparations can conveniently be prepaled by admixing the compound with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions according to the invention will generally contain from 0.1 to 5% w/w of the active compound.
.
Pharm~ceutical compositions suitable for rectal ~dminictration are pl~Çelably presented as unit-dose suppositories. These can be prepared by admixing a compound of formula (I) with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.

Transdermal arlminictration is also possible. Pharm~ce~tic~l co"".)osiLions suitable for transdermal a~minictration can be presented as discrete patches adapted to remain in intim~te contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain the active compound in an optionally buffered, aqueous solution, dissolved and/or dispersed in an adhesive, or dispersed in a polyrner. A suitable conce,.llalion of the active compound is about 1% to 35%, preferably about 3% to 15%.
As one particular possibility, the active compound can be delivered from the patch by ele.,l~ l~,sport or iontophoresis, for example, as described in Pharrmaceutical Research.
3(6), 318 (1986).

The compounds of formulas (I) can be prepared by conventional methods known to askilled person or in an analogous manner tO processes described in the art.

For example, compounds of formula (I) wherein I is 0, R6 and R7 are hydrogen and X is CH ~ can be p, cl~ared by reducing the carbonyl group of a compound formula (II) R5d j~ --)~ (II) R5b~f N-C=O
R5a RY

wherein Rl ,R2 ,R4 and R5a~b~C d are as hereinbefore defined using, for example, a reducing agent such as ~ mimlrn hydride (AIH3), di-isobutvl~lnrninllm hydride (DIBAL) or borane (BH3) in a suitable organic solvent, such as T~.

Compounds of formula II as hereinbefore defined are novel and constitute a further aspect of the present invention.

Compounds of formula (II) can be prepared by a reaction of compounds of formula III

R5d R5b~f ~-C=O
R5a whclcill Rl ,R2 and R5a~b~C~d are as hereinbefore defined, with the appro~";ate R4-Z in the presence of a base, for example potassium carbonate (~C2C03) and optionally in the presence of a catalyst, for example, copper iodide(CiI) wherein R4 is as hereinbefore defined and Z is a suitable leaving group, for example halo. The compounds R4-Z are commercially available or can be p,epared by methods well known or readily available to those skilled in the art.

Compounds of formula m as hereinbefore defined are novel and constitute a further aspect of the present invention.

Compounds of formula (III) can be prepared by cyclising compounds of formula (IV) R5d R5~S--~RI (IV) R5b COOH
1 5a NH2 wherein Rl, R2 and R5ab~C~d are as heleinb~;rore defined, by reaction with an acid, for example an organic acid such as tosic acid, preferably at an elevated temperature, for example 255~ C.

Compounds of formula (IV) can be prepa~cd by reacting compounds of formula (V) with compounds of formula (Va) R5d R5~ SH Z ~Rl (Va) Rsb~NH~ HO~
R5a 0 wherein Rl, R2 and R5a~b~C~d are as hereinbefore defined and Z is a suitable leaving group, for example halo, in the ples~llce of an organic base, for example triethylamine or pyrrolidine. Compounds of formulas(V) and (Va) are co,."ller.,ially available or can be prepared by methods well known or readily available those skilled in the art.

Compounds of formula (I) wherein I is I or 2, can be p,epal~d from the corresponding compound of formula (T) wherein I is O by oxidation of the thio moiety with a suitable W O 96116051 P~ 5slo27 oxidizing agent, for example, hydrogen peroxide, organic peroxy acids, Oxoneg) (potassium peroxymonosl.lf~te), or osmium tetroxide (OSO4).

Compounds of formula (I) wherein R6 and/or R7 are other than hydrogen can be prepared by treating the corresponding compound of formula (I) wherein I is lor 2 and R6 and R7 are hydrogen with a base, for example, n-butyllithium followed by reaction with the appropriate R6-Z or R7-Z wherein R6 and R7 are as defined herein other than hydrogen and Z is a suitable leavmg group as defined herein.

Alternatively, compounds of formula (III) can be prepared from compounds of formula (VI) ~ ' (~) wherein Rl, R2 and R5a~b-C~d are as hereinbefore defined, by reaction with an acid, for example polyphosphoric acid at an elevated te.llpe~al~lre, for example !20~ C.

Compounds of formula (VI) can be prepared from compounds of formula (VII) R5d (VII) R5b~R2 RSa O

wherein Rl, R2 and RSa7b~c~d are hereinbefore defined, by reaction with hydroxyl amine (~2NoH).

Compounds of formula (VII) can be prepared by cyclizing compounds of formula (VIII) R5d ~R~ (Vm) R5a COOH

wherein R1, R2 and R5a~b~C~d are hereinbefore defined, in the presence of an acid, for example sulfuric acid (H2SO4).
Compounds of forrnula (VIII) can be prepared by reacting compounds of forrnula (IX) R5d R5~SH

R5b~
R5a wherein R5a,b.C.d are as hereinbefore defined, with compounds of formula (VI) analogous to the preparation of compounds of formula (IV) described hereinbefore.

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, compounds of formula (II) can be prepared by cyclizing compounds of formula (X) R5d j~ ~R2 Rsb~ COOR

wherein Rl, R2, R4, and R5a~b~C~d are as hereinbefore defined, in the presence of an organic acid, for example tosic acid.

Compounds of formula (X) can be prepared from compounds of formula (XI) R5d R5~ SH (XI) R5b~f NH
Rsa R4 wherein R4 and R5a7b7C7d are as herein before defined, with compounds of formula (Va) analogous to the ~,ep~alion of compounds of formula (IV) described hereinbefore.
Compounds of formula (XI) can be prepared by methods well known or readily available to those skilled in the art, for example by the methods disclosed in H. Gilman and J. Dietrich, J.
Am. Chem. Soc., 80, 380-383 (1958).

Compounds of formula (I) wherein X is C=O can be p~ep~ed following the method for the prepal~ion of compounds of formula (II) described hereinbefore.

Compounds of formula (I) wherein X is C=S can be plepaled from the correspondingcompounds of formula (I) wherein X is C=O by conversion of the C=O moiety with, for example, Lawesson's Reagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,~
disulfide).

The compounds of formula (I) substantially free, of other optical isomers can be obtained either by chiral synthesis, for example, by the use of the applupliate chiral starting material(s), such as a chiral compound of formula (Va), or by resolution of the products obtained from achiral syntheses, for example, by chiral hplc, enzymatic resolution, or by classical resolution with chiral acids.

Optional conversion of a compound of formula (I), or a compound of formula (I) comprising a basic substituent, to a coll~sl)onding acid ~ddition salt may be effected by reaction with a solution of the appropriate acid, for example, one of those recited earlier.
Optional conversion of a compound of formula (I) comprising an acidic substituent to a c~"esponding base salt may be effected by reaction with a solution of the applupliate base, for example, sodium hydroxide. Optional conversion to a physiologically functional derivative, such as an ester, can be carried out by methods known to those skilled in the art or obtainable from the chemical literature.

AM~NDED S; ~--_T
~ p ~

In addition, compounds of the formula (I) may be converted to di~rel,L compounds of the formula (I) by standard methods known or available from the literature to those skilled in the art, for exarnple by alkylation of a hydroxy group.

For a better underst~ntling of the invention, the following Examples are given by way of illustration and are not to be construed in any way as limiting the scope of the invention.

General Procedures. P-oton magnetic resonance spectra were recorded at 300 MHz. Mass spectra were recorded under atmospheric pressure chemical ionization (APCI) conditions on a LCMS instrument or were performed by Oneida Research Services, Inc. under çhemic~l ionization (CI) conditions using meth~ne as the reagent gas. Elemental Analysis were pe-fo,l,.ed by Atlantic Microlab, Inc. All reactions were perforrned under nitrogen atmosphere. TLC plates were Whatman ~vIK6F silica gel 60 plates and were vicu~li7ed under a W lamp. Column chromatography was perforrned with EM Science silica Gel 60 (230-400 mesh). Reagents were obtained from Aldrich Chemical Co. unless otherwise noted and were used without further purification. Solvents were Aldrich anhydrous grade.

Exarnple 1 P~ a- ~Lion of (i)-3 -n-Butyl-3 -ethvl-2~ 3 -dihydro-5 -phenyl- I .5 -benzothiazepin-4-one.

(a) ( l )-2-((Tert-butyldimethylsilyl)oxy)methvl-ethyl-hexanol.
To a slurry of 60% NaH (7.S g, 187.2 mmol) in 400 ml TH~ was added in 3 portions 2-n-butyl-~-ethyl-1,3-propanediol (30.0 g, 187.2 rnmol) and stirred for 45 min. To the resulting gum was added tert-butyldimethylsilyl chloride (28.2 g, 187.2 mrnol) and stirred for 2 h.
The solvent was evaporated and the residue was partitioned between water and ether. The ether layer was washed with bicarbonate solution and brine and conce.,ll~Led. Colurnn chromatography (S% ethyl acetate/petroleum ether) gave the title compound as a colorless oil (50.12 g, 182.6 mrnol, 98%). lH N~ (DMSO-d6) ~ 4.19 (t, lH); 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 (~I+). Calcd for C1sH34O2Si: C, 65.63; H, 12.48. Found: C, 65.87; H, 12.47.

(b) ( I )-2-Ethyl-2-(hydroxyrnethyl)-heAanoic acid.
To a solution of the product of Example 1(a) (4.43 g, 16.0 mmol) in 16 ml CCl4, 16 ml CH3CN, and 24 rnl H20 was added NaIO4 (13.69 g, 64 mmol) and RuCl3 (0.16 g, 0.8 rnmol) and stirred for 16 h. The slurry was col~Ge~ aled and the solvents evaporated. The residue was partitioned between H2O and CH2Cl2. The aqueous phase was extracted 3 times with CH2C12, dried, conce~ ted. The residue was dissolved in 3 ml THF, lM

tetrabutylamrnonium fluoride in THF (1.75 ml, 1.75 mrnol) was added and the solution was stirred for 1 h. The solvent was evaporated, and the resulting oil was partitioned between H2O and CH2C12. The aqueous phase was extracted 3x with CH2C12, dried, concentrated.
Column ch,.,l..dtography (95% CH2C12/4% MeOH/0.5% H20/0.5% acetic acid) gave theproduct as an oil 2.26 g (13.0 rnmol, 81%). lH NMR (DMSO-d6) ~ 11.95 (br s, lH); 4.74 (br s, lH); 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). Calcd for CgHlgO3: C, 62.04; H, 10.41. Found: C, 61.94;
H, 10.44.

(c) ( ~ )-2-(Bromomethvl)-2-ethyl-hexanoic acid.
A solution ofthe product from Example l(b) (2.30 g, 13.2 mmol) in 48% HBr (40 ml) was refluxed for 20 h. After cooling to RT the solution was transferred to a separatory funnel, extracted 3 times with ethyl acetate, dried over Na2S04, and concentrated. A~er pumping at high vacuum to remove traces of HBr, obtained the title compound (2.46 ~, 10.4 mmoL
79%). lH NMR (DMSO-d6) ~ 3.60 (s, 2H); 1.62-1.04 (m, 8H); 0.85 (t, 3H); 0.75 (t, 3H).
MS Dale = 157 (M - Br), 237 (M), 238, 239 (M + 2). Calcd for CgH17O2Br: C, 45.59; H, 7.23; Br, 33.70. Found: C, 46.27; H, 7.17; Br, 32.94.

(d) (~)-2-(r(2-Aminophenyl)thio)methyl)-2-ethvlhexanoic acid.
To a solution of the product from Example l(c) (0.52 g, 2.19 mrnol) in THF (4 ml) was added 2-aminothiophenol (0.41 g, 3.29 mmol, freshly distilled) and pyrollidine (or triethylamine, 3.29 mmol) and stirred for 48 h. The reaction mixture was ~ sÇe~d to a separatory fuMel and partitioned between H2O and CHC13. The aqueous layer was extracted 3 times with CHC13, column chromatographed (30% ethyl acetate in petroleum ether) to give the title compound (0.50 g, 1.78 mmol, 81%). IH NMR (DMSO-d6) ~ 12.40 (br s, lH); 7.25 (d, lH); 7.00 (t, lH); 6.67 (d, lH); 6.48 (t, lH); 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). Calcd for ClsH23NSO2 x (0.8 EtOAc): C, 62.12; H, 8.42; N, 3.98; S, 9.11. Found: C, 62.41; H, 8.28; N, 3.83; S, 8.91.

(e) (1)-3-n-Butyl-3-ethyl-2~3-dihydro- 1.5-benzothiazepin-4-one.
A solution ofthe product from Example 1(d) (0.66 g, 2.35 mmol) and tolueneslllfonic acid (0.15 g, 0.79 mrnol) in tetradec~ne (30 ml) was refluxed for 3 h. A$er cooling to RT the reaction miture was loaded directly onto a silica column and the product eluted with 10%
ethyl acetate/petroleum ether yielding the title compound (0.44 g, 167 mmol, 71%). M.P. =
90.0 ~C. lH NMR (DMSO-d6) o 9.71 (s, lH); 7.39 (d, lH); 7.23 (t, lH); 7.10 (d, lH);
6.95 (t, lH); 2.92 (s, 2H); 1.72-1.20 (m, 4H); 1.15 (m, 4H); 0.78 (m, 6H). MS Da/e= 264 WO 96tl6051 PCT/GB95/02700 (~I+). Calcd for ClSH2lNso: 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-n-Butvl-3-ethvl-~3-dihydro-5-phenyl- 1.5-benzothiazepin-4-one.
To a solution ofthe product from Example l(e) (4.07 g, 15.45 mrnol) 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 rnrnol), and the rnixture was refluxed for 16h. The reaction mixture was allowed to cool and was lo~ded directly onto a silica column and eluted with 5% ethyl acetate/petroleum ether to give the title compound (5.14 g, 15.14 mrnol, 98% yield). M.P.
= 159.4 ~C. lH NMR (DMSO-d6) o 7.67-6.86 (m, 9H); 3.11 (s, 2H); 1. j8-1.13 (m, 8H);
0.77 (m, 6H). MS Da/e = 340 (MH+). Calcd for C21H2sNSO: C, 74.30; H, 7.42; N, 4.13;
S, 9.44. Found: C, 74.11; H, 7.49; N, 4.0~; S, 9.36.

Example 2 ~1 epa, ~tion of (~)-,-n-Butvl-3-ethyl-2 3 -dihvdro-5-phenvl- 1.5-benzothiazepin- 1 -one- 1 I -dioxide.

To a solution ofthe compound of Example l(f) (0.95 g, 2.80 rnmol) in trifluoroacetic acid (9.5 ml) at 0 ~C was added 30% hydrogen peroxide (1.60 g, 14 mrnol) and stirred for 16 h.
The solution was neutralized with sodium carbonate solution and the product extracted 3 times with ethyl acetate. The organic extracts were dried (Na2SO4), concentrated and the resulting oil loaded onto a silica colurnn. The product was eluted with 20% ethyl acetate/petroleum ether giving the title compound as a white powder (0.96 g, 2.58 mmol, 92%). M.P. = 57.6 ~C. lH NMR (DMSO-d6) ~ 7.94-7.06 (m, 9H); 3.73 (s, 2H); 1.72-0.98 (m, 8H); 0.77 (m, 6H). MS Da/e = 372 (MH~). Calcd for C21H25NS03: 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.

Exarnple 3 Preparation of ( I )-3-n-Butvl-3-ethyl-2~3~4~5-tetrahydro-5-phenyl-1.5-bel zothiazephle.

To a solution of AIH3 (44 mmol, generated in si~u from H2S04, 22 mmol, and LiALH4, 44 mmol) in 44 ml diethyl ether was added the compound of Example l(f) (5.00 g, 14.60 mmol) in 40 ml THF at 0 ~C. The reaction mixture was allowed to warm to RT over 2 h and was stirred at RT for 15 h after which time TLC (20% ethyl acetate/petroleum ether) showed complete reaction. The reaction flask was cooled to 0 ~C and the excess AIH3 was quenched by adding 30 of H20/THF (1:2) dropwise followed by 5 ml lM NaOH. The mixture was llans~lled to a sepal~Loly fimnel and extracted 3 times with ether. The ether W O96/16051 PCT/~b5S~'~2700 extracts were combined, dried, concentrated and column chlulllaLographed (petroleum ether) to give the title compound (4.74 ~, 14.55 mmol, 99%). lH NMR (DMSO-d6) o 7.26-6.69 (m, 9H); 3.67 (br s, 2H); 2.78 (m, 2H); 1.21-l.OS (m, 8H); 0.71 (m, 6H). MS
Da/e= 325 (M+), 326 (~+). Calcd for C21H27NS: C, 77.49; H, 8.36; N, 4.30; S, 9.85.
Found: C, 77.51; H, 8.40; N, 4.31, S, 9.73.

Example 4 Pl~ aldlion of (~)-3-n-~utvl-3-ethYI-2~3.~.5-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 THF and 23 ml tert-butanol was added N-methyl-morpholine-N-oxide (5.1 g, 43.6 mmol) and osmium tetroxide (0.8 mmol, 2.5 wt% in 2-methyl-~-propanol). The mixture was stirred at RT for 16 h at which point 50 ml NaHCO3 solution was added to neutralize any acid, the mixture transferred to a separatorv filnnel and ex~racted 3 times with ethyl acetate. The organic layers were washed with sodium hyposulfite and brine, dried (Na2SO4) and concentrated.
Column chromatography (10% ethyl acetate/petroleum ether) yielded the title compound (4.76 g, 13.3 mmol, 92% yield). lH NMR (DMSO-d6) ~ 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+). Calcd for C21H27NSO2: 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 alalion of(~)-3-n-Butvl-2-isobutvl-3-ethvl-2.3~4~5-tetrahvdro-5-phenyl-1~5-bellzoll~azepine-l ~ l-dioxide.

To a solution of the compound of Example 4 (0.56j g, 1.58 mmol) in 10 ml THF wasadded n-butyllithium (2.5 M in THF, 1.74 mmol) at -78 ~C. This was stirred for 20 min at-78 ~C after which iodo-2-methylpropane (1.3 M in THF, 6.32 mmol) was added dropwise at -78 ~C. The reaction mixture was brought up to 0 ~C and stirred for 16 h. The excess base was qu~n~hed by adding brine (10 ml) and the product was extracted with ether (3 x 20 ml). The ether extracts were dried, conct;llLIaLed and the residue applied to a silica gel cûlumn. The prûduct was eluted with 10% ethyl acetate/ petroleum ether giving a yellow oil, (0.48 g, 1.16 mmol, 74 %). IH NMR (DMSO-d6) o 7.89-6.80 (m, 9H); 3.30 ~br m, 2H); 3.09 (br s, lH); 1.88-0.63 (m, 23H). MS Da/e = 414 (~+), 436 (M + Na). Calcd for C2sH3sNSO2 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 P. epa. dlion of 3.3 -Diethyl-2.3-dihvdro-5-phenyl- 1.5-benzothiazepin-4-one.

(a) 2-((Tert-butvldimethylsilyl)oxv)methvl-2-ethvlbutanol.
The title compound was prepared from 2,2-diethyl- 1,3-propanediol according to the procedure for Example l(a) lH N~ (DMSO-d6) ~ 4.20 (t, lH); 3.29 (s, 2H); 3.14 (d, 2H); 1.13 (q, 4H); 0 8a (s, 9H); 0.73 (t, 6H); 0.73 (t, 3H); -0.01 (s, 6H). MS Dale = ~47 (MH+). Calcd for C13H3002Si: C, 63.35, H, 12.26. Found: C, 63.27; H, 12.25.

(b) 2-Ethvl-~-(hvdroxymethvl)-butvric acid.
The title compound was prepared from the product of Exarnple 6(a)(41.28 8, 189 rnmol) using the procedure for Exarnple l(b) yielding (24.4 g, 167 mmol, 88%). lH N~
(DMSO-d6) ~ 3.42 (s, 2H); 1.89 (s, lH); 1.44 (q, 4H); 0.73 (t, 6H). MS Dale = 147 (~). Calcd for C7H14O3 x 0.3(AcOH): C, 55.39; H, 9.33. Found: C, 55.38; H, 9.17.
(c) 2-(Bromomethvl)-2-ethvl-butvric acid.
The title compound was prepared from the product of Example 6(b) ( 22.2 ~" 151 rnmol) accordin, to the procedure outlined for Example l(c). A~er removing the H~r in vacuo obtained lOB (19.8 g, 94.7 mmol, 63%). lH N~ (DMSO-d6) ~ 3.60 (s, 2H); 1.58 (q, 4H); 0.75 (t, 3H). MS Da/e = 209 (M), 211 (M + 2). Calcd for C7H13O2Br: C, 40.21; H, 6.27; Br, 38.21. Found: C, 40.92; H, 6.38; Br, 37.17.

(d) 2-(((~-Aminophenyl)thio)methvl)-2-ethvlbutvric acid.

The title compound was prepared from the compound of Example 6(c) (19.7 g, 94 mmol) according to the procedure for Example l(d). Column ch-o,l~atography yielded theproduct (9.77 g, 40 mmol, 43%). lH NMR (DMSO-d6) ~ 7.24 (d, lH); 7.00 (t, lH); 6.69 (d, lH); 6.49 (t, lH); 2.91 (s, 2H); 1.60 (q, 4H); 0.68 (t, 3H). MS Da/e = 254 (MH+).
Calcd for C13HlgNSO2: C, 61.62; H, 7.57; N, 5.52; S, 12.6S. Found: C, 61.34; H, 7.62;
N, 5.33; S, 12.40.

(e) 3~3-Diethyl-2~3-dihvdro-1~5-benzothiazepin-4-one The title compound was prepared by thermal ring closure of the product of Example 6(d) (9.7 g, 38 mmol) as outlined for Example l(e). Column chro~.,atography (50% ethyl acetate/petroleum ether) yielded the title compound (6.22 g, 26.4 mmol, 70% yield). lH

NMR (DMSO-d6) o 9.73 (s, lH); 7.40 (d, lH), 7.23 (t, lH); 7.10 (d, lH); 6.97 (t, lH);

2.92 (s, 2H); 1.71-1.48 (m, 4H); 0.76 (rn, 6H). MS Da/e = 236 (MH~). Calcd for C13H17NSO: C, 66.34; H, 7.28; N, 5.95; S, 13.67. Found: C7 66.34; H, 7.37; N, 5.96; S, 13.58.

(f) 3.3-Diethyl-2~3-dihydro-5-phenvl- 1 ~ 5-benzothiazepin-4-one.

The N-phenylation of the compound from Example 6(e) (5.40 g, 23 mmol) was accomplished following the procedure for Example l(f) to yield the title compound a~er column chromatography (7.04 g, 22.6 mrnol, 99% yield). M.P. = 86.4 ~C. lH NMR
(DMSO-d6) ~ 7.66-6.87 (m, 9H); 3.09 (s, 2H); 1.45 (m, 4H); 0.76 (m, 6H). MS Da/e =
312 (MH+). Calcd for ClgH21NSO: C, 7~.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-Diethvl-7~3-dihvdro-S-phenyl-1~5-benzothiazepin-4-one 1 ~ I-dioxide.

The oxidation of the compound of Example 6(f) (2.00 g, 6.4 mmol) to the sulfone was accomplished by the procedure outlined for Example 2. Column chromatography (50%ethylacetate/petroleum ether) gave the title product (1.92 g, 5.59 mrnol, 88 % yield). M.P.
= 163.0-165.6 ~C. lH NMR (DMSO-d6) ~ 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 (~I+), 366 (M + Na ). Calcd for ClgH21NSO3:
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 F~ alalion of 3.3-Diethyl-2~3~4~5-tetrahvdro-5-phenyl-1~5-benzothiazepine The reduction of the compound of Example 6(f) (2.43 g, 7.80 mrnol) was accomplished by the procedure outlined for Exarnple 3. Column chromatography (20%
ethyl~cet~te/petroleum ether) gave the title product (2.01 g, 6.76 mmol, 87 % yield). lH
NMR (DMSO-d6) o 7.29-6.71 (rn, 9H); 3.65 (br s, 2H); 2.77 (s, 2H); 1.36-1.15 (m, 4H);
0.67 (m, 6H). MS Da/e = 298 (~I+). Calcd. for ClgH23NS: 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 Fl~p~ralion of 3~3-Diethyl-2~3.4.5-tetrahydro-5-phenyl-1.5-benzothiazepine-1. l-dioxide.

The oxidation ofthe compound of Example 8 (0.53 g, 1.80 mmol) was accomplished by the procedure outlined for Example 4. Colurnn chromatography (50% ethyl acetate/petroleum ether) gave the title product as a yellow solid, (0.55 g, 1.67 mmol, 93% yield). M.P. =
128.0-130.2 ~C. IH N~ (DMSO-d6) ~ 7.88-6.84 (m, 9H); 3.?3 (br s, 2H); 3.32 (s, 2H);
1.55-1.30 (m, 4H); 0.68 (m, 6H). MS Da/e = 330 (MH+), 352 (M + Na+). Calcd. for ClgH23NS02: 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-Dimethvl-~ 3 dihvdro-~-phenyl- I 5-benzothiazepin-4-one.

(a) Bromopivalic acid The title compound was prepared from hydroxypivalic acid (TCI Arnerica, 50.0g, 423 mmol) using the procedure for Example l(c). After removing the HBr under high vacuum the product was obtained (66.42 g, 367 mmol, 87%). lH NMR (DMSO-d6) ~ 12.3 (br s);

3.57 (s, 2H); 1.19 (s, 6H). MS Da/e = 181 (M), 183 (M + 2). Calcd for CsHgO2Br: C, 33.17; H, 5.01; Br, 44.13. Found: C, 34.07; H, 5.08; Br, 42.45.

(b) 2-(((2-Aminophenyl)thio)methvl)-2-methylpropionic acid.

Bromopivalic acid (Example lO(a)) (S9.4 g, 328 mmol) was reacted with 2-aminothiophenol (41 g, 328 mmol, freshly distilled) according to the procedure for Example l(d). Column ch.c,ll,a~ography yielded the title compound (52.3 g, 232 mrnol, 71%). lH
NMR (DMSO-d6) ~ 12.44 (br s, lH); 7.22 (d, lH); 6.99 (t, lH); 6.63 (d, lH); 6.47 (t, lH);
5.27 (br s, 2H); 2.88 (s, 2H); 1.14 (s, 6H). MS Da/e = 226 (MH+), 208 (M - H2O), 180 (M
- CO2). Calcd for Cl lHlsNSO2: C, 58.64; H, 6.71; N, 6.22; S, 14.23. Found: C, 58.41;
H, 6.7B; N, 6.13; S, 14.29.

(c) 3.3-Dimethvl-2 3 dihvdro-1.5-benzothiazepin-4(5H)-one The title compound was prepared by thermal ring closure of the compound of Example lO(b) (33.4 g, 148 mmol) as outlined for Example l(e). Column cl~olllato~aphy (25%
ethyl acetate/petroleum ether) yielded the product (25.39 g, 122 mmol, 83% yield). M.P. =
112.6 ~C. lH N~. (DMSO-d6) ~ 9.71 (s, lH); 7.40 (d, lH); 7.23 (t, lH); 7.11 (d, lH);
6.96 (t, lH); 2.95 (s, 2H); 1.18 (s, 6H). MS Da/e = 208 (~). Calcd for CllH13NSO:
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-DimethYI-'7~3 dihydro-5-Dhenvl-1~5-benzothiazepin-4-one.

The N-phenylation of the compound of Example lO(c) (22.0 g, 106 mrnol) was accomplished following the procedure for Example 1 (f) to yield, after column chromatography, the title compound (28.69 g, 101 mmol, 96% yield). M.P = 103.8 ~C. lH
N~ (DMSO-d6) o 7.68-6.88 (m, 9H); 3.19 (s, 2H); 1.05 (s, 6H). MS Dale 2 284 (MH+), 306 (M + Nal). Calcd for C17H17NSO: C, 72.05; H, 6.05; N, 4.94; S, 11.31.Found: C, 71.85; H, 6.13, N, 4.85; S, 11.26.

Example 11 Pl e~.al dtion of 3 3-Dimethyl-2.3 dihydro-5-phenyl- 1 ~5-benzothiazepin-4-one-1. I -dioxide.

The oxidation of the compound of Example IO(d) (8.69 g, 30.7 mmol) was accomplished following the procedure for Example 2 to give, a~er colurnn chromatography and oven drying, a white powder, the product as (8.80 g, 27.9 mmol, 91% yield). M.P. = 140.8 ~C.
lH N~R (DMSO-d6) o 7.95-7.04 (m, 9H); 3.81 (s, 2H); 1.10 (s, 6H). MS Da/e - 316 (~I+), 338 (M + Na+). Calcd for C17H17NSO3 x (0.5 H20): 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.

Exarnple 12 Preparation of 3~3-Dimethyl-2.3~4.5-tetrahydro-5-phenvl-1.5-benzothiazepine.

The reduction of the compound of Example 11 (8.88 g, 31.05 rnmol) was accomplished following the procedure for Exarnple 3 to give the product, after column chrumaLography (5% ethyl acetate/petroleum ether), as a yellow oil (8.02 g, 29.77 mmol, 96% yield). lH
NMR (DMSO-d6) ~ 7.44-6.68 (m, 9H); 3.31 (br s, 2H); 2.65 (s, 2H); 0.93 (s, 6H). MS
Da/e = 270 (~). Calcd for C17HlgNS: 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.
.

Exarnple 13 ~I.,paldtionof 2.3.4.5Tetrahydro-3.3-dimethyl-5-phenyl-1,5-bellzolhia~ep;l~e-1,1-dioxide.

The oxidation of the compound of Exarnple 12 (5.66 g, 21.01 mmol) was accomplished following the procedure for Example 4 to give, after column cl~.u~ Lography (20% ethyl acetate/petroleum ether), a white powder (S.56 g, 18.45 mmol, 88% yield). M.P. = 168.0-168.6 ~C. lH NMR (DMSO-d6) ~ 7.92-6.83 (rn, 9H); 3.66 (br s, 2H); 3.33 (s, 2H); 1.03 (s, 6H). MS Da/e = 302 (MH+), 324 (M + Na+). Calcd for Cl7Hl9Nso2: 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 p- ~pal ~tion of (+)-3 -n-Butvl-i -ethyl-2~ 3. -dihvdro-5 -phenvl- I .5 -benzothiazepin-4-one.

(a) 2-.~nilinobenzenethiol.

This was prepared according to a procedure from H. Gilman and J. Dietrich, J. Arn. Chem.
Soc. 80 (1958) pp. 380-383. To a solution of phenothiazine (10.0 g, 50.2 mmol) in 50 ml THF was added strips of lithium (2.0 g, 288 mmol) over 45 min. The mixture was stirred for 1 h after which time the solution was pipetted off the unreacted lithium and partitioned between ether and water in a separatory funnel. The product was extracted with 4 N
NaOH. The ether layer yielded unreacted phenothiazine (4.02 g, 20 mmol, 40~/0). The aqueous base layer was neutralized to pH 4 and extracted with ether 3 times. The ether layer was dried, concentrated and the residue chromatographed (5% ethyl acetate/petroleum ether) giving the title compound (5.49 g, 27.3 rnmol, 55% yield). lH NMR (DMSO-d6) o 7.65-6.74 (m, 9H). MS Da/e = 202 (MH+). Calcd for C12HllNS: 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-Anilinophenvl)thio)methyl)-2-ethvlhexanoic acid.

This was prepared by reacting the compound of Example 14(a) (3.06 g, 15.2 mmol) with the compound of Example l(c) (3.50 g, 15.0 mmol) according to the procedure used to prepare in Exarnple l(d). Colurnn cLlu..l~tography (50% ethyl acetate/petroleum ether) gave the title compound (3.70 g, 10.4 mmol, 70%). lH N~ (DMso-d6) o 12.48 (br s,lH); 7.46-6.83 (m, 9H); 3.01 (s, 2H); 1.55-1.03 (m, 8H); 0.73 (m, 6H). MS Da/e = 358 (~I+). Calcd for C21H27NSO2: 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) (1)-3-n-Butvl-3-ethyl-2.3-dihvdro-S-phenvl-l.S-benzothiazepin-4-one.

The ring closure of the compound of Example 14(b) (0.59 g, 1.65 mmol) was carried out using the procedure for Example l(e) giving the title compound (0.17 g, 0.51 rnmol, 31%
yield). lHNMR (DMSO-d6) is ident~ to product of Example 1(f) described above.

Example 15 Plt;p~Lion of ( I )-3-n-Butvl-3-ethvl-2.3-dihvdro-8-methoxv-5-phenyl-1.5-benzothiazepin-4-one.

(a) 2-Amino-5-methoxvlhiophenol A solution of 2-a nino-6-methoxybenzothiazole (36g, 200 mrnol; Aldrich Chemical Co.) and 400 ml 30% aqueous potassium hydroxide was refluxed for 16 h. The dark solution was cooled to 0 ~C and neutralzed to pH 6 with 50% aqueous acetic acid and stirred for 1 h.
The resulting slurry was filtered and the product collected on the filter paper and dried (25.29 g, 81% yield). lH NMR (DMSO-d6) o 6.91-6.44 (m, 3H), 5.90 (br s, 2H), 3.52 (s, 3H). MS Da/e = 154 (M-H).

(b) ( I )-3-n-Butvl-3-ethvl-2~3-dihvdro-8-methoxv- 1 5-benzothiazepin-4(5H)-one.
To a solution of the compound of Example l(c) (25.1 g, 105.8 mrnol) in 150 ml dimethylrollllall~ide was added the compound of Example 15(a) (13.7 g, 88.2 mmol) and 13 nl triethylamine. The mixture was stirred overnight and then ~ r~lled to a separatoly funnel with 200 ml water. The pH was ~jucted to 4 with 0.1 N HCI and the product was extracted with 6x50rnl diethyl ether. The ether extracts were pooled, dried and the solvent evaporated to give a viscous oil. To this was added 200 ml tetr~ec~ne and 825 mg p-tol~lçneslllfonic acid and the mixture refluxed for 1.5 h. The reaction mixture was cooled and loaded onto a silica gel colu nn and the product eluted with 20% ethyl acetate/petroleum ether (15.15 g, 59% yield). M.P. = 100.4 ~C. IH NMR (DMSO-d6) o 9.51 (s, lH); 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+). Calcd for Cl6H23Nso2: 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) ( I )-3-n-Butyl-3-ethyl-2.3-dihydro-8-methoxy-5-phenvl-1.5-be.~o~ e?ill-4-one.

The compound of Exarnple 15(b) (11.0 g, 37.5 mmol) was reacted with phenyl iodide using the procedure outlined for Example l(f) to give the product (13.07g, 94% yield). lH N~
(DMSO-d6) o 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+). Calcd for C22H27NS02 x 0.75 H20: C, 68.99; H, 7.50; N,3.66; S, 8.35. Found: C, 68.95; H, 7.14; N, 3.63; S, 8.25.

-Example 16 Plepa,aLionof(l)-3-n-Butyl-3-ethvl-2., 4 5-tetrahvdro-8-methoxv-5-phenvl-1~5-benzothiazepine.
The compound of Example 15(c) (2.25_, 6.10 mmol) was reacted with AIH3 using theprocedure outlined for Example 3 to give the product (1.95 g, 90% yield). lH NMR(DMSO-d6) ~ 7.11-6.65 (m, 8H,); 3.70 (s, 3H); 3.51 (br s, 2H); 2.66 (s, 2H); 1.40-1.10 (m, 8H); 0.72 (m, 6~. MS Da/e = 356 (MH+). Calcd for C22H2gNSO: C, 74.32; H, 8.22; N, 3.94; S, 9.02. Found: C, 74.20; H, 8.16; N, 3.88; S, 8.95.

Example 17 Pl epa~ dlion of (+)-3-n-Butvl-3-ethvl-2, .~ 5-tetrahvdro-8-methoxv-5-phenvl- 1 5-benzothiazepine- 1.1 -dioxide.

The compound of Example 16 (1.52 g, 4.28 mrnol)was oxidized to the sulfone in analogy with the procedure outlined for Example 4 giving the product (1.61 g, 97% yield). IH
NMR (DMSO-d6) ~ 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+). Calcd for C22H2gNSO3: 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 Ple~)a,alion of(l)-3-n-Butyl-3-ethyl-2.3~4~5-tetrahydro-8-hvdroxy-5-phenvl-1,5-benzol}.iazepine- I . I -dioxide.

To a mixture of ~ mimlm bromide (lM in CH2C12, 16 mmol) and eth~nethiol (7.4 ml, 100 mmol) at 0 ~C was added the compound of Example 17 (0.78 g, 2.01 mmol) in 30 ml CH2C12. The mixture was stirred for lh at 0 ~C and then 25 ml water was added and the product extracted with 3 X 20 ml CH2C12. The organic layer was dried and the solvents e~,a~o.aled. The residue was applied to a silica gel column and the product eluted with 35% ethyl acetate/petroleum ether (0.74g, 98%). IH NMR (DMSO-d6) o 10.00 (s, lH), 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 (~I+). Calcd for C21H27NS03 X 0.4 H20: 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 ~rel)al~ion of (1)-7-Bromo-3-n-butyl-3-ethyl-2~3-dihvdro-8-methoxy-5-phenvl-l.5-benzothiazepin~-one.

(a) ( i )-7-Bromo-3-n-butyl-3-ethyl-2.3-dihvdro-8-methoxv-1.5-benzothiazepin-4(5H)-one.

To a solution of the compound of Example 15(c) (5.59 g, 19.05 mmol) in methylenechloride (120 ml) at 0~C was added N-bromos~lcGinimide (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 onto a silica ael column. The product was eluted with 10% ethyl acetate/petroleum ether (6.60g, 93% ,vield). M.P = 102.0 ~C. lH
N~ (DMSO-d6) ~ 9 60 (s, lH); 7.31 (s, lH); 7.09 (s, lH); 3.80 (s, 3H); 2.91 (S, 2H);
1.71-1.39 (m, 4H); 1.19-1.13 (m, 4H); 0.80 (t, 3H); 0.7~ (t, 3H). MS Dale = 37'', 374 (MH~). Calcd for C16H22BrNS02: C, 51.62; H, 5.96; 1~', 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-dihvdro-8-methoxv-5-phenvl-1.5-benzothiazepin-4-one.

To a solution ofthe compound of Example l9(a) (6.60 g, 17.7 mmol) in bromobenzene (35 ml) was added copper bromide (S00 mg) and potassium carbonate (2.5 g), and the mixture was refluxed for 20 h. The reaction mixture was loaded onto a silica gel column and the product eluted with 10% ethyl acetate/petroleum ether (5.05 g, 64% yield). M.P. = 131.0-132.8 ~C. lH NMR (DMSO-d6) ~ 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 (MH+). Calcd for C22H26BrNS02 x 0.3H20: 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 ~Ic~)al ~lion of (1)-7-Bromo-3-n-butyl-3-ethyl-2~3~4~5-tetrahvdro-8-methoxy-5-phenyl- 1 ~5-bellzolll.azej~ine l~l-dioxide.

To a solution of AIH3 (29 mmol, generated in si~u from H2S04, 15.5 mmol, and LiAlH4, 29 mmol) in 29 ml diethyl ether was added the compound of Example 19(b) (4.38 g, 9.77 mrnol) in 15 ml THF at 0 ~C. The reaction mixture was allowed to warm to RT over 2 h and was stirred at RT for 15 h after which time TLC (20% ethyl acetate/petroleum ether) showed complete reaction. The reaction flask was cooled to 0 ~C and the excess AIH3 was quenrhed by adding 25 ml of H2O/THF (1 :2) dropwise followed by 5 ml lM NaOH. The mixture was transferred to a separatory fuMel and extracted 3 times with ether. The ether extracts were combined, dried, conc~.l,aLed and column chromatographed (5 % ethyl acetateipetroleum ether). The fractions CO~ product were rotary evaporated and the resulting oil was dissolved in 50 ml tetrahydrofuran and t-butanol. To this solution was added osmium tetroxide (2.5% in 2-methyl-2-propanol, 5. I ml) and N-methylmorpholine-N-oxide (2.7 g, 22.9 mmol), and the mixture was stirred at RT for 18 h at which point 50 rnl NaHCO3 solution was added to neutralize any acid, the mixture "~hsr~led to aseparatory funnel and extracted 3 times with ethyl acetate. The organic layers were washed with brine, dried (Na2SO4) and concentrated. Column c~u~.alography (10% ethyl acetate/petroleum ether) yielded the product (3.41 g, 7.30 mmol, 75% yield). M.P. =
107.5-110.0 ~C. lH NMR (DMSO-d6) ~ 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+). Calcd for C22H2gBrNSO3: 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 P~ lalion of ( ~ )-7-Bromo-3-n-butyl-3-ethvl-2 3.4~5-tetrahydro-5-phenvl-1.5-benzothiazepin-8-ol El-dioxide.

The compound of Example 20 (3.19 g, 6.84 mmol) was demethylated using the procedure for Example 18 giving the product (2.48 g, 77% yield). M.P. = 182.5-183.6 ~C. lHNMR (DMSO-d6) o 10.87 (br s, lH), 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 (~$I+). Calcd for C21H26BrNSO3: 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 ~lepal~Lion of(+~-3-n-butyl-3-ethyl-2~3~4~5-tetrahydro-7-methoxy-5-phenyl-1~5-benzothiazepin-8-ol l~l-dioxide.

To the compound of Example 21 (0.50 g, 1.10 mmol) in ethyl acetate (2.0 ml) and sodium mPthoxide (10 ml, 25 wt%) was added copper(I) bromide (57 mg) and the mixture was refluxed for 2 h. The reaction mixture was neutralized with lN HCI and extracted with W O96/16051 PCT/~b55~ 7~~

ether 3 x lS ml. The ether extracts were dried and conc~ Led and the residue wasapplied to a silica gel colurnn. The product was eluted with 20% ethyl acetate/petroleum ether (0.44 g, 99% yield). lH N~ (DMSO-d6) o 9.69 (s, lH), 7.26-6.52 (m, 7H); 3.60 (s, SH); 1.53-1.02 (m, 8H); 0.71 (m, 6H). MS Da/e = 404 (~I+). Calcd for C22H2gNSO4: 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(l)-3-n-butyl-3-ethyl-2.3.4~5-tetrahvdro-7.8-dimethoxy-S-phenyl-1.5-benzothiazepine l.l-dioxide.

The compound of Example 20 (2.62 g, 5.62 mmol) was treated sodium methoxide using the procedure for Example 22 to give the product (1.95 g, 83~/o yield). IH NMR (DMSO-d6) ~ 7.30 (s, lH); 7.21-6.79 (m, 5H); 6.52 (s, lH), 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 (MH+). Calcd for C23H31NSO4: 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 Prepal ~Lion of ( I )-3-n-butyl-3-ethyl-2~3 4.5-tetrahvdro-S-phenvl- l .S-benzothiazepine-7~8-diol l.l-dioxide.

To sodium hydride (60%, 0.19 g, 4.79 mmol) in dimethylforrnamide (20 ml) was added eLl-~nell,;ol (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 h, then 25 ml saturated ~ lonium acetate (aq) was added, the pH ~djl.sted to 7, and extracted with ethyl acetate 3 x 10 ml. The organic layer was dried, concentrated and applied to a silica gel column. The product was eluted with 50% ethyl acetate/petroleum ether (0.40 g, 86% yield). IH NMR (DMSO-d6) o 9.79 (br, 2H); 7.23 (s, lH); 7.19-6.76 (m, SH); 6.37 (s, lH); 3.58 (br s, 2H); 3.11 (s, 2H); 1.50-0.98 (rn, 8H); 0.72 (m, 6H). MS Da/e = 390 (ME~). Calcd for C21H27NS04 XO.S H20: 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.

Exarn~le 25 ~ ~,p~. ~Lion of ( I ~-7-Bromo-3 -n-butyl-3-ethvl-2.3 -dihydro-S-phenvl- 1.5-be.~olhia~e~in-4-one.

W O96/160Sl PCT/~b55,~27 (a) (I)-7-Bromo-3-n-butyl-3-ethyl-2.3-dihydro-1 5-benzothiazepin-4(5H)-one.

To a solution ofthe compound of Example l(e) (8.28 g, 31.1 rnmol) in acetic acid (30 ml) at RT was added dropwise bromine (1.75 ml, 34.2 mrnol) and stirred for 18h. The reaction mixture was washed once with water, extracted 2 x 20 ml ether, and the organic layer was dried, concentrated, and the residue loaded onto a silica gel column. The product was eluted with 50% ethyl acetate/petroleum ether (9.23 g, 87% yield). M.P = 104.4 ~C. IH
NMR (DMSO-d6) ~ 9.81 (s, lH); 7.58 (s, lH); 7.42 (d, lH); 7.04 (d, lH); 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 (MH+). Calcd for C1sH20BrNSO: C, 52.63; 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-dihvdro-5-phenyl-1~5-benzothiazepin-4-one.
The compound of Example 25(a) (8.8 g, 23.61 mrnol) was reacted with phenyl iodide according to the procedure used for Exarnple l(f) giving product (8.96 g, 91% yield) that is a 3:1 ratio of 7-bromide to 7-iodide that can be coverted entirely to the 7-bromide by e~ with LiBr (10 eq) and copper (I) bromide (10 mol%) in reflllxing DMF (18h).
lH NMR (DMSO-d6) ~ 7.84 (d, 1H); 7. j2 (dd, 1H); 7.37-7.03 (m, 5H); 6.84 (d, 1H); 3.15 (S, 2H); 1.57-1.13 (m, 8H); 0.77 (m, 6H). MS Da/e = 418, 420 (~I+). Calcd for C21H24BrNSO: 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 Pr~palalion of ( I )-3-n-butyl-3-ethyl-2.3 4.5-tetrahYdro-7-methoxy-5-phenyl-1.5-benzotL~epi,le l.l-dioxide.

The compound of Example 25(b) (7.71 g, 18.4 mmol) was reacted with AIH3 using the procedure outlined for Example 3 providing an oil that was directly treated with OsO4 according to the procedure for Exarnple 4. The resulting sulfone was treated with sodium lluxide using the procedure for Example 22 giving the product (67% yield overall for the three steps). IH N~ (DMSO-d6) ~ 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 (MH-+). Calcd for C22H2gNSO3: 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.

Exarnple 27 Pl e,l)a~ a~ion of (+)-3-n-butyl-3-ethyl-2~3 4.5-tetrahydro-5-phenyl- 1 ~5-benzothiazepin-7-ol 1. I-dioxide.

The compound of Example 26 (1.05 g, 2.71 mmol) was treated with ~ minllm brornide and eth~n~thiol according to the procedure for Example 18 giving the title product (0.90 g, 89%). 1H NMR (DMSO-d6) ~ 9.99 (s, IH); 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). ,~IS Da/e = 374 (MH+). Calcd for C21H27NS03 x 0.2S H20: 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.

Biolo~ical Assay In vivo inhibition of bile acid reabsorption Male Spra~ue-Dawley rats (CD, Charles River) weighing 220-260 gm were housed in individual cages and fed norrnal chow. The rats were dosed by oral gavage (Iml/100 gm body weight) with test compounds as a suspension in 0.5% methylcellulose at 9:00 a.m.
and 3:30 p.m. for two days. The control group received 0.5% methylcellose. Two hours after the morning dose on day two, the rats were given a trace amount (1.3 nmoles) of 23,25 - 75Se- homocholic acid taurine (75SeHCAT) in 1.0 ml saline orally. 75SeHCAT, a synthetic gamma e...;~l;"D bile acid analog which is absorbed by the ileal bile acid active uptake system similar to taurocholic acid, has been used clinically as a measure of ileal bile acid absorption. Feces were collected over the 24 hours following 75SeHCAT
ad.,.;l-,s~ ion. Fecal content of 75SeHCAT was determined using a Packard Auto-Gamma 5000 Series gamma-counter. The % inhibition of bile acid reabsorption is c~lc~ ted as follows:

total 75SeHCAT - excreted 75SeHCAT oftreated 1 minus X
100 = % inhibition total 75SeHCAT - excreted 75SeHCAT of control The percent of inhibition of bile acid reabsorption in the rat using 75SeHCAT, for the compounds of Examples 2, 4, 7 and 9 at a concen~.alion of 10 mg/Kg was 7, 36, 20 and 29% ~,spcc~ ely. In the same test, the compounds of Examples 18, 22, 23, and 27 at a concentration of 1 mg/kg gave between 50 and 65% inhibition of bile acid readsorption.

Claims (12)

What is claimed is:

1) The compounds of the formula (I) (I) wherein R1 and R2 are the same or different and each is optionally substituted C1-6 alkyl, C3-6 cycloalkyl, or R1 and R2 together with the carbon atom to which they are attached form an optionally substituted C3-6 spiro-cycloalkyl group;

R4 is a C6-14 aryl, or a C3-13 heteroaryl group each optionally substituted with one to eight substituents which are the same or different and are each selected fromhalogen, hydroxy, nitro, phenyl-C1-6 alkoxy, C1-6 alkoxy, optionally substituted C1-6 alkyl, S(O)nR8, SO2NR8R9, CO2R8, O(CH2CH2O)nR8, OSO2R8, O(CH2)pSO3R8, O(CH2)pNR9R10 and O(CH2)pN+R9R10R11 wherein 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 from 1-4 and n is an integer from 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-acetylide, OR8, optionally substituted C1-6 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 wherein R8 to R11, n, and p are as hereinbefore defined; or R5a and R5b, R5b 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 as hereinbefore defined 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 an optionally substituted C3-6 spiro-cycloalkyl group;
X is CH2, C=O, C=S, or C=NR8 wherein R8 is as hereinbefore defined; and

1 is an integer from 0-2;
and salts, solvates or a physiologically functional derivatives thereof.

2) A compound of formula (I) according to claim 1 wherein R1 is methyl or ethyl;

R~ is methyl, ethyl or n-butyl;

R4 is phenyl;

R5a and R5d are hydrogen;

R5b and R5c are the same or different and are each hydrogen, methyl, methoxy, hydroxy, trifluoromethyl or halo;

R6 and R7 are the same or different and are each hydrogen, methyl, ethyl or i-butyl;

X is CH2 or C=O;

1 is 2;
or a salt, solvate, or physiologically functional derivative thereof.

3) A compound of formula (I) according to claim 1 or 2 selected from the group consisting of (~)-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-1,5-benzothiazepin-4-one-1,1-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-1,1-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-phenyl-1,5-benzothiazepin-4-one;
3,3-Diethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one 1,1-dioxide;
3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine;
3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-1,1-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-1,1-dioxide;
3,3-Dimethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine;
3,3-Dimethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-1,1-dioxide;
(~)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide;
3,3-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-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;
(i)-3-n-Butyl-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-benzothiazepin;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-1,5-benzothiazepin-8-ol-1-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.

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 physiologically functional derivative thereof.

5) A method of treating a clinical condition in a mammal for which a bile acid uptake inhibitor is indicated which comprises, administering to a mammal an effective bile acid uptake inhibition amount of a compound of formula (I) according to any of claims 1 to 4 or of a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

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

7) The method of claim 6 wherein the hyperlipidemic condition is atherosclerosis.

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

9) A compound of formula (I) according to any 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 hyperlipidaemic condition.

10) A compound of formula (I) according to any 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 condition.

11) A pharmaceutical composition comprising a compound of formula (I) according to any 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 other physiologically active agents.

12) A process for the manufacture of a compound of formula (I) according to any of claims 1 to 4, or a salt, solvate, or physiologically functional derivative thereof, which comprises either:

(a) reaction of a compound of formula (III) (III) wherein R1 ,R~ and R5a,b,c,d are as hereinbefore defined, with the appropriate R4-Z
wherein R4 is as hereinbefore defined and Z is a suitable leaving group; or (b) cyclizing compounds of formula (X) (X) wherein R1, R~, R4, and R5a,b,c,d are as hereinbefore defined, and then:
(i) when l is to be 1 or 2, oxidation of the thio moiety; and/or (ii) when X is to be C=S, conversion of the C=O moiety; and/or (iii) when X is to be CH2, reduction of the C=O moiety; and/or (iii) when R6 and/or R7 are to be other than hydrogen, reaction with the appropriate compound of formula R6-Z and/or R7-Z wherein R6,R7, and Z are as hereinbefore defined, and/or (iv) optional conversion of the resulting compound of formula(I) to a salt, solvate, or physiologically functional derivative thereof, and/or (v) optional resolution of any optical isomers of the compound of formula (I).