NZ337830A

NZ337830A - Combination therapy employing ileal bile acid transport inhibiting benzothiepines and HMG Co-A reductase inhibitors

Info

Publication number: NZ337830A
Application number: NZ337830A
Authority: NZ
Inventors: Robert E Manning; Kevin C Glenn; Bradley T Keller
Original assignee: G
Priority date: 1997-03-11
Filing date: 1998-03-10
Publication date: 2001-07-27
Also published as: AU730024C; AU730024B2; CN1255864A; AU6440898A; SK125099A3; BR9808013A; NO994390L; HUP0002395A3; JP2002500628A; EP0971744A2; NO994390D0; PL336415A1; WO1998040375A2; BG103793A; HUP0002395A2; IL131872A0; MXPA99008417A; WO1998040375A3; CA2283575A1; RU2247579C2

Abstract

Benzothiepines, derivatives, and analogs thereof; useful in the prophylaxis and treatment of hyperlipidemic conditions such as those associated with atherosclerosis or hypercholesterolemia, in mammals. Also, compositions and methods for combination therapy employing ileal bile acid transport inhibitors and HMG Co-A reductase inhibitors for the treatment of hyperlipidemic conditions.

Description

<div class="application article clearfix" id="description"> Patents Form No. 5 DIVISIONAL APPLICATION OUT OF NZ 337830 Our Ref: JB214840 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION COMBINATION THERAPY EMPLOYING ILEAL BILE ACID TRANSPORT INHIBITING BENZOTHIEPINES AND HMG Co-A ENZYME REDUCTASE INHIBITORS We, G. D. SEARLE & CO., a body corporate under the laws of Delaware, USA of 5200 Old Orchard Road, Skokie, Illinois 60077, United States Of America hereby declare the invention, for which We pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement: (Followed by page 1a) pt0578032 intellectual property OFFICE OF N.Z. - 1 Jl'N 2001 Received % WO 98/4037£ PC7/US98/03792 * 7 ® J ft fj \J) ' -/ COMBINATION THERAPY EMPLOYING ILEAL BILE ACID TRANSPORT INHIBITING BENZOTHIEPINES AND HMG Co-A REDUCTASE INHIBITORS BACKGROUND OF THE INVENTION Fzeld of the Invention The present invention relates to novel benzothiepmes, derivatives and analogs thereof, m combination with HMG Co-A reductase inhibitors, pharmaceutical compositions containing them, and for use in the manufacture of medicaments particularly for the prophylaxis and treatment of hyperlipidemic conditions such as is associated with atherosclerosis or hypercholesterolemia, m mammals. Description of Related Art It is well-settled that hyperlipidemic conditions associated with elevated concentrations of total cholesterol and low-density lipoprotein cholesterol are major risk factors for coronary heart disease and particularly atherosclerosis. Interfering with the circulation of bile acids within the lumen of the intestinal tract is found to reduce the levels of serum cholesterol in a causal relationship. Epidemiological data has accumulated which indicates such reduction leads to an improvement in the disease state of I INTELLECTUAL PROPERTY OFFICE OF NZ. - 1 JUM 2001 R E 0 2 o V E D WO 98/40375 PCT/US98/03792 atherosclerosis. Stedronsky, in "Interaction of bile acids and cholesterol with nonsystemic agents having hypocholesterolemic properties," Biochimica et Biophvsica Acta. 1210 (1994) 255-287 discusses the 5 biochemistry, physiology and known active agents surrounding bile acids and cholesterol. Pathophysiologic alterations are shown to be consistent with interruption of the enterohepatic circulation of bile acids in humans by Heubi, J.E., et 10 al. See "Primary Bile Acid Malabsorption: Defective in -Vitro Ileal Active Bile Acid Transport", Gastroenterology. 1982:83:804-11. In fact, cholestyramine binds the bile acids in the intestinal tract, thereby interfering with their 15 normal enterohepatic circulation (Reihner, E. et al, m "Regulation of hepatic cholesterol metabolism in humans: stimulatory effects of cholestyramine on HMG-CoA reductase activity and low density lipoprotein receptor expression in gallstone patients", Journal of 20 Lipid Research. Volume 31, 1990, 2219-2226 and Suckling el al, "Cholesterol Lowering and bile acid excretion in the hamster with cholestyramine treatment", Atherosclerosis. 89(1991) 183-190). This results in an increase in liver bile acid synthesis by the liver 25 using cholesterol as well as an upregulation of the liver LDL receptors which enhances clearance of cholesterol and decreases serum LDL cholesterol levels. In another approach to the reduction of recirculation of bile acids, the ileal bile acid 30 transport system is a putative pharmaceutical target for the treatment of hypercholesterolemia based on an interruption of the enterohepatic circulation with specific transport inhibitors (Kramer, et al, "Intestinal Bile Acid Absorption" The Journal of 35 Biological Chemistry. Vol. 268, No. 24, Issue of August 25, pp. 18035-18046, 1993). & Printed from Mimosa 09/15/1999 15:09:01 page -4 WO 98/40375 PCT/US98/03792 In a series of patent applications, eg Canadian Patent Application Nos. 2,025,294; 2,078,588; 2,085,782; and 2,085,830; and EP Application Nos. 0 379 161; 0 549 967; 0 559 064; and 0 563 731, Hoechst 5 Aktiengesellschaft discloses polymers of various naturally occurring constituents of the enterohepatic circulation system and their derivatives, including bile acid, which inhibit the physiological bile acid transport with the goal of reducing the LDL cholesterol 10 level sufficiently to be effective as pharmaceuticals and', in particular for use as hypocholesterolemic agents. In vitro bile acid transportinhibition is disclosed to show hypolipidemic activity in The 15 Wellcome Foundation Limited disclosure of the world patent application number WO 93/16055 for "Hypolipidemic Benzodiazepine Compounds" Selected benzothiepines are disclosed in world patent application number W093/321146 for numerous uses 20 including fatty acid metabolism and coronary vascular diseases. Other selected benzothiepines are known for use as hypolipaemic and hypocholesterolaemic agents, especially for the treatment or prevention of 25 atherosclerosis as disclosed by application Nos. EP 508425, FR 2661676, and WO 92/18462, each of which is limited by an amide bonded to the carbon adjacent the phenyl ring of the fused bicyclo benzothiepine ring. The above references show continuing efforts to 30 find safe, effective agents for the prophylaxis and treatment of hyperlipidemic diseases and their usefulness as hypocholesterolemic agents. Additionally selected benzothiepines are disclosed for use in various disease states not within the 35 present invention utility. These are EP 568 898A as abstracted by Derwent Abstract No. 93-351589; WO 89/1477/A as abstracted in Derwent Abstract No. 89- Pnnted from Mimosa 09/15/1999 15:09:01 page 5 WO 98/40375 PCT/US98/03792 5 10 15 20 370688; U.S. 3,520,831 abstracted in Derwent 5Q701R-B; US 3,287,370, US 3,389,144; US 3,694,446 abstracted in Derwent Abstr. No. 6S8S0T-B and WO 92/18462. KMG Co-A reductase inhibitors have been used as cholesterol-lowering agents. This class of compounds inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG Co-A) reductase. This enzyme catalyzes the conversion of HMG Co-A to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol. Benzothiazepine anti-hyperlipidemic agents are disclosed in WO 94/18183, WO 94/18184, WO 96/05188, WO 96/16051, AU-A-30209/92, AU-A-61946/94, AU-A-61948/94, and AU-A- 61949/94. The present invention furthers such efforcs by providing novel pharmaceutical compositions ana medicament for the treatment of hyperlipidemic conditions. SUMMARY OF THS INVENTION Accordingly, among its various apects, the present invention provides compounds of formula (I): group consisting of H, alkyl, alkenyl, alkynyl, haloalky1, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, (I) wherein: q is an integer from 1 to 4; n is an integer from 0 to 2; ■ 1 2 R and R are independently selected from the INlELLECTUAL PROPERTY OFFICE OF N.Z. - 1 JUN 2001 WO 98/40375 PCT/US98,0,792 dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, 5 dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more 9 substituents selected from the group consisting of OR , NR9R10, N*R'R10RWA\ SR9, s+r9r1°a-/ P*R'Rl0RuA', S(0)R9, S02R9, 9 9 9 10 SO3R , CO2R , CN, halogen, oxo, and COIZR R , 10 wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aty 1, and cycloalkyl . 9 optionally have one or more carbons replaced by 0, NR , a Q i{) +.Q + Q 1 0 N R R A-, S, SO, SO2, S R'A-, P RRA-, or phenylene, 9 10 wherein R , R , and Rw are independently selected 15 from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, heteroaryl, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; or 1 2 R and R taken together with the carbon to which they are attached form C3-Cl0 cycloalkylidene; 3 4 20 R and R are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heteroc*ycfe,/pc}R9, NR9R10, SR9, S(0)R9, 9 9 SO2R , and SO3R , wherein R and R10 are as defined above; or 25 R3 and R4 together form =0, =N0R1:L, =S, =NNR11R12, 9 11 12 =NR , or =CR R , 11 12 wherein R and R are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, 30 heterocycle ^carBoicya 1 ky 1, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR9, NR9R10, SR9, S(0)R9, 9 9 9 o 1 n SO2R , SO3R , CO2R . CN, halogen, oxo, and CONR^R , Printed from Mimosa 09/15/1999 15:09:01 page 7 WO 98/40375 PCT/US98/03792 9 10 wherein R and R are as defined above, provided that 3 4 both R and R cannot be OH, nh an<^ SH, or 11 12 R and R together with the nitrogen or carbon atom to which they are attached form a cyclic ring; e c 5 R and R are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle,^quaternary heterocycle, quaternary heteroaryl, SR^,S(0)R^, < and SO^R » wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroarylj 10 heterocycle,f\quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,heteroaryl 15 arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR13, NR13R14, SR13, S(0)R13, S02R13, S03R13, NR13OR14, NR13NR14R15, N02, C02R13, CN, OM, S020M, S02NR13R14, C(0)NR13R14, C(0)0M, COR13, P(0)R13R14, P+R13R14R15A_f P(OR13)OR1', S*RuRuA", and 20 N+R9R1:LR12A", wherein: A~ is a pharmaceutical^ acceptable anion and M is a pharmaceutical^ acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, 25 polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can be further substituted with one or more substituent 7 groups selected from the group consisting of OR , NR7R8, SR7, S(0)R7, S02R7, S03R7,.C02R7, CN, oxo, CONR7R8, N+R7R8R9A-, alkyl, alkenyl, alkynyl, aryl, 30 cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary Printed from Mimosa 09/15/1999 15:09:01 page -8- WO 98/40375 PCT/US98/03792 7 8 heterocycle, quaternary heteroaryl, P(0)R R , P+R7R8R9A", and P(0)(OR7)OR8, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl,heterocycle and heteroaryl 5 can optionally have one or more carbons replaced by o, NR7, N+R7R8A-, S, SO, S02, S+R7A-, PR7, P(0)R?. P+R7R8A-, or phenylene, and R13, R14, and R^ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, 10 arylalkyl, cycloalkyl, heterocycle, heteroaryl quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heteroaryl, heterocycle,^ and polyalkyl optionally have one or more 15 carbons replaced by o, NR*, N+r9r^a~, S, SO, S02, S+R9A", PR9, P+R9R10A-, P(0)R\ phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R13, R14, and R1^ are optionally substituted with one or more groups selected from the group consisting 20 of sulfoa^BcyT^quaternar^Aeterocycle, quaternary heteroaryl, OR9, NR9R10, N+R9R1;LR12A~, SR9, S(0)R9, Q O Q Q If) S02R , SO3R , oxo, C02R , CN, halogen, CONR^R , SO2OM, S02NR9R10, PO(OR16)OR17, P+R9R10R1:LA-, S+R9R10A~, and C(0)0M, 16 1 *7 wherein R and R are independently selected Q 25 from the substituents constituting R and M; or R14 and R15, together with the nitrogen atom to which they are attached, form a cyclic ring; 7 8 R and R are independently selected from the group consisting of hydrogen and alkyl; and 30 one or more Rx are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, Printed from Mimosa 09/15/1999 15:09:01 page -9- WO 98/40375 PCT/US98/03792 haloalkyl, cycloalkyl, heterocycle, heteroaryl^ polyether, quaternary heterocycle, quaternary heteroaryl, OR13, NR13R14, SR13, S(0)R13, S(0)2R13, SO3R13, S+R13R14A-, NR13OR14, NR13NR14R15, N02, C02R13, 5 CN, OM, S020M, S02NR13R14, NR"C(0)Ru, C(0)NR13R14, NR14c(0)R13, C(0)0M, COR13, OR18, S(0)nNR18, NR13R18, NR180R14, N+R9R11R12A~, P+R9R1;LR12A~, amino acid, peptide, polypeptide, and carbohydrate, • wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, 10 polyalkyl, heterocycfee,^alyioxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary 9 9 10 heteroaryl can be further substituted with OR , NR R , N+R9R1:LR12A", SR9, S (O) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, SO2OM, S02NR9R10, PO (OR18) OR17, 15 P+r9r11r12A~, S*R'r"A", or C(0)0M, and 18 wherein R is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl wherein acyl, arylalkoxycarbonyl, arylalkyl, 2 0 heterocycle, heteroaryl, alky1> quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N+R9R11R12A", SR9, S(0)R9, 9 9 9 9 10 9 S02R , SO3R , oxo, CO2R , CN, halogen, CONR R , SO3R , 9 10 16 17 25 SO2OM, S02NR R , PO(OR )OR , and C(0)0M, wherein in Rx, one or more carbons are optionally replaced by O, NR13, N+R13R14A-, S, SO, SO2, S+R13A~, PR13, p(0)R13 P+R13R14A~, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or 30 polyalkyl. Printed from Mimosa 09/15/1999 15:09:01 page 10 WO 98/40375 PCT/US98/03792 wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more 9 +9 10 carbons are optionally replaced by 0, NR , N R R A-, + q q i Q if) • S, SO, S02, S R A-, PR, PR^R A-, or P(0)R; 5 wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocyclfe^^^rylalkyl, halogen, 10 oxo, OR13, NR13R14, SR13, S(O)R13, S02R13, S03R13, NR13OR14, NR13NR14R15, N02, C02R13, CN, OM, S020M, S02NR13R14, C(0)NR13R14, C(0)0M, COR13, P(0)R13R14, P+R13R14r15a_ , P(0R")0R14, S'Rl3Rl4A~, and N+R9R1:LR12A~, provided that both R^ and R^ cannot be hydrogen, 15 OH, or SH,and when R5 is OH, R1, R2, R3, R4, R7 and R8 cannot be all hydrogen; provided that when R5 or R* is phenyl, only one of Rl or RJ is H; provided that when q = 1 and R" is styryl, 20 anilido, or anilinocarbonyl, only one of R5 or R5 is alkyl; or a pharmaceutical^ acceptable salt, solvate, or prodrug thereof. 5 6 Preferably, R and R can independently be 25 selected from the group consisting of H, aryl, heterocycfe^q^aternary heterocycle, and quaternary heteroaryl, wherein said aryi, heterocycle, heteroaryl, quaternary heterocycle, and quaternary heteroaryl can be 30 substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heteroS^Se^arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S(O)R13, S02R13, S03R13, Printed from Mimosa 09/15/1999 15:09:01 page -11- WO 98/40375 PCT/US98/03792 nr13or14, nr13nr14r15, n02, c02r13, cn, oh, s020m, s02nr13r14, c(0)nr13r14, c(ojom, cor13, p(0)r13r14, P+r13r14r15a-, P(or")or14, S+r"r"a-, and n+r9r1:lr12a", wherein said alkyl, alkenyl, alkynyl, polyalkyl, 5 polyether, aryl, haloalkyl, cycloalkyl, heterocycle and betercaryl can optionally have one or more carbons replaced by O, nr7, n+r7r8a-, s, so, s02, s+r7a-, pr7, p(0)r7 i 7 q P R R A-, or phenylene, wherein said alkyl, alkenyl, alkynyl, polyalkyl, 10 polyether, aryl, haloalkyl, cycloalkyl, heterocycle and tetercsryl can be further substituted with one or more substituent 7 groups selected from the group consisting of OR , NR7R8, SR7, S(O)R7, S02R7, SO3R7, C02R7, CN, oxo, CONR7R8, N+R7R8R9A-, alkyl, alkenyl, alkynyl, aryl, heteroaryl, 15 cycloalkyl, heterocycle,^arylalkyl, quaternary 7 8 + 7 8 9 heterocycle, quaternary heteroaryl, P{0)R R , prrra-, and P(O) (OR1)OR'. More preferably, R5 or R* has the formula: -Ar- (Ry) 20 wherein: t is an integer from 0 to 5; 25 Ar is selected from the group consisting of phenyl, thiophenyl, pyridyl, piperazinyl, piperonyl, pyrrolyl, naphthyl, furanyl, anthracenyl, quinolinyl, . isoquinolinyl, quinoxalinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrimidinyl, thiazolyl, 30 triazolyl, isothiazolyl, indolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, and benzoisothiazolyl; and one or more R^ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, 10 Printed from Mimosa 09/15/1999 15:09:01 page -12- WO 98/40375 PCT/US98/03792 cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, 9 9 9 9 9 quaternary heteroaryl OR , SR , S(0)R , SO^R , and SO^R , wherein alkyl, alkenyl, alkynyl, aryl, cycloalkvl, heterocycle, and heteroaryl can be substituted with one or more 5 substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, hebEararyl, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S(0)R13, S02R13, S03R13, NR130R14, NR13NR14R15, NO2, C02R13, CN, 10 OM, SO2OM, S02NR13R14, C(0)NR13R14, C(0)0M, COR13, P(0)R13R14, P+R13R14R15A", P(OR")ORl\ S*RlJRuA", and N+R9R1;1R12A~, wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heberocycls, ard heteroaryl 15 can be further substituted with one or more substituent n groups selected from the group consisting of OR , NR7R8, SR7, S{O)R7, S02R7, SO3R7, C02R7, CN, oxo, CONR7R8, N+R7R8R9A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, betecoaEyl, arylalkyl, qstemary 20 heterocycle, quaternary heteroaryl, P(0)R7R8, p+r7r8f?a-, and P (0) (0R7)0R*, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, and heteroaryl can optionally have one or more carbons replaced by 0, 25 NR7, N+R7R8A-, S, SO, S02, S+R7A-, PR7, P{0)R?, + 78 P R R A-, or phenylene. Most preferably, R5 or R6 has the formula (II): n Printed from Mimosa 09/15/1999 15:09:01 page -13- WO 98/40375 PCT/US98/03792 (II) The invention is further directed to a compound selected from among: R" - R" - R" (Formula DI) 10 R" - R" - Rn (Formula DII), 15 and 20 R - R" (Formula Dili) 25 30 wherein r" is selected from the group consisting of alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can optionally have one or more carbon atoms replaced by o, nr7, n+R7R8, s, so, so2> s R R , imprinted from Mimosa 09/15/1999 15:09:01 page -14- WO 98/40375 PCT/US98/03792 pr7, p + pV. phenylene, heterocycle, heteroaryl, quaterndry heterocycle, quaternary heteroaryl, or aryl, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl/ halogen, oxo, or13, nr13r14, sr13, s(0)r13, s02r13, s03r13, nr13or14, nr13nr14r15, n02, c02r13, cn, om, s02om, s02nr13r14, c(0)nr13r14, c(0)0m, cor13, P(0)r13r14, P+R13R14r15A-, P(0ru)0r14, S*r"ruA\ and n+r9r11r12a~; wherein r1' further comprises functional linkages by which R1' is bonded to R1', R11, or Ra in the coxnpounds of Formulae DXX and Dili, and Ru in the compounds of Formula Dill. Each of R", R>1, or R" and R" comprises a benzothiepine moiety as described above that is therapeutically effective in inhibiting ileal bile acid transport. The invention is also directed to a compound selected from among Formula DI, Formula DII and Formula DXII in which each of R1", Rm, Rn and Rs> comprises a benzothiepine moiety corresponding to the Formula: B Printed from Mimosa 09/15/1999 15:09:01 page -15- WO 98/40375 PCT/US98/03792 wherein R1, RJ, R3, R4, R5, R6, R1, R1, R", q, and n are as defined in Formula I as described above, and R" is 5 either a covalent bond or arylene. In compounds of Formula DIV, it is particularly preferred that each of rj0, r", and r" in Formulae DII and Dili, and R" in Formula Dili, be bonded at its 7-or 8-position to r1'. In compounds of Formula DIVA, it 10 is particularly preferred that R55 comprise a phenylene moiety bonded at a m- or p-carbon thereof to r1'. Examples of Formula DI include: K< ^ 6 ,3A ,7A ,2A R1A -a \ / r8a Y_Z-r7 Vfo' (R*)t y- (RX)q r (RyA)u tin) -x (r**), 15 Printed from Mimosa 09/15/1999 15:09:01 page -16- WO 98/40375 PCT/US98/03792 and ,-IV/, iH*r /-/" k. y (R"), (v) In any of the dimeric or multimeric structures 10 discussed immediately above, benzothiepine compounds of the present invention can be used alone or in various combinations. In any of the compounds of the present invention, R1 and RJ can be ethyl/butyl or butyl/butyl. IS" Printed from Mimosa 09/15/1999 15:09:01 page -17- ^WO 98/4037: PCT/US98/03792 ^ 7 Other compounds useful m the prssenc invention as ileal bile acid transport: inhibitors are shown in Appendix A. In another aspect, the present invention provides 5 a pharmaceutical composition for the prophylaxis or treatment of a disease or condition for which a bile acid transport inhibitor is indicated, such as a hyperlipidemic condition, for example, atherosclerosis. Such compositions comprise any of the compounds 10 disclosed above, alone or in combination, in an amount effective to reduce bile acid levels in the blood, or to reduce transport thereof across digestive system membranes, and a pharmaceutically acceptable carrier, excipient, or diluent. 15 In a further aspect, the present invention also provides a medicament for treating a disease or condition m mammals, including humans, for which a bile acid transport inhibitor is indicated, comprising administering to a patient in need thereof a compound 20 of the present invention in an effective amount in unit dosage form or in divided doses. In yet a further aspect, the present invention also provides processes for the preparation of compounds of the present invention. 25 In yet another aspect, the present invention provides a combination therapy comprising the use of a first amount of an ileal bile acid transport inhibitor and a second amount of a KMG Co-A reductase inhibitor useful to treat hyperlipidemic disorders, wherein said 3 0 first and second amounts together comprise an anti- hyp erlipidemic condition effective amount of said compounds. HMG Co-A reductase inhibitor compounds useful in the present invention are shown in Appendix 3.-35 Further scope of the applicability of the present invention will become apparent from the detailed description provided ioelow. However, it should__be | iisliEL' ECfUA'. PROPERTY j OFFICE OF NZ. - 1 JUN 2001 WO 98/40375 PCT/US98/03792 understood that the following detailed dscription and examples, while indicating preferred embodiments of the invention, are given by way of illustration only since various changes and modifications within the spirit and 5 scope of the invention will beomce apparent to those skilled in the art from this detailed description. DETAILED DESCRIPTION OF THE INVENTION The following detailed description is provided to 10 aid those skilled in the art in practicing the present invention. Even so, this detailed description should not be construed to unduly limit the present invention as modifications and variations in the emobodiments discussed herein can be made by those of ordinary skill 15 in the art without departing from the spirit or scope of the present inventive discovery. The contents of each of the references cited herein, including the contents of the references cited within these primary references, are herein 20 incorporated by reference in their entirety. Definitions In order to aid the reader in understanding the following detailed description, the following 25 definitions are provided: "Alkyl", "alkenyl," and "alkynyl" unless otherwise noted are each straight chain or branched chain hydrocarbons of from one to twenty carbons for alkyl or two to twenty carbons for alkenyl and alkynyl in the 30 present invention and therefore mean, for example, methyl, ethyl, propyl, butyl, pentyl or hexyl and ethenyl, propenyl, butenyl, pentenyl, or hexenyl and ethynyl, propynyl, butynyl, pentynyl, or hexyriyl respectively and isomers thereof. 35 "Aryl" means a fully unsaturated mono- or multi- ring carbocyle, including, but not limited to, Printed from Mimosa 09/15/1999 15:09:01 page -19- WO 98/40375 PCT/US98/03792 substituted or unsubstituted phenyl, naphthyl, or anthracenyl. "Heterocycle" means a saturated or unsaturated mono- or multi-ring carbocycle wherein one or more carbon atoms can be replaced by N, S, P, or 0. This includes, for example, the following structures: or 10 wherein Z, Z', Z" or Z"' is C, S, P, O, or N, with the proviso that one of Z, Z', Z" or Z"' is other than carbon, but is not O or S when attached to another Z atom by a double bond or when attached to another 0 or 15 S atom. Furthermore, the optional substituents are understood to be attached to Z, Z', Z" or Z"' only when each is C. The term "heteroaryl" means a fully unsaturated heterocycle. 20 In either "heterocycle" or "heteroaryl," the point of attachment to the molecule of interest can be at the heteroatom or elsewhere within the ring. The term "quaternary heterocycle" means a heterocycle in which one or more of the heteroatoms, 25 for example, O, N, S, or P, has such a number of bonds that it is positively charged. The point of attachment of the quaternary heterocycle to the molecule of interest can be at a heteroatom or elsewhere. The term "quaternary heteroaryl" means a • 30 heteroaryl in which one or more of the heteroatoms, for example, 0, N, S, or P, has such a number of bonds that it is positively charged. The point of attachment of the quaternary heteryaryl to the molecule of interest can be at a heteroatom or elsewhere. 1% Printed from Mimosa 09/15/1999 15:09:01 page -20 WO 98/40375 PCT/US98/03792 The term "halogen" means a fluoro, chloro, bromo or iodo group. The term "haloalkyl" means alkyl substituted with one or more halogens. 5 The term "cycloalkyl" means a mono- or multi- ringed carbocycle wherein each ring contains three to ten carbon atoms, and wherein any ring can contain one or more double or triple bonds. The term "diyl" means a diradical moiety wherein 10 said moiety has two points of attachment to molecules of -interest. The term "oxo" means a doubly bonded oxygen. The term "polyalkyl" means a branched or straight hydrocarbon chain having a molecular weight up to about 15 20,000, more preferably up to about 10,000, most preferably up to about 5,000. The term "polyether" means a polyalkyl wherein one or more carbons are replaced by oxygen, wherein the polyether has a molecular weight up to about 20,000, 20 more preferably up to about 10,000, most preferably up to about 5,000. The term "polyalkoxy" means a polymer of alkylene oxides, wherein the polyalkoxy has a molecular weight up to about 20,000, more preferably up to about 10,000, 25 most preferably up to about 5,000. The term "cycloaklylidene" means a mono- or multi-ringed carbocycle wherein a carbon within the ring structure is doubly bonded to an atom which is not within the ring structures. 30 The term "carbohydrate" means a mono-, di-, tri-, or polysaccharide wherein the polysaccharide can have a molecular weight of up to about 20,000, for example, hydroxypropyl-methylcellulose or chitosan. The term "peptide" means polyamino acid containing 35 up to about 100 amino acid units. The term "polypeptide" means polyamino acid containing from about 100 amino acid units to about 19 Printed from Mimosa 09/15/1999 15:09:01 page -21- WO 98/40375 PCT/US98/03792 1000 amino acid units, more preferably from about 100 amino acid units to about 750 amino acid untis, most preferably from about 100 amino acid units to about 500 amino acid units. 5 The term "alkylammoniumalkyl" means a NH2 group or a mono-, di- or tri-substituted amino group, any of which is bonded to an alkyl wherein said alkyl is bonded to the molecule of interest. The term "triazolyl" includes all positional 10 isomers. In all other heterocycles and heteroaryls which contain more than one ring heteroatom and for which isomers are possible, such isomers are included in the definition of said heterocycles and heteroaryls. The term "sulfoalkyl" means an alkyl group to 15 which a sulfonate group is bonded, wherein said alkyl is bonded to the molecule of interest. The term "active compound" means a compound of the present invention which inhibits transport of bile acids. 20 When used in combination, for example "alkylaryl" or "arylalkyl," the individual terms listed above have the meaning indicated above. The term "a bile acid transport inhibitor" means a compound capable of inhibiting absorption of bile acids 25 from the intestine into the circulatory system of a mammal, such as a human. This includes increasing the fecal excretion of bile acids, as well as reducing the blood plasma or serum concentrations of cholesterol and cholesterol ester, and more specifically, reducing LDL 30 and VLDL cholesterol. Conditions or diseases which benefit from the prophylaxis or treatment by bile acid transport inhibition include, for example, a hyperlipidemic condition such as atherosclerosis. The phrase "combination therapy" refers to the 35 administration of an ileal bile acid transport inhibitor and a HMG Co-A reductase inhibitor to treat a hyperlipidemic condition, for example atherosclerosis 10 Printed from Mimosa 09/15/1999 15:09:01 page -22- WO 98/40375 PCT/US98/03792 and hypercholesterolemia. Such administration encompasses co-administration of these inhibitors in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or 5 in multiple, separate capsules for each inhibitor agent. In addition, such administration also encompasses use of each type of inhibitor in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug 10 combination in treating the hyperlipidemic condition. ' The phrase "theraputically effective" is intended to qualify the combined amount of inhibitors in the combination therapy. This combined amount will achieve the goal of reducing or eliminating the hyperlipidemic 15 condition. Compounds The compounds of the present invention can have at least two asymmetrical carbon atoms, and therefore 20 include racemates and stereoisomers, such as diastereomers and enantiomers, in both pure form and in admixture. Such stereoisomers can be prepared using conventional techniques, either by reacting enantiomeric starting materials, or by separating 25 isomers of compounds of the present invention. Isomers may include geometric isomers, for example cis isomers or trans isomers across a double bond. All such isomers are contemplated among the compounds of the present invention. 30 The compounds of the present invention also include tautomers. The compounds of the present invention as discussed below include their salts, solvates and prodrugs. 35 Compound Syntheses XI Printed from Mimosa 09/15/1999 15:09:01 page 23 WO 98/40375 PCT/US98/03792 The starting materials for use in the preparation of the compounds of the invention are known or can be prepared by conventional methods known to a skilled person or in an analogous manner to processes described 5 in the art. Generally, the compounds of the present invention can be prepared by the procedures described below. For example, as shown in Scheme I, reaction of aldehyde II with formaldehyde and sodium hydroxide 10 yields the hydroxyaldehyde III which is converted to mesylate IV with methanesulfonyl chloride and triethylamine similar to the procedure described in Chem. Ber. 98, 728-734 (1965). Reaction of mesylate IV with thiophenol V, prepared by the procedure described 15 in WO 93/16055, in the presence of triethylamine yields keto-aldehyde VI which can be cyclized with the reagent, prepared from zinc and titanium trichloride in refluxing ethylene glycol dimethyl ether (DME), to give a mixture of 2,3-dihydrobenzothiepine VII and two 20 racemic steroisomers of benzothiepin-(5H) -4-one VIII when R1 and RJ are nonequivalent. Oxidation of VII with 3 equivalents of m-chloro-perbenzoic acid (MCPBA) gives isomeric sulfone-epoxides IX which upon hydrogenation with palladium on carbon as the catalyst yield a 25 mixture of four racemic stereoisomers of 4-hydroxy- 2,3,4,5-tetrahydrobenzothiepine-l,1-dioxides X and two racemic stereoisomers of 2,3,4,5-tetrahydro-benzothiepine-1,1-dioxides XI when R1 and R1 are nonequivalent. 30 Optically active compounds of the present invention can be prepared by using optically active starting material III or by resolution of compounds X with optical resolution agents well known in the art as described in J. Org. Chem., 39, 3904 (1974), ibid., 42, 2781 (1977), and 35 ibid., 44, 4891 (1979). OX Printed from Mimosa 09/15/1999 15:09:01 page 24 WO 98/40375 PCT/US98/03792 THEEjNT Rj VJ. Sdwim 1 HCOH, N«OH r, >_ HO \ .Rl MaCVBtjN ^Vt0 tfic 'h N 8H O &1" znma s. a1 ^ Ri v- . i R* _>T-S=0 88% T P.* (?) &%\ VI „i al o? ; MCPBA >- 00% Ra H2/Pd-C k. 4* 80 !*1 (ux), Alternatively, keto-aldehyde VI where RJ is H can be prepared by reaction of thiophenol V with a 2-substituted acrolein. Printed from Mimosa 09/15/1999 15:09:01 page -25- WO 98/40375 PCT/US98/03792 Benzothiepin-(5H)-4-one VIII can be oxidized with MCPBA to give the benzothiepin- (5ff) -4-one-l, 1-dioxide XII which can be reduced with sodium borohydride to give 5 four racemic stereoisomers of X. The two stereoisomers of X, Xa and Xb, having the OH group and RJ on the opposite sides of the benzothiepine ring can be converted to the other two isomers of X, Xc and Xd, having the OH group and R5 on the same side of the 10 benzothiepine ring by reaction in methylene chloride with 40-50% sodium hydroxide in the presence of a phase transfer catalyst (PTC). The transformation can also be carried out with potassium t-butoxide in THF. *4 Printed from Mimosa 09/15/1999 15:09:01 page -26- WO 98/40375 PCT/US98/03792 Kl R« NaOH, PTC/CH 2a2 sojy R jpus .'(I'M R2 wt»n R Bu, Ri- Et,Ri"Ph,X"H,q»4 (i>Xi 6b ■ Xb 6c»Xc 6d-Xd The compounds of the present invention where R5 is OR, NRR' or S (0) aR and R* is hydroxy can be prepared by 5 reaction of epoxide IX where R5 is H with thiol, alcohol, or amine in the presence of a base. ast Printed from Mimosa 09/15/1999 15:09:01 page -27- WO 98/40375 PCT/US98/03792 ( R") HOR, or HNRR1 or HS(0)nR base ( R»)j R5 = OR, NRR1, SCO) R 10 Another route to Xc and Xd of the present invention is shown in Scheme 2. Compound VI is oxidized to compound XIII with two equivalent of m-chloroperbenzoic acid. Hydrogenolysis of compound XIII with palladium on carbon yields compound XIV which can be cyclized with either potassium t-butoxide or sodium hydroxide under phase transfer conditions to a mixture of Xc and Xd. Separation of Xc and Xd can. be accomplished by either HPLC or fractional crystallization. Printed from Mimosa 09/15/1999 15:09:01 page -28- WO 98/40375 PCT/US98/03792 The thiophenols XVIII and V used in the present invention can also be prepared according to the Scheme 3. Alkylation of phenol XV with an arylmethyl chloride 5 in a nonpolar solvent according to the procedure in J. Chem. Soc., 2431-2432 (1958) gives the ortho substituted phenol XVI. The phenol XVI can be converted to the thiophenol XVIII via the thiocarbamate XVII by the procedure described in J. Org. Chem., 31, 10 3980 (1966). The phenol XVI is first reacted with dim.ethyl thiocarbamoyl chloride and triethylamine to give thiocarbamate XVII which is thermally rearranged at 200-3 00 °C, and the rearranged product is hydrolyzed with sodium hydroxide to yield the thiophenol XVIII. 15 Similarly, Thiophenol V can also be prepared from 2- acylphenol XIX via the intermediate thiocarbamate XX. XI Printed from Mimosa 09/15/1999 15:09:01 page -29- WO 98/40375 PCT/US98/03792 Scheme 4 shows another route to benzothiepine-1,1-dioxides Xc and Xd starting from the thiophenol XVIII. 5 Compound XVIII can be reacted with mesylate IV to give the sulfide-aldehyde XXI. Oxidation of XXI with two equivalents of MCPBA yields the sulfone-aldehyde XIV which can be cyclized with potassium t-butoxide to a mixture of Xc and Xd. Cyclyzation of sulfide-aldehyde 10 with potassium t-butoxide also gives a mixture of benzothiepine XXIIc and XXIId. Printed from Mimosa 09/15/1999 15:09:01 page -30- WO 98/40375 PCT/US98/03792 compounds of the present invention can be prepared as shown in Scheme 5 and Scheme 6. 2-Chloro-5-5 nitrobenzophenone is reduced with triethylsilane and trifluoromethane sulfonic acid to 2-chloro-5-nitrodiphenylmethane 32. Reaction of 32 with lithium sulfide followed by reacting the resulting sulfide with mesylate IV gives sulfide-aldehyde XXIII. Oxidation of 10 XXIII with 2 equivalents of MCPBA yields sulfone- aldehyde XXIV which can be reduced by hydrogenation to the hydroxylamine XXV. Protecting the hydroxylamine XXV with di-t-butyldicarbonate gives the N,0-di-(t- Printed from Mimosa 09/15/1999 15:09:01 page -31 WO 98/40375 PCT/US98/03792 butoxycarbonyl)hydroxylamino derivative XXVI. Cyclization of XXVI with potassium t-butoxide and removal of the t-butoxycarbonyl protecting group gives a mixture of hydroxylamino derivatives XXVIIc and XXVIId. The primary amine XXXUlc and XXXIIId derivatives can also be prepared by further hydrogenation of XXIV or XXVIIc and XXVIId. 30 Printed from Mimosa 09/15/1999 15:09:01 page -32- WO 98/40375 PCT/US98/03792 Scheme 5 1 LLjS »of <ro - <?b NO,32 NO. MsO "J n IV N02 2-ciIoto-S-, V . ralxuLti tajA'srcae **2 2MCPBA /"^ **2 <ro pro no2 Rg $03 N(B0C)0(BQC) XXVI N02 I Hj-Pd/C XXIV W-^2? F CBOQjO 1 patagnsn t-bimmVVia 2 tad Twsknp f o nhoh XXV Ph 0H HOHN Vs OH I Ph XXVOe Pd/C-Hj-100 pa. 50 *C Ph xxvna Pd/C-Hj-lOOpa. JO'C £Q-\* <V> o* .A> xxxmc Ph xxxma Ri *2 OH In Scheme 6, reduction of the sulfone-aldehyde XXV with hydrogen followed by reductive alkylation of the resulting amino derivative with hydrogen and an 5 aldehyde catalyzed by palladium on carbon in the same reaction vessel yields the substituted amine derivative 31 Printed from Mimosa 09/15/1999 15:09:01 page -33- WO 98/40375 PCT/US98/03792 XXVIII. Cyclization of XXVIII with potassium t-butoxide yields a mixture of substituted amino derivatives of this invention XXIXc and XXIXd. 5 Scheme 7 describes one of the methods of introducing a substituent to the aryl ring at the 5-position of benzothiepine. Iodination of 5-phenyl 10 derivative XXX with iodine catalyzed by mercuric triflate gives the iodo derivative XXXI, which upon palladium-catalyzed carbonylation in an alcohol yields the carboxylate XXXII. Hydrolysis of the carboxylate 33. Printed from Mimosa 09/15/1999 15:09:01 page -34- WO 98/40375 PCT/US98/03792 and derivatization of the resulting acid to acid derivatives are well known in the art. Abbreviations used in the foregoing description have the following meanings: 10 THF tetrahydrofuran 33 Printed from Mimosa 09/15/1999 15:09:01 page -35- WO 98/40375 PCT/US98/03792 10 aid PTC phase transfer catalyst Aliquart 33 6 methyltricaprylylammonium chloride MCPBA m-chloroperbenzoic acid Celite a brand of diatomaceous earth filtering DMF dimethylformamide DME ethylene glycol dimethyl ether BOC t-butoxycarbonyl group R1 and R5 can be selected from among substituted and unsubstituted to C10 alkyl wherein the substituent(s) can be selected from among alkylcarbonyl, alkoxy, hydroxy, and nitrogen-containing 15 heterocycles joined to the Cr to C10 alkyl through an ether linkage. Substituents at the 3-carbon can include ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, -CH,C (=0) C,H5, -CH2OC2H5, and -CH20-(4-picoline). Ethyl, n-propyl, n-butyl, and isobutyl are 20 preferred. In certain particularly preferred compounds of the present invention, substituents R1 and R3 are identical, for example n-butyl/n-butyl, so that the compound is achiral at the 3-carbon. Eliminating optical isomerism at the 3-carbon simplifies the 25 selection, synthesis, separation, and quality control of the compound used as an ileal bile acid transport inhibitor. In both compounds having a chiral 3-carbon and those having an achiral 3-carbon, substituents (Rx) on the benzo- ring can include hydrogen, aryl, alkyl, 30 hydroxy, halo, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkyl, haloalkoxy, (N)-hydroxy-carbonylalkyl amine, haloalkylthip, haloalkylsulfinyl, haloalkylsufonyl, amino, N-alkylamino, N,N-dialkylamino, (N)-alkoxycarbamoyl, (N)-35 aryloxycarbamoyl, (N)-aralkyloxycarbamoyl, trialkyl- ammonium (especially with a halide counterion), (N)-amido, (N)-alkylamido, -N-alkylamido, -N,N- 3H Printed from Mimosa 09/15/1999 15:09:01 page 36 WO 98/40375 PCT/US98/03792 dialkylamido, (N)-haloalkylamido, (N) -sulfonamide), (N)-alkylsulfonamido, (N)-haloalkylsulfonamido, carboxyalkylamino, trialkyl-ammonium salt, (N)-carbamic acid, alkyl or benzyl ester, N-acylamine, 5 hydroxylamine, haloacylamine, carbohydrate, thiophene a trialkyl ammonium salt having a carboxylic acid or hydroxy substituent on one or more of the alkyl substituents, an alkylene bridge having a quaternary ammonium salt substituted thereon, - [O (CH2) Jx-X where x 10 is 2 to 12, w is 2 or 3 and X is a halo or a quaternary ammonium salt, and (N)-nitrogen containing heterocycle wherein the nitrogen of said heterocycle is optionally quaternized. Among the preferred species which may constitute R* are methyl, ethyl, isopropyl, t-butyl, 15 hydroxy, methoxy, ethoxy, isopropoxy, methylthio, iodo, bromo, fluoro, methylsulfinyl, methylsulfonyl, ethylthio, amino, hydroxylamine, N-methylamino, N,N-dimethylamino, N,N-diethylamino, (N)-benzyloxycarbamoyl, trimethylammonium, A", 20 -NHC(=0)CH3, -NHC(=0)C5Hll( -NHC(=0)C6Hu, carboxyethylamino, (N)-morpholinyl, (N)-azetidinyl, (N)-N-methylazetidinium A", (N)-pyrrolidinyl, pyrrolyl, (N)-N-methylpyridinium A", (N)-N-methylmorpholimum A", and N-N'-methylpiperazinyl, (N)-bromomethylamido, (N)-25 N-hexylamino, thiophene, -N* (CH3) 2C02H I", -NCH3CH2C02H, - (N)-N1-dimethylpiperazinium I", (N)-t-butyloxycarbamoyl, (N)-methylsulfonamido, (N)N'-methylpyrrolidinium, and - (OCH2CH2) 3I, where A" is a pharmaceutical^ acceptable anion. The benzo ring 30 can be mono-substituted at the 6, 7 or 8 position, or disubstituted at the 7- and -8 positions. Also included are the 6,7,8-trialkoxy compounds, for example the 6,7,8-trimethoxy compounds. A variety of other substituents can be advantageously present on the 6, 7, 35 8, and/or 9- positions of the benzo ring, including, for example, guanidinyl, cycloalkyl, carbohydrate (e.g., a 5 or 6 carbon monosaccharide), peptide, and 3? Printed from Mimosa 09/15/1999 15:09:01 page -37- WO 98/40375 PCT/US98/03792 quaternary ammonium salts linked to the ring via poly (oxya Iky lene) linkages, e.g., - ( OCHjCHj ) x-N"R"Rl,R"A', where x is 2 to 10. Exemplary compounds are those set forth below in Table 1. 3^ Printed from Mimosa 09/15/1999 15:09:01 page -38- WO 98/40375 PCT/US98/03792 TABLE 1 Alternative compounds #3 (Family F101 .xxx.yyy) * V OH ste'ix Cpdi r1=r2 rs (rx)<r (TTT. aase. vw) *. 01 n-propyl pii- 7-rr.efhyl 02 n-propyl pfc- 7-ethyl 03 n-prooyl ph- 7-iso-propyl 04 n-propyl ph- 7-te;rr-'suryl 05 n-propyl ph- 7-ok os n-propyl ph- 7-och3 07 n-propyl ph- 7-0(iao-propyl) 03 p.-propyl ph- 7-SCH3 09 n-procyl ph- 7-sccs3 10 n-propyl ph- 7-SO2CH3 * General Notes In the description of the substituents " (N)" indicates that a nitrogen bearing substituent is bonded to the ring structure via the nitrogen atom. Similarly, 2-thiophene indicates a bond in the 2 position of the thiophene ring. A similar convention is used for other heterocyclic substituents. Abbreviations and Definitions NH-CBZ is defined as -HNC (=0) 0CH2Ph y\ Printed from Mimosa 09/15/1999 15:09:01 page -39- WO 98/40375 PCT/US98/03792 11 n-propyl Ph- 12 n-propyl Ph- 13 n-propyl Ph- 14 n-propyl Ph- 15 n-propyl Ph- 16 n-propyl Ph- 17 n-propyl Ph- 18 n-propyl Ph- 19 n-propyl Ph- 20 n-propyl Ph- 21 n-propyl Ph- 22 n-propyl Ph- 23 n-propyl Ph-24' n-propyl Ph- 25 n-propyl Ph- 26 n-propyl Ph- 27 n-propyl Ph- 28 n-propyl Ph- 29 n-propyl Ph- 30 n-propyl Ph- 31 n-propyl Ph- 32 n-propyl Ph- 33 n-procyl Ph- 34 n-propyl Ph- 35 n-propyl Ph- 36 n-propyl Ph- 37 n-propyl Ph- 38 n-propyl Ph- 39 n-propyl Ph- 40 n-propyl Ph- 41 n-propyl Ph- 42 n-propyl Ph- 43 n-propyl Ph- 44 n-propyl Ph- 45 n-propyl Ph- 46 n-propyl Ph- 47 n-propyl Ph- 48 n-propyl Ph- 49 n-propyl Ph- 50 n-propyl Ph- 51 n-propyl Ph- 52 n-propyl Ph- 7-SCH2CH3 7-NH2 7-NHOH 7-NHCH3 7-N{CH3)2 7-N+(CH3)3, I" 7-NHC(-0)CH3 7-N(CH2CH3)2 7-NMeCH2C02H 7-N*(Me)2CH2CO2H, I" 7-(N)-morpholine 7-(N)-azetidine 7- (N) -N-nethylazetidinium, I" 7-(N)-pyrrolidine 7- (N) -N-methyl-pyrrolidinim, I" 7— (N) —N—xethyl—morpholiniuri, I" 7- (N) -N' -ir.echylpiperazine 7- (N) -M' -diir.ethylpiperaziniun, I 7-NH-C3Z 7-NHC(O)C5H11 7-NHC(0)CH2Br 7-NH-C(NH)NK2 7-(2)-thiophene 3-raechyl 8-ethyl 8-iso-propyl 8-tert-butyl 8-OH 8-OCH3 8-0 (iso-propyl) 8-SCH3 8-SOCH3 8-SO2CH3 8-SCH2CK3 8-NH2 8-NHOH 8-NHCH3 8-N(CH3)2 8-N+(CH3)3, I- 8-NHC(~0)CH3 8-N(CH2CH3)2 8-NMeCH2C02H *bT> Printed from Mimosa 09/15/1999 15:09:01 page -40- WO 98/40375 PCT/US98/03792 53 n-propyl Ph- 54 n-propyl Ph- 55 n-propyl Ph- 56 n-propyl Ph- 57 n-propyl Ph- 58 n-propyl Ph- 59 n-propyl Ph- 60 n-propyl Ph- 61 n-propyl ph- 62 n-propyl Ph- 63 n-propyl Ph- 64 n-propyl Ph- 65 n-propyl Ph- 66 n-propyl Ph- 67 n-propyl ph- 68 n-propyl Ph- 69 n-propyl Ph- 70 n-propyl ph- 71 n-propyl Ph- 72 n-propyl ph- 73 n-propyl Ph- 74 n-propyl ph- 75 n-propyl Ph- 7 5 n-propyl Ph- 77 n-propyl Ph- 78 n-propyl Ph- 79 n-propyl Ph- 80 n-propyl Ph- 81 n-propyl Ph- 82 n-propyl Ph- 83 n-propyl Ph- 84 n-propyl Ph- 85 n-propyl ph- 8 6 n-propyl Ph- 87 n-propyl Ph- 88 n-propyl Ph- 89 n-propyl Ph- 90 n-propyl Ph- 91 n-propyl Ph- 92 n-propyl Ph- 93 n-propyl ph-93 n-propyl ph-95 n-propyl Ph- 8-N* (Me) 2CH2C02H,PXrENT 8-(N)-morpholine 8-(N)-azetidine 8- (N) -N-roethylazetidiniurn, I" 8-(N)-pyrrolidine 8-(N)-N-methyl-pyrrolidinium, I" 8-(N)-N-methyl-morpholinium, I" 8-(N)-N'-methylpiperazine 8-(N)-N'-dimethylpipera2iniun, I" 8-NH-C82 8-NHC (O) CsHj.i 8-NHC(0)CH2Br 8-NH-C(NH)NH2 8-(2)-thiophene 9-aiethyl 9-ethvl 9-iao-propyl 9-tert-butyl 9~bh__" 9-OCH3 9-0 (iso-propyl) 9-SCH3 9-SOCH3 9-SO2CK3 9-SCH2CH3 9-NK2 9-NHOH 9-NKCH3 9-N(CH3) 2 9-N+{CH3)3, I" 9-NHC(-0)CH3 9-N(CH2CH3)2 9-NMeCH2C02H 9-N*(Me)2CH2C02H, 1" 9-(N)-morpholine 9-(N)-azetidine 9-(N)-N-methylazetidinium, I" 9-(N)-pyrrolidine 9-(N)-N-methyl-pyrrolidinium, I" 9-(N)-N-methyl-morpholinium, I" 9- (N)-N'-methylpiperazine 9-(N)-N'-dimethylpiperazinium, I' 9-NK-CS2 3«=l Printed from Mimosa 09/15/1999 15:09:01 page 41 WO 98/40375 PCT/US98/03792 96 n-propyl Ph- 9-NHC(O)C5H11 97 n-propyl Ph- 9-NHC(O)CH2Br 98 n-propyl Ph- 9-NH-C(NH)NH2 99 n-propyl Ph- 9-(2)-thiophene 100 n-propyl Ph- 7-OCH3, 8-OCH3 101 n-propyl Ph- 7-SCH3, 8-OCH3 102 n-propyl Ph- 7-SCH3, 8-SCH3 103 n-eroovl Ph- 6-OCH3, 7-OCH3, 8-OCH3 . Prefix Cpda & II R5 (R*)q (nr.sxt. vw) F101.002 01 n-butyl Ph- 7-methyl 02 n-butyl Ph- 7-ethyl 03 n-butyl Ph- 7-iso-propyl 04 n-butyl Ph- 7-tert-butyl 05 n-butyl Ph- 7-OK OS n-butyl Ph- 7-OCH3 07 n-butyl Ph- 7-Q(iso-propyl) 08 n-butyl Ph- 7-SCH3 09 n-butyl Ph- 7-SOCH3 10 n-butyl Ph- 7-SO2CH3 11 n-butyl Ph- 7-SCK2CH3 12 n-butyl Ph- 7-NH2 13 n-butyl Ph- 7-NHOH 14 n-butyl Ph- 7-NKCH3 15 n-butyl Ph- 7-N(CH3)2 IS n-butyl Ph- 7—N+(CH3)3, I- 17 n-butyl Ph- 7-NHC (*"0) CH3 18 n-butyl Ph- 7-N(CH2CH3)2 19 n-butyl Ph- 7-NMeCH2C02H 20 n-butyl Ph- 7-N*(Me)2CH2C02H, I" 21 n-butyl Ph- 7-(N)-morpholine 22 n-butyl Ph- 7-(N)-azetidine 23 n-butyl Ph- 7-(N)-N-methylazetidinium, I" 24 n-butyl Ph- 7-(N)-pyrrolidine 25 n-butyl Ph- 7- (N)-N-methyl-pyrrolidinium, X" 2S n-butyl Ph- 7- (N) -N-methyl-morpholinium, I" 27 n-butyl Ph- 7- (N) -N' -nethylpiperazine 28 n-butyl Ph- 7- (N)-N'-dimethylpiperazinium, 1* 29 n-butyl Ph- 7-NH-C3Z 30 n-butyl Ph- 7-NHC (OJCsHu 31 n-butyl Ph- 7-NHC(0)CH2Br 4.0 Printed from Mimosa 09/15/1999 15:09:01 page -42- WO 98/40375 PCT/U S98/03792 32 n-butyl Ph- 33 n-butyl Ph- 34 n-butyl Ph- 35 n-butyl Ph- 36 n-butyl Ph- 37 n-butyl Ph- 38 n-butyl Ph- 39 n-butyl Ph- 40 n-butyl Ph- 41 n-butyl Ph- 42 n-butyl Ph- 43 n-butyl Ph- 44 n-butyl Ph- 45 n-butyl Ph-45 n-butyl Ph- 47 n-butyl Ph- 48 n-butyl Ph- 49 n-butyl Ph- 50 n-butyl Ph- 51 n-butyl Ph- 52 n-butyl Ph- 53 n-butyl Ph- 54 n-butyl Ph- 55 n-butyl Ph- 55 n-butyl Ph-* 57 n-butyl Ph- 58 n-butyl Ph- 59 n-butyl Ph- 60 n-butyl Ph- 61 n-butyl Ph- 62 n-butyl Ph- 63 n-butyl Ph- 64 n-butyl Ph- 65 n-butyl Ph- 66 n-butyl Ph- 67 n-butyl Ph- 68 n-butyl Ph- 69 n-butyl Ph- 70 n-butyl Ph- 71 n-butyl Ph- 72 n-butyl Ph- 73 n-butyl Ph- 7-NK-C(NK)NH2 7-(2)-thiophene 8-methyl 8-ethyl 8-iso-propyl 8-tert-butyl 8-OK 8-OCH3 8-0(iso-propyl) 8-SCH3 8-SOCH3 8-SO2CH3 8-SCH2CH3 8-NH2 8-MKOH 8-NHCK3 8-NtCK3)2 8-N,+ (CH3) 3, I" 8-n«C(=»0)CK3 8-N(CK2CH3)2 8-NMeCH2C02K 8-N*(Me)2CH2C02H, I" 8-{N)-morpholine 8- (N)-azetidine 8- (N) -N-n-.ethvlaretidiniun, X~ 8-(N)-pyrrolidine 8-(N)-N-methyl-pyrrolidinium, I 8-(N) -N-xethyl-morpholiniuia, I" 8- (N) -N' -rr.ethylpiperazine 8- (N) -N' -dimethylpiperazinium, 8-NH-C8Z 8-NHC(O)C5K11 8-NHC(O)CH2Br 8-NK-C(NH)NH2 8-(2)-thiophene 9-methyl 9-ethyl 9-iso-propyl 9-tert-butyl 9-OH 9-OCH3 9-0(iso-propyl) 41 Printed from Mimosa 09/15/1999 15:09:01 page 43 WO 98/40375 PCT/US98/03792 74 n-butyl Ph- 9-SCH3 75 n-butyl Ph- 9-SOCH3 76 n-butyl Ph- 9-SO2CH3 77 n-butyl Ph- 9-SCK2CH3 78 n-butyl Ph- 9-NH2 73 n-butyl Ph- 9-NHOH 80 n-butyl Ph- 9-NHCH3 81 n-butyl Ph- 9-N (CH3) 2 82 n-butyl Ph- 9-N+(CH3)3, I" 83 n-butyl Ph- 9-NHC(~0)CH3 84 n-butyl Ph- 9-N(CH2CH3)2 85 n-butyl Ph- 9-NMeCH2C02H 86 n-butyl Ph- 9-N* (Me) 2CH2CO2H, I" 87 n-butyl Ph- 9- (N) -morpholine 88 n-butyl Ph- 9- (N) -azetidine 89 n-butyl Ph- 9- (N) -N-ir.ethylazetidinium, I" 90 n-butyl Ph- 9-(N)-pyrrolidine 91 n-butyl Ph- 9- (N) -N-methyl-pyrrolidinium, I" 92 n-butyl Ph- 9- (N) -N-methyl-morpholinium, I" 93 n-butyl Ph- 9- (Nf-N' -r.ethylp iperazine 93 n-butyl Ph- 9- (N) -N' -dimethylpiperazinium, I" 95 n-butyl Ph- 9-NH-C3Z 96 n-butyl Ph- 9-NHC (O)CsHn 97 n-butyl Ph- 9-NHC(0)CH23r 98 n-butyl Ph- 9-NK-C(NH)NH2 99 n-butyl Ph- 9-(2)-thiophene 100 n-butyl Ph- 7-OCH3, 8-GCH3 101 n-butyl Ph- 7-SCH3, 8-OCH3 102 n-butyl Ph- 7-SCH3, 8-SCH3 103 n-butvl Ph- 6-OCH3, 7-OCH3, 8-OCH3 Psefix Cpd# RS (RxJq (FFF.X33. VYY) F101.0Q3 01 n-pentyl Ph- 7-methyl 02 n-pentyl Ph- 7-ethyl 03 n-pentyl Ph- 7-iao-propyl 04 n-pentyl Ph- 7-tert-butyl OS n-pentyl Ph- 7-OH 06 n-pentyl Ph- 7-OCH3 07 n-pentyl Ph- 7-0(iao-propyl) 08 n-pentyl Ph- 7-SCH3 09 n-pentyl Ph- 7-SOCH3 4a Printed from Mimosa 09/15/1999 15:09:01 page -44- WO 98/40375 PCT/US98/03792 10 n-pentyl Phil n-pentyl Ph- 12 n-pentyl Ph- 13 n-pentyl Ph- 14 n-pentyl Ph- 15 n-pentyl Ph- 16 n-pentyl Ph- 17 n-pentyl Ph- 18 n-pentyl Ph- 19 n-pentyl Ph- 20 n-pentyl Ph- 21 n-pentyl Ph- 22 n-pentyl Ph- 23 n-pentyl Ph- 24 n-pentyl Ph- 25 n-pentyl Ph- 26 n-pentyl Ph- 27 n-pentyl Ph- 28 n-pentyl Ph- 29 n-pentyl Ph- 30 n-pentyl Ph- 31 n-pentyl Pn- 32 n-pentyl Ph- 33 n-pentyl Ph- 34 n-pentyl Ph- 35 n-pentyl ph- 36 n-pentyl Ph- 37 n-pentyl Ph- 38 n-pentyl Ph- 39 n-pentyl Ph- 40 n-pentyl Ph- 41 n-pentyl Ph- 42 n-pentyl Ph- 43 n-pentyl Ph- 44 n-pentyl Ph- 45 n-pentyl Ph- 46 n-pentyl Ph- 47 n-pentyl Ph- 48 n-pentyl Ph- 49 n-pentyl Ph- 50 n-pentyl Ph- 51 n-pentyl Ph- 7-SO2CH3 7-SCH2CH3 7-nh2 7-nhoh 7-NHCH3 7-n (CH3) 2 7-N+(CH3)3, I" 7-NKC(~0)CH3 7-n(CK2CH3)2 7-NMeCH2C02H 7-N*(Me)2CH2C02H, I" 7- (N) -icorpholine 7-(N)-azetidine 7- (N) -N-methylazetidiniuia, I" 7-(N)-pyrrolidine 7- (N) -N-r.ethyl-pyrrolidiniun, I" 7-(N)-M-rethyl-r-orpholinium, I" 7- (N) -N' -niechylpiperazine 7-(tt)-N'-di:?.ethylpiperariniuni, I 7-N?T-C3Z 7-NKC(O)C5K11 7-NHC(0)CH23r 7-NH-C (Nrl) NH2 7-(2)-thiophene 8-methyl 8-ethyl 8-iso-propyl 8-tert-butyl 8-OK 8-OCH3 8-0(iso-propyl) 8-SCH3 8-SOCK3 8-SO2CH3 8-SCH2CH3 8-NH2 8-NHOK 8-NHCH3 8-n (CH3) 2 8-N+ ICH3) 3, I" 8-NHC(-0)CH3 8-N (CH2CH3) 2 43 Printed from Mimosa 09/15/1999 15:09:01 page -45- WO 98/40375 PCT/US98/03792 52 n-pentyl Ph- 8-NMeCH2C02H 53 n-pentyl Ph- 8-N* (Me) 2CH2CO2H, I" 54 n-pentyl Ph- 8-(N)-morpholine 55 n-pentyl Ph- 8-(N)-azetidine 56 n-pentyl Ph- 8-(N)-N-raethylazetidinium, I" 57 n-pentyl Ph- 8-(N)-pyrrolidine 58 n-pentyl Ph- 8-(N)-N-methyl-pyrrolidinium, I" 59 n-pentyl Ph- 8-(N)-N-methyl-morpholinium, I" 60 n-pentyl ph- 8-(N)-N'-methylpiperazine 61 n-pentyl Ph- 8-(N)-N'-dimethylpiperazinium, I" " 62 n-pentyl Ph- 8-NH-CBZ 63 n-pentyl Ph- 8-NKC (O)CsHu 64 n-pentyl Ph- 8-NHC(0)CH2Br 65- n-pentyl Ph- 8-NH-C(NH)NH2 66 n-pentyl Ph- 8-(2)-thiophene 67 n-pentyl Ph- 9-rr.ethyl 68 n-pentyl Ph- 9-ethyl 69 n-pentyl Ph- 9-iso-propyl 70 n-pentyl Ph- 9-tert-butyl 71 n-pentyl Ph- 9-OK 72 n-pentyl Ph- 9-OCH3 73 n-pentyl Ph- 9-0(iso-propyl) 74 n-pentyl Ph- 9-SCH3 75 n-pentyl Ph- 9-SCCH3 76 n-pentyl Ph- 9-S02CK3 77 n-pentyl Ph- 9-SCH2CK3 78 n-pentvl ph- 9-NH2 79 n-pentyl Ph- 9-NK0H 80 n-pentyl Ph- 9-NHCH3 81 n-pentyl Ph- 9-N(CH3)2 82 n-pentyl Ph- 9-N+(CH3)3, I" 83 n-pentyl Ph- 9-NHC(-0)CH3 8 4 n-pentyl Ph- 9-N(CH2CH3)2 85 n-pentyl Ph- 9-NMeCH2C02H 86 n-pentyl Ph- 9-N* (Me) 2CH2CO2H, I" 87 n-pentyl Ph- 9-(N)-morpholine 88 n-pentyl Ph- 9-(N)-azetidine 89 n-pentyl Ph- 9-(N)-N-methylazetidinium, I" 90 n-pentyl Ph- 9-(N)-pyrrolidine 91 n-pentyl Ph- 9-(N)-N-methyl-pyrrolidinium, I" 92 n-pentyl Ph- 9-(N)-N-methyl-morpholinium, t~ 93 n-pentyl Ph- 9-(N)-N'-methylpiperazine 93 n-pentyl Ph- 9-(N)-N'-dimethylpiperazinium, I" 44 Printed from Mimosa 09/15/1999 15:09:01 page -46- WO 98/40375 PCT/US98/03792 95 n-pentyl 96 n-pentyl 97 n-pentyl 98 n-pentyl 99 n-pentyl 100 n-pentyl 101 n-pentyl 102 n-pentyl ^•03 n-oentvl Ph- 9-NH-C3Z Ph- 9-NHC (O)CsHn Ph- 9-NHC(0)CH23r Ph- 9-NH-C(NH)NH2 Ph- 9-(2)-thiophene Ph- 7-OCH3, 8-OCH3 Ph- 7-SCH3, 8-OCH3 Ph- 7-SCH3, 8-SCH3 Ph- 6-OCH3, 7-OCH3, 8-OCH3 Prefix (FST.: Cpd# R1=R2 RS (Rx)q vw) 01 ' n-hexyl Ph- 7-niethyl 02 n-hexyl Ph- 7-ethyl 03 n-hexyl Ph- 7-iso-propyl 04 n-hexyl Ph- 7-tert-butyl 05 n-hexyl Ph- 7-OH 06 n-hexyl Ph- 7-OCH3 07 n-hexyl Ph- 7-O-tiso-propyl) 08 n-hexyl Ph- 7-SCH3 09 n-hexyl Ph- 7-SOCH3 10 n-hexyl Ph- 7-SO2CH3 11 n-hexyl Ph- 7-SCH2CK3 12 n-hexyl Ph- 7-NH2 13 n-hexyl Ph- 7-NKOK 14 n-hexyl Ph- 7-NHCH3 15 n-hexyl Ph- 7-N(CH3)2 16 n-hexyl Ph- 7-N+(CH3)3, I" 17 n-hexyl Ph- 7-NHC(-0)CH3 18 n-hexyl Ph- 7-N(CH2CH3)2 19 n-hexyl Ph- 7-NMeCH2C02H 20 n-hexyl Ph- 7-N*(Me)2CH2C02H, I" 21 n-hexyl Ph- 7-(N)-morpholine 22 n-hexyl Ph- 7-(N)-azetidine 23 n-hexyl Ph- 7-(N)-N-methylazetidinium, I" 24 n-hexyl Ph- 7-(N)-pyrrolidine 25 n-hexyl Ph- 7-(N)-N-methyl-pyrrolidinium, I" 26 n-hexyl Ph- 7-(N)-N-methyl-morpholinium, I" 27 n-hexyl Ph- 7-(N)-N'-methylpiperazine 28 n-hexyl Ph- 7-(N)-N'-dimethylpiperazinium, I' 29 n-hexyl Ph- 7-NH-CSZ 30 n-hexyl Ph- 7-NHCCO)C5H11 45 Printed from Mimosa 09/15/1999 15:09:01 page 47 WO 98/40375 PCT/US98/03792 31 n-hexyl Ph- 32 n-hexyl Ph- 33 n-hexyl Ph- 34 n-hexyl Ph- 35 n-hexyl Ph- 3 6 n-hexyl Ph- 37 n-hexyl Ph- 38 n-hexyl Ph- 39 n-hexyl Ph- 40 n-hexyl Ph- 41 n-hexyl Ph- 42 n-hexyl Ph- 43 n-hexyl Ph- 44 n-hexyl Ph- 45 n-hexyl Ph- 4 6 n-hexyl Ph- 47 n-hexyl Ph- 48 n-hexyl Ph- 49 n-hexyl Ph- 50 n-hexyl Ph- 51 n-hexyl Ph- 52 n-hexyl Ph- 53 n-hexyl Ph- 54 n-hexyl Ph- 55 n-hexyl Ph- 56 n-hexyl Ph- 57 n-hexyl Ph- 58 n-hexyl Ph- 59 n-hexyl Ph- 60 n-hexyl Ph- 61 n-hexyl ph- 62 n-hexyl Ph- 63 n-hexyl Ph- 64 n-hexyl Ph- 65 n-hexyl Ph- 66 n-hexyl Ph- 67 n-hexyl Ph- 68 n-hexyl Ph- 69 n-hexyl Ph- 70 n-hexyl Ph- 71 n-hexyl Ph- 72 n-hexyl Ph- 7-NKC(O)CH2Br 7-NH-C(NH)NH2 7- (2)-thiophene 8-methyl 8-ethyl 8-iso-propyl 8-tert-butyl 8-OH 8-OCH3 8-0(iso-propyl) 8-SCH3 8-SOCH3 8-SO2CH3 8-SCH2CH3 8-NH2 8-NKOH 8-NHCH3 8-N(CH3)2 8-N*f(C'H3) 3, I" 8-NHC (=0)CH.3 8-N(CH2CH3)2 8-NMeCH2C02H 8-N*(Ke)2CH2CO2H, I" 8-(N)-morpholine 8-(N)-azetidine 8-(N) -N-ntethylazetidinium, I" 8- (N)-pyrrolidine 8-(N)-N-methyl-pyrralidinium, I 8- (N) -N-methyl-morpholiniusi, I" 8-(N)-N'-methylpiperazine 8-(N)-N'-dimethylpiperazinium, 8-NH-CBZ 8-NHC (O)CsHn 8-NHC(0)CH2BE 8-NH-C(NH)NH2 8-(2)-thiophene 9-methyl 9-ethyl 9-iso-propyl 9-tert-butyl 9-OH 9-OCH3 A-C Printed from Mimosa 09/15/1999 15:09:01 page 48 WO 98/40375 PCT/US98/03792 73 n-hexyl Ph- 9-0(iso-propyl) 74 n-hexyl Ph- 9-SCH3 75 n-hexyl Ph- 9-SOCH3 76 n-hexyl Ph- 9-SO2CH3 77 n-hexyl Ph- 9-SCH2CH3 78 n-hexyl Ph- 9-NH2 79 n-hexyl Ph- 9-NHOH 80 n-hexyl Ph- 9-NHCH3 81 n-hexyl Ph- 9-N(CH3)2 82 n-hexyl Ph- 9-N+(CH3)3, 1- 83 n-hexyl Ph- 9-NHC(-0)CH3 84 n-hexyl Ph- 9-N(CH2CH3)2 85 n-hexyl Ph- 9-NMeCH2C02H 86 ' n-hexyl Ph- 9-N*(Me)2CH2CO2K, X" 87 n-hexyl Ph- 9-(N)-morpholine 88 n-hexyl Ph- 9-(N)-azetidine 89 n-hexyl Pn- 3- (N) -N-rr.ethylazetidiniuia, I" 90 n-hexyl Ph- 9-(N)-pyrrolidine 91 n-hexyl Ph- 9- (N) -N-r.ethyl-pyrrolidin.iun, I" 92 n-hexyl Ph- 9-(Ur-N-ir.ethyl-morpholiniun, I" 93 n-hexyl Ph- 9-(N)-N'-methylpiperazine 93 n-hexyl Ph- 9-(N)-N'-dixethylpiperaziniun, I" 95 n-hexyl Ph- 9-NK-C3Z 96 n-hexyl Ph- 9-NHC (OlC5.Hn 97 n-hexyl Ph- 9-NHC(0)CK23r 98 n-hexyl Ph- 9-NH-C(NH)NH2 99 n-hexyl Ph- 9- (2)-thiophene 100 n-hexyl Ph- 7-OCK3, 8-OCH3 101 n-hexyl Ph- 7-SCH3, 8-OCH3 102 n-hexyl Ph- 7-SCH3, 8-SCH3 103 n-hexvl Ph- 6-OCH3, 7-CCH3, 8-OCH3 Prefix CpdJ RS (Rx)<5 (ITS' .xxx. 77V) F101.005 01 iso-propyl Ph- 7-methyl 02 iso-propyl Ph- 7-ethyl 03 iso-propyl Ph- 7-iso-propyl 04 iso-propyl Ph- 7-tert-butyl 05 iso-propyl Ph- 7-OH 06 iso-propyl Ph- 7-OCH3 07 iso-propyl Ph- 7-0(iso-propyl) 08 iso-propyl Ph- 7-SCH3 4-7 Printed from Mimosa 09/15/1999 15:09:01 page -49- WO 98/40375 PCT/U S98/03792 09 iso-propyl Ph- 7-SOCH3 10 iso-propyl Ph- 7-SO2CH3 11 iso-propyl Ph- 7-SCH2CH3 12 iso-propyl Ph- 7-NK2 13 iso-propyl Ph- 7-NHOH 14 iso-propyl Ph- 7-NHCH3 15 iso-propyl Ph- 7-N(CH3)2 16 iso-propyl Ph- 7-N+(CH3)3, I" 17 iso-propyl Ph- 7-NKC(-0)CH3 18 iso-propyl Ph- 7-NtCH2CH3)2 19 iso-propyl Ph- 7-NMeCH2C02H 20 iso-propyl Ph- 7-N*(Me)2CH2C02H, I" 21 iso-propyl Ph- 7-(N)-morpholine 22' iso-propyl Ph- 7-(N)-azetidine 23 iso-propyl Ph- 7- (N) -N-T.ethylazetidiniun, I" 24 iso-propyl Ph- 7-(N)-pyrrolidine 25 iso-propyl Ph- 7-(N)-N-methyl-pyrrolidiniun, X 26 iso-propyl Ph- 7-(N)-N-sethyl-morpholiniun, I" 27 iso-propyl Ph- 7-(N>-N'-methylpiperazine 28 iso-propyl Ph- 7-tNO-N'-dimethylpiperazinium. 29 iso-propyl Ph- 7-NH-C3Z 30 iso-propyl Ph- 7-NKC(O)C5KXI 31 iso-propyl Ph- 7-NKC(O)CK2Br 32 iso-propyl Ph- 7-NH-C(NH)NK2 33 iso-propyl Ph- 7-(2)-thiophene 34 iso-propyl ?h- 8-niethyl 35 iso-propyl Ph- 8-ethyl 36 iso-propyl Ph- 8-iso-propvl 37 iso-propyl Ph- 8-tert-butyl 38 iso-propyl Ph- 8-OH 39 iso-propyl Ph- 8-OCH3 40 iso-propyl Ph- 8-0(iso-propyl> 41 iso-propyl Ph- 8-SCH3 42 iso-propyl Ph- 8-SOCH3 43 iso-propyl Ph- 8-SO2CH3 44 iso-propyl Ph- 8-SCH2CH3 4S iso-propyl Ph- 8-NH2 46 iso-propyl Ph- 8-NHOH 47 iso-propyl Ph- 8-NHCH3 48 iso-propyl Ph- 8-N(CH3)2 49 iso-propyl Ph- 8-N+(CH3)3, I- 50 iso-propyl Ph- 8-NHC(-0)CH3 4-S Printed from Mimosa 09/15/1999 15:09:01 page -50- WO 98/40375 PCT/US98/03792 51 iso-propyl Ph- 52 iso-propyl Ph- 53 iso-propyl Ph- 54 iso-propyl Ph- 55 iso-propyl Ph- 56 iso-propyl Ph- 57 iso-propyl Ph- 58 iso-propyl Ph- 59 iso-propyl Ph- 60 iso-propyl ph- 61 iso-propyl Ph- 62 iso-propyl Ph- 63 iso-propyl Ph- 64 iso-propyl Ph- 65 iso-propyl Ph- 66 iso-propyl Ph- 67 iso-propyl Ph- 68 iso-propyl Ph- 69 iso-propyl Ph- 70 iso-propyl Ph- 71 iso-propyl Ph- 72 iso-propyl Ph- 73 iso-propyl Ph- 74 iso-propyl Ph- 75 iso-propyl Ph- 76 iso-propyl Ph- 77 iso-propyl Ph- 78 iso-propyl Ph- 79 iso-propyl Ph- 80 iso-propyl Ph- 81 iso-propyl Ph- 82 iso-propyl Ph- 83 iso-propyl Ph- 84 iso-propyl Ph- 85 iao-propyl Ph- 86 iso-propyl Ph- 87 iso-propyl Ph- 88 iao-propyl Ph- 89 iso-propyl Ph- 90 iso-propyl Ph- 91 iso-propyl Ph- 92 iso-propyl Ph- 93 iso-propyl Ph- 8-N(CH2CH3)2 8-NMeCH2C02H 8-N*(Ke)2CH2C02H, I" 8-(N)-morpholine 8-(N)-aieticline 8-(N)-N-methylazetidinium, I" 8-(N)-pyrrolidine 8-(N)-N-methyl-pyrrolidinium, I" 8-(N)-N-methyl-morpholinium, I" 8-(N)-N'-methylpiperazine 8-(N)-N'-dimethylpiperazinium, I" 8-NH-CBZ 8-NHC (OJCsHH 8-NHC(0)CH2Br 8-NH-C(NH)NH2 8-(2)-thiophene 9-c.ethyl 9-ethyl 9-iso"-propyl 9-tert-butyl 9-OH 9-OCH3 9-0(iso-propyl) 9-SCH3 9-SOCH3 9-so2ck3 9-SCK2CH3 9-nh2 9-NHOH 9-NHCH3 9-N(CH3)2 9-N+(CH3)3, I" 9-NHC(-0)CH3 9-N(CH2CH3)2 9-NMeCH2C02H 9-N+(Me)2CH2CO2H, I" 9-(N)-morpholine 9-(N)-azetidine 9-(N)-N-methylazetidinium, I" 9-(N)-pyrrolidine 9-(N)-N-methyl-pyrrolidinium, I" 9-(N)-N-methyl-morpholinium, I" 9-(N)-N'-methylpiperazine 4^ Printed from Mimosa 09/15/1999 15:14:35 page 1 wo 98/40375 PCT/US98/03792 93 iso-propyl Ph- 9-(n)-n'-dixnethylpfpSSaSinium, X" 95 iso-propyl Ph- 9-NH-CBZ 96 iso-propyl Ph- 9-NHC(0)C5H11 97 iso-propyl Ph- 9-NHC(0)CH2Br 98 iso-propyl Ph- 9-nh-C(nh)NH2 99 iso-propyl Ph- 9-(2)-thiophene 100 101 102 103 iso-propyl iso-propyl iso-propyl iso-oroovl Ph-Ph-Ph-Ph- 7-OCH3, 8-OCH3 7-SCH3, 8-OCH3 7-SCH3, 8-SCH3 6-OCH3, 7-OCK3, 8-CCH3 Prefix (FFF.33PC c?dS R1=R2 RS . yyvl 01 iso-butyl Ph- 7-methyl 02 iso-butyl Ph- 7-ethyl 03 iso-butyl Ph- 7-iso-propyl 04 iso-butyl Pn- 7-tert-butyl 05 iso-butyl Ph- 7-OH 06 iso-butyl Ph- 7-0tH3 07 iso-butyl Ph- 7-0(iso-propyl) 08 iso-butyl Ph- 7-SCH3 09 iso-butyl Ph- 7-SOCH3 10 iso-butyl Ph- 7-SO2CH3 11 iso-butyl Ph- 7-SCH2CH3 12 iso-butyl Ph- 7-NH2 13 iso-butyl Ph- 7-NHOH 14 iso-butyl Ph- 7-NHCH3 15 iso-butyl Ph- 1-N(CH3)2 16 iso-butyl Ph- 7-N+(CH3)3, I" 17 iso-butyl Ph- 7-NHC("O)CH3 18 iso-butyl Ph- 7-N(CK2CK3)2 19 iso-butyl Ph- 7-NMeCH2C02H 20 iso-butyl Ph- 7-N*(Me)2CH2CO2H, I" 21 iso-butyl Ph- 7-(N)-morpholine 22 iso-butyl Ph- 7-(N)-azetidine 23 iso-butyl Ph- 7-(N)-N-nethylazetidinium, I" 24 iso-butyl Ph- 7-(N)-pyrrolidine 25 iso-butyl Ph- 7- (N) -N-methyl-pyrrolidinium, I~ 26 iso-butyl Ph- 7-(N)-N-tnethyl-morpholinium, X" 27 iso-butyl Ph- 7- (N) -N' -methylpiperazine 28 iso-butyl Ph- 7- (N) -N' -dimethylpiperazinium, I 29 iso-butyl Ph- 7-NH-CBZ F101.006 50 Printed from Mimosa 09/15/1999 15.14.35 page WO 98/40375 PCT/US98/03792 30 31 32 33 34 35 36 37 38 iao-butyl iso-butyl iso-butyl iso-butyl 39 40 41 <2 . 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 63 69 70 71 iso-iso-iso-iso-—iso-iso-iso-iso-iso-iso-iso-iso-iso-iso-iso-iso-iso-iso-iso-iso-iso-iso-iso-iso-iso-iso-iso-iso-iso-iso-iso-iso-isobutyl ■butyl •butyl •butyl •buty] •butyl •butyl ■butyl •butyl •butyl •butyl ■butyl ■butyl •butyl ■butyl ■butyl ■butyl ■butyl •butyl -butyl -butyl -butyl -butyl -butyl -butyl -butyl -butyl -butyl -butyl -butyl -butyl -butyl -butyl Ph- 7-NHC (O)CsHu Ph- 7-NHC(0)CH2Br Ph- 7-NH-C(NH)NH2 Ph- 7-(2)-thiophene Ph- 8-methyl Ph- 8-ethyl Ph- 8-iso-propyl Ph- 8-tert-butyl -Ph- 8—©H iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl Ph- 8-OCH3 Ph- 8-0(iso-propyl) Ph- 8-SCH3 Ph- 8-SOCH3 Ph- 8-SO2CK3 Ph- 8-SCK2CH3 Ph- 8-NH2 Ph- 8-NKOH Ph- 8-NKCH3 Ph- 8-N(CH3)2 Ph- 8-N+(CH3)3, X" Ph- 8-NKC(»0)CH3 Ph- 8-N(CH2CH3)2 Ph- 8-NMeCK2C02K Ph- 8-N* (Me) 2CH2C02H, X" Ph- 8-(N)-r-orpholine Ph- 8-(N)-azetidine Ph- 8-(N)-N-nethylazetidinium, X" Ph- 8-(N)-pyrrolidine Ph- 8-(N)-N-methyl-pyrrolidinium, Ph- 8-(N) -N-methyl-morpholinium, X Ph- 8-(N) -N' -methylpiperazine Ph- 8-(N)-N'-dimethylpiperazinium, Ph- 8-NH-CBZ Ph- 8-NHC (O)CsHh Ph- 8-NHC(0)CH2Br Ph- 8-NH-C(NH)NH2 Ph- 3-(2)-thiophene Ph- 9-methyl Ph- 9-ethyl Ph- 9-iso-propyl Ph- 9-tert-butyl Ph- 9-OH 6*1 Printed from Mimosa 09/15/1999 15:14:35 page -3- WO 98/40375 PCT/US98/03792 72 iso-butyl Ph- 9-OCH3 73 iso-butyl Ph- 9-O(i s o-p ropy1) 74 iso-butyl Ph- 9-SCH3 75 iso-butyl Ph- 9-SOCH3 76 iso-butyl Ph- 9-SO2CH3 77 iso-butyl Ph- 9-SCH2CH3 78 iso-butyl Ph- 9-NH2 79 iso-butyl Ph- 9-NHOH 80 iso-butyl Ph- 9-NHCH3 81 iso-butyl Ph- 9-N(CH3)2 82 iso-butyl Ph- 9-N+ (CH3) 3, X" 83 iso-butyl Ph- 9-NHC(-0)CH3 84 iso-butyl Ph- 9-N{CH2CH3)2 85 iso-butyl Ph- 9-NKeCH2C02H 86 iso-butyl Ph- 9-N+(Me)2CH2CO2H, I" 87 iso-butyl Ph- 9- (N) -ir.orpholine 88 iso-butyl Ph- 9-(N)-azetidine 89 iso-butyl Ph- 9- (N) —N-.T.ethylazetidiniun, I" 90 iso-butyl Ph- 9^-.(K) -pyrrolidine 91 iso-butyl Ph- 9-*-<N) -N-methyl-pyrrolidinium, I" 92 iso-butyl Ph- 9- (N) -N-methyl-morpholinium, I~ 93 iso-butyl Ph- 9- (N) -N' -methylpiperazine 93 iso-butyl Ph- 9-(N)-M'-dimethylpiperazinium, I" 95 iso-butyl Ph- 9-MK-C32 96 iso-butyl Ph- 9-NKC(0)CsHh 97 iso-butyl Ph- 9-NKC(0)CK23r 98 iso-butyl Ph- 9-NH-C(NK)NH2 99 iso-butyl Ph- 9-(2)-thiophene 100 iso-butyl Ph- 7-OCH3, 8-CCK3 101 iso-butyl Ph- 7-SCH3, 8-OCH3 102 iso-butyl Ph- 7-SCH3, 8-SCH3 103 iso-butvl Ph- 6-OCH3, 7-OCH3, 8-OCH3 Prefix Cpd# RX=R2 RS (Rx)q (FFT.xxx. ml F101.007 01 iso-pentyl Ph- 7-methyl 02 iso-pentyl Ph- 7-ethyl 03 iso-pentyl Ph- 7-iso-propyl 04 iso-pentyl Ph- 7-tert-butyl 05 iso-pentyl Ph- 7-OH 06 iso-pentyl Ph- 7-OCH3 07 iao-pentyl Ph- 7-0(iso-propyl) 5" 3 Printed from Mimosa 09/15/1999 15:14:35 page -4- WO 98/40375 PCT/US98/03792 OS iso-pentyl Ph- 7-SCH3 09 iso-pentyl Ph- 7-SOCH3 10 iso-pentyl Ph- 7-SO2CH3 11 iso-pentyl Ph- 7-SCH2CH3 12 iso-pentyl Ph- 7-NH2 13 iso-pentyl Ph- 7-NHOK 14 iso-pentyl. Ph- 7-KKCK3 15 iso-pentyl Ph- 7-N(CH3) 2 16 iso-pentyl Ph- _3.tN+-(CH3) 3, I" 17 iso-pentyl Ph- 7-NHC (-OCH3 18 iso-pentyl Ph- 7-N(CH2CH3)2 19 iso-pentyl Ph- 7-NMeCH2C02H 20 iso-pentyl Ph- 7-N* (Me)2CK2CO2H, I" 21 ' iso-pentyl Ph- 7- (N)-morpholine 22 iso-pentyl Ph- 7-CN)-azetidine 23 iso-pentyl Ph- 7-(N)-N-methylazetidinium, I" 24 iso-pentyl Ph- 7-(N)-pyrrolidine 25 iso-pentyl Ph- 7-CN)-N-methyl-pyrrolidiniun, I 26 iso-pentyl Ph- 7- CN) rN-niechyl—morpholinium, I" 27 iso-pentyl Ph- 7- ('}*)—N' -methylpiperazine 28 iso-pentyl Ph- 7-(N)-N'-dimethylpiperazinium, 29 iso-pentyl Ph- 7-NK-C3Z 30 iso-pentyl Ph- 7-UKC (0)C5K11 31 iso-pentyl Ph- 7-NKC CO)CH23r 32 iso-pentyl Ph- 7-NH-C(NK)NH2 33 iso-pentyl Ph- 7-(2)-thiophene 34 iso-pentyl Ph- 8-methyl 35 iso-pentyl Ph- 8-ethyl 36 iso-pentyl Ph- 3-iso-propyl 37 iso-pentyl Ph- 8-tert-butyl 38 iso-pentyl Ph- 8-OH 39 iso-pentyl Ph- 8-OCH3 40 iso-pentyl Ph- 8-0(iso-propyl) 41 iso-pentyl Ph- 8-SCH3 42 iso-pentyl Ph- 8-SOCH3 43 iso-pentyl Ph- 8-SO2CH3 44 iso-pentyl Ph- 8-SCH2CH3 45 iso-pentyl Ph- 8-NH2 46 iso-pentyl Ph- 8-NHOH 47 iso-pentyl Sh- 8-NHCH3 48 iso-pentyl Ph- 8-N(CH3)2 49 iso-pentyl Ph- 8-N+(CH3>3, 1" S3 Printed from Mimosa 09/15/1999 15:14:35 page 5 WO 98/40375 PCT/US98/03792 50 iao-pentyl Ph- 8-NHC(-0)CH3 51 iao-pentyl Ph- 8-N{CK2CH3)2 52 iao-pentyl Ph- 8-NMeCH2C02H 53 iao-pentyl Ph- 8-N*(Me)2CH2C02H, I" 54 iao-pentyl Ph- 8-(N)-morpholine 55 iao-pentyl Ph- 8-(N)-azetidine 56 iao-pentyl Ph- 8 -(N)-N-methylazetidinium, I" 57 iao-pentyl Ph- 8- (N)-pyrrolidine 58 iao-pentyl Ph- 8-(N)-N-methyl-pyrrolidinium I~— 59— iao-pentyl Ph- 8-(N)-N-methyl-morpholinium, I" 60 iao-pentyl Ph- 8- (N)-N'-methylpiperazine 61 iao-pentyl Ph- 8-(N)-N'-dimethylpiperazinium, 1" 62 iao-pentyl Ph- 8-NH-C3Z 63 iao-pentyl Ph- 8-NKC(O)C5H1X 64 iao-pentyl Ph- 8-NKC(0)CH23r 65 iao-pentyl Ph- 8-NK-C(NH)NH2 66 iao-pentyl Ph- 8-(2)-thiophene 67 iso-pentyl Ph- 9-methyl 63 iso-pentyl Ph- 9-ethyl 69 iso-pentyl Ph- 9-isS-propyl 70 iso-pentyl Ph- 9-tert-butyl 71 iso-pentyl Ph- 9-OH 72 iso-pentyl P.n- 9-OCH3 73 iso-pentyl Ph- 9-0(iso-prooyl) 74 iso-pentyl Ph- 9-SCH3 75 iso-pentyl Ph- 9-SOCH3 76 iso-pentyl Ph- 9-SO2CH3 77 iso-pentyl Ph- 9-SCH2CH3 73 iso-pentyl Ph- 9-NH2 79 iso-pentyl Ph- 9-NKOH 80 iso-pentyl Ph- 9-NKCH3 81 iso-pentyl Ph- 9-N(CH3)2 82 iso-pentyl Ph- g-N+fCHs^, I" 83 iao-pentyl Ph- 9-NKC(-0)CH3 84 iao-pentyl Ph- 9-N(CH2CH3)2 85 iao-pentyl Ph- 9-N«eCH2C02H 86 iao-pentyl Ph- 9-N*(Me)2CH2CO2H, I" 87 iao-pentyl Ph- 9-(N)-morpholine 83 iao-pentyl Ph- 9-(N)-azetidine 89 iao-pentyl Ph- 9-(N)-N-methylazetidinium, I" 90 iao-pentyl Ph- 9-(N)-pyrrolidine 91 iao-pentyl Ph- 9-(N)-N-methyl-pyrrolidinium, I" 92 iao-pentyl Ph- 9-(N)-N-methyl-morpholinium, I" 5f Printed from Mimosa 09/15/1999 15:14:35 page 6 WO 98/40375 PCT/US98/03792 93 iao-pentyl Ph- 9- (N) -N' -methylpijWfflEWtthe 93 iao-pentyl Ph- 9-(N)-N'-dimethylpiperarinium, 95 iao-pentyl Ph- 9-NH-CBZ 96 iao-pentyl Ph- 9-NHC (0)C5HH 97 iao-pentyl Ph- 9-NHC{0)CH2Br 98 iao-pentyl Ph- 9-NH-C(NH)NH2 99 iao-pentyl Ph- 9- (2)-thiophene J/JO^ 101 102 103 iao-pentyl iao-pentyl iao-pentyl iao-oentvl Ph- 7-OCH3,_8^QCH3_ Ph- 7-SCH3, 8-OCH3 Ph- 7-SCK3, 8-SCH3 Ph- 6-OCH3, 7-OCH3, 8-OCH3 Prefix (TTT. Cpd# "a 11 r5 (Rx)q wv) 01 CH2C(-0)C2H3 Ph- 7-methyl 02 CH2C(-0)C2HS Ph- 7-ethyl 03 CH2C(-0)C2Hs Ph- 7-iao-propyl 04 CH2C(-0)C2H5 Ph- 7-tert-butyl OS CH2C(-0)C2H5 Ph- 7-OH- 06 CH2C(-0)C2H5 Ph- 7-OCH3 07 CH2C(-0)C2K5 Ph- 7-0(iso-propyl) 08 CH2C(-0)C2HS Ph- 7-SCH3 09 CH2C(-0)C2H5 Ph- 7-SOCK3 10 CH2C(=0)C2H5 Ph- 7-SO2CH3 11 CH2C(-0)C2H3 Ph- 7-SCH2CH3 12 CH2C(-0)C2Hs Ph- 7-NH2 13 CH2C(-0)C2HS Ph- 7-NKOH 14 CH2C(-0)C2HS Ph- 7-NHCH3 IS CH2C(-0)C2Hs Ph- 7-N (CH3) 2 IS CH2C(-0)C2H5 Ph- 7-N+ (CH3) 3, I" 17 CH2C(-0)C2H5 Ph- 7-NHC("O)CH3 18 CH2C(-0)C2H5 Ph- 7-N(CH2CH3)2 19 CH2C(-0)C2HS Ph- 7-NMeCH2C02H 20 CH2C(-0)C2H5 Ph- 7-N*(He)2CH2C02H, 1" 21 CH2C(-0)C2H5 Ph- 7-(N)-morpholine 22 CH2C(-0)C2H5 Ph- 7-(N)-azetidine 23 CH2C(-0)C2HS Ph- 7-(N)-N-methylazetidinium, I" 24 CH2C(-0)C2HS Ph- 7-(N)-pyrrolidine 2S CH2C(-0)C2H5 Ph- 7- (N) -N-methyl-pyrrolidinium, I" 2S CH2C(-0)C2Hs Ph- 7- (N) -N-methyl-morpholinium, I" 27 CH2C(-0)C2HS Ph- 7- (N) -N' -methylpiperazine 28 CH2C(-Q)C2H5 Ph- 7- (N) -N' -dimethylpiperazinium, I" F101.008 Printed from Mimosa 09/15/1999 15:14:35 page 7 WO 98/40375 PCT/U S98/03792 29 CH2C(-0)C2H5 Ph- 7-NH-C32 30 CH2C (-0) C2H5 Ph- 7-NHC(0)C5H1X 31 CH2C(-0)C2H5 Ph- 7-NKC{0)CH2Br 32 CH2C(-0)C2Hs Ph- 7-NH-C(NH)NH2 33 CH2C(-0)C2Hs Ph- 7-(2)-thiophene 34 CH2C(-0)C2Hs Ph- 8-nethyl 35 CH2C(-0)C2Hs Ph- 8-ethyl 36 CH2C(-0)C2H3 Ph- 8-iao-proovl 37 CH2C(-0)C2H5 Ph- 8-tert-butyl 38 CH2C (-0) C2Hs Ph- 8-OH 39 CH2C(-0)C2Hs Ph- 8-OCH3 40 CH2C (-0) C2Hs Ph- 8-0{iso-propyl) 41 CH2C(-0)C2H3 Ph- 8-SCH3 42 CH2C(-0)C2H5 Ph- 8-SOCH3 43 CH2C(-0)C2H3 Ph- 8-SO2CH3 44 CK2C(-0)C2H3 Ph- 8-SCH2CH3 45 CK2C(-0)C2H5 Ph- 8-NH2 46 CH2C(-0)C2H5 Ph- 8-NKOH 47 CH2C(-0)C2K3 Ph- 8-^HCH3 48 CH2C(-0)C2H5 Ph- 8-N(CK3)2 49 CH2C(-0)C2H3 Ph- 8-N+(CH3)3, I" 50 CH2C(-0)C2H5 Ph- 8-Nr.C (-0) CH3 51 CH2C(-0)C2H3 Ph- 8-N{CH2CH3)2 52 CH2C(=0)C2H3 Ph- 8-NMeCH2C02H 53 CH2C(-0)C2H5 Ph- 8-N"(Me)2CH2C02H, I" 54 CH2C(-0)C2Hs Ph- 8-(N)-morpholine 55 CH2C(=0)C2Hj Ph- 8-(N)-azetidine 56 CH2C(-0)C2Hs Ph- 8-(N)-N-methylazetidinium, I" 57 CH2C(-0)C2H3 Ph- 8-(N)-pyrrolidine 58 CH2C(-0)C2H3 Ph- 8- (N) -N-methyl-pyrrolidinium, I" 59 CK2C{«0)C2Hs Ph- 8-(N)-N-ir.ethyl-morpholinium, I" 60 CH2C(-0)C2Hs Ph- 8- (N) -N' -methylpiperazine 61 CH2C(-0)C2Hs Ph- 8- (N) -N' -dimethylpiperazinium, I" 62 CH2C(-0)C2H3 Ph- 8-NH-CBZ 63 CH2C(-0)C2H5 Ph- 8-NHC COICsHH 64 CH2C(-0)C2Hs Ph- 8-NHC(0)CH2Br 65 CH2C(-0)C2H3 Ph- 8-NH-C(NH)NH2 66 CH2C(-0)C2Hs Ph- 8-(2)-thiophene 67 CH2C(-0)C2H3 Ph- 9-methyl 68 CH2C(-0)C2H3 Ph- 9-ethyl 69 CH2C(-0)C2Hs Ph- 9-iao-propyl 5^ Printed from Mimosa 09/15/1999 15:14:35 page -8 PCT/US98/03792 WO 98/40375 70 CH2C{-0) C2H3 Ph- 9-tert-butyl 71 CH2CC-0)C2Hj Ph- 9—OH 72 CH2C{-0)C2H3 Ph- 9-och3 73 CH2C (-0) C2H3 Ph- 9-0(iso-propyl) 74 CH2C (-0) C2H3 Ph- 9-sch3 75 CH2C(-0)C2H3 Ph- 9-soch3 76 CH2C (-0) C2H5 Ph- 9-s02ch3 77 CH2C(-0)C2H5 Ph- 9-sch2ch3 78 CH2C(-0)C2Hj Ph- 9-nh2 _.79 - - CH2C (-0) C2Hj— Ph-- 9—NHOH 80 CH2C(-0)C2H3 Ph- 9-nhch3 81 CK2C(-0)C2H5 Ph- 9-N(CH3)2 82 CH2C(-0)C2H5 Ph- 9-N+(CH3)3, I- 83 . CH2C (-0) C2H5 Ph- 9-NKC ("0) ch3 84 CH2C (-0)C2H3 Ph- 9-N(CH2CH3)2 85 CH2CC-0)C2Hs Ph- 9-NMeCH2C02H 86 CH2C(-0)C2Hj Ph- 9-N"(Me)2CK2C02H, I" 87 CH2C(-0)C2H3 Ph- 9-(N)-morpholine 88 CH2C(-0)C2H3 Ph- 9- (FJ) -azetidine 89 CH2C(-0)C2Hs Ph- 9- (NT) -N-cethylazetidinium, I~ 90 CH2C(-0)C2Hj Ph- 9-(N)-pyrrolidine 91 CH2C(-0)C2H3 Ph- 9- (N) -N-methyl-pyrrolidiniun, I" 92 CH2C(«0)C2H3 Ph- 9- (N) -N-methyl-aorpholiniun, X" 93 CH2C(=0)C2K3 Ph- 9- (N) -N' -methylpiperazine 93 CH2C (-0) C2H3 Ph- 9- (N) -N' -dmethylpiperaziniun, I" 95 CH2C<-0)C2Kj Ph- 9-NH-C3Z 96 CH2C(=0)C2H3 Ph- 9-NKC(0)C5H11 97 CH2C(-0)C2H3 Ph- 9-NHC(0)CK2ar 98 CH2C(-0)C2H3 Ph- 9-NH-C(NH)NH2 99 CH2C(=0)C2K3 Ph- 9-(2)-thiophene 100 CH2C(-0)C2H3 Ph- 7-OCH3, 8-och3 101 CH2C(-0)C2H3 Ph- 7-sch3, 8-och3 102 CH2C(-0)C2H3 Ph- 7-sch3, 8-sch3 103 CH2C(-0)C2H, Ph- 6-och3, 7-OCH3, 8-och3 Prefix Cpdjf R^ssR2 R5 (Rx)<j (FFF.xxx. vtv) F101.00901 CH2OC2H3 Ph- 7-methyl 02 ch2oc2h3 Ph- 7-ethyl ' 03 ch2oc2h3 Ph- 7-iao-propyl 04 ch2oc2h3 Ph- 7-tert-butyl 51 Printed from Mimosa 09/15/1999 15:14:35 page 9 WO 98/40375 PCT/US98/03792 05 ch2oc2h5 Ph- 7-OH 06 ch2oc2k5 Ph- 7-och3 07 ch2oc2hs Ph- 7-0(iso-propyl) 03 CH2oc2hs Ph- 7-SCH3 09 ch2oc2hs Ph- 7-SOCH3 10 ch2oc2ks Ph- 7-SO2CK3 11 CH2oc2hs Ph- 7-SCH2CH3 12 ch2oc2hs Ph- 7-NH2 13 ch2oc2h5 Ph- 7-NHOH 14 CH2oc2hs Ph- 7-NHCH3 15 ch2oc2h3 Ph- 7-N(CH3)2 16 CH2oc2hs Ph- 7-N+(CH3)3, I- 17 . ch2oc2h5 Ph- 7-NHC(»0)CH3 18 ch2oc2hs Ph- 7-N(CH2CH3)2 19 ch2oc2h5 Ph- 7-NMeCH2C02H 20 ch2oc2k5 Ph- 7-N* (Me) 2CH2C02H, I" 21 ch2oc2h3 Ph- 7-(N)-morpholine 22 ch2oc2h3 Ph- 7-(N)-azetidine 23 CH2oc2hS Ph- 7- (N) ^N-methylazetidinium, I" 24 ch2oc2h3 Ph- 7-(N)-pyrrolidine 25 CK2OC2H3 Ph- 7- (N) -N-tr.ethyl-pyrrolidinium, 26 ch2oc2hs Ph- 7-(N)-N-methyl-morpholinium, I 27 CH2oc2hS Ph- 7- (N) -N' -methylpiperazine 28 CK2oc2hs Ph- 7- (N) -N' -dimethylpiperazinium, 29 ch2oc2h5 Ph- 7-NK-C3Z 30 ck2oc2h5 Ph- 7-nhc (o)cshn 31 CH2oc2ks Ph- 7-nhc(0)ch23c 32 CH2oc2hs Ph- 7-NH-C(NH)NH2 33 ch2oc2h3 Ph- 7-(2)-thiophene 34 ch2oc2h5 Ph- 8-methyl 35 ch2oc2h5 Ph- 8-ethyl 36 ch2oc2h5 Ph- 8-iso-propyl 37 CH2OC2Hj Ph- 8-tert-butyl 38 ch2oc2h5 Ph- 8-OH 39 ch2oc2h5 Ph- 8-OCH3 40 ch2oc2h3 Ph- 8-0(iso-propyl) 41 ch2oc2h5 Ph- 8-SCH3 42 ch2oc2h3 Ph- 8-SOCH3 43 ch2oc2hs Ph- 8-SO2CH3 44 CH2OC2Hs Ph- 8-SCH2CH3 45 ch2oc2h5 Ph- 8-NH2 46 ch2oc2h5 Ph- 8-NHOH 5? Printed from Mimosa 09/15/1999 15:14:35 page 10 WO 98/40375 PCT/US98/03792 47 CH2OC2H5 Ph- 8-NHCH3 48 CH2OC2HS Ph- 8-N(CH3J 2 49 CH2OC2H5 Ph- a-N+5013)3, i" 50 CH2OC2H5 Ph- 8-NHC(-0)CH3 51 ch2oc2hs Ph- 3-N(CK2CH3)2 52 CH20C2H5 Ph- 8-NKeCH2C02K 53 ch2oc2h5 Ph- 8-N* (He) 2CH2C02H, I" 54 CH20C2H5 Ph- 8-(N)-aorpholine 55 CH20C2H5 Ph- 8-(N)-azetidine 56 CH20C2H5 Ph- 8-(N)-N-methylazetidinium, X~ 57 CH20C2H5 Ph- 8-(N)-pyrrolidine 58 CH20C2H5 Ph- 8-CN)-N-ir.ethyl-pyrrolidinium, I" 59 CH20C2H5 Ph- 8-(N) -N-mathyl-morpholinium, I" 60 - CH20C2H5 Ph- 8- (N) -N' -eethyloiperazina 61 ch2oc2hs Ph- 8-(N)-N'-dimethylpiperazinium, I" 62 CH20C2H5 Ph- 8-NH-C32 63 CH20C2H5 Ph- 8-NHC (O)CsHh 64 CH20C2H5 Ph- 8-NKC(O)CK2Br 65 CH2OC2KS Ph- 8-nh-c(n:-:)nh2 66 CH20C2H5 Ph- 8- r2)"-thiophene 67 CH20C2K5 Ph- 9-iechyl 68 CK20C2H5 Ph- 9-ethyl 69 CH20C2K5 Ph- 9-iso-prdayl 70 CK20C2H5 Ph- 9-te=t-Sutyl 71 CK20C2H5 Pn- 3-OK 72 CH20C2H5 Ph- 9-OCH3 73 CH20C2H5 Ph- 9-0(iso-propyl) 74 CH20C2H5 Ph- 9-SCH3 75 CH20C2H5 Ph- 9-SOCH3 76 CH20C2H5 Ph- 9-SO2CH3 77 CH20C2H5 Ph- 9-SCH2CH3 78 CH20C2H5 Ph- 9-NH2 79 CH2OC2HS Ph- 9-NHOH BO ch2oc2h5 Ph- 9-NHCH3 81 CH2OC2HS Ph- 9-N (CH3) 2 82 CH20C2HS Ph- 9-N+(CH3)3, I" 83 CH2OC2HS Ph- 9-NHC(-0)CH3 84 CK2OC2Hs Ph- 9-N(CH2CH3)2 85 CH2OC2H5 Ph- 9-NMeCH2C02H 86 CH2OC2HS Ph- 9-N* (Ms) 2CH2C02H, I" 87 CH20C2H5 Ph- 9-(N)-morpholine SI Printed from Mimosa 09/15/1999 15:14:35 page -11- WO 98/40375 PCT/US98/03792 88 CH20C2H5 Ph- 89 CH2OC2Hs Ph- 90 CH2OC2H5 Ph- 91 CK2OC2Hj Ph- 92 CH2OC2H5 Ph- 93 CH20C2Hs Ph-93 CH20C2HS Ph-95 CH2OC2Hs Ph- 96 CH2OC2H5 Ph— 97 CH2OC2H5 Ph- 98 CH2OC2H5 Ph- 99 CH2OC2Hs Ph- 100 ' CH2OC2H5 Ph- 101 CH2OC2HS Ph- 102 CH2OC2H5 Ph- 103 CH;OC;H5 gh~ 9-(N)-azetidine 9- (N) -N-methylazetidinium, I" 9-(N)-pyrrolidine 9- (N) -N-irethyl-pyrrolidinium, I" 9-(N)-N-methyl-morpholiniun, X" 9- (N) -N' -methylpiperazine 9- (N) -N' -dimethylpiperazinium, I" 9-NH-CB2 9-NHC (OK5H11— 9-NHC(O)CH2Br 9-NH-C(NH)NH2 9-(2)-thiophene 7-OCH3, 8-OCH3 7-SCH3, 8-OCH3 7-SCH3, 8-SCH3 6-OCH3, 7-OCH3, 8-OCH3 Prefix (rFF.xaa;. FLO 1.010 Cpd# It H p£ r5 wv) 01 CH2CH(OK)C2H5 Ph- 7-methyI 02 CH2CH(OH)C2Hs Pn- 7-ethyl 03 CH2CH(OH)C2Hs Ph- 7-iso-propyl 04 CH2CH (OH) C2H5 pfl- 7-tert-butyl os CK2CH(OK)CJH5 Ph- 7-OH os CK2CH(OH)C2H5 Ph- 7-OCK3 07 CH2CH (OK) C2H5 Ph- 7-0(iso-propyl) 08 CK2CH(0H)C2Ks Ph- 7-SCH3 09 CH2CH(OH)C2Hs Ph- 7-SOCH3 10 CK2CH (OH) C2H.3 Ph- •7-SO2CH3 11 CH2CH(OH)C2H5 Ph- 7-SCH2CH3 12 CH2CH(OH)C2H5 Ph- 7-NH2 13 CH2CH(OK)C2H5 Ph- 7-NHOH 14 CH2CH (OH) C2H5 Ph- 7-NHCH3 15 CH2CH(OH)C2Hs Ph- 7-N(CH3)2 16 CK2CH (OH) C2HS Ph- 7-N+(CH3)3, I" 17 CH2CH (OH) C2H5 Ph- 7-NHC(-0)CH3 18 CH2CH (OH) C2HS Ph- 7-N(CH2CH3)2 19 CH2CH(0H)C2HS Ph- 7-NMeCH^C02H 20 CH2CH(OH)C2K5 Ph- 7-N* (Me)jCH2C02H, I" 21 CH2CH(OH)C2Hj Ph- 7-(N)-morpholine 22 CH2CH (OH) C2H5 Ph- 7-(N)-azetidine GO Printed from Mimosa 09/15/1999 15:14:35 page -12- WO 98/40375 PCT/US98/03792 23 ch2ch (oh) c2h5 Ph- 7- (n) -N-cethylaze|^<^jj^im, i" 24 chjch(oh)c2hs Ph- 7-(N)-pyrrolidine 25 ch2ch(oh)c2h5 Ph- 7- (N) -N-methyl-pyrzolidiniua, I" 26 ch2ch(oh)c2hs Ph- 7-(N)-N-cethyl-morpholiniua, I" 27 ch2ch(oh)c2hs Ph- 7- (N) -N' -methylpiperazine 28 ch2ch(oh)c2hs Ph- 7- (N) -N' -dimethylpiperasinium, I" 29 ch2ch(ok)c2hs Ph- 7-nh-cbz 30 ch2ch(oh)c2h5 Ph- 7-nkc(o)C5H11 31 ch2ch(oh)c2h5 Ph- 7-nhc(0)ch23r 32 ch2ch (oh)c2h5 PIT-' 7-nh-c(nh)nh2— 33 ch2ch(oh)c2hs Ph- 7- (2)-thiophene 34 ch2ch(0h)c2hs Ph- 8-methyl 35 " ch2ch(oh)c2hs Ph- 8-ethyl 35 ck2ch(oh)c2hs Ph- 8-iso-prooyl 37 ck2ch(0k)c2k5 Ph- 8-tert-butyl 33 ch2ch(oh)c2h5 Ph- 8-oh 39 ch2ck(ok)c2h5 Ph- 8-OCH3 40 ck2ck(oh)c2k5 Ph- 8-0(iso-propyl) 41 ch2ck(ok)c2h5 Ph- 8-SCH3 42 ck2ch(oh)c2as Ph- 8-soch3 43 ck2ch(0h)c2h5 Ph- 8-SO2CH3 44 ch2ch(oh)c2hJ Ph- 8-SCH2CK3 45 ch2ck(oh)c2h5 Ph- 8-NH2 46 ck2ch(oh)c2h5 Ph- 8-nhoh 47 ch2ck(oh)c2h3 Ph- 8-NHCH3 43 ch2ch(oh)c2h5 Ph- 8-N (CH3) 2 49 ck2cp. coh)c2ks Ph- 8-U+ (Cn3) 3, I" 50 ch2ch(0h)c2hs Ph- 8-nhc("0)CH3 51 CK2ck(OH)cJhS Ph- 8-N (CH2CH3)2 52 ck2ch (oh)c2hJ Ph- 8-NKeCH2C02H 53 ck2CH(oh)c2hs Ph- 8-N*(Me)2ch2c02h, I" 54 ch2ch(oh)c2hs Ph- 8-(N)-morpholine 55 ch2ch(oh)c2h5 Ph- 8-(N)-azetidine 56 ch2ch(oh)c2hJ Ph- 3-(N) -N-methylazetidinium, I" 57 CH2ch(oh)c2hs Ph- 8- IN)-pyrrolidine 58 ch2ch(oh)c2hs Ph- 8-(N)-N-methyl-pyrrolidinium, I" 59 ch2ch(oh)c2hs Ph- 3-(N)-N-methyl-morpholinium, I" 60 ch2ch(oh)c2h5 Ph- 8- (N) -N' -methylpiperaxine 61 ch2ch(oh)c2h5 Ph- 8-(N)-N'-dimethylpiperazinium, I' 62 ch2ch(oh)c2h5 Ph- 8-nh-cs2 63 ch2ch(oh)c2h5 Ph- 8-nhc (0)c5hh 64 ch2ch(oh)c2h5 Ph- 8-nhc(0)CH2Br 61 Printed from Mimosa 09/15/1999 15:14:35 page -13- WO 98/40375 65 ch2ch(oh)c2h5 66 ch2ch(oh)c2hs 67 ch2ch(oh)c2hs 68 ch2ch(oh)c2h3 69 ch2ch{oh)c2h3 70 ch2ch(oh)c2hJ 71 ch2ch(oh)c2h5 72 ch2ch(ohlc2h3 73 ch2ch(oh)c2h5 74 ch2ch(oh)c2h3 75 ch2ch(oh)c2hJ 76 ch2ch(oh)c2k5 77 ch2ch(oh)c2h5 78 ch2ch(oh)c2h5 79 ck2ch(oh)cjhJ 80 ch2ch(oh)c2h3 81 ck2ch(oh)c2h3 82 c:-:2ch (oh) c2k3 83 ch2ch(oh)c2hs 84 chzch (oh) c2:-:3 85 ch2ch(oh)c2h5 86 ch2ch(oh)c2h3 87 ch2ch(oh)c2h3 88 ch2ch(oh)c2h3 89 ck2CH(oh)cJk3 90 ch2ch(oh)c2h3 91 ch2ch(oh)c2h3 92 ch2ch(oh)c2k3 93 ch2ch(oh)c2h5 93 ch2ch(oh)c2h3 95 ch2ch(oh)c2k5 96 ch2ch(oh)c2h; 97 ch2ch(oh)c2h5 98 ch2ch(oh)c2hs 99 ch2ch(oh)c2h3 100 ch2ch(oh)c2hs 101 ch2ch(oh)c2h5 102 ch2ch(oh)c2h5 103 ch2ch(oh)c2h5 PCT/US98/03792 Ph- fl-NH-C(NH)NH2 Ph- 8-(2)-thiophene Ph- 9-siethyl Ph- 9-ethyl Ph- 9-iso-propyl Ph- 9-tert-butyl Ph- 9-QK Ph= S^OCH-3 Ph- 9-0(iao-propyl) Ph- 9-sch3 Ph- 9-soch3 Ph- 9-so2ck3 Ph- 9-sch2ch3 Ph- 9-NK2 Ph- 9-NH0H Ph- 9-NHCH3 Ph- 9-N (ch3) 2 Ph- 9-N+{CH3)3, I" Ph- 9-NSC(-0)CH3 Ph- 9-N(CH2CH3)2 Ph- 9-NMeCH2C02H Ph- 9-JT(.Me)2CK2C02H, I" Ph- 9- (N) -morpholine Ph- 9-(N)-azetidine Ph- 9-(N)-N-methylazetidiniuni, I" Ph- 9-(N)-pyrrolidine Ph- 9-(N) -N-ir.ethyl-pyrrolidinium, I" Ph- 9-(N)-N-ff.ethyl-morpholiniuni, I" Ph- 9- (N) -N' -methylpiperazine Ph- 9-(N)-N'-dimethylpiperazinium, I" Ph- 9-NH-C3Z Ph- 9-NHC(O)CsHix Ph- 9-NHC(0)CH23r Ph- 9-NH-C(NH)NH2 Ph- 9-(2)-thiophene Ph- 7-och3, 8-och3 Ph- 7-sch3, 8-och3 Ph- 7-sch3, 8-sch3 Ph- 6-och3, 7-och3, 8-och3 6a Printed from Mimosa 09/15/1999 15:14:35 page -14- WO 98/40375 PCT/US98/03792 Prefix Cpd# rAsr2 r5 (r*) q (TTT.xxx. wv) F101.011 CHjO- (4-picoline) Ph- 7-methyl 02 CH2O-(4-picoline) Ph- 7-ethyl 03 CH2O-(4-picoline) Ph- 7-iso-propyl 04 CH2O-(4-picoline) Ph- 7-te=t-butyl 05 CH2O-(4-picoline) Ph- 7-OH 06 CH20-(4-picoline) Ph- 7-och3 "07 "CH20^("4-picorine) ~ Eh- 7-0(iso-propyl) 08 CHzO-(4-picoline) Ph- 7-sch3 09 CH20-(4-picoline) Ph- 7-soch3 10 CH20-(4-picoline) Ph- 7-so2ck3 11 . CH20-(4-picoline) Ph- 7-sch2ch3 12 CH2O-(4-picoline) Ph- 7-NH2 13 CH20-(4-picoline) Ph- 7-NKOH 14 CH2O-(4-picoline) Ph- 7-nkch3 15 CH20-(4-picoline) Ph- 7-N(CH3>2 16 CH2O- (4-picoline) Ph- 7-N* (.CH3) 3, I" 17 CH20-(4-picoline) Ph- 7-Nkc(-0)CH3 18 CH20- (4-picolme) Ph- 7-N(CH2CK3)2 19 CH20- (4-picolme) Ph- 7-NMeCH2C02H 20 CH20-(4-picoline) Ph- 7-N*(Me)2CK2CO2H, I" 21 CH20-(4-picoline) Ph- 7-(N)-morpholine 22 CHjO-(4-picoline) Ph- 7-(N)-azetidine 23 CH20-(4-picoline) Ph- 7- (M) -N-methylazetidinium, I" 24 CH20-(4-picoline) Ph- 7-(N)-pyrrolidine 25 CH2O-(4-picoline) Ph- 7-(N)-N-methyl-pyrrolidinium, I" 25 CH2O-(4-picoline) Ph- 7-(N)-N-methyl-morpholinium, I" 27 CH2O-(4-picoline) Ph- 7-(N)-N'-methylpiperazine 28 CH20-(4-picoline) Ph- 7-(N)-N'-dimethylpiperazinium, I" 29 CH20-(4-picoline) Ph- 7-NH-CBZ 30 CH20-(4-picoline) Ph- 7-NKC (O) C5HH 31 CH20-(4-picoline) Ph- 7-NHC(O)CH23r 32 CH20-(4-picoline) Ph- 7-NH-C(NH)NH2 33 CH2O-(4-picoline) Ph- 7-(2)-thiophene 34 CHzO-(4-picoline) Ph- 8-methyl 35 CH2O-(4-picoline) Ph- 8-ethyl 36 CH20-(4-picoline) Ph- 8-iso-propyl 37 CH20-(4-picoline) Ph- 8-tert-butyl 38 CH20-(4-picoline) Ph- 8-OH 39 CH20-(4-picoline) Ph- 8-OCH3 G3 Printed from Mimosa 09/15/1999 15:14:35 page 15 WO 98/40375 PCT/US98/03792 40 ch2o- -picoline) Ph- 8-0{iso-propyl) 41 ch2o- -picoline) Ph- 8-sch3 42 ch2o- -picoline) Ph- 8-soch3 43 ch2o- -picoline) Ph- 8-so2ch3 44 ch2o- -picoline) Ph- 8-sch2ch3 45 ch2o- -picoline) Ph- 8-nh2 46 ch2o- -picoline) Ph- 8-nkoh 47 ch2o- -picoline) Ph- 8-nkch3 48 ch2o- -picoline) Ph- 8-n cch3)2 49 ch2o— -picoline) Ph- 8-n+(ch3)3, i" 50 ch2o- -picoline) Ph- 8-nkc(~0)ch3 51 ch2o- -picoline) Ph- 8-n(ch2ch3)2 52 . ch2o- -picoline) Ph- 8-NMeCH2C02H 53 ch2o- -picoline) Ph- 8-N*(Me)2ch2c02H, I" 54 ch2o- -picoline) Ph- 8-(N)-morpholine 55 ch2o- -picoline) Ph- 8-(N)-azetidine 56 ch2o- -picoline) Ph- 8-(N)-N-r.ethylazetidinium, I" 57 ch2o- -picoline) Ph- 8-(N)-pyrrolidine 53 ch2o- -picoline) Ph- 8-"fN)"-N-=:ethyl-pyrrolidinium, 1 59 ch2o- -picoline) Ph- 8-(N)-N-cethyl-morpholinium, I" 60 ch2o- -picoline) Ph- 8-(N)-N'-cethylpiperazine 61 ch2o- -picoline) Ph- 8- (N) -N' -dimethylpiperaziniuia. 62 ch2o- -picoline) Ph- 8-NK-C3Z 63 ch2o- -picoline) Ph- 8-NHC(O)CgHix 64 ch2o- -picoline) Ph- 8-NKC(O)CK23r 65 ch2o- -picoline) Ph- 8-NH-C(NK)NH2 66 ch2o- -picoline) Ph- 8-(2)-thiophene 67 ch2o- -picoline) Ph- 9-methyl 68 ch2o- -picoline) Ph- 9-ethyl 69 ch2o- -picoline) Ph- 9-iso-propyl 70 ch2o- -picoline) Ph- 9-tert-butyl 71 ch2o- -picoline) Ph- 9-oh 72 ch2o- -picoline) Ph- 9-och3 73 ch2o- -picoline) Ph- 9-0(iso-propyl) 74 ch2o- -picoline) Ph- 9-sch3 75 ch2o- -picoline) Ph- 9-soch3 76 ch2o- -picoline) Ph- 9-so2ch3 77 ch2o- -picoline) Ph- 9-sch2ch3 78 ch2o- -picoline) Ph- 9-nh2 '• 79 ch2o- -picoline) Ph- 9-nhoh 80 ch2o- -picoline) Ph- 9-nkch3 81 ch2o- -picoline) Ph- 9-N(ch3)2 0,4- Printed from Mimosa 09/15/1999 15:14:35 page 16 WO 98/40375 PCT/US98/03792 82 ch2o- 4-picolina) Ph- 9-N+(CH3)3, I- 83 ch2o- 4-picoline) Ph- 9-NHC(-O)CH3 84 ch2o- 4-picoline) Ph- 9-N(CH2CH3>2 85 ch2o- 4-picoline) Ph- 9-NMeCH2C02H 86 ch2o- 4-picoline) Ph- 9-N*(Me)2CH2C02K, I" 87 ch2o- 4-picoline) Ph- 9-(N)-morpholine 83 ch2o- 4-picoline) Ph- 9-(N)-azetidine 89 ch2o- 4-picoline) Ph- 9- (N) -N-methylazetidinium, I" 90 ch2o- 4-picoline)- —Ph— 9-(N)-pyrroiidine 91 ch2o- 4-picoline) Ph- 9- (N) -N-methyl-pyrrolidinium, I" 92 ch2o- 4-picoline) Ph- 9- (N) -N-methyl-morpholiniuia, I* . 93 ch2o- 4-picoline) Ph- 9-(N)-N'-methylpiperazine 93 ch2o- 4-picoline) Ph- 9-(N)-N'-dimethylpiperariniuu, I~ 95 ' ch2o- 4-picoline) Ph- 9-NH-C32 96 ch2o- 4-picoline) Ph- 9-NKC(O)C5H11 97 ch2o- 4-picoline) Ph- 9-NHC(0)CK23r 93 ch2o- 4-picoline) Ph- 9-NH-C(NK)NH2 99 ch2o- 4-picoline) Ph- 9-(2)-thiophene 100 ch2o- 4-picoline) Ph- 7-OCH3, 3-och3 101 ch2o- 4-pj.coline) Ph- 7-SCK3, 3-OCH3 102 ck2o— 4-picoline) Ph- 7-SCH3, 8-SCH3 103 ch2o- 4-picoline) Ph- S-0ch3, 7-oca3, 8-0CH3 (oS Printed from Mimosa 09/15/1999 15:14:35 page -17- WO 98/40375 PCT/US98/03792 Printed from Mimosa 09/15/1999 15:14:35 page 18 WO 98/40375 PCT/US98/03792 (o1 Printed from Mimosa 09/15/1999 15:14:35 page 19 WO 98/40375 PCT/US98/03792 o1 X _0 >*, X V so at the 8-position ^ s >-* X g -3 >> ao V: I i ''QrOi >i X 0 3 u tz 90 y__ PATEN ? i 4°? — a. 0 3> ">» 3 PS, o "E. 0 XI £ >s 3 e tN X *5 *3 N « 2 Cs >, X 0 3 >s X 3 CN X X X X X X X X >s ? 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QC cn S tN Cv ao CN s CN CN CN CN <n CN CN SN CN LH CN CN 61 Printed from Mimosa 09/15/1999 15:14:35 page -21- WO 98/40375 PCT/US98/03792 -jo Printed from Mimosa 09/15/1999 15:14:35 page -22- WO 98/40375 PCT/US98/03792 It Printed from Mimosa 09/15/1999 15:14:35 page -23 WO 98/40375 PCT/US98/03792 0 c 1 a V E •5 tN 7-d imethy lamino 0 1 JS ">% y IN 7-dimethylammo 3 C >» £ ■5 tN 3 c J8 >s J -5 tN r X X X X X Q- C. \ d ■r U. O P X CD o >> T" • r -P X -T K5" 8~ (O c* \ + \\ u \ / N !> #<• u. &S a u + z s K U. 0 P z X £ X X X o X o § X o X o X o "SK 1 c 3 ■a "3s 3 1 J 3 e 5» 3 J3 C >s 3 *? e n-bulyl 3 J3 C 5* *3 •9 e 3 J3 e X 3 •? C 3 C 1015 NO S o ao e £ o © -Imprinted from Mimosa 09/15/1999 15:14:35 page 24 WO 98/40375 PCT/US98/03792 "73 Printed from Mimosa 09/15/1999 15:14:35 page -25 WO 98/40375 PCT/US98/03792 7-dimelhylamino 0 e 1 c* "Z £ 7 cs» 0 s u 1 ■5 N» 0 c 1 rs V £ ■5 s 0 c (S "3s e "7 ts> Z X X X X ,^.Q ^2 2 Q--»-0 ? H. X u + z Ik o £ • r k5" ~o t" - {' z z r X X z 0 z o X 0 X 0 X 0 >» 1 2* 3 B >* 3 ■9 * s j> s >» 3 X) c >» 1 e >. 3 ■9 B 3 «a 3K 1 e 'sk 3 e rs o § 5 e E5 © i "7 + Printed from Mimosa 09/15/1999 15:14:35 page -26- WO 98/40375 PCT/US98/03792 0 c E E ■5 tN 7-d imethy lamino 7-d iinethy lamino 7-dimethylnmino i 9 e E A ">* § *5 tN 9 C c >s V C -5 tN X X X X X X o=^ - r r» * M 8 S cT x u o z + C* (M 5\ £ -3 z o £ j il k>„ \ ° ? <^o X? I X X X X X X o X 0 X o X 0 X o X 0 n-l>utyl n-bulyl 3 .0 s ">N 3 .3 c ■J 3 .9 c 5* 3 .9 e n-bulyl 3* 3 J3 S >* 3 -9 e >. 3 -0 e >s 3 A e £s 3 ja c 5\ CN 9 s o I i 3 o S © ~ls Printed from Mimosa 09/15/1999 15:14:35 page -27- WO 98/40375 PCT/US98/03792 0 e 1 J2 "3s D c •5 Ps 7-dimethylamino i 0 c 1 > "3 E ■u IN 9 e I c >» V e ■5 rs o s c _2 > "3 § -5 pi. 0 E a X "S e T3 tN X X X r X X .2 2 0.-»-O ■ f Kx o . i' "> c u > X C >■ o *n X o +z s *§ 8 4. ~ cT x 5 u o a •w i C*J 2 + PN -2/ E N 5 Xv J S> 1 N — o\ JS u. O = W | O i ) ■ * r- X X X X X X X o X o X o X 0 X o X o 3 •JZ ">■» 3 J3 c > 3 ja c X 3 -? c £■ s JZ e J 3 ja c ">N 3 t e J 3 C 5 3 e 3 fi ">* 3 x e 3 .o c i i ts «n o 3 © ev po o o o -Imprinted from Mimosa 09/15/1999 15:14:35 page -28- WO 98/40375 PCT/US98/03792 11 Printed from Mimosa 09/15/1999 15:14:35 page -29- WO 98/40375 PCT/US98/03792 9 C a J9 ">» *5 ■5 9 e « ■>> e "O rs 7-d imethy lamino 0 c 1 n >> £ V § 7 ts PA' 9 5 ■S 41 J ■u » CN X X X X X r> X a (M X o + z .r o & Q. *r u. o p p oA Q +/ >p u. O (_) (_) o < f 22 X X X X OH § X 0 X 0 X 0 1 I e 5> 3 J e X 3 •o c >» 3 X c n-butyl 3 s 1 3 .3 C >, 3 * e X 3 X e 3 CN -r o a o K o »*• CN IA O TS Printed from Mimosa 09/15/1999 15:14:35 page -30- WO 98/40375 PCT/US98/03792 s JS u CN 7-d imethylamino 0 s 5 >» £ 6 rs. 7-dimethylamino 1 i ■NT 0 s *5 ">* 15 § ts. X £ X X X \ 'a: Cf" 0 X u. o {_) (_) Q • X \/~\/ c, r> /wf. o & o ■ r <5" o - X X X X X X HO X 0 X o ae o X o • n-bulyl >» 3 ■9 e 3 •? 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C ">» 3 A ">■ 3 A 3 -D ">■ A C 3 "? c 3 A ">s A | X 3 A s 5 3 e >» 3 C ">« 3 A C 5 3 •9 S *5. 3 A C 3 J3 >. 3 .3 >. 3 .3 e 5 3 J e 3 J3 C *>. 4 3 c A C 3 .3 e *>. 3 c X 3 A ">■ 3 C > 3 C ">s 4 e ut n s n § 2* r> O ««r -T r> s m rs -T 00 T T o un ut (S un m LT> iA 1A in Printed from Mimosa 09/15/1999 15:14:35 page -42- WO 98/40375 PCT/US98/03792 0 Q. S |M g >s e [S 0 c si 9 >i J3 X ? « ^ 6 -o o >s X 0 a e Cs c e E « U £ •0 ri c '5 fS *X« ■3 pi. 3 c i a "x 7 ts c e £ « x V E 7 ts X, X 4! £ Cs X, X 9 V £ Cs 7-lrimethyUmmonium iodide | V 3 .2 £ 3 E 0 £ £ 13 "x V E w CS O e £ ts "x» •5 S ■5 cs it -5 £ 'c c E E *x H £ ts \ rs X u C "0 W "x, 9- 3 "> ts C E « >s V c 7 rs >s X a Cs ft X a S > es >s c SJ "5. Ps >S ,3 A X u e ts 0 3 _3 CN 9 E f; C X *9 Cs 3 c £ >N V C -O [S X a £ ao 3 3 E E « >. u E cs c 1 X, JJ s £ ri X X 0 al E ts 0 _5 Cs 3 C U k» 3 9 CS ^ ?A 3 pi mr 3 s 3 0 _3 ^ Cs Cv 1 "x, 15 ts V *0 -5 3 E E f! X aj § u fs u ■3 3 c 3 f? X *5 c IS £ 3 Cs. 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X X X X X X X X X X X 0 X 0 X 0 E 5 § § X 0 X 0 X 0 3 -? e X 3 J3 fi 3 J3 C X 3 *? e 5* 3 .3 3 •? e ">■ 3 J C jp .3 X X "x 3 A 3 A e J 3 C X 3 .n e X 3 ■9' c X 3 .a c "> V X 3 *? c "x 3 "? C 3 A 1 r fc cs R CN « 3 fN So CM P4 ac CN so CN ■v X CN LSI as <N Printed from Mimosa 09/15/1999 15:23:06 page 1 WO 98/40375 PCT/US98/03792 IOO Printed from Mimosa 09/15/1999 15:23:06 page 2 WO 98/40375 PCT/US98/03792 IOC Printed from Mimosa 09/15/1999 15:23:06 page 3 WO 98/40375 PCT/US98/03792 o e 6 ei x "u c ■o pi. a e i £ j? e y hi rimelhylammanium iodide 1 > % •c 6, 0 s 1 j* E -5 ri s e 'i jg 3 5 ri i 1 2 >* £ T £ 9t 0 c 1 41 *>. £ « E ■5 pi 0 »S "o "a. o E So 9* i 0 s 1 n >» j: "m E ■S pi 9 u 0 3 9s e E <3 pi T £ n >> x g -o >. pi x "> x" 9/ » > x V ZC e *5 x 2 ■u >« pi >. x v Sr Pn ts r >. s w JZ a. X Z X X X X i i £• S-2 S a X X X T" r X = N *"n X - 5 •=. +V-r' r V X s "ft. X x * £ n >. 5 * >• X £ | m n X Q + Z o 0 ">» e V "si >. x C f E M >. e V "H. 2 0 ,3 Q, \ o / o 0=\ \ o 0 X u. O \ o 7^ s "5. x n s "a. "a. ">* z >. j a. s 5 X Z o X X X X X X X E = X X X 2 X § x x o 5 § s § r o X o r o § § X o X o X o X 0 X 0 * a A s *>» w 2? 3 *9 s 3 t J c 5 3 9 e 5 9 •? e 2> 3 e J 3 A 1 e 5> 3 J> C 3 e >* 3 .9 c >> 5. 3 •J > A c x 3 A c 3 j3 e .3 s X 3 t ">k 3 1 >. 3 *? e | e 3 .a e 3 J3 S f "Z j3 e > IS ■> A c 3 .a e 4 > « > m 1 s i § § 3 en B | Ps O r> i 8 rj © r> <N r) n * ?? ?n toa. Printed from Mimosa 09/15/1999 15:23:06 page 4 WO 98/40375 PCT/US98/03792 > X £ 1 ac 1 at the S-position 7-dimetliylamino 0 u 0 JJ pi. 7-amino J. j-" | -f—- 1 0aa^Z>^8>0'» 9 e i « "Ss •£ w J •u Ps 7-dimethylamino 9 e S « V § •v Ps 1 7-dimelhylamino X x X X X X X E X r s o > \ ZX / Q cn *>» V Ik « s a 5 "a. > c u "S. >» X 0 3J e rn c 3J "a >s e 1J "a. \ u. O e a* s J5 y 3 •v X X X X X X X X r X HO 1 r o X o X 0 X o X o X o X 0 X 0 r o |A<11» | V 5 3 ■9 S | n-butyl | 5 3 JQ C *5* X ■>* 3 J) c >% 3 A e >, 3 Si C 3 A S 3 C % 3 -9 e V "5> ■s £ V 3 -O C '>s 3 jQ C ">> 3 .a e 3 . .3 S 3 J3 e 91CI 1 ps m ae cn ev tn O CN cn cn 3 cn a cn * rs m LA CN cn 103 Printed from Mimosa 09/15/1999 15:23:06 page -5- WO 98/40375 PCT/US98/03792 lo4- Printed from Mimosa 09/15/1999 15:23:06 page 6 WO 98/40375 PCT/US98/03792 loS Printed from Mimosa 09/15/1999 15:23:06 page 7 PCT/US98/03792 WO 98/40375 RffiNT 4) 3 3 ">s V £ ■5 pi. > e '5 t? hm V a 5 £, 1 V Ps 3 e I tg 7K V 6 *? rs > "5 £ Ps 3 J5 IK J? c ■5 Ps *>» C V "ft. 2 5 _3 Cs 3 i a Ps 0 e 1 (7 "SjK n e "U ts •a to £ 3 *5 o c c ^3 > V § 'k \ < 1 V ji o o ?! ?r 0 c S es 4) £ *u cs 9 e I u E ■5 Ps S s i JT > "3 £ pl •3 £ '3 3 e § J5 ">» G 0 c 'i V £ *5 Ps _ — — —— ts Ps X X r x X X X X X X X X X X X Q ^ + "> c u > X X o o \ -C X X a. >> U >s e V "a. X o c V "x 5 s Q. >. X c V V u "x s 4) *a X o n z 2 ! X V c x> in i) ri IA *? w O J3 r> ** cn c 3 n < p £ N & - X X r X X = X X X X X X X X [ 1 1 MO 5 § r 0 r ? w c X 0 X o X o X o X o X 0 5 X o § § 3 3 J S >* 3 e % >■ 2 A ">s 3 A c 3 A G 3 -3 s 5 *9 c > 3 1 "J J3 c "5* £ >» 3 c *>> 3 J1 X 3 .a c 3 •9 S. 3 J C 3 .3 > 3 J c "> >. 3 j3 C "> X ">N ^3 3 A G "> 3 J 3 #J2 "5 "3s 3 .3 C 5» 3 i ps. n S 5* c-> o •r ** cm rf r> ■*r ut *T Ps 90 •«r C\ St n n m n r> r> r> m fn < lot Printed from Mimosa 09/15/1999 15:23.06 page 8 WO 98/40375 PCT/US98/03792 lOl Printed from Mimosa 09/15/1999 15:23:06 page 9 WO 98/40375 PCT/US98/03792 0 e e a >* V c 7 CS 0 e 1 « x V e 7 ts 0 e 1 >» £ S 7 [S 0 e 1 « >* £ V S y Ps X X X X X o N X o + ST -t' -o o ~kt/ cO 2 + \ « - ? o \_) o at o ^C_) X X X X OH X o X o X o J 3 J3 3 A c 5* 3 pfi C "5% 3 A e n-bulyl 3 .3 3 .3 C ">» 3 J3 e 3 n r- ©* IA cn 3 m 3 m IOS Printed from Mimosa 09/15/1999 15:23:06 page 10- WO 98/40375 PCT/US98/03792 0 *1 5 % 7 PS 0 c 1 a X £ 7 CS o c S* v c -5 >» S 1 jg *>» aj s •5 Ps a c 3 "5s a» £ 7 !S X be X X X 0 X o, °W cn «4 •< J rr -o •P o"\ -J 0 - 2: u. O _w X £ X X r X o r o X o § § 3 ■? "ix □ A e !> 3 A C 3 ■9 e >■» 3 ■9 e £ >* 3 .ft C 5* 3 e 5» 3 .£ e 5» 3 £ C fN 2 3 « 3 ro IA vo en 3 cn l©<\ Printed from Mimosa 09/15/1999 15:23:06 page -11 WO 98/40375 PCT/US98/03792 Printed from Mimosa 09/15/1999 15:23:06 page -12- WO 98/40375 PCT/US98/03792 0 e C 5 a ■3 Ps 0 c £ ">» £ ■5 Ps ouiuiL'lXmauiip-/ 7-d imetliy lamina 9 1 >» 1! c ■5 rs r r X X X z -J P" P -4 P P -J P P o p P X X X X r HO X o X o X o X o *>> 3 Ji >» 3 A C 5* 3 A e 3 J3 e IK 3 -? e S* 3 .9 C ">s 3 A C ">s 3 "9 C 3 XI S 3 A C 1371 R n R «n S m k CO i\\ Printed from Mimosa 09/15/1999 15:23:06 page -13- WO 98/40375 PCT/US98/03792 113- Printed from Mimosa 09/15/1999 15:23:06 page -14- WO 98/40375 PCT/US98/03792 l\3 Printed from Mimosa 09/15/1999 15:23:06 page -15- WO 98/40375 PCT7US98/03792 o s 6 £ >» il s ■5 rs. o s 6 >» V c "5 pi 0 e £ ra X w £ "? 9 e 1 £ "? pi o c £ J9 *>» *» £ V ts X X X r X _n *7> X u ft X o +z - r u. O P u. O ■A /^O (/ "-C_> p \_=0> r "* u. O \J I X r X X 5 X o X o 5 ">* I 3 e * 3 C 3 ■9 e 3 A C 3 A C "»» 3 A C *>» 3 A C 5* 3 A C >s I C 1 s n Os 3 a en £ t Imprinted from Mimosa 09/15/1999 15:23:06 page -16- WO 98/40375 PCT/US98/03792 us Printed from Mimosa 09/15/1999 15:23:06 page -17- WO 98/40375 PCT/US98/03792 | 7-dimetliyl.imino i 1 | 0 e 1 rt X U e s 0 c E fl! "3 E ■5 pi 0 s 1 <a ">* jj S Cs 7-dimethylamino i i i r X r X r Qy i- ' ^ 0 .. j n "*n X o + 2 r u. O o S—OH II o "H~_/ \ "• o o u. O hT y r r r r r OH r o z o HO i HO 3 5* 3 S* 3 s* 3 >N 3 S e C •Q e .3 C n-butyl 3 JZ S n-butyl 1 n-butyl n-butyl fs. 5v » SV a s 5 l\k Printed from Mimosa 09/15/1999 15:23:06 page -18- WO 98/40375 PCT/US98/03792 \n Printed from Mimosa 09/15/1999 15:23:06 page 19 WO 98/40375 PCT/US98/03792 o e rt ">» V £ rl o c 6 ra £ | "? 9 e i (9 ">N V £ "U ps» 0 e 1 js ">% u c ■5 Ps 1 0 e 1 n "u £ ■5 pi X X r X X X o. -T u, O P -S X S o o r u. O X <7 o x \ o1 \ V/ ? u. O (y r> *"n X o X o + aT - r u. O P X X X X X OH r o X o X 0 X 0 .a .a 3* 3 A e >» J c ">s 3 .3 >s A G n-bulyl 3 A G 3 jD C 5* 3 ■? C 3 ja c 1407 ( j | 3 s o 5 US Printed from Mimosa 09/15/1999 15:23:06 page 20 WO 98/40375 PCT/US98/03792 HI Printed from Mimosa 09/15/1999 15:23:06 page -21 WO 98/40375 PCT/US98/03792 Printed from Mimosa 09/15/1999 15:23:06 page 22 WO 98/40375 PCT/US98/03792 Ul Printed from Mimosa 09/15/1999 15:23:06 page 23 WO 98/40375 PCT/US98/03792 Printed from Mimosa 09/15/1999 15:23:06 page -24- WO 98/40375 PCT/US98/03792 9 u S f j 7-dimelhylamino !j 7-d imethy lamino ii i i 9 ts E 3 >s U E *? 9 1 rs "5 § ■5 X X X X n X H. X o 1 £ Q , \ 7 o 'n> X SL X o o X o £ + Z u. O <3 ■ o £ X X X X X 5 X o X o § X o >% 3 .a 3 •* s * 3 .D c 3 A C ■>» 3 JS c n-bulyl 3 .3 C X 3 -Q S n-butyl *>» | C -r P? tn m S u*t CO 123 Printed from Mimosa 09/15/1999 15:23:06 page -25- WO 98/40375 PCT/US98/03792 U4- Prmted from Mimosa 09/15/1999 15:23:06 page -26 WO 98/40375 PCT/US98/03792 Printed from Mimosa 09/15/1999 15:23:06 page -27- WO 98/40375 PCT/US98/03792 7-d imethy lamino 7-dimethylamino ! 7-dimethylamino I 7-dlmethylammo r x X X ' n 2 O CO * ° {_) CX\> rV { ">■ £ 5 D. X o* CO X X X X X o X o X o X o ">» 1 e n-butyl 1 n-butyl I ■>. 3 c ">> 3 A e 3 •9 n-butyl | ■>* 3 A c so t T s iO 124 Printed from Mimosa 09/15/1999 15:23:06 page -28- WO 98/40375 PCT/US98/03792 PEG *TCO<=C o'l PEG = 3400 molecular weight polyethyleae glycol polymer chain PEG = 3400 molecular weight polyethylene glycol polymer chain \X1 Printed from Mimosa 09/15/1999 15:23:06 page -29- WO 98/40375 PCT/US98/03792 o f Printed from Mimosa 09/15/1999 15:23:06 page -30- WO 98/40375 PCT/US98/03792 C22 K24 N 03 S 387.543 IT J? 0«$ \ 1 V'HII ox ■ C22 K23 N 03 S 3*7.SO tr C22 H28 03 S 372.323 t °. 0 /s\ ./^ xEr VA A . ** Ph S. OH 13L^ Printed from Mimosa 09/15/1999 15:23:06 page -31- WO 98/40375 PCT/US98/03792 C2I H24 03 S 336.48S C22 K29 0 S 3-40.33 02K29 0 S 3^0.33 \3o Printed from Mimosa 09/15/1999 15:23:06 page 32 WO 98/40375 PCT/US98/03792 C2Z H2B 04 S 3l«.3)t Ph OH C22 K32 03 S . Q2 K29 03 S 743.083 •v • O \l\ C22 H2I 02 3 Si.» n-Bu Printed from Mimosa 09/15/1999 15:23:06 page -33- WO 98/40375 PCT/US98/03792 C2t H41 H 03 S 47J.7C4 lr C22 K27 I 03 S 451.423 0. 0 w 1 It \ £r I X /£ > / n-fl« * i L J " C24 H30 oa s 430. sn 13X Printed from Mimosa 09/15/1999 15:23:06 page 34 WO 98/40375 PCT/US98/03792 C2Z KM N 04 3 403.943 tr C22 K23 N 04 S 403. V3 Cr 0 //^ o II — M , V'MIt CM rr HQ MM C2f H4t N 03 S 471,704 If 133 Printed from Mimosa 09/15/1999 15:23:06 page 35- WO 98/40375 PCT/US98/03792 C2f M40 04 S •<72. CM 0 C24 K3Q 03 S 430,353 0 C36 H43 N 06 S 617.807 0 I imprinted from Mimosa 09/15/1999 15:23:06 page -36- wo 98/40375 PCT/US98/03792 CZ3 H3Q 04 S 402.933 /'w 0 Ph /£^ET n-Bu OH QJ H2» 04 S 311.328 0 \// s >. V'lllI n-Su J- \ ET « OH Ph CZ4 H22 Q4 S 416.392 Ph 135 oq/is/1999 15:23:06 page 37 Printed from Mimosa 09/lb/iyy* WO 98/40375 PCT/US98/03792 C22 M3» 03 3 372.923 C22 H28 03 5 372.323 t 0. 0 C23 WO 04 S <402.335 0 rv V 1 A- . v —' ii n-0u Ph OH 134 Printed from Mimosa 09/15/1999 15:23.06 page 38 WO 98/40375 PCT/US98/03792 CZZ HZ* 04 3 . C22 H2i 03 S 781.038 Z CZ2 H2S 03 SZ 404.333 131 Printed from Mimosa 09/15/1999 15:23:06 page -39- WO 98/40375 PCT/US98/03792 CZZ H2S 12 03 S S24.322 0. 0 xs n- 9m C2I K24 03 S 336.46 Ph OH \3>« Printed from Mimosa 09/15/1999 15:23:06 page -40- WO 98/40375 PCT/US98/03792 C23 W3Q 04 S 4C2.333 C23 H3Q 04 S 4C2.555 Printed from Mimosa 09/15/1999 15:23:06 page -41- WO 98/40375 PCT/US98/03792 CIt H20 03 S 316.421 0 0 \// Cl« WO 03 $ 316.421 Q 0 \// l^O Printed from Mimosa 09/15/1999 15:23:06 page -42 WO 98/40375 PCT/US98/03792 C« H23 02 » 336.321 CI 8 H20 02 S 3C0.«2 0 0 \// Ph C22 HZ8 03 S 372.323 OH 14-1 Printed from Mimosa 09/15/1999 15:23:06 page -43- WO 98/40375 PCT/US98/03792 In further compounds of the present invention, R5 and R* are independently selected from among hydrogen and ring-carbon substituted or unsubstituted aryl, thiophene, pyridine, pyrrole, thiazole, imidazole, 5 pyrazole, pyrimidine, morpholine, N-alkylpyridinium, N- alkyl-piperazinium, N-alkylmorpholinium, or furan in which the substituent(s) are selected from among halo, hydroxyl, trihaloalkyl, alkoxy, amino, N-alkylamino, N,N-di alky lamino, quaternary ammonium salts, a Cx to C, 10 alkylene bridge having a quaternary ammonium salt substituted thereon, alkoxycarbonyl, aryloxycarbonyl, alkylcarbonyloxy and arylcarbonyloxy, (0,0)-dioxyalkylene, - [O (CH2) J xX where x is 2 to 12, w is 2 or 3 and X comprises halo or a quaternary ammonium 15 salt, thiophene, pyridine, pyrrole, thiazole, imidazole, pyrazole, or furan. The aryl group of R5 or R4 is preferably phenyl, phenylene, or benzene triyl, i.e., may be unsubstituted, mono-substituted, or di-substituted. Among the species which may constitute 20 the substituents on the aryl ring of Rs or R4 are fluoro, chloro, bromo, methoxy, ethoxy, isopropoxy, trimethylammonium (preferably with an iodide or chloride counterion), methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, propanoyl, (N)-hexyldimethylammonium, 25 hexylenetrimethylammonium, tri(oxyethylene)iodide, and tetra(oxyethylene)trimethylammonium iodide, each substituted at the p-position, the m-position, or both of the aryl ring. Other substituents that can be present on a phenylene, benzene triyl or other aromatic 30 ring include 3,4-dioxymethylene (5-membered ring) and 3,4-dioxyethylene (6- membered ring). Among compounds which have been or can be demonstrated to have desirable ileal bile acid transport inhibiting properties are those in which'R5 or R4 is selected from 35 phenyl, p-fluorophenyl, m-fluorophenyl, p- hydroxyphenyl, m-hydroxypheny1, p-methoxyphenyl, m-methoxyphenyl, p-N,N-dimethylaminophenyl, m-N,N- Printed from Mimosa 09/15/1999 15:23:06 page -44- WO 98/40375 PCT/US98/03792 dixnethylaminophenyl, I' p--phenyl, I" phenyl. X" m-tCHjJj-jr-CHjCHj-tOCHjCHjJj-O-phanyl, I" p-(CHjlj-N'-CHjCH,-(OCHjCHjJj-O-phanyl, I" ra-(N,N-dimethylpiperazinium) - (N') -CH,- (OCKjCH,)3-0-phenyl, 3-methoxy-4-5 fluorophenyl, thienyl-2-yl, S-cholorothienyl-2-yl, 3 ,4-dif luorophenyl, I" p- (N, N-dimethylpiperazinium) -(N' )-CH,- (OCH,CH,) j-O-pheny 1, 3-f luoro-4-jaethoxyphenyl, - 4-pyridinyl, 2-pyridinyl3-pyridinyl, N-methyl-4-pyridinium, I" N-methyl-3-pyridinium, 3,4- 10 dioxymethylenephenyl, 3,4-dioxyethylenephenyl, and p- methoxycarbonylphenyl. Preferred compounds include 3-ethyl-3-butyl and 3-butyl-3-butyl confounds having each of the above preferred R' substituents in combination with the R* substituents shown m Table 1. It is IS particularly preferred that one but not both of r' and R* is hydrogen. It is especially preferred that R* and R* be hydrogen, that R' and R* not be hydrogen, and that R1 and R* be oriented in the sane direction relative to 20 the plane of the molecule, i.e., both in et- or both in 5-configuration. It is further preferred that, where R* is butyl and R1 is ethyl, then R1 has the same orientation relative to the plane of the molecule as R1 and r' . 25 Set forth in Table 1A are lists of species of A'/RJ. h'/r' and R'. 143 Printed from Mimosa 09/15/1999 15:23:06 page -45- WO 98/40375 PCT/US98/03792 PAG-6 H-4- LEFT ^i_AK><C- 144 Printed from Mimosa 09/15/1999 15:23:06 page -46- WO 98/40375 PCT/US98/03792 Table 1A : Alternative R groups (RX)q- (Rx) o •ehyl n-propyl -a-bucyl a-p«neyl n-haxyL ■* iao-pcopyl , lso-bueyl lio-pencyl C3,C(-0)CjHJ c3]cc2as cH2ca<OH)c2Hj CEjO-(4-pic3line) HO- Ph- H- p-r-?h— m-r-?h- p-CSjO-?h- n-CH20-?.t- p- CCHj) B-(CKj) jN-?h- I". p-(Clj) I". m-(CHj) j-N*-?h- I", p- (CHj) j-H*-CH2C?.2- (CCH2CS2) j-0-?h-I", m-(CHjl j-S*-CH2C?.2- ; (CCHJCHJ) 2-0-?h-I". p-IS.M- di=ec.w.ylj:iperiii.-iel -ijt I-chj-(CCH2C:-:J) 2-O-Ph-I", n-(«,S- dlr«t>.yl3ia«r»ii.-.«) -(S') -C<s2-ICCHJC.-:2) 2-0- Ph- ffl-r. p-CHj5-?h-3, 4, diaxycethyiete-?!! b-C230-, p-r-=h- 4-?yridi.-.« N-neihyi-4-pyTidi.-il.ua, I" 3-pyridi.ie N-sietfiyl-3-?yridi.-.iu.-( I" 2-pyridi.ie p-CK302C-?h-ChianyL-2-yi 5-Cl-ehianyl-2-yl 3,4-di21uoro • m-r, P-CHjO-Ph 7-aac.lyl -7-aehyl 7-lao-propyl 7-eart-bucyL 7-oa 7-CCHj 7-0(i»3-propyl) 7-SC3j 7-SOCHj 7-SOjCHj 7-SCHjC3j 7-MEj 7-SHOH 7-UEC.ij 7-MICHj) 2 7-N*ICHj>3, I" 7-NKC (-0) C3j 7-H(C2jC?.j)2 7-N««ca2co2a 1-H* ^MeJ 2CH2C32n, I" 7- IN)-ssrpholine 7- (SI) -aieeidina 7-[S)-S-=ethylazecidiniun, I" 7- (N)-pyrrolidine 7-(N)-N-=ec?.yi-pyrr3lidiniuo, I 7-(Ml-S-aechyl-aorpholJjiium, I" 7- (N) -H' -aechylptpecazina 7- (N) -N' -di.-.elhy Ipiperaiiniua, 7-NH-C3Z _ „ 7-NKCfO)CJKll 7-HHC(.Q)CKjSr 7-SK-CtSH)J»a2 7-(2) -t!iioph«n« coatinuad naxs pa?*... 14-S" Printed from Mimosa 09/15/1999 15:23:06 page -47- WO 98/40375 PCT/US98/03792 a-saehyl l-echyl 8-ito-peopyi l-eart-bucyl I-OH 8-CCHj 8-0(ijo-propyl) S-SCS] 8-5CC3j 8-SOjCHJ S-SCEjCEJ 8-NHj 8-HEOS 8-HEC3] 8-S(C3,), 8-M*(CSj)J, I" 8-SHC(-0)CEj 8-H(CEJCSj) 2 a-HKeCEjCOj3 JCP.JCOj?.. I" 8-IS) -sorpholiaa 8-IN)-azetidine 8-(N) -s-sectiyiizecidinius, I" 8-IN)-pyrrolidine 8-(N)-N-sezliyl-pyrroLidiniua, I 8-tN) -N-aaciiyi-sorphoiiniun, I" 8- IN) -N' -aaehyipipera.zi.ia 8-(N)-N'-disaehylpiperaziniua, 8-SS-C3Z 8-hsc(0)c5?.li 8-SHC[0)CEj3r 8-Mr.-CtSr.)SRj 8-(2)-ci;ia?hene caosiaued aaxe pa.j«... 14-4 Printed from Mimosa 09/15/1999 15:23:06 page -48- WO 98/40375 PCT/US98/03792 9-e*chyl 9-«chyl 9-iso-propyl 9-e«rt-bueyl 9-OH 9-CCHj 9-0tiJ0-pr0?yl) 9-SCHj 9-SOCHj 9-SOjCHj 9-SC3jCHj 9-NHj 9-HEOH 9-NHCHj 9-N (CKj) 2 9-sr (caa]3rr- 9-NHC(-0) CF.j 9-»(CH,CHj), 9-NHaC31C02H 9-s*(K«>2ca2co2a. i* 9-(SI -aorphollna 9-(H)-a*ecidine 9-(N)-H-saihylazatidiniua, I" 9-(N)-pyrrolidine 9-(S)-M—aechyl-pyrrolidiniua, I 9-tN)-N-nachyl-Earpholiniu-i, I" 9-(S)-N'-aaihyipiperazine 9- (S)-S'-diaechylpiperaziniua, 9-SH-C3Z g-ssctoiCjHij. 9-NHC(0)CH]3r 9-N<-:-C(NH)SE: 9-(2)-cnioahana 7-CCSj, a-CCHj 7-5CHj. 8-CCHj 7-5C.-ij, 8-5CHj S-CCHj, 7-CCHj, 8-OCHj 1^1 Printed from Mimosa 09/15/1999 15:23:06 page -49- WO 98/40375 PCT/US98/03792 Further preferred compounds of the present invention comprise a core structure having two or more pharmaceutically active benzothiepine structures as described above, covalently bonded to the core moiety via 5 functional linkages. Such active benzothiepine structures preferably comprise: 15 where Rl, RJ, R3, R*, R!, R5, Rs, R7, R*, X, q and n are as defined above, and R55 is either a covalent bond or arylene. |4& Printed from Mimosa 09/15/1999 15:23:06 page -50- WO 98/40375 PCT/US98/03792 The core moiety can comprise alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, and peptide, polypeptide, wherein alkane diyl, 5 alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, and peptide polypeptide, can optionally have one or more carbon replaced by .0, NR7,_.N*R7r', S, SO, so2 S*R7r', PR7, P+R7R8, phenylene, heterocycle, quatarnary 10 heterocycle, quaternary heteroaryl, or aryl, •wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can be substituted with one or more 15 substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S(0)R13, S02R13, S03R13, NR130R14, NR13NR14R15, N02, C02R13, CN, 20 OM, S020M, S02NR13R14, C(0)NR13R14, C(0)0M, COR13, P(0)R13R14, P+R13R14r15a_, P (OR13) OR14, S*RuR14A*, and N+R9R1;LR12A~; wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle 25 can be further substituted with one or more substituent n groups selected from the group consisting of OR , NR7R8, SR7, S(0)R7, S02R7, SO3R7, C02R7, CN, oxo, CONR7R8, N+R7R8R9A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary W Printed from Mimosa 09/15/1999 15:28:34 page -1- WO 98/40375 PCT/US98/03792 7 8 + 78- heterocycle, quaternary heteroaryl, P(0)R R , P R R A , and P(0) (OR7)OR', and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by 0, NR7, N+R7R8A-, S, SO, S02, S+R?A-, PR7, P(0)R7, + 78 P"R R A-, or phenylene. Exemplary core moieties include: 10 26 27 15 ,26 27 20 \$0 Printed from Mimosa 09/15/1999 15:28:34 page -2- WO 98/40375 PCT/US98/03792 •H 27 wherein: R" is selected from the group consisting of C and N, and R" and RJ1 are independently selected from the group consisting of: R° x —N— . —0—. s_, —£— —CH2_ 0 S 0 S F?1 i1 11 " « I' N+ -C—. —C— —c——C —' ^3(3— Si-- —NHJJH-, NHSO--. an** k32 2 / \nh2 wherein R1', R", R10 and RM are independently selected from alkyl, alkenyl, alkylaryl, aryl, arylalkyl, • cycloalkyl, heterocycle,—and "heterocycloalkyl, A* is a pharmaceutically acceptable anion, and k 1 to 10. 15\ Printed from Mimosa 09/15/1999 15:28:34 page -3- WO 98/40375 PCT/US98/03792 In compounds of Formula DIV, r", rj1, r" in Formulae DII and Dili, and r" in Formula Dili can be bonded at any of their 6-, 7-, 8-, or 9- positions to r1'. In compounds of Formula DIVA, it is preferred that 5 r" comprises a phenylene moiety bonded at a m- or p- position thereof to r1'. In another embodiment, a core moiety backbone, rl®, as discussed herein in Formulas DII and Dili can be multiply substituted with more than four pendant active 10 benzothiepine units, i.e., rj0, r", r", and r31 as discussed above, through multiple functional groups within the core moiety backbone. The core moiety backbone unit, R1', can comprise a single core moiety unit, multimers thereof, and multimeric mixtures of the 15 different core moiety units discussed herein, i.e., alone or in combination. The number of individual core moiety backbone units can range from about one to about 100, preferably about one to about 80, more preferably about one to about 50, and even more preferably about 20 one to about 25. The number of points of attachment of similar or different pendant active benzothiepine units within a single core moiety backbone unit can be in the range from about one to about 100, preferably about one to about 80, more preferably about one to about 50, and 25 even more preferably about one to about 25. Such points of attachment can include bonds to C, S, 0, N, or P within any of the groups encompassed by the definition of R1'. The more preferred benzothiepine moieties 30 comprising rj\ rn, r" and/or r" conform to the preferred structures as outlined above for Formula I. The 3-carbon on each benzothiepine moiety can be achiral, and the substituents r1, rj, r5, r4, rs and r* ISZ Printed from Mimosa 09/15/1999 15:28:34 page -4- WO 98/40375 PCT/US98/03792 can be selected from the preferred groups and combinations of substituents as discussed above. The core structures can comprise, for example, poly(oxyalkylene) or oligo(oxyalkylene), especially 5 poly- or oligo(oxyethylene) or poly- or oligo(oxypropylene). Dosages. Formulations, and Routes of Administration The ileal bile acid transport inhibitor compounds 10 of the present invention can be administered for the prophylaxis and treatment of hyperlipidemic diseases or conditions by any means, preferably oral, that produce contact of these compounds with their site of action in the body, for example in the ileum of a mammal, e.g., a 15 human. For the prophylaxis or treatment of the conditions referred to above, the compounds of the present invention can be used as the compound per se. Pharmaceutically acceptable salts are particularly 20 suitable for medical applications because of their greater aqueous solubility relative to the parent compound. Such salts must clearly have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the 25 compounds of the present invention when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, 3 0 ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids. The chloride salt is i53 Printed from Mimosa 09/15/1999 15:28:34 page -5- WO 98/40375 PCT/US98/03792 particularly preferred for medical purposes. Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, and alkaline earth salts such as magnesium and 5 calcium salts. The anions of the definition of A" in the present invention are, of course, also required to be pharmaceutically acceptable and are also selected from the above list. 10 The compounds of the present invention can be presented with an acceptable carrier in the form 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 15 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. 20 Other pharmacologically active substances can also be present, including other compounds of the present invention. The pharmaceutical compositions of the invention can be prepared by any of the well known techniques of pharmacy, consisting essentially of 25 admixing the components. These compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic compounds or as a combination of therapeutic compounds. 30 The amount of compound which is required to achieve the desired biological effect will, of course, depend on a number of factors such as the specific compound chosen, the use for which it is intended, the isH Printed from Mimosa 09/15/1999 15:28:34 page 6 WO 98/40375 PCT/US98/03792 mode of administration, and the clinical condition of the recipient. In general, a daily dose can be in the range of from about 0.3 to about 100 mg/kg bodyweight/day, 5 preferably from about 1 mg to about 50 mg/kg bodyweight/day, more preferably from about 3 to about 10 mg/kg bodyweight/day. This total daily dose can be administered to the patient in a single dose, or in proportionate multiple subdoses. Subdoses can be 10 administered 2 to 6 times per day. Doses can be in sustained release form effective to obtain desired results. Orally administrable unit dose formulations, such as tablets or capsules, can contain, for example, from 15 about 0.1 to about 100 mg of benzothiepine compound, preferably about 1 to about 75 mg of compound, more preferably from about 10 to about 50 mg of compound. In the case of pharmaceutically acceptable salts, the weights indicated above refer to the weight of the 20 benzothiepine ion derived from the salt. Oral delivery of an ileal bile acid transport inhibitor of the present invention can include formulations, as are well known in the art, to provide prolonged or sustained delivery of the drug to the 25 gastrointestinal tract by any number of mechanisms. These include, but are not limited to, pH sensitive release from the dosage form based on the changing pH of the small intestine, slow erosion of a tablet or capsule, retention in the stomach based on the physical 3 0 properties of the formulation, bioadhesion of the dosage form to the mucosal lining of the intestinal tract, or enzymatic release of the active drug from the dosage form. The intended effect is to extend the time iSS* Printed from Mimosa 09/15/1999 15:28:34 page -7- WO 98/40375 PCT/US98/03792 period over which the active drug molecule is delivered to the site of action (the ileum) by manipulation of the dosage form. Thus, enteric-coated and enteric-coated controlled release formulations are within the scope of the present invention. Suitable enteric coatings include cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methacrylic acid methyl* ester. When administered intravenously, the dose can, for example, be in the range of from about 0.1 mg/kg body weight to about 1.0 mg/kg body weight, preferably from about 0.25 mg/kg body weight to about 0.75 mg/kg body weight, more preferably from about 0.4 mg/kg body weight to about 0.6 mg/kg body weight. This dose can be conveniently administered as an infusion of from about 10 ng/kg body weight to about 100 ng/kg body weight per minute. Infusion fluids suitable for this purpose can contain, for example, from about 0.1 ng to about 10 mg, preferably from about 1 ng to about 10 mg per milliliter. Unit doses can contain, for example, from about 1 mg to about 10 g of the compound of the present invention. Thus, ampoules for injection can contain, for example, from about 1 mg to about 100 mg. Pharmaceutical compositions according to the present invention include those suitable for oral, rectal, topical, buccal (e.g., sublingual), and parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular compound Iblo Printed from Mimosa 09/15/1999 15:28:34 page -8- WO 98/40375 PCT/US98/03792 which is being used. In most cases, the preferred route of administration is oral. Pharmaceutical compositions suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention; 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-oi-1 emulsion. As indicated, such compositions can be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound(s) and the carrier (which can constitute one or more accessory ingredients). In general, the compositions are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet can be prepared by compressing or molding a powder or granules of the compound, optionally with one or more assessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). Molded tablets can be made by molding, in a suitable machine, the powdered compound moistened with am inert liquid diluent. Pharmaceutical compositions suitable for buccal (sub-lingual) administration include lozenges comprising a compound of the present invention in a flavored base, usually sucrose, and acacia or tragacanth, and pastilles comprising the compound in an 15} Prmted from Mimosa 09/15/1999 15:28:34 page -9- WO 98/40375 PCT/US98/03792 inert base such as gelatin and glycerin or sucrose and acacia. Pharmaceutical compositions suitable for parenteral administration conveniently comprise sterile 5 aqueous preparations of a compound of the present invention. These preparations are preferably administered intravenously, although administration can also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such 10 preparations can conveniently be prepared 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 a compound 15 disclosed herein. Pharmaceutical compositions suitable for rectal administration are preferably presented as unit-dose suppositories. These can be prepared by admixing a compound of the present invention with one or more 20 conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture. Pharmaceutical compositions suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or 25 oil. Carriers which can be used include vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound is generally present at a concentration of from 0.1 to 15% w/w of the composition, for example, 3 0 from 0.5 to 2%. Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal administration can be presented as discrete patches Printed from Mimosa 09/15/1999 15:28:34 page -10- WO 98/40375 PCT/US98/03792 adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain a compound of the present invention in an optionally buffered, aqueous solution, dissolved and/or dispersed in an adhesive, or dispersed in a polymer. A suitable concentration of the active compound is about 1% to 35%, preferably about 3% to 15%. As one particular possibility, the compound can be delivered from the patch by electrotransport or iontophoresis, for example, as described in Pharmaceutical Research. 3(6), 318 (1986). In any case, the amount of active ingredient that can be combined with carrier materials to produce a single dosage form to be administered will vary depending upon the host treated and the particular mode of administration. The solid dosage forms for oral administration including capsules, tablets, pills, powders, and granules noted above comprise one or more compounds of the present invention admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings. Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as 153 Printed from Mimosa 09/15/1999 15:28:34 page -11- WO 98/40375 PCT/US98/03792 wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or setting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Pharmaceutically acceptable carriers encompass all the foregoing and the like. In combination therapy, administration of the ileal bile acid transport inhibitor and HMG Co-A reductase inhibitor may take place sequentially in separate formulations, or may be accomplished by simultaneous administration in a single formulation or separate formulations. Administration may be accomplished by oral route, or by intravenous, intramuscular, or subcutaneous injections. The formulation may be in the form of a bolus, or in the form of aaqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more pharmaceutically-acceptable HoO Printed from Mimosa 09/15/1999 15:28:34 page -12- WO 98/40375 PCT/US98/03792 carriers or diluents, or a binder such as gelatin or hydroxypropylmethyl cellulose, together with one or more of a lubricant, preservative, surface active or dispersing agent. For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension, or liquid. Capsules, tablets, etc., can be prepared by conventional methods well known in the art. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient or ingredients. Examples of dosage units are tablets or capsules. These may with advantage contain one or more ileal bile acid transport inhibitors in an amount described above. In the case of HMG Co-A reductase inhibitors, the dose range may be from about 0.01 mg to about 500 mg or any other dose, dependent upon the specific inhibitor, as is known in the art. The active ingredients may also be administered by injection as a composition wherein, for example, saline, dextrose, or water may be used as a suitable carrier. A suitable daily dose of each active inhibitor is one that achieves the same blood serum level as produced by oral administration as described above. The active inhibitors may further be administered by any dual combination of oral/oral, oral/parenteral, or parenteral/parenteral route. Pharmaceutical compositions for use in the treatment methods of the present invention may be administered in oral form or by intravenous administration. Oral administration of the combination therapy is preferred. Dosing for oral administration Printed from Mimosa 09/15/1999 15:28:34 page -13- o WO 98/40375 PCT/US98/03792 may be with a regimen calling for single daily dose, or for a single dose every other day, or for multiple, spaced doses throughout the day. The inhibitors which make up the combination therapy may be administered 5 simultaneously, either in a combined dosage form or in separate dosage forms intended for substantially simultaneous oral administration. The inhibitors which make up the combination therapy may also be administered sequentially, with either inhibitor being 10 administered by a regimen calling for two-step ingestion. Thus, a regimen may call for sequential administration of the inhibitors with spaced-apart ingestion of the separate, active agents. The time period between the multiple ingestion steps may range 15 from a few minutes to several hours, depending upon the properties of each inhibitor such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the inhibitor, as well as depending upon the age and condition of the patient. The 20 inhibitors of the combined therapy whether administered simultaneously, substantially simultaneously, or sequentially, may involve a regimen calling for administration of one inhibitor by oral route and the other inhibitor by intravenous route. Whether the 25 inhibitors of the combined therapy are administered by oral or intravenous route, separately or together, each such inhibitor will be contained in a suitable pharmaceutical formulation of pharmaceutically-acceptable excipients, diluents or other formulations , i 30 components. Examples of suitable pharmaceutically- acceptable formulations containing the inhibitors for oral administration are given above. I <o% Printed from Mimosa 09/15/1999 15:28:34 page -14- WO 98/40375 PCT/US98/03792 Treatment Regimen The dosage regimen to prevent, give relief from, or ameliorate a disease condition having hyperlipemia as an element of the disease, e.g., atherosclerosis, or to protect against or treat further high cholesterol plasma or blood levels with the compounds and/or compositions of the present invention is selected in accordance with a variety of factors. These include the type, age, weight, sex, diet, and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetics and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized, and whether the compound is administered as part of a drug combination. Thus, the dosage regimen actually employed may vary widely and therefore deviate from the preferred dosage regimen set forth above. Initial treatment of a patient suffering from a hyperlipidemic condition can begin with the dosages indicated above. Treatment should generally be continued as necessary over a period of several weeks to several months or years until the hyperlipidemic disease condition has been controlled or eliminated. Patients undergoing treatment with the compounds or compositions disclosed herein can be routinely monitored by, for example, measuring serum LDL and total cholesterol levels by any of the methods well known in the art, to determine the effectiveness of the combination therapy. Continuous analysis of such data permits modification of the treatment regimen during I bl Printed from Mimosa 09/15/1999 15:28:34 page -15- WO 98/40375 PCT/US98/03792 therapy so that optimal effective amounts of each type of inhibitor are administered at any point in time, and so that the duration of treatment can be determined as well. In this way, the treatment regimen/dosing 5 schedule can be rationally modified over the course of therapy so that the lowest amount of ileal bile acid transport inhibitor and HMG Co-A reductase inhibitor which together exhibit satisfactory effectiveness is administered, and so that administration is continued 10 only so long as is necessary to successfully treat the hyperlipidemic condition. A potential advantage of the combination therapy disclosed herein may be reduction of the amount of ileal bile acid transport inhibitor, HMG Co-A reductase 15 inhibitor, or both, effective in treating hyperlipidemic conditions such as atherosclerosis and hypercholesterolemia. The following non-limiting examples serve to illustrate various aspects of the present invention. I la Printed from Mimosa 09/15/1999 15:28:34 page -16- WO 98/40375 PCT/US98/03792 EXAMPLES OF SYNTHETIC PROCEDURES Preparation 1 V*xc 3 o o ° iO 2-Ethyl-2-(mesyloxymethyl)hexanal (1) w To a cold (10 °C) solution of 12.6 g (0.11 mole) of methanesulfonyl chloride and 10.3 g (0.13 mole) of triethylamine was added dropwise 15.8 g of 2-ethyl-2-(hydroxymethyl)hexanal, prepared according to the procedure described in Chem. Ber. 98, 728-734 (1965), while maintaining the reaction temperature below 3 0 °C. The reaction mixture was stirred at room temperature for 18 h, quenched with dilute HC1 and extracted with methlyene chloride. The methylene chloride extract was dried over MgS04 and concentrated in vacuo to give 24.4 g of brown oil. Preparation 2 2- ((2-Benzoylphenylthio)methyl) -2-ethylhexanal A mixture of 31 g (0.144 mol) of 2- mercaptobenzophenone, prepared according to the ^ procedure described in WO 93/16055, 24.4 g (0.1 mole) of 2-ethyl-2-(mesyloxymethyl)-hexanal (1), 14.8 g (0.146 mole) of triethylamine, and 80 mL of 2-methoxyethyl ether was held at reflux for 24 h. The reaction mixture was poured into 3N HCl and extracted I (e>5 Printed from Mimosa 09/15/1999 15:28:34 page -17- WO 98/40375 PCT/US98/03792 with 3 00 mL of methylene chloride. The methylene chloride layer was washed with 300 mL of 10% NaOH, dried over MgSO, and concentrated in vacuo to remove 2-methoxyethyl ether. The residue was purified by HPLC 5 (10% EtOAc-hexane) to give 20.5 g (58%) of 2 as an oil. Example 1 3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepine (3), cis-3-Butyl-3-ethyl-5-phenyl-2, 3-dihydrobenzothiepin-10 ■ (5i?)4-one (4a) and ti-aias-3-Butyl-3-ethyl-5-phenyl-2/3-dihydro-benzothiepin- (5ff) 4-one (4b) ( ^ (0.047 mole) of TiClj and 80 mL of anhydrous ethylene 15 glycol dimethyl ether (DME) was held at reflux for 2 h. The reaction mixture was cooled to 5 °C. To the reaction mixture was added dropwise a solution of 3.54 g (0.01 mole) of 2 in 3 0 mL of DME in 40 min. The reaction mixture was stirred at room temperature for 16 20 h and then was held at reflux for 2 h and cooled before being poured into brine. The organic was extract into methylene chloride. The methylene chloride extract was dried over MgS04 and concentrated in vacuo. The residue was purified by HPLC (hexane) to give 1.7 g (43%) of 3 25 as an oil in the first fraction. The second fraction was discarded and the third fraction was further purified by HPLC (hexane) to give 0.07 g (2%) of 4a in the earlier fraction and 0.1 g (3%) of 4b in the later fraction. 30 Example 2 cis-3 - Butyl - 3 -ethyl - 5 -phenyl -2,3 - dihydrobenzothiepin-(5JT)4-one-l, 1-dioxide (5a) and trans-3-Butyl-3-ethyl-5-phenyl-2,3-dihydro-benzothiepin-(5H)4-one-l, 1-dioxide 35 (5b) „s«a 5«k, St rsy 0 To a solution of 1.2 g (3.5 mmCTle) of 50-60% MCPBA in 20 mL of methylene chloride was added 0.59 g (1.75 I (o(ff Printed from Mimosa 09/15/1999 15:28:34 page -18- WO 98/40375 PCT/US98/03792 mmole) of a mixture of 4a and 4b in 10 mL of methylene chloride. The reaction mixture was stirred for 20 h. An additional 1.2 g (1.75 mmole) of 50-60% MAPBA was added and the reaction mixture was stirred for an additional 3 h then was triturated with 50 mL of 10% NaOH. The insoluble solid was filtered. The methylene chloride layer of the filtrate was washed with brine, dried over MgSO,, and concentrated in vacuo. The residual syrup was purified by HPLC (5% EtOAc-hexane) to give 0.2 g (30%) of 5a as an oil in the first fraction and 0.17 g (26%) of 5b as an oil in the second fraction. J0 <sf"'y^ -r , Fxamplq 3 "(J) °ri (3a, 4a, 5b) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2, 3,4,5-tetrahydrobenzothiepine-1,1-dioxide (6a), (3a,4b,5a) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2, 3,4, 5-tetrahydro- benzothiepine-1,1-dioxide (6b), (3a,4a,5a) 3-Butyl-3- i oU ethyl-4-hydroxy-5-phenyl-2,3,4,5- t^J tetrahydrobenzothiepine-1,1-dioxide (6c), and (3a, 4b, 5b) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5- tetrahydrobenzothiepine-1,1-dioxide (6d) A. Reduction of 5a and 5b with Sodium Borohydride To a solution of 0.22 g (0.59 mmole) of 5b in 10 mL of ethanol was added 0.24 g (6.4 mmole) of sodium borohydride. The reaction mixture was stirred at room temperature for 18 h and concentrated in vacuo to remove ethanol. The residue was triturated with water and extracted with methylene chloride. The methylene chloride extract was dried over MgS04 and concentrated in vacuo to give 0.2 g of syrup. In a separate experiment, 0.45 g of 5a was treated with 0.44 g of sodium borohydride in 10 mL of ethanol and was worked up as described above to give 0.5 g of syrup which was identical to the 0.2 g of syrup obtained above. These two materials were combined and purified by HPLC using 10% EtOAc-hexane as eluant. The first fraction was 0.18 g (27%) of 6a as a syrup. The second fraction was 0.2 g (sc>; Printed from Mimosa 09/15/1999 15:28:34 page -19- WO 98/40375 PCT/US98/03792 (30%) of 6b also as a syrup. The column was then eluted with 20% EtOAc-hexane to give 0.077 g (11%) of 6c in the third fraction as a solid. Recrystallization from hexane gave a solid, mp 179-181 °C. Finally, the column 5 was eluted with 30% EtOAc-hexane to give 0.08 g (12%) of 6d in the fourth fraction as a solid. Recrystallization from hexane gave a solid, mp 160-161 °C. 10 B. Conversion o£ 6a to 6c and 6d with NaOH and PTC To a solution of 0.29 g (0.78 mmole) of 6a in 10 mL CH2C1j , was added 9 g of 4 0% NaOH. The reaction mixture was stirred for 0.5 h at room temperature and was added 15 one drop of Aliquat-33 6 (methyltricaprylylammonium chloride) phase transfer catalyst (PTC). The mixture was stirred for 0.5 h at room temperature before being treated with 25 mL of ice-crystals then was extracted with CHjClj (3x10 ml), dried over MgSO, and concentrated 20 in vacuo to recover 0.17 g of a colorless film. The components of this mixture were separated using an HPLC and eluted with EtOAc-hexane to give 12.8 mg (4%) of 2-(2-benzylphenylsulfonylmethyl)-2-ethylhexenal in the first fraction, 30.9 mg (11%) of 6c in the second 25 fraction and 90.0 mg (31%) of 6d in the third fraction. Oxidation of 6a to 5b To a solution of 0.20 g (0.52 mmole) of 6a in 5 mL of CHjCl, was added 0.23 g (1.0 mmole) of pyridinium 30 chlorochromate. The reaction mixture was stirred for 2 h then was treated with additional 0.23 g of pyridinium chlorochromate and stirred overnight. The dark reaction mixture was poured into a ceramic filterfrit containing silica gel and was eluted with CH2C1j. The filtrate was 35 concentrated in vacuo to recover 167 mg (87%) of 5b as a colorless oil. Printed from Mimosa 09/15/1999 15:28:34 page -20- WO 98/40375 PCT/US98/03792 Example 4 3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepine-l,1-dioxide (7) 5 To a solution of 5.13 g (15.9 mmole) of 3 in 50 mL of CH2C1jwas added 10 g (31.9 mmole)of 50-60% MCPBA (m-chloroperoxybenzoic acid) portionwise causing a mild reflux and formation of a white solid. The reaction mixture was allowed to stir overnight under N2 and was 10 triturated with 25 mL of water followed by 50 mL of 10% NaOH solution. The organic was extracted into CH3C1j (4x20 mL) . The CH2C1j extract was dried over MgSO, and evaporated to dryness to recover 4.9 g (87%) of an opaque viscous oil. 15 Example 5 (laa,2b,8ba ) 2-Butyl-2-ethyl-8b-phenyl-la,2,3,8b-tetrahydro-benzothiepino[4, 5-i>] oxirene-4, 4-dioxide (8a) (laa,2a,8ba) 2-Butyl-2-ethyl-8b-phenyl-la,2,3,8b-20 tetrahydro-benzothiepino [4,5-Jb] oxirene-4,4-dioxide <8b> , To 1.3 gH4.03 mole) of 3 in 25 mL of CHC13 was added portionwise 5 g (14.1 mmole) of 50-60 % MCPBA causing a 25 mild exotherm. The reaction mixture was stirred under N, overnight and was then held at reflux for 3 h. The insoluble white slurry was filtered. The filtrate was extracted with 10% potassium carbonate (3x50 mL), once with brine, dried over MgSO,, and concentrated in vacuo 30 to give 1.37 g of a light yellow oil. Purification by HPLC gave 0.65 g of crystalline product. This product is a mixture of two isomers. Trituration of this crystalline product in hexane recovered 141.7 mg (10%) of a white crystalline product. This isomer was 35 characterized by NMR and mass spectra to be the (laa,2b,8ba) isomer 8a. The hexane filtrate was concentrated in vacuo to give 206 mg of white film which is a mixture of 30% 8a and 70% 8b by XH NMR. un Printed from Mimosa 09/15/1999 15:28:34 page -21- WO 98/40375 PCT/US98/03792 <sClcr Example $ Q> (c{o^ ^cK~/^ cis-3-Butyl-3-ethyl-5-phenyl-2,3*r<,5-tetrahydro- 0^ benzothiepine-1,1-dioxide (9a), trans-3-Butyl-3-ethyl-5 5-phenyl-2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide (9b), and 3-Butyl-3-ethyl-4-hydroxy-5-cyclohexylidine-2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide (10) A mixture of 0.15 g (0.4 mmole) of a 3:7 mixture of 8a 10 and 8b was dissolved in 15 ml MeOH in a 3 oz. Fisher/Porter vessel, then was added 0.1 g of 10% Pd/C catalyst. This mixture was hydrogenated at 7 0 psi Ha for 5 h and filtered. The filtrate was evaporated to dryness in vacuo to recover 0.117 g of a colorless oil. 15 This material was purified by HPLC eluting with EtOAc- hexane. The first fraction was 4.2 mg (3%) of 9b. The second fraction, 5.0 mg (4%), was a 50/50 mixture of 9a and 9b. The third fraction was 8.8 mg (6%) of 6a . The fourth fraction was 25.5 mg (18%) of 6b. The fifth 20 fraction was 9.6 mg (7%) of a mixture of 6b and a product believed to be 3-butyl-3-ethyl-4,5-dihydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide based on mass spectrum. The sixth fraction was 7.5 mg (5%) of a mixture of 6d and one of the isomers of 10, 25 10a. Example 7 In another experiment, a product (3.7 g) from epoxidation of 3 with excess MCPBA in refluxing CHCIj 30 under air was hydrogenated in 100 mL of methanol using 1 g of 10% Pd/C catalyst and 70 psi hydrogen. The product was purified by HPLC to give 0.9 g (25%) of 9b, 0.45 g (13%) of 9a, 0.27 g (7%) of 6a, 0.51 g (14%) of 6b, 0.02 g (1%) of 6c, 0.06 g (2%) of one isomer of 10, 35 10a and 0.03 g (1%) of another isomer of 10, 10b. 116 Printed from Mimosa 09/15/1999 15:28:34 page -22- WO 98/40375 PCT/US98/03792 oo H Example g V. 2-((2-Benzoylphenylthio)methyl)butyraldehyde (11) To an ice bath cooled solution of 9.76 g (0.116 mole ) of 2-ethylacrolein in 40 mL of dry THF was added 24.6 g (0.116 mole) of 2-mercaptobenzophenone in 40 mL of THF followed by 13 g (0.128 mole) of triethylamine. The reaction mixture was stirred at room temperature for 3 days , diluted with ether, and was washed successively with dilute HCl, brine, and 1 M potassium carbonate. The ether layer was dried over MgSO, and concentrated in vacuo. The residue was purified by HPLC (10% EtOAc-hexane) to give 22 g (64%) of 11 in the second fraction. An attempt to further purifiy this material by kugelrohr distillation at 0.5 torr (160-190 °C) gave a fraction (12.2 g) which contained starting material indicating a reversed reaction during distillation. This material was dissolved in ether (100 mL) and was washed with 50 mL of 1 M potassium carbonate three times to give 6.0 g of a syrup which was purified by HPLC (10% EtOAc-hexane) to give 5.6 g of pure 11. To a mixture of 2.61 g (0.04 mole) of zinc dust and 60 mL of DME was added 7.5 g (0.048 mole) of TiCl,. The reaction mixture was held at reflux for 2 h. A solution of 2.98 g (0.01 mole) of 11 was added dropwise in 1 h. The reaction mixture was held at reflux for 18 h, cooled and poured into water. The organic was extracted into ether. The ether layer was washed with brine and filtered through Celite. The filtrate was dried over MgSO, and concentrated. The residual oil (2.5 g) was purified by HPLC to give 2.06 g (77%) of 12 as an oil in the second fraction. Example 9 3-Ethyl-5-phenyl-2,3-dihydrobenzothiepine (12) nt Printed from Mimosa 09/15/1999 15:28:34 page -23- WO 98/40375 PCT/US98/03792 ,VV Example 10 (laa,2a,8ba) 2-Ethyl-8b-phenyl-la,2,3,8b-tetrahydro-benzothiepino- [4, 5-Jb] oxirene-4,4-dioxide (13) 5 To a solution of 1.5 g (5.64 mmole) of 12 in 25 ml of CHClj was added 6.8 g (19.4 mmole) of 50-60% MCPB portionwise causing an exothem and formation of a white solid. The mixture was stirred at room temperature overnight diluted with 100 ml methylene chloride and 10 washed successively with 10% KjC03 (4x50 ml) , water (twice with 25 ml) and brine. The organic layer was then dried over MgSO, and evaporated to dryness to recover 1.47 g of an off white solid. *H NMR indicated that only one isomer is present. This solid was 15 slurried in 200 ml of warm Et20 and filtered to give 0.82 g (46%) of 13 as a white solid, mp 185-186.5 °C. Example 11 (3a,4b,5a)- 3-Ethyl-4-hydroxy-5-phenyl-2,3,4,5-20 tetrahydro-ben.zoth.iepine-1,1-dioxide (14a), (3a,4b,5b) 3-Ethyl-4-hydroxy- 5-phenyl-2,3,4,5- tetrahydrobenzothiepine-1,1-dioxide (14b), and cis-3-Ethyl-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-l,1- 25 dicid. (15) C°d/ C2) ° „ A mixture of 0.5 g (1.6 mole) of 13, 50 ml of acetic acid and 0.5 g of 10% Pd/C catalyst was hydrogenated with 70 psi hydrogen for 4 h. The crude reaction slurry was filtered and the filtrate was stirred with 150 ml 30 of a saturated NaHCO, solution followed by 89 g of NaHCO, powder portionwise to neutralize the rest of acetic acid. The mixture was extracted with methylene chloride (4x25 ml), then the organic layer was dried over MgSO, and concentrated in vacuo to give 0.44 g 35 ( 87%) of a voluminous white solid which was purified by HPLC (EtOAc-Hexane) to give 26.8 mg (6%) of 15 in the first fraction, 272 mg (54%) of 14a as a solid, mp 142- Printed from Mimosa 09/15/1999 15:28:34 page -24- WO 98/40375 PCT/US98/03792 25 143.5 °C, in the second fraction, and 35 mg (7%) of impure 14b in the third fraction. Example 12 2-Ethyl-2- ((2-Hydroxymethylphenyl) thiomethyl) hexenal (16) "H 4 k A mixture of 5.0 g (0.036 mole) of 2-mercaptobenzyl 10 alcohol, 6.4 g (0.032 mole) of 1, 3.6 g (0.036 mole) of triethylamine and 25 mL of 2-methoxyethyl ether was held at reflux for 7 h. Additional 1.1 g of mercaptobenzyl alcohol and 0.72 g of triethylamine was added to the reaction mixture and the mixture was held 15 at reflux for additional 16 h. The reaction mixture was cooled and poured into 6N HC1 and extracted with methylene chloride. The methylene chloride extract was washed twice with 10% NaOH, dried over MgSO, and concentrated in vacuo to give 9.6 g of residue. 20 Purification by HPLC (20% EtOAc-hexane) gave 3.7 g (41%)of 16 as an oil. Example 13 5 N ° {n} 2-Ethyl-2-( (2-formylphenyl) thiomethyl)hexenal (17) A mixture of 3.7 g of 16, 5.6 g (0.026 mole) of pyridinium chlorochromate, 2 g of Celite and 30 mL of methylene chloride was stirred for 18 h and filtered through a bed of silica gel. The silica gel was eluted 30 with methylene chloride. The combined methylene chloride eluant was purified by HPLC (20% ETOAc-hexane) to give 2.4 g (66%) of an oil. Ex$tmple 14 —' /■ -v 35 3-Butyl-3-ethyl-2, 3-dihydrobenzothiepine (18) A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047 mole) of TiClJ( and 50 mL of DME was held at 113 Printed from Mimosa 09/15/1999 15:28:34 page -25- WO 98/40375 PCT/US98/03792 reflux for 2 h and cooled to room temperature. To this mixture was added 2.4 g (8.6 mmole) of 17 in 20 mL of DME in 10 min. The reaction mixture was stirred at room temperature for 2 h and held at reflux for 1 h then was 5 let standing at room temperature over weekend. The reaction mixture was poured into dilute HC1 and was stirred with methylene chloride. The methylene chloride-water mixture was filtered through Celite. The methylene chloride layer was washed with brine, dried 10 over MgS04, and concentrated in vacuo to give 3.0 g of a residue. Purification by HPLC gave 0.41 g (20%) of 18 as an oil in the early fraction. Example 15 15 (laa,2a,8ba ) 2-Butyl-2-ethyl-la,2,3,8b-tetrahydro- benzothiepino[4,5-i>]oxirene-4,4-dioxide (19a) and (laa,2b,8ba) 2-Butyl-2-ethyl-8b-phenyl-la,2,3,8b-tetrahydro-benzothiepino [4,5 -£>] oxirene-4,4-dioxide .in.) 20 V ^ To a solution of 0.4 g of 0.4 g (1.6 mmole) of 18 in 30 mL of methylene chloride was added 2.2 g (3.2 mmole) of 50-60% MCPBA. The reaction mixture was stirred for 2 h and concentrated in vacuo. The residue was dissolved in 25 3 0 mL of CHC13 and was held at reflux for 18 h under N2. The reaction mixture was stirred with 100 mL of 10% NaOH and 5 g of sodium sulfite. The methylene chloride layer was washed with brine, dried over MgS04 and concentrated in vacuo. The residue was purified by HPLC 30 (20% EtOAc-hexane) to give a third fraction irtiich was further purified by HPLC (10% EtOAc-hexane) to give 0.12 g of syrup in the first fraction. Recrystallization from hexane gave 0.08 g (17%) of 19a, mp 89.5-105.5 °C. The mother liquor from the first 35 fraction was combined with the second fraction and was further purified by HPLC to give additional 19a in the first fraction and 60 mg of 19b in the second fraction. 114- Printed from Mimosa 09/15/1999 15:28:34 page -26- WO 98/40375 PCT/US98/03792 10 15 Crystallization from hexane gave 55 mg of a white solid. Example 16 3 -Bu ty 1 - 3 -e thy 1 -4,5 -dihydr oxy- 5 -phenyl - 2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide (20) %o. tOlE hydrogenation of a mixture of 8a and 8b. (It?) This product was isolated along with 6b from ^JL cm 0 ,■ Example 17 3-Butyl-3-ethyl-4-hydroxy-5-phenylthio-2,3,4,5- ^ tetrahydro-benzothiepine-1,1-dioxide (21) f'of' t-c A mixture of 25 mg (0.085 mmole) of 19b, 0.27 g (2.7 mmole) of thiophenol, 0.37 g (2.7 mmole) of potassium carbonate, and 4 mL of DMF was stirred at room temperature under Na for 19 h. The reaction mixture was poured into water and extracted with methylene 20 chloride. The methylene chloride layer was washed successively with 10% NaOH and brine, dried over MgSO,, and concentrated in vacuo to give 0.19 g of semisolid which contain substantial amounts of diphenyl disulfide. This material was purified by HPLC (5% 25 EtOAc-hexane) to remove diphenyl disulfide in the first fraction. The column was then eluted with 20% EtOAc-hexane to give 17 mg of a first fraction, 4 mg of a second fraction and 11 mg of a third fraction which were three different isomers of 21, i.e. 21a, 21b, and 30 21c, respectively, by lH NMR and mass spectra. Example 18 Alternative Synthesis of 6c and 6d A. Preparation from 2-((2-Benzoylphenylthio)methyl)-2-35 ethylhexanal (2) Step 1. 2-((2-Benzoylphenylsulfonyl)methyl)-2-ethylhexanal (44) —v 8i\ ret ns Printed from Mimosa 09/15/1999 15:28:34 page -27- WO 98/40375 PCT/US98/03792 To a solution of 9.0 g (0.025 mole) of compound 2 in 100 ml of methylene chloride was added 14.6 g (0.025 mol) of 50-60% MCPBA portionwise. The reaction mixture was stirred at room temperature for 64 h then was 5 stirred with 200 ml of 1 M potassium carbonate and filtered through Celite. The methylene chloride layer was washed twice with 300 ml of 1 M potassium carbonate, once with 10% sodium hydroxide and once with brine. The insoluble solid formed during washing was 10 removed by filtration through Celite. The methylene chloride solution was dried and concentrated in vacuo to give 9.2 g (95%)of semisolid. A portion (2.6 g) of this solid was purified by HPLC(10% ethyl acetate-hexane) to give 1.9 g of crystals, mp 135-136 °C 15 Step 2. 2-((2-Benzylphenylsulfonyl)methyl)-2- _ ethylhexanal (45) L^0et C£) |+~ ( A solution of 50 g (0.13 mole) of crude 44 in 250 ml of 20 methylene chloride was divided in two portions and charged to two Fisher-Porter bottles. To each bottle was charged 125 ml of methanol and 5 g of 10% Pd/C. The bottles were pressurized with 70 psi of hydrogen and the reaction mixture was stirred at room temperature 25 for 7 h before being charged with an additional 5 g of 10% Pd/C. The reaction mixture was again hydrogenated with 70 psi of hydrogen for 7 h. This procedure was repeated one more time but only 1 g of Pd/C was charged to the reaction mixture. The combined reaction mixture 30 was filtered and concentrated in vacuo to give 46.8 g of 45 as brown oil. Step 3. (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-l,l-dioxide (6c), and 35 (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5- tetrahydrobenzothiepine-1,1-dioxide (6d) nk Printed from Mimosa 09/15/1999 15:28:34 page -28- WO 98/40375 PCT/US98/03792 To a solution of 27.3 g (73.4 mmole) of 45 in 300 ml of anhydrous THF cooled to 2 °C with an ice bath was added 9.7 g (73.4 mmole) of 95% potassium t-butoxide. The reaction mixture was stirred for 20 min, quenched with 300 ml of 10% HCl and extracted with methylene chloride. The methylene chloride layer was dried over magnesium sulfate and concentrated in vacuo to give 24.7 g of yellow oil. Purification by HPLC (ethyl acetate-hexane) yielded 9.4 g of recovered 45 in the first fraction, 5.5 g (20%) of 6c in the second fraction and 6.5 g (24%) of 6d in the third fraction. £ U B. Preparation from 2-hydroxydiphenylmethane To a 500 ml flask was charged 16 g (0.33 mol) of 60% sodium hydride oil dispersion. The sodium hydride was washed twice with 50 ml of hexane. To the reaction flask was charged 100 ml of DMF. To this mixture was added a solution of 55.2 g (0.3 mol) of 2-hydroxydiphenylmethane in 200 ml of DMF in 1 h while temperature was maintained below 3 0 °C by an ice-water bath. After complete addition of the reagent, the mixture was stirred at room temperature for 3 0 min then cooled with an ice bath. To the reaction mixture was added 49.4 g (0.4 mole) of dimethyl thiocarbamoyl chloride at once. The ice bath was removed and the reaction mixture was stirred at room temperature for 18 h before being poured into 300 ml of water. The organic was extracted into 500 ml of toluene. The toluene layer was washed successively with 10% sodium hydroxide and brine and was concentrated in vacuo to give 78.6 g of a yellow oil which was 95% pure dimethyl 0-2-benzylphenyl thiocarbamate. This oil was heated at 280-300 °C in a kugelrohhr pot under house vacuum for 30 min. The residue was kugelrohr distilled at 1 torr (180-280 °C). The distillate (56.3 g) was crystallized from methanol to give 37.3 g (46%) of the rearranged product dimethyl Step 1. 2-mercaptodiphenylmethane (46) m Printed from Mimosa 09/15/1999 15:28:34 page -29- WO 98/40375 PCT/US98/03792 S-2-benzylphenyl thiocarbamate as a yellow solid. A mixture of 57 g (0.21 mole) of this yellow solid, 30 g of potassium hydroxide and 150 ml of methanol was stirred overnight then was concentrated in vacuo. The residue was diluted with 200 ml of water and extracted with ether. The aqueous layer was made acidic with concentrate HC1, The oily suspension was extracted into ether. The ether extract was dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from hexane to give 37.1 g (88%) of 2-mercaptodiphenylmethane as a yellow solid. Step 2. 2-((2-Benzylphenylthio)methyl)-2-ethylhexanal A mixture of 60 g (03 mole) of yellow solid from step 1, 70 g (0.3 mole) of compound 1 from preparation 1, 32.4 g (0.32 mole) of triethylamine, 120 ml of 2-methoxyethyl ether was held at reflux for 6 hr and concentrated in vacuo. The residue was triturated with 500 ml of water and 30 ml of concentrate HC1. The organic was extracted into 400 ml of ether. The ether layer was washed successively with brine, 10% sodium hydroxide and brine and was dried over magnesium sulfate and concentrated in vacuo. The residue (98.3 g) was purified by HPLC with 2-5% ethyl acetate-hexane as eluent to give 2-((2-benzylphenylthio)methyl)-2-ethyIhexanal 47 as a yellow syrup. Step 3. 2-((2-Benzylphenylsulfonyl)methyl)-2- To a solution of 72.8 g (0.21 mole) of yellow syrup from step 2 in 1 liter of methylene chloride cooled to 10 °C was added 132 g of 50-60% MCPBA in 40 min. The reaction mixture was stirred for 2 h. An additional 13 g of 50-60% MCPBA was added to the reaction mixture. The reaction mixture was stirred for 2 h and filtered (47) ethyIhexanal (45) ns Printed from Mimosa 09/15/1999 15:28:34 page -30- WO 98/40375 PCT/US98/03792 through Celite. The methylene chloride solution was washed twice with 1 liter of 1 M potassium carbonate then with 1 liter of brine. The methylene chloride layer was dried over magnesium sulfate and concentrated to 76 g of 2-((2-benzylphenylsulfonyl)methyl)-2-ethyIhexanal 45 as a syrup. Step 4. (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2, 3,4,5-tetrahydrobenzothiepine-l,1-dioxide (6c), and (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (6d) Reaction of 45 with potassium t-butoxide according to the procedure in step 3 of procedure A gave pure 6c and 6d after HPLC. (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide (25) and (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide (26) Step 1. Preparation of 2-((2-benzoyl-4-methoxy phenylthio)methyl)-2-ethyIhexanal (22) 2-Hydroxy-4-methoxybenzophenone was converted to the dimethyl 0-2-benzoyphenyl thiocarbamate by methods previously described in example 18. The product can be isolated by recrystallization from ethanol. Using this improved isolation procedure no chromatography was needed. The thermal rearrangement was performed by reacting the thiocarbamate( 5 g) in diphenyl ether at 260 °C as previously described. The improved isolation procedure which avoided a chromatography step was described below. The crude pyrolysis product was then heated at 65 °C in 100 ml of methanol and 100 ml of THF in the presence of 3.5 g of KOH for 4 h. After removing THF and methanol Example 19 Printed from Mimosa 09/15/1999 15:28:34 page -31- WO 98/40375 PCT/US98/03792 by rotary evaporation the solution was extracted with 5 % NaOH and ether. The base layer was acidified and extracted with ether to obtain a 2.9 g of crude thiophenol product. The product was further purified by 5 titrating the desired mercaptan into base with limited KOH. After acidification and extraction with ether pure 2-mercapto-4-methoxybenzophenone (2.3 g) was isolated. 2-mercapto-4-methoxybenzophenone can readily be 10 converted to the 2-((2-benzoyl-4- methoxyphenylthio)methyl)-2-ethyIhexanal (22) by reaction with 2-ethyl-2-(mesyloxymethyl)hexanal (1) as previously described. 15 Step 2. 2-((2-Benzoyl-5-methoxyphenylsulfonyl)methyl) - 2-ethyIhexanal (23) ^rsr'5-8^ p- uj) Substrate 22 was readily oxidized to 2-((2-benzoyl-5-methoxyphenyl-sulfonyl)methyl)-2-ethyIhexanal (23) as 20 described in example 18. Step 3. 2-((2-benzyl-5-methoxyphenylsulfonyl)methyl)-2-ethylhexanal (24) 25 Sulfone 23 was then reduced to 2-((2-benzyl-5- methoxyphenyl-sulfonyl)methyl)-2-ethyIhexanal (24) as described in example 18. ^ (§} Step 4. (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-8-methoxy-30 5-phenyl-2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide (25) and (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroscy-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-l,1- 35 A 3-neck flask equipped with a powder addition oH funnel,thermocouple and nitrogen bubbler was charged with 19.8 g (0.05 mole) of sulfone 24 in 100 ml dry THF. The reaction was cooled to -1.6 °C internal [10 Printed from Mimosa 09/15/1999 15:28:34 page -32- WO 98/40375 PCT/US98/03792 temperature by means of ice/salt bath. Slowly add 5.61 g (0.05 mole) of potassium t-butoxide by means of the powder addition funnel. The resulting light yellow solution was maintained at -1.6 °C. After 30 min 5 reaction 400 ml of cold ether was added and this solution was extracted with cold 10 % HCl. The acid layer was extracted with 300 ml of methylene chloride. The organic layers were combined and dried over magnesium sulfate and after filtration stripped to 10 dryness to obtain 19.9 g of product. lH nmr and glpc indicated a 96% conversion to a 50/50 mixture of 25 and 26. The only other observable compound was 4% starting sulfone 24. 15 The product was then dissolved in 250 ml of 90/10 hexane/ethyl acetate by warming to 50 °C. The solution was allowed to cool to room temperature and in this way pure 26 can be isolated. The crystallization can be enhanced by addition of a seed crystal of 26. After 2 20 crystallizations the mother liquor which was now 85.4% 25 and has a dry weight of 8.7 g. This material was dissolved in 100 ml of 90/10 hexane/ethyl acetate and 10 ml of pure ethyl acetate at 40 C. Pure 25 can be isolated by seeding this solution with a seed crystal 25 of 25 after storing it overnight at 0 C. an] Example 20 Qjok (3a, 4a, 5a) 3-Butyl-3-etliyl-4, 8-dihydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide (27) 30 In a 25 ml round bottomed flask, 1 g of 26( 2.5 mmoles) and 10 ml methylene chloride were cooled to - 78 °C with stirring. Next 0.7 ml of boron tribromide(7.5 mmole) was added via syringe. The reaction was allowed 35 to slowly warm to room temperature and stirred for 6 h. The reaction was then diluted with 50 ml methylene chloride and washed with saturated NaCl and then water.The organic layer was dried over magnesium 1*1 Printed from Mimosa 09/15/1999 15:28:34 page -33- WO 98/40375 PCT/US98/03792 sulfate. The product (0.88g) 27 was characterized by NMR and mass spectra. Example 21 5 General Alkylation of phenol 27 A 25 ml flask was charged with 0.15 g of 27(0.38 mmole), 5 ml anhydrous DMF, 54 mg of potassium carbonate(0.38 mmole) and 140 mg ethyl iodide (0.9 mmole). The reaction was stirred at room temperature 10 .overnight.The reaction was diluted with 50 ml ethyl ether and washed with water (25 ml) then 5% NaOH (20 ml) and then sat. NaCl. After stripping off the solvent the ethoxylated product 28 was obtained in high yield. The product was characterized by NMR and mass spectra. 15 This same procedure was used to prepare products listed in table 1 from the corresponding iodides or bromides. For higher boiling alkyl iodides and bromides only one equivalent of the alkyl halide was used. Printed from Mimosa 09/15/1999 15:28:34 page -34- WO 98/40375 PCT/US98/03792 Compound No. 27 26 5 28 29 30 31 10 Example 22 (3a,4a,5a) 3-Butyl-3-ethy 1 -4-hydroxy-7-hydroxyamino-5-phenyl-2, 3,4,5-tetrahydrobenzothiepine-l, 1-dioxide (37) and (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-7-hydroxyamino-5-pheny1-2,3,4,5-1etrahydrobenz othiepine-15 1,1-dioxide (38) Step 1. Preparation of 2-chloro-5-nitrodiphenylmethane (32) (35 0 Wt. Procedure adapted from reference :Synthesis -Stuttgart 20 9 770-772 (1986) Olah G. Et al Under nitrogen, a 3 neck flask was charged with 45 g (0.172 mole ) of 2-chloro-5-nitrobenzophenone in 345 ml methylene chloride and the solution was cooled to 25 ice/water temperature. By means of an additional funnel, 150 g( 0.172 mole) of trifluoromethane sulfonic acid in 345 ml methylene chloride was added slowly. Next 30 g of triethylsilane (0.172 mole) in 345 ml methylene chloride was added dropwise to the chilled 30 solution. Both addition steps( trifluoromethane sulfonic acid and triethylsilane)were repeated. After the additions were completed the reaction was allowed to slowly warm up to room temperature and stirred for 12 h under nitrogen. The reaction mixture was then 35 poured into a chilled stirred solution of 1600 ml of saturated sodium bicarbonate. Gas evolution occurred. Poured into a 4 liter separatory funnel and separated layers. The methylene chloride layer was isolated and m Printed from Mimosa 09/15/1999 15:28:34 page -35- Table 1 R H Me Et hexyl Ac (CH2)6-N-pthalimide WO 98/40375 PCT/US98/03792 10 combined with two 500 ml methylene chloride extractions of the aqueous layer. The methylene chloride solution was dried over magnesium sulfate and concentrated in vacuo. The residue was recrystallized from hexane to give 39 g product. Structure 32 was confirmed by mass spectra and proton and carbon NMR. ss- oL W Step 2. Preparation of 2-((2-benzyl-4- V1 /{ nitrophenylthio)methyl)-2-ethyIhexanal (33) The 2-chloro-5-nitrodiphenylmethane product 32 (40 g, 0.156 mole) from above was placed in a 2 liter 2 neck flask with water condenser. Next 150 ml DMSO and 7.18 g (0.156 mole) of lithium sulfide was added and the 15 solution was stirred at 75 °C for 12 h. The reaction was cooled to room temperature and then 51.7 g of mesylate IV was added in 90 ml DMSO. The reaction mixture was heated to 80 °C under nitrogen. After 12 h monitored by TLC and added more mysylate if necessary. 20 Continued the reaction until the reaction was completed. Next the reaction mixture was slowly poured into a 1900 ml of 5% acetic aqueous solution with stirring, extracted with 4 X 700 ml of ether, and dried over MgS04. After removal of ether, 82.7 g of product 25 was isolated. The material can be further purified by silica gel chromatography using 95% hexane and 5 % ethyl acetate. If pure mysylate was used in this step there was no need for further purification. The product 33 was characterized by mass spectra and NMR. 30 Step 3. Oxidation of the nitro product 33 to the sulfone 2-((2-benzyl-4-nitrophenylsulfonyl)methyl)-2-ethyIhexanal (34) 35 The procedure used to oxidize the sulfide 33 to the sulfone 34 has been previously described. .S°L-V-S' 0 H U tg) m Printed from Mimosa 09/15/1999 15:28:34 page -36- WO 98/40375 PCT/US98/03792 m - ^ ,t°"a «fs*> Step 4. Reduction of 34 to 2-((2-benzyl-4-hydroxyaminophenylsulfonyl) methyl) -2-ethylhexanal (35) A 15 g sample of 34 was dissolved in 230 ml of ethanol 5 and placed in a 500 ml rb flask under nitrogen. Next 1.5 g of 10 wt.% Pd/C was added and hydrogen gas was bubbled through the solution at room temperature until the nitro substrate 34 was consumed. The reaction could be readily monitored by silica gel TLC using 80/20 10 hexane/EtOAc. Product 35 was isolated by filtering off the Pd/C and then stripping off the EtOH solvent. The product was characterized by NMR and mass spectra. Step 5. Preparation of the 2-((2-benzyl-4-W, O-di-(t-15 butoxy-carbonyl)hydroxyaminophenylsulfonyl) methyl)-2-o ethy Ihexanal (36). A 13.35 g sample of 35 (0.0344 mole) in 40 ml of dry® h l THF was stirred in a 250 ml round bottomed flask. Next ' added 7.52 g (0.0344 mole) of di-t-butyl dicarbonate in 20 7 ml THF. Heated at 60 °C overnight. Striped off THF and redissolved in methylene chloride. Extracted with 1 % HC1; and then 5% sodium bicarbonate. The product was further purified by column chromatography using 90/10 hexane/ethyl acetate and 25 then 70/30 hexane/ethyl acetate. The product 36 was obtained (4.12 g") which appeared to be mainly the di-(t-butoxycarbonyl) derivatives by proton NMR. Step 6. (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-7- c 30 hydroxyamino-5-phenyl-2, 3,4, 5-tetrahydrobenzothiepine 1,1-dioxide (37) and (3a,4b,5b) 3-Butyl-3-ethyl-4- _(3l) hydroxy-7-hydroxyamino-5-phenyl-2,3,4, 5-tetrahydrobenzothiepine-1,1-dioxide (38) (i o <£> OU (H) 35 A 250ml 3-neck round bottomed flask was charged with 4 g of 36 (6.8 mmoles), and 100 ml of anhydrous THF and cooled to -78 °C under a nitrogen atmosphere. Slowly add 2.29 g potassium tert-butoxide(20.4 mmoles) with l%5" Printed from Mimosa 09/15/1999 15:28:34 page -37- WO 98/40375 PCT/US98/03792 stirring and maintaining a -78 °C reaction temperature. After 1 h at -78 °C the addition of base was completed and the temperature was brought to -10 °C by means of a ice/salt bath. After 3 h at -10 °C, only trace 36 remained by TLC. Next add 35 ml of deionized water to the reaction mixture at -10 °C and stirred for 5 min. Striped off most of the THF and added to separatory funnel and extracted with ether until all of the organic was removed from the water phase. The combined ether phases were washed with saturated NaCl and then dried over sodium sulfate. The only products by TLC and NMR were the two BOC protected isomers of 37 and 38. The isomers were separated by silica gel chromatography using 85% hexane and 15 % ethyl acetate; BOC-37 (0.71 g) and BOC- 38 (0.78 g). Next the BOC protecting group was removed by reacting 0.87 g of BOC-38 (1.78 mmoles) with 8.7 ml of 4 M HC1 (34.8 mmoles) in dioxane for 30 min. Next added 4.74 g of sodium acetate (34.8 mmoles) to the reaction mixture and 16.5 ml ether and stirred until clear. After transferring to a separatory funnel extracted with ether and water and then dried the ether layer with sodium sulfate. After removing the ether, 0.665 g of 38 was isolated. Isomer 37 could be obtained in a similar (3a, 4a,5a) 3-Butyl-3-ethyl-7-(n-hexylamino)-4-hydroxy-5 -phenyl-2,3,4,5-tetrahydrobenzothiepine-l, 1-dioxide (40) and (3a,4b,5b) 3-Butyl-3-ethyl-7-(n-hexylamino)-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-l, 1-dioxide (41) Step 1. 2-((2-Benzyl-4-(n- hexylamino)phenylsulfonyl)methyl) -2-ethylhexanal (39) In a Fischer porter bottle weighed out 0.5 g of 34 (1.2 mmoles) and dissolved in 3.8 ml of ethanol under procedure. Example 23 Printed from Mimosa 09/15/1999 15:28:34 page -38- WO 98/40375 PCT/US98/03792 nitrogen. Next added 0.1 g of Pd/C and 3.8 ml of hexanal. Seal and pressure to 50 psi of hydrogen gas. Stirred for 48 h. After filtering off the catalyst and removing the solvent by rotary evaporation 39 was 5 isolated by column chromatography (0.16 g) using 90/10 hexane ethyl acetate and gradually increasing the mobile phase to 70/30 hexane/ethyl acetate. The product was characterized by NMR and mass spectra. 10 Step 2. (3a,4a,5a) 3-Butyl-3-ethyl-7-(n-hexylamino)-4- hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide (40) and (3a,4b,5b) 3-Butyl-3-ethyl-7-(n-hexylama.no) -4-hydroxy-5-phenyl-2,3,4,5- 15 35 tetrahydrobenzothiepine-1,1-dioxide (41) A 2-neck, 25 ml round bottomed flask with stir bar was charged with 0.158 g 39 (0.335 mmole) and 5 ml anhydrous THF under nitrogen. Cool to -10 °C by means of a salt/water bath. Slowly add 0.113 g of potassium 20 tert butoxide (0.335 mmole). After 15 min at -10 °C all of the starting material was consumed by TLC and only the two isomers 40 and 41 were observed. Next added 5 ml of chilled 10% HC1 and stirred at -10 °C for 5 min. Transferred to a separatory funnel and extract with 25 ether. Dried over sodium sulfate. Proton NMR of the dried product (0.143 g) indicated only the presence of the two isomers 40 and 41. The two isomers were separated by silica gel chromatography using 90/10 hexane ethyl acetate and gradually increasing the 30 mobile phase to 70/30 hexane/ethyl acetate. 40 ( 53.2 mg) ; 41(58.9 mg) . x>, 8K Example 24 ^ Q J Quateroization of amine substrates 40 and 41 Amine products such as 40 and 41 can be readily alkylated to quaternary salts by reaction with alkyl halides. For example 40 in DMF with 5 equivalents of Printed from Mimosa 09/15/1999 15:28:34 page -39- WO 98/40375 PCT/US98/03792 methyl iodide in the presence of 2,6 dimethyl lutidine produces the dimethylhexylamino quaternary salt. Example 25 rft) 'oil 5 (3a,4b,5b) 3-Butyl-3-ethyl-4-liydroxy-5-(4-iodophenyl)- 2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide (42) In a 25 ml round bottomed flask 0.5 g (1.3 mmole) of 6d , 0.67 g of mercuric triflate were dissolved in 20 ml 10 of dry methylene chloride with stirring. Next 0.34 g of 'Iodine was added and the solution was stirred at room temperature for 30 h. The reaction was then diluted with 50 ml methylene chloride and washed with 10 ml of 1 M sodium thiosulfate; 10 ml of saturated KI ; and 15 dried over sodium sulfate. See Tetrahedron, Vol.50, No. 17, pp 5139-5146 (1994) Bachki, F. Et al.Mass spectrum indicated a mixture of 6d , mono iodide 42 and a diiodide adduct. The mixture was separated by column chromatography and 42 was characterized bt NMR and mass Ik&M A %a C 4-3) Example 26 (3a,4b,5b) 3-Butyl-5-(4-carbomethoxyphenyl)-3-ethyl-4-hydroxy-2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide 25 (43) 20 spectra. fljf A 0.1 g sample of 42 ( 0.212 mmole), 2.5 ml dry methanol, 3 8 ul triethylamine (0.275 mmole) , 0.3 ml toluene and 37 mg of palladium chloride (0.21 mmole) 30 was charged to a glass lined mini reactor at 300 psi carbon monoxide. The reaction was heated at 100 °C overnight. The catalyst was filtered and a high yield of product was isolated. The product was characterized by NMR and mass spectra. 35 Note the ester functionalized product 43 can be converted to the free acid by hydrolysis. Printed from Mimosa 09/15/1999 15:28:34 page -40- WO 98/40375 PCT/US98/03792 Example 27 (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide (48), and (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-7-5 methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-l,1- dioxide (49) Step 1. 2-Mercapto-5-methoxybenzophenone (50) 1^3 (SC^ Reaction of 66.2 g of 4-methoxythiophenol with 3 60 ml 10 of 2.5 N n-butyllithium, 105 g of tetramethylethylenediamine and 66.7 g of benzonitrile in 600 ml cyclohexane according to the procedure in WO 93/16055 gave 73.2 g of brown oil which was kugelrohr distilled to remove 4-methoxythiophenol and gave 43.86 15 g of crude 50 in the pot residue. Step 2. 2-((2-Benzoyl-4-methoxyphenylth.io)methyl)-2-ethyIhexanal (51) \ 20 Reaction of 10 g (0.04 mole) of crude 50 with 4.8 g (0.02 mole)of mesylate 1 and 3.2 ml (0.23 mole) of triethylamine in 50 ml of diglyme according to the procedure for the preparation of 2 gave 10.5 g of crude product which was purified by HPLC (5% ethyl acetate-25 hexane) to give 1.7 g (22%) of 51. Step 3. 2-((2-Benzoyl-4-methoxyphenylsulfonyl)methyl)-2-ethyl-hexanal (52) 30 A solution of 1.2 g (3.1 mmoles) of 51 in 25 ml of methylene chloride was reacted with 2.0 g (6.2 mmoles) of 50-60% MCPBA according to the procedure of step 2 of procedure A in example 18 gave 1.16 g (90%) of 52 as a yellow oil. 35 Step 4. 2-((2-Benzyl-4-methoxyphenylsulfonyl)methyl)• 2-ethylhexanal (53) v Printed from Mimosa 09/15/1999 15:28:34 page -41- WO 98/40375 PCT/US98/03792 Hydrogenation of 1.1 g of 52 according to the procedure of step 3 of procedure A of example 18 gave 53 as a yellow oil (1.1 g). Step 5. (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide (48), and (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-l, 1-dioxide A solution of 1.1 g of 53, 0.36 g or potassium t-butoxide and 25 ml of anhydrous THF was held at reflux for 2 h and worked up as in step 4 of procedure A of example 18 to give 1.07 g of a crude product which was purified by HPLC to give 40 mg (4%) of 48 as crystals, mp 153-154 °C and 90 mg (8%) of 49 as solid, mp 136-140 5-Phenyl-2,3-dihydrospirobenzothiepine-3,1'-cyclohexane (57) Step 1. 1-(Hydroxymethyl)-cyclohexanecarboxaldehyde (54) To a cold (0*C' mixture of 100 g (0.891 mole) of cyclohexanecarboxaldehyde, 76.5 g of 37% of formaldehyde in 225 ml of methanol was added dropwise 90 ml of 1 N Sodium hydroxide in 1 h. The reaction mixture was stirred at room temperature over 48 then was evaporated to remove methanol. The reaction mixture was diluted with water and extracted with.methylene chloride. The organic layer was washed with water, brine, and dried over sodium sulfate and concentrated under vacuum to give 75 g (59.7%) of thick oil. Proton NMR and mass spectra were consistent with the product. Step 2. 1-(mesyloxymethyl) cyclohexanecarboxaldehyde (55) 0 Example 2 8 °C. Printed from Mimosa 09/15/1999 15:28:34 page -42- WO 98/40375 PCT/US98/03792 To a cold (0 "c*mixture of alcohol 54 (75 g, 0.54 mole) and 65.29 g (0.57 mole) of methanesulfonyl chloride in 80 ml of methylene chloride was added a solution of 5 pyridine (47.96 g, 0.57 mole) in 40 ml of methylene chloride. The reaction mixture was stirred at room temperature for 18 h then quenched with water, acidified with conc. HC1 and extracted with methylene chloride. The organic layer was washed with water, 10 brine, and dried over sodium sulfate and concentrated under vacuum to give 91.63 g (77.8%) of thick oil. Proton NMR and mass spectra were consistent with the product. 15 Step 3 . l-( (2- Benzoylphenylthio)methyl)cyclohexanecarboxaldehyde (56) A mixture of 69 g (0.303 mole) of 2- mercaptobenzophenone, 82 g (0.303 mole) of mesylate 55, 20 32 g of triethylamine, and 150 ml of diglyme was stirred and held at reflux for 24 h. The mixture was cooled, poured into dil. HC1 and extracted with methylene chloride. The organic layer was washed with 10% NaOH, water, brine, and dried over sodium sulfate 25 and concentrated under vacuum to remove excess diglyme. This was purified by silica gel flush column (5% EtOAc: Hexane) and gave 18.6 g (75.9%) of yellow oil. Proton NMR and mass spectra were consistent with the product. 30 Step 4. 5-Phenyl-2,3-dihydrospirobenzothiepine-3,l'- cyclohexane (57) ~ ^ ^ CSOo (5-)} © To a mixture of 6.19 g of zinc dust and 100 ml of dry DME was added TiClj(16.8 g, 0.108 mole) . The reaction 35 mixture was heated to reflux for 2 h. A solution of compound 56 (8.3 g, 0.023 mole) in 50 ml of DME was added dropwise to the reaction mixture in 1 h and the mixture was held at reflux for 18 h. The mixture was 1M Printed from Mimosa 09/15/1999 15:28:34 page -43- WO 98/40375 PCT/US98/03792 cooled, poured into water and extracted with ether. The organic layer was washed with water, brine, and dried over sodium sulfate, filtered through celite and concentrated under vacuum. The residue was purified by HPLC (10% EtOAc: Hexane) to give 4.6 g (64%) of white solid, mp 90-91 *C. Proton and carbon NMR and mass spectra were consistent with the product. 10 Exfrnipl? 29 8b-Phenyl-la,2,3,8b-tetrahydrospiro(benzothiepino[4,5-b]oxirene-2,1'-cyclohexane)-4,4-dioxide (58) To a solution of 57 (4.6 g, 15 mmole) in 50 ml 15 chloroform under nitrogen was added 55% MCPBA (16.5 g, 52.6 mmole) portionwise with spatula. The reaction was held at reflux for 18 h and washed with 10% NaOH(3X), water, brine, and dried over sodium sulfate and concentrated under vacuum to give 5 g of crude product. 20 This was recrystallized from Hexane/EtOAc to give 4.31 g (81%) of yellow solid, mp 154-155 "C. Proton and carbon NMR and mass spectra were consistent with the produc t. 25 Example 3 0 oU trans-4-Hydroxy- 5-phenyl-2,3,4,5-tetrahydro spiro(benzothiepine-3,1'-cyclohexane)-1,1-dioxide (59) A mixture of 0.5 g (1.4 mmoles) of 58 , 20 ml of 30 ethanol, 10 ml of methylene chloride and 0.4 g of 10% Pd/C catalyst was hydrogenated with 70 psi hydrogen for 3 h at room temperature. The crude reaction slurry was filtered through Celite and evaporated to dryness. The residue was purified by HPLC (10% EtOAc-Hexane, 25% 35 EtOAc-Hexane) . The first fraction was 300 mg (60%) as a white solid, mp 99-100 *C. Proton NMR showed this was a trans isomer. The second fraction gave 200 mg of solid which was impure cis isomer. ( Printed from Mimosa 09/15/1999 15:28:34 page -44- WO 98/40375 PCT/US98/03792 Example 31 (() c is-4-Hydroxy-5-phenyl-2,3,4,5-1etrahydro spiro(benzothiepine-3,1* -cyclohexane) -1,1-dioxide (60) To a solution of 0.2 g (0.56 mmole) of 59 in 20 ml of CH,C13, was added 8 g of 50% NaOH and one drop of Aliquat-336 (methyltricaprylylammonium chloride) phase transfer catalyst. The reaction mixture was stirred for 10 h at room temperature. Twenty g of ice was added to the mixture and the mixture was extracted with CHjCl, (3x10 ml) washed with water, brine and dried over MgS04 and concentrated in vacuo to recover 0.15 g of crude product. This was recrystallized from Hexane/EtOAc to give 125 mg of white crystal, mp 209-210 "c . Proton and carbon NMR and mass spectra were consistent with (3a,4a,5a) 3-Butyl-3-ethy1-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine (61), and (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine (62) To a solution of 0.5 g (1.47 mmole) of compound 47 in 5. ml of anhydrous THF was added 0.17 g (1.47 mmole) of 95% potassium t-butoxide. The reaction mixture was stirred at room temperature for 18 h and quenched with 10 ml of 10% HCl. The organic was extracted into methylene chloride. The methylene chloride extract was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by HPLC (2% EtOAc-hexane) to give 47 mg of 61 in the second fraction and 38 mg of 62 in the third fraction. Proton NMR and mass spectra were consistent with the assigned structures. Printed from Mimosa 09/15/1999 15:28:34 page -45- Exanvole 32 the product. WO 98/40375 PCT/US98/03792 (3a,4a,5a) 3-Butyl-3ethyl-4-hydroxy-7-amino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide (63) and (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-7-amino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide(64) 5 An autoclave was charged with 200 mg of 37 in 40 cc ethanol and .02 g 10 % Pd/C. After purging with nitrogen the clave was charged with 100 psi hydrogen and heated to 55 C. The reaction was monitored by TLC 10 and mass spec and allowed to proceed until all of 37 was consumed. After the reaction was complete the catalyst was filtered and the solvent was removed in vacuo and the only observable product was amine 63. This same procedure was used to produce 64 from 38. Example 34 (45) ' ^ (3a, 4a, 5a) 3-Butyl-3-et3hyl-4-hydroxy-7-methoxy-5- (3 ' -methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-l,1-20 dioxide (65), and (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy- 7-methoxy-5-(3'-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (66). Alkylation of e-methoxyphenol with 3-methoxybenzyl chloride according to the procedure described in J. 25 Chem. Soc, 2431 (1958) gave 4-methoxy-2-(3'- methoxybenzyl)phenol in 35% yield. This material was converted to compound 65, mp 13 8.5-141.5 °C, and compound 66, mp 115.5-117.5 °C, by the procedure similar to that in Example 18 method B. 30 Example 35 (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-(31 -(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (67), and 35 (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-(3'- (trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (68). S o,^ e. o\ L i e ft.* o \» rS) IM- Printed from Mimosa 09/15/1999 15:28:34 page -46- WO 98/40375 PCT/US98/03792 Alkylation of 4-methoxyphenol with 3-(trifluoromethyl)benzyl chloride according to the procedure described in J. Chem. Soc. 2431 (1958) gave 4-methoxy-2-(3'-(trifluoromethyl)benzyl)phenol. This 5 material was converted to compound 67, mp 226.5-228 °C, and compound 68, mp 188-190°C, byu the procedure similar to that in Example 18 method B. Example 3 6 ^"J'° (g, '°M 10 (3a,4a,5a) 3-ButyT-3-ethyl-5-(4'-fluorophenyl)-4- hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide (69), and (3a,4b,5b) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (70). 15 Alkylation of 4-methoxyphenol with 4-fluorobenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-methoxy-2-(4'-fluorobenzyl)phenol. This material was converted to 20 compound 69 and compound 70 by the procedure similar to that in Example 18 method B. fcTY" iSs> a Y° ^ Example 37 f FX$} (3a,4a,5a) 3-Butyl-3-ethyl-5-(3'-fluorophenyl)-4-25 hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-l,1- dioxide (71), and (3a,4b,5b) 3-Butyl-3-ethyl-5-(3'-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (72). 30 Alkylation of 4-methoxyphenol with 3-fluorobenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-methoxy-2-(3'-fluorobenzyl)phenol. This material was converted to compound 71 and compound 72 by the procedure similar to 35 that in Example 18 method B. ftrample 38 \ <£) m) i<*S Printed from Mimosa 09/15/1999 15:28:34 page -47- WO 98/40375 PCT/US98/03792 (3a,4a,5a) 3-Butyl-3-ethyl-5-(2'-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide (73), and (3a,4b,5b) 3-Butyl-3-ethyl-5-(2'-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-5 tetrahydrobenzothiepine-1,1-dioxide (74). Alkylation of 4-methoxyphenol with 2-fluorobenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-methoxy-2-(2'-10 fluorobenzyl)phenol. This material was converted to compound 73 and compound 74 by the procedure similar to that in Example 18 method B. fo| 6k \jQ\ xfc-T Example 3 9 CIS") 15 (3a, 4a, 5a) 3-Butyl-7-bromo-3-ethyl-4-iiydroxy-5-(3J methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide (75), and (3a,4b,5b) 3-Butyl-7-bromo-3-ethyl-4-hydroxy-5-(3'-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (76). 20 Alkylation of 4-bromophenol with 3-methoxybenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-bromo-2-(3'-methoxybenzyl)phenol. This material was converted to 25 compound 75, mp 97-101.5 °C, and compound 76, mp 102- 106 °C, by the procedure similar to that in Example 18 method B. jC§X 30 Example 40 >-* v" (T^ (3a,4a,5a) 3-Butyl-3-ethyl-7-fluoro-5-(4' fluorophenyl)-4-hydroxy-2,3,4,5-' tetrahydrobenzothiepine-1,1-dioxide (77), "and (3a,4b,5b) 3-Butyl-3-ethyl-7-fluoro-5-(41 -fluorophenyl)-4-hydroxy-2,3,4,5- . 35 tetrahydrobenzothiepine-1,1-dioxide (78). Alkylation of 4-fluorophenol with 4-fluorobenzyl chloride according to the procedure described in J. 14& Printed from Mimosa 09/15/1999 15:28:34 page -48- WO 98/40375 PCT/US98/03792 Chem. Soc, 2431 (1958) gave 4-fluoro-2-(4 * -fluorobenzyl)phenol. This material was converted to compound 77, mp 228-230 °C, and compound 78, mp 134.5-139 °C, by the procedure similar to that in Example 18 method b. c p p /—< r JS— c-vfi <*£,„?« '*<0 Example 41 ' (3a,4a,5a) 3-Butyl-3-ethyl-7-fluoro-4-hydroxy-5-(3' methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-l,1-10 dioxide (79), and (3a,4b,5b) 3-Butyl-3-ethyl-7-fluoro- 40hydroxy-5-(3'-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (80). Alkylation of 4-fluorophenol with 3-methoxybenzyl 15 chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-fluoro-2-(3 ' -methoxybenzyl)phenol. This material was converted to compound 79, as a solid and compound 80, mp 153-155 °C, by the procedure similar to that in Example 18 method 20 B. r3rso^~ueu O l"Et Example 42 f<\. o i* oi* V CD) (3a,4b,5b) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4-25 hydroxy-7-methylthio-2,3,4,5-tetrahydrobenzothiepine- 1,1-dioxide (81). A mixture of 0.68 (1.66 mmol) of compound 77, 0.2 g (5 mmol) of sodium methanethiolate and 15 ml of anhydrous 30 DMF was stirred at room temperature for 16 days. The reaction mixture was dilute with ether and washed with water and brine and dried over M9S04. The ether solution was concentrated in vacuo. The residue was purified by HPLC (20% ethyl acetate in hexanes). The 35 first fraction was impure (3a,4a,5a) 3-butyl-3-ethyl-4- hydroxy-7-methylthio-5-(4'-fluorophenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide. The second fraction was compound 81, mp 185-186.5 °C. Wl Printed from Mimosa 09/15/1999 15:28:34 page -49- WO 98/40375 PCT/US98/03792 VJ Co) ou U r* Example 43 Vs (3a,4b,5b) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4-hydroxy-7-(1-pyrrolidinyl)-2,3,4,5-5 tetrahydrobenzothiepine-1,1-dioxide (82). A mixture of 0.53 g (1.30 mmol) of compound 78 and 5 ml of pyrrolidine was held at reflux for 1 h. The reaction mixture was diluted with ether and washed with 10 water and brine and dried over MS04. The ether 9 • solution was concentrated in vacuo. The residue was crystallized from ether-hexanes to give compound 82, mp 174.5-177 °C. r^oY'SOJ'— 15 Example 44 ^ ^ (3a, 4b, 5b) 3-Butyl-3-ethyl-5-(4 '-fluorophenyl)-4-hydroxy-7-(1-morpholinyl)-2,3,4,5- ^ JZ£ tetrahydrobenzothiepine-1,1-dioxide (83). v—' f T (8^ 20 A mixture of 0.4 g (0.98 mmol) of compound 78 and 5.0 g (56 mmol) of morpholine was held at reflux for 2 h and concentrated in vacuo. The residue was diluted with ether (3 0 ml) and washed with water and brine and dried over M9S04. The ether solution was concentrated in 25 vacuo. The residue was recrystallized from ether- hexanes to give compound 83, mp 176.5-187.5 °C. Exfrtnpig 45 (3a,4a,5a) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4-30 hydroxy-7-methyl-2,3,4,5-tetrahydrobenzothiepine-l, 1- dioxide (84), and (3a,4b,5b) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4-hydroxy-7-methyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (85) . 35 Alkylation of 4-methylphenol with 4-fluorobenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-methyl-2-(4'-fluorobenzyl)phenol). This material was converted to m Printed from Mimosa 09/15/1999 15:28:34 page -50- WO 98/40375 PCT/US98/03792 compound 84 and compound 85 by thegjprocedure similar to that in Example 18 method B. ""Ir- Example 46 hydroxyphenyl)-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (86), and (3a,4b,5b) 3-Butyl-3-ethyl-4,7-dihydroxy-5-(4' -hydroxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide (87). To a solution of 0.52 (1.2 mmol) of compound 66 in 20 ml of methylene chloride was added 1.7 g (6.78 mmol) of born tribromide. The reaction mixture was cooled to -78 °C and was stirred for 4 min. An additional 0.3 ml of boron tribromide was added to the reaction mixture and the reaction mixture was stirred at -78 °C for 1 h and quenced with 2 N HC1. The organic was extracted into ether. The ether layer was washed with brine, dried over MgS04, and concentrated in vacuo. The residue (0.48 g) was purified by HPLC (30% ethyl acetate in hexanes). The first fraction was 0.11 g of compound 86 as a white solid, mp 171.5-173 °C. The second fraction was crystallized from chloroform to give 0.04 g of compound 87 as a white solid, mp 264 °C fluorophenyl)-2,3,4,5-tetrahydrobenzothiepine-l, 1-dioxide (88). Reaction of compound 70 with excess boron tribromide at Example 47 (3a,4b,5b) 3-Butyl-3-ethyl-4,7-dihydroxy-5-(4'- (dec). room temperature and worked up as in Example 46 gave compound 88 after an HPLC purification. Example 48 r Printed from Mimosa 09/15/1999 15:34:31 page -1- WO 98/40375 PCT/US98/03792 (3a,4b,5b) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4-hydroxy-7-(1-azetidinyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (89). 5 A mixture of 0.20 g (0.49 mmol) of compound 78, and 2.0 g (35 mmol) of aztidine was held at reflux for 3 h and concentrated in vacuo. The residue was diluted with ether (30 ml) and washed with water and brine and dried over MgS04. The ether solution was concentrated on a 10 steam bath. The separated crystals were filtered to give 0.136 g of 89 as prisms, mp 196.5-199.5 °C. rST^-v a* Example 4? i <^Tu (3a, 4a, 5a) 3-Butyl-3-e't'kyl-S- (3 ' -methoxyphenyl) -4-15 hydroxy-7-methylthio-2,3,4,5-tetrahydrobenzothiepine- 1,1-dioxide (90). (3a,4b,5b) 3-Butyl-3-ethyl-5-(3'-methoxyphenyl)-4-hydroxy-7-methylthio-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (91) . 20 A mixture of 0.4 g (0.95 mmol) of compound 79, 0.08 g (1.14 mmol) of sodium methanethiolate and 15 ml of anhydrous DMF was stirred at 60 °C for 2 h. An additional 1.4 mmol of sodium methanethiolate was added to the reaction mixture and the mixture was stirred at 25 60 °C for an additional 2 h. The reaction mixture was triturated with 100 ml of water and extracted methylene chloride. The methylene chloride water mixture was filtered through Celite and the methylene chloride layer was dried over MgS0, and concentrated in vacuo. 30 The first fraction (0.1 g) was compound 90, mp 117-121 °C. The second fraction [0.16 g) was compound 91, mp 68-76 °C. oo Printed from Mimosa 09/15/1999 15:34:31 page -2- WO 98/40375 PCT/US98/03792 10 15 Example 50 20 Preparation of polyethyleneglycol functionalized benzothiepine &. No. 141 136 25 No. A 50 ml rb flash under a nitrogen atmosphere was charged with 0.54 g of M-Tres-5000 (Polyethyleneglycol SlO I Printed from Mimosa 09/15/1999 15:34:31 page -3- WO 98/40375 PCT/US98/03792 Tresylate [methoxy-PEG-Tres,MW 5000] purchased from Shearwater Polymers Inc., 2130 Memorial Parkway, SW, Huntsville, Alabama 35801), 0.055 g Compound No. 136, 0.326 C.COj and 2cc anhydrous acetonitrile. The 5 reaction was stirred at 30 C for 5 days and then the solution was filtered to remove salts. Next, the acetonitrile was removed under vacuum and the product was dissolved in THF and then precipitated by addition of hexane. The polymer precipitate was isolate by 10 filtration from the solvent mixture (THF/hexane). This precipitation procedure was continued until no Compound No. 13 6 was detected in the precipitated product (by TLC Si02). Next, the polymer precipitate was dissolved in water and filtered and the water soluble polymer was 15 dialyzed for 48 hours through a cellulose dialysis tube (spectrum® 7 ,45 mm x 0.5 ft, cutoff 1,000 MW). The polymer solution was then removed from the dialysis tube and lyophilized until dried. The NMR was consistent with the desired product A and gel 20 permeation chromatography indicated the presence of a 4500 MW polymer and also verified that no free Compound No. 13 6 was present. This material was active in the IBAT in vitro cell assay. 25 Printed from Mimosa 09/15/1999 15:34:31 page -4- WO 98/40375 PCT/US98/03792 Example 51 Preparation of Compound 140 No. Ill 10 A 2-necked 50 ml round bottom Flask was charged with 0.42g of Tres-3400 (Polyethyleneglycol Tresylate [Tres-PEG-Tres,MW 3400] purchased from Shearwater Polymers 15 Inc., 2130 Memorial Parkway, SW, Huntsville, Alabama 35801), 0.1 potassium carbonate, O.lOOg of Compound No. Ill and 5 ml anhydrous DMF7~Stir for 6 days at 27 °C. TLC indicated the disappearance of the starting Compound No. 111. The solution waS transferred to a 20 separatory funnel and diluted with 50 cc methylene chloride and then extracted with water. The organic layer was evaporated to dryness by means of a rotary AoS Printed from Mimosa 09/15/1999 15:34:31 page -5- WO 98/40375 PCT/US98/03792 evaporator. Dry wgt. 0.4875 g. Next, the polymer was dissolved in water and then dialyzed for 48 hours at 40 °C through a cellulose dialysis tube (spectrum® 7 ,45mm x 0.5 ft, cutoff 1,000 MW). The polymer solution was then removed from the dialysis tube and lyophilized until dried 0.341 g). NMR was consistent with the desired product B. Example 52 A 10 cc vial was charged with 0.21 g of Compound No. 136 (O.Smmoles), 0.17g (1.3 mmoles)potassium carbonate, 0.6g (1.5 mmoles) of 1,2-bis-(2-iodoethoxy)-ethane and 10 cc DMF. The reaction was stirred for 4 days at room temperature and then worked up by washing with ether/water. The ether layer was stripped to dryness and the desired product Compound No. 134 was isolated on a silica gel column using 80/20 hexane ethyl acetate. o No. 134 dotr Printed from Mimosa 09/15/1999 15:34:31 page -6- WO 98/40375 Example 53 PCT/US98/03792 Example 54 0^ •nil No. 113 QjoS Printed from Mimosa 09/15/1999 15:34:31 page -7- WO 98/40375 PCT/US98/03792 A two necked 25 ml round bottom Flask was charged with 0.5g (1.24mmoles) of 69462, 13 mis of anhydrous DMF, 0.055g of 60% NaH dispersion and 0.230g (0.62 mmoles) of 1,2-Bis [2-iodoethoxylethane] at 10 °C under nitogen. Next, the reaction was slowly heated to 40 °C. After 14 hours all of the Compound No. 113 was consumed and the reaction was cooled to room temperature and extracted with ether/water. The ether layer was evaporated to dryness and then chromatographed on Silicage (80/2 0 ethyl acetate/hexane). Isolated Compound No. 112 (0.28 g) was characterized by NMR and mass spec. Example 55 No. 135 ,o No. 136 Xot Printed from Mimosa 09/15/1999 15:34:31 page WO 98/40375 PCT/US98/03792 In a 50 ml round bottom Flask, add 0.7g (1.8 mmoles) of Compound No. 136, 0.621g of potassium carbonate, 6 ml DMF, and 0.33g of 1,2-Bis [2-iodoethoxylethane]. Stir at 40 °C under nitrogen for 12 hours. The workup and isolation was the same procedure for Compound No. 112. 10 Examples 56 and 57 (Compound Nos. 131 and 137) The compositions of these compounds are shown in Table 3 . The same procedure as for Example 55 except appropriate benzothiepine was used. 15 Example 58 (Compound No. 13 9) The composition of this compound is shown in Table 3. Same procedure as for Example 55 with appropriate benzothiepine 1,6 diiodohexane was used instead of 1,2-Bis [2-iodoethoxylethane]. 20 Example 59 (Compound No. 101) No. 101 25 This compound is prepared by condensing the 7-NH2 benzothiepine with the 1,12-dodecane dicarboxylic acid or acid halide. SLOT Printed from Mimosa 09/15/1999 15:34:31 page -9- WO 98/40375 PCT/US98/03792 Example 6 0 (Compound No. 104) 5 No> 104 2-Chloro-4-nitrobenzophenone is reduced with triethylsilane and trifluoromethane sulfonic acid to 2-chloro-4-nitrodiphenylmethane 32. Reaction of 32 with 10 lithium sulfide followed by reacting the resulting sulfide with mesylate IV gives sulfide-aldehyde XXIII. Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIV (see Scheme 5). Reduction of the sulfone-aldehyde XXV formaldehyde and 100 psi hydrogen 15 and 55 C for 12 hours catalyzed by palladium on carbon in the same reaction vessel yields the substituted dimethylamine derivative XXVIII. Cyclization of XXVII with potassium t-butoxide yields a mixture of substituted amino derivatives of this invention 20 Compound No. 104. Printed from Mimosa 09/15/1999 15:34:31 page -10- WO 98/40375 PCT/US98/03792 Scheme 6 Example 61 10 o=s No. 102 15 A 1 oz. Fisher-porter bottle was charged with 0.14 g (0.34 mmoles) of 70112, 0.97 gms (6.8 mmoles) of methyl iodide, and 7 ml of anhydrous acetonitrile. Heat to 50 °C for 4 days. The quat. Salt Compound No. 192 was Printed from Mimosa 09/15/1999 15:34:31 page -11- WO 98/40375 PCT/US98/03792 isolated by concentrating to 1 cc acetonitrile and then precipitating with diethyl ether. 0.1O Printed from Mimosa 09/15/1999 15:34:31 page -12- WO 98/40375 PCT/US98/03792 Example 62 I i • No. 125 A 0.1 g (0.159 mmoles) sample of Compound No. 134 was dissolved in 15 ml of anhydrous acetonitrile in a Fischer-porter bottle and then trimethylamine was bubbled through the solution for 5 minutes at 0 °C and then capped and warmed to room temperature. The reaction was stirred overnight and the desired product was isolated by removing solvent by rotary evaporation. Example 63 (Compound No. 295) 0 No. 295 SLU Printed from Mimosa 09/15/1999 15:34:31 page -13- Sodium Hydride 60% (11 mg, 0.27 mmoles) in 1 cc of 5 acetonitrile at 0 °C was reacted with 0.248 mmoles (.10 g) of Compound No. 54 in 2.5cc of acetonitrile at 0 °C. Next, 0.(980g 2.48 mmoles) of 1,2-Bis [2-iodoethoxylethane]. After warming to room temperature, stir for 14 hours. The product was isolated by column 10 chromatography. Example 64 (Compound No. 2 86) v° PhCH, 2 H j 'OH A o 15 No. 286 Following a procedure similar to the one described in Example 86, infra (see Compound No. 118), the title compound was prepared and purified as a colorless 20 solid; mp 180-181 °C; lH NMR (CHClj) 5 0.85 (t, J = 6 Hz, 3H_, 0.92 (t, J = 6 Hz, 3H), 1.24-1.42 (m, 2H), 1.46-1.56 (m, 1H), 1.64-1.80 (m, 1H), 2.24-2.38 (m, 1H), 3.15 (AB, J„ = 15 Hz. Av = 42 Hz, 2H), 4.20 (d, J Printed from Mimosa 09/15/1999 15:34:31 page -14- WO 98/40375 PCT/US98/03792 = 8 Hz, 1H), 5.13 (s, 2H), 5.53 (s, 1H), 6.46 (s, 1H), 6.68 (s, 1H), 7.29-7.51 (ra, 10H), 7.74 (d, J = 8 Hz, 1H) , 8.06 (d, J = 8 Hz, 1H) . FABMS m/z 494 (M+H), HRMS calcd for (M+H) 494.2001, found 494.1993. Anal. Calcd. for Cj,H31N05S: C, 68.13; H, 6.33; N, 2.84. Found: C, 68.19; H, 6.56; N, 2.74. Printed from Mimosa 09/15/1999 15:34:31 page -15- WO 98/40375 PCT/US98/03792 Example 65 (Compound No. 287) H. '2 OH o No. 287 Following a procedure similar to the one described in Example 89, infra (see Compound No. 121), the title compound was prepared and purified as a colorless solid: mp 245-246 °C, lH NMR (CDC1,) 8 0.84 (t, J = 6 Hz, 3H), 0.92 (t, J = 6 Hz, 3H), 1.28, (d, J = 8 Hz, 1H), 1.32-1.42 (m, 1H), 1.48-1.60 (m, 1H), 1.64-1.80 (m, 1H), 2.20-2.36 (m, 1H), 3.09 (AB, J„ = 15 Hz, Av = 42 Hz, 2H), 3.97 (bs, 2H), 4.15 (d, J = 8 Hz, 1H), 5.49 (s, 1H), 5.95 (s, 1H), 6.54 (d, J = 7 Hz, 1H), 7.29-7.53 (m, 5H), 7.88 (d, J = 8 Hz, 1H); ESMS 366 (M+Li). Anal. Calcd. for C20HjsNO5S : C, 66.82; H, 7.01; N, 3.90. Found: C, 66.54; H, 7.20; N, 3.69. Example 66 (Compound No. 288) No. 288 Prmted from Mxmosa 09/15/1999 15:34:31 page -16- WO 98/40375 PCT/US98/03792 Following a procedure similar to the one described in Example 89, infra (see Compound No. 121), the title compound was prepared and purified by silica gel chromatography to give the desired product as a colorless solid: mp 185-186°C; 'h NMR (CDC15) 81.12 (s, 3H), 1.49 (s, 3H), 3.00 (d, J = 15 Hz, 1H), 3.28 (d, J = 15 Hz, 1H) , 4.00 (s, 1H), 5.30 (s, 1H), 5.51 (s, 1H), 5.97 (s, 1H), 6.56 (dd, J = 2.1, 8.4 Hz, 1H), 7.31-7.52 (m, 5H), 7.89 (d, J = 8.4 Hz, 1H). MS (FAB+) (M+H) m/z 332. Example 67 (Compound No. 289) Following a procedure similar to the one described in Example 89 (see Compound No. 121), the title compound was prepared and purified by silica gel chromatography to give the desired product as a white solid: mp 205-206 °C; lH NMR (CDC1,) 8 0.80-0.95 (m, 6H), 1.10-1.70 (m, 7H), 2.15 (m, 1H), 3.02 (d, J = 15.3 Hz, 2H), 3.15 (d, J = 15.1 Hz, 2H), 3.96 (s, br, 2H), 4.14 (d, J = 7.8 Hz, 1H), 5.51 (s, 1H), 5.94 (d, J = 2.2, 1H), 6.54 (dd, J = 8.5, 2.2 Hz, lH), 7.28-7.50 (m, 6H), 7.87 (d, J = 8.5 Hz, 1H). MS (FAB): m/z 388 (M+H). Example 68 (Compound No. 290) No. 289 Printed from Mimosa 09/15/1999 15:34:31 page -17- WO 98/40375 PCT/US98/03792 h 2 i 'OH o No. 290 10 15 Following a procedure similar to the one described in Example 89, infra (see Compound No. 121), the title compound was prepared and purified as a colorless solid: mp = 96-98 °C, SH NMR (CDC1,) 5 0.92 (t, J = 7 Hz, 6H) , 1.03-1.70 (m, 11H), 2.21 (t, J = 8 Hz, 1H), 3.09 (AB, =- 18 Hz, Av = 38 Hz, 2H), 3.96 (bs, 2H), 4.14 (d, J = 7 Hz, 1H), 5.51 (s, 1H), 5.94 (s, 1H), 6.56 (d, J = 9 Hz, 1H), 7.41-7.53 (m, 6H), 7.87 (d, J = 8 Hz, 1H); FABMS m/z 416 (M+H). Example 69 Following a procedure similar to the one described in Example 86, infra (see Compound-No. 118), the title compound was prepared and purified as a colorless solid: JH NMR (CDC1,) 5 0.91 (t, J = 7 Hz, 6H) , 1.02-1.52 (m, 11H), 1.60-1.70 (m, 1H), 2.23 (t, J = 8 Hz, Printed from Mimosa 09/15/1999 15:34:31 page -18- No. 291 WO 98/40375 PCT/US98/03792 1H), 3.12 (AB, = 18 Hz, Av = 35 Hz, 2H), 4.18 (d, J = 7 Hz, 1H), 5.13 (s, 2H), 5.53 (s, 1H), 6.43 (s, 1H) , 6.65 (s, 1H), 7.29-7.52 (m, 10H), 7.74 (d, J = 9 Hz, 1H), 8.03 (d, J = 8 Hz, 1H); ESMS m/z 556 (M+Li). a.n Printed from Mimosa 09/15/1999 15:34:31 page -19- WO 98/40375 PCT/US98/03792 Example 7 0 (Compound No. 292) H t)H No. 292 10 15 Following a procedure similar t6 the one descried in Example 89, infra (see Compound No. 121), the title compound was prepared and purified as a colorless solid: mp = 111-112.5°C, *H NMR (CDC13) 5 0.90 (t, J = 8 Hz, 6H), 1.03-1.50 (m, 10H), 1.55-1.70 (m, 2H), 2.18 (t, J = 12 Hz, 2H), 3.07 (AB, JM = 15 Hz, Av = 45 Hz, 2H), 4.09 (bs, 2H), 5.49 (s, 1H), 5.91 (s, 1H). 6.55 (d, J = 9 Hz, 1H), 7.10 (t, J = 7 Hz, 2H), 7.46 (t, J = 6 Hz, 2H), 7.87 (d, J ~ 9 Hz, 1H). Example 71 (Compound No. 293) During the preparation of Compound No. 290 from Compound No. 291 using BBrj, the title compound was Printed from Mimosa 09/15/1999 15:34:31 page -20- No. 293 a is WO 98/40375 PCT/US98/03792 isolated: lH NMR (CDC1,) 5 0.85 (t, J = 6 Hz, 6H), 0.98-1.60 (m, 10H), 1.50-1.66 (m, 2H), 2.16 (t, J = 8 Hz, 1H), 3.04 (AB, J„ = 15 Hz, Av = 41 Hz, 2H). 4.08 (s, 1H) , 4.12 (s, 1H), 5.44 {s, 1H), 5.84 (s, 1H) , 6.42 (d, J = 9 Hz, 1H), 7.12 (d, J = 8 Hz, 2H), 7.16-7.26 (m, 10H), 7.83 (d, J = 8 Hz, 1H); ESMS m/z 512 (M+Li). Example 72 (Compound No. 294) Following a procedure similar to the one described in Example 60 (Compound No. 104), the title compound was prepared and purified as a colorless solid: 'H NMR (CDClj) 5 0.90 (t, J = 6 Hz, 6H), 1.05-1.54 (m, 9H), 1.60-1.70 (m, 1H), 2.24 (t, J = 8 Hz, 1H), 2.80 (s, 6H), 3.05 (AB, J„ = 15 Hz, Av = 42 Hz, 2H), 4.05-4.18 (m, 2H) , 5.53 (s, 1H), 5.93 (s, 1H), 6.94 (d, J = 9 Hz, 1H), 7.27-7.42 (m, 4H), 7.45 (d, J = 8 Hz, 2H), 7.87 (d, J = 9 Hz, 1H); ESMS m/z 444 (M+H). Structures of the compounds of Examples 33 to 72 are shown in Tables 3 and 3A. Examples 73-79, 87. 88 and 91-102 Using in each instance a method generally described in those of Examples 1 to 72 appropriate to the substituents to be introduced, compounds were prepared having the structures set forth in Table 3. The starting materials illustrated in the reaction schemes shown above were varied in accordance with principles of organic synthesis well known to the art to introduce the indicated substituents in the 4- and 5- positions (R1, R4, R5, Rs) and in the indicated position on the benzo ring (R*) . Printed from Mimosa 09/15/1999 15:34:31 page -21- WO 98/40375 PCT/US98/03792 10 15 20 25 Structures of the the compounds produced in Examples 73-102 are set forth in Tables 3 and 3A. Examples 80-84 Preparation of 115, 116, 111, 113 Preparation of 4-chloro-3-[4-methoxy-phenylmethyl]-nitrobenzene. In a 500 ml 2-necked rb flask weigh out 68.3 gms phosphorus pentachloride (0.328 mole 1.1 eq). Add 50 mis chlorobenzene. Slowly add 60 gms 2-chloro-5-nitrobenzoic acid (0.298 mole). Stir at room temp overnight under N2 then heat 1 hr at 50C. Remove chlorobenzene by high vacuum. Wash residue with hexane. Dry wt=55.5 gms. In the same rb flask, dissolve acid chloride (55.5 g 0.25 mole) from above with 100 mis anisole (about 3.4 eq). Chill solution with ice bath while purging with N2. Slowly add 40.3g aluminum chloride (1.2 eq 0.3 mole) . Stir under N3 for 24 hrs. After 24 hrs, the solution was poured into 300 mis IN HC1 soln. (cold). Stir this for 15 min. Extract several times with diethyl ether. Extract organic layer once with 2% aqueous NaOH then twice with water. Dry organic layer with MgS04, dry on vac line. Solid is washed well with ether and then ethanol before drying. Wt=34.57g (mixture of meta, ortho and para). Elemental theory 57.65 3 .46 found C 57.45 H 5.51 N 4.8 4.8 CI 12.15 12.16 Printed from Mimosa 09/15/1999 15:34:31 page -22- WO 98/40375 PCT/US98/03792 With the next step of the reduction of the ketone with trifluoromethane sulfonic aid and triethyl silane, crystallization with ethyl acetate/hexane affords pure 4-chloro-3-[4-methoxy-phenylmethyl]-nitrobenzene. 5 4-Chloro-3-[4-methoxy-phenylmethyl]-nitrobenzene was then reacted as specified in the synthesis of 117 and 118 from 2-chloro-4-nitrophenylmethane. From these procedures 115 and 116 can be synthesized. Compounds 111 and 113 can be synthesized from the procedure used 10 to prepare compound 121. Compound 114 can be prepared by reaction of 116 with ethyl mercaptan and aluminum trichloride. Examples 8 5 and 86 15 Preparation of 117 and 118 2-Chloro-4-nitrobenzophenone is reduced with triethylsilane and trifluoromethane sulfonic acid to 2-chloro-4-nitrodiphenylmethane 32. Reaction of 32 with lithium sulfide followed by reacting the resulting 20 sulfide with mesylate IV gives sulfide-aldehyde XXIII. Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIII. Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIV (see Scheme 5). 25 The sulfone-aldehyde (31.8 g) was dissolved in ethanol/toluene and placed in a parr reactor with 100 ml toluene and 100 ml of ethanol and 3.2 g of 10% Pd/C and heated to 55 C and 100 psi of hydrogen gas for 14 hours. The reaction was then filtered to remove the 3 0 catalyst. The amine product (.076 moles, 29.5 g) from this reaction was then reacted with benzyl chloroformate (27.4g) in toluene in the presence of 35 g of potassium carbonate and stirred at room Printed from Mimosa 09/15/1999 15:34:31 page -23- WO 98/40375 PCT/US98/03792 temperature overnight. After work up by extraction with water, the CBZ protected amine product was further purified by precipitation from toluene/hexane. The CBZ protected amine product was then reacted with 3 equivalents of potassium t-butoxide in THF at O C to yield compounds 117 and 118 which were separated by silica gel column chromatography. Examples 89 and 90 Preparation of 121 or 122 Compound 118 (.013 moles, 6.79g) is dissolved in 135 ml of dry chloroform and cooled to -78 C, next 1.85 ml of boron tribromide (4.9 g) was added and the reaction is allowed to warm to room temperature. Reaction is complete after 1.5 hours. The reaction is quenched by addition of 10% potassium carbonate at 0 C and extract with ether. Removal of ether yields compound 121. A similar procedure can be used to produce 122 from 117. Examples 93-96 Compounds 126, 127, 128 and 129 as set forth in Table 3 were prepared substantially in the manner described above for compounds 115, 116, 111 and 113, respectively, except that fluorobenzene was used as a starting material in place of anisole. Printed from Mimosa 09/15/1999 15:34:31 page -24- WO 98/40375 PCT/US98/03792 table 3 Specific conmounds (§102-111,113-130,132-134,136,138,142-144,262-296) CRx)q—7T7 Ex. Cp#' ' R1 R2 R3 R< R5 R6 (Hx)q 61 102 Et- n-Bu- EO- H- Ph- E- I"/ 7- (CE3)3N+- 73 103 n-3u- Et- EO- E- Ph- E- I-/ 1- (CE3)3N+- 60 104 Et— n-Bu- F.O- E- Ph-. _ E- 7-(CE3)2N- 74 105 Et- n-Bu- EO- E- •/ Ph- E- 7- CE3S02NE- 75 106 Et- n-Bu- HO- E- Ph- E- 7-3r-CE2-CONE- 76 107 n-Bu- Et- EO- E- p-n-CioE2i--O-Ph- E- 7-NE2- 77 108 Et- n-3u- EO- E- Ph- E- 7- C5E11CONE- 78 109 Et- n-Bu- EO- E- P-n-CioE2i--O-Ph- E- 7-NH2- 79 110 Et- n-Bu- EO- E- Ph- H- 7-CE3CONE- 80 111 n-Bu- Et- EO- E- p-EO-Ph- E- 7-KH2- 81 113 Et- n-Bu- HO- H- p-EO-Ph- H- 7-NE2- 82 114 Et- n-Bu- EO- E- p-CH30-Ph- E- 7-NH2- 83 115 n-3u- Et- EO- E- p-CHjO-Ph- H- 7-NS-CBZ 84 116 Et- n-Bu- EO- H- p-CE30-Ph- H- 7-NH-CBZ Printed from Mimosa 09/15/1999 15:34:31 page -25- WO 98/40375 PCT/US98/03792 85 117 n-Bu- Et- HO- H- Ph- H- 7-NE-CBZ 86 118 Et- n-Bu- HO- H- Ph- H- 7-NH-CBZ 87 119 Et- n-Bu- HO- H- Ph- E- 7-NEC02-t-Bu 88 120 n-Bu- Et- HO- H- Ph- H- 7-NEC02"t-Bu 89 121 Et- n-Bu- HO- E- Ph- K- 7-NH2- 90 122 n-Bu- Et- KO- H- Ph- H- 7-NH2- 91 123 Et- n-Bu- KO- E- Ph- H- 7-n-CgEi3-NH- 92 124 n-Bu- Et- EO- H- Ph- H- 7-n-CgEi3-NE- 62 125 Et- n-3u- EO- E- Ph-- E- I-, 8- (CE3)3 N+( CH2CE2O)3- 93 126 n-3u- Et- EO- E- p-F-?h- E- 7-NE-C3Z 94 127 n-Bu- Et- EO- E- p-F-Ph- E- 7-NE2- 95 128 Et- n-Bu- EO- E- p-F-Ph- E- 7-NH-CBZ 96 129 Et- n-Su- EO- H- p-F-?h- H- 7-NK2- 97 130 Et- n-Bu- EO- E- Ph- E- I", 8- (CH3)3N+ CsH12O- 98 132 Et- n-su- EO- H- Ph- H- 8-phthal-imidyl-CSHI20- 99 133 Et- n-Bu- EO- H- Ph- H- 8-n-CioE2i" 52 134 Et- n-Bu- HO- H- Ph- H- 8- I-(C2H4O)3- 100 136 Et- n-Bu- HO- E- Ph- H- 8- HO- 3^4- Printed from Mimosa 09/15/1999 15:34:31 page -26- 101 49 49 48 34 34 35 35 46 46 36 36 47 39 39 40 40 41 41 37 38 37 WO 98/40375 PCT/US98/03792 .38 n-Bu- Et- HO- E- Ph- E- 8- ce3co2- 90 Et- n-3u- H- HO- E- ra-CE30-Ph- 7-ch3s- 91 Et- tv-Bu- HO- E- m-CK30-Ph- E- 7-ce3s- 89 Et- n-Bu- EO- E- p-F-Ph.- E- 7— (N) — azetidine 66 Et- n-Bu- KO- E- nv-CEjO-Ph— E- 7-ce3o- 65 Et- n-Bu- H- EO- E- m-c:-:3o-?h- 7-ce3o- 68 Et- n-Bu- KO- E- m-CF3-?h- E- 7-ck3o- 67 Et- n-Bu- E- EO- K~ ■ tr-CF3-Ph- 7-ch3o- 87 Efc- n-3u- EO- E- R-HO-Ph- E- 7-EQ- 86 Et- n-Su- HO- K- n-HO-Ph- E- 7-ch3o- 70 Et- n-Bu- EO- E- p-F-Ph- H- 7-ce3o- 69 Et- n-Bu- K- EO- E- p—F—Ph— 7-ce3o- 88 Et- n-Bu- HO- E- p-F-Ph- E- 7-EO- 76 Et- n-Bu- EO- H- m-CK30-Ph- H- 7-3r- 75 Et- n-Bu- E- EO- E- m-CE30-Ph- 7-Br- 77 Et- n-Bu- H- EO- E- p-F-Ph- 7-F- 78 Et- n-Bu- RO- E- p-?-?h- H- 7-F- 79 Et- n-Bu- H- KO- E- m-CF.30-Ph- 7-F- 80 Et- n-Bu- EO- E- m-CE30-Ph- H- 7-F- 72 Et- n-Bu- SO- E- n-F-Ph- H- 7-ce3o- 73 Et- n-Bu- H- EO- E- o-F-Ph- 7-ch3o- 71 Et- n-Bu- E- EO- E- m-F-Ph- 7-CE30- ^*5 Printed from Mimosa 09/15/1999 15:34:31 page -27- 38 42 45 45 44 43 64 65 66 67 68 69 70 71 72 63 102 WO 98/40375 PCT/US98/03792 74 Et- n-3u- HO- H- o-r-?h- H- 7-CH30- 81 Et- n-Bu- HO- H- p-F-Ph- H- 7-CH3S- 85 Et- n-Bu- HO- K- p-F-Ph- H- 7-CH3- 84 Et- n-Bu- H- KO- H- p-F-Ph- 7-ch3- 83 • Et- n-Bu- HO- K- p-F-Ph- H- 7- (N) — morpholine 82 Et- n-Bu- HO- K- p-F-Ph- H- 7- (N) -pyrrolidine 286 Et- • Et- KO- E- Ph- H- 7-NE-C3Z 287 Et- Et- EO- E- Ph- H- 7-NE2- 288 c:-:3- ch3- KO- E- Ph- E- 7-ne2- 289 n-c3h7- n-C3k7— HO- E- Ph- K- 7-KK2- 290 n-3u- n-3u- HO- E- Ph- K- 7-NE2- 291 n-3u- n-3u- EO- K— Ph- E- 7-NE-C3Z 292 n-3u- n-3u- EO- E- p-F-Ph- H- 7-nh2- 293 n-3u- n-Bu- EO- E- Ph- K- 7-PhCE2N- 294 n-3u- n-3u- KO- K- Ph- K- 7-(CK3)2N- 295 Et- n-Bu- KO- E- p-I-(c2h4o)3-Ph- K- 7-NE2- 296 Et- n-Bu- EO- k- i-/ p- (ch3)3n+{c2 e4o)3-Ph- h- 7-NE2" SM Printed from Mimosa 09/15/1999 15:34:31 page -28- WO 98/40375 PCT/US98/03792 table 3a Bridged Benzothiephenes (5101,112,131,135,137,139-141) o CPD #101 (Ex. 59) 3a C?D #112 (Ex. 53) CPD#131 (Ex. 56) a xi Printed from Mimosa 09/15/1999 15:34:31 page -29- WO 98/40375 PCT/US98/03792 CPD #135 (Ex. 55) CPD #137 (Ex. 57) CPD #139 (Ex. 58) reprinted from Mimosa 09/15/1999 15:34:31 page -30- WO 98/40375 PCT/US98/03792 3400 MW polyethyleneglycol bridge CPD #140 (Ex. 51) ZV\ Printed from Mimosa 09/15/1999 15:34:31 page -31- WO 98/40375 PCT/US98/03792 Examples 104-231 Using in each instance a method generally described in those of Examples 1 to 72 appropriate to the substituents to be introduced, including where 5 necessary other common synthesis expedients well known to the art, compounds are prepared having the structures set forth in Table 4. The starting materials illustrated in the reaction schemes shown above are varied in accordance with principles of 10 organic synthesis well known to the art in order to introduce the indicated substituents in the 4- and 5-positions (R5, R4, R', R8) and in the indicated position on the benzo ring (Rx) . 2.2)0 Printed from Mimosa 09/15/1999 15:34:31 page -32- WO 98/40375 PCT/US98/03792 table 4 Alternative coapounds §1 (§302-312, 314-430) Cpdf R5 (R*)ct 302 p-F-Ph- 7-(1-aziridine) 303 p-F-Ph- 7-EtS- 304 p-F-Ph- 7-ch3s(0)- 305 p-F-Ph- 7-ch3s(0)2~ 306 p-F-?h- i,- 7-?hS- 307 p-F-Ph- 7-ck3s- S-ch3s- 308 p-F-Ph- 7-ch3o- 9-ch3o- 309 p-F-Ph- 7-Et- 310 p-F-Ph- 7-iPr- 311 p-F-Ph- 7-t-Bu- 312 p-F-Ph- 7-(1-pyrazole)- 314 m-CH30-Ph 7-(1-azetidine) 315 _ m-CH30-Ph- _7^-(1-aziridine) 316 ra-CH30-Ph- 7-EtS- 317 m-CH30-Ph-_ 7-CH3S(0)- 318 m-CH30-Ph- 7-CH3S(O)z~ 319 m-CH30-Ph- 7-PhS- 2.31 Printed from Mimosa 09/15/1999 15:34:31 page -33- WO 98/40375 PCT/US98/03792 320 m-CH30-Ph 7-ch3s- 9-ch3s- 321 m-CH30-Ph 7-ch3o- 9-CH30— 322 m-CH30-Ph 7-Et- 323 m-CH30-Ph 7-iPr- 324 m-CH30-Ph 7-t-Bu- 325 p-F-Ph- 6-CK30- 7-ck3o— 8-CH30— 326 p-F-Ph- 7-(1-azetidine) 9-ck3- 327 p-F-Ph- 7-FtS- . 9-ce3- 328 o-F-Ph- 7-c:-:3S(0)- 9-ch3- 329 p-F-Ph- 7-CH3S(O)2- 9-ch3- 330 p-F-Ph- 7-PhS- 9-ch3- 331 p-F-Ph- 7-ch3s- 9-ck3- 332 p-F-Ph- 7-ch3o- 9-ch3- 333 p-F-Ph- 7-ch3- 9-ch3- 334 p-F-Ph- 7-ch3o- 9-ch3o- 335 p-F-Ph- 7-(1-pyrrole) 336 p-F-Ph- 7- (NHJ' -methylpiperazine 232- Printed from Mimosa 09/15/1999 15:34:31 page -34- WO 98/40375 337 p-F-Ph- 338 p-F-Ph- 339 p-F-Ph- 340 p-F-Ph- 341 p-F-Ph- 342 p-F-Ph- 343 p-F-Ph- 344 m-CH30-Ph- 345 m-CH30-Ph- 346 m-CH30-Ph- 347 m-CK30-Ph- 348 m-CroO-Ph-34 9 ra-CH30-Ph- 350 m-CH30-Ph- 351 m-CH30-Ph- 352 m-CH30-Ph- 353 m-CH30-Ph- 354 m-ch30-Ph- PCT/US98/03792 Ph- 7-CH3C(=CH2)- 7-cyclpropyl 7-(CH3)2NH - 7- (N)-azetidine 9-CH3S- 7-(N-pyrrolidine) 9-ch3s- 7-(CH3)2N-9-ck3s- 7-(1-pyrazole) 7- (N)-5J'-methylpiperazine Ph- 7-CH3C(=CK2)- 7-cyclopropyl 7—(ch3)2NH - 7- (N)-azetidine 9-ch3s- 7-(N-pyrrolidine)- 9-ch3s- 7-(ch3) 2N-9-ch3s- 6-ch3o- 7-ch3o- 8-ch3o- 7-(1-azetidine) 9-CH3- 233 Printed from Mimosa 09/15/1999 15:34:31 page -35- WO 98/40375 355 m-CH30-Ph- 356 m-CH30-Ph- 357 m-CH30-Ph- 358 m-CH30-Ph- 359 m-CH30-Ph-3 60 m-CH30-Ph-3 61 m-CH30-Ph-3 62 m-CH30-Ph- 363 thien-2-yl 364 thien-2-yl 3 65 thien-2-yl 3 66 thien-2-yl 3 67 thien-2-yl 368 thien-2-yl 369 thien-2-yl 370 thien-2-yl 371 thien-2-yl 372 thien-2-yl 373 thien-2-yl 374 thien-2-yl PCT/US98/03792 7-EtS-9-ch3- 7-CH3S(O)— 9-ch3- 7-ch3s(0)2" 9-ch3— 7-PhS-9-ch3- 7-CH3S-9-ch3- 7-ck3o— 9-ch3- 7-ch3-9-ch3- 7-ch3o- . 9-ck3o- 7- (1-aziridine) 7-EtS- 7-ch3s(o)— 7-ch3s(0)2- 7-PhS- 7-ch3s-9-ch3s- 7-ch3o-9-ch3o- 7-Et- 7-iPr- 7-t-Bu- 7-(1-pyrrole)- 7-CH30- 5-2>4- Prmted from Mimosa 09/15/1999 15:34:31 page -36- WO 98/40375 375 thien-2-yl 376 thien-2-yl 377 thien-2-yl 378 5-Cl-thien-2-yl 379 5-Cl-thien-2-yl 380 5-Cl-thien-2-yl 381 5-Cl-thien-2-yl 382 5-Cl-thien-2-yl 383 5-Cl-thien-2-yl 384 5-Cl-thien-2-yl 385 5-Cl-thien-2-yl 386 5-Cl-thien-2-yl 387 5-Cl-th.ien-2-yl 388 5-Cl-thien-2-yi 389 5-Cl-thien-2-yi 390 5-Cl-thien-2-yl 391 5-Cl-thien-2-yl 392 thien-2-yl 393 thien-2-yl 394 thien-2-yl 395 thien-2-yl PCT/US98/03792 7-ch3s-7- (l-azetidine) 7-Me- 7-(1-azetidine) 7- (1-aziridine) 7-EtS- 7-ch3s(0)— 7-ch3s(0)2~ 7-PhS- 7-ch3s-9-ch3s- 7-ch3o-9-ch3o- 7-Et- 7-iPr- 7-t-Bu- 7-ch3o- 7-CH3S- 7-Me 7- (1-azetidine) 9-ch3- 7-EtS-9-ch3- 7-ch3s(0)-9-CH3- 7-ch3s(0)2~ 9-CH3- Printed from Mimosa 09/15/1999 15:34:31 page -37- WO 98/40375 PCT/US98/03792 396 thien-2-yl 397 thien-2-yl 3 98 thien-2-yl 399 thien-2-yl 4 00 thien-2-yl 401 thien-2-yl 402 thien-2-yl 403 thien-2-yl 404 thien-2-yl 405 thien-2-vl 40 6 thien-2-yl 407 thien-2-yl 408 thien-2-yl 409 thien-2-yl 7-PhS-9-CH3- 7-ch3s-9-ch3- 7-ch3o-9-ch3- 7-ch3-9-ch3- 7-ch3o-9-ch3o- 7- (1-pyrazrole) 7- -methylpiperazine Ph- 7-cs3c(=CH2)- 7-cvclpropyl 7-(CK3)2NH - 7-(N)-azetidine 9-ch3s- 7-(N-pyrrolidine) 9-ck3s- 7-(CH3)2N-9-ch3s- 411 5-Cl-thien-2-yl 7-(1-pyrazrole) 412 _5-Cl-thien-2-yl~ 7- (N)-N' -methylpiperazine 413 5-Cl-thien-2-yl Ph- 414 5-Cl-thien-2-yl 7-ch3c(=CH2) — 415 5-Cl-thien-2-yl 7-cyclopropyl 416 5-Cl-thien-2-yl 7- (ch3) 2NK - 22) t> Printed from Mimosa 09/15/1999 15:34:31 page -38- WO 98/40375 PCT/US98/03792 417 5-Cl-thien-2-yl 418 5-Cl-thien-2-yl 419 5-Cl-thien-2-yl 7-(N)-azetidine 9-ch3s- 7-(N-pyrrolidine) • 9-ch3s- 7-(CH3) 2N-9-ch3s- 420 5-Cl-thien-2-yl 7-(1-azetidine) 9-ch3- 421 5-Cl-thien-2-yl 422 5-Cl-thien-2-yl 423 S-Cl-thien-2-yl 424 5-Cl-thien-2-yl 425 5-Cl-thien-2-yl 425 5-Cl-thien-2-yl 427 5-Cl-thien-2-yl 428 5-Cl-thien-2-yl 429 thien-2-yl 430 5-Cl-thien-2-yl 7-EtS-9-ch3- 7-CK3S(0)-9-ch3- '7-ch3s (O) 2-9-ch3- 7-PhS-9-ch3- 7-ch3s-9-ch3- 7-ch3o-9-ch3- 7-ch3-9-ch3- 7-ch3o-9-ch3o- 6-ch3o- 7-ch3o-" 8-ch3o-- 6-ch3o- 7-ch3o- 8-ch3o- Printed from Mimosa 09/15/1999 15:34:31 page -39- WO 98/40375 PCT/US98/03792 Examples 232-1394 Using in each instance a method generally described in those of Examples 1 to 72 appropriate to the substituents to be introduced, including where necessary other common synthesis expedients well known to the art, compounds are prepared having the structures set forth in Table 1. The starting materials illustrated in the reaction schemes shown above are varied in accordance with principles of organic synthesis well known to the art in order to introduce the indicated substituents in the 4- and 5-positions (R3, R*, R5, R*) and in the indicated position on the benzo ring (R*) . Example 1395 Dibutyl 4-fluorobenzene dialdehyde Step 1: Preparation of dibutyl 4-fluoro benzene dialdehyde To a stirred solution of 17.5 g (123 mmol) of 2,5-difluorobenzaldehyde (Aldrich) in 615 mL of DMSO at ambient temperature was added 6.2 g (135 mmol) of lithium sulfide (Aldrich). The dark red solution was stirred at 75 C for 1.5 hours. or until the starting material was completely consumed, and then 34 g (135 mmol) of dibutyl mesylate aldehyde was added at about 50 C. The reaction mixture was stirred at 75 C for three hours or until the reaction was completed. The cooled solution was poured into water and extracted with ethyl acetate. The combined extracts were washed with water several times, dried (MgS04) and O Br A3? Printed from Mimosa 09/15/1999 15:34:31 page -40- WO 98/40375 PCT/US98/03792 concentrated in vacuo. Silica gel chromatographic purification of the crude product gave 23.6 g (59%) of fluorobenzene dialdehyde as a yellow oil: ^-H NMR (CDCI3) d 0.87 (t, J= 7.05 Hz, 6H), 1.0-1.4 (m, 8H), 5 1.5-1.78 (m, 4H), 3.09 (s, 2H), 7.2-7.35 (m, 1H), 7.5- 7.6 (m, 2H), 9.43 (s, 1H), 10.50 (d, J = 2.62 Hz, 1H). Step 2: Preparation of dibutyl 4-fluorobenzyl alcohol To a solution of 22.6 g (69.8 mmol) of the dialdehyde 10 obtained from Step 1 in 650 mL of THF at -60 C was added 69.8 mL (69.8 mmol) of DIBAL (1M in THF) via a syringe. The reaction mixture was stirred at -40 C for 20 hours. To the cooled solution at -40 C was added sufficient amount of ethyl acetae to quench the excess 15 of DIBAL, followed by 3 N HC1. The mixture was extracted with ethyl acetate, washed with water, dried (MgSO,) , and concentrated in vacuo. Silica gel chromatographic purification of the crude product gave 13.5 g (58%) of recovered starting material, and 8.1 g 20 (36%) of the desired fluorobenzyl alcohol as a colorless oil: XH NMR (CDCI3) d 0.88 (t, J = 7.05 Hz, 6H), 1.0-1.4 (m, 8H) , 1.5-1.72 (m, 4H), 1.94 (brs, 1H) , 3.03 (s, 2H), 4.79 (s, 2H), 6.96 (dt, J= 8.46, 3.02 Hz, 1H), 7.20 (dd, J = 9.47, 2.82 Hz, 1H), 7.42 25 (dd, J= 8.67, 5.64, lH), 9.40 (s, 1H). Step 3: Preparation of dibutyl 4-fluorobenzyl bromide To a solution of 8.1 g (25 mmol) of benzyl alcohol obtained from Step 2 in 100 mL of DMF at -40 C was 30 added 47 g (50 mmol) of bromotriphenyphosphonium bromide (Aldrich). The resulting solution was stirred cold for 30 min, then was allowed" to~~warm to 0~C. To~ the mixture was added 10% solution of sodium sulfite and ethyl acetate. The extract was washed a few times 35 with water, dried (MgS04), and concentrated in vacuo. The mixture was stirred in small amount of ethyl acetate/hexane mixture (1:4 ratio) and filtered through a pad of silica gel, eluting with same solvent mixture. Printed from Mimosa 09/15/1999 15:34:31 page -41- WO 98/40375 PCT/US98/03792 The combined filtrate was concentrated in vacuo to give 9.5 g (98%) of the desired product as a colorless oil: *H NMR (CDCI3) d 0.88 (t, J = 7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.55-1.78 (m, 4H), 3.11 (s, 2H), 4.67 (s, 2H), 5 7.02 (dt, J = 8.46, 3.02 Hz, 1H), 7.15 (dd, J = 9.47, 2.82 Hz, 1H), 7.46 (dd, J= 8.67, 5.64, 1H), 9.45 (s, 1H) . Step 4: Preparation of sulfonyl 4-fluorobenzyl 10 bromide To a solution of 8.5 g (25 mmol) of sulfide obtained from Step 3 in 200 mL of CH2C1j at 0 was added 15.9 g (60 mmol) of mCPBA (64% peracid). The resulting solution was stirred cold for 10 min, then was allowed 15 to stirred ambient temperature for 5 hours. To the mixture was added 10% solution of sodium sulfite and ethyl acetate. The extract was washed several times with saturated Na2C03, dried (MgSOJ , and concentrated in vacuo to give 10.2 g (98%) of the desired product as 20 a colorless oil: *H NMR (CDCI3) d 0.91 (t, J = 7.05 Hz, 6H), 1.03-1.4 (m, 8H) , 1.65-1.82 (m, 2H) , 1.90-2.05 (m, 2H), 3.54 (s, 2H), 5.01 (s, 2H), 7.04-7.23 (m, 1H), 7.30 (dd, J = 8.87, 2.42 Hz, 1H), 8.03 (dd, J = 8.86, 5.64, 1H), 9.49 (s, 1H). 240 Printed from Mimosa 09/15/1999 15:34:31 page -42- WO 98/40375 PCT/US98/03792 M I Printed from Mimosa 09/15/1999 15:34:31 page -43- WO 98/40375 PCT/US98/03792 Generic Scheme X -CC CHO 1. Li2S, DMSO, heat 2. mesylate aldehyde, heat 1. BuLi, PMETA -40 °C, THF 2. DMF -CrF PMETA: -COS R2 DIBAL, THF -40 °C r*. /VSA>R' n T Ar2 ■< Br BrPh3PBr, -40 °C DMF cho ho mCPBA O. .o R ^AOHC Br R5 B(OR>2, heat *- Pd(Ph3P)4, NajCOj EtOH, toluene or DME or R5 SnRj, heat Pd(Ph3P)4, solvent R = H, or short alkyl (C1-C6) o. p R v^\0HC 5r base; e.g. KOtBu R*—jr R5 Generic Scheme X: The nucleophilic substitution of an appropriately substituted 2-fluorobenzaldehyde with P-4X Printed from Mimosa 09/15/1999 15:34:31 page -44- WO 98/40375 PCT/US98/03792 lithium sulfide or other nucleophilic sulfide anion in polar solvent (such as DMF, DMA, DMSO, etc), followed by the addition of dialkyl mesylate aldehyde (X), provided a dialkyl benzene dialdehyde Y. DIBAL 5 reduction of the dialdehyde at low temperature yielded benzyl alcohol monoaldehyde Z. Conversion of benzyl alcohol to benzyl bromide, followed by oxidation of sulfide to sulfone yielded the key intermediate W. Preparation of N-propvlsulfonic acid To a solution of 51 mg (111 um) Compound X in ethanol (400 ul) was added 1,3 propane sultone (19.5 ul, 222 15 urn) . The reaction was stirred in a sealed vial at 55 °C for 25 hr. Sample was concentrated under a nitrogen stream and purified by reversed phase chromatography using acetonitrile/water as eluent (30-45%) and afforded the desired material as an off-white solid 20 (28.4 mg, 44%): lH NMR (CDCL,) d 0.82-0.96 (m, 6H) , 1.11-1.52 (m of m, 10H), 1.58-1.72 (m, 1H) , 2.08-2.21 (m, 1H), 2.36-2.50 (m, 2H), 2.93 (s, 6H), 3.02-3.22 (m of m," 5H) , 3.58-3.76 (m, 2H) , 4.15 (s, 1H) , 5.51 (s, 1H), 6.45-6.58 (m, 1H) , 6.92-7.02 (m, 1H) , 7.35-7.41 25 (m, 1H), 7.41-7.51 (m, 2H), 8.08 (d, J= 8.1 Hz, 1H), 8.12-8.25 (m, 1H); MS ES- M-H m/z 579. 30 Example 1397 The 7-fluoro, 9-fluoro and 7,9-difluoro analogs of benzothiepine compounds of this invention can "be reacted with sulfur and nitrogen nucleophiles to give the corresponding sulfur and nitrogen substituted 35 analogs. The following example demonstrates the synthesis of these analogs. 3,3-Dibutyl-5a-(4'-fluorophenyl)-4a-hydroxy-7-methylth.io-2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide. 343 Printed from Mimosa 09/15/1999 15:34:31 page -45- WO 98/40375 PCT/US98/03792 MeS Bu Bu OH F 10 15 20 A mixture of 0.4 g Of 3,3-dibutyl-7-fluoro-5a-(4'-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide, prepared by previously described method, 0.12 g of sodium methanethiolate and 20 ml of DMF was stirred at 50 C for 3 days. An additional 0.1 g of sodium methanethiolate was added to the reaction mixture and the mixture was stirred for additional 20 h at 50 C then was concentrated in vacuo. The residue was triturated with water and extracte wiith ether. The ether extract was dried over MgS04 and concentrated in vacuo to 0.44 g of an oil. Purification by HPLC (10% EtOAc in hexane) gave 0.26 g of needles, mp 164-165.5 3,3-Dibutyl-9-dimethylaroino-7-fluoro-5a-(4'-fluorophenyl)-4a-hydroxy-2,3,4, 5-tetrahydrobenzothiepine-1,1-dioxide and 7,9-Bis(dimethylami.no)-3,3-dibutyl-5a-(4'-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide. F F Printed from Mimosa 09/15/1999 15:34:31 page -46- WO 98/40375 PCT/US98/03792 A solution of 0.105 g of 3,3-dibutyl-7,9-difluoro-5a-(4'-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide, prepared by the 5 method described previously, in 20 ml of 2 N dimethylamine in THF was heated at 160 C in a sealed Parr reactor overnight. The reaction mixture was cooled and concentrated in vacuo. The residue was triturated with 25 ml of water and extracted with ether. The ether 10 extract was dried over MgS04 and concentrated in vacuo. The resdue was purified by HPLC (10% EtOAc in hexane) to give 35 mg of an earlier fraction which was identified as 3,3-dibutyl-9-dimethylamino-7-fluoro-5a-(4'-fluorophenyl)-4a-hydroxy-2,3,4,5-15 tetrahydrobenzothiepine-1,1-dioxide, MS (CI) m/e 480 (M+ +1), and 29 mg of a later fraction which was identified as 7,9-bis(dimethylamino)-3,3-dibutyl-5a-(4'-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide, MS (CI) m/e 505 20 (M+ +1). The compounds of this invention can also be synthesized using cyclic sulfate (A, below) as the reagent as shown in the following scheme. The following 25 example describes a procedure for using the cyclic sulfate as the reagent. Printed from Mimosa 09/15/1999 15:34:31 page -47- WO 98/40375 PCT/US98/03792 ,R2 OH OH SOC1, Rt 2 Rtv RuC13, NaI04 O /O n o .Rz °^S/0 A* o o l.NaH, diglyme Rr 'Rz 2. Ck A o o 3. H2S04 Dibutyl cyclic sulfite: Printed from Mimosa 09/15/1999 15:34:31 page -48- WO 98/40375 PCT/US98/03792 Q. 5 A solution of 2,2-dibutyl-l,3-propandiol (103g, 0.548 mol) and triethylamine (221g, 2.19 mol) in anhydrous methylene chloride (500 ml) and was stirred at 0 degrees C under nitrogen. To the mixture, thionyl chloride (97.8 g, 0.82 mol) was added dropwise 10 and within 5 min the solution turned yellow and then turned black when the addition was completed within half an hour. The reaction mixture was stirred for 3 hrs. GC showed that there was no starting material left. The mixture was washed with ice water twice then 15 with brine twice. The organic phase was dried over magnesium sulfate and concentrated under vacuum to give the cyclic sulfite 128 g (100%) as a black oil. Mass spectrum (MS) was consistent with the product. 20 To a solution of the above compound (127.5g , 0.54 mol) in 600 ml acetonitrile and 500 ml of water cooled in an ice bath under nitrogen was added ruthenium(III) chloride (1 g) and sodium periodate (233 g, 1.08 mol). The reaction was stirred overnight and the color of 25 the solution turned black. GC showed that there was no starting material left. The mixture was extracted with 3 00 ml of ether and the ether extract was washed three -times with brine. The_organic phase^was dried_over magnesium sulfate and passed through celite. The 30 filtrate was concentrated under vacuum and gave the cyclic sulfate 133 g (97.8%) as an•oil. Proton, carbon NMR and MS were consistent with the product. 2-[(2-(4'-Fluorobenzyl)-4-35 methylphenylthio)methyl]-2-butylhexanol: W Printed from Mimosa 09/15/1999 15:34:31 page -49- WO 98/40375 PCT/US98/03792 Sodium hydride (60% oil dispersion), 0.27 g (6.68 mmole), was washed with hexane and the hexane wash was decanted. To the washed sodium hydride was added 20 ml of 2-methoxyethyl ether (diglyme) and the mixture was 10 cooled in an ice bath. A solution of 1.55 g (6.68 mmole) of 2-(4'-fluorobenzyl)-4-methylbenzenethiol in 10 ml of 2-methoxyethyl ether was added dropwise to the reaction mixture in 15 min. A mixture of 2.17 g (8.68 mmole) of the dibutyl cyclic sulfate in 10 ml of 2-15 methoxyethyl ether was added once and stirred for 30 min at 0 C then at room temperature for 1 hr under nitrogen. GC showed that there was no thiol left. The solvent was evaporated and triturated wth water then was extracted with ether twice. The water layer was 20 separated, treated with 20 ml of 10% NaOH then was boiled for 3 0 min and cooled, acidified with 6N HC1 and boiled for 10 min. The reaction mixture was cooled and extracted with ether. The organic layer was washed successively with water and brine, dried over magnesium 25_ " sulfate and concentrated under vacuum -to~give.-2-47 g ( 92.5%) of an oil. Proton NMR , 13C NMR and MS were consistent with the product. 2-[(2-(4'-Fluorobenzyl)-4-3 0 methylphenylthio)methyl]-2-butyIhexanal: a** Printed from Mimosa 09/15/1999 15:34:31 page -50- WO 98/40375 PCT/US98/03792 H3C F To a solution of the above product (2 g , 4.9 mmol) in 40 ml methylene chloride cooled in an ice bath under nitrogen was added pyridinium chlorochromate (2.18 g, 9.9 mmol) at once. The reaction was stirred with 3 hrs and filtered through a bed of silica gel. The filtrate was concentrated under vacuum to give 1.39 g (70%) of an oil. Proton, carbon NMR and MS were consistent with the product. 2-[(2-(4'-Fluorobenzyl) -4 -methylphenylsulfonyl)methyl]-2-butyIhexanal To a solution of the above product (0.44 g ,1.1 mmole) in 20 ml methylene chloride solution cooled in an ice bath under nitrogen was added 70% m-chloroperbenzoic acid (0.54 g, 2.2 mmol) at once. The reaction mixture was stirred for 18 hrs and filtered. h3c I f Printed from Mimosa 09/15/1999 15:40:52 page -1- WO 98/40375 PCT/US98/03792 The filtrate was washed successively with 10% NaOH (3X), water and brine, dried over magnesium sulfate and concentrated under vacum to give 0.42 g (90%) of an oil. Proton, carbon NMR and MS were consistent with 5 the product. 3,3-Dibutyl-7-methyl-5a-(4'-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide: O ^ J3 H 3 C 10 A mixture of 0.37 g (0.85 mmol) of the above product in 3 0 ml of anhydrous THF was stirred at 0 %C. Then potassium t-butoxide (102 mg, 0.85 mmol) was 15 added. After 3 hrs, TLC showed that there was a product and some starting material left. The crude reaction mixture was acidified with 10% HCl and extracted with ether. The ether extract was washed successively with water and brine, dried with MgSO^ and concentrated 20 under vacuum. The residue was purified by HPLC (10% EtOAc-Hexane). The first fraction was 0.1 g of starting material as an oil and the second fraction was a white solid, 0.27 g (75%). Proton NMR and carbon NMR were consistent-with-the-desired product. Mass spectrum (CI) 25 also confirmed the product, m/e 433 (M+ 1). 55 o Printed from Mimosa 09/15/1999 15:40:52 page -2- WO 98/40375 PCT/US98/03792 Example 1398 Step 1 5 Cl4HloClN04 fw=291.69 In an inert atmosphere, weigh out 68.3 gms phosphorus pentachloride (0.328mole Aldrich 15,777-5) into a 2-necked 500ml round bottom flask. Fit flask D with a N, inlet adapter and suba seal. Remove from inert atmosphere and begin N, purge. Add 50mls anhydrous chlorobenzene (Aldrich 2 8,451-3) to the PCI, via syringe and begin stirring with magnetic stir bar. 5 Weigh out 60 gms 2-chloro-5-nitrobenzoic acid (0.298 mole Aldrich 12,511-3). Slowly add to the chlorobenzene solution while under N, purge. Stir at room temperature overnight. After stirring at room temperature for -20hrs, place in oil bath and heat at 0 50C for lhr. Remove chlorobenzene by high vacuum. Wash residue with anhydrous hexane. Dry acid chloride wt=61.95gms. Store in inert and dry atmosphere. In inert atmosphere, dissolve acid chloride with 105mls anhydrous anisole (0.97 mole Aldrich 29,629-5). 5 Place, solution in_.a 2-necked 500ml_ round-bottom flask.- Weigh out 45.1gms aluminum chloride (0.34 moles Aldrich 29,471-3) and place in a solid addition funnel. Fit reaction flask with addition 'funnel and a N, inlet 0 adapter. Remove from inert atmosphere. Chill reaction solution with ice bath and begin N, purge. Slowly add AlCl, to chilled solution. After addition is complete, allow to warm to room temperature. Stir overnight . AS I Printed from Mimosa 09/15/1999 15:40:52 page -3- WO 98/40375 PCT/US98/03792 Quench reaction by pouring into a solution of 300 mis IN HCl and ice. Stir 15 min. Extract twice with ether. Combine organic layers and extract twice with 2% NaOH, then twice with deionized HjO. Dry with MgSO,, 5 filter and rotovap to dryness. Remove anisole by high vacuum. Crystalize product from 90% ethanol 10% ethyl acetate. Dry on vacuum line. Wt=35.2gms. Yield 41%. Obtain NMR and mass spec (m/z=292). 10 Step 2 Cj.HjjClNOj fw=277.71 Dissolve 38.10gms (0.131 moles) of the 15 benzophenone from step 1 in 250mls anhydrous methylene chloride. Place in a 3 liter flask fitted with N, inlet, addition funnel and stopper. Stir with magnetic stir bar. Chill solution with ice bath. Prepare a solution of 39.32 gms trifluoromethane 20 sulfonic acid (0.262 mole Aldrich 15,853-4) and 170 mis anhydrous methylene chloride. Place in addition funnel and add dropwise to chilled solution under N3. Stir 5 minutes after addition is complete. Prepare a solution of 22.85 gms triethyl silane 25 (0.197mole Aldrich 23,019-7) and 170mls anhydrous methylene" chloride. "Place in addition furmel'and add dropwise to chilled solution under N,. Stir 5 minutes after addition is complete. Prepare a second solution of 39.32 gms 30 trifluoromethane sulfonic acid and 170mls anhydrous methylene chloride. Place in addition funnel and add dropwise to chilled solution under Na. Stir 5 minutes after addition is complete. Printed from Mimosa 09/15/1999 15:40:52 page -4- WO'8/4M'5 PCT/US98/03792 Prepare a second solution of 22.85 gms triethyl silane and 170mls anhydrous methylene chloride. Place in addition funnel and add dropwise to chilled solution under Na. After all additions are made allow to slowly 5 warm to room temperature overnight. Stir under N2 overnight. Prepare 1300 mis saturated NaHCO, in a 4 liter beaker. Chill with ice bath. While stirring vigorously, slowly add reaction mixture. Stir at 10 chilled temperature for 30 min. Pour into a separatory funnel and allow separation. Remove organic layer and extract aqueous layer 2 times with methylene chloride. Dry organic layers with MgSO,. Crystallize from ethanol. Dry on vacuum line. Dry wt=28.8gms. Confirm 15 by NMR and mass spec (m/z=278). Step 3 NO, 2 0 C„HJ3NO, S fw= 4 4 3.61 Dissolve 10.12 gms (0.03 6 moles) of product 2 with 200 mis anhydrous DMSO. Place in a 500 ml round bottom flask with magnetic stir bar. Fit flask with water 25 condenser, Na inlet, and stopper. Add 1.84 gms LiaS (0.040 moles Aldrich 21,324-1). Place flask in oil bath and heat at 75°C under Na overnight then cool to room temperature. Weigh out 10.59 gms dibutyl mesylate (0.040 30 moles). Dissolve with anhydrous DMSO and add to reaction solution. Purge well with N,, heat overnight as 3 Printed from Mimosa 09/15/1999 15:40:52 page -5- WO 98/40375 PCT/US98/03792 at 80°C. Cool to room temperature. Prepare 500 mis of 5% acetic acid in a 2 liter beaker. While stirring, slowly add reaction mixture. Stir 30 min. Extract 5 with ether 3 times. Combine organic layers and extract with water and sat'd NaCl. Dry organic layer with MgSO,, filter and rotovap to dryness. Dry oil on vacuum line. Obtain pure product by column chromatography using 95% hexane and 5% ethyl acetate as the mobile 10 phase. Dry wt=7.8 gms. Obtain NMR and mass spec (m/z=444). 15 Step 4 C„H„N0,S fw=475.61 Dissolve 9.33 gms (0.021 moles) of product 3 with 20 120 mis anhydrous methylene chloride. Place in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N4 inlet and stopper. Chill solution with ice bath under N} purge. Slowly add 11.54 gms 3-chloroperbenzoic acid (0.0435 moles, Fluka 25800, 25 -65%). After addition is complete warm to room temperature and monitor reaction by TLC. Reaction goes quickly to the sulphoxide intermediate but takes 8 hrs to convert to the sulphone. Chill solution over night in freezer. Filter solid from reaction, extract 30 filtrate with 10% K,COj. Extract aqueous layer twice with methylene choride. Combine organic layers and dry Printed from Mimosa 09/15/1999 15:40:52 page -6- WO 98/40375 PCT/US98/03792 10 with MgS04. Filter and rotovap to dryness. Obtain pure product by crystallizing from ethanol or isolating by column chromatography. Obtain NMR and mass spec (m/z=47 6). Step 5 C2,H„N04S fw=473.68 Reaction is done in a 300 ml stainless steel Parr stirred mini reactor. Place 9.68 gms (0.0204 moles) of product 4 in reactor base. Add 160 mis ethanol. For safety reasons next two compounds are added in a N3 15 atmosphere glove bag. In glove bag, add 15.3 mis formaldehyde (0.204 moles, Aldrich 25,254-9, about 37 wt% in water) and 1.45 gms 10% Pd/Carbon (Aldrich 20,569-9). Seal reactor before removing from glove bag. Purge reactor three times with H3. Heat to 55°C 20 under Ha. Run reaction at 200 psig Ha, 55°C, and a stir rate of 250 rpm. Run overnight under these conditions. Cool reactor and vent H,. Purge with N,. Check progress of run by TLC. Reaction is a mixture of desired product and intermediate. Filter reaction 25 mixture over a bed of celite washing well with ether. Rotovap and redissolve with ether. Extract with water. Dry organic layer with MgS04, filter and rotovap to dryness. Dry on vacuum line. Charge reactor again with same amounts, seal 30 reactor and run overnight under same conditions. asS" Printed from Mimosa 09/15/1999 15:40:52 page -7- WO 98/40375 PCT/US98/03792 After second run all of the material has been converted to the desired product. Cool and vent H, pressure. Purge with Na. Filter over a bed of celite, washing well with ether. Rotovap to dryness. Dissolve with 5 ether and extract with water. Dry organic layer with MgSO,, filter and rotovap to dryness. Dry on vacuum line. Obtain NMR and mass spec (m/z=474). Step 6 C2,H„N0,S fw=473 .68 Dissolve 8.97 gms (0.0189 mole) of product 5 with 15 135 mis anhydrous THF. Place in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N, inlet and stopper. Chill solution with ice/salt bath under N, purge. Slowly add 2.55 gms potassium t-butoxide (0.227 mole Aldrich 15.667-1). After addition is 20 complete, continue to stir at -10°C monitoring by TLC. Once reaction is complete, quench by adding 135 mis 10% HCl stirring 10 min. Extract three times with ether. Dry organic layer with MgSO,, filter and rotovap to dryness. Crystallize from ether. Obtain 25 NMR and mass spec (m/z=474). Step 7 Printed from Mimosa 09/15/1999 15:40:52 page - WO 98/40375 PCT/US98/03792 /\ HjC CHj C„H„NO,S fw=459.65 5 Dissolve 4.67 gms (0.01 moles) of product 6 with 100 mis anhydrous chloroform. Place in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N, inlet adapter and suba seal. Chill solution with dry ice /acetone bath under a Na purge. Slowly add, via 10 syringe, 2.84 mis boron tribromide (0.03 moles Aldrich 20,220-7). Stir at cold temperature for 15 min after addition then allow to warm to room temperature. Monitor reaction progress by TLC. Reaction is usually complete in 3 hrs. 15 Chill solution with ice bath. Quench with 100 mis 10% KjCO, while stirring rapidly. Stir 10 min. then transfer to sep funnel and allow separation. Remove aqueous layer. Extract organic layer once with 10% HCl, once H,0, and once with saturated NaCl solution. 20 Dry organic layer with MgSO,, filter and rotovap to dryness. Crystallize product from ether. Obtain NMR and mass spec (m/z=460). Step 8 asi Printed from Mimosa 09/15/1999 15:40:52 page -9- WO 98/40375 PCT/US98/03792 25 C„H„NO,SI fw=701.71 Weigh 0.38 gms NaH (9.57 mmoles Aldrich 19,923-0 5 60% disp. in mineral oil) in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N3 inlet and stopper. Chill NaH with ice bath and begin N2 purge. Dissolve 4.0 gms (8.7 mmoles) of product 7 with 60 10 mis anhydrous DMF. Add to the cold NaH. Stir at cold temperature for 30 min. Add 1.33 gms KsCOj (9.57 mmoles Fisher P-208). Dissolve 16.1 gms 1,2-bis-(2-iodoethoxy)ethane (43.5 mmoles Aldrich 33,343-3) with 60 mis anhydrous 15 DMF. Add to cold reaction mixture. Warm to room temperature then heat to 4 0°C overnight under N2. Cleanup by diluting with ether and extracting sequentially with 5% NaOH, H20, and saturated NaCl. Dry organic layer with MgSO,, filter and dry. Obtain 20 pure product by column chromatography using 75% hexane 25% ethyl acetate as the mobile phase. Obtain NMR and mass spec (m/z=702). Step 9 3.58 Pointed, from Mimoss 09/15/1999 15:40:52 page —10 — WO 98/40375 PCT/US98/03792 r K C»,H.,N,O.SI fw=802.90 10 15 Dissolve 1.0 gms (1.43 mmoles) of product 8 with 10 mis anhydrous acetonitrile. Place in a 3 ounce Fischer-Porter pressure reaction vessel with magnetic stir bar. Add 2.9 gms triethyl amine (28.6 mmoles Aldrich 23,962-3) dissolved in 10 mis anhydrous acetonitrile. Purge well with N2 then close system . Heat at 45°C. Monitor reaction by TLC. Reaction is usually complete in 48 hrs. Perform cleanup by removing acetonitrile under vacuum. Redissolve with anhydrous chloroform and precipitate quaternary ammonium salt with ether. Repeat several times. Dry to obtain crystalline product. Obtain NMR and mass spec (m/z=675). Printed from Mimosa 09/15/1999 15:40:52 page -11- WO 98/40375 PCT/US98/03792 Example 1399 5 To a solution of 144 g of KOH (2560 mmol) in 1.1 L of DMSO was added 120 g of 2-bromobenzyl alcohol (641 mmol) slowly via addition funnel. Then was added 182 g of methyliodide (80 mL, 1282 mmol) via addition funnel. Stirred at ambient temperature for fifteen minutes. 10 Poured reaction contents into 1.0 L of water and extracted three times with ethyl acetate. The organic layer was dried over MgSO, and concentrated in vacuo. Purified by silica-gel chromatography through a 200 mL plug using hexanes (100%) as elutant yielded 103.2 g 15 (80%) of 1 as a clear colorless liquid. lH NMR (CDCl,) d 3.39 (s, 3H), 4.42 (s, 2H), 7.18-7.27 (m, 2H), 7.12 (d, J = 7.45, 1H) , 7.50 (s, 1H) . Step 2. Preparation of 2 20 v^OCH 3 To a cooled (-78 ®C) solution of 95 g (472 mmol) of 1 in 1.5 L THF was added 240 mL of 2.5 M n-butyl lithium (576 mmol). The mixture was stirred for one hour, and 25 then to it was added 180 g of zinc iodide (566 mmol) dissolved in 500 ml THF. The mixture was stirred thirty minutes, allowed to warm to 5 C, cooled to -10 °C and to it was added 6 g of Pd(PPhj), (5.2 mmol) and 125 g 2,5-difluorobenzoyl chloride (708 mmol). The 30 mixture was stirred at ambient temperature for 18 hoursand then cooled to 10 °C, quenched with water, partitioned between ethyl acetate and water, and washed 2.6 O Printed from Mimosa 09/15/1999 15:40:52 page -12- WO 98/40375 PCT/US98/03792 organic layer with IN HCL and with IN NaOH. The organic layer was dried over MgS04 and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500) using 5% ethyl acetate/hexanes as 5 elutant gave 53.6 g (43 %) of 2 as an orange oil. lH NMR (CDClj) d 3.40 (s, 3H), 4.51 (s, 2H) , 7.12-7.26 (m, 3H), 7.47 (t, J = 7.50, 1H), 7.57 (d, J = 7.45, 1H), 7.73 (d, J = 7.45, 1H), 7.80 (s, 1H). 10 Step 3. Preparation of 3 A solution of 53 g (202.3 mmol) of 2 and 11.2 g Li2S (242.8 mmol) in 250 mL DMF was heated to 100 °C for 18 hours. The reaction was cooled (0 °C) and 60.7 g of X' 15 (the cyclic sulfate compound of example 1397) (242.8 mmol) in 50 mL DMF was added. Stirred at ambient temperature for 18 hours then condensed in vacuo. Added 1 L water to organic residue and extracted twice with diethyl ether. Aqueous layer acidified (pH 1) and 20 refluxed 2 days. Cooled to ambient temperature and extracted with methylene chloride, dried organic layer over MgS04 and condensed in vacuo. Purification by silica gel chromatography (Waters Prep-500) using 10% ethyl acetate / hexanes as elutant gave 42.9 g (48 %) 25 of 3 as a yellow oil. JH NMR (CDC1,) d 0.86 (t, J = 7.25 Hz, 6H), 1.10 - 1.26 (m, 12H), 2.83 (s, 2H), 3.32 (s, 2H), 3.40 (s, 3H), 4.48 (s, 3H), 7.02 (dd, J = 8.26 Hz and 2.82 Hz, 1H), 7.16 (dt, J = 8.19 Hz and 2.82 Hz, 1H), 7.45 (t, J = 7.65 Hz, 1H), 7.56-7.61 (m, 2H), 7.69 30 (d, J = 7.85 Hz, 1H), 7.74 (s, 1H). Step 4. Preparation of 4 7LC ( Printed from Mimosa 09/15/1999 15:40:52 page -13 WO 98/40375 PCT/US98/03792 J Bu (-Bu CH2OH F' .OCH3 10 15 20 To a cooled (-40 cC) solution of 42.9 g (96.2 mmol) of 3 in 200 mL of methylene chloride was added 21.6 g trifluoromethane sulfonic acid (12.8 mL, 144 mmol) followed by the addition of 22.4 g triethyl silane (30.7 mL, 192.4 mmol). Stirred at -20 °C for two hours, quenched with water and warmed to ambient temperature. Partitioned between methylene chloride and water, dried the organic layer over MgSO, and condensed in vacuo. Purification by silica gel chromatography (Waters Prep-500) using 10% ethyl acetate/ hexanes as elutant gave 24.2 g (60%) of 4 as a oil. *H NMR (CDCl,) d 0.89 (t, J = 7.05 Hz, 6H), 1.17 - 1.40 (m, 12H), 1.46 (t, J = 5.84 Hz, 1H), 2.81 (s, 2H), 3.38 (s, 3H) , 3.43 (d, J = 5.23 Hz, 2H), 4.16 (s, 2H), 4.42 (s, 2H), 6.80 (d, J = 9.67 Hz, 1H), 6.90 (t, J = 8.46 Hz, 1H), 7.09 (d, J = 7.45 Hz. 1H), 7.15 - 7.21 (m, 2H), 7.25 - 7.32 (m, 2H), 7.42 (m, 1H). Step 5. Preparation of 5 To a cooled (15-18 °C) solution of 24.2 g (55.8 mmol) of 4 in 100 mL DMSO was added 31.2 g sulfur trioxide pyridine complex (195 mmol). Stirred at ambient temperature for thirty minutes. Poured into cold water and extracted three times with ethyl acetate. Washed organics with 5% HCl (300 mL) and then with brine (300 mL), dired organics over MgSO, and condensed in vacuo to give 23.1 g (96 %) of 5 as a light brown oil. lH NMR Printed from Mimosa 09/15/1999 15:40:52 page -14- WO 98/40375 PCT/US98/03792 (CDClj) d 0.87 (t, J = 7.05 Hz, 6H), 1.01 - 1.32 (m, 8H), 1.53 - 1.65 (m, 4H), 2.98 (s, 2H), 3.38 (s, 3H), 4.15 (s, 2H), 4.43 (s, 2H) , 6.81 (dd, J = 9.66 Hz and 2.82 Hz, 1H), 6.91 (t, J = 8.62 Hz, 1H), 7.07 (d. J = 7.46 Hz, 1H), 7.14 (s, 1H), 7.19 (d, J = 7.65 Hz, 1H) , 7.26 - 7.32 (m, 1H) , 7.42 (dd, J = 8.66 Hz and 5.64 Hz, 1H) , 9.40 (s, 1H). Step 6. Preparation of 6 To a cooled (0 °C) solution of 23.1 g (53.6 mmol) of 5 in 200 mL methylene chloride was added 28.6 g meta cholorperoxy-benzoic acid (112.6 mmol). Stirred at ambient temperature for 24 hours. Quenched with 100 mL 10% Na2S03, partitioned between water and methylene chloride. Dried organic layer over MgS04 and condensed in vacuo to give 24.5 g (98%) of 6 as a light yellow oil. *H NMR (CDC1,) d 0.86 - 1.29 (m, 14H) , 1.58 - 1.63 (m, 2H), 1.82 - 1.91 (m, 2H), 3.13 (s, 2H), 3.39 (s, 3H), 4.44 (s, 2H), 4.50 (s, 2H), 6.93 (d, J = 9.07 Hz, 1H), 7.10 - 7.33 (m, 5H), 8.05 (s, 1H), 9.38 (s, 1H). Step 7. Preparartion of 7 To a solution of 24.5 g (52.9 mmol) of 6 in 20 mL of THF contained in a stainless steel reaction vessel was added 100 mL of a 2.0 M solution of dimethyl amine and 2.C3 Printed from Mimosa 09/15/1999 15:40:52 page -15- WO 98/40375 PCT/US98/03792 10 15 20 25 20 mL of neat dimethyl amine. The vessel was sealed and heated to 110 °C for 16 hours. The reaction vessel was cooled to ambient temperature and the contents concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500) using 15 % ethyl acetate/hexanes gave 21.8 g (84 %) of 7 as a clear colorless oil. lH NMR (CDC1,) d 0.85 (t, J = 7.25 Hz, 6H), 0.93 - 1.29 (m, 8H). 1.49 - 1.59 (m, 2H), 1.70 -1.80 (m, 2H), 2.98 (s, 8H), 3.37 (s, 3H). 4.41 (s, 2H). 4.44 (s, 2H), 6.42 (s, 1H), 6.58 (dd, J = 9.0 Hz and 2.61 Hz, 1H), 7.13 (d, J = 7.45 Hz, 1H), 7.21 (s, 1H), 7.28 (t, J = 7.85 Hz, 1H), 7.82 (d, J = 9.06 Hz, 1H), 9.36 (s, 1H). Step 8. Preparation of 8 A solution of 21.8 g (44.8 mmol) of 7 in 600 mL of THF was cooled to 0 "C. 58.2 mL of a 1 M solution of potassium t-butoxide was added slowly, maintaining the temperature at <5 °C. Stirred for 3 0 minutes, then quenched with 50 mL of saturated ammonium chloride. The organic layer was partitioned between ethyl acetate and water, dried over MgS04 and concentrated in vacuo. Purification by recrystalization from -10% ethyl acetate/hexanes gave 15.1 g of 8 as a white solid. The mother liquor was purified by silica gel chromatography (Waters Prep-500) using 30% ethyl acetate/hexanes as the elutant to give 3.0 g of 8 as a white solid. MS (FABLi*) m/e 494.6. HRMS (EI*) calculated for M+H 487.2756. Found 487.2746. Prmted from Mimosa 09/15/1999 15:40:52 page -16- WO 98/40375 PCT/US98/03792 Step 9. Preparation of 9 MezN i ''OH A solution of 2.0 g (4.1 mmol) of 8 in 20 mL of methylene chloride was cooled to -60 °C. 4.1 mL of a 1M solution of boron tribromide was added. Stirred at ambient temperature for thirty minutes. Cooled reaction to -10 °C and quenched with 50 mL of water. The organic layer was partitioned between methylene chloride and water, dried over MgSO, and concentrated in vacuo. Purification by recrystalization from 50% ethyl acetate/methylene chloride gave 1.95 g (89%) of 9 as a white solid. MS (FABH*) m/e 537. HRMS (FAB) calculated for M 536.1834. Found 536.1822. Step 10. Preparation of 10 A solution of 1.09 g (2.0 mmol) of 9 and 4.9 g (62 mmol) of pyridine in 30 mL of acetonitrile was stirred at ambient temperature for 18 hours. The reaction was concentrated in vacuo. Purification by recrystallization from methanol/ diethyl ether gave 1.19 g (96%) of 10 as an off white solid. MS (FAB*) m/e 535.5. O i 'OH Printed from Mimosa 09/15/1999 15:40:52 page -17- WO 98/4037S PCT/US98/03792 Example 1398 Step 1. Preparation of 2 To a solution of 6.0 g of dibutyl 4-fluorobenzene dialdehyde of Example 1395 (14.3 mmol) in 72 mL of toluene and 54 mL of ethanol was added 4.7 g 3-nitrobenzeneboronic acid (28.6 mmol), 0.8 g of tetrakis (triphenylphosphine) palladium(O) (0.7 mmol) and 45 mL of a 2 M solution of sodium carbonate in water. This heterogeneous mixture was refluxed for three hours, then cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was dried over MgSO, and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-2000) using ethyl acetate/hexanes (25/75) gave 4.8 g (73%) of the title compound as a yellow solid. NMR (CDClj) d 0.88 (t. J = 7.45 Hz, 6H). 0.99-1.38 (m, 8H), 1.62-1.75 (m, 2H) , 1.85-2.00 (m, 2H), 3.20 (s, 2H), 4.59 (s, 2H), 6.93 (dd, J = 10.5 and 2.4 Hz, 1H), 7.15 (dt, J = 8.4 and 2.85 Hz, 1H), 7.46-7.59 (m, 2H), 8.05-8.16 (m, 3H), 9.40 <s, 1H). 9-66 Printed from Mimosa 09/15/1999 15:40:52 page -18- WO 98/40375 PCT/US98/03792 Step 3. Preparation of 3 A solution of 4.8 g (10.4 mmol) of 2 in 500 mL THF was cooled to 0 °C in an ice bath. 20 mL of a 1 M solution of potassium t-butoxide was added slowly, maintaining the temperature at <5 °c. Stirring was continued for 3 0 minutes, then the reaction was quenched with 100 mL of saturated ammonium chloride. The mixture was partitioned between ethyl acetate and water; the organic layer was washed with brine, then dried (MgSO,) and concentrated in vacuo. Purification by silica gel chromatography through a 100 ml plug using CH2Clj as eluent yielded 4.3 g (90%) of 3 as a pale yellow foam. 'H NMR (CDClj) d 0.93 (t, J = 7.25 Hz, 6H) , 1.00-1.55 (m, 8H), 1.59-1.74 (m, 3H), 2.15-2.95 (m, 1H), 3.16 (9AB' jAB = 15.0 Hz, AV = 33.2 Hz, 2H), 4.17 (d, J = 6.0 Hz, 1H), 5.67 (s, 1H), 6.34 (dd, J=9.6 and 3.0 Hz, 1H), 7.08 (dt, J = 8.5 and 2.9 Hz, 1H), 7.64 (t, J = 8.1 Hz, 1H), 7.81 (d, J = 8.7 Hz, 1H), 8.13 (dd, J = 9.9 and 3.6 Hz, 1H), 8.23-8.30 (m, 1H), 8.44 (s, 1H). MS(FABH+) m/e (relative intensity) 464.5 (100), 446.6 (65). HRMS calculated for M+H 464.1907. Found 464.19057 Printed from Mimosa 09/15/1999 15:40:52 page -19- WO 98/40375 PCT/US98/03792 Step 4. Preparation of 4 Q» 5 To a cooled (0 °C) solution of 4.3 g (9.3 mmol) of 3 in 30 ml THF contained in a stainless steel reaction vessel was added 8.2 g dimethyl amine (182 mmol). The vessel was sealed and heated to 110 °C for 16 hours. The reaction vessel was cooled to ambient temperature 10 and the contents concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-2000) using an ethyl acetate/hexanes gradient (10-40% ethyl acetate) gave 4.0 g (88%) of 4 as a yellow solid. JH NMR (CDC1,) d 0.80-0.95 (m, 6H), 0.96-1.53 (m, 8H), 15 1.60-1.69 (m, 3H), 2.11-2.28 (m, 1H). 2.79 (s, 6H). 3.09 ((3^3, = 15.0 Hz, DV= 45.6 Hz, 2H) , 4.90 (d, J = 9.0 Hz, 1H), 5.65 (s, 1H), 5.75 (d, J = 2.1 Hz, 1H), 6.52 (dd, J = 9.6 and 2.7 Hz, 1H), 7.59 (t, J = 8.4 Hz, 1H), 7.85 (d, J = 7.80 Hz, 1H), 7.89 (d, J = 9.0 Hz, 20 1H), 8.20 (dd, J = 8.4 and 1.2 Hz, 1H), 8.43 (s, 1H). MS(FABH+) m/e (relative intensity) 489.6 (100), 471.5 (25). HRMS calculated for M+H 489.2423. Found 489.2456. 3£X Printed from Mimosa 09/15/1999 15:40:52 page -20- WO 98/40375 PCT/US98/03792 Step 5. Preparation of 5 To a suspension of 1.0 g (2.1 mmol) of 4 in 100 ml ethanol in a stainless steel Parr reactor was added 1 g 10% palladium on carbon. The reaction vessel was sealed, purged twice with H}, then charged with H, (100 psi) and heated to 45 °C for six hours. The reaction vessel was cooled to ambient temperature and the contents filtered to remove the catalyst. The filtrate was concentrated in vacuo to give 0.9 g (96%) of 5. lH NMR (CDC1,) d 0.80-0.98 (m, 6H) , 1.00-1.52 (m, 10H) , 1.52-1.69 (m, 1H), 2.15-2.29 (m, 1H), 2.83 (s, 6H) , 3.07 (<3a£. JAB = 15*1 Hz' Dv = 44-2 Hz' 2H> ' 3-70 {s' 2H) , 4.14 (s, 1H), 5.43 (s, 1H), 6.09 (d, J = 2.4 Hz, 1H), 6.52 (dd, J = 12.2 and 2.6 Hz, 1H), 6.65 (dd, J = 7.8 and 1.8 Hz, 1H), 6.83 (s, 1H), 6.93 (d, J = 7.50 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.89 (d, J = 8.9 Hz, 1H). MS(FABH+) m/e (relative intensity) 459.7 (100). HRMS calculated for M+H 459.2681. Found 459.2670. Printed from Mimosa 09/15/1999 15:40:52 page -21 5 10 15 20 25 WO 98/40375 PCT/US98/03792 Step 6, Preparation of 6 To a solution of 914 mg (2.0 mmol) of 5 in 50 ml THF was added 800 mg (4.0 mmol) 5-bromovaleroyl chloride. Next was added 4 g (39.6 mmol) TEA. The reaction was stirred 10 minutes, then partitioned between ethyl acetate and brine. The organic layer was dried (MgS04) and concentrated in vacuo. Purification by silica gel chromatography through a 70 ml MPLC column using a gradient of ethyl acetate(20-50%) in hexane as eluent yielded 0.9 g (73%) of 6 as a pale yellow oil. 'H NMR (CDClj) d 0.84-0.95 (m, 6H) . 1.02-1.53 (m, 10H) , 1.53-1.68 (m, 1H) , 1.80-2.00 (m, 4H), 2.12-2.26 (m, 4H) , 2.38 (t, J = 6.9 Hz, 2H) , 2.80 (s, 6H) , 3.07 (q^, JAB = 15-6 Hz' Dv = 40-4 Hz' 2H)' 3-43 (t' J = 6*9 Hz' 2H), 4.10 (s, 1H), 5.51 (s, 1H), 5.95 (d, J = 2.4 Hz, 1H), 6.51 (dd, J = 9.3 and 2.7 Hz, 1H), 7.28 (s, 1H), 7.32-7.41 (m, 2H), 7.78 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 9.0 Hz, 1H). Step 7. Preparation of 7 To a solution of 0.9 g (1.45 mmol) of 6 in 25 ml acetonitrile add 18 g (178 mmol) TEA. Heat at 55 °C for 16 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. Purification by reverse-phase silica gel chromatography (Waters Delta Prep 3000) using an acetonitrile /water gradient containing 0.05% TFA (20-65% acetonitrile) a.io Printed from Mimosa 09/15/1999 15:40:52 page -22- WO 98/40375 PCT/US98/03792 gave 0.8 g (73%) of 7 as a white foam. 1H NMR (CDC13) d 0.80-0.96 (m, 6H), 0.99-1.54 (m, 19H), 1.59-1.84 (m, 3H) , 2.09-2.24 (m, lH), 2.45-2.58 (m, 2H), 2.81 (s, 6H), 3.09 (q^S' JAB = 15•6 Hz' DV = 18•5 Hz' 2H)* 3-13~ 3.31 (m, 8H), 4.16 (s, 1H), 5.44 (s, 1H), 6.08 (d, J = 1.8 Hz, 1H) , 6.57 (dd, J = 9.3 and 2.7 Hz, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.34 (t, J = 8.4 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.74 (s, 1H), 7.88 (d, J = 9.0 Hz, 1H), 9.22 (s, 1H). HRMS calcd 642.4304; observed 642.4343. Example 14 00 Step 1 A 12-liter, 4-neck round-bottom flask was equipped with reflux condenser, N2 gas adaptor, mechanical stirrer, and an addition funnel. The system was purged with N2. A slurry of sodium hydride (126.Og/4.988mol) in toluene (2.5 L) was added, and the mixture was cooled to 6 C. A solution of 4-fluorophenol (560.5g/5.OOOmol) in toluene (2.5 L) was added via addition funnel over a period of 2.5 h. The reaction mixture was heated to reflux (100 C) for lh. A solution of 3-methoxybenzyl chloride (783.Og/5.OOOmol) in toluene (750 mL) was added via addition funnel while maintaining reflux. After 15 h. refluxing, the mixture was cooled to room temperature and poured into H20 (2.5 L). After 20 min. stirring, the layers were separated, and the organic layer was extracted with a solution of potassium hydroxide (720g) in MeOH (2.5 L). The MeOH layer was added to 20% aqueous potassium hydroxide, and the OH C14H13°2F fw=232.25 2.1 ( Printed from Mimosa 09/15/1999 15:40:52 page -23- WO 98/40375 PCT/US98/03792 mixture was stirred for 30 min. The mixture was then washed 5 times with toluene. The toluene washes were extracted with 20% aq. KOH. All 20% aq. KOH solutions were combined and acidified with concentrated HCl. The 5 acidic solution was extracted three times with ethyl ether, dried (MgSC^), filtered and concentrated in vacuo. The crude product was purified by Kugelrohr distillation to give a clear, colorless oil (449.0g/39% yield), b.p.: 120-130 C/50mtorrHg. XH NMR and MS t(M 10 + H)+ = 233] confirmed desired structure. Step 2 15 OMt F c17h18n02fs fw=319.39 A 12-liter, 3-neck round-bottom flask was fitted with mechanical stirrer and N2 gas adaptor. The system was purged with N2. 4-Fluoro-2-(3-methoxybenzyl)-phenol (455.5g/l.961mol) and dimethylformamide were added. 20 The solution was cooled to 6 C, and sodium hydride (55.5g/2.197mol) was added slowly. After warming to room temperature, dimethylthiocarbamoyl chloride (242.4g/l.961mol) was added. After 15 h, the reaction mixture was poured into H20 (4.0 L), and extracted two 25 times with ethyl ether. The combined organic layers were washed with H20 and saturated aqueous NaCl, dried (MgS04), filtered, and concentrated in vacuo to give the product (605.3g, 97% yield). *H NMR and MS [(M+H)+ = 320] confirm desired structure. 30 a/1 imprinted from Mimosa 09/15/1999 15:40:52 page -24- WO 98/40375 PCT/US98/03792 Step 3 SH c14H13OFS f«=248.32 5 A 12-liter, round-bottom flask was equipped with N2 gas adaptor, mechanical stirrer, and reflux condenser. The system was purged with N2. 4-Fluoro-2-(3- methoxybenzyl)-phenyldimethylthiocarbamate 10 (605.3g/1.895mol) and phenyl ether (2.0kg) were added, and the solution was heated to reflux for 2 h. The mixture was stirred for 64 h. at room temparature and then heated to reflux for 2 h. After cooling to room temperature, MeOH (2.0 L) and THF (2.0 L) were added, 15 and the solution was stirred for 15 h. Potassium hydroxide (425.9g/7.590mol) was added, and the mixture was heated to reflux for 4 h. After cooling to room temparature, the mixture was concentrated by rotavap, dissolved in ethyl ether (1.0 L), and extracted with 20 H20. The aqueous extracts were combined, acidified with concentrated HCl, and extracted with ethyl ether. The ether extracts were dried (MgSO,) , filtered, and concentrated in vacuo to give an amber oil (463.Og, 98% yield). *H NMR confirmed desired structure. 25 Step 4 an I Printed from Mimosa 09/15/1999 15:40:52 page -25- WO 98/40375 PCT/US98/03792 C25H35O2FS fw=418.61 A 5-liter, 3-neck, round-bottom flask was equipped with 5 N2 gas adaptor and mechanical stirrer. The system was purged with N2. 4-Fluoro-2-(3-methoxybenzyl)-thiophenol (100.0g/403.2mmol) and 2-methoxyethyl ether (1.0 L) were added and the solution was cooled to 0 C. Sodium hydride (9.68g/383.2mmol) was added slowly, and 10 the mixture was allowed to warm to room temparature, 2,2-Dibutylpropylene sulfate {110.89g/443.6mmol) was added, and the mixture was stirred for 64 h. The reaction mixture was concentrated by rotavap and dissolved in H2O. The aqueous solution was washed with 15 ethyl ether, and concentrated H2SO4 was added. The aqueous solution was heated to reflux for 30 min, cooled to room temperature, and extracted with ethyl ether- The ether solution was dried (MgSO.4) , filtered, and conc'd in vacuo to give an amber oil (143.94g/85% 20 yield). NMR and MS [ (M + H)+ = 419] confirm the desired structure. Step 5 21+ Printed from Mimosa 09/15/1999 15:40:52 page -26- WO 98/40375 PCT/US98/03792 10 15 OMe c25h33°2fs fw=416.59 A 2-liter, 4-neck, round-bottom flask was equipped with N2 gas adaptor, and mechanical stirrer. The system was purged with N2. The corresponding alcohol (143.94g/343.8mmol) and CH2C12 (1.0 L) were added and cooled to 0 C. Pyridinium chlorochromate (140 .53g/651.6mmol) was added. After 6 h., CH2Cl2 was added. After 20 min, the mixture was filtered through silica gel, washing with CH2C12. The filtrate was concentrated in vacuo to give a dark yellow-red oil (110.6g, 77% yield). XH NMR and MS [(M + H)+ = 417] confirm the desired structure. Step 6 OMa C25H33°4FS fw=448.59 20 A 2-liter, 4-neck, round-bottom flask was equipped with N2 gas adaptor and mechanical stirrer. The system was purged with N2. The corresponding sulfide an 5* Printed from Mimosa 09/15/1999 15:40:52 page -27- WO 98/40375 PCT/US98/03792 (110.6g/26S.Smmol) and CHjClj (1-0 I») were added. The Solution was cooled to 0 C, and 3-chloroperbenzoic acid (158.21g/531.7mmol) was added portionwise. After 30 min, the reaction mixture was allowed to warm to room 5 temperature After 3.S h, the reaction mixture was cooled to 0 C and filtered through a fine fritted funnel. The filtrate was washed with 10% aqueous K2CO3. An emulsion formed which was extracted with ethyl ether. The organic layers were combined, dried 10 (MgSOi). filtered, and concentrated in vacuo to give the product (93.2g, 78% yield). NMR confirmed the desired structure. Printed from Mimosa 09/15/1999 15:40:52 page -28- WO 98/40375 PCT/US98/03792 Step 7 0 B» C25H33°4FS fw*44B.S9 A 2-liter, 4-neck, round-bottom flask was equipped with N2 gas adaptor, mechanical stirrer, and a powder addition funnel. The system was purged with N2. The corresponding aldehyde (93.2g/208mmol) and THF (1.0 L) were added, and the mixture was cooled to 0 C. Potassium cert-butoxide (23.35g/208.lmmol) was added via addition funnel. After lh, 10% aq/ HCl (1.0 L) was added. After 1 h, the mixture was extracted three times with ethyl ether, dried (MgSO^), filtered, and concentrated in vacuo. The crude' product was purified by recryst. from 80/20 hexane/ethyl acetate to give a white solid (32.18 g). The mother liquor was concentrated in vacuo and recrystelized from 95/5 toluene/ethyl acetate to give a white solid (33.60g/ combined yield: 71%). NMR confirmed the desireQ product. Printed from Mimosa 09/15/1999 15:40:52 page -29- WO 98/40375 PCT/US98/03792 Step 8 c27h39°4ns fw=473.67 A Fisher porter bottle was fitted with N2 line and magnetic stirrer. The system was purged with N2• The corresponding fluoro-compound (28.lg/62.Gmmol) was added, and the vessel was sealed and cooled to -78 C. Dimethylamine (17.lg/379mmol) was condensed via a CO2/acetone bath and added to the reaction vessel. The mixture was allowed to warm to room temperature and was heated to 60 C. After 20 h, the reaction mixture was allowed to cool and was dissolved in ethyl ether. The ether solution was washed with H20, saturated aqueous NaCl, dried (MgS04), filtered, and concentrated in vacuo to give a white solid (28.5g/96% yield). NMR confirmed the desired structure. Printed from Mimosa 09/15/1999 15:40:52 page -30- WO 98/40375 PCT/US98/03792 Step 9 OH c25h37°4NS fw=459.64 5 A 250-mL, 3-neck, round-bottom flask was equipped with N2 gas adaptor and magnetic stirrer. The system was purged with N2. The corresponding methoxy-compound (6.62g/14.Ommol) and chci3 {150 mL) were added. The reaction mixture was cooled to -78 C, and boron 10 tribromide (10.50g/41.9mmol) was added. The mixture was allowed to warm to room temperature After 4 h, the reaction mixture was cooled to 0 C and was quenched with 10% K2CO3 (100 mL). After 10 min, the layers were separated, and the aqueous layer was extracted two 15 times with ethyl ether. The CHCI3 and ether extracts were combined, washed with saturated aqueous NaCl, dried (MgSO^), filtered, and concentrated in vacuo to give the product (6.27g/98% yield). NMR confirmed the desired structure. 2.11 Printed from Mimosa 09/15/1999 15:40:52 page -31 WO 98/40375 PCT/US98/03792 Step 10 (HsCfe J Bu i OH Q 0 J In a 250 ml single neck round bottom Flask with stir bar place 2- diethylamineoethyl chloride hydochloride (fw 172.lOg/mole) Aldrich D8, 720-1 (2 .4 mmol,4.12g), 34 ml dry ether and 34 ml of IN KOH(aqueous). Stir 15 minutes and then separate by ether extraction and dry over anhydrous potassium carbonate. In a separate 2-necked 250 ml round bottom flask with stir bar add sodium hydride (60% dispersion in mineral oil, 100 mg , 2.6 mmol) and 34 ml of DMF. Cool to ice temperature. Next add phenol product(previous step) 1.1 g (2.4 mmilomoles in 5 ml DMF and the ether solution prepared above. Heat to 40C for 3 days. The product which contained no starting material by TLC was diluted with ether and extracted with 1 portion of 5% NaOH, followed by water and then brine. The ether layer was dried over magnesium sulfate and isolated by removing ether by rotary evaporation (1.3 gms).The product may be further purified by chromatography (Si02 99% ethyl acetate/1% NH40H at 5ml/min.). Isolated yield: 0.78 g (mass spec , and HI NMR) Printed from Mimosa 09/15/1999 15:40:52 page -32 *80 WO 98/40375 PCT/US98/03792 Step 11 (HjCfel 10 The product from step 10 ( 0.57gms, 1.02 millimole fw 558.83 g/mole) and 1.6 gms iodoethane (10.02 mmol) was placed in 5 ml acetonitrile in a fischer-porter bottle and heated to 45 C for 3 days. The solution was evaporated to dryness and redissolved in 5 mis of chloroform. Next ether was added to the chloroform solution and the resulting mixture was chilled. The desired product is isolated as a precipitate 0.7272 gms. Mass spec M-I = 587.9 , H NMR). 15 Example 1401 20 Step 1 OMe C14h13°2f fw=232.25 A 12-liter, 4-neck round-bottom flask was equipped with AS I Printed from Mimosa 09/15/1999 15:40:52 page -33- WO 98/40375 PCT/US98/03792 reflux condenser, N2 gas adaptor, mechanical stirrer, and an addition funnel. The system was purged with N2. A slurry of sodium hydride (126.Og/4.988mol) in toluene (2.5 L) was added, and the mixture was cooled to 6 C. A solution of 4-fluorophenol (560.5g/5.OOOmol) in toluene (2.5 L) was added via addition funnel over a period of 2.5 h. The reaction mixture was heated to reflux (100 C) for lh. A solution of 3-methoxybenzyl chloride (783.Og/5.OOOmol) in toluene (750 mL) was added via addition funnel while maintaining reflux. After 15 h. refluxing, the mixture was cooled to room temperature and poured into H20 (2.5 L). After 20 min. stirring, the layers were separated, and the organic layer was extracted with a solution of potassium hydroxide (720g) in MeOH (2.5 L). The MeOH layer was added to 20% aqueous potassium hydroxide, and the mixture was stirred for 30 min. The mixture was then washed 5 times with toluene. The toluene washes were extracted with 20% aq. KOH. All 20% aqueous KOH solutions were combined and acidified with concentrated HCl. The acidic solution was extracted three times with ethyl ether, dried over MgS04, filtered and concentrated in vacuo. The crude product was purified by Kugelrohr distillation to give a clear, colorless oil (449.0g/39% yield), b.p.: 120-130 C/50mtorrHg. ^■H NMR and MS [ (M + H)+ = 233) confirmed desired structure. Step 2 Printed from Mimosa 09/15/1999 15:40:52 page -34- WO 98/40375 PCT/US98/03792 c17h18N02fs fw=319.39 A 12-liter, 3-neck round-bottom flask was fitted with mechanical stirrer and N2 gas adaptor. The system was purged with N2. 4-Fluoro-2-(3-methoxybenzyl)- phenol (455.5g/l.961mol) and dimethylformamide were added. The solution was cooled to 6 C, and sodium hydride (55.5g/2.197jnol) was added slowly. After warming to room temperature, dimethylthiocarbamoyl chloride (242.4g/l.961mol) was added. After 15 h, the reaction mixture was poured into H20 (4.0 L), and extracted two times with ethyl ether. The combined organic layers were washed with H20 and saturated aqueous NaCl, dried over MgSC^, filtered, and concentrated in vacuo to give the product (605.3g, 97% yield). ^-H NMR and MS [(M+H)+ = 320] confirm desired structure. Step 3 SH Printed from Mimosa 09/15/1999 15:40:52 page -35 WO 98/40375 PCT/US98/03792 c14h13°FS fw=248.32 10 15 20 A 12-liter, round-bottom flask was equipped with N2 gas adaptor, mechanical stirrer, and reflux condenser. The system was purged with N2. 4-Fluoro-2- (3-methoxybenzyl)-phenyldimethylthiocarbamate (605.3g/l.895mol) and phenyl ether (2.0kg) were added, and the solution was heated to reflux for 2 h. The mixture was stirred for 64 h. at room temperature and then heated to reflux for 2 h. After cooling to room temperature, MeOH (2.0 L) and THF (2.0 L) were added, and the solution was stirred for 15 h. Potassium hydroxide (425.9g/7.590mol) was added, and the mixture was heated to reflux for 4 h. After cooling to room temperature, the mixture was concentrated by rotavap, dissolved in ethyl ether (1.0 L), and extracted with H2O. The aqueous extracts were combined, acidified with conc. HCl, and extracted with ethyl ether. The ether extracts were dried (MgS04) , filtered, and concentrated in vacuo to give an amber oil (463.Og, 98% yield). NMR confirmed desired structure. 25 Step 4 OMe C25H35°2FS fw=418.'61 A 5-liter, 3-neck, round-bottom flask was equipped with N2 gas adaptor and mechanical stirrer. The system 2.3* Pnnted from Mimosa 09/15/1999 15:40:52 page -36- WO 98/40375 PCT/US98/03792 was purged with N2. 4-Fluoro-2-(3-methoxybenzyl)- thiophenol (100.0g/403.2mmol) and 2-methoxyethyl ether (1.0 L) were added and the solution was cooled to 0 C. Sodium hydride (9.68g/383.2mmol) was added slowly, and 5 the mixture was allowed to warm to room temperature 2,2-Dibutylpropylene sulfate (110.89g/443.6mmol) was added, and the mixture was stirred for 64 h. The reaction mixture was concentrated by rotavap and dissolved in H2O. The aqueous solution was washed with 10 ethyl ether, and conc. H2SO4 was added. The aqueous solution was heated to reflux for 30 min, cooled to room temperature, and extracted with ethyl ether. The ether solution was dried (MgSO^), filtered, and concentrated in vacuo to give an amber oil (143.94g/85% 15 yield). XH NMR and MS [(M + H)+ = 419) confirm the desired structure. Step 5 Bu 20 F C25H33°2FS fw=416.59 A 2-liter, 4-neck, round-bottom flask was equipped with N2 gas adaptor, and mechanical stirrer.. .The , f 25 system was purged with N2. The corresponding alcohol (143.94 g/343.8 mmol) and CH2CI2 (1.0 L) were added and cooled to 0 C. Pyridinium chlorochromate (140.53g/651.6mmol) was added. After 6 h., CH2CI2 was Printed from Mimosa 09/15/1999 15:40:52 page -37- WO 98/40375 PCT/US98/03792 added. After 20 min, the mixture was filtered through silica gel, washing with Cf^C^. The filtrate was concentrated in vacuo to give a dark yellow-red oil (110.6g, 77% yield). NMR and MS [(M + H)+ = 417] confirm the desired structure. Printed from Mimosa 09/15/1999 15:40:52 page -38 WO 98/40375 PCT/US98/03792 Step 6 C25H23O4FS fw=448.59 A 2-liter, 4-neck, round-bottom flask was equipped with N2 gas adaptor and mechanical stirrer. The system was purged with N2. The corresponding sulfide (110.6g/265.5mmol) and CH2CI2 (1.0 L) were added. The solution was cooled to 0 C, and 3-chloroperbenzoic acid (158.21g/531.7mmol) was added portionwise. After 30 min, the reaction mixture was allowed to warm to room temperature After 3.5 h, the reaction mixture was cooled to 0 C and filtered through a fine fritted funnel. The filtrate was washed with 10% aqueous K2CO3. An emulsion formed which was extracted with ethyl ether. The organic layers were combined, dried (MgS04>, filtered, and concentrated in vacuo to give the product (93.2g, 78% yield). ■'■H NMR confirmed the desired structure. Ml Printed from Mimosa 09/15/1999 15:40:52 page -39- WO 98/40375 PCT/US98/03792 Step 7 OM« c25h33°4fs fw=448.59 A 2-liter, 4-neck, round-bottom flask was equipped with N2 gas adaptor, mechanical stirrer, and a powder addition funnel. The system was purged with N2. The corresponding aldehyde (93.2g/208mmol) and THF (1.0 L) were added, and the mixture was cooled to 0 C. Potassium tert-butoxide (23.35g/208.lmmol) was added via addition funnel. After lh, 10% aq/ HCl (1.0 L) was added. After 1 h, the mixture was extracted three times with ethyl ether, dried (MgSC^), filtered, and concentrated in vacuo. The crude product was purified by recrystallized from 80/20 hexane/ethyl acetate to give a white solid (32.18g). The mother liquor was concentrated in vacuo and recrystallized from 95/5 toluene/ethyl acetate to give a white solid (33.60g, combined yield: 71%) . -^H NMR confirmed the desired product. Printed from Mimosa 09/15/1999 15:40:52 page -40- WO 98/40375 PCT/US98/03792 Step 8 C27H39°4NS fw=473.67 A Fisher porter bottle was fitted with N2 line and magnetic stirrer. The system was purged with N2. The corresponding fluoro-compound (28.lg/62.6mmol) was added, and the vessel was sealed and cooled to -7 8 C. Dimethylamine (17.lg/379mmol) was condensed via a CC^/acetone bath and added to the reaction vessel. The mixture was allowed to warm to room temperature and was heated to 60 C. After 20 h, the reaction mixture was allowed to cool and was dissolved in ethyl ether. The ether solution was washed with H2O, saturated aqueous NaCl, dried over MgSC>4, filtered, and concentrated in vacuo to give a white solid (28.5g/96% yield). NMR confirmed the desired structure. Printed from Mimosa 09/15/1999 15:40:52 page -41- WO 98/40375 PCT/US98/03792 Step 9 C26H37°4NS" fw=459.64 A 250-mL, 3-neck, round-bottom flask was equipped with N2 gas adaptor and magnetic stirrer. The system was purged with . The corresponding methoxy-compound (6.62g/14.Ommol) and CHCI3 (150 mL) were added. The reaction mixture was cooled to -78 C, and boron tribromide (10.50g/41.9mmol) was added. The mixture was allowed to warm to room temperature After 4 h, the reaction mixture was cooled to 0 C and was quenched with 10% K2CO3 (100 mL). After 10 min, the layers were separated, and the aqueous layer was extracted two times with ethyl ether. The chci3 and ether extracts were combined, washed with saturated aqueous NaCl, dried over MgSO^, filtered, and concentrated in vacuo to give the product (6.27g/98% yield). NMR confirmed the desired structure. 10 15 ^ O Printed from Mimosa 09/15/1999 15:40:52 page -42- WO 98/40375 Step 10 PCT/US98/03792 5 In a 250 ml single neck round bottom flask with stir bar place 2- diethylamineoethyl chloride hydochloride (fw 172.lOg/mole) Aldrich D8, 720-1 (2.4 millimoles, 4.12g), 34 ml dry ether and 34 ml of IN KOH (aqueous). Stir 15 minutes and then separate by ether 10 extraction and dry over anhydrous potassium carbonate. In a separate 2-necked 250 ml round bottom flask with stir bar add sodium hydride (60% dispersion in mineral oil, 100 mg, (2.6 mmol) and 3 4 ml of DMF. Cool 15 to ice temperature. Next add phenol product (previous step) 1.1 g (2.4 mmol in 5 ml DMF and the ether solution prepared above. Heat to 40C for 3 days. The product which contained no starting material by TLC was diluted with ether and extracted with 1 portion of 5% 20 NaOH, followed by water and then brine. The ether layer was dried over Magnesium sulfate and isolated by removing ether by rotary evaporation (1.3 gms). The product may be further purified by chromatography (silica 99% ethyl acetate/1% NH40H at 5ml/min.). 25 Isolated yield: 0.78 g (mass spec , and HI NMR) Step 11 Ml Printed from Mimosa 09/15/1999 15:40:52 page -43 WO 98/40375 PCT/US98/03792 The product from step 10 (0.57gms, 1.02 millimole 5 fw 558.83 g/mole) and iodoethane (1.6 gms (10.02 mmol)was place in 5 ml acetonitrile in a Fischer-Porter bottle and heated to 45 C for 3 days. The solution was evaporated to dryness and redissolved in 5 mis of chloroform. Next ether was added to the chloroform 10 solution and the resulting mixture was chilled. The desired product is isolated as a precipitate 0.7272 gms. Mass spec M-I = 587.9, :H NMR). 15 BIOLOGICAL ASSAYS The utility of the compounds of the present invention is shown by the following assays. These assays are performed in vitro and in animal models 20 essentially using a procedure recognized to show the utility of the present invention. In Vitro Assay of compounds that inhibit iBAT-xnediated uptake of r"ci-Taurocholate (TC) in H14 Cells 25 Baby hamster kidney cells (BHK) transfected with the cDNA of human IBAT (H14 cells) are seeded at 60,000 cells/well in 96 well Top-Count tissue culture plates for assays run within in 24 hours of seeding, 3 0,000 Printed from Mimosa 09/15/1999 15:40:52 page —44— WO 98/40375 PCT/US98/03792 cells/well for assays run within 48 hours, and 10,000 cells/well for assays run within 72 hours. On the day of assay, the cell monolayer is gently washed once with 100 ml assay buffer (Dulbecco's Modified Eagle's medium with 4.5 g/L glucose + 0.2% (w/v) fatty acid free bovine serum albumin- (FAF)BSA). To each well 50 ml of a two-fold concentrate of test compound in assay buffer is added along with 50 ml of 6 mM [MC]-taurocholate in assay buffer (final concentration of 3 mM ["c]-taurocholate). The cell culture plates are incubated 2 hours at 37" C prior to gently washing each well twice with 100 ml 4° C Dulbecco's phosphate-buffered saline (PBS) containing 0.2% (w/v) (FAF)BSA. The wells are then gently washed once with 100 ml 4° C PBS without (FAF)BSA. To each 200 ml of liquid scintillation counting fluid is added, the plates are heat sealed and shaken for 3 0 minutes at room temperature prior to measuring the amount of radioactivity in each well on a Packard Top-Count instrument. 5^3 Printed from Mimosa 09/15/1999 15:40:52 page -45- WO 98/40375 PCT/US98/03792 In Vitro Assay of compounds that inhibit uptake of f"ci-Alanine The alanine uptake assay is performed in an identical fashion to the taurocholate assay, with the 5 exception that labeled alanine is substituted for the labeled taurocholate. Xn Vivo Assay of compounds that inhibit Rat Ileal uptake of ruC1-Taurocholate into Bile 10 (See"Metabolism of 3a,7b-dihydroxy-7a-methyl-5b- cholanoic acid and 3a,7b-dihydroxy-7a-methyl-5b-cholanoic acid in hamsters* in Biochimica et Biophysica Acta 833 (1985) 196-202 by Une et al.) Male wistar rats (200-300 g) are anesthetized with 15 inactin @100 mg/kg. Bile ducts are cannulated with a 10" length of PE10 tubing. The small intestine is exposed and laid out on a gauze pad. A canulae (1/8" luer lock, tapered female adapter) is inserted at 12 cm from the junction of the small intestine and the cecum. 20 A slit is cut at 4 cm from this same junction (utilizing a 8 cm length of ileum). 20 ml of warm Dulbecco's phosphate buffered saline, pH 6.5 (PBS) is used to flush out the intestine segment. The distal opening is cannulated with a 20 cm length of silicone 25 tubing (0.02" I.D. x 0.037" O.D.). The proximal cannulae is hooked up to a peristaltic pump and the intestine is washed for 20 min with warm PBS at 0.25 ml/min. Temperature of the gut segment is monitored continuously. At the start of the experiment, 2.0 ml 30 of control sample (["c]-taurocholate @ 0.05 mi/ml with 5 mM cold taurocholate) is loaded into the gut segment with a 3 ml syringe and bile sample collection is begun. Control sample is infused at a rate of 0.25 ml/min for 21 min. Bile samples fractions are' 35 collected every 3 minute for the first 27 minutes of the procedure. After the 21 min of sample infusion, the ileal loop is washed out with 20 ml of warm PBS (using a 30 ml syringe), and then the loop is washed out for 21 min with warm PBS at 0.25 ml/min. A second Printed from Mimosa 09/15/1999 15:40:52 page -46- WO 98/40375 PCT/US98/03792 perfusion is initiated as described above but this with test compound being administered as well (21 min administration followed by 21 min of wash out) and bile sampled every 3 min for the first 27 min. If necessary, a third perfusion is performed as above that typically contains the control sample. Measurement of Hepatic Cholesterol Concentration (HEPATIC CHOL) Liver tissue was weighed and homogenized in chloroform.-methanol (2:1). After homogenization and centrifugation the supernatant was separated and dried under nitrogen. The residue was dissolved in isopropanol and the cholesterol content was measured enzymatically, using a combination of cholesterol oxidase and peroxidase, as described by Allain, C. A., et al. (1974) Clin. Chem. 20, 470. Measurement of Hepatic HMG CoA-Reductase Activity (HMG CPA) Hepatic microsomes were prepared by homogenizing liver samples in a phosphate/sucrose buffer, followed by centrifugal separation. The final pelleted material was resuspended in buffer and an aliquot was assayed for HMG CoA reductase activity by incubating for 60 minutes at 37° C in the presence of l4C-HMG-CoA (Dupont-NEN). The reaction was stopped by adding 6N HCl followed by centrifugation. An aliquot of the supernatant was separated, by thin-layer chromatography, and the spot corresponding to the enzyme product was scraped off the plate, extracted and radioactivity was determined by scintillation counting. (Reference: Akerlund, J. and Bjorkhem, I. (1990) J. Lipid Res. 31, 2159). Determination of Serum Cholesterol (SER.CHOL. HPL-CHOL. TGX and VLDIi + LDL) Total serum cholesterol (SER.CHOL) was measured enzymatically using a commercial kit from Wako Fine MS Printed from Mimosa 09/15/1999 15:40:52 page -47- WO 98/40375 PCT/US98/03792 Chemicals (Richmond, VA); Cholesterol Cll, Catalog No. 276-64909. HDL cholesterol (HDL-CHOL) was assayed using this same kit after precipitation of VLDL and LDL with Sigma Chemical Co. HDL Cholesterol reagent, Catalog No. 352-3 (dextran sulfate method). Total serum triglycerides (blanked) (TGI) were assayed enzymatically with Sigma Chemical Co. GPO-Trinder, Catalog No. 337-B. VLDL and LDL (VLDL + LDL) cholesterol concentrations were calculated as the difference between total and HDL cholesterol. Measurement of Hepatic Cholesterol 7-a-Hvdroxvlase Activity (7a-OHase) Hepatic microsomes were prepared by homogenizing liver samples in a phosphate/sucrose buffer, followed by centrifugal separation. The final pelleted material was resuspended in buffer and an aliquot was assayed for cholesterol 7-a-hydroxylase activity by incubating for 5 minutes at 37° C in the presence of NADPH. Following extraction into petroleum ether, the organic solvent was evaporated and the residue was dissolved in acetonitrile/ methanol. The enzymatic product was separated by injecting an aliquot of the extract onto a Cu reversed phase HPLC column and quantitating the eluted material using UV detection at 240nm. (Reference: Horton, J. D., et al. (1994) J. Clin. Invest. 93, 2084). Measurement of Fecal Bile Acid Concentration (FBA) Total fecal output from individually housed hamsters was collected for 24 or 48 hours, dried under a stream of nitrogen, pulverized and weighed. Approximately 0.1 gram was weighed out and extracted into an organic solvent (butanol/water). Following separation and drying, the residue was dissolved in methanol and the amount of bile acid present was measured enzymatically using the 3a-hydroxysteroid steroid dehydrogenase reaction with bile acids to reduce NAD. (Reference: Mashige, F., et al. (1981) Printed from Mimosa 09/15/1999 15:40:52 page -48- WO 98/40375 PCT/US98/03792 Clin. Chem. 27, 1352). f'HI taurocholate Uptake in Rabbit Brush Border Membrane Vesicles (BBMV) Rabbit Ileal brush border membranes were prepared from frozen ileal mucosa by the calcium precipitation method describe by Malathi et al. (Reference: (1979) Biochimica Biophysica Acta, 554, 259) . The method for measuring taurocholate was essentially as described by Kramer et al. (Reference: (1992) Biochimica Biophysica Acta, 1111, 93) except the assay volume was 200 pi instead of 100 pi. Briefly, at room temperature a 190 pi solution containing 2pM [3H]-taurocholate (0 .75 pCi) , 2 0 mM tris, 100 mM NaCl, 100 mM mannitol pH 7.4 was incubated for 5 sec with 10 pi of brush border membrane vesicles (60-120 pg protein). The incubation was initiated by the addition of the BBMV while vortexing and the reaction was stopped by the addition of 5 ml of ice cold buffer (20 mM Hepes-tris, 150 mM KC1) followed immediately by filtration through a nylon filter (0.2 pm pore) and an additional 5 ml wash with stop buffer. Acvl-CoA;cholesterol Acvl Transferase (ACAT) Hamster liver and rat intestinal microsomes were prepared from tissue as described previously (Reference: (1980) J. Biol. Chem. 255, 9098) and used as a source of ACAT enzyme. The assay consisted of a 2.0 ml incubation containing 24 pM Oleoyl-CoA (0.05 pCi) in a 50 mM sodium phosphate, 2 mM DTT ph 7.4 buffer containing 0.25 % BSA and 200 pg of microsomal protein. The assay was initiated by the addition of oleoyl-CoA- The reaction went for 5 min at 37° C and was terminated by the addition of 8.0 ml of chloroform/ methanol (2:1). To the extraction was added 125 pg of cholesterol oleate in chloroform methanol to act as a carrier and the organic and aqueous phases of the extraction were separated by centrifugation after thorough vortexing. The chloroform phase was taken to Ml Printed from Mimosa 09/15/1999 15:40:52 page -49- WO 98/40375 PCT/US98/03792 dryness and then spotted on a silica gel 60 TLC plate and developed in hexane/ethyl ether (9:1). The amount of cholesterol ester formed was determined by measuring the amount of radioactivity incorporated into the cholesterol oleate spot on the TLC plate with a Packard instaimager. Data from each of the noted compounds in the assays described above is as set forth in TABLES 5, 6, 7, and 8 as follows: Printed from Mimosa 09/15/1999 15:40:52 page -50- WO 98/40375 PCT/US98/03792 table 5 COMPOUND IC50 uM* In vitro % Inhibition of TC Uptake @ 100 uM # % Inhibition of Alanine Uptake @ 100 uM # % of Control Transport of TC in Rat Ileum @ O.lmM # Benzothiaze pine= 2 0 45.4 +/- 0.7 12 25 3 0 4a 3 | 5a 34 J 5b 40 0 72.9 ± 5.4 @ 0.5 mM 1 4b 9 18 6 1 14b 18 1 14a 13 13 23 1 15 60 j 19a 0 19b 15 8a 41 Mixture of 8a and 8b 69 Mixture of 9a and 9b 6 6a 5 6b 85 Printed from Mimosa 09/15/1999 15:46:45 page -1- WO 98/40375 PCT/US98/03792 19a 5 0% @ 25 mM 53.7 + /- 3.9 j Mixture of 6a and 20 13 Mixture of 6d and 10a 0.8 14% @ 25 mM 21a 37 21c 52 21b 45 6c 2 58.5 68.8 +/- 5.7 at 0.4 mM 6d 0.6 77 .7 16.1 +/- 1.1 @ 0.5 | mM 30.2 +/- 0.9 @ 0.15 mM 17 10 1 7 50 49.3 10a 7 77 .6 62.4 =/- 2.5 @ 0.2 mM I 10b 15 68.6 25 0.1 4% @ 10 mM 26.0 +/- 3.3 j 26 2 31% @ 25 mM 87.9 +/- 1.5 27 5 7% @ 20 mM 28 8 31% @ 20mM 29 88 @ 50 mM • 30 96 @ 50 mM 31 41 @ 50 mM 37 3 0% @ 5 mM 38 0.3 11% @ 5mM 20.6 +/- 5.7 40 49 @ 50 mM 1>oO Printed from Mimosa 09/15/1999 15:46:45 page -2- WO 98/40375 PCT/US98/03792 41 2 0% @ 20 mM I 42 1.5 43 1.5 16% 0 25 mM 48 2 22% @ 20 mM 49 0.15 21% @ 200 mM 21.2 +/- 2.7 57 51 @ 50 mM 58 20 @ 50 mM 59 70 60 9 59 61 30 175 62 10 63 90 @ 6 mM 64 100 @ 6 mM * In vitro Taurocholate Cell Uptake # Unless otherwise noted = Comparative Example is Example No. 1 in WO 93/16055 3^1 Printed from Mimosa 09/15/1999 15:46:45 page -3 WO 98/40375 PCT/US98/03792 TABLE 6 1 Compound TC-uptake TC-uptake TC-uptake ACAT ACAT (H14 cells) Ileal Loop (BBMV) (liver) intestine IC(50) EC(50) IC(50) IC(50) IC(50) COMP. EXAMPLE* 1 mM 74 mM 3 mM 20 mM 20 mM 6d 0.6 mM 31 mM 1.5 mM 25 mM 20 mM 38 0.3 mM 12 mM 2 mM 15 mM N.D. 49 0.1 mM 12 mM N.D. 6 mM N.D. 0.1 mM 20 mM 0.8 mM 8 mM 8 mM Comparative Example is Example No. 1 in WO 93/16055 TABLE 7 EFFICACY OF COMPOUND NO. 25 IN CHOLESTEROL- FED HAMSTERS PARAMETER CONTROL 4% CHOLESTYRAMINE 0.2% CPD. NO. 25 WEIGHT (G) (mean ± SEM, *p<0.05, A- Student's t, B- Dunnett1s) day 1 117 (2) 114(6) 117(5) day 14 127(3) 127(3) 132(4) LIVER WEIGHT (G) 5.4(0.3) 4.9(0.4) 5.8(0.2) SER.CHOL(mg%) 143 ("7) 119^4)-* At* — 126(2)^A,B > HDL-CHOL(mg%) 89(4) 76(3)*A,B 76(1)*A,B. VLDL + LDL 54(7) 42(3)*A 50(3) TGI(mg%) 203 (32) • 190(15) 175(11) HEPATIC CHOL(mg/g) 2.5(0.3) 1.9(0.1)*A, B 1.9(0.1)*A,B HMG COA (pm/mg/min.) 15.8(7.6) 448.8(21.6) * 312.9(37.5)*A A, B ,B 7a-OHase (pm/mg/min.) 235.3(25.1 2>oDL_ Printed from Mimosa 09/15/1999 15:46:45 page -4- WO 98/40375 PCT/US98/03792 I 24 HR. FECAL Wt (G) ) 3 57.2(28.3)* 291.0(6.0)*A J FBA (mM/24H/100g) 2.3(0.1) A,B 2.4(0.04) 6.2(0.8) 2.7(0.1)*A,B 11.9(0.5)*A,B J 12.3(1.5)*A, 1 B 1 2>03 Printed from Mimosa 09/15/1999 15:46:45 page -5- WO 98/40375 PCT/US98/03792 TABLE 8 EFFICACY OF COMPOUND NO. 25 IN RAT ALZET MINIPUMP MODEL 1 PARAMETER CONTROL 20 MPL/DAY CPD. NO. 25 WEIGHT (G) (mean ± SEM, *p<0.05 Dunnett's) A-Student's t, B- day 1 307 (4) 307 (3) day 8 330 (4) 310 (4)*A,B LIVER WEIGHT (G) 15.5 (0.6) 14.6 (0.4) SER.CHOL(mg%) 85 (3) 84 (3) I HEPATIC CHOL(mg/g) 21 (0.03) 2.0 (0.03) J HMG COA pm/mg/min 75.1 (6.4) 318.0 (40.7)*A,B 7a-OHase (pm/mg/min) 281.9 (13.9) 535.2 (35.7)*A,B 24 HR. FECAL WT (G) 5.8 (0.1) 5.7 (0.4) FBA (mM/24H/100g) 17.9 (0.9) 39.1 (4.5)*A,B Additional taurocholate uptake tests were conducted in the following compounds listed in Table 9. 2>o* Printed from Mimosa 09/15/1999 15:46:45 page -6- WO 98/40375 PCT/US98/03792 TAILS' ^ Biological Assay Data for Some Compounds of the Present Invention Compound Number Human TC , IC50 (UM) Alanine Uptake Percent Inhibition © |lM 101 0 @ 1.0 102 0.083 103 13 @ 0.25 104 0.0056 105 0.6 106 0.8 107 14.0 @ 0.063 108 0.3 109 2.0 © 0.063 110 0.09 111 2.5 112 3.0 113 0.1 114 0.19 115 8.0 116 0.3 117 12.0 © 0.625 118 0.4 119 1.3 120 34.0 © 5.0 121 0.068 122 1.07 123 1.67 124 14.0 © 6.25 125 18.0 126 18 @ 1.25 127 0.55 128 0.7 129 0.035 131 1.28 132 5.4 @ 0.063 133 16.0 • 134 0.3 135 22.0 136 0.09 2>oST Pnnted from Mimosa 09/15/1999 15:46:45 page -7- WO 98/40375 PCT/US98/03792 137 2.4 138 3.0 139 >25.0 142 0.5 143 0.03 144 0.053 262 0.07 263 0.7 264 0.2 265 2.0 266 0.5 267 0.073 268 0.029 269 0.08 270 0.12 271 0.07 272 0.7 273 1-9 274 0.18 275 5.0 @ 0.25 276 0.23 277 0.04 278 3.0 279 0.4 280 0.18 281 0.019 282 0.021 283 0.35 284 0.08 286 19.0 287 4.0 288 10.0 @ 6.25 289 0.23 290 0.054 291 0.6 292 0:046 293 1.9 294 0.013 295 1.3 . 296 1.6 1005 0.0004 1006 0.001 30(o Printed from Mimosa 09/15/1999 15:46:45 page -8- WO 98/40375 PCT/US98/03792 1007 0.001 1008 0.001 1009 0.001 1010 0.001 1011 0.001 1012 0.0015 1013 0.002 1014 0.002 1015 0.002 1016 0.002 1017 0.002 1018 0.002 1019 0.002 1020 0.002 1021 0.002 1022 0.002 1023 0 002 1024 0.002 1025 0 002 1026 0.002 1027 0.002 1028 0.002 1029 0.002 1030 0.002 1031 0.002 1032 0.002 1033 0.002 1034 0.002 1035 0.002 1036 0.002 1037 0.0022 1038 0.0025 1039 0.0026 1040 0.003 1041 0.003 1042" 0.003 1043 0.003 1044 0.003 1045 0.003 1046 0.003 1047 0.003 1048 0.003 2>ol Printed from Mimosa 09/15/1999 15:46:45 page -9- WO 98/40375 PCT/US98/03792 1049 0.003 1050 0.003 1051 0.003 1052 0.003 1053 0.003 1054 0.003 1055 0.003 1056 0.003 1057 0.003 1058 0.003 1059 0.003 1060 0.0036 1061 0.004 1062 0.004 1063 0.004 1064 0.004 1065 0.004 1066 0.004 1067 0.004 1068 0.004 1069 0.004 1070 0.004 1071 0.004 1072 0.004 1073 0.004 1074 0 004 1075 0.0043 1076 0 0045 1077 0 0045 1078 0.0045 1079 0.005 1080 0.005 1081 0.005 1082 0.005 1083 0.005 - 1084 0.005 - 1085 0.005 1086 0.005 1087 0.005 1088 0.0055 1089 0.0057 1090 0.006 3 OS Printed from Mimosa 09/15/1999 15:46:45 page -10- WO 98/40375 PCT/US98/03792 1091 0.006 1092 0.006 1093 0.006 1094 0.006 1095 0.006 1096 0.006 1097 0.006 1098 0.006 1099 0.0063 1100 0.0068 1101 0.007 1102 0.007 1103 0.007 1104 0.007 1105 0.007 1106 0.0073 1107 0.0075 1108 0.0075 1109 0.008 1110 0.008 1111 0.008 1112 0.008 1113 0.009 1114 0.009 1115 0 0098 1116 0 0093 1117 0.01 1118 0.01 1119 0.01 1120 0.01 1121 0.01 1122 0.011 1123 0.011 1124 0.011 1125 0.012 1126 0.013 _ 1127 0.013 ——^____ 1128 0.017 1129 0.018 1130 0.018 1131 0.02 1132 0.02 30^ Printed from Mimosa 09/15/1999 15:46:45 page -11- WO 98/40375 PCT/US98/03792 1133 0.02 1134 0.02 1135 0.021 1136 0.021 1137 0.021 1138 0.022 1139 0.022 1140 0.023 1141 0.023 1142 0.024 1143 0.027 1144 0.028 1145 0.029 1146 0.029 1147 0.029 1148 0.03 1149 0.03 1150 0.03 1151 0.031 1152 0.036 1153 0.037 1154 0.037 1155 0.039 1156 0.039 1157 0.04 1158 0.06 1159 0.06 1160 0.062 1161 0.063 1162 0.063 1163 0.09 1164 0.093 1165 0.11 1166 0.11 1167.. 0.12 1168 0.12 1169 0.12 1170 0.13 1171 0.14 1172 0.14 1173 0.15 1174 0.15 3lO Printed from Mimosa 09/15/1999 15:46:45 page -12- WO 98/40375 PCT/US98/03792 1175 0.17 1176 0.18 1177 0.18 1178 0.19 1179 0.19 1180 0.2 1181 0.22 1182 0.25 1183 0.28 1184 0.28 1185 0.28 1186 0.3 1187 0.32 1188 0.35 1189 0.35 1190 0.55 1191 0.65 1192 1.0 1193 1.0 1194 1.6 1195 1.7 1196 2.0 1197 2.2 1198 2.5 1199 4.0 1200 6.1 1201 8.3 1202 40.0 1203 0 @ 0.063 1204 0.05 1205 0.034 1206 0.035 1207 0.068 1208 0.042 1209 0 @ 0.063 1210 0.14 ~ 1211 0.28 1212 0.39 1213 1.7 1214 0.75 1215 0.19 1216 0.39 3W Printed from Mimosa 09/15/1999 15:46:45 page -13- WO 98/40375 PCT/US98/03792 1217 0.32 1218 0.19 1219 034 1220 0.2 1221 0.041 1222 0.065 1223 0.28 1224 0.33 1225 0.12 1226 0.046 1227 0.25 1228 0.038 1229 0.049 1230 0.062 1231 0.075 1232 1.2 1233 0.15 1234 0.067 1235 0.045 1236 0.05 1237 0.07 1238 0.8 1239 0.035 1240 0.016 1241 0.047 1242 0 029 1243 0.63 1244 0.062 1245 0.32 1246 0.018 1247 0.017 1248 0.33 1249 10.2 1250 0.013 1251 0.62 1252 29. 1253 0.3 1254 0.85 1255 0.69 1256 0.011 1257 0.1 1258 0.12 V2- Prxnted from Mimosa 09/15/1999 15:46:45 page -14- WO 98/40375 PCT/US98/03792 1259 16.5 1260 0.012 1261 0.019 1262 0.03 1263 0.079 1264 0.21 1265 0.24 1266 0.2 1267 0.29 1268 0.055 1269 0.02- 1270 0.02- 1271 0.01; 1272 0.047 1273 0.029 1274 0.028 1275 0.024 1276 0.029 1277 0.018 1278 0.017 1279 0.028 1280 0.76 1281 0.055 1282 0.17 1283 0.17 1284 0.011 1285 0.027 1286 0.068 1287 0.071 1288 0.013 1289 0.026 1290 0.017 1291 0.013 1292 0.025 1293 0.019 1294 0.011 1295 0.014 1296 0.063 1297 0.029 1298 0.018 1299 0.012 1300 1.0 Printed from Mimosa 09/15/1999 15:46:45 page -15- WO 98/40375 PCT/US98/03792 1301 0.15 1302 1.4 1303 0.26 1304 0.25 1305 0.25 1306 1.2 1307 3.1 1308 0.04 1309 0.24 1310 1.16 1311 3.27 1312 5.0 1313 6.1 1314 0.26 1315 1.67 1316 3.9 1317 21.0 1319 11.0 ® 0.25 1321 11.1 @ 5.0 1322 3.0 @ 0.0063 1323 4.0 @ 0-0063 1324 43.0 @ 0.0008 1325 1.0 @ 0.0063 1326 36.0 @ 0.0008 1327 3.0 @ 0.0063 1328 68.0 @ 0.0063 1329 2.0 @ 0.0063 1330 9.0 @ 0.0063 1331 57.0 @ 0.0008 1332 43.0 @ 0.0008 1333 0 @ 0.0063 1334 50.0 @ 0.0008 1335 38.0 @ 0.0008 1336 45.0 @ 0.0008 1337 0 @ 0.0063 1339 0 @ 0.063 1340 9.0 @ 0.063 1341 1.0 @ 0.063 1342 1.0 @ 0.063 1345 13.0 ® 0.25 1347 0.0036 y* Printed from Mimosa 09/15/1999 15:46:45 page -16- WO 98/40375 PCT/US98/03792 1351 0.44 1352 0.10 1353 0.0015 1354 0.006 1355 0.0015 1356 0.22 1357 0.023 1358 0.008 1359 0.014 1360 0.003 1361 0.004 1362 0.019 1363 0.008 1364 0.006 1365 0.008 1366 0 015 1367 0.002 1368 0.005 1369 0.005 1370 0.002 1371 0.004 1372 0.004 1373 0.008 1374 0.007 1375 0.002 1449 0.052 1450 0.039 1451 0.014 3»5- Printed from Mimosa 09/15/1999 15:46:45 page -17- WO 98/40375 PCT/US98/03792 The examples herein can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples. Novel compositions of the invention are further illustrated in attached Exhibits A and B. The invention being thus described, it is apparent that the same can be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the present invention, and all such modifications and equivalents as would be obvious to one skilled in the art are intended to be included within the scope of the following claims. 2^ Printed from Mimosa 09/15/1999 15:46:45 page -18 WO 98/40375 PCT/US98/03792 Table C2: Alternative compounds #2 (Families F101-F123) (Rx)q OH Family Cpd# RS (**)<? F101 F102 F103 F104 F105 F106 F107 F108 F109 F110 Fill F112 CHOSEN FROM TABLE D * CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TA3LE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D Ph- p-F-Ph- m-F-Ph- p-CK30-Ph- n-CH30-Ph- p-(CK3)2N-?h- tr.-(CK3)2N-Ph I", p-(CH3)3-N+-Ph- I~, m-(CH3)3-N+-Ph- I", p-(CH3)3-N+-CH2CH2-(OCH2CH2)2-O-Ph- I", m- (CH3I 3-N+-CH2CH2-~ (0CH2CH2)2-O-Ph- I", p-(N,N-dimethvlpiperazine)-(N') • CH2-(OCH2CH2)2-0-Ph- CHOSEN FROM TABLE D CHOSEN FROM TA3LE D CHOSEN FROM TA3LE D CHOSEN FROM TABLE D CHOSEN FROM TA3LE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D -CHOSEN FROM-TABLE D CHOSEN FROM •TABLE D 3H Exhibit A Printed from Mimosa 09/15/1999 15:46:45 page -19- WO 98/40375 PCT/US98/03792 F113 F114 F115 F116 F117 F118 F119 F120 F121 F122 F123 CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TA3LE D CHOSEN FROM TABLE D I", m-(N,N-dimethylpiperazine)-(N')-CH2-(OCH2CH2)2-O-Ph- m-F-Ph-P-CH3O- 3,4, dioxy-raethy lene-Ph- m-F-Ph-p-F-Ph- m-CH30-p-F-Ph- 4-pyridine N-methy1-4-pyridinium 3-pvridine N-methyl-3-pyridinium 2-pyridine p-CH302C-Ph- CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D chosen from table d Similar families can be generated where R1<>R2, such as R1 «* Et and r2 o n-Bu, but (Rx)q is chosen from table CI. Printed from Mimosa 09/15/1999 15:46:45 page -20 WO 98/40375 PCT/US98/03792 MeO MeO MeO Et Bu OH NCCH332 Et Bu OH NCCH3D3 •*N—CH, | Exhibit B 2>\^ Printed from Mimosa 09/15/1999 15:46:45 page -21- WO 98/40375 PCT/US98/03792 Printed from Mimosa 09/15/1999 15:46:45 page -22- WO 98/40375 PCT/US98/03792 33l\ Printed from Mimosa 09/15/1999 15:46:45 page -23- 322 APPENDIX A Toe ileal bile acid transport inr.iDitors used m ~ne present invention mcXucs, ifoir 3\5rr.c]_0 trics-5 Aocendix A. ' ' c<- nq: A_]_ The compounds of the formula (I) (0, (I) ^Y^N-X R: RSl I, R wnerein R^ and R- arc the same cr different and eacn is optionally substituted alkyl C3.5 cycloalkyl, or R' and R- together wth the carcon atom to wpjen tr.ev are artached form an optionally substituted C3.5 spiro-c%cloaikyl grouD, R4 is a C5.[4 aryl. or a C3.13 heteroaryl grouo eaca oouonally substituted with one to eight substituents which are the same or d.ffere.ir and a:e each selected froi" halogen, hydroxy, racro, pncnyl-Ci.5 aikoxy, Cj.^ alkoxy, optionally substituted Ci.^ alkyl, S(0)nRs, S02NRs.R9, C02Rs, 0(CH2CH20)PR3, 0S02Rs, 0(CH2)pS03R8, 0(CH2)pNR^R10 and O(CH2)pN~R9R10R11 wnerein R8 to R11 are the same or different and are independently selected rrom hydrogen or oouonally substituted Cj.g alkyl , and whercn 0 is an integer from 1-4 and n is ar. integer rom 0-3, R5a, R5b, R5c, and RSd eacn represent atoms or groups which are the same or different and each is hydrogen, halogen, cyano, R8-acetylide, OR3, ocnor.ally subsnmtcd alkyl, COR8, CH(0H)R8, S(0)nR8, S02NR8R9, P(OXORs)2, 0C0R8, OCF3i OCN, SCN, NHCN, CH20R8, CHO, (CH2)pCN, CONR5R10, (CH2)pC02R8, (CH23piNR9R10, C02R8, NHCOCF3, NHS02Rs, OCH2OR8, OCH-CKR8, 0(CH2CH20)nR8, 0SO2R8, 0(CH2)pS03R81 0(CH2)pNR9R10 and 0(CH7)pN4H^R^'^R^ * wherein R8 to R^', n, and p arc as hereinbefore denned, or R^a and R^b, r5o ^ r5cj or ^5c ^ j^5d together with the ring to which they arc attached form a cyclic group -0(CR^R^)m0- wherein R^ and R^ are as hereinbefore denned and m is 1 or 2, AMENDED SHEET 323 R& and R' arc the same or different ar.d eacn :s hydrogen, ccticnaiK suost.tutec Ci _h aiicyL, C3.6 cycloalkyl, cr R° ar.d R' togetner wth tr.e carbon atom to whicn :*ev arc attached form an ontionaily substituted C3.5 sciro-cycicdl'cvl grout:, X is CPo, C=0, C=S, or ONR3 wherein R^ is is hereinoefore denned, and I is an integer from 0-2, and salts, solvates or a physiologically functional derivatives thereof ^_2 A compound of formula (I) above wherein R1 is methyl or ethyl, R- is methyl, ethyl or n-buryl, R^ is phenyl, R^a and R^ arc hydrogen, R-b and R^c are the same or different and are each hydrogen, methyl, methoxy, hydroxy, tnflucromcthy! or halo, R^ and R^ are the same or different and are each hydrogen, methyl, ethyl or 1-bucyi, X is CH2 or C=0, 1 is 2, or a salt, solvate, or physiologically functional derivative thereof A-3 A compound of formula (I) selected from the group consisting of (±)-3-n-Butyl-3-ethyl-2,3-dihydro-5-pheny!-l,5-bcnzotniazcpin-4-one, (=)-3-n-Butyl-3-ethyl-2,3-dihydro-5-phenyi-l,5-benzot)uzzcpin-4-one-l, 1 -dioxide, (i)-3-n-Butyl-3-ethy!-2,3,4,5-tetrahydro-5-phenyl-l,5-bcnzothiazepme, (=)-3-n-Butyl-3-ethyl-2,3>415-tctrahydro-5-phenyl-l,5-b<nzotj,uazepine-l, 1 -dioxide, (i)-3-n-Butyl-2-isobuty!-3-cthyl-2,3,4,5-tetrahydro-5-phenyi-l,5-benzothiazcpmc-1,1-dioxade; 3,3-Diethyl-2,3-dihydro-5-phcnyl-l,5-benzothi22rpin-:*-onc, 3,3-Diethyl-2,3-dihydro-5-phenyl-l,5-benzoth:azcpm-4-onc 1,1-dioxide, 3>3-Dicthyl-2,3,4l5-tetrahydro-5-phenyl-l,5-benzothiazcpine, 3,3-Diethyl-2,3,4,5-tetrahydro-5-phcnyl-l,5-benzothiazcpine-l, 1-dioxide, MAfcUOffl sheet 32H j.j-Dur.ctnyl-Z^-dinyaro-S-pr.snyi-i.f-berjrcthLiiecin-i-onc, 3,3-Dirnc:hyi-2,3-dihydro-5-phcr.yi- l.S-benzocniizecin-ior.c-1, i-coxice, 3.3-DiTis:hyI-2,3,4,5-tcmhvdro-5-c!h£nyl-!,5-bsnzothi^:cD!r.s, 3,3-Dimcthyl-2,3,4,5-tc:rahycro-5-phcnyi-l,5-bcru:otn-izcpir.:-!. 1-cioxiae, (=0-3-n-ButyI-3-ethyl-2,3,4,5-ce:rahydro-7,8-di:netnoxy-5-pncnYl-l,5-benzothiazepine-l.l-dioxide; * 3,3-Diethyl-2,3,4,5-tetrahydro-7,3-duntthoxy-S-ph.cnyl-l ,5-benzothiazcpine-l, 1 -dioxide; (=)-3-n-Buryl-3-e:hyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-bcnzotruaz;p;ne-I,!-dioxide, 3,3-Diethyl-2,3,4,5-te:rahydro-8-T.ethoxy-5-phenyl-l .S-ber-zotniazep'.ne-l,! -dioxide, (=)-3-n-Butyi-3-ethyi-2,3,4,5-ter.rinvdro-5-prenyl-l,5-ber^othiazepin-8-ol-1,1-dioxide, 3(3-Dieihyl-2,3,4,5-tet:ahydro-5-pr.er.yl-l,5-Der.zotn:azeoin-8-ol- 1,1-aioxide, (=)-3-n-Butyl-3-ethyl-2,3,4,5-tetrah>dro-7-me'.hoxy-5-phenyI-l,5-benzo:hi2zepin-8-ol-1,1-dioxide, 3,3-Dis:hyl-2,3,4,5-ie!rzhydro-7-mtthoxy-5-phenyl-l,5-benzotruazeptn-8-ol-l, 1-dioxide, (=)-7-bromo-3-n-Bucyl-3-ethyl-2,3,-i,5-ietrahydro-8-rre:hoxy-5-oheny[-1,5-beazothiazspine-1,1-dioxide, 7-bromo-3,3-Di«hyl-2,3,4,5-te:rah\dro-8-methoxy-5-phenyi-l ,5-benzotn:azeptne-1,1-dioxide, (=)-3-n-Butyl-3-e:hyl-2,3,4,5-ie!r2hydro-5-phenyi- l,5-ber^othi22spin-7,8-dio!-l, 1 -dioxide, 3,3-Diethyl-2J,415-te:rahydro-5-phenyl-l,5-benzothi2zepin-7,S-diol-l, 1 -dioxide, (=)-3-n-Butyl-3-ethyi-2,3,4,5-te:rahydro-8-me:hoxy-5-phenyl- 1,5-benzotruzzepme-1-monoade; 3,3-Diethyl-2,3,4,5-tetrahydro-8-meTi0xy-5-phenyI-l,5-benz0thiazepine-1- monoxide, (=)-3-n-Butyl-3-ethyl-2,3,4,5-tetnhydro-5-phenyl-l,5-benzothja2cpin-8-oI-l- monoxide; 3,3-Diethyl-2,3,4,5-tetrahydro-5-pheayI-l,5-benzothiazcpin-8-oI-l-mono;ade, (=)-3-n-Butyl-3-ethyl-2,3-dihydro-8-meihoxy-5-phenyl-l,5-benz.othia2-pin—one, (±}-3-n-Butyl-3-e£hyl-2,3,4,5-tetranydro-3-methoxy-5-phcnyi-lI5-bcnzothia2epir.£; (±)-3-n-Biityl-3-cthyl-2,3,4,5-tetrahydro-8-mcthoxy-5-phcny!-l,5-benzotkiizepine-1,1-dioxide, (±)-3-n-Butyl-3-ethyl-2,3,4,5-tctrahydro-8-hydroxy-5-phenyl-l,5-benzotra2Lzepir.e-1,1 -dioxide; AMENDED SHEET 32£ (=)-7-3romo-3-n-ou£yI-3-e£hyi-2,3-c:r.ydro-3-me:roxy-5-pneny!-1,5osrj:o;r^cj;;c;n-4-one, (=)-7-3romo-3-n-bur/l-3-e£hyl-2,3,4,5-te:rahycro-3-n:e£Rcxy-5-Dhenvi-1,5-oenzcuhiazepine i,l-dioxide, (=0-7-Bromo-3-n-butyl-3-e£hyl-2,3,4,5-te£rahydro-5-phenyl-I,5-bcnzo;ruazecin-8-ol 1,1-dioxidc, j (±)-3-n-butyl-3-«£hyl-2,3,4,5-Ee:rahydro-7-rneEhoxy-5-chenyl-l ,5-ber-zothiazepin-8-ol 1,1-dioxide; (=)-3-n-butyl-3-ethyi-2,3,4,5-teirahydro-718-dimc:hoxy-5-phenyl- 1,5-oenzothiizeoine 1,1-dioxjde, (=)-3-n-butyl-3-ethyI-2,3,4,5-tetranydro-5-pheriyl-1,5-benzoEhiaz£ptne-7,8-aiol 1,1-dioxide, (=)-7-Bromo-3-n-butyi-3-echyl-2,3-c.hydro-5-phenvl-1,5-benzothiazepi;]-4-one, (=)-3-n-butyl-3-e:hyl-2,3,4,5-£etranydro-7-rr.etRoxy-5-phenyl-! ,5-beazo:hiaz:pine 1,1-dioxide, and (=)-3-n-butyl-3-e£hyl-2,3,4,5-tetrahydro-5-pher.yl- !,5-benzothiazepin-7-oi 1,1-dioxide A compound of formula (I) selected from (=)-3-n-bucyl-3-eEhyl-2,3t4,5-EeErahycro-7-meEhoxY-5-phcnyl-1,5-benzo fhiazepm-S-oi 1,1-dioxide, and (=)-3-n-Bu£yl-3-ethyl-2,3,4,5-te£rahydro-8-hydroxy-5-phenyl- 1,5-benzochi azepine-1,1 -dioxide or a salt, solvaEe, or physiologically fur.cuoaaJ derivative thereof AMENDED SHEET 32b (=)-3-n-Bi:r/l-3-ctriyl-2,3-<lLhydro-5-phsT'i-1.S-bcr-zoirjazeom-i-or.e-!, 1 cx.^c, (i)-3-i-3utyl-3-cthyi-2t3,4,5-:ctnhycro-5-prenyl-1 .S-bf-zcthuzzecir.s, (=)-3-n-Buryi-3-etRyi-2,3,4,5-'eTrzhycro-5-Dhenyi -1 .i-'rer-zo'hiizepine-1,. -(=)-3-n-Butyi-2-isobuty!-3-ethyl-2,3,4,5-te:rahvdro-5-ph:nyi-1,5-benzothi2zscme-1,1-dioxide, 3,3-Diethyl-2,3-dihydro-5-pher.yI-l15-ben2othiazspin-4-one, 3I3-Diethyl-2,3-dihydro-5-phenyl-l,5-benzo:hjazepin-4-one 1,1-dioxide, 3,3-Die:hyI-2,3,4,5-tetrihydro-5-pr.er.yl- l,5-benzocfua=spine, 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-l,5-benzo:hja2epine-l,l -dioxide, 3,3-DimethYl-2,3-dihydro-5-ph£nyl-l,5-benzo:hiaz£pin-4-or.e, 3,3-Dime[hyl-2,3-dihydro-5-phcnyi-l,5-oer^:othj3LZcpm-4-one -1,1 -dioxide, 3,3-Dime,.hyl-2,3,4,5-tetrihydro-5-phenyi-l,5-benzothiizep!ne, 3,3-Dimethy!-2,3,4,5-te:rahydro-5-pnenyi-1,5-benzothiazeom:-1,1 -dioxide. (=)-3-n-Batyl-3-e'.hyl-2,3,4,5-te:rahydro-7J8-dimcrhoxy-5-pnenyl- l,5-ben2c:.i:aze2tne -!, 1 -dioxide, 3,3-Dic:nyI-2t3,4t5-tetrahydro-7,8-dimethoxy-5-pncnyl-l ,5-benzothiazeptr.e-l, 1-dioxide, (=)-3-n-3uryI-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-ohenyi-1,5-oenzochiizecme-l, 1 -dioxide, 3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-pnenyl-1,5-benzo:hia2ecine-1,1-aioxide, (=)-3-n-Buryl-3-ethyl-2,3,4,5-ce:r;ihydro-5-pneny!-l,5-beazo:kizzzpin-8-ol- i, 1-dioxide, 3,3-Diethyl-2,3,4,5-tctnhydro-5-phenyl-' ,5-ben20thiazcpin-8-0l-l, 1-dioxide. (=)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-me:hoxy-5-phenyl- l.S-benzothiizeoin-S-ol-l, 1 -dioxide, 3,3-Diethy!-2,3,4,5-tetrihydro-7-rnemoxy-5-phenyI-1,5-beizothjizepin-S-ol-1,1 -cioxice, (=)-7-bromo-3-n-3utyI-3-«thyi-2,3,4,5-cetrahyaro-8-me:noxy-5-pnenyl-1,5-bcrizothiazepine-1,1 -dioxide, 7-bromo-3,3 -Dieinyl-2,3,4,5-te:rahydro-8-mcLhoxy-5-phcnyl-1,5-bcnzothi azepme-1, !-dioxide, (=)-3-n-3utyl-3-ethyl-2,3t4,5-tetrahydro-5-phenyl-l,5-ben20thiazepm-7,8-diol-l, 1-dioxide, 3,3-Diethy!-2,3,4,5-tetrahydro-5-phenyl-l,5-benzouuazepin-7,8-diol-l, 1-dioxide, (=)-3-n-3i!Cyl-3-ethyi-2,3,4,5-tcrrahydro-8-mcthoxy-5-phenyl-l,5-bcnzothiazepine-l-monoxide; 3, 3-Diethyl-2,3,4,5-tetr2hydro-8-me,Jioxy-5-phenyl-l,5-benzoLhjazepine-l-monoxide, (=)-3-n-Butyi-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,5-bcrizcthiazcpin-8-ol-l -monoxide, 3,3-Dicthyl-2t3,4,5-tetrahydro-5-phenyi-l,5-benzothi£L2:epin-8-ol-l-monoxide, (=)-3-n-Butyl-3-ethyl-2,3-dihydro-8-methoxy-5-phenyl-l,5-b£nzothiazrpLn-4-one; (±)-3-n-3utyl-3-ethyl-2,3,4,5-teLrahydro-8-methoxy-5-phenyl-l,5-bcnzochiizepinc, AMENDED SHEET, (=)-3-n-3utyi-3-e:nyl-2,3,4,5-tetranydro-8-rr.:::noxy-5-phenyI-1,5-bcnzc:rjiz:c:r:-!. i-aioxide, (=)-3-n-3uty!-3-e'.hy!-2 3t4(5-tetnLhydro-3-nydroxy.5-ohenyi-l,5-benzoth:2j:;s:ne-j,! -dioxicc, (±)-7-Brcmo-3-n-butyl-3-ethyl-2,3-dihydro-8-methoxy-5-phenyi- l,5-beazotn:az=pin-4-onc, (=)-7-Bromo-3-n-buryl-3-ethyl-2,3,'i,5-tctrahydro-8-methoxy-5-phcayl-l,5-benzotruazcpin: 1,1 -dioxide; (±)-7-Bromo-3-n-butyl-3-eihyl-2,3,4,5-i£'.rihydro-5-phenyl-l,5-berizothiazeoin-S-ol 1,1-dioxid:, (=)-3-a-butyl-3-ethyl-2,3,4,5-t£tranydro-7-mcr.haxy-5-ph:r.yI-1,5-benzochj2zeptn-8-ol 1.1-d'.oxjdc; (=)-3-n-buryl-3-ethyl-2,3,4,5-te[rahydro-7,S-dimeihoxy-5-phenyi-l ,5-benzolrepine 1.1 -dioxide. (=)-3-n-butyl-3-ethyl-2,3,4,5-teiranydro-5-pheny[-1,5-benzothiize::ine-7,8-diol 1,1 -dioxice, (=}-7-3rorno-3-n-butyl-3-echyI-2,3-dihydro-5-phenyl-l,5-benzoih:izepin-4-one. (=)-3-n-butyi-3-ethyl-2,3,4,5-tctrahycro-7-m:choxy-5-phcnyl-1,5-benzcthiareptne 1.1-dioxide. and (=)-3-n-butyl-3-er.hyl-2,3,4,5-tetrahydro-5-phenyl-l,5-berLZOthiaze3:n-7-ol 1.1 -dioxide Particularly preferred comcounds include (=)-j-n-bury 1-3- ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phcny[-1,5-benzothjazepin-8-ol 1,1-dioxjdc, and (=)-3-n-Bucyi-3-ethyl-2,3,4,5-tcirahydro-S-hydroxy-5-phcnyl-1,5-benzocruazeaine-l. 1-aioxide. AMENDED SHEET J2S 5 3,3-Dicthyl-2,3,4,5-tetrahydro-1,1 -dioxo-5-phenyl-1,4-benzcthiazcpin-8-yi aspartate (3R,5R)-3-Buryi-3-ethy[-2,3,4,5-tetradhydro-7,8-dirr.ethoxy-5-phsnyi- 1,^-benzoduazeome 1,1-dioxide, (3R,5R}-3-Butyl-3-e:hyl-2,3,415-tetrahydro-7,8-dunethoxy-5-phenyl-l,4-beazothiazepm— ol 1,1 -dtoxide, f+-VTraii5-3-buryl-3-ethyl-2,3,4,5-tea^hycLrc-7,SKiLmc:hoxy-5-pbefiyt-l,4-ben2othiazcpLn^ 1,1-dioxidc, (+-)-Traiis-3-buryI-3-cthyl-2,31415-tctraiiydro-7,8-<lLine^ioxy-5-phenyl-l,4,-berLzothiazroLn 4-ol 1,1-dioxide, (3R,5R)-7-Brcmo-3-butyl-3-e:hyl-2,31415-ietrahydro8-racthoxy-5-phcnyi-1,4-benzothiazepme 1,1-dioxide; (3R,5R)-7-Brorno-3-butyl-3-ethyl-2,3,4,5-tetra}iydro-8-methoxy-5-phenyl-l,4-benzothiazepLn-4-ol 1,1-dioxide; (3R,5R)-3-Butyl-3-<rthyi-2,314,5-tctrahydro-5-phenyi-l,4-beruotiiiazepine-7,8-dio!l, 1-dioxide; (3R,5R)-3-Butyl-3-ethyl-2,3,4,5-te:nLhydro-8-methoxy-5-pheny!-l,4-benzothiazcpin-7-oi 1,1-dioxide; AMENDED SHEET - • 323 (3?.,5R)-3-3ur-i-3-cthyI-2,3,4i5-:;:rsi;%C'::-7-rrc:hcvv-i-::':c~;l - i, — seizctruaze-.-'-S-ci I, I-dlOXJCC, (~-)-Trans-3-butyl-3-ethyl-2,3,4,;-te:rihydro-8-rTiethoxy-5-phcr:yi-l ,4-beruoihiazcpine 1,1-dioxide; j nins-3-butyl-3-ethyI-2,3,4,5-tetrahydro-5-phenyl-l,4-oenzathjazepin-8-oll, 1-dioxide, (-r-)-Trans-3-butyl-3-ethyl-2,3,4,5-tctrahydro-5-phcnyl-l,4-b=azothiazcpine-4,8-ciol, (-r-)-Trans-3-buryl-3-ethyl-2,3,4i5-tcirihyc!ro-8-meihoxy-5-phcnyl-l ,4-beazothiazep!ne-7-carbaldehyde 1,1-dioxide, (--)-Trans-2-((3-butyl-3 -ethyl-2,3,4,5-titrahydro-8-methoxy-5-phenyl-l,4-benzothiazepin-7-yl)mcthoxy) ethanol S.Snoioxide, (-r-)-Trans-j-butyl-3-ethyl-2,3,4,5-tetrahydro-8-hydroxy-5-prienyl-l,4-berLzothiaLz:?ine-7-carbaldehyde 1,1-dioxide, (-*--VTr2Jis-3-buryl-3-ethyl-2,3,4,5-tetr2hydro-5-phenyl-1,4-b:izothiazepin-8-thioll, 1-dioxide, (—-)-Trans-3-buryl-3-ethyl-2,3,4,5-tstrahydro-5-phenyl-1,--be:uothiazepin-8-suifonic acid-1,1 -dioxide; (7R,9R)-7-Butyl-7-ethyl-6,7,8,9-tetrahydro-9-phcnyl-l,3-cioxcio(4,5-H)(i,4)- benzothiazepLne 5,5-dioxide, (--)-Trans-3 -butyl-3 -ethyl-2,3,4,5-te£raJiydro-8,9-diraethoxy-5-phenyl-l,4-benzothiazepine-1,1-dioxide; (3R, 5R)-3 -butyl-3-ethyl-5-(4-fluorophcnyl)-2,3,4,5-tetrahydro-7,8-dimethoxy-1,4-benzothiazpLn-4-ol 1,1-dioxide; (+-)-Trans-3-bury!-3-ethyl-2,3f4,5-tetrahydro-8-mcthoxy-5-phenyl-l ,4-benzothiazepine-7-raethanol S,S-dioxide, AMENDED SHEET 33D (3R,5R1-3-bur/i-3-c:r.yl-2,3,-i,5-te:rariydro-3-rr.cLho,'c/-7-p^;ro-5-Drsny!-1 ~-bcnzothi izepme-1,!-dioxide, (_r-)-Tr2ns-3-buryl-3-cthyI-2,3,4,5-tetrahyaro-S-mc:noxy-7-(rncthoxymethyl)-5-ph£nyl-l benzothiazepine 1,1-dioxide, (3R,5R)-3-butyI-3-cthyI-2,3,4,5-tctrahydro-5-phcnyt-l,4-bcnzothiazcDin-7,8-<iiyI diaccuite-1,1-dioxide, (8R, 10R)-8-BuryI-3-e,Lhyl-2,3,7,8,9110-hcxzhydro-10-1,4-dioxono(2.3-PD( 1,4)-benzothiazepine 6,6-dioxidc, (3R,5R)-3-butyl-7,8-d!Sthoxy-2,3,4)5-tetrahydro-S-phenyl-l,4-benzothj2zenir.e 1,1 -dioxide, (-r-)-Trans-3-buryl-8-e'iioxy-3-ethyl-2)3l4,5-tctrahydro-5-phenyi-l ,4-benzothjazepine-l, 1-dioxidc, (--)-Trans-3-butyi-3-ethyl-2,3,~,5-tetraiiydro-8-isoproDOxy-5-phenyl-l,4-bcnzouhiazcpine 1,1 -dioxide hydrochloride, (+-}-Trans-3-buryl-3-ethyI-2,3,4,5-ietranydro-5-phenyl-I,4-benzothiazepm-8-carbaldehyde-1,1-dioxide, 3,3-Diethyl-2,3,4,5-ce:rahydro-7,8-dimethoxy-5-phenyI-l,-i-benzochiazepine 1,1-dioxide, 3,3-Dieihyl-5-{4-Qucropheny!)-2,3,4i5-tcr2i,iydro-3-meuhcwcy-l,-i-berc:othj2zepine 1,1-dioxidc; S^-Diethyi-Z^^.S-tetraitydro-S-methoxy-S-phenyl-l^-bcnzothiazepmcl, 1-dioxide, S.S-Diethyl^^^.S-tecrzhydro-S-phenyl-l^benzothiazpuv^.S-dioll, 1-dioxide; (R5)-3t3-Diethy!-2,3,4.5-tetrahydro-4-hydroxy-7,S-<limethoxy-5-phcnyl-l,4-benzothiazepme 1,1-dioxide; (+-}-Trans-3-buryl-8-ethoxy-3-ethyI-2,3,4,5-tctrahydro-5-phenyl-lI4-bcnzouiiazepm-4-oI-1,1-dioxide; amended sheet 32 A f—)-T rans-3-butyl-3-ethy 1-2,3,**, S-'etrihydro-S-isccroDOxy-5-phenyl-1 - o! 1, '-dioxide, (+-)-Trans-3-butyl-3-ethyl-2,3,4i5-tetrahydro-7,S,9-tnmethc'c/-5-pnenyl-l ,4-beazothiazeptn-4-oI 1,1-dioxide; (3R,5R)-3-buryl-3-cthyl-2,3,4,5-:etrahydro-5-phcnyl-l,--ben2othiazp!n-4i7i8-tncl 1,1-dioxide, (-^-)-Trajis-3-butyl-3-ethyl-2,3,415-tctnihydro-4,71S-tnmc:hoxy-5-phcnyl-l,4-benzodiazepine 1,1-dioxide, (-i--)-Trans-3-butyI-3-e:hyI-5-phenyl-2,3,4,5-tctrahydro-7,8-dimethoxy-l .-i-benzothiazepin-4—yl acetate S,S-dioxidc, 3,3-Diethyl-2,3,4,5-te:nahydro-5-phenyl-l,4-benzathiazepin-8-ol 1,1-dioxide, 3,3-Diethyl-2,314,5-tetrahydro-7-m«hoxy-5-phenyl-l,4-be.izothia2cpin-8-ol 1,1-dioxide, 3,3-Dibutyl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazepin-8-o! 1,1-dioxide, (-<--)-Trans-3-Buty!-3-ethyl-2,3,4,5-tetrahydro-l, 1-dioxo-5-phenyl-l,4-benzothiazepm-8-yl hydrogen sulfate, (f-)-Trans-3-BuryI-3-ethyi-2,3,415-tetrahydro-l, l-dioxo-5-pher:vl-l,4-oenzotruazepin-S-vl dihydrogcn phosphate, 3,3-Dicthyl-2,3,4,5-tetrahydro-l,l-dioxo-5-phenyl-l,4-benzothjazepin-8-yl hydrogen sulfate; 3,3-DicthyI-2,3,4,5-tctrzhydro-l,l-dioxo-5-phenyl-l,4-benzot>jazepin-8-yi-dihydrogcn phosphate, (+-)-Trans-3-Butyl-3-ethyl-2,3,415-tetrahydro-l, l-dioxo-5-phenyl-l,4-benzotiiiazcpLn-8-y! aspartate, and AivitNOtD SHEET (--)-Trzns-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l ,4-beazothiaxepine-7-methanol S,S-cuox:dc, mp 122-123° C (3 R,5R)-3 -butyl-3-cthyl-2,3,4,5-tetrahydro-8-methoxy-7-rutro-5-phenyl-1,4-benzothiaxepine 1,1-dtoxide 0 40 hydrate, mp 122-123° C (+-)-Trans-3-buryl-3-ethyl-2,3,4,5-;etrahydro-8-nriethoxy-7-(methaxyrnethyl)-5-phenyl-1,4-benzothuazepme 1,1-dioxide, mp 118-119° C (+-)-Trajis-7-bromo-3-butyl-3-ethyl-2,3,4,5-tetranydro-5-phenyl-1,4-be.izothiazepm-8-ol 1,1-dioxide 0 40 hydrate, mp 137-138° C (+-)-TrarLS-3-butyl-3-€thyl-2,3,4,5-tetrahydro-7,8,9-u-Lriethoxy-5-pnenyi-l,4-benzothiazcpine 1,1-dioxide, mp 169-170° C (3R,5R}-3-buryl-3-ethyl-2,3,4,5-tetrahydro-5-phenyI-l)4-benzotruazcpin-7,8-diyl diacetate 1,1-dioxide, tnp 79-81° C (8R, 10R)-8-Buty]-8-cthyl-2,3,7,8,9,10-hexahydro-10-1 ,--<uoxono(2,3-H)( 1,4 V benzothiazepme 6,6-dioxide, mp 82° C (3R,5R)-3-birtyl-7,&-diethoxy-2,3,4,5-letrahydw-5-phenyl-1,4-benzothiazepme 1,1 dioxide 0 20 hydrate, mp 110-111° C AMENDED SHEET 333 (—-)-Tr2ns-3-butyi-S-etr.oxy-3-ethy!-2,3,~,5-te:raRydro-f-onenu-1 benzotruazepme 1,1-dioxide, mp 45-54° C (-<--)-Trans-3-outyl-3-cthyl-2,jl4,5-teirahydro-s-(rT".etr.yi:h;oj-i-cr.cv:-: benzothiazepins 1,1 -dioxide hydrochloride, mp 19--1970 C J (+-)-Traas-3-butyl-j-ethyl-2,3,415-tetrahydro-8-'Sopropoxy-5-phenyl-l,4-bcnzothiazepine 1,1-dioxide hydrochlonde, mp 178-181° C (-r-)-Trans-3-butyi-3-e:hyl-2,3,4,5-tetrahydro-5-phenyi-l,4-berj:o;h!azepin-S-caibaldehydc 1,1-dioxide, mp 165-170° C 3,3-DieThyl-2,3,4,5-tetrahycLro-l,l-dioxo-5-phenyl-l,4-ber.zoLxaj:£CLn-8-yi aspartate 3,3-Diethyl-2,3,4,5-tetr2iiydro-7,8-dLrncchcxy-5-phenyl-] ,4-benzothjazepme-l, 1-dioxide, mp 163-164° C 3,3-Diethyl-5-(4-fluorophenyi)-2,j,4,5-ietrahycro-8-me:hoxy-l ,~-benzotmacepine-1,1-dioxide mp 101-103° C 3,3-Diethyl-2,3,4,5-tctrahydro-8-methoxy-5-phenyl- l,4-bcr-zothiaz;D^e-l,l-dioxide, mp 132-133° C 3,3-Diethyi-2,3,4,5-tetrahydro-5-phenyl-l,4-berizothiazepin-4i8-diol-1,1-dioxide, mp 225-227° C (RS)-3,3-Diethyl-2,3>4I5-istrahydro-4-hydroxy-7,8-dunerhoxy-5-phenyI-i,4-bcnzotiuaxcpinc 1,1-dioxide, mp 205-206° C (+-)-Trans-3-butyl-8-eihoxy-3--ethyl-2,3,4,5-tcfj-ahydro-5-phenyl-l,4-bcnzothiaxcptn-4-ol 1,1-dioxide, mp 149-150° C (+-}-Trans-3-butyI-3-cthyl-2,3,4,5-tctr2hydro-8-isopropoxy-5-phenyl-l,4- bcnzothiazcpm-^-ol 1,1-dioxide, mp 109-115° C (+-)-Trans-3-butyl-3-cthyl-2,314,5-tetrahydro-718,9-trLmethoxy-5-phenyl-l,4-bcnzothiazcpm^-ol 1,1-dioxide, mp 84-96° C amended sheet jjy (3R,5R)-3-burvl-3-ethyl-2,3,4,5-'etrahycro-5-pheryi- i, 4-benzo t:i:izs:n-4,3 -••nci-1,1-dioxjcc, mo 215-220° C (->--)-Trans-3-butyI-3-ethyI-2,3,4,5-tetnahydro-4,7,8-tnmcchoxy-5-oneny!-l,4-benzothiazepine 1,1-dioxide, rnp 169-387° C (+-)-Trans-3-butyl-3-ethyl-5-phenyl-2,3,4,5-tetrahydro-71S-cimctnoxy-l ,4-bcnzothiazepin-4-yl acclatc S,S-diox:de, mp 154-156° C 3,3-Diethyl-2,3,415-tetrahydro-5-phenyl-l,4-bcnzothiazepin-8-oll, 1 -dioxide, rnp 177-178° C 3,3-Diethyl-2,3,4,5-tetrahydro-7-Tiethoxy-5-pheny!-1,4-benzoth>azepin-8-ol 1,1- diox:de 3,3-DibutyI-2,3,4,5-tetrahydro-5-phenyi-l,4-benzothiazepm-8-ol 1,1 -dioxide (--)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-l, l-dioxo-5-pheny'-l,4-berLzoLhxazcpin-8-yl hydrogen sulfate, mo 196 5-200°C (+-)-Trans-3-Butyl-3-€thyl-2,3,4,5-tetrahydro-l, l-dioxo-5-pnenyl-l,4-benzothjazcpin-8-yl dihydrogcn phosphate 3,3-DicthyI-2,3,4,5-tctrahydro-l, l-dioxo-5-pncnyl-l ,4-bcnzothiazcDin-8-yihydrogen sulfate 3,3-Dieihyl-2,3,4,5-tetr ahydro-1,1-dioxo-5-phenyl-l,4-benzothi2zepin-8-yldihydrogen phosphate (-r-)-Trans-3-Butyl-3-cthyi-2I3,4,5-tctrahydro-l,l-Gioxo-5-phenyl-l,4-benzothiazepin-8-yl aspartate ^MRiMOFO SHfET 33 S _g The compounds of the formula (I) wherein Rl is a straight crimed Cj.g aiky! group, R2 is a straight chained C;_6 aJkyl group, R3 is hydrogen or a group OR11 in which R^ is hydrogen, oauonaliy substituted Cj.g alley! or a alkylcarbonyl group, R4 is pyndyl or optionally substituted phenyl, R5, R^, R^ and R3 are the same or different and each is selected from hydrogen, halogen, cyano, R^-aceryhde, OR'5, optionally subsututcd C[.$ alkyl, COR15, CH(OH)R15, S(0)nR15, P(0)(0R15)2, OCOR15, OCF3, OCN, SCN, NHCN, CH2OR15, CHO, (CH2)pCN, CONR12R13, (CH^CO^R15, (CH2)pNR12R13, C02R15, NHCOCF3, NHS02R15, OCH2OR15, OCH=CKR15. 0(CH2CH20)nR^, 0(CH2)pS03R15, 0(CH2)pNR12R13 and 0(CH2)pN*Tl12R^-)R^ wherein p is an integer from 1-4, n is an integer from 0-3 andR12, R13, R14 and R15 are independently selected from hydrogen anc optionally substituted C[_£ alkyl, or R^ and R^ arc linked to form a group -O {CR'"R^)m -0 wherein R12 and R^3 arc as hereinbefore defined and m is 1 cr 2, and R^ and R1^ axe the same or different and each is hydrogen or Cj.q alkyl", wth the proviso that when R3 is hydrogen either R^ is not hydrogen or at least two of R5, R^, r" and R^ arc not hydrogen, and salts, solvates and physiologically functional derivatives thereof. N'|-MUcn SHI-F" 33b 1 i ns compounds as n=cr— r-pri zr A-o wrucn are of the formula ( u*) f<\ /p-'io ' ^ , ,R S~J/ n 1 (ID wherein R1 to R^ are as hereinbefore denned and R^a is selected from halogen, cyano, R15-acctyhde, OR15, optionally substituted Cj.g alkyl, COR'5, CH(OH)R15, S(0)nR15, P(0)(0R15)2, OCOR15, OCF3, OCN, SCN, HNCN, CHoOR15, CHO, (CH2)pCN, CONRI2R13, (CH^pCO^15, (CH2)pNR12R13, C02R15, NHCOCF3, NHS02R15, 0CH20R15, OCHCHR15, 0(CH2CH20)nR15, 0(CK2)pS03R!5, 0(CH2)pNRl2R13 ar.d 0(CH2)pN~R12R13R'4 wherein n, p and R^2 to R*5 arc as hereinbefore defined, and salts, solvates or physiologically functional derivatives thereof -8 The compounds as cescnrsl m A-6 4 ^ jj sjc of the formula (EH) ^ A> S^!/ R1 R2 an) wherein R'-R^3 arc asce9cncsi in A-6, and salts, solvates and physiologically functional derivatives thereof 9 The compounds as r^o-r-i'r-Q^ m A-6 which are of the formula (TV) wherein R^-R10 are as cescntsj. m A-6, and salts, solvates and physiologically functionaJ derivatives thereof. .^KJUPD qw-c 33^ LO The compounds as d ^ ;,-5whicn ire of the torrr.uia (I~v a( R R4 (IVa) wherein R^-R^ are as described m A-6 a^d sdts, solvates and phvsioiogicaiiy functional derivatives thereof A-11 The comDounds asdesznzad m A-6 v. herein R' and R2 are straight chained Cj^ alkyl, R^ is hydrogen or hydroxy, R4 is unsubsututed phenyl, R5 is hydrogen, R9 and R10 are both hydrogen, and either R7 is selected from halogen, hydroxy, C 1.5 alkoxy, optionally susstirjtcd Cj.g alkyl, -S(0)nR15, -0C(0)R15, and -CH2OR15 wherein R15 is hydrogen or Cj_6 alkyl; and R^ and R^ arc independently selected from hydrogen and those groups listed in the definition of R', or R8 is hydrogen and R^ and R^ are Linked to form a group -0-(Crt2)m-0- wherein m is 1 or 2, and salts, solvates, and physiologically functional derivatives thereof A-12 A compound according to any of A_g to A_2j_wherem R^ and R7 arc both mcthoxy A-13 A compound selected from the group consisting of. (3R,5R)-3-Butyi-3-cthyl-2,3,4,5-tcrrahydro-7,S-<iunethoxy-5-phenyl-l,4-bcnzothiazcpinc 1,1-dioxide, r ipn jjf (3R,5R)-3-3utyi-3-ethyi-2,3,4,5-[e:rahyaro-T,S-G:lT.c:hoxy-5-Dr.cr.yl-!,-:. benzochiazecin-t-oi 1,1 -dioxide, (_-}-Trans-3-curvi-3-ethyi-21314,5-t£:rahydro-7,3-c;mc:.ioxy-3-Dh=iy-'' ,4. benzothiazrpine 1,1-dioxide, j (--)-Trans-3-buryl-3-cthyl-213,4,5-tetrahydro-7,8-dirReLnoxy-5-phenyI-l,4i-benzothiazepm-4-ol 1,1-dioxide, (3R,5R)-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahycro-8-me:hoxY-5-pheiyl-! ,4-benzothiazepir.e 1,1-dioxide, (3 R,5R}-7-3romo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,--bcnzothiazepm-4-oI 1,1-dioxide, (3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetraLhydro-5-phcnyi-l,4-benzothiazepmc-7 S-dioi 1,1-dioxide, (3R,5R)-3-Butyl-3-€LhyI-2,3,4,5-te^rahycro-8-medioxY-5-ohenyl-1,4-benzothiazepm-7-ol 1,1-dioxide, (3R,5R)-3-3utyl-3-ethyl-2,3,4,5-tetnLhydro-7-methoxy-5-phenyi-l,4-benzothiazepm-8-ol 1,1-dioxide; (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-terrahydro-8-methoxy-5-phenyi-1,4-benzothiazepme 1,1-dioxide, (-i--)-Trans-3-butyl-3-cthyl-2,3,4,5-tctrahydro-5-phenyl-l,4-benzodua2cpin-8-ol 1,1-dioxide, (+-)-Trans-3-buryI-3-cthyl-2I3,4,5-tetrahydro-5-phenyl-l ,4-benzothiazcpmc-4,8-diol, (+-)-Trans-3-butyl-3-cthyl-2,3,4l5-tetrahydro-8-mc:riOxy-5-phenyl-l,4-bcnzothiazepme-7-carbaldehyde 1,1-dioxide; AMENDED SHEET 33 9 (--}-Trziis-2-((3-bur/!-3-c,.hy:-2.3,-1,5-f.ctranyaro-3-Tc,.ncv.'-5-c:r.£r.> i-1,4-oe.nzoth:azccin-7-y|)rr.ctho>r/) cthif.ol S,S-a:ox:de, i fuiis-->- oucyl-j-ciny 1-2, j , 5-ceir an vdro-6-nydr cxvo - p n eny i - i, 4-ber^othiazcpmc-7-carbaidenyde 1,1 -dioxide, (~-)-Trans-3-butyl-3-e:hyI-2,3,4,5-tetnihydrc-5-phcnyl-l,4-berLzochi3L:eptn-8-thiol 1,1-dioxide; (+-)-TrarLS-3-butyi-3-eth>l-2,3,4,5-tetrahydro-5-phsnyl-l,4-benzo:h::u:cpin-8-sulfonic acid 1,1-dioxide, (7R,9R)-7-ButyI-7-e:hyI-617,8,9-tc'J"ahyciro-9-ph=.riyl-l,3-dioxoio(4i5-K)(l,4)-benzothiazcpmc 5,5-dioxide, (+-)-Trans-3 -butyI-3-ethyl-2,3,4,5-tetrahydro-8,9-dimetnoxy-5-phenyl-1,4-benzothiazepme 1,1-dioxide, (3 R,5R)-3-butyl-3-cthyl-5-(4-fluoroDhenyl)-2,3,4,5-t:trihydro-7, S-dL.mcthoxy-1,4-bcnzotiuazpin-4-oI 1,1-dioxide, (+-)-Tnms-3-buryl-3-«hyl-2,3,4,5-tetraiiy(iro-8-.T,ethoxy-5-phcnyl-l,4-benzodmzcpme^-rr.cthanol S,S-dioxide, (3 R,5R}-3-butyl-3-ethyl-2,3,4,5-tetrahydro-S-methoxy-7-rjtro-5-phenyI-1,4-beruothiazrome 1,1-dioxide, (J--)-Tr3xis-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-7-(mcthoxymethyl)-5-phcnyl-l,4-bcnzothiazcpinc 1,1-dioxide, (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-ohenyl-l,4-berizothia2ecin-7,8-diYl diaccute 1,1-dioxide, (8R,10R)-8-Butyl-8-ethyl-2,3,7,8,9110-hex2hyciro-l0-l)4-dioxono(2,3-K)(l,4)-benzothiazcpine 6,6-dioxide, amended sheet 3Hd (3?^5R)-3-butyi-7,3-diethoxy-2,3,~,5-;e:r;ihydro-5-Qr.er,yi-! :, dioxide; (+-)-Trans-3-butyl-8-cthoxy-3-e:hyl-2,3,-,5-tetrahydro-5-phenyl-l,'i-bcnzothiaz:pinc 1,1-dioxide, j (i--)-Trans-3-butyi-3-<thyl-2,3,4,5-tctrahydro-8-isopropoxy-5-phcnyl-l,4-bcnzothiazcpine 1,1-dioxide hydrochioridc, (-r-)-Trin5-3-butyl-3-cthyl-2,3,4,5-tctrahydro-5-DhcnyI-l)4-bcnzocr-.aj:com-8-carbaldehyde 1,1-dioxide, 3,3-Dis:hyl-2,3,4,5-tetrahydro-7,8-dirncLhoxy-5-phenyl-l,4-ber-roch:aj:sBLnc 1,1-dioxidc; 3,3-Diethyl-5-(4-fluoraphenyi)-2,3,4,5-cetrahydro-3-methoxy-l,4-bcnzcthjazepine 1,1-dioxide, 3,3-Diethyl-2,3,4,5-tctrahydro-8-me;hoxy-5-phenyl-1,4-bcnzothiizcpune 1,1-dioxide, 3,3-Diethyl-2,3,4,5-tctrahydro-5-phcnyl-l,4-bcazo:hiazpm-4,8-diol 1,1-dioxide, (TLS)-3,3-Dicthyl-2,3,4,5-tctrahydro-4-hydroxy-7,8-dLmethoxy-5-phcnyl-l,4-benzothiazepme 1,1-dioxide, (+-)-Trans-3-butyl-8-<thoxy-3-ethyl-2,3)4,5-ietrahydro-5-phenyi-l,4-bep.zothiazcpm-4-ol 3,1 -dioxide, (+-)-Trans-3-butyl-3-cthyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-l,4-benzothiazepm-4-ol 1,1-dioxidc, (+-)-Trans-3-butyl-3-cthyl-2,3,4,5-tctrahydro-7,8,9-tamethoxy-5-phcnyl-l,4-bcnzothiazcput-4-ol 1,1-dioxide; (3R,5R)-3-butyI-3-cthyl-2,3,4I5-t«rahydr0-5-phcnyl-l,4-ben20thia2pin-4,7,8-tn0l l.l-dioxide; ''••hWOEQ SHEET 3>u (•*--)-Trar^-3-but\i-3-etnyl-2,3>4,5-tctrzhydro—,'',8-cnme'Lnov/-5-crlc".';i- 1,-i-bcnzothiazcnu-e 1,1 -i'.DXids, (i-)-Traris-3-butyl-3-e'.hyl-5-phenyl-2,3,4,5-?eL'ahydro-7,S-dirncThoxy-l,-i-benzothiazepm-4-yl acetate S,S-<iioxidc, 3,3-Dicthyl-2,3,415-te:rihydro-5-phcnyi-l,4-bcnzothiazepin-8-ol 1,1-dioxide, 3,3-Diethyl-2,3,4,5-tetrahydro-7-mcthoxy-5-phenyl-l,':i-benzothiazepin-8-ol 1 dioxide, 3,3-Dibutyl-2,3,4,5-tetrahydro-5-phenyl-l,4-ber.zoth:3_z:epin-8-o! 1,1-dioxide, (-r-)-Tran£-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-l, l-dioxo-5-ohenyl-l,4-benzothiazepm-8-yi hydrogen sulfate, (--)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-1, l-dioxo-5-pnenyl-1,4-bcnzothiazepin-8-yl dihydrogcn phosphate, 3,3-Diethyl-2,3,4,5-tetrahydro-I, I-dioxo-5-phenyl-I,4-benzothiazepin-8-yl hydrogen sulfate, 3,3-Diethyl-2,3,4,5-tetrahydro-1, l-dioxo-5-phenyl-l,4-bcnzothiax£pm-8-yl dihydrogcn phosphate, (--)-Tran5-3-Butyl-3-ethyl-2,3,4,5-tctrahydro-l,'l-dioxo-5-phenyl-l,4-benzothiazepin-8-yl aspartate; and 3,3 -Diethyl-2,3,4,5-t etrahydro-1,1 -dioxo-5 -phenyl-1,4-beazathiazcpin-8-yi aspartate (3R,5R)-3-Butyi-3-ethyl-2,3,4,5-tetrahydro-7, S-dimethoxy-5-phcny!-I,4-bcazothazcpinc 1,1-dioxide, or a salt, solvate, or physiologically funcnonal derivative thereof. "••iPMOFO 3hz 14 ComDOunds having exceptional hypolipidemic Dropemes include - (-r-)-trans-3-ethyl-2,3,4,5-tetrahydro-3-((2R)-2-hydroxybury l)-5-phenyl-1,4-benzothiazepme 1,1-dioxide, (+-)-trans-l-(3-ethyl-2,3,4,5-tetrariydro-8-mc:hoxy-5-pnenyl-l,4-bc;izothiazcpm-3-yl-2(R)-2-butanol S,S-dioxide, (+-)-trans-1-(3-ethy 1-2,3,4,5-cetrahydro-8-methoxy-5-pneny 1-1,--benzo thiazepin-3-yl)-3-bu:anol S,S-dtoxide; (-r-)-trans-l -(3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-l ,4-benzoihiaz=pin-3-yl)-2(R)-2-butanol S,S-dioxide, (J--)-Lrans-l-(3-ethyi-5-(4-fluoroDhenyl)-2,3,4,5-tetrzhYdro-7-meLhoxy-l,4-benzothiazepin-3-yl)-2(R)-2-butanol S,S-dioxide, (--)-trans-l -(3-ethvl-5-('i-hydroxyphenyl)-2,3,4,5-tetrinydro-l ,4-benzothiazepin-3-yl)-2(R)-2-'outanol S,S-dioxide 0 5 hydrate, AMENDED SHEET 3f2 (--)-trans-3-bur/l-3-eihyl-2,3,415-'etrcuivcro-5-(4-.-.vcroxypasnvi')-l. benzcthiczeome l.l-dicxice hyc;ccn;oncs. (--)-cis-3-ethyi-2,3,4,5-te:rahvdro-3-{--T.d:oxyci:r/,)-5-Dr.env!-l 1,1-dioxide hydrochionce, (-r-)-trans-3-e ihyl-2,3,4,5-tetrahydro-3-(4-hYdroxybur/l )-5-pheny 1-1,4-benzothiazepme 1,1-dioxide; (+-)-trans-3-butyl-3-ethyl-2,3I4,5-tetrahydro-"-hydroxy-5-pher.yl-i)4-benzothiazepme 1,1 dioxide, (-r-)-trans-l-(3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,--benzothiazepm-3-yl}-4,4,— tnfluoro-(2S)-2-butanol- S,S-aioxide, (--)-trans-l-(3-ethyl-2,3,4,5-teirahydro-7-msthoxy-5-phenyl-l,--benzo th: azeom-3-yl)-4,4,4-tnfluoro-(2S)-2-but2nol-S,S-dioxjdeI (+-)-trans-3-Eihyl-2.3,-,5-tetrahydro-3-(3-hydroxybucyl)-5-phenyl-l,4-benzothiazepme 1,1-dioxide; (+-)-trans-3-Ethyl-2.3,4,5-teLranydro-3-(2(xl)-2-hydroxvbutyl)-5-(':i- hydroxyphenyl)-l ,4-benzothiazepine 1,1-dioxide; (-r-)-trans-l-(S-Ethyl-5-(4-fluorophenyl)-2,3,4,5-teLT2iiydro-l,-- benzothiazepin-3-yl)-2(R)-2-butanol S,S-dioxide, (--)-trans-l-(3-Ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-l,4 benzothi2zspm-3-yl)-4,414-tnfluoro-2(S)-2-butanoi S,S-aioxide, (--)-trans-l-(3-Ethyl-2,3,4,5-tetrahydro-8-metnoxy-5-phenyl-l,4- benzothjazepin-3-yi)-4,4,4-tnfluoro-2(S)-butanol S,S-dioxide, (-1--)-trans-l-(3-ethyl-2,3A5-tetrahydro-7 S-dimsthoxy-5-Dhenyl-l,4-berczothiaze:)in 3-yI-2(R)-2-bucanol S,S dioxide; (+-)-trans-l-(3-Ethyl-2,3,4,5-tetrahydro-7 S-dimethox)0-phenyi-l,4-benzothiazepin-3-yl)-4,4,4-tnfluoro-2-buumol S,S-aioxide; (--)-trans-l-(3-Eihyl-2>j,-15-Letnihydro-7,S-diinethoxy-5-phenyl-l,4-benzothiazspin-3-yI)-3,3,4,4,4-pentafluoro-2-butanol S,S-dioxide, (-r-)- trans-3-((3-ethyl-2,3,4,5-tetrahydro-5-phenyl-3-(-,4,--influoro-2-hydroxybutyl)-l, 4-benzothiazepin-8-yl)oxy)propanesulforuc acid 1, 1-dioxide, (+-)-trans-3-((3-ethyI-2 3,4,5-tetrahydro-3-(2-hydroxyburyl)-5-phenyl-l,4-benzochiazepin-8-yl)oxy)ethyltnmethylammontum iodide 1, 1-dioxide; (-l--)-trans-l-(3-Ethyl-2,3,4,5-tetrahydro-7,8-dieLhox>-5-phenyl-l ,4-benzothiazepin-3-yl)^4 4,<Mrifluoro-2-butinoI S.S-dioxide, (J--)-irans-3-((3-ethyl-2,3.4.5-ieirahydro-5-phenvl-3(<:1,4,4-tnfluoro-2-hydroxybutyl)-1,4-benzoihiazcoin-S-yl)o\y)eihyltnmeihylammomum iodide 1.1-dioxide; 3m (--)-trar.s-3-((3-er.nyi-2,3,-,f-te'J-cjivdro-3-i2-hvc:ox) &uty!)-5-pnery-1 --benzochiazeptn-3-ynoxy)prcc:ar.esjlfc:i:c ac.c I -nicxide, (--)-trans-l-(3-ettvyi-2 3,4,5-:e:nn\dro-7,3-a:i::hoxy-5--n=n>;-! aenzothi2Z£pin-3-v"I)-2-outanol S,5-dioxjce, (--)-trans-l-(3-(2,2,2-tnfiuaro£thyl)-2,3,i,5-terj'ahydro-7,S-d'.msri:oxy-3-phenyl-l,4-beazothiazspin-3-yi)-4,4,4-trinuaro-2-butano I S,S-ctoxicie; 3 (+-)-trans-1 -(3-Ethyl-2,j,4,5-tetrahydro-7,8-dihvdroxy-5-phenyl-1,4-benzothiazcpm-3-yl)-4,4,4-*.nfluoro-2-butanol S,S-dioxide; (—)-trans-1 -(3-emyl-2,3,4,5-tetranydro-7,8-dimethoxy-5-pbenyl-1A-benzothiazepin-3-yl)-l-butanol S,S-dioxiGe, (--)-tr^is-l-(3-E'jiyl-2,3,4,5-tetrahydro-7,S-ciihy(ircxy-5-phsr.yl-l,4-bsnzothiazspm-3-yl)-2-butanol S,S-dioxide; (--)-uans-I-(3-e±yl-2,3,4,5-tecrahydio-8-me,iioxy-5-phenyl-l ,4-berLzothiazspm-3-yl)--,-,4-tnnuoro-l-butanol S,S-dioxide, (--)-Lrans-l-(3-efvhyl-2,3,4)5-tetrahydro-7,8-dihydroxy-5-phsnyl-l,4-benzothiazepm-3-yl)-2-butanone S,S-diox;de, Of the above the following compounds are most preferred - (-f-)-tr2rLS-l-(3-ethyl-5-(4-fluorophenyl)-2,3,4,5-tetx2h>dro-7-methoxy-l,4-benzothiazepin-3-yl)-2(R)-2-'ou:anoI S,S-dioxide, (--)-trans-l-(3-e:hyl-2,3,4,5-tetmhydro-5-phenyI-l,4-benzouuazepin-3-yi)-4,i-tmluoro-(2S)-2-butanol- S,S-dioxide; (-r-)-trans-l -(3-ethyl-2,3,4,5-;.ecrahydro-7-Tie'aioxy-5-pnen\ 1-1,4-benzouuaze:;Li-3-yi)-4,4,4-tnfluoro-(2S)-2-buianoI-S,S-dioxide, (-r-)-txzns-l-(3-Ethyl-2,3,4,5-tetrahydro-8-methoxy-5-pnenyl-l,4-benzo*Juizepin-3-yi)-4,414-tniluoro-2(S)-btiuinol S,"S-dioxide; (-r-)-trans-l-(3-emyl-2,3,-,5-tctrahydro-7,8-dimcthoxy-5-phenyl-!,--benzotrja2epin-3-yl-2(R)-2-butanol S.S dioxide, 3hs (~-)-Xl2HS-2,3,4,5-1 etrahydro-3-mechy l-5-pnenyl-l ,4-benzothiazepine methanol 1,1-dioxide, mp 79-80°C, f—VCis-2.3 ,d,5-1 etrahydro-3-methyl-5-pheny 1-1 ,--benzothjazepu:e-3 methanol 1,1-dioxide hydrochloride 0 25 hydrate mp 222-224°C, (.~-)-±I2ZH~-(3-Butyl-3-ethyl-2 3,-,5-tetrahyaro-l .--benzothiazepino yl)pnenol hydrochionde, mp 234-235°cC(dsc ), T--'>-Tr?.n<;-5-(4-BenzYloxyphenyl'>-3-ethYi-2.j.4.5-tecrahydro-l .4-benzothiazcpLne-3-methanol, mp 138-143°C, r--VTrans-3-Ethyl-2.3.4.5-tetrahvdro-5-phenyl-1.4-ber^zothiapzepme-*. methanol 1.1-dioxide, mp 134-137°C; (—)-Xr2iis-3-Ethyl-2,3,4,5-tetrahydro-3-(3-hyaroxyburyl)-5-phenyl-l ,4 benzodiazepine 1,1 -dioxide, mp 151-155°C, (--)-Cis-3-Ethyl-2.3.4.5-tegahydro-3-butyl-4-hydroxv-5-(3-pyncvl)-l. benzodiazepine 1,1-dioxide, mp 202-205°C, (—)-ClS-r-(3-Butyl-3-ethyl-2,3,4,5-tetrahydro-l,4-ben20thia2epin-5-yl)phenol hydrochionde, mp 236-237°C(dec ); (+-)-Cis-3-Butyl-3-ethy!-2,3,4.5-tetrahydro-5-(4-h>droxyphcnyl)-l,4-benzothiazepine 1,1-dioxide, mp 163-165°C, C+-VCis-3-Ethvl-2.3.4 5-tetrahydro-3-(3-h\ droxvbutyl))-5-pheny 1-1,4-benzothiazepine 1,1-dioxide hydrochionde. mp 206-209°C, (--)-Il2J15-3-Ethyl-2 3 A5-tetrahydro-3-(2(R)-2-hyaroxvoucyl)-5-(4-hydroxyphenvl)-1.4-benzothiazepme 1.1-dioxide, mp 197-198°C, hydroxy pr.enyi)-!,4-benzc:h:2Z£pir;£ !.'-dioxide, mp :73-17?°C, i~-)-Trans-3-Ethyl-2.3.^,5-LsrranyQro-5-pngn\ i-! .--benzo'uKazepineo-methanol, mp 104-10o3C, (--)-Cl£-5-(4-BenzyIoxyphenyi)-3-ethyl-2,3,-,5-tetrahydro-l,4-benzothiazepine-3-methanol, mp 123-12S°C, (+-)-TE2HS-l-(3-Ethyl-5-(4-fluorophcnyl)-2,3,4,5-tetr2hycro-l,4-benzothjazepin-3-yi)-2(R)-2-butanol S,S-dioxide, rr.D 130-132°C, (--VTrans-l-(3-Echy 1-2.3,-.5-tecrahydro-5-pheny 1-1.4-benzothiaze3in-3-yl)-4.d.4-trifluoro-2(R)-2-buiinol S.S-dioxide, rnp !~0-l-5°C, C--VT ran*;-1 -(3-Ethyl-2,3 4, vterrahydro-5-pheny 1-1,--benzo thiazepm-3-yl)^-fluoro-2-(RS)-2-butanol S,S-dioxide 0 50 hydrate, mp 130-147°C, (~-)-Xr2llS-1-(3-Ethyl-2,3,4,5-te:rahydro-5-pheny 1-1,--benzoihi azepm-3-yl)-^,4,'i-tnfluoro-2(S)-2-butanol S,oxide, mp 159-161 °C, (--)-lEHS-l-(3-E:hyl-2.3,4,5-tetranydro-7-meihoxy-5-pnenyl-l,4-beriZothiazeptn-3-vl)-4,4,-i-tniluoro-2(S)-2-butanol S,S-aioxide, mp 168-170°C, ("--VTrans-1 -(3-Ethyl-2,3,4,5-tetrahydro-8-methox>-5-phenyl-l ,4-benzothi2zepin-3-yi)~,-,--tnfiuoro-2(S)-2-butaco! S,S-aioxide, mp 175-179°C, (--)-Trans-l-(3-ethyl-2,3,^,5-teLrahydro-7,8-airnethoxy-5-phenyl-l,4-benzotmazepin-3-yl-2(R)-2-butanol S,S-dioxiae, mp 156-157°C, fT-)-Tr3n!;-i-(3-Ethyi-2.3.4,5-tetrahyQro-7.S-QimethoxY-5-phenvl-1.4-benzothiazepm-3-yl)-4,4,4-tnfluoro-2-butanol S,S-dioxids, f-^-VTrans-1 -(3-Ethyl-2,3,^,5-tetrahydro-8-rnethoxy-5-Dhenyl-1 /-benzothiazepin-3-yl)-3,3,4,4,4-pentafluoro-2-butanol S,S-dioxide, f--VTrans-1 -(3-Ethyl-2.3.4.5-tetrahydro-7.8-dimethoxv-5-phenvl-l A-benzoth]azepin-3-yl)-3,3,4,4,4-pen,.afluoro-2-buianol S,S-dioxide, (--)-Itans-3-((3-ethyl-2,3.4,5-tetrahydro-5-phenyl-3-(414,4-tnfluoro-2-hydroxybuty 1)-1.4-benzothiazeom-7-yl)oxy)propanesu!fonic ac;d 1,1-dioxide, C--V I ranc-3-<'C3-ethyl-2.3.4.5-tetrah>dro-5-phenvl-3-('4.4.4-tnfluoro-2- J?7- h>aroxyoc:yl)-! --ber-Zomiizeom-S-vl)ox>jprocanecuifcruc cic-.c i,l-c,cx:c f--)-Tran<i-3-((3-ethyl-2.3 ~.>ietrahydro-3-(2-hyaroxy cur/!)-5-nhervi-i ,i-berLZCthja2eD;n-7-y!)oxv)e'ak".vitr,rnethylamrr.oni,^.-n 'cd'de 1, l-c:cx.ce, f—)-Trans-3-ff3-ethyl-2.3AS-tetrahvdro-S-Q-hvdror/sur/IVj-nhgnyl-' 4-bsnzoth:a2£p;n-8-yI)oxy)euiyitnmetnylaminoruuTi .odide 1,1 -dioxiae, (,--VTrans-l-(3-EthvI-2.3.4.5-t£trahvdro-7.8-diethox7^-5-Dhenvl-l.— beazothiaz£pin-3-yl)-4,-,--tnfluoro-2-buianol S,S-dtoxice, (+-)-Iraa5-3-((3-eLhyl-2,3,4,5-teLrahydro-5-pheny!-3(-,-,^-tniluoro-2-hydroxybutyl)-l,4-benzothiazepin-7-yl)oxy)ethyitrirriemyi2irjxioriiurn iodic 1,1-dioxide (~-)-Trans-3-f(3-eth> 1-2.3 A5-tetrahvdro-5-pfaeriyi-3f4 A4-tn fluoro-2-hyaroxyburyi)-l Abe^othiazcpin-8-yl)oxy)er.hyitru'neihyl2iimonium lodid 1,1-dioxias, (--)-Il2nS-3-((3-ethyi-2,3,-,5-tetrahydro-3-(2-h>aroxybutyl)-5-pheayl-l,--benzothiazepm-8-yl)oxy)propaiiesulforuc acid 1,1-dioxide, (T-)-]j£iLi-3-((3-e:hyl-2,3 A5-f.etrahydro-3-(2-hydroxybucy!)-5-phenyl-l A berizothi2Zspm-7-yl)oxy)propancsulfonic acid 1,1 -dioxide, (^-Irans-1-(3-ethyl-2,3,4,5-ietrahvdro-7,S-diethoxy-5-pnenyl-1,4-benzothiazepin-3-yl)-2-butanol S,S-dioxide; (--)-Ican5-l-(3-(2.2,2-trifluoroethyl)-2,3,4,5-tccranydro-7,S-diineihoxy-5-phcnyl-1,4-ben20thia2:pin-3-yl)-4,4,4-5ifluoro-2-ouianol S,S-dioxide, (--)-Xl3J15-l-(3-(2,2,2-tnn'Joroethyl)-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1 /-benzothiazepm-3-yl)-^1,£l,-i-L'ifl,Joro-2zbucanol S,S-d:oxids, (~-)-Tran'i-l-(3-Ethyl-2.3.4.5-tetiahvdro-9-meTiioxv-5-ohenYl-1.4-bcnzothiazspin-j-ylJA.^.i-cnfluoro^-butanol S,S-dioxide; (■"•-)-]lE2HS-l-(3-ethyl-2,3A5-;etrahydio-9-meLhoxy-5-phcnyl-l A benzothiazepin-3-yl)-2-butanol S,S-dioxide; (-r--)-Trans-l-f3-Ethyl-2,3.4.5-teirahydro-7.8-dihydroxy-5-phenyl-i,--benzothiazepin-3-yl)-414,4-tnfluoro-2-butanol S,S-dioxide, (+-)-Xl2H5-l-(3-ethyl-2.3.4.5-tetrahydro-8-methoxy-5-phenyl-l A benzothiazeptn-3-yl)-l-buianol S.S-dioxide, 3^ f-r-VT r?.rr:-1 -i'3-s:hy!-2.3,-,5-iiL-ahycro-7,3-c.icr.eii~ox;. -f-pncnyi-' b z nco itl zz z p i a ■- 3 - y i) ■-- c u: zr.;: S, 3 - c: o x; c c, '--%>\iI22£-t-(3-Eth\ 1-2.3 - :-*srahvcr'!-7,3-dihyd:3 w-f-^hsr/ !-l beazomiaz2pin-3-yi)-2-out2noi S,S-dioxids, (-i--)-Trans-l-{3-e[nyl-2,3,-1,5-tetr3iiydro-8-memox>-5-pheayl-l,4-benzathiazspin-S-yi^pAtnfluoro-l-but&riol S,S-ciox:ds; (+-)-Trans-l-(3-ethyl-2,3,4,5-:etrahydro-7,S-diir.eihoxy-5-phcnyl-l, oenzomiazepm-3-yl)-4,4,'i-trifluoro-l-buiaiiol S,S-a:oxiae f~-VTr?.ns-l-f 3-£Lhyl-2.3.-.5-t£Lrahvdro-7.8-CLiivdrQX\-5-phenyl-1, benzouuazspm-3-y[)-2-butanons S,S-dioxide A-15 A compound of formula (II 1 is an integer of from 0 to % n is an integer of from 0 to 2, R is an atom or group selected from halogen, cyano, hydroxy, rutro, alkyl, alkoxy, aryi, heteroaryl, aryloxy, arylalkoxy, araikyl, aikar/1, -0(CH2)pS03R1!, -0(CK2)pNR11R12, -0(CH2)pN-R11R12RI4, -COR11, -C02R11, -CONRl'lR12, -CH2ORl 1, -NR1W, -NHCOR11, -NHSO2R1-SR1!, -SO2R1 \ -SO2NR1 *R12 and -SO3R11 or R is a group -OCK2O- whicn forms a further nng attached to X wherein p is an integer of from 1 to 4, R11 R12 are independently selected from hydrogen, Cj.g alkyl and phenyl and R14 is hydrogen or Ci .5 alkyl, wherein said alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, araikyl and alkaryl grouos are optionally substituted b> one or more atoms or grouos selected from halogen, hydroxy, rutro, mtnie, alkyl, alkoxy, -COR11, -CO2R11, -SO3R11 wnerein R11 is as hereinbefore defined and -NR14R1:) wherein R14 is as hereinbefore defined and R1:> is hydrogen or Cj.g alkyl R1 is hydrogen or C 1.5 aJkyl, R2 is an atom or group selected from hydrogen, Cj.5 alkyl (including cycloalkyl and cycloaikyialkyl), Cj_4 alkoxy, pynyl, thienyl, pyr.dyl, 1,3-benzodioxolo, phenyl and naphthyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, cyano, hydroxy, nitro, carboxyl, phenyl, pnenoxy, benzvloxy, -COR1 1, -CO2R1-CONR1 'R12, -CH2OR1 -NR11R12. -NHCOR11, -NHS02Rn, -SR11, -SO2R11, -SO3R11 (wherein R11 and R12 are as hereinbefore defined), -OCHt)dNR1 'R12, -O(CH-j) N^R1 JR^R1^ " H " P 3Z0 and -O(CH-j) SO*:?.11 ; v,r.e:e:n o, R1 112 R1- are as here'.r.oefcre cefmec. arc d ' R1 J is nvcrogen or C, .5 2.1 kyl), is hydrogen. hvcrox; C, _q cll~\, aikoxy 0: -Q-C (.5 Acy t, R4 is a group independently selected from Cj.g aikyl (including c\cioalkyi and cycloaikyialkyl), C2_£ alkenyl, and Ci-S alkynyl, which groups are optionally substituted by one or mors atoms or groups independently selected from halogen, oxo, -OR*4, -C02R14, -NR14Ri5, -SR14, -S(0)C1.6 alkyl, -S02R14 and -SO3R14 (wherein R14 and R1:> are as hereinbefore defined ); R5 is a group independently selected from C2.g alkyl (including cycloalkyl ana cycloaikyialkyl), C2_5 alkenyl and C-2-6 alkynyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, oxo, -OR14, -C02R14, -NR14R15, -SR14, -S(0)Ci_6 alkyl, -S02R14 and -SO3R14 (wherein R14 and R15 are as hereinbefore defined), or R4 and R5, together with the carbon atom to which they are attached, form a C3.7 spiro cycloalkyl group which is optionally substituted by one or more atoms or groups independently selected from halogen, -OR14, -C02R14, -SO3R14 and -NR14R15 (wnerein R14 and R15 are as hereinbefore defined), R° and P? are independently selected from hydrogen and Cj.g alkyl, and X is an aromatic or non-aromatic monocyclic or bicychc ring system having from 5 to 10 carbon atoms (including the two carbon atoms forming part of the thiazepine ring) wherein optionally one or more of the caroon atoms is/are replaced by heteroatom(s) independently selected from nitrogen, oxygen and sulphur; with the proviso that at least one of R. R-, R4 and R^ is hydroxy or a group containing hydroxy; and salts, solvates and pnysiologicallv functional derivatives thereof -16 A compound as r^cmhFri in A-15 wherein. AMENDED SHEET 3&/f 1 is 0, i, or 2, n is 1 or 2, and R1, R° and R7 are all hydrogen; and j r^ is hydrogen or hydroxy A-17 A compound as described in A-15which is a trans isomer wherein (a) 1 is 0 or 1; n is 2, and R4 and R5 are grouos independently selected from Cj_6 alkyl (including cycloalkyl and cycloaikyialkyl), C2.5 alkenyl and Cj.q alkynyl, wnerein said alkyl, alkenyl, or alkynyl group may be substituted by one or more hydroxy groups, or R4 and R^, together with the carbon atom to which they arc attached, form a C3.7 spiro cycloalkyl group which can be substituted by one or more h> droxy groups, or (b) 1 is 0 or 1, n is 2, R2 is a phenyl group which may be substituted oy one or more atoms or groups independently selected from halogen, cyano, hydroxy, mtxo, carboxyl, phenyl, phenoxy, benzyloxy, -COR11, -CO2R1 ^ -CONR^R12, -CH2OR1 1, -NRnR12, -NHCOR11, -NHSOjR11, -SR11, -SO2R11, -SO3R11 (wherein R11 and R12 arc independently selected from hydrogen, Cj.g alkyl and phenyl), -0(CH2) NRnR12, -0(CH2) NR+ nR12R13 ana -0(CH2) SO3R11 (wherein p is an integer of from 1 to 4, R11 and R12 are as hereinbefore defined and R13 'S hydrogen or C1.5 alkyl), R4 and R^ are groups independently selected from C j .5 alkyl (including cycloalkyl and cycloaikyialkyl), C2-6 alkenyl and Ci.fi alkynyl, wherein said alkyl, alkenyl, or alkynyl group may be substituted by one or more hydroxy groups, or R4 and R^, amended sheet 352 together wth the carcon atom to wmcn "n.cy are attaches, term a C; 7 s-^rc cycloalkyl group v.hicn car. oe sussututea oy or.e cr more nyorox;. erouos, or (c) 1 ;s 0 or i n is 2; R2 is a phenyl group which may be substituted by one cr more atoms or groucs independently selected from halogen, cyano, hydroxy, rutro, carooxyl, pnen>l, phenoxy, benzyloxv, -COR11, -CO2R1!, -CONR11R12, -CH2ORl1. -NRI!R12, -NHCOR11, -NHSO2R1-SR11, -S02R!1, -SO3R1-1 (unerem R11 and R12 are independently selected from hydrogen, C|_g alkyl and phenyl), - 0(CH2) NRnR12.-0(CH2) NR" nRi2R13 and -0(CH2) SO3R11 (therein p is P ^ 1 1 "? P 1 an integer of from 1 to 4, R'1 and R1^ are as hereinbefore defined and Rlj is hydrogen or C j .5 alkyl), R4 and are groups independently selected from C]_g alky! (including cycloalkyl and cycloaikyialkyl), C2_£ alkenyl and C7.5 alkynyl, v/ruch groups can be substiruted by one or more hydroxy groups; and X is a fused phenyl, naphthyl, pyrcyl, thisnyl, or pyndvl group, A-18 A compound as recr-rVrpH m a-13vhich is (--)-trans-3-ethy 1-2,3 ."i,5-tetrahydro-3-((2R)-2-hyarox> butyl)-5-phenyl-l,--benzothiazepine 1,1-dioxide; (+-)-trans-l-(3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l,--'benzothiazepLn-3-yl-2(R)-2-butanol S.S-dioxide; (—-)-trans-l-(3-e thy 1-2,3,4,5-tetrahydro-8-mstho xy-5-phenyl-1 ,,i-benzothiazeDin-3-yl)-3-'outanol S,S-dioxide; (-f--)-trans-l-(3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-l,4-benzothiazepin-3-yl)-2(R)-2-butanol S,S-dioxide; (--)-trans-l-(3-ethyl-5-(4-fluorophenyl)-2,3,4,5-tetranydro-7-methoxy-l,4-benzothiazepm-3-yl)-2(R)-2-butanol S,S-dioxide; (--)-trans-l-(3-eth>l-5-(4-hydroxvphenyl)-2,3,4,5-tetrahydro-l,4-benzothia2e3in-3-vl)-2(R)-2-butanol S.S-dioxide 0 5 hydrate; AMENDED SHE£' 3 5^3 t,--)-trans-3-buryi-3-ethyi-2.3,- 5-reranvc:o-5-(--"i\c::)xypreriy1'',- i ^cru.ouiiine i, 1 -cuoxice n>cxocr.ioncc, (--)-cis-3-ethyl-2,3,4,5-teLnnycro-3-Ahyc:ox)bu7y i)-5-pr.er.yi- < csnzoihiaccpm: 1,1 -dioxias h;uroch:onde. (+-)-trans-3-ethyl-2,3,4,5-teirahydro-3-(--hydrox>butyl)-5-chsnyi-i,4-benzothiazeptne 1,1-dioxide; . (—)-trans-3-butyl-3-ethyl-2,3,4,5-teuahydro-7-hydroxy-5-pheny 1-1,4.-benzothiazepine 1,1 dioxide, (--)-trans-l-(3-ethyl-2,3,4.5-teuznydro-5-phenyi-l ,4-benzothiazepin-3-yl)-4,4,4-tnfmoro-(2S)-2-butanol- S,S-dioxids, (--)-trans-1 -(3-ethyl-2,3,4, 5-tetrihyc^-o-7-rnethoxy-5-pheny!-1,4-benzothizzeom-yl)-4,4,4-tnfluoro-(2S)-2-butanol-S,S-dioxide, (~-)-trans-3-Ethyl-2,3,4,5-tetranydro-3-(3-hydroxyouty l)-5-phenyl-1,4-benzothiazepine 1,1-dioxide; (+-)-trans-3-Ethyl-2,3,4,5-tetnLhydro-3-(2(R)-2-hydroxvbuty!)-5-(--hydroxyphcny 1)-1,4-benzothiazepme 1,1 -dioxide; (~-)-trans-1 -(3-Ethyl-5-(4-fluorophenyl)-2.3,4,5-tetrahydro-1,4-benzothiazepm-3-yl)-2(R)-2-bucanol S.S-dioxide, (+-)-lrans-l-(3-Ethyl-2,3 A5-te:rahydro-7-methoxy-5-phen>l-l,4 benzothiazepin-3-yl)-4,-,--tnfluoro-2(S)-2-but2nol S,S-dioxide, (J--)-trans-l-(3-Ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benxothiazepin-3-yIM,4,':!"tniluoro-2(S)-buano! S,S-dioxide, (-r-)-trans-l-(3-ethyl-23,4,5-tetrahydro-7.8-dimethoxy-5-phenyl-l, 4-benzothiazepin-3-yi-2(R)-2-butanol S,S dioxide; (—)-trans-l-(3-Ethyl-2,3,4,5-tetrahydro-7,S-dimethox>-5-phenyl-1,--benzothiazepin-3-yl)-4,4,4-trifluoro-2-but:inal S,S-dioxide, (--)-traiLS-l-(3-Ethyl-2,3,4,5-cetiahydro-7 8-duneihoxy-5-phenyl-l,4-benzothiazepin-3-yl)-3,3,4 4i4-pentafluoro-2-butanol S S-dioxide; (->--)- trans-3-((3-ethyl-2,3,4,5-tetrahydro-5-phenyl-3-(-,-,4-tnfluoro-2-hvdroxybutyl)-l, 4-benzothaazepin-8-yl)o\y)propanesuifomc acid 1, 1-dioxide; (+-)-trans-3-((3-ethyl-2,3,4,5-tetrahydro-3-(2-hydroxybutyI)-5-phenyl-l,4-benzoihi22cpm-8-yl)oxy)eihyltnmcthylammoniuni loaids 1, 1-dioxide, (+-)-tnms-l-(3-Ethyl-2,3,4,5-tetrahvdro-7.S-diethoxy-5-phenyl-l,4-benzothiazepin-3-vl)-4 4,4-trifluoro-2-butcnol S,S-dioxide, (+-)-trans-3-((3-ethy 1-2.3,4.5-tetrahvdro-5-pheny 1-3(4,-,4-tn fluoro-2-hydroxybutyl)-1.4-benzothiazepin-3-yl)o\v )ethyknmeth> lammomum iodide 1.1-dioxide; •MKNOtD v<tc 3St (--}-trans-3-((3-ethyl-2,3,-,5-fe!r£nyaro-3-(I-h\cr0\\ourv'O-5-Dnenv!-i,-i-benzoL"uazepin-3-yl)oxy)propanesuIfo:uc acid 1,1 -dioxide, )-*rar.s-i-(3-ethyl-2,3,4,5-tctrahycro-7.8-dietnox>-5-Dheny 1-1 ,~-beriZoUiiazepin-j-yi^Z-buiancl S,S-aicxide, (--)-traas-l-(3-(2,2,2-tnfluoroeihyl)-2,3,'i,5-tetnihydro-7,8-<iiiTLethoxy-5-phenyl-1,4-benzothia2cpin-3'syl)-:t,4,4-tnfluoro-2-butaiiol S,S-dioxide; trans-l-(3-Ethy!-2,3,4,5-tetrahydro-7,8-dihydroxy-5-pheay I-1,4-'oenzothiazepin-3-yl)-4,4,4-tnfluoro-2-butanol S,S-dioxide; (T-)-trans-l-(3-ethyl-2,3,4,5-tetrahydro-7,8-dtmethoxy-5-phenyl-l,4-benzothiazepm-3-yl)-l-butanol S.S-dioxide; (--)-tr ans-1-(3-Ethyl-2,3,4,5-tetrar.ydro-7,8-dinydroxyo-pheayl-1 ,— benzo thiazcpm-3-yl)-2-butanol S,S-dioxide; (-r-)-trans-l-(3-ethyl-2,3,4,5-tetrahydro-8-msthoxy-5-phenyl-l,4-benzothiazepin-3-Yl)-4,4,4-tnfluoro-l-butanol S,S-dioxide, or (--)-trans-l-(3-ethyi-2,3,4,5-tetrahydro-7,S-dLhyaroxy-5-phenyl-l,--benzothiazcpm-3-yl)-2-butanone S,S-dioxide 19 A compound as descnbHi an A-15of the formula (la) 1 is an integer of from 0 to 4; n is an integer of from 0 to 2; R is an atom or group selected from halogen, cyano, hydroxy, nitro, alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, araikyl, aikaryl, -COR11, -CO2R11, -CONRnR12, -CH20R11, -NR1!R12, -NHCOR11, -NHSO2R11, -SR11, -SO7R11 and -SO3R11 wherein R11 and R12 are independently selected from hydrogen, Cj.g alk\l and phenyl, wherein said alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, araikyl and aikaryl groups arc ODtionallv substituted by one or more atoms or groups selected from halogen, hydroxy, nitro, nitnle, alkyl, alkoxy, -COR11, -CO2R11, - n'-MI .'rO "FfF 3SS SO3R11 wnerein R11 is as hc-e:nbc:ore defined arid -NR^pJ- wnerein p.'" anc R-- are as hereinbefore dennea, is hydrogen or Cj.g aikyi, R2 is an atom or group selected from hydrogen, Cj.g alkyl (including cycloaJkyl and cycloaikyialkyl), C i_4 alkoxy, pyrryl, thienyl, pyridyl, 1,3-fcenzodioxolo, phenyl anc naphthyl, which groups arc optionally substituted by one or more atoms or groups independently selected from halogen, cyano, hydroxy, nitro, carboxyi, phenyl, phenoxy, benzyloxy, -COR1!, -CCbR11, -CONR1 iR12, -CH2ORl1, -NH1 5R12, -NHCOR11, -NHSO2R11, -SR11, -SO2R11, -SO3R11 (wnerein R11 and R12 are independendy selected from hydrogen, Cj.5 aikyl and phenyl), -0(CH2) NR11R * -0(CH2) N+R11 R^R13 and -0(CH2) SO3R11 (wnerein p is an integer of from 1 to 4, R1 l^and R12 are as hereinbefore defined and R13 is hydrogen or Cj.g alkyl), R3 is selected from hydrogen, hydroxy and C\.& alkyl; R4 is a group independently selected from Cj.5 aikyl (including cycloalkyl and cycloaikyialkyl), Ci-S alkenyl and C2-6 alkynyl, wruch groups are opaonally substituted by one or more atoms or groups mdenendently selected from halogen, -OR14, -C02R14, -NRl4R15 and -SO3R14 (whe rem R14 and R1^ are independendy selected from hydrogen and Cj .5 alkyl); R^ is a group independently selected from C2.5 alkyl (including cycloalkyl and cycloaikyialkyl), C2-6 alkenyl and C2.6 alkynyl, which groups are opuonallv substituted by one or more atoms or groups independendy selected from halogen, -OR14, -CO?R14, -NR14R1:^ and -SO3R14 (wherein R14 and R15 are independently selected from hydrogen and Cj.g alkyl), or R4 and R^, together with the carbon atom to which they arc attached, form a C3.7 spiro cycloalkyl group which is optionally substituted by one or more atoms or grouos independently selected from halogen, -OR14, -CO2R14, -SO3R14 and -NR^R1^ (where R14 and R1^ are as hereinbefore defined; R^ and R^ are independently selected from hydrogen and C|.g alkyl; 2nd X is an aromatic or non-aromatic monocyclic or bicyclic nng system amended sheet 3£b having from 5 to !0 carbon atoms ('including the caroon atoms fc the thiazepme nng) wherein optionally one or mere of the carbon retraced by heteroatom(:"i nderer.der.U; selected fron nitrogen, oxy wth the proviso tha„ at least one of R, R2, R4 and R3 is hydroxy or a groun containing hydroxy; and salts, solvates and physiologically functional derivatives thereof A-20 A compound of formula (I): a) R- RJ wherein 1 is an integer of from 0 to 4; n is an integer of from 0 to 2, R is an atom or group selected from halogen, cyano_hydroxy, rutro, alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, araikyl, aikaryl, -0(CK2)pS03R1 ^ -0(CH2)pNR11R12, -0(CK2)pN'rRllR12R14> -COR11, -CCbR11, -CONR11R12, -CH2OR11, -NR11R12, -NKCOR1-NHSO2R11, -SR11, -SO^11 -SO-7NR1 iR12 and -SO3R11 or R is a group -0CH2O- which forms a further nng attached to X wherein p is an integer of from 1 to R11 and R12 are independently selected from hydrogen, Cj.g alkyl and phenyl and R14 is hydrogen or Ci_6 alkyl, wherein said alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, araikyl and aikaryl grouos are optionally substituted by one or more atoms or grouos independently selected from halogen, hydroxy, rutro. nitnle, aikyl, alkoxy, -COR.1 *, -COoR1-SO3R11 wherein R11 is as hereinbefore defined and -NR14Rl5 wherein R14 is as hereinbefore defind and R13 is hydrogen or C | .5 alkyl; amended c.hfcc" 35? R.1 ,s hydrogen or C 1.5 aikyl, r2 is 2t. atom or group selected :rcm nyarogen, C\.^ alky! (including cjcioaikvi and cycloaikyialkyl), C]_i aikoxy, pyrryl, thier.vl, pyndyl, 1,3-benzoaioxolo, phenyl ana naphthyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, cyano, hydroxy, nitro, carboxyl, phenyl, phcaoxy, benzyloxy, -COR1 -CO2R1 \ -CONR11R1^j -CH2OR11, -NRnR12, -NHCOR11, -NHSO2R11, -SR11, -S02Rn, -SO3R11 (wherein R11 and R12 arc independently selected from hydrogen, Cj.g aJkyi and phenyl), -0(CH2) NR'^R1-, -0(CH2) N~RllR12R13 and-0(CK2) SO3R11 (wnerein p :s ^ P T 1 0 P ~ I"1 an integer of from 1 to 4, R-1 and R1- are as hereinbefore deimed and RlJ is hydrogen or Cj.g alkyl), R3 is hydrogen, hydroxy C].5 alkyl, alkoxy or -O-Cj.^ Acyl, R4 is a group independently selected from Cj.g aikyl (including cycloalkyl and cycloaikyialkyl), C2-6 alkenyl and C9.5 aikynvl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, oxo, -OR14, -C02R14, -NR14R15, -SR14, -3(0)^.6 aikyl, -S02R14 and -SO3R14 (wherein R14 and R13 ore as hereinbefore defined), R3 is a group independently selected from C2-6 alkvl (including cycloalkyl and cycloaikyialkyl), C?_5 alkenyl and C2.g alkynyl, wtuch groups are optionally suostituted by one or more atoms or groups independently selected from halogen, oxo, -OR14, -C02R14, -NR14R15, -SR14,-S(0)C1_6 alkyl, -S02R14 and -SO3R1-(wherein R14 and R13 are as hereinbefore defined), ~ or R4 and R3, together with the carbon atom to which they are attached, form a C3.7 spiro cycloalkyl grouD which is optionally substituted by one or more atoms or groups independently selected from halogen, -OR14, -CO2R14, -SO3R14 and -NR14Rl3 (where R14 and Rl3 are as hereinbefore defined, and R^ are independently selected from hydrogen ana C[_6 alkyl, and X is an aromatic or non-aromatic monocyclic or bicyclic ring system amended sheet 3SS having from 5 to 10 carbon atoms (including the two carbon atoms forming part of the thiazepine ring) wherein optionally one or more of the carbon atoms is/are replaced by heteroatom(s) independently selected from nitrogen, oxygen and sulphur; with the proviso that at least one of R, R2, R4 and R^ is hydroxy or a group containing hydroxy; and salts, solvates and physiologically functional denvatives thereof, for use in the prophvlaxis or treatment of clinical conditions for which a bile acid uptake inhibitor in indicated. amended sheet. 3^ A-21 Compounds of formula (I) having exceptional hypohpicaemic orooeraes include - (-)-(RP.)-3-butyl-3-ethyi-2,3,4,5-tetrahydro-5-phcnyl-l,4-beiizatniazepine i .i-dioxiae, (--)-trans-3-((E)-2-butcny])-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,4-berizothiazepinel,l-dioxide, 3 (-r-)-tr2ns-3-ethyl-2.3,4,5-tecrahydro-3-(3-methoxypropyi)-5-pr.enyl-l,4-beru:oth:2zep:ne 1,1-dioxide; (--)-trans-l-(3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,4~benzothi£zepin-3-yI)-2-but2noi:eS,S-dioxide; (-r-)-ttans-l-(3-edvl-2,3,4,5-tetrahydro-S-rnethoxy-5-phenvi-l,--benzotiuazepm-3-yi)-2-butanonc S,S-dioxide hydrochloride 1 1 hydrate, (~-)-trans-3-(l -butenyl^-ethyl^JAf-tetrahvdro-S-pheny 1-1,4-benzothiazepine 1,1 -dioxide hydrochionde 0 4 hydrate; (+-)-trans-3-(ethoxyethyl)-3-ethyl-2,3,4,5-ietrahydro-5-phenyl-l ,~-'oenzothiazepinel ,1-dioxide hydrochionde hemihycirate, (+-)-trans-3-(ethoxymethyl)-3-eihyl-2,3>4,5-tetr2hydro-5-phcnyl-l,4-benzothiazepinel,l-dioxide hydrochionde; (~-)-trans-ethyl 3-(3-ethyl-2,3,4,5-tetrahyQro-5-phenyl-l ,4-bcn20thja2epin-3->l)propionate 1,1-dioxide, (+-)-trarLS-(E)-4-(3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,ll-ben2othiazcDLn-3-yl)-3-buten-2-one 1,1-dioxide, (+-)-2,3,4,5-tetrahydro-8-methoxy-5-Dhenylspiro(I,4-benzothia2epune-3,l-cyclohexane) 1,1-dioxide; (--)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydra-5-(4-pyridyl)-l,4-bsazoth:azepme 1,1-dioxide; (--)-trans-3-buryl-3-ethyi-2,3 4,5-tetrahyaro-4-hydroxy-5-('i-pynd>l)-l,4-bcEi2othiazspmc 1,1-dioxide; (J--)-trans-3-butyl-3-ethyl-2,3)4,5-tetrahydro-5-(2-thienyi)-l,~-benzotliiaz5pine 1,1-dioxide; (a--)-trarLS-3-buryl-3-ethyl-2,3,4,5-tctrzhyciro-5-( 1 H-pyrrol-1-yl)-l ,4-benzothiazepine 1,1 -dioxide; (--)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenylpyndo(4,3-F)-1,4-berrzothiazcpme 1,1-dioxide; (+-)-trans-3-butyl-3-ethyI-3.4,5,7-tetrahydro-5-phenyl-2H-pyrroio(3,4-F)-l,4-benzothisLzeoine 1.1 -dioxide 0.1 hydrate, (+-)-trans-3-butyl-3-ethyl-2.3,4.5-tetrahydro-5-phcnylthieno(2.3-F)-l ,4-benzothja2epins 1,1-dioxide; ^mended shefr 3 to (—-)-*-rar.s-3-ethy!-2.3,-1,5-tetrahydro-5-p.ier.;-1-j-v-.-.-l-'riniiorociiiiYl}-'; i, I-dioxide, (—-)-trans-2.3,-.5-rsirahyc.ro-3-isoprooy!-3-meihy!-5-pneay!-1 4-benzotni2zs3ins i,;-dicxide 0 25 K2O, (+-)-trans-3-((E)-2-Butenyl)-3-ethyl-2,3,4.5-teLrahydro-5-phcnyl-l ,4-benzothiaze::mc: (+-)-Cis-2.3,415-Tetrahydro-3-isopropyl-3-methyl-5-Dnenyl-l,4-benzothiazepme 1,1-dtoxioe 0 66 H20; (+-)-trans-3-(3-Ethyl-2,3,4,5-tearahydro-5-phenyl-l ,4-ber.zothjazepin-3-yl)propanol 1,1 dioxide, (+-)-trans-3-Eihyl-5-(4-Fluorophcnyl)-2,3,ii,5-tetrahydro-7-metho>'y-3-(3-methoxypropyl)-1,4-benzothiazepine 1,1-dioxide hydrochiond:, (--)-2,3,4.5-Teirahyaro-7-methoxy-5-pher.ylsairo(l,4-berjzoihia2£cine-3,l-cyciohexar.:) 1,1-dioxide, (--)-crans-l-(3-Ethy 1-2.3,^,5-tetrah%dro-7-nns,JioxY-5-ph:nyl-l,--bep^othiazspm-3-yl)-2-butanonc S,S-dioxide hydrochionde, (--)- trans-3-butyl-3-ethyl-2,3I4,5-ietrah)dro-5-ph:nylnaphtho(3,2-F)-1.4-benzothia2£pinc 1,1-dioxide, (--)-trans-l-(3-Eihyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phcnyl-l,4-be:izouuaz£pifl-3-yi)- 2-butanone S,S-dioxide; (J--)-trans-3-(l-butenyl)-3-ethyl-2,3,415-t£trahydro-7,8-d:jnctho\Y-5-phenyl -1 benzothiazepme 1,1-dioxide, (+-)-trans-l-(3-Ethyl-2,3,4,5-tetrahydro-7 S-dunethoxy-5-phenyl-l,4-benzothiazcpin-3-yl)- 3-butanone S.S-dioxide, (--}-trans-l-(3-Ethyl-2,3,~,5-tetrahydio-8-me:hoxY-5-phcnyI-l ,4-benzoth:azepin-3-yl)-l-butanonc S,S-dioxide; (-f--)-trans-l-(3-Ethyl-2,3,-:1,5-tec-ahycro-7,8-diracthoxy-5-phcnyl-l ,--ben2othiazcp:n-3-yi)-1-butanonc S.S-dioxidc; (--)-trans-l-(3-eihyl-2,3,4,5-tetrahydro-7,8-dimcthoxy-5-phen> 1-1,4-benzothiazepin-3-yl)-4,4,4-tnfluoro-1 -butanonc S,S-dioxide; (+-}-trans-l-(3-ethyl-2.3,4,5-tetrahydro-7 8-dimethoxy-5-phenyl-l,4-benzothiazcpin-3-yl)-3,3,4,4,4-pentafluoro-2-butanone S,S-dioxide; (--)-trans-l-(3-ethyl-2,3,4,5-tetrahydio-7 S-dimcthoxy-5-pncnyl-l,-i-beiizothiazcpin-3-yl)-4,4,4-tntluoro-2-butanonc S,S-dioxidc; (~-)-trans-3-ethyl-2.314,5-tctrahydro-718-dimethoxy-5-phsnyi-3-(-',4,--tnfluorobutyl)-! ,<*-bsnzothiazcpinc 1,1-dioxide; (+-)-cnms-l -(3-(2.2.2-tnfluoroethyl)-2.3,4,5-ietrahydro-7.8-dimethoxy-5-phenyl-l ,4-benzothiazepin-3-yl)-2-butanonc S.S-dioxide: amended ~ 3u (-r-)-trar.s-!-(3-Ethyi-2,3,-1 5-te::zr.ycro-7 3-dietho\>-5-pher.>!-1.4-benzo;h::izc;::r-3-;^)-2-butanone S.S-dioxide; (—-}-trarLS-3-f(3-e'.hy 1-2,3,•i,5-,e:rar.vd:o-3-{2-oxobu:yi^-5-pner.vi-l ,-i-'osnzotr.:aztoin-S- yl)oxy)prcpanesulfon;c acid 1,1-dioxide, (--)-tRms-2-((3-ethyI-2,3,4,5-tctrahydro-3-(2-oxobutyi)-5-phsnyi-l ,4-b»n2:othi22spin-8-yl)oxy)ethyltnmethylammoruum iodide 1.1-dioxide, (-)-(PJl)-3-butyl-3-ethyi-2,3,4,5-ietrahYGro-5-ph£nyl-'i,--ben2otruazcpL"1e 1,1-dioxide, (-r-)-trens-l-(.3-eLhyl-2,3)4,5-tetrah>dro-8-metho\y-5-pnsnyl-l,--ber^otiuazspm-3-yl)-2-butanone S,S-dioxide hydrochionde 1 1 h>drate; (--)-C:s-2,3,415-Tetrahydro-3-isopropyl-3-methylo-Dnen>l-i,--benzo truazepme 1,1-dioxide 0 66 H20; (T--)-aans-l-(3-Ethyl-2,3,4,5-ietrahyd:o-7,8-dimethoxy-5-phen>I-!,4-benzoth:azepm-3-yl)-2-butanone S,S-dioxide; AMENDED "• zu (--)-2.3,4I5-Tec^nycro-5-Dneny!sDi:o(l ,--benzo;njizeoir.e-3, i'-cyclo'nexane) 1,1-dioxide, mp 177-179°C, (~-)-Xnns-2,3,-.5-terranydro-3-isocrop> l-j-methvlo-phenyl-l ,4-benzounazepme 1.1-dioxide 0 25 HoO, mp 130-132°C, (-)-(S)-2.3,4,5-Tsraiydro-5-phenylspiron,4-benzoth:a2£pine-3,r-cyclohexane) 1,1-dioxide. mp 210-211°C, (-HR)-2,3,4,5-7etrahydro-5-phenyispLro(l,4-be:Lz:othizz:pine-3,r-cyclonexane) 1,1-dioxide, mp 210-21 l°C, f-M-Trans-23 A5-terT^yriro-3-isoprnpyl-3-methyl-5-phenyl-l .4-benzothiazepine hydrocnlonde, mp 211-213°C, f— VCis-2.3.4.5-tetrahyciro-3-isQpropyl-3-mc'iiv 1-5-ohenyl-1 ,<i-benzothiazepme hydrochionde. mD 263-270°C, (-r-V3-sec-Buryl-2.3.4.5-tejahydro-3-methyl-5-phenyl-1.4-beazotinazepine nvarochlonde, mp 202-205°C, (—)-4,5-Dihydro-5-phcnylsoiro(l,4-beiizothia2:ain:-3-(2H),r-cvclopentane) hydrochloride 0 25 H2O, mp 224-226°C, (-r-)-2,3,4,5-TetrahyQro-5-phenylsDiro(l,4-bersoCiua2eoine-3,r-cvclonexane) hydrochionde H2O. mp 167-169°C (eff), (—)-5-(2-Fluorcphenyl)-2.3,4,5-tetmhvdrospiro(lbenzo thiazspine-3 1'-cyclohexane) 1.1-dioxide, mo 160-101 °C, (--VCi^-3-(2.3.4-5-temihvdro-"-methyl-5-o'nenvl-1 --benzothiazeam-yHpropionic acid 1.1-dioxide 0 5 HiO. mp 132-13 3°C, AMENOFD " 363 ( —-)-Ii2HS-H'u~vi 3-(2.3.4 aro-3-T.ethvi-5-or.envi-1 b:n2ouua2coin-3-yl)pronion:at2 !.!-Gi0x:ce. no l-3-:-S°C. 5-chsavl-' ,-i-i21-122°C. (--)-Xiaas-3-((E)-2-Butenyl)-3-eth> 1-2,3 ,-.5-tetranydro-5-pnenyi-l,-i-benzothjazenine, rav 69-74°C, ' 3 f—)-Trens-3-Ethyl-2.3.4 5-ietrahyaro-3-iSopropyl-5-phenyl-l,4-benzothiazepine 1,1 -dioxide, .up 116-118°C, (~-}-Ci5-3-ilQ-3utyl-3-cthyl-2.3,-.5-i:txahydro-5-pheny!-!.— benzothiazepms 1-oxide, mp 91-93°C, (—)-£i5-3-i*c-3utyl-3-ethvl-2.3 - 5-'etrahvdro-5-phenyl-l A-benzothiazeptne 1,1-aioxice. mo 149-151 °C, f--VTr?-ns-3-!so-Butyl-3-ethyl-2.3 4 5-tetrahydro-5-phenyl-l,4-benzothiazepine 1-oxide, mp 92-93°C, (--)-Il2HS-3-^Q-Butyl-3-eihyl-2.3 -,5-ceaahydro-5-pnenyl-l,4-benzothiazcpus; 1,1-dioxide, mp 101-103°C, (--)-Cis-3-Buryl-3-ethyl-2,3,4.5-ter2hydro-5-(3-py7idylV 1,4-benzothiazcpine l,i-dioxide, mo 60-6l°C, (--)-Cis-Ethyl-2.3.4.5-ie;rafaydro-5-phcnyl-1.4-benzoth:azepme-3-carDaidehvde 1,1-dioxide, mp 162-164°C; (--)-C.is-2.3.4.5-Tetranycro-3-isonronyl-3-methvl-5-ohenyl-1.4-ber-zothiazepine 1,1-dioxide 0 66 H2O, rnp 119-120°C, (--VTrar. s-3-Ethy 1-2.3.4. S-tetrahvciro-l-isopropvl-S-pheny 1-1.4-bczzothiaxrpine 1,1-dioxide, mp 121-124°C, (— )-Cis-3-Ethyl-2.3.4.5-ietrahvd-o-j-isoaropvi-5-phenyl-1.4-benzothiazepine 1,1 -dioxide, mp 150-152°C, (~-)-Cl5-3-Buryl-3-ethvl-2.3,4,5-tez2h> dro—-hydroxy-5-(3-pyndyl)-l, benzothiazcpme 1,1-dioxide. mo 202-205°C, {--)-XE2JlS-3-(3-Ethyl-2.3.4,5-teraivdro-5-phenyl-1 --benzothiazcpui->npropanol 1,1-dioxide mp 164-165°C, (--VTnns-3-Ethyl-5-(4-F!uorophen\ 11-2.3.4.5-ietrahvdro-7-Tieihoxv-3 f--VC:s-cthvl 5-{2,3,-,5-cc:rc.T/cro-5-'T.eth\ 1-. be"Cthi2zecm-3-v!)vii;r2r.e 1 -iioxide. rro ' (3-methoxyorco-. il-1 --berjicdi.aze-ir.e i ,.-eicx:ce .v.crcc.iior.ce. -r.c 179-181°C. (^-)-ClS-3-3ur. i-3-e:ny!-2.3 4t5-rS'j-2r.\Grc-5-phsr''io'^do(4 3--)-! — ihiazeome i.l-aiox'ce 0 to M1-^2^C ("r-)-Qli-3 -Bur, !-3-ethyl-2,3,4.5-ie:rahyaro-5-( 1 H-pyrrol- i -y 1)-1,4-benzothiazcpinc l.l-oiox:ae, mp 50-52°C, 3 f-^-VCis-3-3ur/l-3-ethyl-2,3,4 5-teLrahvdro-5-pnenvl-7H-pyrrolo(3,4-F)-1,4-thiazepme 1.1 -dioxide 0 125 HjO, mp 75-77°C, (--)-2.3,4,5-Tetrahydro-7-methoxv-5-pheny!sDiro(l 4-ber.zothiazepmc-3,l-c%c>ohexar.e) l,i-dioxiae. mp i42-143°C, (--)-Iraa5.-l-(3-ELhvi-2.3.4,5-teL-ahydro-7-methoxv-5-onenyl-l,4-benzothiazepLn-3-yl)-2-butanone S,S-dioxide hyarochior.ae, mp i75-176°C, Trans-3-buryl-3-ethyl-2,3,4,5-:e:rahydro-5-phenYinapntno(3 2-F)-1,4-benzotiuazepir.e 1,1-dioxide, mp 128-131 °C, (—)-lEm-3-Bur,'i-3-ethyl-2,3.4 5-ter2hydro-5-(2-pynd>l)-l ,4-benzothiazeptne 1,1-dioxiae, mp 50-53°C, (--)-Inms-3-8uty4-3-ethy!-2,3 4,5-tetrahydro-5-(3-oYr;ayl)-l ,4-benzothiazepme l'.l^dioxiae 0 25 hydrate, mo 153-155°C, (-r--)-Ir2Jis-l-{3-Ethyl-2.3 4i5-tstxahycro-7,8-dimeri:ox>'-5-phenyl-l,— benzothiazepm-3-yl)-2-butanone S,S-dioxide, mp 142-146° C, (--)-Il2llS-3-(l-butenyl)-3-ethvl-2,3,4,5-tetrahydro-8-methox> -5-pheayl -1,4-beazotruazepme 1,1-aioxide (~-)-Xi2^2-3-(l-bvncnyi)-3-ethyl-2,3,4 5-tetrahydro-7,8-dimethoxy-5-phenyl -1,4-benzoihiazeDuce 1,1-aioxide f-r- VTirns-l -(3-Ethyl-2-3.4.5-ferahvdro-8-methoxv-5-Dhenvl-1.4-benzothiazcpui-5-yl)-3-'outanone S,S-dioxide r+-VTr?.ns-l-(3-Ethyl-2-3 4i5-tetr2hyd:o-7,8-dur.etaoxv-5-phenyl-1.4-benzothiazepin-3-yl)-3-but2nor.e S.S-dioxide (~-)-Tr?.ns-1 -(3-Ethvl-2.3 4.5-tet^ahydro-8-metho\^-5-ohenvl-l,4-benzotruazeptn-3-yl)-l-butanone S.S-dioxide (-^-)-Trans-1-(3-E[hyl-2," 4.5-tecrahyaro-7.3-dimethoxv-5-ohenyl-l .4- ameuded sheet cenzothiazepin-j-yiVl-butanone 5.S-d:o\:ce f--)-Trans-l-G-etnyl-2.3 4J-'ecrihvc."o-8-rne:r,ov.'-;-ohs"''-1-' benzothjazeptn-3-yi)— - 4-tr.nuoro-l-butanone S S-diox:de (--)-Traas-l-(3-ethyl-2.3A5-re::ar.Ydro-7,8-airr.etr.cxy-3-::her.v!-I.4-benzothiazeptn-3-yl)-4.4.4-tnrluoro-!-butanone S.S-d:oxide (—)-Trans-l-(3-ethvi-2,3,4?5-te!raiyciro-7,S-dLmethoxy-5-pheny[-l,4-benzothi22epin-3-yl)-3,3,4,4,—pentafluoro-2-butanone S,S-dioxide (—)-Trans-l-(3-ethyl-2.3,4,5-tetrahydro-8-methoxy-5-phenyl-l,4-bcnzothiazepm-S-yO-S^,4^ 4-per.iafluoro-2-butar.one S,S-dioxide (-r-)-Trans-l-(3-ethyl-2.3,;1-,5-tetrahydro-7,S-d!methoxy-5-phenyi-I,4-benzothj2z^pin-3-yl)-4 ~,~mf]uoro-2-butanor.e S,S-<l<oxids (--)-Tr24is-l-(3-ethyl-2.3A5-'etrahvdro-8-rnethoxyo-pnenyI-l ,4-benzothiazcpin-3-yl)-4.414-tnfluoro-2-bui2none S,S-dioxide (+-)-Trans-3-ethyl-2,3,4,5-tetrahvdro-8-methoxy-5-phenyl-3-(4,4, 4-cnfluorobutyl)-1,4-benzothiazepinc 1,1 -dioxide (--)-Trans-3-ethyl-2,3,4,5-te:r2hv<iro-7,8-dimethoxy-5-pnenyl-3-(4 4, 4-tnfluorobutyl)-l,4-benzothiazepuie 1,1-dioxide (--)-Inins-1 -(3-(22--cnfluoroethvl)-2,3,4,5-tenzhydro-8-methoxy-5 -phenyl-1,4- benzothiazepin-3-yl)-2-butanone S,S-oioxide (-r-)-T£3H5-l-(3-(2.2,2-tniluoroethyl)-2.3,4,5-;etrahydro-7 S-dimethoxy-5-pncnyl-1,4- beazothiazepLn.-3-yl)-2-butanor.e S.S-dioxide (-r-)-Tj2m-l-(3-Ethyl-2,3,4,5-tec2hydro-9-methoxy-5-pnenyl-l,4-ben20thiazepin-3-yl)-2-outar.oce S,S-dioxide (+-)-Trans-3-((3-ethyl-2.3,4,5-tettahyQro-3-(2-oxobu^,l)-5-phenyl-l,4-benzothiazepin-7-yl)oxy)propanesulfonic acid 1,1-aioxide (+-)-Ir2EL2-l-(3-Ethyl-2.3,4,5-tetrahydro-7,S-diethox-v,-5-pheny i-l,4-bcnzothiazepin-3-yI)-2-butanone S.S-dioxide (—)-Isns-l-(3-Ethyl-2.3.4,5-tetrar.vdro-7,8-ciirr.ethoxy—-hydro xv-5-pher.yl-1 .--benzothi2zepin-3-yD-2-butanone S.S-dioxide (-r-)-Trans-3-((3-eihvl-2.3.4,5-teaahydro-3-(2-oxobur/i)-5-pher1vi-l ,4-benzoth.iazepin-8-vl)oxy)propanesulfonic acid l.l-aioxide amended swee' m (--)-Trzr.s-2-Cf3-e:r.vi-2.3.4 5-tcT2TiVcro-3-(2-oxoci:r.'I)-5-ar.sr.vi-' 4. ben2oth:2Zscm-7-yi)oxy)ethyIr.r:cLny!arr^no"ium 'oaics 1 1-aioxice (--)-Trins-2-f(3-ethy1-2,3,4.5-fe'.rahvdro-3-(2-cxocur/i)-:-phsr.v!-I.— b"nzcC;i2Z-u'.r.~S-^cthvi'T'r'i^Lhvi3jnr*icnjiirr. 'OGiGs 1 1 -~"^v >s 'c-iprrj ^PfTC— 3t"? \ compound of formula (I) (O)n 7 T _JU« s K *% V: / R- a) (R)1 r N R- RJ v.ncrein 1 is an integer of from 0 to 4, n is an integer of from 0 to 2; R is an atom or group selected from halogen, cyano, rutro, alley 1, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, araikyl, aikaryl, -0(CH2)DS03R1 ^, -0(CH2)pNRl 1Rl2> -0(CH2)pN-Rl !r12R14, COR1 \ -CO2R11, -CONR1 lR12, -CH2OR11, -NR1 iR12, -NHCOR1!, -NHSO2R11, -SR11, -SOiR1 -S02NR11r12, -SO3R11, wherein p is an integer from 1 to 4, R11 and R12 are independently selected from hydrogen. Cj.g alkyl and phenyl, and R14 is hydrogen or C alkyl, or R is a grouo -OCHoO- which forms a further nng attached to X, wherein said alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, araikyl and aikaryl groups arc optionally substituted by one or more atoms or groups selected from haiogen, nitro, nitnle, aikyl, alkoxy, -COR11, -CCL2?*.11, -SO3R11 wherein R11 is as hereinbefore defined and -NR^R1^ wherein R14 is as hereinbefore defined and R15 is hydrogen or C|.g alkyl; rl is hydrogen or Cj^ aikyi; R2 is an atom or group selected from hydrogen. C[.g alkyl (including cyctcaikM and cycloaikyialkyl), C\_i alkoxy-. pyrryl, thienvl. pynayl, 1,3-benzodioxolo, phenyl and naphthyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, cyano. nitro, carboxyl, phenyl, pnenoxv, benzvloxy, -COR11, -COoR' -CONR11R12, -CHtOR1 1. -NR1 'R12. ju -NHCOR1 K -NKSOiR1 -SR1! -S02R;1 -SO3R1 1 (.^rerein R11 anc R; - ore ^ hereinbefore defined).-Gi'Cr^jrjNR11 R1- -0(CI~t2)o^ R'''R;-R - ar.a -0(CH2)DS03R! 1 (\s herein 0, R1 ' ana R'~ are as hercnoefore defined zr.z R1 J ;s hydrogen or Cj.g alkvi), RJ is hydrogen. OH, Cj.g alkyl. Cj.g alkoxy or -OCi.g acyl, R4 is a group independently selected from Cj.g alkyl (including cycloalkyl and cycloaikyialkyl), C2-6 alkenyl and Ci-S alkynyl, wntch groups are optionally substituted by one or more atoms or groups independently selected from halogen, oxo, CM alkoxy, -C02R14, -NR14R15, -SR141, -S(0)Ci_6 alkyl, -S02Ri4, -SO3R14 (wherein R14 and Rl3 are hereir.oefore denned), R3 is a croup independently selected from C2_5 alkyl (including cycloalk}! ana cycloaikyialkyl), C2-6 alkenyl, and C2-6 alkynyl, which grouos are optionally substituted by one or more atoms or grouos independently selected from halogen, oxo, C]_4 alkoxy, -C02R14, -NR14R15, -SR14, -S(O) Cj.g alkyl, -S02 R14, -SO3R14 (wherein R14 and R^ are hereinbefore defined), or R4 and R3, togetr.er with the carbon atom to which they are attached, form a C3.7 spiro cycloalkyl group which is optionally substituted by one or more atoms or gioups mdependentlv selected from halogen, Cj.g alkoxy, -CO2R14, -SO3R14 and -NR^R1- (where R14 and R1^ are as hereinbefore defined); R^ and R? are independently selected from hydrogen and C alkyl, and X is an aromauc or non-aromatic monocyclic or "oicycuc nng system having fcoai 5 to 10 carbon atoms (including the two carbon atoms forming part of the thiazepme nng) wherein optionally one or more of the carbon atoms is/are replaced by heteroatom(s) independently selected from nitrogen, oxygen and sulphur; with the proviso that when 1 is an integer of from 0 to 4, R1 = R^ = R? = H, R3 = H or OH, R- = unsubstituted Dnenvl or phenyl substimted by one or more atoms cr groups independently selected from halogen, nitro. phenvlalkoxy, C]_i alkoxy, Cj.g alkyl and -0(CH2)pS03R11 wherein p and R11 are as hereinbefore defined, wherein said phenvlalkoxy, alkoxy and alkyl groups are optionally substituted by one or more halogen atoms, and X is a fused phenyl nng, then R4 is other than a C1.5 amended sheet J'13 straignt aik_ ! groun ana R3 :s otrer than a C2-5 "raicr.t a:\\: grout: ar.c sans solvates ar.d Dhysio'ocica:!'.' '"ur.cticr.ai derive:, ves thereof 1 is 0, 1 or 2. n is 1 or 2; R1, R^ and R*^ are al! hydrogen, RJ is hydrogen or hydroxy, and X is a fused phenyl, naphthyl, pvrryl, thienyl or pynayl, group 25 A compound as rV=*yr~irr=ri in A-23 cr A-24 wherein 1 is 0 or 1, n is 2, and -j R- is pyrryl, thienyl, pyndyl, phenyl or naphthyl, such groups being opaonally substituted by one or more atoms or groups independently selected from halogen, cyano, rutro. carboxyi, phenyl, phenoxy, benzyloxy, -COR1 *, -CO2R11, -CONR1 1R12, -CH2OR11, -NR11R1-, -NHCOR11, -NHS02R11, -SR11, -S02Rn, -SO3R11 (wherein R11 and R1- are independently selected from h> drogen, Cj.g alkyl ana phenyl), - -0(CH2)pNR11R12, -OtCh^N'R^R^R13 and -0(CH2)pS03R11 (wherein p is an integer of from 1 to 4, Rll and R12 2re as hereinbefore dencea and R13 is hydrogen or C 1.5 aikyl). AMENDED sheet) 370 _26 A compound as it VZ3 which :s (-V(RR)-3-but>!-3-ethyi-2.3.-i 5-te'-ahycro-5-Dhsnyl-i --benzothiazirir.c 1 I-dlOXide. (-r-)-trans-3-((E)-2-butenyl}-3-ethyl-2,3,4.5-tetrahydro-5-phenyi-1.4-benzothiazepme 1.1 -dioxide; ^ (+-)-trans-3-ethyl-2.3,4 5-tetrahydro-3-(3-methoxypropyl)-5-phenyl-l,4-benzothiazcpme 1,1-dioxide; (--)-trans-l-(3-ethyi-2.3,4,5-tetrahydro-5-phenyl-l ,4-benzothiazep:n-3-y!)-2-butanoneS.S-dioxide: (--)-u'ans-l-(3-ethyl-2,3.4.5-tet:ah\aro-8-methoxy-5-pher.yl-l,4-bepj;o,juazep:r.-yl)-2-bu:anone S.S-dioxide hydrochionde 1 1 hydrate, (—)-U"ans-3-(l-butenyl)-3-ethyi-2.3,4 5-tetrahydroo-Dhenyi-l 4-benzothi2zepinc dioxide hydrochloride 0 4 hydrate, (T--)-trans-3-(ethoxyethyl)-3-ethyl-2.3,4j5-tetrahydro-5-Dhenyl-! ,4-benzothiazepine 1,1-dioxide hydrochionde hemihydrate, (--)-trans-3-(ethoxymethyi)-3-ethyl-2,3 AS-tetrahydroo-phenyl-M-benzothiazepine 1,1 -dioxide hydrochionde, (-r-)-trirLS-eihyl 3-(3-ethyl-2,3,4,5-tetrahydro-5-phenyi-1.4-benzothia2epin-3-yl)propionate 1,1-dioxide, (+-)-trans-(E)-4-(3-ethv!-2.3 4,5-tetrahydro-5-pnenyi-1,4-benzothiazepm-3-yl)-3-buten-2-one 1,1-dioxide; (-i--)-2.3,4 5-tetrahydro-8-methoxy-5-phenylspiro(l 4-beazothiazepme-3,l-cyclohexanc) 1,1-dioxide. (~-)-trans-3-butyl-3-ethvl-2.3,4 5-tetrahydro-5-(4-pyndyl)-l,4-benzothiazepine 1 dioxide, (-r-)-trans-3-butyl-3-ethyl-2,3,4,5-ietrahydro-4-hyaroxy-5-(4-pyndyl)-l A-beazothiazepme 1,1-dioxide; (~-)-tr2Jis-3-butyl-3-eth) l-2.3,4,5-tetrahydro-5-(2-thienyl)-l ,4-bsnzcthiazepme 1 dioxide; (+-)-trans-3-butyl-3-ethyl-2,314,5-tetrahydro-5-(lH-pynol-l-yl)-lI4-benzothiazepine 1,1 -dioxide; (4--)-trans-3-butyl-3-ethyl-2.3,4 5-tetrahydro-5-Dhcnyipyndo(4,3-F)-1,4-benzothiazepine 1 1 -dioxide, (+-)-trans-3-butyl-3-ethyl-3.4.5 7-tetrahydro-5-phen\l-2H-pyrro!o(3,4-F)-l A-benzodiazepine 1.1 -dioxide 0.1 hydrate. aMF.NOED 3H£Ei J7J (—)-trans-3-butyl-3-em\ i-2.3,- nyc:o-5-phenvi^r.icno(Z,3-F)-1 ,-t- bsnzothiazepme 1. i -dioxide. (—)-tr2ns-3-ethyl-2.3,-15-ic::ahydro-5-:3hc:iyi-3-{'-i,-,--ir.uuorocutyi)-; oenzothiazeptne 1,1 -dioxide. (-i--)-trans-2,3,4,5-tetrahycro-3-isopropyl-3-rr.su:yi-5-pr.sny!-l,--bsnzoth:22ecr.c 1,1-dioxide 0 25 HiO; (+-)-trans-3-((E)-2-Butenyl)-3-ethyl-2 3,4,5-tetrahydro-5-phenyl-l,4-benzothiazepme; (--)-Cis-2,3,4,5-Tetrahydro-3-isopropyl-3-me:hy!-5-phenyl-l ,4-benzothiazepine 1,1-dioxide 0 66 H2O; (--)-irar.s-3-(3-Ethyl-2,3,4.5-teU'd'1ydro-5-phenyi-l,--benzothia2epin-3->l)propanoi 1.1 dioxide; (+-)-irans-3-Ethyl-5-(4-Fiuorophenyl)-2,3,4,5-tetr:Lhydro-7-metnoxy-3-(2-rnethoxypropy 1)-1,4-benzothiazepme 1.1 -aioxiae hydrocnionde, (--)-2,3,4,5-Tetrahydro-7-methoxy-5-phenylspiro(l ,--oenzothiazepir.e-3.1-cyclo'nexane) 1,1-dioxide; (--)-trans-l-(3-Ethyi-2,3,4,5-tetrahydro-7-methoxy-5-phcnyl-l ,4-bcnzotruazepin-3-yl)-2-butanone S,S-dioxide hydrochionde, (t-)— trans-3-butyl-3-ethyl-2,3,4.5-tetrahydro-5-phen>lnaphtho(3,2-F)-l,4-benzothiazepme 1,1-dioxide, (--)-traxis-l-(3-Ethyl-2,3,4,5-tetrahydro-7,S-dirneinoxy-5-pnen>l-l,4-benzothiazepm-3-yl)-2-butznone S.S-dioxide; (-r-)-tr2ns-3-(l-butenyi)-3-ethyl-2,3,4,5-tetrahydro-7,S-dime,Jioxy-5-phenyl -1,--benzothiazepine 1.1-dioxide; (-r-)-trans-l-(3-Ethyl-2,314,5-ten-anydro-7,8-aimethoxy-5-phenyl-l,4-bcnzothiazepin-3-yl)-3-butanone S,S-dioxide, (1--)-trans- l-(3-Euiyi-2,3,4.5-ierahycro-S-ir.eLhosy-5-phen> I-1 ,-i-benzothiazcpin-3-yl)-1-butanone S,S-dioxide; (+-)-trans-l-(3-Ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyi-l,4-benzothiazepin-3-yl)-l-butanone S,S-dioxide; (—)-trans-l-(3-ethyl-2.3,4,5-tetrahydro-7.8-aimethoxy-5-p'nenyl-l,4-bcnzothiazepin-3-yl)-4.4,4-trifluoro-I-butanone S,S-Qioxide; (-r-)-trans-l-(3-ethyl-2.3.4.5-tetrahydro-7.8-dimethoxy-5-phenyl-l,4-benzot'niazepin-3-yl)-3.3.4.4,4-pentafluoro-2-but3none S,S-dioxide, (--)-trans-l-(3-e[hyl-2.3.4.5-teirahydro-7,8-aimeihoxy-5-pnenyi-l,4-benzothiazepin-3-yl)-4,4 4-;rifluoro-2-butanone S S-aioxide, '■-il 3?z (--)-trans-3-ethvl-2.3.-.5-retrohydro-7.3-<iLme:hGXY->pneny[-3-{-!- 4 -t. tnfluorobutyl)-lbenzcthiazcsme i ,1-dioxice, (—)-tians-l-(3-(2.2,2-tnfluGroe:hy^-2.3 A5-tetrahycrc-7,8-ai:r:etr:axv-5-::hen7!- I,-- bcnrcthiazeoir.o-yiVI-butar.cr.e S S-dicx:ce. (--)-trans-l-{3-Hthyi-2,3.4.5-tetrahyGro-7,8-dieuioxy-5-pnsnyi-l,i-b£azoth;az5Din-3-yl)-2-butanone S,S-dioxiae, (~-)-trans-3-((3-ethyl-2,3,'1,3-te:rahydro-3-(2-oxobutyi)-5-pheny!-l,i-benzothiazepm-8-yl)oxy)propanesuLfoaic acid 1,1-dioxide; (+-)-trans-2-((3-ethyl-2,3,4,5-tetr2hydro-3-(2-oxobutyi)-5-phenyl-l,— benzotkiazepin-8-yl)oxy)ethyltrimethylammonium iodide 1,1-dioxice, 27 A compound as describe! in A-23>f the formula (la). wherein 1 is an integer of from 0 to 4, n is an integer of from 0 to 2; R is an atom or group selected from halogen, cyano, rutro, aikyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, araikyl, aikaryl, -COR11, -CO^R^, -CONR^R1-, -CH2OR11, -NR1 iR^ -NHCOR11, -NHSO2R11, -SR11, -SO^11, -SO3R11 wherein R11 and R1- are independently selected from hydrogen, Cj_5 alkyl and phenyl, wnerein said alkyl, alkoxy, aryl, heteroaryi, aryioxy, arylaikoxy, aralyi and aikaryl groups are optionally substituted by one or more atoms or groups selected from halogen, rutro. rutnie. aikyi, aikoxy, -COR1 -C02R1 -SO3R11 wherein R11 is as hereinbefore defined and -NR14Rl3 wherein R1-4 and R1^ are as hereinbefore defined; R1 and R3 are independently selected from hydrogen and Cj.5 alkyl: " >r isi | ".rlf-P" j 373 R- is an atom or grouD selected from hydrogen, C1.5 aikyi (inducing cycloalkyl ar.c cycloaikyialkyl), Cj_i alkoxy, pyrryl, thienyl, pynayl, i.3-oenzodioxoio, -nenyi ar.a naphthyl, which grcu-s are octionally substituted by ens or mere atoms grc-3s independently selected from halogen, cyano, nitro, carboxyl, phenyl, phenoxy, benzyloxy, -COR11, -ObR1 -CONR1 !R12, -CH0OR11, -NR11R1-, -NHCOR11, -NHSO2R11, -SR11, -SO2R11. -SO3R11 (wherein R11 and R12 are independently selected from nydrogen, Cj.g alkyl and phenyl), -0(CH2) NR11R12, -0(CH2) N^R1 JR^R13 and -0(CH2) SO3R11 (wherein p is an integer of from 1 to 4,RllPandR12 are as hereinbefore defined and R13 is hydrogen or Cj.g alkyl), R4 is a group independently selected from Cj.g alkyl (including cycloalkyl and cycloaikyialkyl), C2-6 alkenyl and Cj-S alkynyl, wruch groups are opuonally substituted by one or more atoms or groups independently selected from halogen, CM alkoxy, -C02R14, -NRi4R15, -SO3R14 (wherein R14 and R15 are independently selected from hydrogen and Cj.g aLkyl) ana R^COR1^ where R1^ is a C}_4 alkylene group and R1^ is a Cj_4. alkyl group; R5 is a group independently selected from Cj.fi alkyl (including cycloalkyl and cycloaikyialkyl), C2-6 alkenyl and Cj-6 alkynyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, Cj.4 alkoxy, -C02R14, -NR^R1^, -SO3R14 (wherein R14 and R1^ arS independently selected from hydrogen and Cj.g alkyl) and -R^COR1"'' where K.1^ is a Ci_4 alkylene group and R1? is a C 1.4 aikyl group; or R4 and R^, together with the carbon atom to which they are attached, form a C3.7 spiro cycloalkyl group which is optionally substituted by one or more atoms or groups independendy selected from halogen, Cj.g alkoxy, -C02R14, -SO3R14 and -NR14R15 (where R14 and R1^ arc as hereinbefore defined; R^ and R^ arc independently selected from hydrogen and Cj.g alkyl; and X is an aromatic or non-aromatic monocyclic or bicyclic nng system having from 5 to 10 carbon atoms (including the two carbon atoms forming pan of the thiazepine nng) wherein optionally one or more of the carbon atoms is/are replaced by heteroatom(s) independently selected from nitrogen, oxygen and sulphur, 3?v with the proviso mat when 1 is on integer of from 0 to 4, Rl = R- = = R~ = 3_2 = unsubstituted phenvi or phenvi substituted by one cr more atcrrs cr grcu-s .ndependendy selected from halogen, nitro, phenvlalkoxy, Cj^t aikoxy, C; ,<5 alkM and -0(CK->) SO3R11 wherein 0 ana Rare as hereinbefore defined, where::; sazc " 0 phenylalkoxy, aikoxy ana aikyi groups are optionally substituted oy one or more halogen atoms, and X is a fused phenyl ring, then R4 is other than a C j.g straight alkyl group and R3 is other than a C2.5 straight alkyl grouo; and salts, solvates and physiologically functional denvauves thereof. -28 A compound of formula (I): where in I Is an integer of from 0 to 4; n is an integer of from 0 to 2; R is an atom or group selected from halogen, cyano, nitro, alkyl, aikoxy, aryl, heteroaryl, aryloxy, arylalkoxy, araikyl, aikaryl, -0(CH2)pS03R11, -0(CH2)pNRl1R12, -0(CH2)pN-RnR12R14, -COR11, -CCbR11, -CONR11R12, -CH2OR11, -NR^R12, -NHCOR11, -NHSO^11, -SR11, -S02R11,-s02NR11R12, -SO3R11 wherein p is an integer of from 1 to 4, R11 and R12 are independently selected from hydrogen, Cj.g alkyl and phenyl, and R14 is hydrogen or C^_g alkyl, or R is a group -0CH20- which forms a further nng attached to X, wherein said alkyl, alkoxy, aryl, heteroaryl, arvloxy, arylalkoxy, araikyl and aikaryl groups arc optionally substituted by one or more atoms or grouos selected from halogen, nitro, nitnle. alkyl, alkoxy. -COR11, -CO^R11, -SO3R11 wherein R11 is as hereinbefore defined and -NR14R^ wherein R14 is as hereinbefore defined and Rl3 is hydrogen or C[_^ aikyl; ' 41 M~) # 376- PJ is h>crogen or Cj.q aikyi, R- is an atom or group selected from hydrogen. Cj.,5 alkyl (inducing c\cioal.<M and cycloaikyialkyl), C1.4 alkoxy, pyrryl, thienyl, pyncyl, 1.3-cenzodioxolo, phenyl and naphthyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, cyano. nitro, carboxyl, phenyl, phenoxy, benzyioxy, -COR1-CCbR' -CONR1 Jr1^, -CH2OR1 -NR1 ^R1^, -NHCOR11, -NHSO2R11, -SR11, -SO2R11 -SO3R11 (wherein R11 and R12 are as hereinbefore defined), -0(CH2)pNR11R1^, -0(CH2)pN~R1 JR^R13 and -0(CH2)pS03R11 (wherein p, R11 and R1- are as h erembefore defined ar.d P.13 ;s hydrogen or Cj.g alkyl); R3 is hydrogen, OH. Cj.g alkyl, Cj.g alkoxy or -OCi_6 acyl, R4 is a group independently selected from Cj.6 alkyl (including cycloalkyl and cycloaikyialkyl), C2-6 alkenyl and C2-6 alkymyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, oxo, CM ^oxy, -C02R14, -NR14R15, -SR14, -S(0)C!.6 alkyl, -S02R14, -SO3R14 (wherein R14 and R1^ are as hereinbefore described); R3 is a group independently selected from C2-6 alkyl (including cycloalkyl and cycloaikyialkyl), C2-6 alkenyl, and C2-6 alkymyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, oxo, CM alkoxy, -C02R14, -NR14R^, -SR14, -S(0)C!_6 alkyl, -S02R14 -SO3R14 (wherein R14 and R1^ are as hereinbefore defined), or R4 and r5, together with the carbon atom to which they arc attached, form a C3.7 spiro cycloalkyl group which is optionally substituted by one or more atoms or groups independently selected from halogen. Ci.g alkoxy, -CO2R14, -SO3R14 and -NR14R15 (where R14 and R15 are as hereinbefore defined, R^ and R^ are independently selected from hydrogen and Cj.g alkyl; and X is an aromatic or non-aromatic monocyclic or bicyciic nng system having from 5 to 10 carbon atoms (including the two carbon atoms forming pan of the thiazepme nng) wherein optionally one or more of the carbon atoms is/are replaced by heteroatom(s) independently selected from nitrogen, oxygen and sulphur, amended sheet, J# with the proviso that when 1 is ar. integer of rrorn 0 to 4. R1 = R° = R/ = H, R- = H or OH, R- = unsubstituted pner.vi or phe~>i subs:.rated by one cr no re atc—.s or groups indepenaently selected from naiogen, nitro, phenyialkoxy, C]_i alkoxy, C-t_5 alkyl and -CKCI-fo^SOjR11 wherein p and R11 are as hereinbefore defined, wnerein said phenyialkoxy, alkoxy* and alkyl groups are optionally substituted by one or more halogen atoms, ana X is a fused phenyl ring, then R~ is other than a Ci.g straight alk> 1 group and R^ is other than a Cj-S straight alkyl group, and salts, solvates and physiologically functional derivatives thereof for use m therapy, amended sheet -29 3 -Etnyl - 3 -raechyl -2,3,4,5- tazrar./dro - 5 - or a-y 1 - L , - - oe-z: ;r.:a; at me , =o 124 -125°C, (-) - 3 , 3 - Dieznyl -2,3,4,5- cetranydro- 5 - pner.y 1 - i , 4 - oenzotniazepine 1,1-dioxide, mp 100-102°C, 3 - Butyl- 2,3,4,5-cerr,anydro-3-rae thy 1 - 5 - pr.er.y 1 -1, 4 - oenzo chiazeo me 1,1-dioxide, nro 103-104°C; 3 - Methyl - 3 - propyl - 2 ,3,4,5- tazrahydro - 5 - or.eryl-1, 4-benzothiazet me 1,1-dioxide, no 120-121°C, 3 , 3 - Die chyl - 2,3,4,5- catrahydro - 5 - ohanyl -1. 4 - benzo cn laze pine 1,1-dioxide, co li5-li6°C, ( + )- T r ar s - 3 -Bucyl- 3 -echyl- 2,3,4,5-ta tranydro- 5 -phery1-1,4 -benzo-chiazepme 1,1-dioxide, mo 101°C, (-<-) -Trans - 2 , 3 , 4 , 5 - Te crahydro - 3 - caetny 1 - 5 - obaryl - 3 - Drooyl -1, 4 -benzoch.ia.zeoine 1,1-dioxide, tzo 129-130°C, ( -)- 3,3 -Diethyl-2,3,4,5-cetrahydro- 5 -pnenv1 -1,4 -benzochiazeome 1,1-dioxide, h:d 101-103°C, 3 - ethyl -2,3,4,5- tatrahydro - 3 -nechyl - 5 -onery1 -1, 4-benzotr.iazea me , nrp 110 - 112°C . 3 - Ethyl - 2,3,4,5- tatrahydro - 3 - methyl - 5 - onenv 1 -1, 4 - benzo thiazeome hydrochloride 0 25^0, mp 162-164°C (eff.), 3 - Ethyl - 2,3,4,5- "a tranydro - 3 - methyl - 5 - oher.v 1 -1, 4 - benzo tr.iazeo me 1,1-dioxide, mp 128-129°C, 3 , 3 - Diethyl- 2,3,4,5-cecrahydro- 5 - phenyl -1,4-benzotniazepme hydrochloride, mo 211-214°C, AMENDED 3Hc": 37S - 2 , 3 , ^ , 5-Te rrmvc.ro - I-T.ecn,il-D-ops"VL-2-^ro'3-l-l,--berz;;"".a-:aair.e, ~o 101-103°C, 2,3,4,5 -Tecranydro - 3 -raechyl -5-onenvl-3-orooyl-l,4-oerzoc.-Maze- Q pme, eo 72-74 C, J 3 - Echyl- 2,3,4,5- cecranydro- 5 -pneny I - 3 - propyl -1, 4 - oenzo cniazepme hydrochloride 0 25^0, np 205-207°C, 3-Ecnyl-2,3,4,5- ce crahvdro - 5 - pneny 1 - 3- orooyl-l,4-oe"i;omazeoire 1,1-dioxide 0 25'rf^O, mp 115-118°C, 2,3,4,5 -Tecra'nydro - 5 - pneny 1 - 3 , 3-dmroD'-1 -1,4-berrocnu.i;eoirs hydrochloride, 209-211°C, 3 - Echyl -2.3,4,5- cecranydro -5-pnenyl-3-oro::yl-L,4-oenzacr'.iazeoire 1,1-dioxide hydrochloride 0 3 3.-i.jO, 206-209°C, 2,3,4,5-Te crahydro- 5 - oneny I - 3 , 3 - Gipr oo \ 1 • 1, 4 - oenzoc.hia.zso me 1.1-dioxide , rr.D 104-106°C, 3,3-Dibucyl-2,3,4,5-ce cranydro- 5 - ohenv1•1 4-benzo chiazeome hydrochloride, mo 209-212°C, 3 -Bucvl- 2,3,4,5 -cecranydro- 3-mechyl- 5•onenvl-1,4 -oenzocmazeo me 0 — hycirocnloride , mp 203-205 C. 3 - Bucvl - 3 - echyl - 2,3,4,5- cecranydro - 5 - cnanv 1 -1,4 - oer.ro c?. lazeome hydrochloride, mp 205-2Q7°C, 3 -Bucyl- 3 -echyl- 2,3,4,5-cecranydro - 5 -oneny1 -1,4 -benzochiazeome 1,1-dioxide hydrocnloride, mo 209-212°C, 2.3,4,5 - Te cranydro - 3 - me chyl - 3 -pency 1 - 5 - ohenv 1 -1 4 - oenzo ch lazeome maleace. mo 132-183°C, J?3 3 - Ethyl -2,3,4,5- tetrar.vcro -5-oreryl-3-oro;:yl-l,4-oe™z otr-azecire hydrocnlonce , cn 19 3-200°C, (t--) - Cs - 3 - Butyl- 3 - e t.-y 1 -2,3,4,5- ce crar./aro - 7 - ne cny 1 - 5 - or er.y 1 - Q 1,4-benzothiazeDir.e 1,1-dioxide, to 133-140 C; 3 (+- ) ~ C1 s - 3 - Butyl - 3 - ethyl - 2,3 ,4,5-cetrahydro-7- tie tnoxy - 5 -pneny1-1, 4-benzo thiazeome , light yellow oil, ( + -) -Trar.s - 3 - Butyl - 3 -e thyl -2,3,4,5- te trahydro - 7 - ?e tr.oxv - 5 - onenvl -1,4-benzothiazeome , lignc yellow oil, ( + -) - C i s - 3 - Butyl - 3 - e tnyl -2,3,4,5- cecranydro - 7 - ne tr.o\y - 5 - ohenv i - > - ° 1, 4 - ber.zo thiazeo me 1,1-dioxide, ro 113-ili C, (-*•-) -Cis - 3 - Butyl - 3 - e tnyl - 2 , 3 . 4 , 5 - cs tranycro - 7 - ne thoxy - 5 - oneny 1 -1,4-benzothiazeome 1-oxide, mo 103-105°C, ( + -)-Trars- 3 -3uty1- 3 -e thyl-2,3,4,5-te tranydro- 7 - rrethoxy- 5 -oneny1-1, 4-benzo tniazeo me 1,1-dioxide nyarocnlor ide , rr.o 1S9-201°C, (•*•-)-Trars-3-3utyl-3-ethyl-5-Dneryl-2,3,4,5-tetrahvdro-l 4 -benzotniazeoine 1-oxj.de, tio 98-101°C, ( + -)-Trars- 3 - Butyl - 3-ethyl-2,3,4,5-tetrahvdro- 5 -oneny1-1,4-oenzothiazeome 1-oxide, rro 133-136°C,_ (+-)-Cis-7-Chloro-3-butyl-3- ethyl-2,3,4,5-cetranycro- 5 -pneny1-1,4-benzothiazenme 0 4 toluene, light yellow oil, ( + -) - Trans - 7 -Chloro - 3 - outy 1 - 3 - e thy L - 2 , 3 , 4 , 5 - te tranydro - 5 - otier.y 1 -1,4-benzochiazepine 0 3 toluene, lignt yellow oil, (+-) -Trans -3 - Butyl - 7 - Chloro - 3 - e chyl -2,3,4,5- te tranvo.ro - 5 - Dner.yl-1.4-oenzothiazeoine 1.1-dioxide mp 100-I02°C, 3fd /l) -1, 4-ber.zc cn:;:eo-~e 1, 1 - :io •.i ca iroc"'.::.::, to .---.T-0;, ber.zothiazepme 1,1-dioxide nydroc.nLonce , ~o 2C4-206°C. 3 (+-)-Cis- 3 - Butyl-3-echyl-2,3,4,5-cetranycro■5 -(4 -coly1)-1,4 -benzodiazepine 1,1 - dioxide , iro 155 -156C; ( —-)-Cis-3 - Butyl - 3 -ethyl- 2 , 3 , 4 , 5 - ce tran;. cro-5-(4-pg cncxyonenyl)-1, 4 - oenzo tr. lazeD ire , mo 75-77°C, (+- ) -Cis- 3 - 3uty L - 3 - e tny L - 2 , 3 , 4 5 - ce tr any cr o - 5 - (4 - me c-,o\y or eny 1) -1, 4 - benzo cniazep me L,l-dioxide, mp 109 - lli°C , ( + -) -Cis- 3 - Butyl - 3 - e tny 1 - 5 - (4 - f luoroone-,-, 1) - 2 . 3 , 4 5 -ce cranvdro-1 , 4-benzocniazeair.e , rap 76 -73°C, ( + -)-Trjr_s - 3 - Buty 1 - 5 - ( 3 , 4 - dicnloroonery i) - 3 - e chy 1 - 2 3 4 5-cecra-hydro -1, 4-benzo cmazeome , i?o 98 - 100°C, ( + -)-Trans -3-Butyl-3-(4-cnlorooner/11-3-ecnyl-2,2,- 5-te tranycro-1, 4-benzothiazeome 1 l-cioxiae hycracnlorice 0 3 H.,0 mp 178 -180°C, ( + -) -Cis-3-Buty 1 - 5 - (4-c.nlorotneny 1) - 5 - e tny 1 • 2 , 3 , 4 5 - cetranvdro- — Q 1, 4 - oenzothiazeo ir.e 1,1-dioxide hvdroc.nlor-ce mo 186- 133 C, Trans - 3 - Butyl - 3 - ec.ny 1 - 2,3,4,5-tetranydro-5-(3-mcroonenyL)-1.4- o berizothiazeoine 1 1-cioxide, mc 139- 142 C Trans - 3 - Butvl - 3 - ethyl -2.3,4,5-zetranvcro-5-(4-ru.croonenvL,;-l,4- Q benzothiazepine 1,1-dioxide, rao 139-142 C 3*a ( + -) -Trsrs - 5- (4 - Benzyioxyoreny1) - 2-bucy1- 3 - a cny 1 -2,3,4,5-ca crshydro -1, 4 - oenzc chiazeo me 1 , 1 - d:o '.ice , rs S4-95°C, () -Cis- 5 - (4 - Benzy loxypnenyl) - 3 - bucy i - 3 - ecny I - 2,3,4,5-cecra-nydro-1,4-benzochiazepme 1,1-dioxide, so 137-133°C, 3 ( + -) -Trayis - 5 - (4 -Benzy loxypnenyl) - 3 - busy! - 3 - echyl - 2,3,4,5-cecra-hydro - 1, 4-benzo chiazeome , mp 97-98°C, (t-)-Trans - 3 -(4 -(3 -Bucyl - 3 - echyl - 2,3,4,5-cecranydro-1,4 -oenzo -cniazeoin-5-yl)ohenoxy j prooanesulohomc acid 1,1-cioxide mp 270°C (dec ), ( + -)-Trans - 3 -Bucy1 - 3 -echyl - 2,3,4,5- cecranvcro-5 - (2-fluoroohenyl) 1,4-benzochiazeoine 1,1-dioxide hycrocnlonde, mp 194- 196°C, ( + -)-Trars- 3 -3ucyl-3-ecnyl-2,3,4,5-ce cranydro- 5 -(3 -fluoroohenyl) 1,4-bencochiazeoir.e 1,1-dioxide, ir.o 143- 145°C, ( + -) -Cis - 3 - 3ucyl - 3 - ecnyl- 2,3,4,5- cecranydro - 5- (4-oyndyl) -1,'*-benzochiazepine 1,1-dioxide, mo 121-123°C, (-"--) -Trars - 3 - Bucyl - 3 - echyl -2,3,4,5- ce cr anycro - 5 - (4 - pyndyl) -1,4-benzochiazepme 1,1-dioxide, ip 110-111°C, (■>--) -Cis - 3 - Bucyl - 3 - ecnyl -2,3,4,5- cecrany czo-5-(4-crifluorome chyl phenyl) -1, 4-benzochiazepine 1,1-dioxide, .7,0 64-65°C, ( + -)-Trans - 3-3ucyl- 3-echyl - 2,3.4, 5 -cscrihydro- 5 -(3 -crifluoro-raechylphenyl) -1,4-benzochiazepme 1 1-dioxide, mo 110-112 C, (-»•-) -Trans - 3 - Bucyl - 3 - ecnyl - 2,3,4 5 - cscra.nvdro - 5 - (3 . 4- dif luoro -phenyl) - L.4-benzocniazepme 1 1-dicxice. mo 205-215°C, Jiz (--) -Trars - 3-Sucy 1-3-ecny 1-2,3,'♦.S-cecrar ycro-5-(2,-'-G. :i"__=ro-pneny 1) - 1 , - - oenioch-siaoire 1 , 1 - c - , ~o ?7-99 C (- -) - Trans - 3 - .socencvi - 3 - e '**.% 1- 2 , 3 , - , :■ - cecrar,/c,ro-; • onsr > - Q benzodiazepine 1,1-dioxide , rap 86-57 C, and ( + -) -Cis- 3 -1 soDencyl - 3 - echyl -2,3,4,5- ca crahydro - 5 - or.ery 1 -1, 4 -benzochiazspme 1,1-dioxide, mo 123-125 C (--■>. -3-bucvl -3-echvl- 2 . 3 4 5 - cacrahvdro-^-o'nenvl-1 ^-be^zochiazeome 1. 1-dioxide hydrochloride ( + -)-Trans - 3 -3ucyl- 3 -e chyl- 2,3,U , 5 - cecranvcro- 5 - phenyl -1,U-benzo-chiazeoine 1,1-dioxide, r.o 98-100°C, (-)-Trans - 3-He chyl-3-Drouy1-2.3,^,5-ca cranydro- 5 -onenv1 -1,U-benzodiazepine 1,1-dioxide, ma 129- 130°C, amended sheet 3fS -30 A coicour.d of formula (I) unerem (I) 1 is an integer o£ from 0 to U , n is an integer of from 0 to 5 n is an integer of from 0 to 2 R and ?.' are atoms or grouos indeoencently selected from nalogen, nitro, uhenylalkoxy, C. , alkoxy, C, , alkvi and -0(CH.) SO.R" L-t» ' l-o ' ^ p J •-•herein o is an integer of from 1 to ^ and R" is nydrogen or g alkyl, --herein said phenyialkoxy, alkoxy and alkyl grouos are optionally substituted by one or more halogen atoms, R is a C , straight aikyl group, and R5 is a C. , straight alkyl group; I - 0 and salts, solvates and physiologically functional derivatives thereof. amended sheet m \ compound of fornuLa (I) as 14. R is methyl, echyl, n-propyl, or n-butyl, anc R^ is ecnyl, n-propyl, or n-bucyl, and sales, solvates and physiologically functional cenvatives thereof 33 A compound of formula (I) as rpcmhpH tji A-31 '-.'hicn co-pourc is j.n the trars configuration as herei" cafired or a salt, solvate, or physiologically functional cerivaci"s thereof 34 A compound of formula (I) as Hpgrr-i'r-pri m A-32 . -ni.cn compound is trans - 3-butyl- 3 -etnyl - 2.3.4,5 -te tranydro- 5 -ohenvl-1, --bento-thiazepine 1,1-dioxide, or a salt, solvate, or pnysiologicall^ functional derivative tnereof 35 The compound of formula (I) descries! in A-33 , v-nich compound is m the (RR)-, (SS) - , or (RR..SS) - form or is a salt, solvate or pnys10 logically functional derivative of any tnereof (-)-(RR)- 3 - Butyl-3-ethyl-2 ,3,4,5-tetran/cro-5-phenyl-l,"-benzo-thiazepine 1,1-dioxide or a salt, solvate, or pnvsiologically functional derivative thereof. (-)-(RR)- 3 -Butvl- 3 -echyl-2,3,4,5- ce cranydro- 5 -oneryl-1,C-bento -thiazepine 1,1-dioxide ) - (P.JR. SS) - 3 - Bucyl - 3 -echyl - 2.3 '->■ 5 - te tranycro - 5 • phen> I -1, ^ -benzo cn lazeo ine 1,1-dioxide or a salt sol%'ate or physiologically functional thereof -mk,:=n v*.r (-- ) - (RS., SS) -3- Butyl-;-echyl - 2 , 3 , - , 5 - re rrar.ycr: oen^ccniazeoir.e 1,1-cioxice jnanvi'i, iv-r. A-36 A polymeric or oligomeric bile acid, prepared by polymerization of a monomeric bile acid of the formula I G—X—A (I) m which G is a free bile acid or its alkali metal salt or a bile acid having rings A, B, C, D esterified on ring D and which is bonded via its ring A, B or C, to the group X, X is a bridge group and A is a polymerizable, ethylenically unsaturated group, or by copolymerization with a monomer containing a polymerizable, ethylenically unsaturated double bond, or by copolymerization with N-vinyipyrrolidone or its derivatives, and/or by copolymerization with ethylenically unsaturated dicarboxylic anhydrides and ethylenically unsaturated dicarboxylic acids each having 2 to 6 caroon atoms; their esters cr half esters, esters being understood as alkyl esters having 1-6 carbon atoms, cycloalkyl esters having 5 to 8 carbon atoms, benzyl esters or phenyl esters. A-37 A polymer or oligomer as claimed in A-36, wherein G is a free bile acid or its alkali metal salt or a bile acid esterified on ring D and which is bonded via its ring A, B or C, to the group X, to which the formula II applies INTELLECTUAL PROP'iPTY OFFICE OF N Z. - 1 jun 2001 UEGIti^ EO W 33 J 0 7 .<?> ;y)0 — (z)p (id in which Y is adjacent to G and is —0—, —NR' o o a ii —O—C— or —MR'—C— is (Ci~Ci2) -alkylene or (C7 -Ci3) -aralkylene, where individual methylene groups in the alkylene chain of the alkylene or aralkylene radical can be replaced by one or more groups selected from —0—, — NR'—, — N'R. —C —, — 3 — C— —NR' —C—SR" li H II o o O o and p independently of one another are zero or 1, where o and p are not simultaneously zero, A is an ethylenically unsaturated group of the formula o m which R1 is hydrogen or CH3 and R2 is O Q 11 II -NR'—C— —Q—C—. INTEL LECTUAL PROPERTY OFFICE OF NZ. - 1 jun 2001 U 2 5 'i ^ G 0 JLaj —0—, —NR'— or a single bond, where the carbonyl groups are adjacent to the C—C double bona, R' and R" independently of one another are hydrogen or {Cx -C6) -alkyl. A-38 A polymer or oligomer as described in A-37, wherein G corresponds to the formula III in which RJ to R8 independently of one another are hydrogen, OH, NH2 or an OH group protected by an OH protective O (HI) group and one of the radicals RJ to R6 is a bond to the group X, where this bona starts from the positions 3 (R3 or R4) or 7 (R3 or Rs) , and the other position 7 or 3 in each case carries an OH group or a protected OH group, B is —OH, —O-alkali metal, —O-alkaline earth metal, —0—(Cx -C^)-alkyl, —O-aiiyl or —0-benzyl where alkyl is either n-alkyl or iso-alkyl and where the ester group formed o is an ester which can be saponified both by acid and by base, Y is —0—, —NR'—, o o INTELLECT! UAL IT-O^TY OFFICE OF NZ — O—C— or —S'R—C — - 1 jun 2cc1 3S9 Z is (Ci -C12) -alkylene, (C7 -C13)-aralkylene, where to 3 methylene groups m the alkylene chain are replaced by the groups —0—, —NR1, — NR—C— —O—C—. or —NR—C—NR'— II II 11 OO O and o and p independently of one another are zero or 1, where o and p are not simultaneously zero, A is R1 I or CH:=C—R—. where R1 is hydrogen or CH3 and R2 is o I) — N*R'—C—. —NR'— or a single bond, in which B' and R" independently of one another are hydrogen or (Ci -C6) -alkyl. 39 The polymeric or oligomerie bile acia of A-36 wherein said monomer containing a polmerizable, ethylenically unsaturated double bond is a monomer of formula IV INTELLECTUAL PROPS" IY OFFICE OF NZ - 1 jum 2001 390 L C m which R9 is hydrogen or methyl and R10 is O O 0 II I! II —C—G—R.11. —C—N7.lIR13, — O— C— —CN, —0—R15, hydrogen halogen —S03 H, or —0— (CH2 —CH20)nR16, in which R11 is hydrogen, (Cx -Ci0) -alkyl, (Ci-Cio)- monohydroxyalkyl or —(CH? CH2 —0—) nR16, R1^, R13, R15, and R16 are identical or different: and are (Ci -C10) -alkyl, R14 is (Ci -C18) -alkyl and n is 1 to 50. A-40 A polymer or oligomer as described in A-36, wherein the weight-average molecular weight is up 250,000 g/mo 1. A-41 A polymer or oligomer as described m A-36, wherein m the case of copolymers the molar ratio of bile acid units to copolymerized monomer units is between 300:1 and 1:300. A-42 A polymer or oligomer as described in A-36, wherein the crosslinking is carried out by means of copolymerization with ethylenically polyunsaturated monomers. A-43 A polymer or oligomer as described in A-42, wherein the crosslinking is carried out with ethylenically polyunsaturated acrylic acid and methacrylic acid derivatives. INTELLECTUAL PROP I, OFFICE OF N.Z. - 1 jun 2gg1 UErSElVEB A-4 4 A polymer or oligomer as described in A-42, wherein the crosslinking is carried out with acid amiaes of the formula V I e R.' O OK9 I II II I H2C=C—C—NH—D—NH—C—C=CHi in which R9 is hydrogen or methyl and D is — (CHE) m —, wnere m is 1 to 10 and E is hydrogen or OH. A-45 A pharmaceutical composition comprising a compound of A-36 and a pharmaceutically acceptable carrier. A-4 6 The polymer or oligomer as described in A-40, wherein the weight-average molecular weight is between 2,000 and 100,000 g/mol. A-47 The polymer or oligomer as described in A-46, wherein the weight-average molecular weight is between 3,000 and 60,000 g/mol. A-48 The polymer or oligomer as described m A-38, wherein B is —OH, —O-alkaii metal, —0—(Cx -C6) -alkyl, —0-allyl or —O-benzyl. A-49 The polymer or oligomer as described in A-38, wherein R3 to R8 independently of one another are hydrogen, OH, NH2 or an OH group protected by an OH protective group and one of the radicals R3 to R6 is a bond to the group X, where this bond starts from the positions 3 (R3 or R4} or 7 (R5 or R6) m the (3-position, and the ! INTELLECTUAL P^Or OFFICE CF N.Z " 1 JUN 2001 other position 7 or 3 m each case carries an OH group or a protected OH group. A-50 The polymer or oligomer as described in A-37 wherein G is a free bile acid or its alkali metal salt or a bile acid esterfied on ring D which is bonded via its ring A to the group X. A-51 A polymer or oligomer as described m A-39, wherein the monomers are compounds according to the formula IV (meth)acrylic acid, (meth)acrylic acid esters, acrylamide and its derivatives, carboxylic acid vinyl esters having 3-20 carbon atoms or N-vinylpyrrolidone and its derivatives. A-52 The polymeric or oligomerie bile acid of A-39, wherein said halogen is chlorine, bromine, or iodine. A-53 EXAMPLE 1 48 g (122 mmol) of 3a, 7a,12a.-trihydroxy~24-nor-23-cholanic acid (=norcholic acid), 200 ml of formic acid and 1 ml of perchloric acid (60%) are stirred at 50°C. for 1.5 hours, the mixture is cooled to room temperature, 160 ml of acetic anhydride are added and the mixture is stirred for a further 15 minutes. It is poured onto 1.5 I of water wo'- o: H I INTELLECTUAL PROPER' || OFFICE OF NZ. - 1 2001 and the solid constituents are filtered off with suction and washed with 11 of water. The residue is dissolved m 700 ml of ether and washed three times with water. The organic phase is dried (MgSOa) and concentrated. Yield 52 g (89%) of Example 1. MS (FAB, 3-NBA/LiCl) C26H3808 ( 4 7 8 ) , 485 (M+Li+) EXAMPLE 2 5 g (10.4 mmol) of Example 1 are dissolved in 20 ml of trifluoroacetic acid/5 ml of trifluoroacetic anhydride at 0°C. 840 mg (12 mmol) of sodium nitrite are added in portions in the course of one hour. The mixture is subsequently stirred at 0°C for a'"further hour then at 40°C for 2 hours. The solution is cooled to 0°C again, neutralized with 5N NaOH and extracted with dichloromethane. The organic phase is dried (MgS04) and concentrated. Chromatography of the residue over silica gel (cyclohexane/ethyl acetare=2:l) gives 3.1 g (67%) of Example 2. I1 lNTcLLECTUAL FTlOPcETY OFFICE OF NZ. i - 1 jum 2001 394 MS (FAB, 3-NBA/LiCl) C25H35NO6 ( 4 4 5 ) , 45; 7 t! (M- EXAMPLE 3 C = N 0 1.5 g (3.37 mmol) of Example 2 and 5 g of KQH are dissolved in 50 ml of ethanol/water (=1:1) and the solution is heated under reflux. When the reaction has ended (monitoring by thin layer chromatography), the ethanol is stripped off and the residue is washed with ether. The aqueous phase is acidified with 2N HCl and extracted three times with ethyl acetate. The combined organic phases are dried (MgS04) and concentrated. 1.25 g (97%) of Example 3 are obtained. MS (FAB, 3-NBA/LiCl) C^HasOs (380), 387 (M+Li+) EXAMPLE 4 N COOK HO' 500 mg (12.87 mmol) of 3a, 7a, 12a-trihydroxy-24-nor-23-cholanic acid and 37 0 mg (36 mmol) of N-methylmorpholine are dissolved in 20 ml of THF. 0.34 ml (36 mmol) of ethyl chloroformate is added at 10°C. After 15 minutes, a solution of 270 mg (36 mmol) of glycine m 5 ml of IN NaOH is added dropwise. The mixture is subsequently stirred at room temperature for 18 hours. The reaction mixture is concentrated and the residue is chromatographed over silica gel (dichloromethane/methanol=8:2). 320 mg (56%) of Example 4 are obtained. MS (FAB/3-NBA) c25h4in06 (451), 452 (M+H+) EXAMPLE 5 H N INTELLECTUAL PROFEI OFFICE OF NZ. - 1 jun 20g1 3% 7 o '• ^ 340 mg (53%) of Example 5 are obtained from 500 mg (12.67 mmol) of norcholic acid and 450 mg (836 mmol) of taurine by the process described for Example 4. MS (FAB, 3-NBA) C25H43NO7S (501), 502 (M+Hf) EXAMPLE 6 10 g (25.3 mmol) of norcholic acid are dissolved m 50 mi of pyridine. 2.6 ml of methanesulfonyl chloride are added dropwise at 0°C. The reaction mixture is then stirred at room temperature for 3 hours. It is poured onto ice-water and extracted three times with ethyl acetate. The organic phase is dried (MgS04) and concentrated. The crude product is crystallized from diisopropyl ether, filtered off with suction and then dried in vacuo. 11.2 g (93%) of Example 6 are obtained. MS (FAB, 3-NBA/LiCl) C24H4o07S (472), 485 (M+2Li+-H+) INTELLECTUAL property OFFICE of n.z. JUN 2001 1 - n r? I] h £ D 397 EXAMPLE 7 II HjC—S—O' II o o v :o o H 38.7 g (81.9 mmol) of Example 6 and 6.9 g (106 mmol) of sodium azide are stirred in 350 ml of dimethylformamide at 130°C for 2.5 hours. After cooling, the mixture is poured onto 1.5 1 of ice-water and extracted three times with ethyl acetate. The organic phase is dried (MgS04) and concentrated. The crude product is esterified m a methanolic hydrochloric acid solution, prepared from 100 ml of methanol and 14 ml of acetyl chloride, at room temperature for 2 hours. For working up, the mixture is partly concentrated and the product is poured onto 1 1 of water and extracted three times with ethyl acetate. After drying and concentration of the organic phase, the crude product is chromatographed over silica gel (cyclohexane/ethyl acetate=6:4). 9.0 g (25%) of Example 7 are obtained. MS (FAB, 3-NBA/LiCl) C24H39N3O4 (433), 440 (M+LiT) r - ■ - j iiMTcLLECTUAL PROPERTY OFFICE OF N.Z. - 1 ju.m 2001 398 EXAMPLE 8 & / QMc HjK QMc 8.0 g (18.5 mmol) of Example 7 are hydrogenated with hydrogen in 220 ml of erhyl acetate m the presence of about 50 mg of 10% Pd/C. When the reaction has ended, the catalyst is filtered off and the filtrate is concentrated. Chromatography of the residue (methanol/triethylamine=95:5) gives 6.0 g (80%) of Example 8 . MS (FAB, 3-NBA/LiCi) C24H41N04 (407), 414 (M+Li") EXAMPLE 9 o I! KiC— S — O' II 0 COCO--) NiCH INTELLECTUAL PROPERTY OFFICE OF N.Z. - 1 jun 20g1 399 , / 4.3 g (8.6 mmol) of the mesylate (cf. EP-A-0 48S 423) are heated at 100 to 110°C. in 80 ml of dry DMF with 0.42 g (8.6 mmol) of sodium cyanide for 3 hours. The mixture is poured onto ice-water and extracted with ethyl acetate, and the residue from the organic phase is filtered over silica gel. (Ethyl acetate/heptane=2:1). 890 mg (25%) of nitrile are obtained. MS (FAB, 3-NBA/LiCl) C26H4iN04 (431), 438 (M+Li") 1.5 g (3.48 mmol) of the nitrile from Example 9 are hydrogenated in 100 ml of methanol with addition of 10 ml of concentrated ammonia solution and 1 g of 5% strength rhodium-on-Al2 O3 under 140 bar at 50°C for 24 hours. The catalyst is filtered off with suction, the filtrate is concentrated and the residue is purified over silica gel (CH2C12 /MeOH/concentrated NH3 solution=100:15:2 ) . 1.1 g (73%) of amine (Example 10) are obtained. MS (FAB, 3-NBA/LlCl) C26H45NO4' (435) , 442 (M+Li~) EXAMPLE 10 EXAMPLE 11A - 1 jum 20c1 PJ r= ^ - 1 <1" ^ -n A fa o i. 1 j j 4= w m COCC-h NC H H '' OSDrfcn n OSiMej 270 mg of dry zinc iodide are added to 9 g (21.4 mmol) of ketone (see equation 4) under argon m 50 ml of dry dichloromethane, and 10 ml (3.5 equivalents) of trimethylsilyl cyanide are added m portions, while cooling with ice. After about 1.5 hours, the reaction has ended. The residue which remains after concentration is purified with n-heptane/ethyl acetate=10:l over silica gel. 12.1 g (85%) of the product are obtained as a colorless oil which predominantly (>9:1) comprises one stereoisomer. MS (FAB, 3-NBA/LiCl) C35H65NO5S i3 (664 ) , 671 (M+Li+) EXAMPLE 1IB QSifej COOCHi OH :iM TEL''EC.'JAL rr.3,J-Or-r-ICE Or N z. - 1 ju;j 20c1 • 401 Si 2.1 ml (27.4 mmol) of trifluoroacetic acid are first added to a suspension of 1.036 g (827.4 mmol) of sodium borohydride in dry THF, the mixture is stirred for 15 minutes and 12.1 g (18.2 mmol) of the nitrile from Example 11A m 40 ml of dry THF are then added, while cooling with ice. After 24 hours at room temperature, the mixture is worked up by addition of water and ether, the organic phase is extracted by shaking with hydrogen-carbonate solution and the residue is purified by chromatography with CH2Cl2/CH3OH/concentrated NH3 solution=100:10:1.5. 7.83 g (48%) of the amine are obtained. MS (FAB, 3-NBA/LiCl) c32H61n05Si2 (596), 603 (M+Li+) EXAMPLE 12A _^o AcO -0H AcO J « K AcO' ' OAc H 20 g (42 mmol) of methyl ketone (cf. equation 2) are dissolved m 400 ml of methanol, 2.48 g (64 mmol) of sodium borohydride are added and the mixture is stirred at room temperature for 45 minutes. After addition of 400 ml of water, 2N HCl is carefully added until the pH reaches 3. The mixture is concentrated, water is added again and the mixture is extracted with EA. The organic phase is INTELLECTUAL PROPERTY 1 OFFICE OF N.Z. -1 2cei us. dried and concentrated, and the residue is chromatographed over silica gel (cyclohexane/ethyl acetate 1:1). Yield: 15.1 g (75%) MS (FAB, 3-NBA/LiCl) C27H42O7 (478), 485 (M+Li+) AcO' EXAMPLE 12B OH A cQ* 15.1 g (31.5 mol) of alcohol (Example 12A) are dissolved in 250 ml of dichioromethane/250 ml of pyridine, 4 g (35 mmol) of methanesulfonyl chloride are added at 0°C and the mixture is stirred at room temperature for 2 hours. For working up, water is added and the mixture is extracted with KO J |1 KO"' H 0 2.0 g (5.01 mmol) of 3a,7a,12a-trihydroxy-24-nor-23-cholanic acid, 2.1 g (4.98 mmol) of methyl 3j3-amino-7a,12a-aihydroxy-24-cholanate (cf. EP-A-0 417 725), 1.36 g (10 mmol) of hydroxybenzotriazole and 1.04 g (5.4 mmol) of dicyclohexylcarbodiimide are stirred m 100 ml of dry tetrahydrofuran at room temperature for 24 hours. The reaction mixture is concentrated and the residue is chromatographed over silica gel (chloroform/methanol=85:15). 3.0 g (75%) of Example 13 are obtained. MS (FAB, 3-NBA/LiCl) C48H79NOg (798), 805 (M-t-Li+) Examples 14 to 31 of Tables I to 3 are obtained analogously to Example 13 (reactive —X—G2 derivatives are described m EP-A-0 489 423 or EP-A-0 417 725). 7ASLH 1 n MS (FAS 3-rioAJL.G.) n3 r ' n " f 3 I Ui v!: l -1 JU:J 2001 ! TABLE 1-continued Ex. X-C2 MS (FA3, 3-NBAyliG) CnHnNO,0(88«. 893 (M-U*) OMs. C*.J„NO, (598), 50J (M-U') OMe C,'+->'0(732). 739 (M-U*) C,H.,N0,(S12). 819 (M+U*) CisHnNO,Sij(972). 979 (m+u*) f INTELLECTUAL PROPERTY OFFICE OF N.Z. -1 jum 2cci ! p»rjji/^r7nrr,~^r^ j I Vv La ^ r i i i lira L-i/ TABLE 2 • JAL FRO'iriY \ OFriCc OF N.Z. - 1 ju:j 2cg1 •' INTELLECT, JAL FKOP^i OFFICc OF N.Z. -1 ju:j ?oci u57 TABLE Cw'i.N,Oio(8«), 3SI (M-U*) O<rtnV0»C745) 7-7CM.U*) CMHriXOr (75-5. 761 CMrL:*) O^^OMc -HN ; 'iMrELLPcrj/.L Fr.c.-: 1/ OFFICE Or fJZ. - 1 Ml 2cc1 i; ACS v r~-; ^ - KO" 3.0 g (3.76 mmol) of Example 13 are dissolved m 80 ml of ethanol, 30 mol of IN aqueous NaOH are added and the mixture is stirred at room temperature for 16 hours. For working up, 30 ml of water are added ana the alcohol is stripped off completely. After acidification with IN HCl, the precipitate is filtered off with suction, washed with water and dried in vacuo. 2.5 g (85%) of Example 32 are obtained. MS (FAB, j—NBA/LiCl) C47H77NOg (784) , 791 (M+Li ) Examples 33 to 50 of Tables 4 to 6 are oJotained analogously to Example 32 from the methyl esters (Tables 1-3) . NfELLECT'JAL PROP OFFICE OF N.Z ~ 1 j07j 2001 409 TABLE 4 If U (D ho' <-C2 ms (fab. 3-nba/liq) 33 35 c„h,,no, (82s). £35 (m+lo (572), 879 (m+lt) cnh„vo, (s3-!). 391 c-t+ut 36 37 c.js^.so, (765). 775 (m+lo c^.-j^vo, (798), 805 (m+lo i iMT~LL:CT'JAL PIOPE?, ; OFFICE OF N.Z. ! - 1 jum 20c1 I 2 t""- V a 3 :M i - ■ _ -c JAL . J- j or-,:]Cc c,- nz. 1 ju;j 2cci 411 43 C«K„N07 C7S-1}. 755 CM+LH C„HVOt 09%). SOS (M+UT OH H ' OH 45 C,HnN0, CSOO). S07 (M+LT) -Ktf OH "OH H OH I, ,M\ £LL-C". 'JAL P"OP: | OFFICE OF NZ. i - 1 ju:j 2cq1 ■ -~y c&.y r-r—7 TABI.E 6 X—02 -X-C2 MS (FAB, 3-NBA/UC) 46 47 4s 50 —HH c„h,,.n0, (742), 749 (m+lo c^:-:,3.no, c7s6) 793 (m+ln c.,h.^\0,0 (330) 837 (m+ut c„:-:7ino7 (72«). 733 (m+i_n c.jhn.s'o, (740), 747 (M+LD Examples 51 to 54 from Table 7 are obtained analogously to Example 5 from the acids described above. | 'NTH' TC" 'J/1' "C?: oivicz or tji. -1 JU:J 2cci a *2 / \ „ TABLE 7 Ex. HO -G1 MS (FAB. J-VBArt-G) il SOjH C«AjN:0 CS (391), 392 (M+K*) 52 53 C^H^N-OnS (°35), 942 (M+H*) C^H^V.O ,S (976). 1024 (M+H*) 54 C„H,jN,0^ (875). 920 (M+H*) SO}H Examples 55 to 57 of Table S are oota^icd analogously to Esampie 4. u% TABLE 8 -G2 MS (FAB. 3-KBAA-Q) 55 56 57 CQOH (S-i 11. 842 (m+h-) cstkunioto css5-). 392 (m+u*) Ciin.1.N'i0.1C929). 936 CM^-L") Examples 58 to 63 of Table 9 are obtained analogously to Example 13 ■M i cLLSEC7'JAL~ P"OP OFFICE OF N Z - 1 JU.M 2CC1 TABLE 9 1 f) 0M= Gl-i Cm the foUowms fonraLse, the frw vikacy of CI « cot ihoorn). G1 - MS (FAB, 3-.VBA/UC2) 58 59 SO 52 cuh-^no, (798), 805 (m+u*) cirfn.n'ch (782). 789 (m+u*) c,|k-no<(782). 789 (m+u") CiHt»NO,(798). 805 (M+U') gihnnoi (784), 751 (m+u*) r— - - (.^r;; -r. \v 'i oi-.-: o.- ,iz. 1 ju:j 20G1 n "i I vi Uj v 3 .U 416 il ii (a 5 TABLE 9-continucci OMc 53 GI- (ia the fallowing femnhr. ttw &s= vmlcacy of G i u not ihowra) GI— MS (FAB. >N*BAA_Q) C«H7jNO,C770). 777 CM+U*) HO1' Examples 64 to 69 of Table 10 arc obtained analogously to Example 32. TABLE 10 (A (The frze vairocr or CI is act Jhcwn m fallowicg fcmilac) GI— VIS (FAS 3-N3A/LiG) GiHnN'Oia84). 79i (M+Lr) 'M."2L' :C L.7M or-r-icc of n.z. -1 ju:j 2cci U 7 ■53 r TABLE 10-cammued 66 (The free valency of GI u sot lbo"*n a die follow^ famzdic) GI - MS (FAB. 3-NBAyUQ) CnHnNO, (763). 775 (M+L»') HO" H r0H 67 G)H77NOi(7S4), 791 The sodium salts of Exanioie 32 and all the examoles of Tables 4 to 8 and 10 can be prepared. The compound is dissolved m methanol, an equimolar amount of IN aqueous NaOH is added and the mixture u then evaporated m vacuo. |Ni ■ •=' i :C j,.\L r OrrlCE OF im. *1 2cci mb A-54 A bile acid derivative of the formula I li 1 \ / g i—x—2 wherein Gi is linked via tne side chain on atom No. 17 witn the bonding member X.to atom No. 3 of Go, and Gi is a radical of the formula II o R(2) R(3) z—-— V ck, / KXDC K(i) R(5) m which Z is one of the following radicals k-jc k \ \ ch—chi—chj—. ch—chj —. hjc \ ch—. or a single bond, B(l) is H, an alkyl radical having 1 to 10 carbon atoms or an alkenyl radical having 2 to 10 carbon atoms, R(2), R(3), R(4), R(5) are independently H, OH or R(2) and R(3), or R(4) and R(5) together form the oxygen of a carbonyl group, X is a single bond or a bridge member of the formula ill 'jal p.iopihy :i office of n.z. - 1 jum 20c1 y 9 BEJ7 0 0 11 II -(n),—a— h—c—(b),— UU I LCI\ LO) m which A is an alkylene chain, which is branched or unbranched, and which is optionally interrupted by —0—, —S—, or phenylene, the linkage of the phenyl ring being m the ortho-, meta- or para-position and the chain comprising 2 no 12 chain members, B is an alkylene chain which is branched or unbranched, and which is optionally interrupted by —0—, —S—, or phenylene, the linkage of the phenyl ring being m the ortho-, meta- or para-position and the cftam comprising 2 to 12 chain members, L(l), L(2) and L(3) are identical or different and are selected from H, an alkyl radical or alkenyl radical having up to 10 carbon atoms, a cycloalkyl radical having 3 to 8 carbon acorns, a phenyl radical, which is unsubstituted or mono- to crisubstituted by F, CI, Br, (Ci-C4-alJcyl or (Ci-C4-alkoxy, or a benzyl radical, which is unsubstituted or mono- to trisubstituted by F, CI, Br, (Ci~C4) -alkyl or (C1-C4)-alkoxy, q is 0 to 5; r is 0 or 1; s is 0 or 1; and t is 0 or 1, G2 is a radical of the formula IV 'nfcl'.ict'jal fwopriy office of n z. ju:j 2cci n 420 xn which Z is one of the followmcr radicals H,C K 3C^ CH-CK-.-C-:-— VH—CPV x\ or a single bond, with the proviso that: Z may be H]C\ CH—CKi—Z£-> — in only one of formulas II and IV; V is —O— or \ / or X ! H when W is H or, V is —CH2— or —CH.2—CH2— when W is H or OH, Y is —OL, NHL, —H / f \ 2'' 'A'. r""3.-2 .'1 ( Ol riCc Cr 1 1 Z. ' - 1 Ml 20c1 ^ ? n j or an amino acid or amino-sulfonic acid bonded via the ammo group, selected from the group consisting of —NH—CH2—COOH, —NH—CH2—CH2—-, SO3H, —N—C-n—CQOH wd —!jf—C-ij—CH?—SOjH, CH, CK, m which L is H, an alkyl radical or alkenyl radical having up to 10 carbon atoms, a cycloalkyl radical having 3 to 8 carbon atoms, a phenyl radical, which is unsubstituted or mono- to trisubstituted by F, CI, Br, (C1.-C4) -alkyl or (C1-C4)-alkoxy, or a benzyl radical, which is unsubstituted or mono- to trisubstituted by F, CI, Br, (C1-C4) -alkyl or (C1.-C4)-alkoxy, and R(6), R(7), R(8), R(9) are independently H, OH or R(6) and R(7) or R(8) and R(9) together form the oxygen of a carbonyl group. A-55 The bile acid derivative of the formula I, as described m A-54, wherein L is an alkenyl radical having 2 to 10 caroon atoms. A-56 The bile acid derivative of formula I, as described m A-54, wherein one or more of L(l), L(2) or L(3) is an alkenyl radical having 2 to 10_carbon atoms. uMTILLECT'JAL PROPERTY OFFICE OF N.Z. - 1 JU.M 2001 n 7^ n n ^ 1 A LT-J v .. j | J it-a LLy Non-absorbable, insoluble- ^asic, crosslinked polymers have been used for many years for binding bile acids and utilized therapeutically Bile acid derivatives described in Patent Application EP-A-0 439 423 have a high affinity for the ( WTZL'.ECT'IAl FROPZP. OFFICE OF N.Z. ' - 1 jum 20g1 4B ^ntestinal brie acid transportation system and therefore cillow specific inhibition of the enterohepatic circulation. <=97 r 7< // O A A-58 diineric bile acid derivatives of the formula 30 G1-X-G2 in which GI and G2 are linked in positions 3, 7 or 12 or by the side chain via the linker X. Bile acid derivatives in which GI is bonded to X via positions 7 or 12 and G2 is bonded to X via positions- 3, 7 or 12 or the side chain iimtzllecvja'. pp.opep.t office of n.z. -1 JU;J 2oci F5 r ^ r? i WlU not described in Lhe examples of the European Patent Application cited. / Pi A-59 of the formula I bile acid derivatives in which Y has the following meaning: OKa, in which Ka is an alkali metal, alkaline earth metal or quaternary 10 a-mmonium ion, -0L, -NHL, -NLj, an amino acid or aminosulfonic acid bonded via the amino group, such as, for example ■ riCOO„. 0,H ch3 ch3 and (Cj-C^)-alkyl esters, alkali metal and alkaline 15 earth metal salts and quaternary ammonium salts thereof, and in which L is H, an alkyl or alkenyl radical -having up to 10 carbon atoms, which is branched or unbranched, a cycloalkyl radical having 3 to 8 carbon atoms or a 20 phenyl or benzyl radical, which are unsubstituted or mono- to trisubstituted by F, Cl, Br, (C1-Ci}-alkyl- 1,4,:i":cruAL_pr.oP2?:i On ICE or- N.Z. - 1 JUN 2001 33 7 ^ or (C^-CJ-alkoxy, R1 is H, an alkyl or alkenyl radical having up to 10 carbon atoms, which is branched or unbranched, a cycloalkyl radical having 3 to 8 carbon atoms, a 5 benzyl radical, a biphenylmethyl or a triphenyl- methyl radical, in which the nuclei are unsubstituted or mono- to trisubstituted by F, Cl, Br, (C1-C<)-alkyl or (C^-CJ-alkoxy, or 10 a radical 0 O II II 0 -P-OL , -S-OL | II I -C-L 0 0 in which L has the abovementioned meaning, R2 to R5, R3 and R3 or R* and Rs in each case together being the oxygen of a carbonyl group, or indi-15 vidually and in each case independently of one another being 0 0 O 0L 0 II H 3 1 I H, -0T, -ST, -NHT, 0-C-T. -S-C-T, -NH-C-T. -0-P-0T. -O-S-OT, -T I u o o 20 in which T has the meaning of L or is a free valency for bonding the group X, and in which in total only one free valency starts from GI for bonding the group X, is a single bond or a group of the formula III 0 0 (III), -!-(N)s-A-N-C-[CH2) C-]r-N-[B)r L L' in which ,!\| i :i' ACTUAL PROPERTY office or- nz. - 1 jum 2cc1 nip —\ „ j j, y 10 At a t> G2 are alkylene chains, which ara branched cr unbranched, it being possible for the chains to be optionally interrupted by -0- or -S-, L ana are identical or different ana is have the meaning of L and q is zero to 5, r is zero or 1, s is zero or 1 and t is zero or 1 and a radical of the formula IV r9 r10 ( i v CJ ^ in wnicn 2 is a free valency no the group X or has the meaning given under Y, R* is a free valency to the group X or has the meaning 15 given under R1 and R7 to R10 have the meaning given under R2 to R5, and in which in total only one free valency starts from G2 to the group X. !' liNfZ! LEC/jAL r-r.J/I.TiY oh-ic: 0.- hz. - 1 ju.m 2cc1 Particularly preferred compounds of the formula I are those in which Gl is a radical of the formula II O^Y (id in which Y OH. 0-(CrC4)-A!kYi.-NHCH2COOH, -NCH-jCOOH, -NHCH2CH2SO3H, -NCH2CH2SO3H 1 1 CH3 CH3 R2 is H, benzyl, biphenylmethyl, fonnyl or acetyl, R2 to R5, R2 and R3 or and R5 in each case together being the oxygen of a carbonyl group, or individually and in each case independently of one another being q q I 1 H, -0T, -NHT, -O-C-T, -NH-C-T, -T in which T is H, a branched or unbranched (Cj-C^) -alkyl radical or a free valency to bridge group X, and in which a total of one free valency starts from GI for bonding the group X, is a bond, -n- . h -ch2ch2nh--ch2ch2ch2nh- 0 .(ch2)n-n-c-(ch2)m-c-n-(ch2)0-h h where n is 2 or 3, m is 1 to 4 and o is 2 or 3, and G2 is a radical of the formula IV r 3 R 10 o-^z 5 R 0 ( iv) in which Z is a free valency to group X or has the meaning 10 given above under Y, R4 is a free valency to group X or has the meaning given above under R1 and R7 to R10 have the meaning given above under R2 to R5, and in which only one free valency starts from G2 to the 15 group X. The process for the preparation of compounds of the formula I, i, INTELLECTUAL PROPE.T1Y | "office of nz. - 1 ju?j 20c1 RE-MSVE D comprises 57830 • ■) 5 b) c) 10 15 a) 20 25 30 in the case where X is a single bona, reacting suitable forms of GI and G2 with one another by processes which are known in principle, or in the case where X is a bridge group, reacting a) reactive forms of Gl-X with G2 or P) reactive forms of G2-X with GI by processes which are known in principle, or preparing compounds of the formula I (G1-X-G2) frcm Gl-Xl and X2-G2 by processes which are known or, where they are not known, by the processes described below in more detail, X being formed from XI and X2 by formation of a covalent bend, in particular within a condensation or substitution reaction. X is a single bond The bile acids GI are employed either in the free form or in protected form. After linking with G2, which is likewise present in a free or protected form, the protective groups are split off, if appropriate, and the C-24 carboxyl function is converted into a derivative, if appropriate. Suitable protective groups for the alcohol groups are expediently formyl, acetyl, tetrahydropyranyl or t-butyIdinethylsilyl. Various alkyl or benzyl esters, and also, for example, orthoesters, are suitable protective groups for the C-24 carboxyl group. For example, bile acid preferentially reacts at position 3, but also at position 7, with activated forms of carboxylic acids, such as acid chlorides or mixed anhydrides, with addition of bases, such as trialkylamine or pyridine, but also NaOH, at room temperature in suitable solvents, such as tetra-hydrofuran, methylene chloride or ethyl acetate, but also dimethylformamide (DMF) or dimethoxyethane (DME) . _ _ _ MO The various isomers can be separated, for example by chromatography. The reaction can be carried out selectively by using suitable protective groups. M * The corresponding amino-bile acids can be converted into corresponding amides analogously. Here also, the reaction can be carried out either with protected or with free bile acids. Other compounds can be linked analogously by known standard processes. 10 15 X is a bridge group The processes specified under a) are also used to carry out the linking of Gl-X with G2 or GI with X-G2. Here also, the bile acid portion is expediently employed either in protected or in unorotected form. 20 A preferred preparation process comprises reacting reactive forms of GI with reactive forms of X-G2. If appropriate, the linking reaction is followed by splitting-of£ of protective groups and conversion of C-24 carboxyl into derivatives. The preparation of reactive bile acid units Gl-X and X-G2 is shown in the following equation. R "0 OUt i iNTELLECJAL | j OF,-ICE Or N Z. j -1 ju;j 2cc1 33 & oN ou« + h2c ro 'OU t (vi ) (VII) 0 u« + ou« (ix) 1 iNrzL'ic JAL P?o?:rn jj or-r-icE of nz. - 1 jum 2cc1 n 17 <-> -r —■ n 432 R = H, forrny 1 or acetyl, R' = H or OH, R" = formyl or acetyl (XII) ( X ! I 1 ) ! wr—ic '/-| o;r:~: c: r - ! - 1 jit) 2cc1 X or x R 0' 0U» 0-(CH2h-HH2 433 ^ 4 .. v J XI or XI H2H-(CH2h-0 ^ _ J OU e (XIV) (XV) ho rr^^H-(cH2)„-o 0 = OU t 0-{CH1),-N h 0 oh QW j (IYI I) R = H, formyl or acetyl, R' = H or OH, n = 2 or 3 Compounds of the type V in which the 3-position is 5 protected are reacted with allyl bromide/Hiinig base or triethylamine. If the compound V has one OH group, the alkylation is unambiguous; if two free OH groups are present, monoalkylation takes place at positions 7 and 12 in approximately equal proportions and only traces of the 10 dialkylated product are formed. The protective group in the 3-position can either be split off with sodium methyiate or retained for further reactions. r The , —- — - ! ACTUAL FRO?:?:./ office of nz. ' - 1 JUM 2CC1 ip "t> r7 ^ V R 7\ IfiL 3378 monoalkylated compounds VI and VII can be split with ozone or with OsO^/NalO^ to give the aldehydes VIII and IX. The 7-and 12-hydroxyethyl compounds X and XI are readily accessible from these by simple reduction, for 5 example with NaBH4. The corresponding 7- and 12-hydroxy-propyl derivatives XII and XIII can be synthesized from the allyl compounds VI and VII by hydroboration. The aminoalkyl derivatives XIV and XV can be prepared from the hydroxyalkyl compounds of the type X to XIII by a 10 reaction sequence which is known in principle (mesylation of the primary OH group with methanesulfonyl chloride/ pyridine, azide exchange with NaN-, in dimethylformamide, reduction of the azide function with hydrogen under catalytic conditions). Further reaction of the amino 15 functions of these compounds with succinic anhydride gives bile acid units of the type XVI and XVII. Suitable bile acid units furthermore are described in EP-A-0 489 423. .NTELLECV'JA1- IT-OPE?/! / ,1 OFrlCE Or N.Z. -1 ju:j 2cci n „ ^ ^ L U l_a v >. i J 435 £j ' j , ,1 A-60 Examples 1 and 2 150 g (0.32 mol) of methyl 3-acety 1-cholate, 500 ml of dimethylformamide, 125 ml of N-ethyl-diisopropylamine and 7 0 ml of allyl bromide are heated under reflux for 16 20 hours. New allyl bromide (25 ml) is added every 2 hours. The reaction solution is evaporated on a rotary evaporator. The residue is partitioned between water/methylene chloride and the organic phase is separated off and dried with magnesium sulfate. After column chromatography 25 (ethyl acetate/cyclohexane 1:2, silica- gel 70-200 ^m) , the product fractions are evaporated on a rotary evaporator. Yield = 92.2 g of 7-/12-allyl mixture. ' ,m7"l'.ec7'jal f"q?;?ty i j office of nz. - 1 jum 2cc1 | C30H<8Os (504TJ, MS 511 (M + Li") The mixture was separated by fractional crystallization with n-heptane. ExamDle 3 1 & "Z AcO OW e A c ow s 5 50 g (0.1 mol) of Example 1, 250 ml of diethyl ether and 250 ml of water are initially introduced into the reaction vessel, while stirring vigorously. 503 mg (0.002 mol) of osmium tetroxide are added. The mixture is stirred at room temperature for 15 minutes. 53 g 10 (0.25 mol) of sodium periodate are added in portions over the course of 1 hour, and the mixture is subsequently stirred for 8 hours, while stirring vigorously. The ether phase is separated off, dried with magnesium sulfate and evaporated on a rotary evaporator. 15 Yield: 47 g of crude C23H,s07 (506), MS 513 (H + Li') Example 3 is further reacted without additional purification . Example 4 4.2 g (0.11 mol) of sodium borohydride are added in 20 portions to 47 g (0.093 mol) of Example 3 and 250 ml of [ IN fELL-CV'JAL PROP:;; OFFICE OF N.Z. -1 ju:j 2oci r* f ^ ^ i ,,r"1 7 10 methanol a.t 0°C. After 2 hours at Q°C, the reaction ^solution is poured onto saturated ammonium chloride solution, the mixture is extracted 3 times with ethyl acetate and the combined organic phases are dried with magnesium sulfate and evaporated on a rotary evaporator. After column chromatography (ethyl acetate/cyclohexane 1.5:1, silica gel 35 - 70 tim) , the product fractions are evaporated on a rotary evaporator and the residue is crystallized with' diisopropyl ether. Yield: 25 g of C„H„07 (508), MS 515 (M + Li*) Example 5 AcO 10 g (0.02 mol) of Example 1 and 250 ml of tetrahydro-furan were initially introduced into a reaction vessel at room temperature, and 4 0 ml (0.04 mol) of borane-tetra-15 hydrofuran complex (1 molar) were added dropwise at room temperature. The mixture was subsequently stirred at room temperature for 2 hours, and 25 ml of water, 25 ml of 2 N sodium hydroxide solution and 25 ml of 35% strength hydrogen peroxide solution were added dropwise in 20 succession. The mixture was subsequently stirred at room temperature for a further 15 minutes. The reaction solution was poured onto water, the mixture was extracted 3 times with diethyl ether and the combined organic phases were dried with magnesium sulfate and evaporated 25 on a rotary evaporator. Yield: 8.5 g of C30H50O7 (522), MS 529, (H + Li*) Example 5 was further reacted without additional purification . 1 T-'I/VI D«0'3—17V o.rTcz of nz. - 1 JU?J 2CC1 A c 0^ H 0 U e H 10 g (0.02 mol) of Example 4 and 100 ml of pyridine are initially introduced into a reaction vessel at 0°C. 1.7 ml (0.022 mol) of methanesulfonyl chloride are added 5 dropwise at 0"C and the mixture is subsequently stirred at 0°C for a further 30 minutes and at room temperature for 2 hours. The reaction solution is poured onto water, the mixture is extracted 3 times with ethyl acetate, and the combined organic phases are dried with magnesium 10 sulfate and evaporated on a rotary evaporator. The residue is dissolved in 100 ml of dimethylf onnamide, 1.4 g ( 0 . 022 mol) of sodium azide are added and the mixture is stirred at 80°C for 2 hours. The reaction solution is poured onto water and the mixture is worked L5 up as described above. The residue is dissolved in 100 ml of methanol, 100 mg of palladium-on-charcoal (10%) are added and hydrogenation is carried out under normal pressure for 2 hours. The catalyst is filtered off and the filtrate is evaporated on a rotary evaporator. After 20 column chromatography (ethyl acetate/ HeOH/Et3N 10:1:1, silica gel 70-200 Jim), Example 6 is obtained. Yield -= 7.3 g of C„H„NOt (507), MS 514 (M + Li*) Example 7 H H OH 0 9 8.^mg (0.001 mol) of succinic anhydride are added to 500 mg (0.001 mol) of amino compound, 20 ml of tetra-hydrofuran and 4 ml of triethylamine at room temperature. The mixture is subsequently stirred at room temperature for 1 hour. The reaction solution is poured onto 25% strength sodium dihydrogen phosphate solution, the mixture is extracted 3 times with ethyl acetate and the organic phase is dried with magnesium sulfate and evaporated on a rotary evaporator. Yield: 580 mg of C33H53NO, (607), MS 614 (M + Li*) Example 7 was further reacted without additional purification . Examples 8 to 12 were prepared analogously to Examples 3 to 7. Examples 8-12 Example R11 MS 8 -CHjCHO 513 (M + Li") 9 -CHjCHJOH 515 (M + Li") 10 -CH2CH2CH20H 529 (M + Li*) 11 -ch2ch3nh2 514 (M + Li") 12 -ch2ch2nhcoch2ch2cooh 614 (M + Li") intellect. jal rr.ofip office of i 1 z. - 1 ju:j 2GC1 440 3 Example 13 ho °^o u« + cholic acid HH H oh H 300 mg (0.73 mmol) of cholic acid, 330 mg (0.78 ininol) of methyl 7P-amino-3a , 12a-dihydroxy-S[5-cholanate (Redel, Bull. Soc. Chim. Fr. , page 877 , 1949), 240 mg (0.97 mmol) of EEDQ and 0.25 ml of diisopropylethylamine are stirred in 20 ml of DMF at 90°C for 4 hours. After cooling, the reaction mixture is concentrated and the residue is chromatographed over silica gel (CH2Cl2/MeOH 8.2) . C<5H31N03 (812) 819 (M + Li*). The two bile acid derivatives can also be linked with triethylamine in methylene chloride or with dicyclohexylcarbodiimide, hydroxybenzotriazole or triethylamine in tetrahydrofuran. The compounds of Table 1 were prepared analogously to Example 13. Table 1 1 2 h R .NTcLLECV'JAL PP3PZPJY I ' OFFICE OF N.Z. - 1 2cc1 441 7 <n ? <t) / "* / Example R12 Rn Ru MS (FAB, 3-NBA/Licl) 14 a-OH H -OH C,,H91N07 (796) 803 (M + Li*) 15 P-OH H -OH C<jHs1N07 (796) 803 (M + Li+) 16 H H -OCHO C50H31NO7 (808 .5) 809.5 (M-fH+) 10 The examples of Table 2 were obtained analogously to Example 13 from Examples 7 and 8. j OFFICE OF NZ. - 1 jum 2cc1 Example x] R15 MS (FAD, 3-NBA/LiCl) 17 -'NU- H CsjHstNOio (098) 905 (M + Li+) 18 -NH- diphenylmetliyl C^H^NO^ (1064) 1071 (H + Li+) 19 -NHCO (CH,) jCONH (CII3) 3NH — H Cio"„N3Ou ( 1054) 1061 (M + Li+) 20 i -NHCO (CIlj) jCOMH (CIlj) jNH- diphenylmetliyl «—ij1 :-i,-———1 ■ ■ —- ( 1220) 1227 (M + Li4) 443 7 n The examples of Tables 3 and analogously to Example 13. 4 were likewise obtained Table 3 AcO \ s 5 Example R1S MS (FAB, 3-NEA/LiCl) 21 H_° w« JPh K C„H100N3014 (1097) 1104 (M+L*) 22 'U -% 1 o s 1 X 1 CtoH5SN2013 (1055) 1104 (M+L"*) E .iSifE!Lr:C,( , | OFrlCc OF N.Z. J -1 ju;i ?cci ! |l r ^ . n v . r-i ^ I 444 Example R17 MS (FAB, 3-NBA/LiCl) 23 0 HO H Qv ^X^V/0 H H CS3H37NOia (893) 905 (M+L*) 24 OH <J °r#P A «ov H H CgjH100N2O14 (1097)1104 (M+L") 25 8 y* 9 1 CtoE,,N013 (1055 ) 1062 (M+L*) 1 Mi £1L ~-C, JAL } OivlCE CF NZ. ; - 1 ju;j 2GC1 250 mg (0.31 mmol) of Example 13 are dissolved in 20 ml of ethanol, 2 ml of IN NaOH solution are added and the mixture is stirred at room temperature for 16 hours. For 5 working up, the mixture is concentrated, the residue is dissolved in H20, the pH is brought to 1-2 with 2N HCl and the mixture is concentrated again. The residue is chromatographed over silica gel (CHCl3/MeOH 8 :2). 220 mg of free acid are obtained (90%). 10 MS (FAB, 3-NBA/LiCl) C4,H7sNO, (798 ) 805 (M + Li*) The examples of Tables 5 to 8 are obtained analogously to Example 26. Table 5 ■\l i £'i . 7 ... i' i i ( Orriv-C Or 1^1 Z. !U! 2CC1 446 Example R1J R13 MS 27 a-OH H C,8H79N07 (782) 789 (M+Li*) 28 p-OH H C48H7,N07 (782) 7 89 (M+Li*) 29 H H C43H7,N07 (766) 773 (M+Li*) -• ' J/\'_ r .-> of 1 JU;I 20C1 Example X3 R15 MS 30 -NH- . II C50II,5NO10 (060) 067 (M + Li+) 31 -NH- diphenylmethyl CnIl,5NOJ0 (1026) 1033 (M + Li+) 32 -NHCO (CH,) jCONU {CH,) ,NH- H C5?H,7N30.3 ( 1016) 1023 (M + Li+) 33 -NIICO (CH,) ,CONH (CH,) 3NH- diphenylmethyl C10flio7N3On ( 1102) 1109 (M + Li+) 448 Example R1' MS 34 HJ? 1 I H J H- H C34H„N2012 ( 985) 992 (M+Li*) 35 0 » xOtlT" H C5aH,sN2012(985) 992 (M+Li*) iNrr^c"-o: :^".Y '< c ;iz. • -1 ju:j 2cci ; ...... ™»J 449 ExairiDle 36 37 38 R 17 MS (FAB, 3-NBA/LiCl) C50Hs3NO, (842) 849 (M+Li/ C5<Hs2N2Ol2 (985) 992 (M+Li") (985) 992 (M+Li*) The foiiowxng glycine conjugates and. taurine conjugates were obtained analogously to synthesis processes which have already been described (EP 489 423). i^Nf-I' cC'TlUPROP-RTY "office of n.z. - 1 ju;j 2CC1 Example R" Rn MS (TAD, 3-tlOA/LiCl 39 a-OH a-OH C50H„,HjO)0S (905) 910 (M + 2Li+-H+) 40 a-OU U C50»b4 NjO,S (089) 890 (H + H+) 41 p-OII H C,„H,4NaO,S (009) 912 (M ,+ Na+) 42 U H C5oH84Nj°bs (B72 .5) 095.5 (M + Na+) \ Example X3 R" MS 43 -NH- 11 C5JH,0N3O13S (967) 974 (M + Li+) 44 -NB- diphenylmethyl ( 1133) 1140 (H + Li+) 45 -NHCO(CH3) 3CONH{CHj)3NH- H ( 1123) 1130 (M + Ll+) 46 ~NHCO (CH3) jCOND (CH3) 3NH- diphenylmethyl ■ CtjH.^N.O^S ( 1209) 1296 (H + Li+) 452 Example 47 h MS (FAB, 3 -NBA/LiCl) Ci0HxolN3O1AS ( 1092) 1099 (M + Li") Exanrole 48 ,s 0 j h MS (FAB, 3-NBA/LiCl) C72Hll0N«O„ (1239) 1246 (M + Li+) Table 11 shows measurement values for the inhibition of the uptake of [ 3H]-taurocholate in brush border membrane vesicles from the ileum of rabbits. The quotients of the IC30 and IC50 Na values of the reference substance tauro-chenodeoxycholate (TCDC) and of the particular test substance are stated. 453 rahie XI 10 15 20 25 30 ComDOund from Example IC50-TCDC [ jimol ] IC50x*~TCDC [ pmol ] IC30-substance[ pmol ] ICJ0lu-substance [ pmol ] 20 0.00 0. 12 26 0.00 0.29 , , 27 0.64 0.44 28 0 .54 0.43 29 0 .23 0.17 30 0.93 0 .85 32 1.00 0.80 39 0.92 1.05 40 0.54 0.52 43 • H-1 1 CD ! 0.96 47 0 . 35 0.26 00 0. 75 0.71 INTELLECTUAL PROPERTY OFFICE OF NZ. - 1 JUN 2001 RECEIVED 454 ^A-61 A bil6" acid derivative of the formula I GI - X - G2 I 13 in which GI is a radical of the formula II r 1 in which O^Y (id 10 Y has the following meaning: OKa, in which Ka is an alkali metal, alkaline earth metal or quaternary ammonium ion, -OL, -NHL, -NLj, an amino acid or aminosulfonic acid bonded via the amino group, such as, for example .NHCU COOH. -NHCH2CH2S03H, -NCH2C00H, -NCH2CH2SO3H i i CH, CH, 15 20 and (C,-C<)-alkyl esters, alkali metal and alkaline earth metal salts and quaternary ammonium salts thereof, and in which L is H, an alkyl or alkenyl radical having up to 10 carbon atoms, which is"branched or unbranched, a cycloalkyl radical having 3 to 8 carbon atoms or a phenyl or benzyl radical, which are unsubstituted or mono- to trisubstituted by F, C1, Br, (Cj-CJ-alkyl or )-alkoxy ( R1 is H, an alkyl or alkenyl radical having up to 10 carbon atoms, which is branched or unbranched, a cycloalkyl radical having 3 to 8 carbon atoms, a INTELLECTUAL PROPERTY OFFICE OF NZ. - 1 JUN 2001 DECEIVED berrzyl radical, a biphenylmethyl or a triphenyl-methyl radical, in which the nuclei are unsubstituted or nono-to trisubstituted by F, CI, Br, (C,-C<)-alkyl or (C1-CA)-alkoxy, or a radical 0 O 8 8 o -p-ol , -s-ol 8 1 I -c-i o o in which L has the abovementioned meaning, R2 to R5, R3 and R3 or R* and R5 in each case together 10 being the oxygen of a carbonyl group, or indi vidually and in each case independently of one another being 0 0 0 0l o II I I 3 h. -0t. -57, -nht, 0-c-t, -s-c-t, -nh-c-t, -o-p-ot. -0-s-0t. -t 0 0 in which T has the meaning of L or is a free valency for bonding the group X, 15 and in which in total only one free valency starts from GI for bonding the group X, X is a single bond or a group of the formula III 0 0 8 1 ■[-(N),-a-n-c-(ch2),-c.],-n-(b];- (111), U '3 l1 l2 l3 in which A and B are alkylene chains, which are branched 20 or unbranched, it being possible for the chains to be optionally interrupted by -O- or -S-, L1, LJ and L3 are identical or different and INTELLECTUAL PROPERTY OFFICE OF NZ. - 1 JUN 2001 456 331P y, ^ have the meaning of L and " ^ ^ q is zero to 5, r is zero or 1, s is zero or 1 and t is zero or 1 and G2 is a radical of the formula IV Z is a free valency to the group X or has the meaning given under Y, R' is a free valency to the group X or has the meaning given under R1 and R7 to R10 have the meaning given under R2 to Rs, and in which in total only one free valency starts from G2 to the group X. A bile acid derivative of the formula I as ^ i , in which GI is a radical of the formula II INTELLECTUAL PROPERTY OFFICE OF NZ. - 1 JUN 2001 RECEIVED 457 in which $53 !i ^ y is OH, O-tC-j-C^}-Alkyl, -NHCH2COOH, -nch2c00h, -nhch2ch2so3h, -nch2ch2so3h 1 CH CH3 3 RJ is H, benzyl, biphenylmethyl, formyl or acetyl, R2 to R4, R2 and R3 or R^ and R5 in each case 5 together being the oxygen of a carbonyl group, or individually and in each case independently of one another being 0 0 S 1 H, -0T, -NHT. -Q-C-T, -NH-C-T, -T in which T is 10 H, a branched or unbranched (Cj-C<)-alkyl radical or a free valency to bridge group X, and in which a total of one free valency starts from GI for bonding the group X, X is a bond, -n- , h -ch2ck2nh- -ch2ch2ch2nh- 0 0 • 1 u -{ch2)n-n-c-(ch2)m-C-n-(CH2]0-H H where n is 2 or 3, m is 1 to 4 and o is 2 or 3, and G2 is a radical of the formula IV 15 INTELLECTUAL PROPERTY OFFICE OF NZ. - 1 JUiM 2001 RECEIVED 458 /H 4 ^ (IV) in which Z is a free valency to group X or has the meaning given above under Y, R' is a free Valency to group X of has the meaning given above under R1 and R7 to R10 have the meaning given above under R2 to R5, and in which only one free valency starts from G2 to the group X. INTELLECTUAL PROPERTY OFFICE OF NZ - 1 JUN 2001 DECEIVED 459 33 79 y "W A-63 Monomeric bile acid derivatives or the formula I, Z-X-GS in. which GS is a bile acid radical having an acid function m the side chain or a salt thereof, X is a covalenn bond or a bridge group of the formula (CH2)n where n=l to 10, in which the alkylene chain can contain 1 to 3 oxygen atoms, NH or a a, groups, and in which GS is bonded via X as desired, and Z 13 KQ~ c-:3-o-, hq-gh,-c-; = c-'-c-.,- o (CUijJj — CH — 0 —, JOkak-O —3_TQa_ II 0 n 0 fl II KO— 3—0 —, (KiCi)0 — a—O — I I QH CXCH,) 0 0 11 II CHj=CKJ— C-Vrf —, HjN—C —S-H— O Nri il II Hjs—C — — KtH — C — N"—'— I 3 — MRh sr —NCR)] INTELLECTUAL PROPERTY OFFICE OF N Z. - 1 JUN 2001 RECEIVED 460 where R is in each case Ci-C7 alkyl, or H2-N- (CH2) e-, C8 d g4? — btk— (cht)s-u —kh- (Cj—Cx c> AJty t-C—NH, where the alkyl moiety is optionally substituted by a COOH group, INTELLECTUAL PROPERTY OFFICE OF NZ. - 1 JUN 2001 RECEIVED ?3?0 where A is in each case OH or NH(Ci-Cio) alkyl. Preferred compounds of the formula I are those in which GS is linked to X in the 3-position, linking taking place in the a- or Imposition . An acid function is understood as meaning, m particular, the COOH group or the sulfonic acid group. Alkyl radicals are straight-chain or branched. The compounds of the formula (I) according to the invention have a high affinity for the specific bile acid transportation system of the small intestine and inhibit bile acid absorption in a concentration-dependent and competitive manner. By competitive inhibition, intervention m the enterohepatic circulation can be considerably more selective. Avitaminoses are not to be expected, and a qualitative change m the bile acid composition m the bile is ]ust as unlikely. A controlled reduction m the serum cholesterol level can be achieved with compounds according to the invention, without the known side effects being observed. Because of their high affinity for the bile acid transportation system, very much lower daily doses than with the commercially available polymers are sufficient; this also leads to a high acceptance by patient and doctor. The compounds have valuable pharmacological properties and are therefore particularly suitable as hypolipidemic agents. The invention thus also relates to medicaments based on the compounds of the formula (I) and to the use of the compounds as medicaments, in particular for reducing the cholesterol level. The compounds according to the invention were tested biologically by determination of the inhibition of [JH] INTELLECTUAL PROPERTY 1 OFFICE OF N Z. - 1 JUN 2001 461 RECEIVED 462 I <j\j xh y taurocholate uptake in the brush border membrane vesicles from the ileum of rabbits. The inhibition test was carried out as follows: 1. Preparation of brush border membrane vesicles from the ileum of rabbits. Brush border membrane vesicles were prepared from the intestinal cells of the small intestine by the so-called Mg2+ precipitation method. Male New Zealand rabbits (2 to 2.5 kg body weight) were sacrificed by intravenous infection of 0.5 ml of an aqueous solution of 2.5 mg of tetracaine HCl, 100 T 61r and 25 mg of mebezonium iodide. The small intestine was removed and rinsed with ice-cold physiological saline solution. The terminal 7/10 of the small intestine (measured m the oral-rectal direction, i.e. the terminal ileum, which contains the active Na+ dependent bile acid transportation system) was used for preparation of the brush border membrane vesicle. The intestines were frozen in plastic bags under nitrogen at -80°C. For preparation of the membrane vesicles, the frozen intestines were thawed at 30°C, in a water bath. The mucosa was scraped off and suspended m 60 ml of ice-cold 12 mM Tris/HCl buffer (pH 7.1)/300 mM mannitol, 5 mM EGTA/10 mg/1 of phenylmethylsulfonyl fluoride/1 mg/1 of trypsin inhibitor from soybeans (32 U/mg)/0.5 mg/1 of trypsin inhibitor from bovine lung (193 CJ/mg)/5 mg/1 of bacitracin. After dilution to 300 ml with ice-cold distilled water, the mixture was homogenized with an Ultraturrax (18-rod, IKA Werk Staufen, FRG) for 3 minutes at 75% of the maximum output, while cooling with ice. After addition of 3 ml of 1M MgCl2 solution (final concentration 10 mM), the mixture was left to stand at 0°C, for exactly 1 minute. The cell membranes aggregate by addition of Mg2+ and precipitate, with the exception of the brush border membranes. After centrifugation at 3000x g (5000 rpm, SS-34 INTELLECTUAL PROPERTY OFFICE OF NZ. - 1 JUN 2001 RECEIVED 463 rotor) for 15 minutes, the precipitate was discarded, and the ^ _ pi supernatant, which contained the brush border membranes, was centrifuged at 267000x g (15000 rpm, SS-34 rotor) for 30 minutes. The supernatant was discarded and the precipitate was rehomogenized m 60 ml of 12 mM Tris/HCl buffer (pH 7.1)/60 mM mannitol, 5 mM EGTA using a Potter Elvejhem homogenizer (Braun, Melsungen, 900 rpm, 10 strokes). After addition of 0.1 ml of 1 M MgCl2 solution and an incubation time of 15 minutes at 0°C, the mixture was centrifuged again at 3000x g for 15 minutes The supernatant was then centrifuged again at 46000x g (15000 rpm, SS-34 rotor) for 30 minutes. The precipitate was taken up m 30 ml of 10 mM Tris/Hepes buffer (pH 7.4)/300 mM mannitol and resuspended homogeneously by 20 strokes m a Potter Elvejhem homogenizer at 1000 rpm. After centrifugation at 48000x g (20000 rpm, SS-34 rotor) for 30 minutes, the precipitate was taken up m 0.5 to 2 ml of Tris/Hepes buffer (pH 7.4)/230 mM mannitol (final concentration 20 mg/ml) and resuspended with the aid of a tuberculin syringe with a 27 gauge needle. The vesicles were either used immediately for transportation studies after preparation, or stored at -196°C. in portions of 4 mg m liquid nitrogen. 2. Inhibition of Na^-dependent [°H]-taurocholate uptake in tne brush border membrane vesicles of the ileum. The uptake of substrates into the brush border membrane vesicles described above was determined by means of the so-called membrane filtration technique. 10 jllI of the vesicle suspension (100 jag of protein) were pipetted as drops onto the wall of a polystyrene incubation tube (11x70 mm) which contained the incubation medium with the corresponding ligands (90 p.1) . The incubation medium contained 0.75 jil=0.75 fiCi of [JH (G) ]-taurocholate (specific activity: 2.1 Ci/mmol)/0 .5 j-il of 10 mM taurocholate/8 . 75 jxl of sodium INTELLECTUAL PROPERTY OFFICE OF NZ. - 1 JUN 2001 RECEIVED 464 ^ ti 8 3 0 transportation buffer (10 mM Tris/Hepes (pH 7.4)/100 mM mannitol/100 mM NaCl) (Na-T-P) or 8.75 jil of potassium transportation buffer (10 mM Tris/Hepes (pH 7.4)/100 mM mannitol/100 mM KC1) (K-T-P) and 80 jj,1 of the inhibitor solution in question, dissolved m Na-T buffer or K-T buffer, depending on the experiment. The incubation medium was filtered through a polyvmylidene fluoride membrane filter (SYHV LO 4NS, 0.45 jam, 4 mm (|>, Millipore, Eschborn, FRG) . The transportation measurement was started by mixing the vesicles with the incubation medium. The concentration of taurocholate m the incubation batch was 50 |-iM. After the desired incubation time (usually 1 minute), the transportation was stopped by addition of 1 ml of ice-cold stopping solution (10 mM Tris/Hepes (pH 7.4)/150 mM KC1) . The mixture formed was immediately filtered off with suction over a membrane filter of cellulose nitrate (ME 25, 0.45 |um, 25 mm diameter, Schleicher & Schuell, Dassell, "FRG) under a vacuum of 25 to 35 mbar. The filter was rinsed with 5 ml of ice-cold stopping solution. To measure the uptake of the radioactively labeled taurocholate, the membrane filter was dissolved with 4 ml of the scintillator Quickszint 361 (Zinsser Analytik GmbH, Frankfurt, FRG) and the radioactivity was measured by liquid scintillation measurement m a TriCarb 2500 measuring instrument (Canberra Packard GmbH, Frankfurt, FRG). After calibration of the instrument with-the aid of standard samples and after correction for any chemilummescence present, the values measured were obtained as dpm (decompositions per minute). The control values were m each case determined in Na-T-P and K-T-P. The difference between the uptake in Na-T-P and K-T-P was the Na^-dependent transportation content. The concentration of inhibitor at which the Na+-dependent INTELLECTUAL PROPERTY OFFICE OF NZ. - 1 jun 2001 K E C E1 ¥ E D 465 • 33 ~ rransportacion content was inhibited by 50%-based on tire control-was designated as the ICsoNa". The table shows the measurement values of the inhibition of the [3H]-taurocholate uptake m brush border membrane vesicles from the ileum of rabbits. The quotients of the IC50 and IC50Na values of the taurochenodesoxycholate (TCDC) investigated as the standard m each vesicle preparation and the particular substance are stated. stance Example: IC50 (TCDC) ICsONa (TCDC) IC50 (Substance) ICsoNa (Substance) 3 0 . 4 0 .35 4 0.77 0 . 69 18 0 . 47 0 . 42 21 0.34 0 . 33 33 0.33 0.35 35 1.0 1. 02 36 0 .19 0.20 38 0 .49 0 .41 40 0 .52 0 . 50 43 0.78 0 .73 The invention furthermore relates to the use of the compounds according to the invention for the preparation of a medicine. For this, the compounds of the formula I are dissolved or suspended in pharmacologically acceptable organic solvents, such as mono- or polyhydric alcohols, such as, for example, ethanol or glycerol, or in triacetm, oils, for example INTELLECTUAL PROPERTY OFFICE OF NZ. - 1 JUN 2001 466 33 7 sunflower oil or cod-liver oil, ethers, such as, for example, diethylene glycol dimethyl ether, or also polyethers, for example polyethylene glycol, or also m the presence of other pharmacologically acceptable polymeric carriers, such as, for example, polyvinylpyrrolidone, or other pharmaceutically acceptable additives, such as starch, cyclodextrin or polysaccharides. The compounds according to the invention furthermore can be administered m combination with other medicaments. The compounds of the formula I are administered in various dosage forms, preferably orally m the form of tablets, capsules or liquids. The daily dose varies m the range from 3 mg to 5000 mg, but preferably m the dose range of 10 to 1000 mg, depending on the body weight and constitution of the patient. The particular monoisotopic molecular weights calculated are stated in the following examples. Unless stated otherwise, mass spectra were recorded by the FAB technique with addition of LiCl and 3-nitrobenzaldehyde [3-NBA]. Starting compounds which have the bile acid structure have already been described m some cases (cf., for example, EP-A-0 417 725, EP-A-0 489 423 and EP-A-0 548 793. R1 is defined m Example 6. EXAMPLE 1 \ H (CH?),—OH intellectual pf OFFICE OF - 1 JUN 2 KEGE3V - 1 JUN 2 467 COOK H O '' QH \ K (CHi'v — OH 1 g (1.96 mmol) of the methyl ester a is dissolved in 15 ml of tetrahydrofuran (THF) or 1,4-di'oxane and"" the solution is stirred intensively with 10 ml of 2N NaOH overnight at room temperature. It is then diluted with a large quantity of water and acidified with half-concentrated hydrochloric acid, while cooling with ice. Precipitation is brought to completion by subsequent stirring for 1 hour, while cooling with ice, and the precipitate formed is filtered off with suction and rinsed with cold water. Recrystallization from ethanol/water and drying m vacuo give 940 mg (96%) of Example 1. C29H50O6 (494) MS: 501 (M+Li+) . The following Examples 2 to 7 are prepared analogously to "Example 1" from the corresponding bile acid esters: Example As "Example 1" Empirical No. where n = Formula MW MS 2 6 C30H52O6 508 515 (M + Li+) 5 4 10 8 9 C32H56O6 536 543 (M + Li+) C33H58O6 550 557 (M + Li ) C34H60O6 564 571 (M 4- Li+) - 1 jun 2001 received 468 HO- EXAMPLE 6 COQH Cufi.,0,(496) MS. 503 (M + li') EXAMPLE 7 HG Ciorij^3, (540) MS. 517 (M-U') EXAMPLE 8 COOK 100 mg (0.2 mmol) of the methyl ester are dissolved m 10 ml of dioxane and the solution is stirred with 3 ml of half-concentrated sodium hydroxide solution at room temperature for 6 hours. The mixture is diluted with water and acidified with half-concentrated hydrochloric acid to give, after filtration with suction and washing, the acid "Example 8" (50 mg, 51%). C29H47NO5 (489) MS: 496 (M+Li+) intellectual property office of nz. - 1 jun 2001 PUGGED 469 \ -4.J The following substance examples were Example 8": EXAMPLE 9 prepared as for H?C. C2*RoN0»(505) MS. 512 CM - U*) EXAMPLE 10 o H,C (CHi)« NH" i = 5 CnHnXQt&-tT) MS.554 (M-U4) EXAMPLE 11 HjC 'HH' (CKi)*" -R.1 CjjHjjtN'Ofi (561) MS.5&8 (hi + W) EXAMPLE 12 " N7f NTT C3;HnNi07 C5~6) MS. 533 CM - L-*) EXAMPLE 13 KH—(CKi)« H,C —Cf Cj4K59.NO7C.s93) MS SCQ(M-rU-) EXAMPLE 14 HjC—O" ' N"H—(CHi), — R1 a = .' ZnHfjSO, (575) MS. 586 (M t LI") INTELLECTUAL PROPERTY OFFICE OF N.Z. - 1 JUN 2001 DECEIVED 470 EXAMPLE 1! 33783 H-jC—O' CjoHSINOJ (£51) Nr-(CKi)„-=l MS. 544 CM + Li"! i , -i EXAMPLE 16 OK OK 0 0.84 ml of triethylamine is added to 3.14 g (6 mmol) of the primary alcohol a (n=6) m 100 ml of dry methylene chloride and the mixture is cooled to -10°C. 0.4 ml (6 mmol) of chlorosulfonic acid in 20 ml of dry methylene chloride is added to the solution at this temperature. After 1 hour at 0°C. and 1 hour at room temperature, water is added, the organic phase is separated off, the aqueous pnase is extracted several times with ethyl acetate and the combined organic phases are dried and concentrated. The residue is purified by chromatography (Si02, ethyl acetate/methanol=3:1). 1.45 g (40%) of "Example 16" are obtained. C33H54O9S (602) MS: 631 (M-H>Li+Na + ) 615 (M-H+2Li + ) EXAMPLE 17 0 II Compound ."rora Eii.Tp!c 1 6 NaO — S— O—— =1' J INTELLECTUAL PROPERTY OFFICE OF N.Z. - 1 JUN 2001 RECEIVED 33 g (0.83 mmol) of "Example 16" is stirred in 20 ml of dioxane with 7 ml of half-concentrated soaium hydroxide solution at room temperature for 6 hours. The mixture is then acidified with half-concentrated hydrochloric acid, while cooling, and is concentrated m vacuo. The residue is purified by column, filtration (SiCb, ethyl acetate/methanol=3:1). 254 mg (52%) of "Example 17" are obtained.. C30H51O9S (610) MS = 617 (M+Li1") 601 (M-Na++2Li+) ^ > EXAMPLE 18 15 ml of phosphoric acid diphenyl ester chloride are added dropwise to a solution of 2.6 g (5.12 mmol) of "Example 2" m 20 ml of pyridine at 0 to 5°C and the mixture 13 subsequently stirred at room temperature for 2 hours. It is poured onto 200 ml of ice-water, about 15 mi of concentrated sulfuric acid are added, while stirring and cooling, and the mixture is extracted several times with ethyl acetate. The organic phase is dried and concentrated and the residue is purified by chromatography (Si02, CH2Cl2/CH3OH=10:1). 1.78 g (47%) of "Example 18" are obtained. C^HgxOgP (740) MS: 747 (M+Li"") EXAMPLE 19 HO — 3 — 0—(CHO* — R' I OH INTELLECTUAL PROPERTY j OFFICE OF N.Z. - 1 JUiM 2001 RECEIVED 472 37 1 g (1.35 mmol) of "Example 18" is hydrogenated in 50 ml of glacial acetic acid with a spatula-tip of platmum-on-charcoal in a shaking vessel. When the reaction has ended (about 4 hours), the catalyst is filtered off with suction and the filtrate is concentrated. The residue is purified by column filtration (Si02, ethyl acetate/CH3OH=2:1) . 270 mg (34%) of "Example 19" are obtained. C30H53O9P (588) MS: 601 (M-H++2Li+) 595 (M+Li+) KiN--(CH,)s-0 EXAMPLE 20 OH COOCh) HiN :OQCro ' VK — (CKz)*. — O 2.24 g (4 mmol) of amine h and 324 mg (4 mmol) of potassium cyanace are suspended in 60 ml of water and the suspension is heated to boiling point. A solution is formed, from which a solid precipitates after a short time. The mixture is stirred at boiling point for 30 minutes and cooled, about 40 ml of water are added and the mixture is acidified with dilute hydrochloride acid. It is extracted several times with ethyl acetate, the organic phase is dried and concentrated in vacuo and the residue is purified by chromatography (S1O2, EtOAc/CH3OH=10:1). 520 mg (23%) of "Example 20" are obtained. C32H56N205 (564) MS: 571 (M+Li+) EXAMPLE 21 K-jiV XK— —R1 intellectual property OFFICE OF NZ. - 1 JUN 2001 DECEIVED 473 33783 4^) mg (O.mmol) of "Example 20" are stirred m 10 ml of dioxane with 5 ml of half-concentratea sodium hydroxide solution at room temperature for 6 hours. When the reaction has ended, the mixture is diluted with water, acidified with hydrochloric acid and subsequently stirred m an ice-bath for 1 hour. The precipitate is filtered off with suction and rinsed with water to give, after drying m vacuo, 430 mg (97%) of "Example 21". 2 mmol of phenyl isocyanate in 5 ml of methylene cftlorxae are added to 1.04 g (2 mmol) of amine b (Example 20) in 50 ml of dry methylene chloride and 28 ml of triethylamine at 0°C. The mixture is subsequently stirred at room temperature for 6 hours and worked up as described under "Example 16", the aqueous phase being acidified. After column filtration (CH2C12/CH3OH=10:1), 6540 mg (51%) of "Example 22" are obtained. C38H6oN206 (640) MS: 647 (M+Li+) C3iH54N206 (550) MS: 557 (M4-Li+) EXAMPLE 22 EXAMPLE 2 3 0 C37H38N,09 MS: 633 (M+L:~) intellectual property office of nz. - 1 JUN 2001 474 m 33 EXAMPLE 2 4 COOCK-, (H>QjN-(C-:IJs—0 1 ^ ,e H OH 2.08g (4 mmol) of amine b, 10 ml of trxxsobutylamxne and 5 ml of lodomethane are heated at boxlxng poxnt xn 50 ml of acetronxtrxle for 2 hours. All the volatile constituents are removed m vacuo and the residue is purified by chromatography (Si02, CH2C12/CH3OH=10: 1). 1.2 g (43 %) of "Example 24" are obtained. C34H62INO5 (691) MS (FAB, 3-NBA) : 564 (M-l0) EXAMPLE 2 5 CKjChbN—(CH,)*-*' Compound Example 25 is prepared from Example 24 analogously to "Example 21". The crude product is purified by medium pressure chromatography over RP-8 silica gel (CH30H/H20=7:3) C33H6oCIN05 (585) MS (FAB, 3-NBA) : 550 (M-Cl0) EXAMPLE 2 6 CHj N A HN NHi NH JL zKBr NHj >TH—(CH*), —O iHBr COOChj intellectual property office of nz - 1 JUN 2001 ^ E 0 E S ¥ E 0 475 # 1.04 g (2 mmol) of amine b and 276 mg (2 mmol! of pyrazole c are heated under reflux m 40 ml of ary acetonitrile for 10 hours. After cooling and addition of ether, a precipitate is formed, and is filtered off with suction ana rinsed with dry ether. After drying, 450 mg of "Example 26" are obtained. C32H53ErN305 (643) MS: 570 (M-HBr+Li+) 564 (M-BRe) 1.0 g (1.9 mmol) of amine b, 265 mg of NaBH3CN ana 610 mg of heptanal are stirred m 10 ml of ary methanol at room temperature for 48 hours. The mixture is concentrated m vacuo, the residue is partitioned between ethyl acetate and saturated bicarbonate solution and the residue of the organic phase is purified by chromatography. In addition to a small amount of monoheptylamino derivative, 650 mg (49%) of "Example 28" are obtained. C45H83N05 (718 ) MS : 725 (M+LiT) EXAMPLE 27 is prepared analogously to "Example 21". C3iHssC1N305 (585) MS: 556 (M-HCl+Li+) 550 (M-Cl9) EXAMPLE 2 8 intellectual property office of nz - 1 JUN 2001 476 tC-^ 2 / n C,u-'2 iHQ is prepared analogously no "Example 21". The aqueous phase is decanted off from the oily crude product after acidification, and the residue is extracted by stirring with ethyl acetate and then filtered off with suction and dried. C44H82CINO5 (740) MS: 711 (M-HCl+Li4") 705 (M-Cl0) ^7/ n n ,5 is prepared analogously to "Example 28" and "Example 29" by reductive amination of anthracene-9-carbaldehyde with metnvl 3a-(ammoethyl)-7a, 12a-aihydroxy-24-cholanate (d) and subsequent alkaline hydrolysis. CaiH55N04 (625) MS: 632 (MtLi") EXAMPLE 31 is prepared analogously to "Example 30" using cyclododecanone as the carbonvl component. C38H87N04 (602) MS: 609 (M+Li + ) intellectual property office of nz. - 1 J UN 2001 R E e E fi I? E D 477 33 0 EXAMPLE 32 CQOR R=CH 0 c—XH— CH, — c- H 0.38 G (2 mmol) of naphthoyl chloride m 5 ml of CH2C12 is added to 0.9 g (2 mmol) of amine d and 0.6 ml of triethylamine in 20 ml of dry CH2CI2, while cooling with ice. The mixture is subsequently stirred at 0°C. for 1 hour and left to stand overnight. Water is added, and the mixture is acidified and extracted several times with CH2CI2. The residue from the organic phase is purified by chromatography (Si02, EtOAc/cyclohexane=311). 1 g (83%) of "Example 32" is obtained. C38H53NO5 (603) MS: 610 (M+Li") EXAMPLE 33 Is prepared analogously to "Example 21". C37H51NO5 (589) MS: 596 (M+Li+) INTELLECTUAL PROPERTY j OFFICE OF N Z. - 1 JUiM 2001 DECEIVED 478 33 EXAMPLE 3 4 C—NK—Crii—CHj COOH is prepared analogously to "Example 32" and "Example 33' using anthracene-9-carbonyl chloride. C41H53NO5 (639) MS: 646 (M+Li+) EXAMPLE 35 HjC S02 —NH—— is prepared analogously to "Example 34" using p-toluene-sulfonyl chloride and amine b. C37H59NO7S (661) MS: 668 (M+Li+) EXAMPLE 3 6 HjC SO7 — N—— R' I CHi is prepared analogously to "Example 35". The methyl ester obtained as an intermediate product is methylated in dimethylformamide, after deprotonation by sodium hydride, 1 INTELLECTUAL PROPERTY OFFICE OF NZ. - 1 JUN 2001 ^ [EC ES¥ED 479 ^.th lodomethane at room temperature. The product is then subjected to alkaline hydrolysis analogously to "Example 35" C38H6iN07S (675) MS: 688 (M-H++2LiT) 682 (M+Lix) '' x> EXAMPLE 37 NH—CCHj^-R1 COOH is prepared analogously to "Example 34" using o-phthalic anhydride and amine b. C38H57N08 (655) MS: 668 (M-fT+2Li + ) 662 M+Li+) EXAMPLE 3 8 C — VH —CChJtf — R1 is prepared analogously to "Example 32"/"Example 33" using amine b. C41H59NO5 (661) MS. 668 (M+Li + ) EXAMPLE 3 9 ci 0 I! CHJ—CHj —sch—0CHj : \ (I OCTi 0 v, 0 (O)- C - NH-CH7 —CHj —{0)~s°i'~— 0 OCHj INTELLECTUAL PROPERTY OFFICE OF NZ. - 1 J'JN 2001 480 vv / y 426 mg (1 mmol) of uretnane and 732 mg (15 mmol) of amine b are heated under reflux m 50 ml of dioxane for 4 hours. The mixture is then concentrated ana the residue is purified by chromatography (Si02, CH2Cl2/CH30H=10:1). 540 g (59%) of "Example 3 9" are obtained. C47H70CIN3O10S (915) MS: 922 (M+Li") EXAMPLE 4 0 j ^—SO7 — NK Vn—^ QH] is prepared analogously to "Example 21". C47HS8C1N3OioS (901) MS (electrospray) : 902 (M+H ) 750 mg (3.6 mmol) of dicyclohexylcarbodiimide are added to a solution of 1.56 g (3 mmol) of amine b, 576 mg (3 mmol) of China acid and 490 mg (83.6 mmol) of hydroxybenzotriazole m 100 mi of THF. The mixture is stirred at room temperature for 40 hours. The urea formed is filtered off, the solution INTELLECTUAL PROPERTY OFFICE OF NZ - 1 JUN 2001 481 3 is concentrated and the residue is taken up m ethyl acetate. The solution is washed with saturated NaHC03 solution, 2N citric acid, saturated NaHC03 solution and water. The residue from the organic phase is purified by chromatography (S1O2, ethyl acetate/CH30H= 5:1). 1.2 g (58%) of^Example 41" are obtained. C38H65NOio (695) MS: 702 (M+Lit) EXAMPLE 4 2 0 OH is prepared analogously to "Example 21". C37HS3NOio (681) MS (FAB, 3-NBA) : 682 (M+H") EXAMPLE 4 3 c I H—C—OH 1 HO—C-H 1 H—C—QH I H—C—OH I CKtOH Is prepared analogously to "Example 41"/"Example 42" using gluconic acid. C36He3NOii (685) MS: 714 (M-H++Li++Na+) INTELLECTUAL PROPERTY OFFICE OF N Z. - 1 JUM 2001 R E (S E G r c: 482 33 7 3 j EXAMPLE 4 4 N-cch^-O CQQC-i] 0 a COO,H 1.04 g (4 mmol) of acid chloride e, 2.1 g (4 mmol) of amine b and a spatula-tip of 4-dimethylaminopyridme are stirred in 40 ml of dry pyridine at room temperature for 6 hours. After standing overnight at room temperature, the mixture is concentrated m vacuo. "Example 44" is isolated after purification by chromatography (Si02, CH2C12/CH30H=20 :1) . C43H69N09 (743) MS: 750 (M+Li1") EXAMPLE 4 5 w o Is prepared analogously to "Example 21". C42H67N09 (729) MS: 742 (M-H++2Li + ) 736 (M+Li + ) EXAMPLE 4 6 INTELLECTUAL PROPERTY \ OFFICE OF NZ. K - 1 JUN 2001 U S € E£ 3 E 0 483 c/7 2.6 g (5 mmol) of amine b m CH2CI2 are added to 1.3 g (5 mmol) of acid chloride e and 0.8 ml of triethylamine in 50 ml of dry CH2CI2/ while cooling with ice, and the mixture is stirred at 0°C. for 1 hour. An excess of methanol is then added, the mixture is allowed to come to room temperature, water is added and the mixture is acidified with dilute hydrochloric acid. The aqueous phase is extracted several times by shaking with CH2C12. After purification of the residue from the organic phase by chromatography (S1O2, CH2Cl2/CH3OH=10 :1) , "Example 46" is obtained. c44h73no10 (775) MS: 783 (M+LO EXAMPLE 4 7 is prepared analogously to "Example 21". C42H69NO10 (7 4 7) MS: 760 (M-H++2LiT) 754 (M+Li+) EXAMPLE 4 8 484 3370/^ 3.14 g (6 mmol) of alcohol a (n=6; are heated at 100°C; with 3 ml of ethyldiisopropylamine and 1.5 g of diphenylmethyl bromide m 5 0 ml of DMF for 8 hours. After aqueous working up and purification by chromatography (Si02, 20 CH2C12/CH30H=10:1), "Example 48" is obtained. C44H64O6 (688) MS: 695 (M+Li+) is prepared analogously to "Example 21". C43HS20S (674) MS: 681 (M+Li+) The following compounds are prepared analogously to Example 1 from the corresponding bile acid esters by-alkaline ester hydrolysis: EXAMPLE 4 9 EXAMPLE 50 COOH cjsh<a04 mw: 478 ms: 485 (m+li~ 485 EXAMPLE 51 HO 33 COOH P TU ^ c23h.6oj mw- 462 ms. 469 (m-l:+) EXAMPLE 52 H7N — (Chik—0' c3qh33nom mw- 491 ms. 498 (m-h*) EXAMPLE 53 rN--(CH:«—o COOH CQOCKj —(CK})j —CKj is prepared from Example 44 and n-hexylamrne analogously to Example 41 with a reaction time of 25 hours. C49H82N2O9 (827) MS: 834 (M+Li+) EXAMPLE 54 ■NH—(CHjis —R' COOH C — N"H — (CKi)3 ~~ Otj INTELLECTUAL PR' OFFICE OF N ~ 1 JUiM 2001 U E S E PJ 486 33 7 © ^ 170 mg of "Example 53" are dissolved in 5 ml of dioxane, 1.5 ml of half-concentrated sodium hydroxide and 25 ml of water are added, and the mixture is stirred at room temperature for 12 hours. A suspended solid filtered off and the filtrate is acidified with dilute hydrochloric acid, stirring is continued for 1 hour, and the precipitate formed is filtered off with suction. After drying, 154 mg of "Example 54" are obtained. C48H82N209 (831) MS: 838 (M+Li") EXAMPLE 55 HO CONrt— (CH;)s — H1 Prepared analogously to "Example 53" and "Example 54' from fluoresceine and amine b. C5OH63N09 (821) MS: 828 (M+Li+) EXAMPLE 5 6 C-v nh-tchiji-r1 ch3 Prepared analogously to "Example 55" from pivalic acid and amine b. C35H6iN06 (591) MS: 598 (M+Li + ) INTELLECTUAL PROPERTY OFFICE OF N Z - 1 JL'N 2331 KESf-ff ED 487 33 EXAMPLE 57 N"H —(CK&— is prepared analogously to "Example 55" from 2-sthylnexanoic acid and amine b. C38H57N06 (633) MS: 640 (M+Li") EXAMPLE 53 H-jC \ KH— \CKw— is prepared analogously to "Example 55" from clofibric acid and amine b. C40H62CINO7 (703) MS: 710 (M+Li+) EXAMPLE 5 9 a NH—(O.0« — is prepared analogously to "Example 55" from gemfibrocil and amine b. C45H73NO7 (740) MS: 747 (M+Li+) INTELLECTUAL PROPERTY j OFFICE OF N Z J - 1 JoN 2301 488 33 EXAMPLE 60 HjC Prepared from 522 mg of amine b and 94.1 mg of di-n-propylmalonxc acid m THF m the presence of DCC/HOBT. Isolated after 54 h. The yield is 69%. C4oH69N08 (690) MS: 697 (M+Li+) EXAMPLE 61 HjC. CQ,H 250 mg of "Example 60" are hydrolyzed m dioxane using 2N NaOH. After aqueous work-up and purification by column chromatography ,(Et0Ac/CH30H 10:1), 160 mg of compound 61 are obtained. C39H67NO8 (676) MS: 677 (M+l) A-6 4 A monomeric bile acid derivative of the formula 1A coos. INTELLECTUAL PKO.-LITIY OFFICE OF N "?.. - 1 JUN 2001 489 33 Wherein R is H, CH3 or M and M is a metal capable of forming a salt, X is a bridge group of the formula (CH2)nc where n=l to 3, m which 1 to 3 (CH2) -groups can be replaced by NH or Nn'C — li 0 groups, or a bridge group of the formula (CH2)n where n=4 to 10, m which 1 to 3 (ch2)- groups can be replaced by oxygen atoms, NH or NHC — II o groups with the proviso that no neighboring (CH2) - groups ars replaced by oxygen atoms and m which GS is bonded via X as desired; and Z is HO— CH-j — 0— KO - CH, - Cn = C-. - C-U -, a II (CoHjh—CH — O —, Aikiil-O — 3 — O—, I! o 0 o II II HO — 9— 0 —, (HjQJQ — s—O—, 1 I OK O(CiHj) 0 0 li ' II CH: = C~';—C—NH—, Hj<\—C —HH —, 0 kh li II HN—C—HI!-. fljN' — C — NK —, I C+K; a —N'fRh.. ^ —N'(&h or —NCR), y intellectual property office of n z. - 1 JUN 2901 EflWEiS) 490 where R is xn each case C1-C7 aikyi, or H2~N-(CH2) ?/■ 33 RFT7 c-:,-kk- (chj)3_H ck-vh- (Ci-Ci^Aikyi-C—N"H—, where the alkyl moiety is optionally substituted by a COOH group, >th— -NH- H}C- / \ - SO1 — N"H - f intellectual PROPERTY O-fice OF N.Z. 1 JUN 2001 491 where A is in each case OH or NH (C1-C10) alkyl. A-65 A bile acid derivative of the formula I as described m A-64, m which GS is linked to X in the 3-position, linking taking place m the a- or p-position. W7ELLECTUAL property" OFFICE OF NZ. - 1 JUM 492 APPENDIX B HMG CoA Reductase Inhibitors 33 COMPOUNDS and COMPOUND CLASSES CAS NUMBERS for SPECIFIC and REPRESENTATIVE COMPOUNDS REFERENCE l Benfluorcx 23602-78-0 ES 474498 Euvastatin 93957-54-1 EP 244364 Lovastatin 75330-75-5 EP 22478 Pravastatin 81093-37-0 DE 3122499 Simvastatin 79902-63-9 EP 33538 Atorvastatin 134523-00-5 EP 409281 Cerivastatin 145599-86-6 JP 08073432 Bervastatin and related benzopyrans 132017-01-7 EP 380392 BMS 180431 129829-03-4 Sit, Parker, Motoc, Han, Balasubra-manian, Catt, Brown, Hane, Thompson, and Wright, J.Med Chem. (1990), 33(11), 2982-99. NK-104 141750-63-2 Takano, Kami ku bo, Sugihara, Suzuki, Ogasawara, Tetiahedron:Assymetry (1993), 4(2), 201-4 if M (Car boxydihydroxyheptenyl)sulfbnylpyrro les including S-4522 148966-78-3.139993^4-5,139993-45-6,139993-46-7,139993-47-8, 139993-48-9,139993^9-0,139993-50-3,139993-51-4, 139993-52-5, 139993-53-6,139993-54-7,139993-55-8,139993-56-9,139993-57-0, 139993-58-1,139993-59-2,139993-60-5,139993-61-6,139993-62-7, 139993-63-8,139993-64-9,139993-65-0,139993-66-1,139993-67-2, 139993-68-3,139993-69-4,139993-70-7,139993-71-8, 139993-72-9, 139993-73-0,139993-74-1,139993-75-2,139993-76-3,139993-77-4. 139993-78-5,139993-79-6,139993-80-9,140110-63-0,140128-98-9, 140128-99-0,140157-62.6- EP 464845 Boron Analogs of di- and tripepudes 125894-01-1,125894-02-2,125894-03-3,125894-04-4,125894-05-5, 125894-08-8,125894-09-9,125914-96-7 Sood, Sood, Spielvogel, Hall, Eur. J. Med. Chem. (1990), 25(4), 301-8. Zaragozic acids 157058-13-4,157058-14-5,157058-15-6,157058-16-7,157058-17-8, 157058-18-9,157058-19-0 GB 2270312 !Ni£LLECTUAL PROPERTY OFFICE OF NZ. - 1 JUN 2GG1 ^ ^ r-i n r " r-j r-* U n i} li II \j Li LJ 493 3 e> 1 b 3 Seco-oxysterol analogs including U-88156 157555-23-7,157555-29-8 pyridopyri mi dines including acitemate 64405-40-9,101197-99-3 Larsen, Spilman, Yagi, Dinh, Hart, and Hess, J. Med. Chem. (1994), 37(15), 2343-51. Hermecz, Meszaros, Vasvari-Debreczy, Horvath, Virag, and Sipos, Hung. Arzneim-Forsch. (1979), 29(12), 1833-5 BMY 22566 Coles tolone CP-8310I Dalvastatin Dihydromevinolin 129829-03-4 50673-97-7 130746-82-6,130778-27-7 132100-55-1 77517-29-4 Sit, Parker, Motoc, Han, Balasubra-manian, Can, Brown, Harte, Thompson, and Wright, J.Med. Chem. (1990), 33(11), 2982-99. Raulston, Mishaw, Parish and Schroepfer, Biochem. Biophys. Res. Common. (197(5), 71(4), 984-9. Wint and McCarthy, J. Labelled Compd. Radiopharm. (1988), 25(11), 1289-97. Kumar, Windisch, Trivedi and Golebioivski, J. Chromatogr., A (1994), 678(2), 259-63. Falck and Yang. Tetrahedron Lett (1984), 25(33), 3563-66. DMP-565 Pyridyl and Pyrimidinylethenyldesmethyl- 122254-45-9 mevalonates including glenvastin OR 95030 157243-22-6 130581-42-9,130581-43-0,130581- EP 369323 44-1, 130581-45-2,130581^6-3, 130581-47-4,130581-48-5,130581-49-6,130581-50-9,130581-51-0, 130581-52-1,130619-07-7, 130619-08-8,130619-09-9 Isoxazolopyridylmevalonates, carboxylic adds and esters Lactones of 6-phenoxy-3,5-dibydroxy-hcxanoic adds 127502-48-1,136006-66-1,136034-04-3 Ko, Trzaskos, Chen, Hausner, Brosz, and Srivastava, Abstr. Papers Am. Chem. Soc. (207th National Meeting, Pan 1, MEDl10,1994) Beck, Kesseler, Baader, Bartmann, Bergmann, Granzer, Jendralla, Von Kerekjano, Krause, et al, J. Med. Chem. (1990), 33(1), 52-60. US 5316765 Jenderella, Granzer, Von Kerekjano, Krause, Schacht, Baader, Bartmann, Beck, Bergmann, "et al., J. Med. Chem. (1991), 34(10), 2962-83. I INTELLECTUAL PROPERTY \ 1 OFFICE OF NZ. | j - 1 JUN 2301 1 I | 494 *5 L659699 L669262 Mevastafl'n Pannorin Rawsonol RP 61969 Bile arid derived HMG CoA reductase inhibitors including Na S-2467 and 5-2468 SC 32561 SC 45355 Phosphorus containing HMG CoA reductase inhibitors including SQ 33600 6-Aiy!oxyrathyl-4-hydroxytetrahydro-pyran-2-ones, carboxylic acids and salts Atorvastatin calcium (CI 981) 29066-42-0 130468-11-0 73573-88-3 137023-81-5 125111-69-5 126059-69-6 76752-41-5 125793-76-2 133983-25-2 135054-71-6,136215-82-2,136215-83-3,136215-84-4,136215-85-5, 136315-18-9,136315-19-0,136315-20-3,136315-21-4,136316-20-6 134523-03-8 Chiang, Yang, Heck, Chabala, and Chang, J. Org. Chem. (1989), 54(24), 5708-12. Stokker," J. Org. Chem. (1994), 59(20), 5983-6. JP 56051992 Ogavva, Hasumi, Safcai, Murakana and Endo, J. Andbiot. (1991), 44(7), 762-7 Carte, Troupe, Chan, Westley and Faulkner, Phytochemistry (1989), 28(11), 2917-19 EP 326386 Kramer, Wess, Enhsen, Bock, Falk, Hoffmann, Neckermann, Gantz, Schulz, et al., Biochirn. Bioohys. Acta D (1994), 1227(3), 137-54. US 4230626 EP 329124 US 5274155 EP41864S Baumann, Butler, Deering, Mennen, Millar, Nanninga, Palmer and Roth, Tetrahedron Lett. (1992), 33(17), 2283-4 Fenofibrate Benzaftbrate Etofibrate Mevinolin analogs I^rajjone derivatives 2,2,4-TriazoIidIne-3t5-<iiones 49562-28-9 41859-67-0 31637-97-5 16044-43-2 DE 2250327 DE 2149070 US 3723446 EP 245003 US 4937259 W090GG897 INTELLECTUAL PROPERTY OFFICE OF NZ. - 1 JUN 2001 R G G G G V1 D 495 Isoazo!idine-3,5-dtones 124756-24-7 CS-514 81181-70-6 l,10-bis(carboxyraethylthio)decane 32827-49-9 a-, P-, and y -alkylaininophenone analogs including N-phenylpiperazinopropio-phenone 3-Amino-l-(2,3,4-mononitro-, mono-, or dihalophenyl)propan-l-ones including 3-morpholino- or piperidino-l-(3-nitrophenyl)propan-l-ones Substituted isoxazolo pyridinones 64769-68-2 Biphenyl derivatives 4-[l-(Subsdtuted phenyl)-2-oxo-pyrroticSn-4-yl]methoxy benzoic adds Dihydroxy(tetrahydxoindazo(yl, tetrahydrocyclopenapyrazolyl, or hexahydrocydohep(apyrazole)heptenoa£e derivatives EP 321090 DE 3122499 DE 2038835 Huang and Hall, Eur. J. Med. Chem. (1996), 31(4),281-90. Huang and Hall, Arch. Pharm. (1996), 329(7), 339-346. US 4049813 JP 07089898 ' Watanabe, Ogawa, Ohno, Yano, Yamada and Shirasaka, Eur. J Med. Chem. (1994), 29(9), 675-36. US 5134155 il INTELLECTUAL PROPERTY OFFICE OF NZ. - 1 JUN 2001 R 3 S 2 3 V E 0 496 t benfluores fluvastatin lovastatin pravastatin simvastatin atorvastatin cerivastatin bervastatin BMS-180431 NK-104 S-4522 Boron Analogs HMG-CoA Reductase Inhibitors HMG-CoA Reductase Inhibitors U-8815S Servier Sandoz Merck & Co Sankyo Merck &. Co Warner-Lambert Bayer Merck KGaA Bristol-Myers Squibb Nissan Chemical Shionogi Boron Biologicals British Biotech & Japan Tobacco Merck &, Co Pharmacia & Upjohn A-1233 Kitasato University acitemate Mitsubishi Chemical BAY-w-9533 Bayer BB-47S British Biotech BMS-18043S Bristol-Myers Squibb BMY-225SS colestolone American Home Products CP-8310I Pfizer dalvastatin Rhone-Poulenc Rorer dihydromevino1 in Merck & Co DMP-565 DuPont Merck glenvastatin Hoechst Marion Roussel GR-95030 Glaxo Wellcome HMG-CoA Reductase Inhibitors Bristol-Hyers Squibb HMG-CoA Reductase Inhibitors Ono HMG-CoA Reductase Inhibitors, Chiral Chiroscience HMG-CoA Reductase Inhibitors, isoxazolo- Nissan Chemical pyridine HMG-CoA Reductase Inhibitors, seco-oxysterol Pharmacia & Upjohn HMG-CoA Reductase Inhibitors, thiophene Sandoz HMG-CoA Reductase Inhibitors, S-phenoxyr. Hoechst Marion Roussel 3 , 5- dihydoxyhexanoic acids hypolipaemics, Warner-Lambert Warner-Lambert L-SS9S99 Merck & Co L-S69262 Merck & Co mevastatin - Sankyo N-((1-me thyIpropy15 carbonyl)- Sandoz 8- (2- {tetrahydro-4-hydroxy-S-oxo-2H-pyran-2-yD ethyl) -perhydro-isoquinoline INTELLECTUAL PROPERTY OFFICE OF NZ. - 1 JUN 2001 R E S 21! V E i 497 N-{1-oxododecyl)-4 alpha,10-dimethyl-8- aza-trans -decal-3beta-ol P-882222 pannorin rawsonol RP 619S9 S-24S8 S-853758A (S) -4- {(2-{4-{4-fluorophenyl)-5-methyl- 2- (1-me thyl ethyl) -S -phenyl-3 -pyridinyl) e thenyl 5 hydroxypho sphinyl) - 3-hydroxybutanoic acid, disodium. salt SC-325S1 sc-45355 SDZ-265859 SQ-33S00 (4R-(4alpha, fibeta(E)))-6- {2-(5-{4-fluorophenyl)-3-{1-methyl-ethyl)-1-(2-pyr idinyH-pyrazo 1 - 4-yl) ethenyl) tetrahydro -4 -hydroxy- 2H-pyran-2 -one 5-b e ta-amino - e thy 1 thi op ent ano i c acid derivatives S - amino - 2 -mercap t o - 5 -me thy Ipvr iiai dine -4-carboxylic acid S-phenoxymethyl- & 6-phenylethylen- (4-hydroxy-tetrahydrapyran-2-one) analogues Koechst Marion Roussel Nissan Chemical Tokyo Noko University SmithKline Beecham Rhone-Poulenc Rorer Hoechst Marion Roussel Hoechst Marion Roussel Bristol-Myers Squibb Monsanto Non-industrial source Sandoz Bristol-Myers Squibb Warner Lamberc Boehringer Mannheim North Carolina Univ Hoechst Marion Roussel atorvastatin (4R- (4alpha, Sfceta(E))) -6- (2- (5- (4-f luorophenyl) -3- (1-methyl-ethyl5 -1- (2-pyriainyH-pyrazol-4-yl} ethenyl) t e trahydro - 4-hydr oxy-2H-pyran-2-one intellectual property office of n z. - 1 JUN 2001 K ^ ^ r? n 4? Li S V ED </div>

Claims

<div class="application article clearfix printTableText" id="claims"> What is Claimed is: 1. A composition, comprising an ileal bile acid transport inhibitor and an HMG Co-A reductase inhibitor. 2. The composition of claim 1 wherein the HMG Co-A reductase inhibitor is selected from the group consisting of lovastatin, simvastatin, pravastatin and fluvastatin. 3. The composition of claim 1 wherien the HMG Co-A reductase inhibitor is pravastatin. 4. The composition of claim 1 wherein the HMG Co-A reductase inhibitor is simvastatin. 5. The composition of claim 1 wherein the HMG Co-A reductase inhibitor is lovastatin. 6. The composition of claim 1 wherein the HMG Co-A reductase inhibitor is atorvastatin. 7. A pharmaceutical composition, comprising: a first amount of an ileal bile acid transport inhibitor, and a second amount of an HMG Co-A reductase inhibitor, wherein said first and second amounts of said inhibitors together comprise an anti-hyperlipidemic condition effective amount of said inhibitors, and a pharmaceutically acceptable carrier. 8 . The pharmaceutical composition of claim 7 wherein the HMG Co-A reductase inhibitor is selected from intellectual property" office of N.z - 1 JUN 2001 deceived 499 H3 / the group consisting of lovastatin, simvastatin, pravastatin and fluvastatin. 9. The pharmaceutical composition of claim 7 wherein the HMG Co-A reductase inhibitor is pravastatin. 10. The pharmaceutical composition of claim 7 wherein the HMG Co-A reductase inhibitor is simvastatin. 11. The pharmaceutical composition of claim 7 wherein the HMG Co-A reductase inhibitor is lovastatin. 12. The pharmaceutical composition of claim 7 wherein the HMG Co-A reductase inhibitor is atorvastatm. 13. The composition of any one of the preceding claims wherein the ileal bile acid transport inhibitor is a compound of formula (I): wherein: q is an integer from 1 to 4; n is an integer from 0 to 2; R1 and R2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, I intellectual property office of nz. - 1 JUN 2001 U2ZH !¥ED %% 1 n ~ Q j-y *- " 1 10 alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are 15 substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N+R9R10RWA-, SR9, S+R9R10A" , P+R9R10R11A", S (0) R9, S02R9, S03R9, C02R9, CN, halogen, oxo, and CONR9R10, wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, 20 alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or more carbons replaced by 0, NR9, N+R9R10A~, S, SO, S02, S+R9A", P+R9R10A~, or phenylene, wherein R9, R10, and Rw are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, 2 5 cycloalkyl, aryl, acyl, heterocycle, heteroaryl, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; or R1 and R2 taken together with the carbon to which they are attached form C3-C10 cycloalkylidene; R3 and R4 are independently selected from the group 3 0 consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, heteroaryl, OR9, NR9R10, SR9, S(0)R9, S02R9, and S03R9, wherein R9 and R10 are as defined above; or R3 and R4 together form =0, =NORxl, =S, =NNR1XR12, =NR9, or =CRUR12, 3 5 wherein R11 and R12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, heteroaryl, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR9, NR9R10, SR9, S(0")R9, S02R9, S03R9, C02R9, CN, 4 0 halogen, oxo, and CONR9R10, wherein R9 and R10 are as defined above, provided that both R3 and R4 cannot be OH, NH2, or SH, or R11 and R12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; 4 5 R5 and R6 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, quaternary INTELLECTUAL PROPERTY OFFICE OF NZ. - 1 JUN 2201 RECEIVED 501 1 9 50 55 60 65 70 75 heterocycle, quaternary heteraryl, SR9, S(0)R9, S02R9, and S03R9, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR13, NR13R14, SR13, S(0)R13, S02R13, SO3R13, NR13OR14, NR13NR14R15, N02, C02R13, CN, OM, SO2OM, SO2NR13R14, C(0)NR13R14, C(0)0M, COR13, P(0)R13R14, P+R13R14R15A", P(OR13)OR14, S+R13R14A", and N+R9R11R12A", Wherein: A" is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can be further substituted with one or more substituent groups selected from the group consisting of OR7, NR7R8, SR7, S (O) R7, S02R7, S03R7, C02R7, CN, oxo, CONR7R8, N+R7R8R9A", alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(0)R7R8, P+R7R8R9A', and P(0) (OR7) OR8, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can optionally have one or more carbons replaced by O, NR7, N+R7R8A", S, SO, S02, S+R7A", PR7, P(0)R7, P+R7R8A", or phenylene, and R13, R14, and R15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, heteroaryl and polyalkyl optionally have one or more carbons replaced by O, NR9, N+R9R10A", S, SO, S02, INTELLECTUAL PROPERTY Or-flCE OF NZ. - 1 JUN 2001 502 1 t 90 95 100 105 110 115 120 S+R9A", PR9, P+R9R10A", P(0)R9, phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R13, R14, and R1S are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR9, NR9R10, N+R9RX1R12A", SR9, S (O) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S020M, S02NR9R10, P0(0R1S)0R17, P+R9R10R11A" , S+R9R10A~, and C (0) OM, wherein R1S and R17 are independently selected from the substituents constituting R9 and M; or R14 and R15, together with the nitrogen atom to which they are attached, form a cyclic ring; R7 and R8 are independently selected from the group consisting of hydrogen and alkyl; and one or more Rx are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR13, NR13R14, SR13, S (0) R13, S(0)2R13, S03R13, S+R13R14A", NR13OR14, NR13NR14R15, N02, C02R13, CN, OM, S020M, S02NR13R14, NR14C (O) R13, C(0)NR13R14, NR14C(0)R13, C(0)0M, COR13, OR18, S (O) nNRls, NR13R18, NRlsOR14, N+R9R1xR12A" , P+R9R11R12A", amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, heteroaryl, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR9, NR9R10, N+R9R1xR12A-, SR9, S (O) R9, S02R, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S020M, S02NR9R10, PO (OR16) OR17, P+R9RnR12A', S+R9R10A", or C(0)0M, and wherein R18 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle and quaternary heteroaryl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, CTUAL V 1 C ICt OF N Z j - 1 JUN 2001 503 1 t / 125 130 135 140 145 150 and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N+R9R"R12A-, SR9, S(0)R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S03R9, S020M, S02NR9R10, PO(OR16)OR17, and C(0)0M, wherein m Rx, one or more carbons are optionally replaced by O, NR13, N+R13R14A", S, SO, S02, S+R13A~, PR13, P(0)R13, P+R13R14A", phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by 0, NR9, N+R9R10A~, S, SO, S02, S*R9A~, PR9, P+R9R10A~, or P(0)R9; wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S (0) R13, S02R13, S03R13, NR13OR14, NR13NR14R1S, N02, C02R13, CN, OM, S020M, S02NR13R14, C(0)NR13R14, C (0) OM, COR13, P(0)R13R14, P+R13R14R1sA" , P(OR13)OR14, S+R13R14A", and N+R9RuR12A- , provided that both R5 and Rs cannot be hydrogen, OH or SH, and when R5 is OH, R1, R2, R3, R4, R7 and R8 cannot be all hydrogen; provided that when Rs or R6 is phenyl, only one of R1 or R2 is H; provided that when q = 1 and Rx is styryl, anilido, or anilinocarbonyl, only one of R5 or R6 is alkyl; or a pharmaceutically accepta'ble salt, solvate, or prodrug thereof. 14. The composition of claim 13, wherein R5 and R6 are independently selected from the group consisting of H, aryl, heterocycle, heteroaryl, quaternary heterocycle, and quaternary heteroaryl, wherein said aryl, heterocycle, heteroaryl, quaternary heterocycle, and quaternary heteroaryl can be 504 era <-*-1 /T^ 7 T: \ ^ substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, 10 haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S(0)R13, S02R13, S03R13, NR13OR14, NR13NR14R15, N02, C02R13, CN, OM, S020M, SO2NR13R14, C(0)NR13R14, C(0)0M, COR13, P(0)R13R14, P+R13R14R1sA\ P (OR13) OR14, S+R13R14A", and N+R9R11R12A", 15 wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can optionally have one or more carbons replaced by 0, NR7, N+R7R8A~, S, SO, S02, S*R7A", PR7, P(0)R7, P+R7R8A", or phenylene, 2 0 wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can be further substituted with one or more substituent groups selected from the group consisting of OR7, NR7R8, SR7, S (0) R7, S02R7, S03R7, C02R\ CN, oxo, 25 CONR7R8, N+R7R8R9A~, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(0)R7R8, P+R7R8R9A", and P (O) (OR7) OR8. 15. The composition of claim 14, wherein R5 and R6 has the formula: -Ar- (Ry) t wherein: 5 t is an integer from 0 to 5; Ar is selected from the group consisting of phenyl, thiophenyl, pyridyl, piperazmy-1, piperonyl, pyrrolyl, naphthyl, furanyl, anthracenyl, quinolinyl, isoquinolinyl, quinoxalinyl, imidazolyl, pyrazolyl, 10 oxazolyl, isoxazolyl, pyrimindinyl, thiazolyl, triazolyl, isothiazolyl, indolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, and benzoisothiazolyl; and one or more Ry are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, 15 cycloalkyl, heterocycle, heteroaryl, quaternary INTELLECTUAL PROPERTY j OTICE-OF NZ - 1 JUN 2201 K L G L «\j E y 505 20 25 30 35 heterocycle, quaternary heteroaryl, OR9, SR9, S(0)R9, S02R9, and S03R9, wherein said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, and heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl,' alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S(0)R13, S02R13, S03R13, NR13OR14, NR13NR14R15, N02, C02R13, CN, OM, S020M, S02NR13R14, C(0)NR13R14, C(0)0M, COR13, P(0)R13R14, P+R13R14R15A", P(0R13)0R14, S+R13R14A", and N+R9RnR12A~, wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can be further substituted with one or more substituent groups selected from the group consisting of OR7, NR7R8, SR7, S (0) R7, S02R7; S03R7, C02R7, CN, oxo, CONR7R8, N+R7R8R9A", alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(0)R7R8, P+R7R8R9A", and P(O) (OR7) OR3; and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can optionally have one or more carbons replaced by 0, NR7, N+R7R8A", S, SO, S02, S+R7A~, PR7, P(0)R7, P+R7R8A", or phenylene . 16. The composition of claim 14, wherein R5 or R6 has the formula (II) : CRy3 INTELLECTUAL PROPERTY OFFICE OF N.Z. - 1 JUN 2001 506 17. The use of an ileal bile acid transport inhibitor and an HMG Co-A reductase inhibitor, in the manufacture of a medicament wherein said medicament comprises an anti-hyperlipidemic condition effective amount of said inhibitors for the prophylaxis or treatment of a hyperlipidemic condition m a mammal. 18. The use of claim 17 wherein the HMG Co-A reductase inhibitor is selected from the group consisiting of lovastatin, simvastatin, pravastatin and fluvastatm. 19. The use of claim 17 wherein the HMG Co-A reductase inhibitor is pravastatin. 20. The use of claim 17 wherein the HMG Co-A reductase inhibitor is simvastatin. 21. The use of claim 17 wherein the HMG Co-A reductase inhibitor is lovastatin. 22. The use of claim 17 wherein the HMG Co-A reductase inhibitor is atorvastatin. 23. The use of any one of claims 17 to 22 wherein the ileal bile acid transport inhibitor is a compound of \ -L I b= p wherein: g is an integer from 1 to 4; n is an integer from 0 to 2; R1 and Rz are independently, selected from the grouc consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein aikyl, alkenyl, alkynyl, haloalkyl, 15 20 25 30 35 40 45 50 507 $yj) ^7 alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N+R9R10RWA~, SR9, S*RsR10A" , P+R9R10RUA-S (O) R9, S02R9, S03R9, C02R9, CN, halogen, oxo, and CONR9R10, wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or more carbons replaced by 0, NR9, N+R9R10A~, S, SO, S02, S*R9A~, P+R9R10A-, or phenylene, wherein R9, R10, and Rw are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, heteroaryl, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; or R1 and R2 taken together with the carbon to which they are attached form C3-C10 cycloalkyliaene; R3 and R.4 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, heteroaryl, OR9, NR9R10, SR9, S(0)R9, S02R9, wherein R9 and R10 are as defined above; or R3 and R4 together form =0, =N0R11, =S, =NNR11R12, =NR9, CRX1R12, wherein R11 and R12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, heteroaryl, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR9, NR9R10 halogen, oxo, and C0NR9R defined above, provided that both R3 and R4 cannot be OH, NH2, or SH, or R11 and R12 together with the nitrogen or carbon atom to which the/ are attached form a cyclic ring; R5 and R6 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, neterocycle, heteroaryl, quaternary heterocycle, quaternary heteraryl, SR9, S(0)R9, S02R9, and S03R9, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, ■J and S03R9 or SR9, S (0) R9, S02R9, S03R9, C02R9, CN, 9id10 wherein R9 and R10 are as C< f'J . rv. N O 2 UL <0 Z> LU Drr i— z C3 e-j r -■ IL s »» ty o LtS 55 polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR13, NR13R14, SR13, S(0)R13, S02R13, S03R13, NR13OR14, NR13NR14R15, N02, C02R13, CN, OM, S020M, S02NR13R14, C(0)NR13R14, C(0)0M, COR13, P(0)R13R14, P+R13R14R15A", 60 P (OR13) OR14, S+R13R14A', and NH'R9R11R12A", Wherein: A' is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, 65 aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can be further substituted with one or more substituent groups selected from the group consisting of OR7, NR7R8, SR7, S (0) R7, S02R7, S03R7, C02R7, CN, oxo, CONR7R8, N+R7R8R9A~, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, 70 heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(0)R7R8, P+R7R8R9A~, and P (0) (OR7) OR8, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can optionally nave one or more carbons 75 replaced by 0, NR7, N+R7R8A", S, SO, S02, S+R7A", PR7, P(0)R7, P+R7R8A", or phenylene, and R13, R14, and R1S are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, 8 0 quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, heteroaryl and polyalkyl optionally have one or more carbons replaced by 0, NR9, N+R9R10A", S, SO, S02, 85 S+R9A~, PR9, P+R9R10A", P(0)R9, phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R13, R14, and R1S are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, heterocycle, heteroaryl, quaternary 90 heterocycle, quaternary heteroaryl, OR9, NR9R10, N+R9RUR12A", SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, INTELLECTUAL PROPERTY OFFICE OF NZ. - 1 JUN 2001 RECEIUPn 509 O S020M, S02NR9R10, PO (OR16) OR17, P+R9R10RUA-, S+R9R10A', and C (0)OM, wherein R16 and R17 are independently selected from 95 the substituents constituting R9 and M; or R14 and R15, together with the nitrogen atom to which they are attached, form a cyclic ring; R7 and R8 are independently selected from the group consisting of hydrogen and alkyl; and 100 one or more Rx are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR13, 105 NR13R14, SR13, S (0) R13, S(0)2R13, S03R13, S+R13R14A", NR13OR14, NR13NR14R1S, N02, C02R13, CN, OM, S020M, S02NR13R14, NR14C(0)R13, C(0)NR13R14, NR14C(0)R13, C(0)0M, COR13, OR18, S (0) nNR18, NR13R18, NR1S0R14, N+R9R1xR12A", P+R9RUR12A", amino acid, peptide, polypeptide, and carbohydrate, 110 wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, heteroaryl, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR9, NR9R1Q, N+R9Ri;lR12A- , SR9, S (O) R9, S02R, S03R9, oxo, C02R9, CN, 115 halogen, CONR9R10, S020M, S02NR9R10, PO (OR16) OR17, P+R9R11R12A", S+R9R10A', or C (0) OM, and wherein R18 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle and quaternary 12 0 heteroaryl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or .more substituents selected from the group ?9T?10 cd9 q lrs\t?9 cn d? 125 consisting of OR9, NR9R10, N+R9RX1R12A", SR9, S(0)R9, S02R9, )3Rq, S02C 2A S03R9, oxo, C02R9, CN, halogen, CONR9R10, S03Rq, S020M, S02NR9R10, PO(OR16)OR17, and C(0)0M, wherein in Rx, one or more carbons are optionally replaced by O, NR13, N+R13R14A~, S, SO, S02, S+R13A", PR13, INTELLECTUAL PROPERTY OTICE OF NZ. - 1 JUN 2001 fiEfiPIUPn 13 0 P(0)R13, P+R13R14A", phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by 0, NR9, N+R9R10A~, S, SO, 135 S02, S+R9A~, PR9, P+R9R1QA", or P(0)R9; wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, 14 0 cycloalkyl, heterocycle, heteroaryl, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S (O) R13, S02R13, S03R13, NR130R14, NR13NR14R15, N02, C02R13, CN, OM, S020M, S02NR13R14, C(0)NR13R14, C (0) OM, COR13, P(0)R13R14, P+R13R14R1SA", P(OR13)OR14, S+R13R14A', and N+R9RX1R12A-, 145 provided that both R5 and R6 cannot be hydrogen, OH or SH, and when R5 is OH, R1, R2, R3, R4, R7 and R8 cannot be all hydrogen; provided that when R5 or R6 is phenyl, only one of R1 or R2 is H; 150 provided that when q = 1 and Rx is styryl, anilido, or anilinocarbonyl, only one of Rs or Rs is alkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 24. The use of claim 23, wherein R5 and R° are independently selected from the group consisting of H, aryl, heterocycle, heteroaryl, quaternary heterocycle, and quaternary heteroaryl, 5 wherein said aryl, heterocycle, heteroaryl, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, 10 haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S(0)R13, S02R13, S03R13, NR13OR14, NR13NR14R15, N02, C02R13, CN, OM, S020M, INTELLECTUAL PROPERTY OFflCE OF N Z. - 1 J'JN 2001 REGii SUES _ * <=$ ^ <=7 511 ^ ^ % 'J ^ S02NR13R14, C(0)NR13R14, C(0)0M, COR13, P(0)R13R14, P+R13R14R15A", P(OR13)OR14, S+R13R14A", and N+R9Ri:lR12A~ , 15 wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can optionally have one or more carbons replaced by 0, NR7, N+R7R8A", S, SO, S02, S+R7A", PR7, P(0)R7, P+R7R8A", or phenylene, 2 0 wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can be further substituted with one or more substituent groups selected from the group consisting of OR7, NR7R8, SR7, S (0) R7, S02R7, S03R7, C02R7, CN, oxo, 25 CONR7R8, N+R7R8R9A", alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(0)R7R8, P+R7R8R9A", and P (0) (OR7) OR8. 25. The use of claim 24, wherein R5 or R6 has the formula: -Ar- (Ry) t wherein: 5 t is an integer from 0 to 5; Ar is selected from the group consisting of phenyl, thiophenyl, pyridyl, piperazinyl, piperonyl, pyrrolyl, naphthyl, furanyl, anthracenyl, quinolinyl, isoquinolinyl, quinoxalinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 10 pyrimindinyl, thiazolyl, triazolyl, isothiazolyl, indolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, and benzoisothiazolyl; and one or more Ry are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, 15 cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR9, SR9, S(0)R9, S02R9, and S03R9, wherein said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, and heteroaryl can be substituted 2 0 with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, 1 INTELLECTUAL PROPERTY c -'H Or NZ - 1 JUN 2001 D r •• f. 1 U f* Q 512 £ polyalkyl^ polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, halogen, oxo, OR13, NR13RX\ SR13, S (0) R13, SO,R13, S03R13, NRi3ORi4, NR-NR^R15, N02, 25 C02R13, CN, OM, S020M, S02NR13R14, C(0)NR13Ri\ C(O)0M, COR13, ?(0)R°R14, P"R13RX4R1SA", P(0Ru)0R14, S+R13R14A\ and rR9RL1RnA", wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can be further substituted with one or more 30 substituent groups selected from the group consisting of OR7, NR7Ra, SR7, S(0)R\ S02R7, S03R7, C02R7, CN, oxo, C0NR7R3, N*R7R3R9A", alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary neterocycle, quaternary heteroaryl, ?(0)R7R\ ?"R7RaR3A", and P (0) (OR7) OR3, 3 5 and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can optionally have one or more carbons replaced by 0, NR7, N-R7RaA", S, SO, S02, S*R7A\ PR7, P(0)R7, P~R7RaA~, 40 or ohenylsne. 26. The use of claim 25, wherein R5 and Rb has the formula (II)- 27. The use of claim 23 wherein the HMG Co-A reductase inhibitor is pravastatin. 28. The use of claim 23 wherein the HMG Co-A reductase inhibitor is simvastatin. 29. The use of claim 23 wherein the HMG Co-A reductase inhibitor is lovastatin. INTELLECT UAL PROPERTY ' OFFICE OF NZ. ii ~ 1 JUN 2G01 ft r: S 0 V 2 D 513 30. The use of claim 23 wherein the HMG Co-A reductase inhibitor is atorvastatin. 31. A pharmaceutical composition, comprising: a first"amount of an ileal bile acid transport inhibitor, and a second amount of an HMG Co-A reductase inhibitor selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatm and atorvastatin, and a pharmaceutically acceptable carrier, wherein said first and second amounts of said inhibitors together comprise an anti-hyperlipidemic condition effective amount of said inhibitors, and wherein the ileal bile acid transport inhibitor is a compound of formula (LX): (LX) wherein: R1 and R2 are independently selected from alkyl; R5 is substituted phenyl; and one or more Rx are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR13, NR13R14, g MJ . _ nN <=» §: ^ LL. riO E2 3 uu Gr II LU J lo i fej L-J L2. '■ Z 8 - SR13, S (0) R13, S(0)2R13, S03R13, s+r13r14a~, nr13or14, nr13nr14r15, no2, co2r13, cn, om, S02OM, S02NR13R14, NR14C(0)R13, C(0)NR13R14, NR14C(0)R13, C (0) OM, COR13, OR18, S(0)nNR18, NR13R18, NR18OR14, N+R9Ri:lR12A", P+R9Ri:iR12A~, amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, heteroaryl, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR9, NR9R10, N+R9RUR12A~, SR9, S(0)R9, S02R, SO3R9, oxo, C02R9, CN, halogen, CONR9R10, S020M, S02NR9R10, PO (OR16) OR17, P+R9RnR12A~, S+R9R10A~, or C (0) OM, and wherein in Rx, one or more carbons are optionally replaced by 0, NR13, N+R13R14A~, S, SO, S02, S+R13A~, PR13, P(0)R13, P+R13R14A", phenylene, ammo acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein m said polyalkyl, phenylene, ammo acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by 0, NR9, N+R9R10A~, S, SO, S02, S+R9A_, PR9, P+R9R10A", or P(0)R9; and wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S(0)R13, S02R13, SO3R13, NR13OR14, NR13NR14R15, N02, C02R13, CN, OM, S020M, S02NR13R14, C (0) NR13R14, C(0)0M, COR13, P (0) R13R14, P+R13R14R15A~, P(0R13)0R14, S+R13R14A~, and N+R9R1XR12A", and wherein R9 and R10 are independently selected from the group consisting of H, aikyl, alkenyl, alkynyl, INTELLECTUAL PROPERTY OFFICE OF NZ. - 1 JUM 2001 cycloalkyl, aryl, acyl, heterocycle, heteroaryl, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; and wherein R11 and R12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, 'heteroaryl, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR9, NR9R10, SR9, S(0)R9, SO2R9, SO3R9, C02R9, CN, halogen, oxo, and CONR9R10, or R11 and R12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; wherein R13, R14, and R15 are independently selected from'the group consisting of hydrogen, aikyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, heteroaryl and polyalkyl optionally have one or more carbons replaced by 0, NR9, N+R9R10A~, S, SO, S02, S+R9A-, PR9, P+R9R10A", P(0)R9, phenylene, carbohydrate, ammo acid, peptide, or polypeptide, and wherein R13, R14, and R15 are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR9, NR9R10, N+rvw, SR9, S(0)R9, S02R9, SO3R9, oxo, C02R9, CN, halogen, CONR9R10, S020M, S02NR9R10, PO (OR16) OR17, P+R9R10RnA~, S+R9R10A~, and C(0)OM, or R14 and R15, together with the nitrogen atom to which they are attached, form a cyclic ring; and IliMTCL'.XTUAL PROPERTY 3 OFFICE OF N.Z. " 1 JUN 2001 wherein R16 and R17 are independently selected from the substituents constituting R9 and M; and wherein R18 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle and quaternary heteroaryl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N+R9R11R12A~, SR9, S (0) R9, S02R9, SO3R9, oxo, C02R9, CN, halogen, CONR9R10, SO3R9, S020M, S02NR9R10, PO (OR16) OR17, and C(0)OM; and wherein A" is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 32. The composition of claim 31 wherein the HMG Co-A reductase inhibitor is selected from the group consisting of lovastatin, simvastatin, pravastatin and fluvastatin. 33. The composition of claim 31 wherein the HMG Co-A reductase inhibitor is pravastatin. 34. The composition of claim 31 wherein the HMG Co-A reductase inhibitor is simvastatin. 35. The composition of claim 31 wherein the HMG Co-A reductase inhibitor is lovastatin. intellectual pnopepty office or r 7 - 1 JUN 2001 n r1 (**1 ■ > - cy ^ V 517 ; 1 36. The composition of claim 31 wherein the HMG Co-A reductase inhibitor is atorvastatin. 37. The composition of claim 31 wherein R1 and R2 are independently selected from the group consisting of ethyl, n-propyl, n-butyl and isobutyl. 38. The composition of claim 37 wherein one or more Rx are independently selected from the group consisting of methyl, ethyl, isopropyl, t-butyl, hydroxy, methoxy, ethoxy, isopropoxy, methylthio, iodo, bromo, fluoro, methylsulfinyl, methylsulfonyl, ethylthio, amino, hydroxylamine, N-methylamino, N, N-dimethylamino, N, N-diethylammo, (N)-benzyloxycarbomoyl, trimethylammonium A", -NHC(=0)CH3, -NHC (=0) C5HH, -NHC (=0) C6H13, carboxyethylamino, (N)-morpholinyl, (N)-azetidinyl, (N)-N-methylazetidinium A", (N)-pyrrolidinyl, pyrrolyl, (N)-N-methylpyridinium A", (N)-N-methylmorpholinium A", N-N' -methylpiperazmyl, (N)-bromomethylamido, (N) -N-hexylammo, thiophene, -N+ (CH3) 2C02H I-, -NCH3CH2C02H, -(N)-N'-dimethylpiperazinium I", N-t-butyloxycarbamoyl, (N)-methylsulfonamido, (N)N'-methylpyrroiidinium and -(OCH2CH2) 3I, wherein A" is a pharmaceutically acceptable anion. 39. A use of an ileal bile acid transport inhibitor and an HMG Co-A reductase inhibitor selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin and atorvastatin, in the manufacture of a medicament SNTELLECTUAL PRO.-Z OFFICE of N Z." - 1 JUN 2001 P B7 f4 f I 11 ■ 518 33 V' ,jt V wherein said medicament comprises an anti-hyperlipidemic condition effective amount of said inhibitors for the treatment or prophylaxis of a hyperlipidemic condition in a mammal in need thereof, and wherein the ileal bile acid transport inhibitor is a compound of formula (LX): (LX) wherein: R1 and R2 are independently selected from alkyl; R5 is substituted phenyl; and one or more Rx are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR13, NR13R14, SR13, S (0) R13, S(0)2R13, S03R13, S+R13R14A", NR"ORa% NR±jNR14R±q, N02, C02R1j, CN, OM, S020M, S02NR13R14, NR14C(0)R13, C(0)NR13R14, NR14C(0)R13( ,13 ,14 ,13 14-r-l IS ,13 C(0)OM, COR 13 OR18, S (0) nNR18, NR13R18/ nr18or14, N+R9R11R12A , P+R9R11R12A , amino acid, peptide, I £ h az >' i u . ,<° 3 LU polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, z aryl, polyalkyl, heterocycle, heteroaryl, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR9, NR9R30, N+R9RnR12A~, SR9, S(0)R9, O r-j c=ra O tcj £2 S02R, SO3R9, oxo, CO2R9, CN, halogen, CONR9R10, S020M, S02NR9R10, PO (OR16) OR17, PVR^R^A', S+R9R10A~, or C(0)0M, and wherein in Rx, one or more carbons are optionally replaced by 0, NR13, N+R13R14A~, S, SO, S02, S+R13A~, PR13, P(0)R13, P+R13R14A~, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by 0, NR9, N+R9R10A~, S, SO, S02, S+R9A~, PR9, P+R9R10A~, or P(0)R9; and wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S(0)R13, S02R13, SO3R13, NR130R14, NR13NR14R15, N02, C02R13, CN, OM, S020M, S02NR13R14, C(0)NR13R14, C(0)0M, COR13, P(0)R13R14, P+R13R14R15A~, P(0R13)0R14, S+R13R14A", and N+R9RnR12A", and wherein R9 and R10 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, heteroaryl, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; and wherein R11 and R12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl 1 J . heterocycle, heteroaryl, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR9, NR9R10, 4 l| ^ ^ ^ ^ SR9, S(0)R9, S02R9, SO3R9, C02R9, CN, halogen, oxo, and|t3^ CONR9R10, or R11 and R12 together with the nitrogen or carbon 520 atom to which they are attached form a cyclic ring; wherein R13, R14, and R15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, heteroaryl and polyalkyl optionally have one or more carbons replaced by 0, NR9, N+R9R10A~, S, SO, S02, S+R9A", PR9, P+R9R10A", P(0)R9, phenylene, carbohydrate, amino acid, peptide, or polypeptide, and wherein R13, R14, and R15 are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR9, NR9R10, N+R9RUR12A~, SR9, S(0)R9, S02R9, S03R9/ oxo, C02R9, CN, halogen, CONR9R10, S020M, S02NR9R10, PO (OR16) OR17, P+R9R10RuA~, S+R9R10A~, and C(0)OM, or R14 and R15, together with the nitrogen atom to which they are attached, form a cyclic ring; and wherein R16 and R17 are independently selected from the substituents constituting R9 and M; and 18 wherein R is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, Ci heteroaryl, alkyl, quaternary heterocycle and 'ft . I 0- M es (J 7 quaternary heteroaryl, i gf c-j -jo z wherein acyl, arylalkoxycarbonyl, arylalkyl, p 1— u ' CJ — heterocycle, heteroaryl, alkyl, quaternary , , "5— I UJ ^ ' heterocycle, and quaternary heteroaryl optionally artez substituted with one or more substituents selected 521 il ' from the group consisting of OR9, NR9R10, N+R9R11R12A~, SR9, S (0) R9, S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S03R9, S020M, S02NR9R10, PO (OR16) OR17, and C(0)OM; and wherein A" is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 40. The use of claim 39 wherein the HMG Co-A reductase inhibitor is selected from the group consisting of lovastatin, simvastatin, pravastatin and fluvastatin. 41. The use of claim 39 wherein the HMG Co-A reductase inhibitor is pravastatin. 42. The use of claim 39 wherein the HMG Co-A reductase inhibitor is simvastatin. 43. The use of claim 39 wherein the HMG Co-A reductase inhibitor is lovastatin. 44. The use of claim 39 wherein the HMG Co-A reductase inhibitor is atorvastatin. It I CZ rj . CL Nj 45. The composition of claim 31 wherein R1 and > ^ ^ a i nhcinanrlcinf 1 v cq! -f-v~ /-m-n o I LLI : u consisting of ethyl, n-propyl, n-butyl and isobutyl. 46. The composition of claim 45 wherein one or more Rx are independently selected from the group consisting of methyl, ethyl, isopropyl, t-butyl, hydroxy, methoxy, ethoxy, isopropoxy, methylthio, t- C-J c-~j R are independently selected from the group .< zd {' 3 I ■ ■ ' I— i u L_ ' rrlO i 522 iodo, bromo, fluoro, methylsulfinyl, methylsulfonyl, ethylthio, amino, hydroxylamine, N-methylamino, N,N-dimethylamino, N, N-diethylamino, (N)-benzyloxycarbomoyl, trimethylammonium A", -NHC(=0)CH3, -NHC (=0) C5H11, -NHC (=0) C6H13, carboxyethylamino, (N) -morpholmyl, (N)-azetidinyl, (N)-N-methylazetidmium A-, (N)-pyrrolidinyl, pyrrolyl, (N)-N-methylpyridinium A", (N)-N-methylmorpholinium A", N-N'-methylpiperazinyl, (N)-bromomethylamido, (N)-N-hexylamino, thiophene, -N+ (CH3) 2C02H I', -NCH3CH2CO2H, -(N)-N' -dimethylpiperazinium I", N-t-butyloxycarbamoyl, (N)-methylsulfonamido, (N) N' -methylpyrrolidimum and -(OCH2CH2) 3I, wherein h is a pharmaceutically acceptable anion. 47. A pharmaceutical composition according to any one of claims 1 to 16 or 31 to 38, 45 and 46 substantially as herein described with reference to the Examples thereof. 48. A use according to claim 17 or claim 39 substantially as herein described. 49. A use according to any one of claims 17 to 30 or 39 to 44 substantialy as herein described. ♦ The Intellectual Property Office of New Zealand Levin House 330 High Street LOWER HUTT Our Ref JB212568 To* BALDWIN SHELSTON WATERS WELLINGTON V Filing receipt regarding. \ APPLICATION FOR A PATENT NO 337830 \ ENTRY INTO NATIONAL PHASE DATE: 14 Septemberr 1999 APPLICANT: TITLE OF INVENTION: International Application No International Filing Date: Priority Date. G. D. SEARLE & CO. COMBINATION THERAPY EMPLOYING ILEAL BILE ACID TRANSPORT INHIBITING BENZOTHIEPINES AND HMG Co-A REDUCTASE INHIBITORS PCT/US98/03792 10 March 1998 11 March 1997 RECEIVED THE FOLLOWING. Request for Entry into National Phase form (formal) pfile58359 "TiQiMAL PATENT COOPERATION TREATY NEW ZEALAND JB212568 REQUEST FOR ENTRY INTO NATIONAL PHASE NEW ZEALAND APPLICATION NUMBER 337830 IN THE MATTER OF PCT International Application No. PCT/US98/03792 filed on 10 March 1998 In the name of (a) G. D. Searle & Co.

1.(i) We (b) G. D. Searle & Co. of Corporate Patent Dept., P.O. Box 5110, Chicago, Illinois 60680-5110, United States Of America hereby request entry into the National Phase in New Zealand.

2. We hereby declare that the true and first inventors of the invention disclosed in the complete specification filed with the present application are: as per the attached list of inventors and that our right to apply for a patent for the invention is as follows: by virtue of an assignment

3. We declare that the following application was the first application in a convention country in respect of the relevant invention by usjdt by any person from whom we derive title:

4. We are the assignees of the inventors as per the attached list by virtue of an assignment

5. We request that all communications relating to this application be sent to: BALDWIN SHELSTON WATERS, 342 Lambton Quay, Wellington, New Zealand who are appointed to act for us. Country Date of Filing Applicants United States of America 11 March 1997 As per the attached list of inventors G. D. Searle & Co. Signature Roger A. Williams Assistant General <305085997 Capacity Date October 28, 1999 LIST OF INVENTORS - RE: PCT/US98/03792 Bradley T Keller, a United States citizen of 1780 Canyon View Court, Chesterfield, MO 63017, United States of America Kevin C. Glenn, a United States citizen of 1816 Pheasant Run Drive, Maryland Heights, MO 63043, United States of America Robert E. Manning, a United States citizen of 1298 South Mason Road, St. Louis, MO 63131, United States of America ♦ htH COMBINATION THERAPY EMPLOYING ILEAL BILE ACID TRAN^PJRJ INHIBITING BENZOTHIEPINES AND HMG Cc-A ENSYM^ REDUCTASE INHIBITORS dvqVi c. 0 ci 3 it 0 ^o^r01 ir0rizocn2.":a'oz-"^£is z ~ 3 P 3" CC;s t P. 0 2T 3 O f ^ P. 3. ITT 3.C0U C 1C2.I CC^CCSltlOP. S C ^~ 1. ^ C them, ar.d mecnods cf using c.iese cc^-pounds and conccsi; icr.s of hyperlipidemic conditions such as tnose associated .^itr. atherosclerosis or hypercholesterolemia, m mammals. Also orovided are compositions and mechods for combination therapy employing ileal bile acid cransport inhibitors and HtMG Co-A reductase inhibitors for che treatment of hyperlip-demic conditions </div>