AU6440898A - Combination therapy employing ileal bile acid transport inhibiting benzothiepines and hmg co-a reductase inhibitors - Google Patents

Description

COMBINATION THERAPY EMPLOYING ILEAL BILE ACID TRANSPORT INHIBITING BENZOTHIEPINES AND HMG Co-A REDUCTASE INHIBITORS

This application claims the benefit of priority of U.S. provisional application Serial No. 60/040,660, filed March 11, 1997. This application is also a continuation- in-part application of U.S. Serial No. 08/831,284, filed March 31, 1997, which is a continuation application of U.S. Serial No. 08/517,051, filed August 21, 1995, which is a continuation-in-part application of U.S. Serial No. 08/305,526 filed September 12, 1994; and is a continuation-in-part application of U.S. Serial No. 08/816,065, filed March 11, 1997, which claims priority from U.S. provisional application Serial No. 60/013,119, filed March 11, 1996.

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to novel benzothiepines, derivatives and analogs thereof, in combination with HMG Co-A reductase inhibitors, pharmaceutical compositions containing them, and use of these compositions in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions such as is associated with atherosclerosis or hypercholesterolemia, in 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 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 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 al. See "Primary Bile Acid Malabsorption: Defective in -Vitro Heal Active Bile Acid Transport", Gastroenteroloσv, 1982:83:804-11.

In fact, cholestyramine binds the bile acids in the intestinal tract, thereby interfering with their normal enterohepatic circulation (Reihner, E. et al, in "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 ioid 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 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 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 Biolo^gical Chemistr^y. Vol. 268, No. 24, Issue of August 25, pp. 18035-18046, 1993).

& 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 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 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 Wellcome Foundation Limited disclosure of the world patent application number WO 93/16055 for "Hypolipidemic Benzothiazepine Compounds"

Selected benzothiepines are disclosed in world patent application number W093/321146 for numerous uses 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 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 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 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- 370688; U.S. 3,520,891 abstracted in Derwent 50701R-B; US 3,287,370, US 3,389,144; US 3,694,446 abstracted in Derwent Abstr. No. 65860T-B and WO 92/18462.

HMG 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 efforts by providing novel pharmaceutical compositions and methods for the treatment of hyperlipidemic conditions.

SUMMARY OF THE INVENTION

Accordingly, among its various apects, the present invention provides compounds of formula (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 group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, 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 substituted with one or more substituents selected from the group consisting of OR ,

NR⁹R¹⁰, N^*R'R¹⁰R^WA-, SR⁹, S⁺R⁹R¹⁰A_V p-R'^W, S(0)R⁹, S0₂R⁹, 9 9 Q 10

SO3R , CO2R , CN, halogen, oxo, and CONR'R , wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl . optionally have one or more carbons replaced by 0, NR ,

N⁺R⁹R¹⁰A-, S, SO, SO2, S⁺R⁹A-, P⁺R⁹R¹⁰A-, or phenylene,

9 10 wherein R , R , and R^w are independently selected 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 C_:-C₁₀ cycloalkylidene;

3 4 R and R are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, , NR⁹R¹⁰, SR⁹, S(0)R⁹,

9 9

S02R , and SO3R , wherein R⁵ and R¹⁰ are as defined above; or R and R together form =0, =N0R^1:L, =S, =NNR^1:LR¹²,

11 12 wherein R and R are independently selected from the group consisting of H, alkyl, alkenyl, alkenylalkyl , alkynylalkyl , heterocycle,^ca^>xyalkyl , carboalkoxyalkyl , ^' cycloalkyl, cyanoalkyl, OR⁹, NR⁹R¹⁰, SR⁹, S(0)R⁹,

S02R⁹, SO3R , C02R⁹, CN, halogen, oxo, and CONR⁹R¹⁰, wherein R9 and R10 are as defined above, provided that

3 4 both R and R cannot be OH, NH ^{and S} ' ^or R 11 and R12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; R and R are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl,

-,, -, , ..heteroaryl, cycloalkyl, heterocycle,^quaternary heterocycle, quaternary _heteroaryl, SR⁹,S(0)R⁹, S0₂R⁹, and S0₃R , wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl} heterocycle,Λquaternary 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, eteroaryl 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)OM, COR¹³,

P(0)R¹³R¹⁴, P⁺R¹³R¹⁴ _R15_A__f P(OR¹³)OR¹⁴, S^*R^l3R¹⁴A\ and wherein:

A^~ is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, _heterocyc_le and _heteroaryl can be further substituted with one or more substituent groups selected from the group consisting of OR ,

NR⁷R⁸, SR⁷, S(0)R⁷, S02R⁷, S03R⁷, . C0₂R⁷, CN, oxo,

CONR⁷R⁸, N⁺R⁷R⁸R⁹ -, 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, eterocycle and heteroaryl can optionally have one or more carbons replaced by 0,

NR⁷, N⁺R⁷R⁸A-, S, SO, Sθ2 , 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, heteroaryl, heterocycle, A and polyalkyl optionally have one or more carbons replaced by 0, NR^J, N⁺R⁹R¹⁰A-, S, SO, Sθ2 ,

■ q q j, q in

S R A^", PR , P R R A-, P(0)R\ phenylene, carbohydrate, amino acid, peptide, or polypeptide, and

R , R , and R are optionally substituted with one or more groups selected from the group consisting of sulfoa kyiTA quaternary heterocycle, quaternary heteroaryl, OR⁹, NR⁹R¹⁰, N⁺R⁹R^1:LR¹²A^", SR⁹ , S(0)R⁹,

S02R⁹, SO3R⁹, oxo, C02R⁹, CN, halogen, CONR⁹R¹⁰, SO2OM,

S0₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷ , P⁺R⁹R¹⁰RⁿA- , S⁺R⁹R¹⁰A- , and C(0)OM, wherein R 16 and R17 are independently selected from the substituents constituting R and M; or R 14 and R15 , together with the nitrogen atom to which they are attached, form a cyclic ring;

R 7 and R8 are independently selected from the group consisting of hydrogen and alkyl; and one or more R^x 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 _/ Nθ2 , C02R¹³ , CN, OM, S020M, S02NR¹³R¹⁴, NR^X4C(0)R", C(0)NR¹³R¹⁴,

NR¹⁴C(0)R¹³, C(0)OM, COR¹³, OR¹⁸, S(0)_nNR¹⁸, NR¹³R¹⁸,

NR¹⁸OR¹⁴, N⁺R⁹R R¹²A~, P+RW ^-, amino acid, peptide, polypeptide, and carbohydrate,

- wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryli polyalkyl, heterocycle,y acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A^", SR⁹, S(0)R⁹, S0₂R⁹, S03R⁹, oxo, C0₂R⁹, CN, halogen, CONR⁹R¹⁰, SO2OM, Sθ2NR⁹R¹⁰, P0(0R^1S)0R¹⁷, P⁺R⁹R¹¹R¹²A~, S^*R⁵R¹⁰A^", or C(0)OM, and wherein R 18 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl wherein acyl, arylalkoxycarbonyl, arylalkyl, 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 i n 9

SO2R , SO3R , oxo, CO2R , CN, halogen, CONR R , SO3R , S020M, Sθ2NR⁹R¹⁰, PO (OR¹⁶) OR¹⁷, and C(0)OM, wherein in R^x, one or more carbons are optionally replaced by 0, NR¹³ , N⁺R¹³R¹⁴A-, S, SO, SO2 , S⁺R¹³A-,

P P(0)R^{13 p R} R A-, phenylene, amino acid, peptid.e, 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, NR 9 , N+R9R10A-,

S, SO, S02, S⁺R⁹A-, PR⁹, P⁺R⁹R¹⁰A-, or P(0)R*; 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, heterocycT^^afylalkyl , 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⁺R¹³R¹⁴ _R ¹⁵ _A_, P(OR")OR¹⁴, S^*R¹³R¹⁴A\ and N+RW , provided that both R and R cannot be hydrogen, OH, ojrr SSHH-,, aanndd wwhheenn RR⁵ iis OH, R¹, R² , R³ , R⁴, R⁷ and R⁸ cannot be all hydrogen; provided that when R or R is phenyl, only one of R¹ or R² is H; provided that when q = 1 and R^x is styryl, anilido, or anilinocarbonyl, only one of R⁵ or R^β is alkyl ; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

Preferably, R and R can independently be selected from the group consisting of H, aryl, heterocycle^quaternary heterocycle, and quaternary heteroaryl, 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 aryl, haloalkyl, cycloalkyl, heter cyS'e^arylalkyl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(0)R¹³, S02R¹³ , S03R¹³ , NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, N02 , C02R¹³ , CN, OM, SO2OM,

S02NR¹³R¹⁴, C(0)NR¹³R¹⁴, C(0)OM, COR¹³, P(0)R¹³R¹⁴,

P⁺R¹³R¹⁴R¹⁵A- , P (OR¹⁵ ) OR¹⁴ , S+R¹³R¹⁴A- , and N⁺R⁹R^{1 :L}R¹²A- , wherein said alkyl , alkenyl , alkynyl , polyalkyl , polyether, aryl , haloalkyl , cycloalkyl , heterocycle and h-d-eroaryl can optionally have one or more carbons replaced by 0,

NR⁷, N⁺R⁷R⁸A-, S, SO, Sθ2 , S⁺R⁷A- , PR⁷, P(0)R⁷

P +R7R8A-, or phenylene, wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and tetercaryl 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, heteroaryl, cycloalkyl, heterocycle,Λ arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(0)R 7R8 , P+R7R8R A-, and P(O) (OR⁷) OR*.

More preferably, R^s or R^β has the formula:

-Ar-(R^y)_t

wherein: 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, pyri idinyl, thiazolyl, triazolyl, isothiazolyl, indolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, and benzoisothiazolyl; and one or more R^y are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, 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 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, NO2 , C02R¹³ , CN, OM, S020M, S02NR¹³R¹⁴, C(0)NR¹³R¹⁴, C(0)OM, COR¹³,

P(0)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A-, P(OR¹³)OR¹⁴, S^*R¹³R¹⁴A\ and

N⁺R⁹R¹¹R¹²A^", wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl,b-5terccyc]-3, erri teteroaryl can be further substituted with one or more substituent

7 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, heteroaryl, arylalkyl, pu-iternary 0 +7 g Q heterocycle, quaternary heteroaryl, P(0)R R , P R R R A-, and P(O) (OR⁷) OR', 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, Sθ2 , S⁺R⁷A-, PR⁷, P(0)R⁷,

P +R7R8A- , or phenylene .

Most preferably, R⁵ or R⁶ has the formula (II) :

w

The invention is further directed to a compound selected from among:

R²⁰ - R^1J - R²¹ (Formula DI )

R²⁰ - R" - R²¹ ( Formula DID

and

R²⁰ - R" - R²¹ ( Formula Dili )

wherein R¹' 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, S0₂, S⁺R R ,. PR⁷, P⁺P⁷R⁸, phenylene, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, or aryl, wherein alkane diyl, alkenβ 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, Nθ2, C02R¹³, CN,

OM, S020M, S02NR¹³R¹⁴, C(0)NR¹³R¹⁴, C{0)OM, COR¹³,

P(0)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵ _A_, P(0R^u)0R", S^*R"R¹⁴A\ and N⁺R⁹R^1:LR¹²A~; wherein R -,1* further comprises functional linkages by which R" is bonded to R^a\ R^J1, or R^M in the compounds of Formulae DII and Dill, and R^M in the compounds of Formula Dili. Each of R^,β, R", or R^M and R^M comprises a benzothiepine moiety as described above that is therapeutically^' effective in inhibiting ileal bile acid transpor .

The invention is also directed to a compound selected from among Formula DI, Formula DII and Formula Dili in which each of R^al, R^M and " comprises a benzothiepine moiety corresponding to the Formula:

(Formula DIV)

or: (Formula DIVA)

wherein R¹, R², R³, R⁴, R⁵, R^β, R⁷, R\ R^x, q, and n are as defined in Formula I as described above, and R⁵⁵ is either a covalent bond or arylene.

In compounds of Formula DIV, it is particularly preferred that each of R²⁰, R²¹, and R²² in Formulae DII and Dili, and R²³ in Formula Dili, be bonded at its 7- or 8-position to R¹'. In compounds of Formula DIVA, it is particularly preferred that R^5S comprise a phenylene moiety bonded at a m- or p-carbon thereof to R¹⁹.

Examples of Formula DI include:

and

In any of the dimeric or multimeric structures 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 R² can be ethyl/butyl or butyl/butyl.

JS^* Other compounds useful in the present invention as ileal bile acid transport inhibitors are shown in Appendix A.

In another aspect, the present invention provides 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 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. In a further aspect, the present invention also provides a method of treating a disease or condition in mammals, including humans, for which a bile acid transport inhibitor is indicated, comprising administering to a patient in need thereof a compound 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. 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 HMG Co-A reductase inhibitor useful to treat hyperlipidemic disorders, wherein said first and second amounts together comprise an anti- hyperlipidemic condition effective amount of said compounds .

HMG Co-A reductase inhibitor- compounds useful in the present invention are shown in Appendix B.- Further scope of the applicability of the present invention will become apparent from the detailed description provided below. However, it should be

lb 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 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 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 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 incorporated by reference in their entirety.

Definitions

In order to aid the reader in understanding the following detailed description, the following 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 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. "Aryl" means a fully unsaturated mono- or multi- ring carbocyle, including, but not limited to, 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:

wherein Z, Z', Z" or Z"' is C, S, P, 0, or N, with the proviso that one of Z, Z', Z" or Z" ' is other than carbon, but is not 0 or S when attached to another Z atom by a double bond or when attached to another 0 or 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. 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, 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 heterocycle to the molecule of interest can be at a heteroatom or elsewhere. The term "quaternary heteroaryl" means a • 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. The term "halogen" means a fluoro, chloro, bromo or iodo group.

The term "haloalkyl" means alkyl substituted with one or more halogens . 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 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 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, 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, 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. 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 up to about 100 amino acid units.

The term "polypeptide" means polyamino acid containing from about 100 amino acid units to about

15 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. The term "alkylammoniumalkyl" means a NH. 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 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 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 . 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 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 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 administration of an ileal bile acid transport inhibitor and a HMG Co-A reductase inhibitor to treat a hyperlipidemic condition, for example atherosclerosis 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 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 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 condition.

Compounds

The compounds of the present invention can have at least two asymmetrical carbon atoms, and therefore 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 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. The compounds of the present invention also include tautomers.

The compounds of the present invention as discussed below include their salts, solvates and prodrugs .

Compound Syntheses

ai 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 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 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 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 racemic steroisomers of benzothiepin- (5Jf) -4-one VIII when R¹ and R² are nonequivalent . Oxidation of VII with 3 equivalents of -chloro-perbenzoic acid (MCPBA) gives isomeric sulfone-epoxides IX which upon hydrogenation with palladium on carbon as the catalyst yield a 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 R^l and R² are nonequivalent . 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), ii>id. , 42, 2781 (1977), and ijbid., 44, 4891 (1979).

Alternatively, keto-aldehyde VI where R² is H can be prepared by reaction of thiophenol V with a 2- substituted acrolein.

33

Benzothiepin- (5H) -4-one VIII can be oxidized with MCPBA to give the benzothiepin- (5H) -4-one-l, 1-dioxide XII which can be reduced with sodium borohydride to give four racemic stereoisomers of X. The two stereoisomers of X, Xa and Xb, having the OH group and R^s 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 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.

^

The compounds of the present invention where R⁵ is OR, NRR' or S(0)_nR and R^* is hydroxy can be prepared by reaction of epoxide IX where R⁵ is H with thiol, alcohol, or amine in the presence of a base.

AS" HOR, or HNRR¹ or HS (O) R base

R⁵ = OR, NRR¹, S(0)R

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.

ώ 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 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, 3980 (1966) . The phenol XVI is first reacted with dimethyl thiocarbamoyl chloride and triethylamine to give thiocarbamate XVII which is thermally rearranged at 200-300 °C, and the rearranged product is hydrolyzed with sodium hydroxide to yield the thiophenol XVIII. Similarly, Thiophenol V can also be prepared from 2- acylphenol XIX via the intermediate thiocarbamate XX.

AT

Scheme 4 shows another route to benzothiepine-1, 1- dioxides Xc and Xd starting from the thiophenol XVIII. 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 with potassium t-butoxide also gives a mixture of benzothiepine XXIIc and XXIId.

S

Examples of amine- and hydroxylamine-containing compounds of the present invention can be prepared as shown in Scheme 5 and Scheme 6. 2-Chloro-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 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-

A^<\ butoxycarbonyDhydroxylamino 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 XXXIIIc and XXXIIId derivatives can also be prepared by further hydrogenation of XXIV or XXVIIc and XXVIId.

°

In Scheme β, reduction of the sulfone-aldehyde XXV with hydrogen followed by reductive alkylation of the resulting amino derivative with hydrogen and an aldehyde catalyzed by palladium on carbon in the same reaction vessel yields the substituted amine derivative

XXVIII. Cyclization of XXVIII with potassium t-butoxide yields a mixture of substituted amino derivatives of this invention XXIXc and XXIXd.

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 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

Z 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:

THF tetrahydro furan PTC phase transfer catalyst

Aliquart 336 methyltricaprylylammonium chloride

MCPBA m-chloroperbenzoic acid

Celite a brand of diatomaceous earth filtering aid

DMF dimethylformamide

DME ethylene glycol dimethyl ether

BOC t-butoxycarbonyl group

R¹ and R^s can be selected from among substituted and unsubstituted C_x to C₁₀ alkyl wherein the substituent (s) can be selected from among alkylcarbonyl, alkoxy, hydroxy, and nitrogen-containing heterocycles joined to the C_L 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) C₂H₅, -CH₂OC₂H₅, and -CH.0-.4- picoline) . Ethyl, n-propyl, n-butyl, and isobutyl are preferred. In certain particularly preferred compounds of the present invention, substituents R^l and R^J 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 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 (R^*) on the benzo- ring can include hydrogen, aryl, alkyl, hydroxy, halo, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkyl, haloalkoxy, (N) -hydroxy- carbonylalkyl amine, haloalkylthip, haloalkylsulfinyl, haloalkylsufonyl, amino, N-alkylamino, N,N- dialkylamino, (N) -alkoxycarbamoyl, (N) - aryloxycarbamoyl , (N) -aralkyloxycarbamoyl, trialkyl- ammonium (especially with a halide counterion) , (N) - amido, (N) -alkylamido, -N-alkylamido, -N,N-

3H dialkylamido, (N) -haloalkylamido, (N) -sulfonamido, (N)- alkylsulfonamido, (N) -haloalkylsulfonamido, carboxyalkylamino , trialkyl-ammonium salt, (N) -carbamic acid, alkyl or benzyl ester, N-acylamine, 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, - [0(CH₂)^' _x-X where x 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^x are 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-diethylamino, (N) -benzyloxycarbamoyl, trimethylammonium, A^", -NHC(=0)CH₃, -NHC^OC-H,,, - HC ( =0) C.H , carboxyethylamino, (N) -morpholinyl, (N) -azetidinyl, (N) -N-methylazetidinium A^", (N) -pyrrolidinyl , pyrrolyl, (N) -N-methylpyridinium A^", (N) -N-methylmorpholinium A^", and N-N' -methylpiperazinyl, (N) -bromomethylamido, (N) - N-hexylamino, thiophene, -N^* (CH₃) ₂C0₂H I^', -NCH₃CH₂C0₂H, - (N) -N' -dimethylpiperazinium I^", (N)-t- butyloxycarbamoyl , (N) -methylsulfonamido, (N)N'- methylpyrrolidinium, and - (OCH₂CH₂).I, where A^" is a pharmaceutically acceptable anion. The benzo ring 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, 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 quaternary ammonium salts linked to the ring via poly (oxyalkylene) linkages, e.g., - (OCH₂CH₂)_X-N^*R"R"R¹⁵A^", where x is 2 to 10. Exemplary compounds are those set forth below in Table 1.

3k TABLE 1 Alternative compounds #3 (Family F101.x-Kx.yyy) *

P=e-^».--x Ca S R!=R² R^S (R^x) a ( s . xxx . vw)

FlOl.OOl 01 n-?roαyl Ji— 7-π.etϊ.yl

02 n-prop l P - 7-et yl

03 n-propyl P - 7-iso-propyl

04 n-prαpyl ?h- 7-cer -b cyl

OS n- rop i ?h- -OH

OS n-propyl Ph- 7-OCK3

07 n-prαpyl Pn- 7-0 (iao- ropyl)

03 n-propyl P - 7-SCK3

09 n-propyl Pϊi- 7-SCCH3

10 n-propyl P - 7-SO2CK3

* 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

\ n-propyl Ph- 7-SCH2CH3 n-propyl P - 7-NH2 n-propyl Ph- 7-NHOH n-propyl Ph- 7-NHCH3 n-propyl Ph- 7-N (CH3) 2 n-propyl Ph- 7-N⁺ (CH3) 3, I" n-propyl Ph- 7-NHC (-0) CH3 n-propyl Ph- 7-N (CH2CH3) 2 n-propyl Ph- 7-NMeCH2C02H n-propyl Ph- 7-N⁺ (Me) ₂CH2C02H, I" n-propyl Ph- 7- (N) - orpholinβ n-propyl Ph- 7- (N) -azβtidinβ n-propyl Ph- 7-{N)-N-methylazetidinium, I" n-propyl Ph- 7- (N) -pyrrolidine n-propyl Ph- 7- (N) -N-methyl-pyrrolidinium, I" n-propyl Ph- 7- (N) -N-.τ.ethyl-raorpholiniu-n, I" n-propyl Ph- 7- (N) -N' -∑πethylpipera∑ine n-propyl Ph- 7-{N) -N'-diπethylpiperaziniun, ] n-propyl Ph- 7-NH-C3Z n-propyl Ph- 7--ώc(0)C5Hn n-propyl Ph- 7-NHC(0)CH2Br n-propyl Ph- 7-NK-C(NH)NH2 n-propyl Ph- 7- (2) -thiophene n-propyl Ph- 8-methyl n-propyl Ph- 8-ethyl n-propyl Ph- 8-iso-propyl n-propyl Ph- 8-tert-butyl n-propyl Ph- 8-OH n-propyl Ph- 8-OCH3 n-propyl Ph- 8-0 (iso-propyl) n-propyl Ph- 8-SCH3 n-propyl Ph- 8-SOCH3 n-propyl Ph- 8-SO2CH3 n-propyl Ph- 8-SCH2CH3 n-propyl Ph- 8-NH2 n-propyl Ph- 8-NHOH n-propyl Ph- 8-NHCH3 n-propyl Ph- 8-N(CH3)2 n-propyl Ph- 8-N⁺(CH3)3, I- n-propyl Ph- 8-NHC(^'«0)CH3 n-propyl Ph- 8-N(CH2CH3)2 n-propyl Ph- 8-NMeCH2Cθ2H n-propyl Ph- 8-N* (Me) ₂CH2C02H,PfflE T n-propyl Ph- 8- (N) -morpholine n-propyl Ph- 8- {N) -azetidine n-propyl Ph- 8- (N) -N-methylazetidiniuιn, I" n-propyl Ph- 8- (N) -pyrrolidine n-propyl Ph- 8-(N) -N-rπethyl-pyrrolidinium, I" n-propyl Ph- 8- (N) -N-methyl-morpholinium, I" n-propyl Ph- 8- (N) -N' -me hylpiperazinβ n-propyl Ph- 8-(N)-N'-di-nethylpiperaziniun, I" n-propyl Ph- 8-NK-CBZ n-propyl Ph- 8-NHC(0)CsHn n-propyl Ph- 8-NHC(0)CH2Br n-propyl Ph- 8-NH-C(NH)NH2 n-propyl Ph- 8- (2) -thiophene n-propyl Ph- 9-methyl n-propyl Ph- 9-ethyl n-propyl Ph- 9-iso-ρroρyl n-propyl Ph- 9-tert-butyl n-propyl Ph- 9- __^" n-propyl Ph- 9-OCH3 n-propyl Ph- 9-0 (iso-propyl) n-propyl Ph- 9-SCK3 n-propyl Ph- 9-SOCH3 n-propyl Ph- 9-SO2CK3 n-propyl Ph- 9-SCH2CH3 n-propyl Ph- 9-NK2 n-propyl Ph- 9-NHOH n-propyl Ph- 9-NKCH3 n-propyl Ph- 9-N(CH₃)₂ n-propyl Ph- 9-N⁺(CK3)3, I" n-propyl Ph- 9-NKC(-0)CH3 n-propyl Ph- 9-N(CH2CH3)2 n-propyl Ph- 9-NMeCH2C02H n-propyl Ph- 9-N*(Me)₂CH2Cθ2H, I" n-propyl Ph- 9- (N) -morpholine n-propyl Ph- 9-{N)-azetidine n-propyl Ph- 9- (N) -N-methylazetidiniu , I" n-propyl Ph- 9- (N) -pyrrolidine n-propyl Ph- 9- (N) -N-methyl-pyrrolidinium, I" n-propyl Ph- 9- (N) -N-methyl-morpholinium, 1" n-propyl Ph- 9- (N) -N' -methylpiperazine n-propyl Ph- 9-(N)-N'-di ethylpiperaziniu , I" n-propyl Ph- 9-NH-CSZ

2>^<\ 96 n-propyl Ph- 9-NHC(0)CsHιι

97 n-propyl Ph- 9-NHC(0)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-proovl Ph- 6-OCH3, 7-OCH3, 8-OCH3

Prefix CpdS Rl=R2 R⁵ (R^x) q (FFF.xx-c. yyy)

F101 . 002 01 n-butyl Ph- 7-me hyl

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

06 n-butyl Ph- 7-OCH3

07 n-butyl Ph- 7-Q(iso-propyl)

03 n-butyl Ph- 7-SCH3

09 n-butyl Ph- 7-SOCH3

10 n-butyl Ph- 7-SO2CK3

11 n-butyl Ph- 7-SCH2CH3

12 n-butyl Ph- 7-NK2

13 n-butyl Ph- 7-NHOH

14 n-butyl Ph- 7-NKCH3

15 n-butyl Ph- 7-N(CK₃)₂

16 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-MMeCK2C02H

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, I"

26 n-butyl Ph- 7- (N) -N-methyl-morpholinium, I"

27 n-butyl Ph- 7- (N) -N'-methylpiperazine

28 n-butyl Ph- 7- (N) -N' -dimethylpiperaziniura, I"

29 n-butyl Ph- 7-NH-CBZ

30 n-butyl Ph- 7-NHC(0)C5Hιι

31 n-butyl Ph- 7-NHC(0)CH2Br n-butyl Ph- 7-NH-C (NH) NH2 n-butyl Ph- 7- (2) -thiophene n-butyl Ph- 8-methyl n-butyl Ph- 8-ethyl n-butyl Ph- 8-iso-proρyl n-butyl Ph- 8-tert-butyl n-butyl Ph- 8-OH n-butyl Ph- 8-OCH3 n-butyl Ph- 8-0 (iso-propyl) n-butyl Ph- 8-SCH3 n-butyl Ph- 8-SOCH3 n-butyl Ph- 8-SO2CH3 n-butyl Ph- 8-SCH2CH3 n-butyl Ph- 8-NH2 n-butyl Ph- 8-NKOH n-butyl Ph- 8-NKCK3 n-butyl Ph- 8-N(CK3)2 n-butyl Ph- 8-N+ (0.3)3, ^I_ n-butyl Ph- 8-NgC(-0)CH3 n-butyl Ph- 8-N⁽CH2CH.3)2 n-butyl Ph- 8- MeCH2C02H n-butyl Ph- 8-N^*(Me)₂CK2C02H, I~ n-butyl Ph- 8- (N) -morpholine n-butyl Ph- 8-(N) -azetidine n-butyl Ph- 8- (N) -N-rr.ethylazetidinium, I" n-butyl Ph- 8- (N) -pyrrolidine n-butyl Ph- 8- (N) -N-methyl-pyrrolidinium, I" n-butyl Ph- 8- (N) -N-methyl-morpholinium, I" n-butyl Ph- 8 - (N) -N' -methylpiperazine n-butyl Ph- 8- {N) -N' -dimethylpiperazinium, n-butyl Ph- 8-NH-CBZ n-butyl Ph- 8-NHC (0) CsHil n-butyl Ph- 8-NHC (0) CH2Br n-butyl Ph- 8-NH-C CNHJ H2 n-butyl Ph- 8- (2) -thiophene n-butyl Ph- 9-methyl n-butyl Ph- 9-ethyl n-butyl Ph- 9-iso-propyl n-butyl Ph- 9-tert-butyl n-butyl Ph- 9-OH n-butyl Ph- 9-OCH3 n-butyl Ph- 9-0 (iso-propyl) 74 n-butyl Ph- 9-SCH3

75 n-butyl Ph- 9-SOCH3

76 n-butyl Ph- 9-S02CH3

77 n-butyl Ph- 9-SCH2CH3

78 n-butyl Ph- 9-NH2

79 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-MeCH2C02H

86 n-butyl Ph- 9-N*(Me)₂CH2C02H_/ I"

87 n-butyl Ph- 9- (N) -morpholine

88 n-butyl Ph- 9-(N)-azetidine

89 n-butyl Ph- 9- (N) -N-methylazetidinium, 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- (NT-N' -methylpiperazine

93 n-butyl Ph- 9- (N) -N' -dimethylpiperaziniuai, .

95 n-butyl Ph- 9-NH-C3Z

96 n-butyl Ph- 9-NHC(0)CsHιι

97 n-butyl Ph- 9-NHC(0)CH23r

93 n-butyl Ph- 9-NH-C(NH)NH2

99 n-butyl Ph- 9- (2) -thiophene

100 n-butyl Ph- 7-OCK3 , 8-CCH3

101 n-butyl Ph' 7-SCH3, 8-OCH3

102 n-butyl Ph- 7-SCH3, 8-SCH3

103 n-butyl Ph' 6-OCH3 , 7-OCH3, 8-OCH3

Prefix Cpd R!=R2 (Fr- .xxx (R^x) q -SZL

1.003 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

05 n-pentyl Ph- 7-OH

06 n-pentyl Ph- 7-OCH3

07 n-pentyl Ph- 7-0(iso-prop;

08 n-pentyl Ph- 7-SCH3

09 n-pentyl Ph- 7-SOCH3 n-pentyl Ph- 7-SO2CH3 n-pentyl Ph- 7-SCH2CH3 n-pentyl Ph- 7-NH2 n-pentyl Ph- 7-NHOH n-pentyl Ph- 7-NHCH3 n-pentyl Ph- 7-N (CH3) 2 n-pentyl Ph- 7-N⁺ (CH₃) 3, I" n-pentyl Ph- 7-NHC (-0) CH3 n-pentyl Ph- 7-N (CH2CH3) 2 n-pentyl Ph- 7-NMeCH2C02H n-pentyl Ph- 7-N* (Me) ₂CH2C02H, I" n-pentyl Ph- 7- (N) -morpholine n-pentyl Ph- 7- (N) -azetidine n-pentyl Ph- 7- (N) -N- ethylazetidinium, I" n-pentyl Ph- 7- (N) -pyrrolidine n-pentyl Ph- 7- (N) -N-methyl-pyrrolidiniu-n, I" n-pentyl Ph- 7- (N) -N-methyl-morpholinium, I" n-pentyl Ph- 7- (N) -N' -mathylpiperazine n-pentyl Ph- 7- (^) -N' -dimethylpiperaziniuπ, I" n-pentyl Ph- 7-Nff-C3Z n-pentyl Ph- 7-NKC(0)C5Kn n-pentyi Ph- 7-NKC(0)CK23r n-pentyl Ph- 7-NK-C (NK) NK2 n-pentyl Ph- 7- (2) -thiophene n-pentyl Ph- 8-methyl n-pentyl Ph- 8-ethyl n-pentyl Ph- 8-iso-propyl n-pentyl Ph- 8-tert-butyl n-pentyl Ph- 8 -OH n-pentyl Ph- 8-OCH3 n-pentyl Ph- 8-0 (iso-propyl) n-pentyl Ph- 8-SCH3 n-pentyl Ph- 8-SOCH3 n-pentyl Ph- 8-SO2CH3 n-pentyl Ph- 8-SCH2CH3 n-pentyl Ph- 8-NH2 n-pentyl Ph- 8-NHOH n-pentyl Ph- 8-NHCH3 n-pentyl Ph- 8-N (CH₃) 2 n-pentyl Ph- 8-N⁺ (CH3) ₃, I- n-pentyl Ph- 8-NHC (-0) CH3 n-pentyl Ph- 8- ⁽CH2CH3) 2 n-pentyl Ph- 8-NMeCH2C02H n-pentyl Ph- 8-N*(Me)₂CH2C02H, I" n-pentyl Ph- 8- (N) -morpholine n-pentyl Ph- 8-(N) -azetidine n-pentyl Ph- 8- (N) -N-methylazetidinium, I" n-pentyl Ph- 8- (N) -pyrrolidine n-pentyl Ph- 8- (N) -N-methyl-pyrrolidinium, I" n-pentyl Ph- 8- (N) -N-methyl-morpholinium, I" n-pentyl Ph- 8- (N) -N' -methylpipera∑ine n-pentyl Ph- 8- (N) -N' -dimethylpiperazinium, 1" n-pentyl Ph- 8-NH-CBZ n-pentyl Ph- 8-NKC(0)C5Hιι n-pentyl Ph- 8-NHC(0)CH2Br n-pentyl Ph- 8-NH-C(NH)NH2 n-pentyl Ph- 8- (2) -thiophene

n-pentyl Ph- 9-methyl n-pentyl Ph- 9-ethyl n-pentyl Ph- 9-iso-propyl n-pentyl Ph- 9-tert-butyl n-pentyl Ph- 9-0? n-pentyl Ph- 9-OCH3 n-pentyl Ph- 9-0(iso-ρropyl) n-pentyl Ph- 9-SCH3 n-pentyl Ph- 9-SCCH3 n-pentyl Ph- 9-SO2CK3 n-pentyl Ph- 9-SCH2CH3 n-pentyl Ph- 9-NH-2 n-pentyl Ph- 9-NKOH n-pentyl Ph- 9-NHCH3 n-pentyl Ph- 9-N⁽CH3)2 n-pentyl Ph- 9-N⁺(CH3)3, I" n-pentyl Ph- 9-NHC(-0)CH3 n-pentyl Ph- 9-N(CH2CH3)2 n-pentyl Ph- 9-NMeCH2C02H n-pentyl Ph- 9-N⁺(Me)₂CH2C02H, I^" n-pentyl Ph- 9- (N) -morpholine n-pentyl Ph- 9- (N) -azetidine n-pentyl Ph- 9- (N) -N-methylazetidinium, I" n-pentyl Ph- 9- (N) -pyrrolidine n-pentyl Ph- 9- (N) -N-methyl-pyrrolidinium, I" n-pentyl Ph- 9- (N) -N-methyl-morpholinium, I" n-pentyl Ph- 9- (N) -N' -methylpiperazine n-pentyl Ph- 9- (N) -N' -dimethylpiperazinium, I" 95 n-pentyl Ph- 9-NH-C3Z

96 n-pentyl Ph- 9-NHC(0)C5Hn

97 n-pentyl Ph- 9-NHC (0) CH2Br

98 n-pentyl Ph- 9-NH-C(NH)NH2

99 n-pentyl Ph- 9- (2) -thiophene

100 n-pentyl Ph- 7-OCH3, 8-OCH3

101 n-pentyl Ph- 7-SCH3, 8-OCH3

102 n-pentyl Ph- 7-SCH3, 8-SCH3

103 n-Dβntvl Ph- 6-OCH3, 7-OCH3, 8-QCH3

Prefix CpdJf l= 2 (R^X) q (FIT . -tone

F101.004 01 ^' n-hexyl Ph- 7-methyl

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-OHiso-ρropyl) ^•

08 n-hexyl Ph- 7-SCK3

09 n-hexyl Ph- 7-SOCH3

10 n-hexyl Ph- 7-SO2CH3

11 n-hexyl Ph- 7-SCH2CH3

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-NKC(-0)CK3

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-CBZ

30 n-hexyl Ph- 7-NHC(0)CsHn n-hexyl Ph- 7-NKC (0) CH2Br n-hexyl Ph- 7-NH-C (NH) NH2 n-hexyl Ph- 7- (2) -thiophene n-hexyl Ph- 8-methyl n-hexyl Ph- 8-ethyl n-hexyl Ph- 8-iso-propyl n-hexyl Ph- 8-tert-butyl n-hexyl Ph- 8-OH n-hexyl Ph- 8-OCH3 n-hexyl Ph- 8-0 (iso-propyl) n-hexyl Ph- 8-SCH3 n-hexyl Ph- 8-SOCH3 n-hexyl Ph- 8-SO2CH3 n-hexyl Ph- 8-SCH2CH3 n-hexyl Ph- 8-NH₂ n-hexyl Ph- 8-NKOH n-hexyl Ph- 8-NHCH3 n-hexyl Ph- 8-N(CH.3)2 n-hexyl Ph- 8-N^"+JCH₃)3, l- n-hexyl Ph- 8-NHC(=0)CH3 n-hexyl Ph- 8- (CH.2CH.3)2 n-hexyl Ph- 8-NMeCH2C02H n-hexyl Ph- 8-N⁺( e)₂CH2C02H, I" n-hexyl Ph- 8- (N) -morpholine n-hexyl Ph- 8-(N) -azetidine n-hexyl Ph- 8- (N) -N-methylazetidinium, I" n-hexyl Ph- 8- (N) -pyrrolidine n-hexyl Ph- 8- (N) -N-methyl-pyrrolidinium, I n-hexyl Ph- 8- (N) -N-methyl-morpholinium, I" n-hexyl Ph- 8- (N) -N' -methylpiperazine n-hexyl Ph- 8- (N) -N' -dimethylpiperazinium, n-hexyl Ph- 8-NH-CBZ n-hexyl Ph- ^• 8-NHC(0)CsHn n-hexyl Ph- 8-NHC(0)CH2Br n-hexyl Ph- 8-NH-C(NH)NH2 n-hexyl Ph- 8- (2) -thiophene n-hexyl Ph- 9-methyl n-hexyl Ph- 9-ethyl n-hexyl Ph- 9-iao-propyl n-hexyl Ph- 9-tert-butyl n-hexyl Ph- 9-OH n-hexyl Ph- 9-OCH3 73 n-hexyl Ph- 9-0(iao-ρropyl)

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, I-

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)₂CH2C02H, I"

87 n-hexyl Ph- 9- (N) -morpholine

88 n-hexyl Ph- 9- (N) -azetidine

89 n-hexyl Ph- 9- (N) -N-.τ.ethylazetidinium, I"

90 n-hexyl Ph- 9- (N) -pyrrolidine

91 n-hexyl Ph- 9- (N) -N-methyl-pyrrolidinium, I"

92 n-hexyl Ph- 9- (NJ'-N-methyl-morpholinium, I"

93 n-hexyl Ph' 9- (N) -N' -methylpiperazine

93 n-hexyl Ph- 9- (N) -N' -dimethylpiperazinium, :

95 n-hexyl Ph- 9-NK-C3Z

96 n-hexyl Ph' 9-NKC(0)C5Hn

97 n-hexyl Ph- 9-NKC(0)CH2Br

98 n-hexyl Ph' 9-NX-C(NK)NH2

99 n-hexyl Ph- 9- (2) -thiophene

100 n-hexyl Ph' 7-OCH3, 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 Cpdif !«R2 (R^X) J (ϊ F.:

F101.005 01 iso-propyl Ph- 7-methyl

02 iso-propyl Ph- 7-ethyl

03 iso-propyl Ph- 7-iso-propyl

04 iao-propyl Ph- 7-tert-butyl

05 iao-propyl Ph- 7-OH

06 iso-propyl Ph- 7-OCH3

07 iso-propyl Ph- 7-0(iso-prop

08 iso-propyl Ph- 7-SCH3 iso-propyl Ph- 7-SOCH3 iso-propyl Ph- 7-SO2CH3 iso-propyl Ph- 7-SCH2CH3 iso-propyl Ph- 7-NH.2 iso-propyl Ph- 7-NHOH iso-propyl Ph- 7-NHCH3 iso-propyl Ph- 7-N(CH3)2 iso-propyl Ph- 7-N⁺(CH3)3, I- iso-propyl Ph- 7-NKC(-0)CH3 iso-propyl Ph- 7-N(CH2CH3)2 iso-propyl Ph- 7- MeCH2C02H iso-propyl Ph- 7-N*( e)₂CH2C02H, I" iso-propyl Ph- 7- (N) -morpholine iso-propyl Ph- 7- (N) -azetidine iso-propyl Ph- 7- (N) -N-methylazetidinium, I" iso-propyl Ph- 7- (N) -pyrrolidine iso-propyl Ph- 7- (N) -N-methyl-pyrrolidinium, I iso-propyl Ph- 7- (N) -N-methyl-morpholinium, I" iso-propyl Ph- 7-(N;-N' -methylpiperazine iso-propyl Ph- 7- TO -N' -dimethylpiperazinium, iso-propyl Ph- 7-NK-C3Z iso-propyl Ph- 7-NKC(0)CsH.ιι iso-propyl Ph- 7-NKC(0)CK2Br iso-propyl Ph- 7-NH-C(NK)NK2 iso-propyl Ph- 7- (2) -thiophene iso-propyl Ph- 8-methyl iso-propyl Ph- 8-ethyl iso-propyl Ph- 8-iso-propyl iso-propyl Ph- 8-tert-butyl iso-propyl Ph- 8 -OH iso-propyl Ph- 8-OCH3 iso-propyl Ph- 8-0 (iso-propyl) iso-propyl Ph- 8-SCH3 iso-propyl Ph- 8-SOCH3 iso-propyl Ph- 8-SO2CH3 iso-propyl Ph- 8-SCH2CH3 iso-propyl Ph- 8-NH2 iso-propyl Ph- 8-NHOH iso-propyl Ph- 8-NHCH3 iso-propyl Ph- 8-N ⁽CH3) 2 iso-propyl Ph- 8-N⁺ (CH3) 3, I- iso-propyl Ph- 8-NHC (-0) CH3

4 iso-propyl Ph' 8-N(CH2CH3)2 iso-propyl Ph' 8-N eCH2C02H iso-propyl Ph' 8-N*(Me)₂CH2C02H I" iso-propyl Ph- 8- (N) -morpholine iso-propyl Ph' 8- (N) -azetidine iso-propyl Ph- 8- (N) -N-methylazetidinium, I" iso-propyl Ph- 8- (N) -pyrrolidine iso-propyl Ph- 8- (N) -N-methyl-pyrrolidinium, I" iso-propyl Ph- 8- (N) -N-methyl-morpholinium, I" iso-propyl Ph- 8- (N) -N' -methylpiperazine iso-propyl Ph- 8- (N)-N' -dimethylpiperazinium, 3 iso-propyl Ph- 8-NH-CBZ iso-propyl Ph- 8-NHC(0)C5Hn iso-propyl Ph- 8-NHC(0)CH2Br iso-propyl Ph- 8-NH-C(NH)NH2 iso-propyl Ph- 8- (2) -thiophene iso-propyl Ph- 9-methyl iso-propyl Ph- 9-ethyl iso-propyl Ph- 9-iso-propyl iso-propyl Ph- 9-tert-butyl iso-propyl Ph- 9-OH iso-propyl Ph- 9-OCH3 iso-propyl Ph- 9-0 (iso-propyl) iso-propyl Ph- 9-SCH3 iso-propyl Ph- 9-SOCH3 iso-propyl Ph- 9-SO2CK3 iso-propyl Ph- 9-SCK2CH3 iso-propyl Ph- 9-NH2 iso-propyl Ph- 9-NHOH iso-propyl Ph- 9-NHCH3 iso-propyl Ph- 9-N(CH₃)2 iso-propyl Ph- 9-N⁺(CH3)3, I- iso-propyl Ph- 9-NHC (-0) CH3 iso-propyl Ph- 9-N(CH2CH3)2 iso-propyl Ph- 9-NMeCH2C02H iso-propyl Ph- 9-N*(Me)₂CH2C02H, I" iso-propyl Ph- 9- (N) -morpholine iao-propyl Ph- 9- (N) -azetidine iso-propyl Ph- 9- (N) -N-methylazetidinium, 1" iso-propyl Ph- 9- (N) -pyrrolidine iso-propyl Ph- 9- (N) -N-methyl-pyrrolidinium, I" iso-propyl Ph- 9- (N) -N-methyl-morpholinium, I" iso-propyl Ph- 9- (N) -N' -methylpiperazine

4^ 93 iso-propyl Ph- 9- (N) -N' I"

95 iso-propyl Ph- 9-NH-CBZ

96 iso-propyl Ph- 9-NHC (0) C5Hn

97 iso-propyl Ph- 9-NHC (0) CH2Br

98 iso-propyl Ph- 9-NH-C (NH) H2

99 iso-propyl Ph- 9- (2) -thiophene

100 iso-propyl Ph- 7-OCH3, 8-OCH3

101 iso-propyl Ph- 7-SCH3, 8-OCH3

102 iso-propyl Ph- 7-SCH3, 8-SCH3

103 iso-oroDvl Ph- 6-OCH3, 7-OCH3, 8-OCH3

Pre-Jix Cp .# Rl=R2 R^S ( ^ j (STF . yyy) 01.006 01 iso-butyl Ph- 7-me h l

02 iso-butyl Ph- 7-ethyl

03 iso-butyl Ph- 7-iso-propyl

04 iso-butyl Ph- 7-tert-butyl

05 iso-butyl Ph- 7-OH

06 iso-butyl ?h- 7-OCE3

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-NKOH

14 iso-butyl Ph- 7-NHCH

15 iso-butyl Ph- 7-N(CH3)₂

16 iso-butyl Ph- 7-N⁺(CH₃)3, I-

17 iso-butyl Ph- 7-NHC(-0)CH₃

18 iso-butyl Ph- 7-N⁽CH₂CH3⁾ ₂

19 iso-butyl Ph- 7-MeCH2C02H

20 iso-butyl Ph- 7-N^*(Me)₂CH2C02H, I"

21 iso-butyl Ph- 7- (N) -morpholine

22 iso-butyl Ph- 7- (N) -azetidine

23 iso-butyl Ph- 7- (N) -N-methylazetidinium, I^"

24 iso-butyl Ph- 7-(N) -pyrrolidine

25 iso-butyl Ph- 7- (N) -N-methyl-pyrrolidiniura, I~

26 iso-butyl Ph- 7- (N) -N-methyl-morpholinium, 1^"

27 iso-butyl Ph- 7- (N) -N' -methylpiperazine

23 iso-butyl Ph- 7- ⁽N⁾-N'-dimethylpiperazinium, r

29 iso-butyl Ph- 7-NH-CBZ 30 iso-butyl Ph- 7-NHC(0)C5Hn

31 iso-butyl Ph- 7-NHC(0)CH2Br

32 iso-butyl Ph- 7-NH-C (NH) H2

33 iso-butyl Ph- 7- (2) -thiophene

34 iso-butyl Ph- 8-methyl

35 iso-butyl Ph- 8-ethyl

36 iso-butyl Ph- 8-iso-propyl

37 iso-butyl Ph- 8-tert-butyl

38 iso—bufcvl P 4>hU— 8—OH

39 iso-butyl Ph- 8-OCH3

40 iso-butyl Ph- 8-0 (iso-propyl)

41 iso-butyl Ph- 8-SCH3

42. iso-butyl Ph- 8-SOCH3

43 iso-butyl Ph- 8-SO2CH3

44 iso-butyl Ph- 8-SCK2CH3

45 iso-butyl Ph- 8-NH2

46 iso-butyl Ph- 8-NKOH

47 iso-butyl Ph- 8-NKCH3

48 iso-butyl Ph- 8-IT(CH3)2

49 iso-butyl Ph- 8-N⁺(CH3)3, I-

50 iso-butyl Ph- 8-NKC(-0)CH3

51 iso-butyl Ph- 8-N⁽CH2CH3⁾2

52 iso-butyl Ph- 8- eCH.2C02H

53 iso-butyl Ph- 8-N^* (Me) 2CH2CO2H, I"

54 iso-butyl Ph- 8- (N) -morpholine

55 iso-butyl Ph- 8- (N) -azetidine

56 iso-butyl Ph- 8- (N) -N-methylazetidinium, I"

57 iso-butyl Ph- 8- (N) -pyrrolidine

58 iso-butyl Ph- 8- (N) -N-methyl-pyrrolidinium, I

59 iso-butyl Ph- 8- (N) -N-methyl-morpholinium, I"

60 iso-butyl Ph- 8- (N) -N' -methylpiperazine

61 iso-butyl Ph- 8- (N) -N' -dimethylpiperazinium.

62 iso-butyl Ph- 8-NH-CBZ

63 iso-butyl Ph- 8-NHC(0)C5Hιι

64 iso-butyl Ph- 8-NHC(0)CH2Br

65 iso-butyl Ph- 8-NH-C(NK⁾NH2

66 iso-butyl Ph- 8- (2) -thiophene

67 iso-butyl Ph- 9-methyl

68 iso-butyl Ph- 9-ethyϊ

69 iso-butyl Ph- 9-iso-propyl

70 iso-butyl Ph- 9-tert-butyl

71 iso-butyl Ph- 9-OH 72 iso-butyl Ph- 9-OCH3 73 iso-butyl Ph- 9-0 (iso-propyl)

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, I-

83 iso-butyl Ph- 9-NKC(-0)CH3

84 iso-butyl Ph- 9-N(CH2CH3)2

85 iso-butyl Ph- 9-NMeCH2C02H

86 iso-butyl Ph- 9-N⁺ (Me) ₂CH2Cθ2H, I"

87 iso-butyl Ph- 9-(N) -morpholine

88 iso-butyl Ph- 9-(N) -azetidine

89 iso-butyl Ph- 9- (N) -N-methylazetidinium, I"

90 iso-butyl Ph- 9τ-.(N) -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) -N' -dimethylpiperazinium, I"

95 iso-butyl Ph- 9-NK-C3Z

96 iso-butyl Ph- 9-NKC(0)C5Hn

97 iso-butyl Ph- 9-NKC(0)CK2Br

98 iso-butyl Ph- 9-NK-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$ !=R2 _R5 (R^X)«I (PFP.-t-xx. yw)

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 iso-pentyl Ph- 7-0 (iso-propyl)

S7 iso-pentyl Ph- 7-SCH3 iso-pentyl Ph- 7-SOCK3 iso-pentyl Ph- 7-SO2CH3 iso-pentyl Ph- 7-SCH2CH3 iso-pentyl Ph- 7-NH2 iso-pentyl Ph- 7-NHOH iso-pentyl Ph- 7-NKCH.3 iso-pentyl Ph- 7-N (CH.3⁾ 2 iso-pentyl Ph- 7L-H⁺ iso-pentyl Ph- 7-NHC (-0) CH3 iso-pentyl Ph- 7-N (CH₂CH₃) 2 iso-pentyl Ph- 7-NMeCH2C02H iso-pentyl Ph- 7-N* (Me) ₂CK2Cθ2H, I" iso-pentyl Ph- 7- (N) -morpholine iso-pentyl Ph- 7- (N) -azetidine iso-pentyl Ph- 7- (N) -N-methylazetidinium, I" iso-pentyl Ph- 7- (N) -pyrrolidine iso-pentyl Ph- 7- (N) -N-methyl-pyrrolidinium, I" iso-pentyl Ph- 7- (N) rN-methyl-morρholinium, I" iso-pentyl Ph- 7- (Nr-N' -methylpiperazine iso-pentyl ?h- 7- (N) -N' -dimethylpiperazinium, 3 iso-pentyl Ph- 7-NK-C3Z iso-pentyl Ph- 7-NKC(0)C5Kn iso-pentyl Ph- 7-NHC(0)CH23r iso-pentyl Ph- 7-NH-C(NK)NK2 iso-pentyl Ph- 7- (2) -thiophene iso-pentyl Ph- 8-methyl iso-pentyl Ph- 8-ethyl iso-pentyl Ph- 3-iso-propyl iso-pentyl Ph- 8-tert-butyl iso-pentyl Ph- 8 -OH iso-pentyl Ph- 8-OCH3 iso-pentyl Ph- 8-0 (iso-propyl) iso-pentyl Ph- 8-SCH3 iso-pentyl Ph- 8-SOCH3 iso-pentyl Ph- 8-SO2CH3 iso-pentyl Ph- 8-SCH2CH3 iso-pentyl Ph- 8-NH2 iso-pentyl Ph- 8-NHOH iso-pentyl Ph- 8-NHCH3^' iso-pentyl Ph- 8-N (CH3) 2 iso-pentyl Ph- 8-N⁺ (CH₃ ) ₃, I-

63

67 iso-pentyl Ph- 9 -me hyl

68 iso-pentyl Ph- 9-e thyl

69 iso-pentyl Ph- 9-i-s5-propyl

70 iso-pentyl Ph- 9-tert-butyl

71 iso-pentyl Ph- 9-OH

72 iso-pentyl Ph- 9-OCH

73 iso-pentyl Ph- 9-0 (iso-propyl)

74 iso-pentyl Ph- 9-SCH3

75 iso-pentyl Ph- 9-SOCH3

76 iso-pentyl Ph- 9-SO2CH3

77 iso-pentyl Ph- 9-SCH2CH3

78 iso-pentyl Ph- 9-NH2 9 iso-pentyl Ph- 9-NHOH 0 iso-pentyl h- 9-NKCH3 1 iso-pentyl Ph- 9-N⁽CH3)2 2 iso-pentyl Ph- 9-N⁺(CH3)3, I" 3 iso-pentyl Ph- 9-NKC (-0) CH3 4 iso-pentyl Ph- 9-N(CH2CH3)2 5 iso-pentyl Ph- 9-NMeCH2C02H 6 iso-pentyl Ph- 9-N^*(Me)₂CH2C02H, I" 7 iso-pentyl Ph- 9- (N) -morpholine 3 iso-pentyl Ph- 9- (N) -azetidine 9 iso-pentyl Ph- 9- (N) -N-methylazetidinium,. I" 0 iso-pentyl Ph- 9- (N) -pyrrolidine 1 iso-pentyl Ph- 9- ⁽N) -N-methyl-pyrrolidinium, I" 2 iso-pentyl Ph- 9- ⁽N) -N-methyl-morpholinium, I"

5* 93 iso-pentyl Ph- 9- (N) -N' -methylpi'PfflS-NS-ne

93 iso-pentyl Ph- 9- (N) -N' -dimethylpiperazinium, I"

95 iso-pentyl Ph- 9-NH-CBZ

96 iso-pentyl Ph- 9-NHC(0)CsHn

97 iso-pentyl Ph- 9-NHC(0)CH2Br

98 iso-pentyl Ph- 9-NH-C(NH)NH2

99 iso-pentyl Ph- 9- (2) -thiophene

100 iso-pentyl

101 iso-pentyl Ph- 7-SCH3, 8-CCH3

102 iso-pentyl Ph- 7-SCH3, 8-SCH3

103 iso-Dβntvl Ph- 6-OCH3, 7-OCH3, 8-OCH3

Prefix C?d3 *l=n2 (R*)q 01.008 ⁰¹ CH₂C(-0)C₂H₅ Ph- -me hyl 02 CH₂C(-0)C₂H₅ Ph- 7-ethyl

03 CH₂C(-0)C₂H5 Ph- 7-iso-propyl

04 CH₂C(-0)C₂H₅ Ph- 7-ter -butyl

OS CH₂C (-0) C₂H₅ Ph- 7- H-

06 CH₂C(-0)C₂H₅ Ph- 7-OCH3

07 CH₂C(-0)C₂H Ph- 7-0 (iso-propyl)

08 CH₂C(-0)C₂H_S Ph- 7-SCH3

09 CH C(-0)C₂H₃ Ph- 7-SOCK3

10 CH₂C(=0)C₂H₅ Ph- 7-SO2CH3

11 CH₂C(-0)C₂H₃ Ph- 7-SCK2CH3

12 CH₂C(-0)C₂H_s Ph- 7-NF.2

13 CH₂C(-0)C₂H_S Ph- 7-NKOK

14 CH₂C(-0)C₂H_S Ph- 7-NKCF.3

15 CH₂C{-0)C₂H₅ Ph- 7-N(CH3)2

16 CH₂C(-0)C₂H5 Ph- 7-N⁺(CH₃)3, I"

17 CH₂C(-0)C₂H₅ Ph- 7-NHC(-0)CH3

18 CH₂C (-0) C₂H₅ Ph- 7-N⁽CH2CH3)₂

19 CH₂C(-0)C₂Hs Ph- 7-NMeCK2C02H

20 CH₂C(-0)C₂H₅ Ph- 7-N*£Me)₂CH2C02H, I"

21 CH₂C(*0)C₂H5 Ph- 7- (N) -morpholine

22 CH₂C(-0)C₂H_S Ph- 7- (N) -azetidine

23 CH₂C(-0)C₂H_S Ph- 7- (N) -N-methylazetidinium, I"

24 CH₂C(-0)C₂H Ph- 7- (N) -pyrrolidine

25 CH₂C(-0)C₂H₅ Ph- 7- (N) -N-methyl-pyrrolidinium, I"

26 CH₂C(-0)C₂H_S Ph- 7- (N) -N-methyl-morpholinium, I"

27 CH C(-0)C₂Hs Ph- 7- (N) -N' -methylpiperazine

28 CH C(-0)C₂H5 Ph- 7- (N) -N' -dimethylpiperazinium, I^'

s 29 CH₂C(-0)C₂H₅ Ph- 7-NH-C3Z

30 CH₂C(-0)C₂Hs Ph- 7-NHC(0)CsHn

31 CH₂C(-0)C₂H₅ Ph- 7-NKC (0) CH2Br

32 CH₂C(-0)C₂H₅ Ph- 7-NH-C (NH) NH2

33 CH₂C(-0)C₂H₅ Ph- 7- (2) -thiophene

34 CH₂C(-0)C₂H₅ Ph- 8-methyl

35 CH₂C(-0)C₂H₅ Ph- 8-ethyl

36 CH₂C(-0)C₂H_s Ph- 8-iso-p_ropyl_

37 CH₂C(-O)C₂H_S Ph- 8-tert-butyl

38 CH₂C(-0)C₂H_S Ph- 8-OH

39 CH₂C(-0)C₂H_s Ph- 8-OCH3

40 CH₂C(-0)C₂H_S 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)C₂H₅ Ph- 8-SCK2CH3

45 CH₂C(-0)C₂H₃ Ph- 8-NH2

46 CH₂C(-0)C₂H₃ Ph- 8-NKOK

47 CK₂C(-0)C₂H₃ Ph- 8-^fJCH3

48 CH₂C(-0)C₂K₃ Ph- 8-N⁽CH3⁾2

49 CK₂C(-0)C₂H₃ Ph- 8-N⁺(CH3)3, I-

50 CH₂C(-0)C₂H₅ Ph- 8-NKC(-0)CH3

51 CH₂C(-0)C₂H₃ ?h- 8-N(CH2CH3⁾2

52 CH₂C(=0)C₂H₃ Ph- 8-NMeCK2C02H

53 CH₂C(-0)C₂H₅ Ph- 8-N^* (Me) ₂CH2C02H, I"

54 CH₂C(»0)C₂H₃ Ph- 8- (N) -morpholine

55 CH₂C(=0)C₂H₃ Ph- 8- (N) -azetidine

56 CH₂C(-0)C₂H₅ Ph- 8- (N) -N-methylazetidinium, I"

57 CH₂C(-0)C₂H₅ Ph- 8- (N) -pyrrolidine

58 CH₂C(-0)C₂H_S Ph- 8- (N) -N-methyl-pyrrolidinium, I"

59 CH₂C(-0)C₂H₅ Ph- 8- (N) -N-methyl-morpholinium, I"

60 CH₂C{-0)C₂H_s Ph- 8- (N) -N' -methylpiperazine

61 CH₂C(-0)C₂H_S Ph- 8- (N) -N' -dimethylpiperazinium, I

62 CH₂C(-0)C₂H_S Ph- 8-NH-CBZ

63 CH₂C(-0)C₂H_S Ph- 8-NHC(0)CsHn

64 CH₂C(-0)C₂H_s Ph- 8-NKC(0)CH2Br

65 CH₂C(-0)C₂H₅ Ph- 8-NH-C(NH)NH2

66 CH₂C(-0)C₂H₅ Ph- 8- (2) -thiophene

67 CH₂C(-0)C₂H_S Ph- 9-methyl

68 CH₂C(-0)C₂H_S Ph- 9-ethyl

69 CH₂C(-0)C₂H_S Ph- 9-iso-propyl

5^ 70 CH₂C(-0)C₂H₃ Ph- 9-tert-butyl

71 CH₂C(-0)C₂H₅ Ph- 9 -OH

72 CH₂C(-0)C₂H₅ 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) C₂H₃ Ph- 9-SO2CH3

77 CH₂C(-0)C₂H₅ Ph- 9-SCH2CH3

78 CH₂C(-0)C₂H₅ Ph- 9-NH2

C ι_.HΛmr^ft«.

80 CH₂C (-0) C₂H₅ Ph- 9-NHCH3

81 CH₂C(-0)C₂H₅ Ph- 9-N(CH₃)2

82 CH₂C(-0)C₂H₃ 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 CH₂C(-0)C₂H₃ Ph- 9-NMeCH2C02H

86 CH₂C(^«0)C₂H₃ Ph- 9-N*(Me)₂CK2C02H, I"

87 CH₂C(-0)C₂H₃ Ph- 9- (N) -morpholine

88 CH₂C(-0)C₂H_S Ph- 9-{N) -azetidine

89 CH₂C(-0)C₂H_S Ph- 9- ⁽S)^'-N-methylazetidinium, I~

90 CK₂C(*>0)C₂H₃ Ph- 9- (N) -pyrrolidine

91 CH₂C(-0)C₂H₅ Ph- 9- ⁽N) -N-methyl-pyrrolidinium, I"

92 CH₂C(-0)C₂H₃ Ph- 9- ⁽N) -N-methyl-morpholinium, I"

93 CH₂C(=»0)C₂H_S Ph- 9- ⁽N) -N' -methylpiperazine

93 CH₂C(-0)C₂H₃ Ph- 9- ⁽N⁾ -N' -dimethylpiperazinium, I"

95 CH₂C(-0)C₂H₅ Ph- 9-NH-C3Z

96 CH₂C(=0)C₂H₃ Ph- 9-NHC(0)CsHιι

97 CH₂C(-0)C₂H_S Ph- 9-NKC(0)CK23r

98 CH₂C(-0)C₂H_s Ph- 9-NH-C (NH) H2

99 CH₂C(=0)C₂H₅ Ph- 9- (2) -thiophene

100 CH₂C(-0)C₂H_s Ph- 7-OCH3, 8-OCH3

101 CH₂C(-0)C₂H₅ Ph- 7-SCH3, 8-OCH3

102 CH₂C(«0)C₂H₃ Ph- 7-SCH3, 8-SCH3 103 CH₂C(-0)C₂H₅ Ph- 6-OCH3, 7-OCH3, 8-OCH3

Prefix Cpdjf Rl=R² R5 (Ϊ P.-----X. yvy) (R^x)q

F101.00901 CH₂OC₂H₃ Ph- 7 -methyl

02 CH₂OC₂H₃ Ph- 7-ethyl ^•

03 CH₂OC₂H₅ Ph- 7-iso-proρyl

04 CH₂OC₂H₅ Ph- 7-tert-butyl

si CH₂0C₂H_S Ph- 7-OH CH₂0C₂H_S Ph- 7-OCH3 CH₂OC₂H_S Ph- 7-0 (iso-propyl) CH₂OC₂H₅ Ph- 7-SCH3 CH₂0C₂H_S Ph- 7-SOCH3 CH₂OC₂H_S Ph- 7-SO2CH3 CH₂OC₂H_S Ph- 7-SCH2CH3 CH₂OC₂H₃ Ph- 7-NH2

CH₂0C₂H_S Ph- 7-NHOH

CH₂0C₂H₅ Ph- 7-NHCH3

CH₂OC₂H₃ Ph- ^■. -N (CH₃) 2

CH₂0C₂H_S Ph- 7-N⁺ (CH3) ₃, I"

CH₂0C₂H_S Ph- 7-NHC (-0) CH3

CH₂OC₂H₅ Ph- 7-N (CH2CH3 ) 2

CH₂OC₂H_s Ph- 7- MeCH2Cθ2H

CH₂0C₂H_S Ph- 7-N+ (Me) ₂CH2C02H, I"

CH₂0C₂H₃ Ph- 7- (N) -morpholine

CH₂0C₂H₃ Ph- 7- (N) -azetidine

CH₂0C₂K₃ Ph- 7- ({j) --N-methylazetidinium, I^*

CH₂0C₂H₃ Ph- 7- (N) -pyrrolidine

CH₂OC₂K₃ Ph- 7- ⁽N⁾ -N-methyl-pyrrolidinium, I"

CH₂OC₂H_s Ph- 7- (N) -N-methyl-morpholinium, I"

CH₂OC₂H₃ Ph- 7- (N) -N' -methylpiperazine

CH₂0C₂H_S Ph- 7- ⁽N⁾-N' -dimethylpiperazinium, I"

CH₂0C₂H_S Ph- 7-NK-C3Z

CK₂OC₂H₃ Ph- 7-NHC (O)CsKn

CH₂OC₂K₃ Ph- 7-NHC (0)CH23r

CH₂OC₂H₃ Ph- 7-NH-C(NK)NH2

CH₂OC₂H₃ Ph- 7- (2) -thiophene

CH₂OC₂H_s Ph- 8-methyl CH₂0C₂H_S Ph- 8-ethyl CH₂OC₂H₅ Ph- 8-iso-propyl CH₂OC₂H₅ Ph- 8-tert-butyl CH₂0C₂H₅ Ph- 8-OH CH₂OC₂H_S Ph- 8-OCH3 CH₂OC₂H₅ Ph- 8-0 (iso-propyl) CH₂OC₂H_s Ph- 8-SCH3 CH₂OC₂H₃ Ph- 8-SOCH3 CH₂0C₂H_S Ph- 8-SO2CH3 CH₂0C₂H₅ Ph- 8-SCH2CH3 CH₂OC₂H_S Ph- 8-NH2 CH₂OC₂H₅ Ph- 8-NHOH

S^<B CH₂OC₂H₅ Ph- 8-NHCH3

CH₂0C₂H_S Ph- 8-N ⁽CH3⁾ 2

CH₂0C₂H_S Ph- 8-N+ (CH3) 3, I"

CH₂OC₂H₅ Ph- 8-NHC (-0) CH3

CH₂OC₂H_s Ph- 8- ⁽CH2CH3) 2

CH₂OC₂H₅ Ph- 8-NMeCH2C02H

CH₂OC₂H₅ Ph- 8-N* (Me) ₂CK2C02H, I"

CH₂OC₂H_s Ph- 8- (N) -morpholine

CH₂OC₂H₅ Ph- 8- (N) -azetidine

CH₂0C₂H_S Ph- 8- (N) -N-mathylazetidinium, I"

CH₂OC₂H_s Ph- 8- (N) -pyrrolidine

CH₂OC₂H₅ Ph- 8- (N) -N-methyl-pyrrolidinium, I"

CH₂OC₂H₅ Ph- 8- (N) -N-mathyl-morpholinium, I"

CH₂OC₂H₃ Ph- 8- (N) -N' -methylpiperazine

CH₂0C₂H_S Ph- 8- (N) -N' -dimethylpiperazinium, .

CH₂OC₂H₃ Ph- 8-NH-C3Z

CH₂OC₂H₃ Ph- 8-NHC(0)CsHn

CH₂OC₂H₃ Ph- 8-NKC(0)CH2Br

CH₂OC₂K₃ Ph- 8-NH-C⁽NH⁾NH2

CH₂OC₂H₅ Ph- 8- r2)^"-thiophene

CH₂OC₂Hs Ph- 9-methyl

CH₂OC₂H₅ Ph- 9-ethyl

CH₂OC₂K₅ Ph- 9-iso-ρropyl

CH₂OC₂H_s Ph- 9-tert-butyl

CH₂OC₂H₃ Ph- 9-0H

CH₂OC₂H₃ Ph- 9-OCH3

CH₂OC₂H_S Ph- 9-0 (iso-propyl)

CH₂OC₂H₅ Ph- 9-SCH3

CH₂OC₂H₃ Ph- 9-SOCH3

CH OC₂H₅ Ph- 9-SO2CH3

CH₂OC₂H₅ Ph- 9-SCH2CH3

CH₂OC₂H₅ Ph- 9-NH2

CH₂OC₂H₃ Ph- 9-NH0H

CH₂OC₂H₅ Ph- 9-NHCH3

CH₂0C₂H_S Ph- 9-N⁽CH3)2

CH₂OC₂H_s Ph- 9-N⁺(CH₃)3, I-

CH₂OC₂H_S Ph- 9-NHC(-0)CH3

CH₂OC₂H₃ Ph- 9- ⁽CH2CH3)2

CH₂0C₂H_S Ph- 9-NMeCH2C02H

CH₂OC₂H₅ Ph- 9-N*(Me)₂CH2C02H, I"

CH₂OC₂H₅ Ph- 9- (N) -morpholine

S 88 CH₂0C₂H_S Ph- 9- (N) -azetidine

89 CH₂0C₂H_S Ph- 9- (N) -N-methylazetidinium, I"

90 CH₂OC₂H₃ Ph- 9- (N) -pyrrolidine

91 CH₂OC₂H₃ Ph- 9- (N) -N-methyl-pyrrolidinium, I"

92 CH₂OC₂H₃ Ph- 9- (N) -N-methyl-morpholinium, I~

93 CH₂OC₂H₃ Ph- 9- (N) -N' -methylpiperazine

93 CH₂0C₂H_S Ph- 9- (N) -N' -dimethylpiperazinium, ]

95 CH₂0C₂H₅ Ph- 9-NH-CBZ

96 Λ CnU₂-flOC₂.«tT5. Ph-^~ 9- H (θrC5Hιι—

97 CH₂OC₂H₃ Ph- 9-NHC(0)CH2Br

98 CH₂OC₂H₃ Ph- 9-NH-C (NH)NH2

99 CH₂OC₂H₃ Ph- 9- (2) -thiophene

100 ^' CH₂OC₂H₃ Ph- 7-OCH3, 8-OCH3

101 CH₂OC₂H₃ Ph- 7-SCH3, 8-OCH3

102 CH₂OC₂H₅ Ph- 7-SCH3, 8-SCH3

103 CH₂OC₂H₅ Ph- 6-OCH3, 7-OCH3, 8-OCH3

Prefi-r Cpd* l=R² (R*,;* (-TTF.: yyy)

FIOI.OIO 01 CH₂CH(OK)C₂H₃ Ph- 7 -methyl

02 CH₂CH(OH)C₂H₃ Ph- 7-ethyl

03 CH₂CH(OH)C₂H₃ Ph- 7-iso-propyl

04 CH₂CH (OH) C₂H_S Ph- 7-tert-butyl

05 CK₂CH(OK)C₂H₃ Ph- 7 -OK

06 CK₂CH (OH) C₂H₃ Ph- 7-OCH3

07 CH₂CH (OK) C₂H₃ Ph- 7-0 (iso-propyl)

08 CH CH (OH) C₂H₃ Ph- 7-SCH3

09 CH₂CH(OH)C₂H₃ Ph- 7-SOCH3

10 CH₂CH (OH) C₂K₃ Ph- 7-SO2CK3

11 CH₂CH(OH)C₂H₃ Ph- 7-SCH2CH3

12 CH₂CH(OH)C₂H₃ Ph- 7-NH2

13 CH₂CH(OH)C₂H₃ Ph- 7-NHOH

14 CH₂CH (OH) C₂H₃ Ph- 7-NHCH3

15 CH₂CH(OH)C₂H₃ Ph- 7-N(CH3)2

16 CK₂CH (OH) C₂H_S Ph- 7-N⁺(CH3)3, I"

17 CH₂CH (OH) C₂H₃ Ph- 7-NHC (-OCH3

18 CH₂CH (OH) C₂H₃ Ph- 7- (CH2CH3)2

19 CH₂CH(OH)C₂H_s Ph- 7-NMeCH2C02H

20 CH₂CH (OH) C₂H₃ Ph- 7-N* (Me) ₂CH2C02H,

21 CH₂CH(OH)C₂H₃ Ph- 7- (N) -morpholine

22 CH₂CH (OH) C₂H₅ Ph- 7- (N) -azetidine CH₂CH (OH) C₂H₅ Ph- 7- (N) -N-methylaze^y^nm, 1"

CH₂CH(0H)C₂H_S Ph- 7- (N)

CH₂CH(OH)C₂H₃ Ph- 7- (N) -N-methyl-pyrrolidinium, I"

CH₂CH (OH) C₂K_S Ph- 7- (N) -N-methyl-morpholinium, I"

CH₂CH (OH) C₂H₃ Ph- 7- (N) -N' -methylpiperazine

CH₂CH(OH)C₂H₅ Ph- 7- (N) -N' -dimethylpiperazinium, 1"

CH₂CH (OK) C₂H_S Ph- 7-NH-CBZ

CH₂CH(OH)C₂H₃ Ph- 7-NKC(0)CsHn

CH₂CH(OH)C₂H_s Ph- 7-NHC (0)CH2Br

— CH₂CH (OH) C₂H₃ — p = 7-NH-C (NH) NH2

CK₂CH (OH) C₂H₃ Ph- 7- (2) -thiophene

CH₂CH (OH) C₂H₃ Ph- 8-methyl ^• CH₂CH (OH) C₂H₃ Ph- 8-ethyl

CK₂CH(OH)C₂H₅ Ph- β-iao-propyl

CH₂CH(OH)C₂K₃ Ph- 8-ter -butyl

CH₂CH (OH) C₂H₃ Ph- 8-OH

CH₂CK (OK) C₂K₃ Ph- 8-OCH3

CH2CH(OH)C₂K₃ Ph- 8-0.(iso-propyl)

CH₂CK(OH)C₂H₃ Ph- 8-SCH3

CK₂CH(OH)C₂H« Ph- 8-SOCH3

CK₂CH (OH) C₂H₃ Ph- 8-SO2CH3

CK₂CH(OH)C₂H₃ Ph- 8-SCH2CK3

CK₂CH (OH) C₂H₃ Ph- 8-NH2

CH₂CH(OH)C₂H₅ Ph- 8-NKOH

CH₂CH (OH) C₂H₃ Ph- 8-NHCH3

CH₂CH (OH) C₂H₃ Ph- 8-N(CF.3⁾2

CF.₂CH(OH)C₂H₃ Ph- 8-N⁺(CH3)₃, 1-

CH₂CH(OK)C₂H₃ Ph- 8-NHC(-0)CK3

CH₂CK(OH)C₂H₃ Ph- 8-N(CH₂CH3⁾2

CH₂CK (OH) C₂H₅ Ph- 8-NMeCH2C02H

CK₂CH(OH)C₂H_s Ph- 8-N*(Me)₂CH2C02H, I"

CH₂CH(OH)C₂H₅ Ph- 8- (N) -mo pholine

CH₂CH(OH)C₂H₅ Ph- 8- (N) -azetidine

CH₂CH(OH)C₂H₃ Ph- 8- (N) -N-methylazetidinium, 1"

CH₂CH(OH)C₂H₃ Ph- 8- (N) -pyrrolidine

CH₂CH(OH)C₂H₅ Ph- 8- (N) -N-methyl-pyrrolidinium, I"

CH₂CH(OH)C₂H_s Ph- 8- (N) -N-methyl-morpholinium, I"

CH₂CH(OH)C₂H_s Ph- 8- (N) -N' -methylpiperazine

CH₂CH(OH)C₂H₅ Ph- 8- (N) -N' -dimethylpiperazinium, I"

CH₂CH (OH) C₂H₅ Ph- 8-NH-CSZ

CH₂CH(0H)C₂H_S Ph- 8-NHC(0)CsHn

CH₂CH(OH)C₂H₅ Ph- 8-NHC(0)CH2Br

ώ( CH₂CH (OH) C₂H₃ Ph- 8-NH-C(NH)NH2

CH₂CH(OH)C₂H₃ Ph- 8- (2) -thiophene

CH₂CH (OH) C₂H₃ Ph- 9-methyl

CH₂CH(OH)C₂H₃ Ph- 9-ethyl

CH₂CH (OH) C₂H₃ Ph- 9-iso-propyl

CH₂CH(OH)C₂H₃ Ph- 9-tert-butyl

CH₂CH(OH)C₂H₃ Ph- 9-OH

CH₂CH(OH)C₇H₅ Ph- 9-OCH3

CH₂CH(OH)C₂H₃ Ph- 9-0(iao-propyl)

CH₂CH(OH)C₂H₃ Ph- 9-SCH3

CH₂CH (OH) C₂H₃ Ph- 9-SOCH3

CH₂CH (OH) C₂K_S Ph- 9-SO2CH3

CH₂CH (OH) C₂H₃ Ph- 9-SCH2CH3

CH₂CH(OH)C₂H₃ Ph- 9-NH2

CH₂CH(OH)C₂H₃ Ph- 9-NHOH

CH₂CH(OH)C₂H₃ Ph- 9-NHCK3

CK₂CH (OH) C₂H₃ Ph- 9-N(CH₃)₂

CH₂CH (OH) C₂K₃ Ph- 9-N^(CH₃)₃, I'

CH₂CH (OH) C₂H_S Ph- 9-NH (-0)CH3

CH₂CH (OH) C₂K₃ Ph- 9-N(CK₂CH₃)2

CH₂CH(OH)C₂K₃ Ph- 9-N eCH2C02H

CH₂CH(OH)C₂H₃ Ph- 9-N¹-(Me)₂CH₂C02H I"

CH₂CH (OH) C₂H₃ Ph- 9- (N) -morpholine

CH₂CH(OH)C₂H₃ Ph- 9- (N) -azetidine

CK₂CH(OH)C₂K₃ Ph- 9- (N) -N-methylazetidinium, I-

CH₂CH (OH) C₂H₃ Ph- 9- (N) -pyrrolidine

CH₂CH(OH)C₂H₃ Ph- 9- (N) -N-methyl-pyrrolidinium, I~

CH₂CH(OH)C₂K₃ Ph- 9- (N) -N-methyl-morpholinium, I^"

CH₂CH (OH) C₂H₃ Ph- 9- (N) -N' -methylpiperazine

CH₂CH (OH) C₂H₃ Ph- 9- (N)-N' -dimethylpiperazinium, I^"

CH₂CH (OH) C₂H₃ Ph- 9-NH-C32

CH₂CH (OH) C₂H₅ Ph- 9-NHC(0)C₅H_n

CH₂CH (OH) C₂H₃ Ph- 9-NHC(0)CH2Br

CH₂CH(OH)C₂H₃ Ph- 9-NH-C (NH) NH2

CH₂CH(OH)C₂H₃ Ph- 9- (2) -thiophene

CH₂CH (OH) C₂H₃ Ph- 7-OCH3, 8-OCH3

CH₂CH (OH) C₂H₃ Ph- 7-SCH3, 8-OCH3

CH₂CH (OH) C₂H₃ Ph- 7-SCH3, 8-SCH3

CH₂CH(OH)C H₅ Ph- 6-OCH3, 7-OCH3, 8-OCH3

3. Prefi-x Cpdi, Rl=R2 R5 (R^x)q (∑TΓ.X-CX. W)

F101.011 ⁰¹ CH₂0- (4-picoline) Ph- 7-methyl

02 CH₂0- (4-picoline) Ph- 7-ethyl

03 CH₂0- (4-picoline) Ph- 7-iso-propyl

04 CH₂0- (4-picoline) Ph- 7-tert-butyl

05 CH₂0- (4-picoline) Ph- 7-OH

06 CH₂0- (4-picoline) Ph- 7-OCH3

—07— CH^O^T4-picbTine) Ph- 7- (iso-propyl)

08 CH₂0- (4-picoline) Ph- 7-SCH3

09 CH₂0- (4-picoline) Ph- 7-SOCH3

' 10 CH₂0- (4-picoline) Ph- 7-SO2CH3

11 . CH₂0- (4-picoline) Ph- 7-SCH2CH3

12 CH₂0- (4-picoline) Ph- 7-NH.2

13 CH₂0- (4-picoline) Ph- 7-NHOH

14 CH₂0-(4-picoline) Ph- 7-NHCH3

15 CH₂0- ( 4-ρicoline) Ph- 7-N(CH3)2

16 CH₂0- (4-picoline) Ph- 7-N-⁺f_CH₃)3, I-

17 CH₂0- (4-picoline) Ph- 7-NKC(=0)CH3

18 CH₂0- ( -picoiine) Ph- 7-N⁽CH2CH3⁾2

19 CH₂0- (4-picoiine) Ph- 7-NMCH.2C02H

20 CH₂0- (4-ρicoline) Ph- 7-N"" (Me) ₂CH2C02H, T~

21 CH₂0- (4-picoline) Ph- 7- (N) -morpholine

22 CH₂0- (4-picoline) Ph- 7-(N) -azetidine

23 CH₂0- (4-picoline) Ph- 7- (N) -N-methylazetidinium, I"

24 CH₂0- (4-ρicoline) Ph- 7- (N) -pyrrolidine

25 CH₂0- (4-picoline) Ph- 7- (N) -N-methyl-pyrrolidinium, I"

26 CH₂0- (4-ρicoline) Ph- 7- (N) -N-methyl-morpholinium, I"

27 CH₂0- (4-picoline) Ph- 7- (N) -N' -methylpiperazine

28 CH₂0- (4-picoline) Ph- 7- (N) -N' -dimethylpiperazinium, I"

29 CH₂0-(4-picoline) Ph- 7-NH-C32

30 CH₂0- (4-picoline) Ph- 7-NKC(0)C5Hu

31 CH₂0- { 4-picoline) Ph- 7-NHC (0)CH2Br

32 CH₂0-(4-picoline) Ph- 7-NH-C(NH)NH2

33 CH₂0- (4-picoline) Ph- 7- (2) -thiophene

34 CH₂0- (4-ρicoline) Ph- 8-methyl

35 CH₂0- (4-picoline) Ph- 8-ethyl

36 CH₂0- (4-picoline) Ph- 8-i3θ-proρyl

37 CH₂0- (4-picoline) Ph- 8-tert-butyl

38 CH₂0- (4-picoline) Ph- 8-OH

39 CH₂0- (4-picoline) Ph- 8-OCH3

03 40 CH₂0- (4-picoline) Ph- 8-0 ( iao-propyl) 41 CH₂0- ( 4-picoline) Ph- 8-SCH3 42 CH₂0- ( 4-picoline) Ph- 8-SOCH3 43 CH₂0- ( 4-picoline) Ph- 8-SO2CH3 44 CH₂0- ( 4-picoline) P - 8-SCH2CH3 45 CH₂0- ( 4-picoline) Ph- 8-NH2 46 CH₂0- ( 4-picoline) Ph- 8-NHOH 47 CH₂0- ( 4-picoline) Ph- 8-NHCH3 ^~ 8^~ CH 0- (4-picoline) Ph- 8-N⁽CH3)2 49 CH₂0- (4-picoline) Ph- 8-N⁺(CH3)3, I"

50 CH₂0- ( 4-picoline) Ph- 8-NKC(-0)CH3

51 CH₂0- ( 4-picoline) Ph- 8-N(CH2CH3)2

52 . CH₂0- ( 4-picoline) Ph- 8-NMeC.H2C.O2H

53 CH₂0- ( 4-picoline) Ph- 8-N*(Me)₂CH2C02H, I'

54 CH₂0- ( -picoline) Ph- 8- (N) -morpholine

55 CH₂0- ( 4-ρicoline) Ph- 8- (N) -azetidine

56 CH₂0- ( 4-picoline) Ph- 8- (N) -N-methylazetidinium, 1~

57 CH₂0- ( 4-picoline) Ph- 8- (N) -pyrrolidine

58 CH₂0- ( 4-ρicoline) Ph- 8-_:fN)^'-N- ethyl-pyrrolidinium, 1"

59 CH₂0- ( 4-picoline ) Ph- 8- (N) -N-methyl-morpholinium, I"

60 CH₂0- ( 4-picoline) Ph- 8- (N) -N' -methylpiperazine

61 CH₂0- ( 4-ρicoline) Ph- 8- (N) -N' -dimethylpiperazinium, I"

62 CH₂0- ( 4-picoline) Ph- 8-NH-C32

63 CH₂0- ( 4-picoline) Ph- 8-NKC(0)C5.Hιι

64 CH₂0- ( 4-picoline) Ph- 8-NKC(0)CH2Br

65 CH₂0- ( 4-picoline) Ph- 8-NH-C(NK)NH2

66 CH₂0- ( 4-picoline ) Ph- 8- (2) -thiophene

67 CH₂0-(4 -picoline) Ph- 9-methyl 68 CH₂0-(4-picoline) Ph- 9-ethyl 69 CH₂0-(4-picoline) Ph- 9-iso-propyl 70 CH₂0-(4-picoline) Ph- 9-tert-butyl 71 CH₂0-(4-picoline) Ph- 9-OH 72 CH₂0-(4-picoline) Ph- 9-OCH3 73 CH₂0-(4-picoline) Ph- 9-0 (iso-propyl) 74 CH₂0-(4-picoline) Ph- 9-SCH3 75 CH₂0-{4-picoline) Ph- 9-SOCH3 76 CH₂C-(4'-picoline) Ph- 9-SO2CH3 77 CH₂0-{4'-picoline) Ph- 9-SCH2CH3 78 CH₂0-(4--picoline) Ph- 9-NH.2 - 79 CH0-{4--picoline) Ph- 9-NHOH 80 CH₂0-(4--picoline) Ph- 9-NHCH3 81 CH₂0-(4--picoline) Ph- 9-N(CH3)2

<_* + 82 CH₂0- (4-picoline) Ph 9-N⁺(CH₃)3, I-

83 CH₂0- (4-picoline) Ph 9-NHC(-0)CH3

84 CH₂0- (4-picoline) Ph 9- ⁽CH2CH3)2

85 CH₂0- (4-picoline) Ph 9-NMeCH2C02H

86 CH₂0- (4-picoline) Ph 9-N⁺ (Me) ₂CH2C02H, I"

87 CH₂0- (4-ρicoline) Ph 9- (N) -morpholine

88 CH₂0- (4-picoline) Ph- 9- (N) -azetidine

89 CH₂0- (4-picoline) Ph- 9- (N) -N-methylazetidinium, I"

-90 CH₂0- (4-pico-l-ine)- —Ph- 9- (N) -pyrrolidine

91 CH₂0- (4-picoline) Ph- 9- (N) -N-methyl-pyrrolidinium, I"

92 CH₂0- (4-ρicoline) Ph- 9- (N) -N-methyl-morpholinium, I"

93 CH₂0- (4-ρicoline) Ph- 9- (N) -N' -methylpiperazine

93 CH₂0- (4-picoline) Ph- 9- (N) -N' -dimethylpiperazinium, .

95 ^" CH₂0- (4-picoline) Ph- 9-NH-C32

96 CH₂0- (4-ρicoline) Ph- 9-NKC(0)C5Hιι

97 CH₂0- (4-picoline) Ph- 9-NKC(0)CK23r

98 CH₂0- (4-ρicoline) Ph- 9-NH-C(NK)NH2

99 CH₂0- (4-picoline) Ph- 9- (2) -thiophene

100 CH₂0- [4-picoline) Ph- 7-θ^"cK3, 8-OCH3

101 CH₂0- ;4-picoline) Ph- 7-SCH_3/ 8-OCH3

102 CH₂0- ; 4-picoline) Ph- 7-SCH3, 8-SCH3

103 CH₂0- [4-picoline) Ph- 6-OCH3, 7-OCK3, 8-OCH3

(cS Additional Structures of the Present Invention

IO[

\OX 1316 n-butyl ethyl OH H phenyl 1317 n-butyl ethyl OH H phenyl

PEG = 3400 molecular weight polyethylene glycol polymer chain

PEG = 3400 molecular weight polyethylene glycol polymer chain

Ul

PEG = 3400 molecular weight polyethylene glycol polymer chain

*

CZ2 rOS N 03 S 387.3-13

\2^<\ C2I H2-I 03 S 336.466

C22 H2β 0 S i

3-40.33

C22 H2β 0 S

\ 3 C22 Mβ 04 S 388.923

C22 H32 03 S . C22 H23 03 S 743.083

C22 H28 02 S 396.929

\b\ C28 r I H 03 S 471.704

C22 K27 I 03 S 498.423

C24 N30 03 S 430.363

13X C22 K23 N 04 S

403.343

C22 H23 N 04 S

403 343

C28 H41 N 03 S

471 704

C28 H40 04 S 472.689

C24 H30 03 S

430.963

C36 H43 N 06 S

617.807

tM- C23 H30 04 S

402.333

C22 H28 04 S

388.329

13S C22 H28 03 3

372.929

C22 H28 03 S 372.323

C23 H30 04 S

402.33S

Ph OH

134 C22 H28 04 S . C22 M28 03 S 761.036

2 C22 K2β 03 S2

4(34.339

131

C23 H30 04 5

4C2.333

C23 H30 04 3 402.533

\

CI8 H2003 S 316.421

C18 H2003 S 316.421

l C22 H28 02 3 336.929

Clβ H20 02 S 3C0.422

C22 H28 03 $ 372.329

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, pyrazole, pyrimidine, morpholine, N-alkylpyridinium, N- alkyl-piperaziniu , N-alkylmorpholinium, or furan in which the substituent (s) are selected from among halo, hydroxyl, trihaloalkyl, alkoxy, amino, N-alkylamino, N,N-dialkylamino, quaternary ammonium salts, a C_x to C_t alkylene bridge having a quaternary ammonium salt substituted thereon, alkoxycarbonyl , aryloxycarbonyl , alkylcarbonyloxy and arylcarbonyloxy, (0,0)- dioxyalkylene, -[0(CH₂)_w]_xX where x is 2 to 12 , w is 2 or 3 and X comprises halo or a quaternary ammonium salt, thiophene, pyridine, pyrrole, thiazole, imidazole, pyrazole, or furan. The aryl group of R^! or R^β is preferably phenyl, phenylene, or benzene triyl, i.e., may be unsubstituted, mono-substituted, or di- substituted. Among the species which may constitute the substituents on the aryl ring of R⁵ or R^s are fluoro, chloro, bromo, methoxy, ethoxy, isopropoxy, trimethylammonium (preferably with an iodide or chloride counterion) , methoxycarbonyl, ethoxycarbonyl, for yl, acetyl, propanoyl, (N) -hexyldimethylammonium, 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 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 R^! or R⁶ is selected from phenyl, p-fluorophenyl, m-fluorophenyl, p- hydroxyphenyl , m-hydroxyphenyl , p-methoxyphenyl, - methoxyphenyl, p-N,N-dimethylaminophenyl, m-N,N-

IH2 dimethylaminophenyl, I^" p- (CH,),-N^*-phenyl, I^" m- (CH,),-N^"- phenyl. I^" m- (CH,),-N^*-CK-CH_I-(OCH-CH.).-0-phenyl, I^" p- (CH-) .-N^"-CH.CH-- (OCH.CH,)_a-0-phenyl, I^" ra- (N,N-dimethyl- piperazinium) - (N' ) -CH.- (0CH_jCH,)₃-0-phenyl, 3-methoxy-4- fluorophenyl, thienyl-2-yl, S-cholorothienyl-2-yl, 3, 4-difluorophenyl, I^* p- (N,N-dimethylpiperaziniuai)- (N- )-CH_a-(0CH_JCH_a).-O-phenyl, 3-fluoro-4-π.ethoxyphenyl, - 4-pyridinyl. 2-pyridinyl,- 3-ρyridinyl_. N-methyl-4- pyridinium, I^* N-methyl-3-pyridinium, 3,4- dioxyme hylenephenyl, 3.4-dioxyethylenephenyl, and p- methoxycarbonylphenyl. Preferred compounds include 3- ethyl-3-butyl and 3-butyl-3-butyl compounds having each of the above preferred R' substituents in combination with the R^m substituents shown in Table 1. It is particularly preferred that one but not both of ' and R^* is hydrogen.

It is especially preferred that R' and R* be hydrogen, that R¹ and R' not be hydrogen, and that R¹ and ' be oriented in the same direction relative to the plane of the molecule, i.e., both in ex- or both in β-configuration. It is further preferred that, where R* is butyl and R^l is ethyl, then R¹ has the same orientation relative to the plane of the molecule as R¹ and R'. Set forth in Table 1A are lists of species of

R'/Ά⁷. R^l/B.' and -R\

a-saehyl a-βchyl β-lso-?rβpyl

8-ctrr-bucyl

8-OH β-CCHj

8-OCisβ-proρyl)

8-CN)-azβcidinβ a-CNl-S-aβchyiarecidiniua, Σ~ a-(H)-pyrraiidinβ

8- CN) -N-set yl-pyrrolidiniua. I" a-CN)-N-=β=Λyl-π:orρhaliniu.-π. X"

8- CN) -it' -ϊiβc ylpipβraziΛβ β- CN) -N' -di-sβehylpipβraziniua. .

8-HE-C3Z

8-SKCtO)C5?.

8-NEC CO) C3₂3r

8-HH.-CtN<i)NK₂

8-C2)-C ieph*n« continued next page...

1+6 9-eechyl

9-echyl

9-iso-ρcoρyl

9-cerc-butyl

9-08

9-cca₃

9-OCis^'o-ρropyl) 9-SC3₃

9-soca₃ 9-so₂ca₃

9-SC3₂CH₃

9-na₂

9-NHOa

9- CN) -aorpholine

9-{N)-azecidine

9-CN)-N-sechylazetidiniu.-a. I"

9- (N) -pyrrolidine

9- CN) -N-.-aechyl-pyrrolidiniu.-3, I"

9-CN) -S-mechyl-sorpholini n, I"

9-CN) -M* -sezhylpiperazine

9- (N) -N' -disec ylpiperaziniua, I"

9-NH-C32 g- HCtOlC.Ξij.

9-NKC(0)CH₂3r

9-NH-C(NK)NE₂

9- (2) -thiophene

i+l 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 functional linkages. Such active benzothiepine structures preferably comprise:

(Formula DIV)

or:

(Formula DIVA)

where R¹, R², R³, R\ R⁶, R⁵, R^β, R⁷, R\ X, q and n are as defined above, and R^ss is either a covalent bond or . arylene.

m 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, 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 O, NR⁷, N^*RR*, S, SO, so_ S^*R⁷R^β, PR , p⁺R R , phenylene, heterocycle, quatarnary 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, arylalkyl, halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(0)R¹³,

S0₂R¹³, S0₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, N0₂ , C0₂R¹³ , CN, OM, S020M, S02NR¹³R¹⁴, C(0)NR¹³R¹⁴, C(0)OM, COR¹³,

P(0)R¹³R¹⁴, P⁺R¹³R¹⁴R15_A__# P(₀R¹³)OR¹⁴, S^*R¹³R¹⁴A\ and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR ,

NR⁷R⁸, SR⁷, S(0)R⁷, S02R⁷, S03R⁷, C02R⁷, CN, oxo,

CONR R⁸, N⁺R⁷R⁸R⁹A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(0)R7R8 , P+R7R8A- , and P(O) (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, Sθ2 , S⁺R⁷A-, PR⁷, P(0)R⁷,

P^"R R A-, or phenylene.

Exemplary core moieties include:

wherein:

R" is selected from the group consisting of C and N, and

R²' and R²⁷ are independently selected from the group consisting of:

wherein R^a\ R^M, R^,β and R¹¹ are independently selected from alkyl, alkenyl, alkylaryl, aryl, arylalkyl. • cycloalkyl,_L__heteroc cle-,—-and he'terόcycloalkyl, A^* is a pharmaceutically acceptable anion, and k

1 to 10.

ιs\ In compounds of Formula DIV, R²⁰, R²¹, R²¹ in Formulae DII and Dili, and R²³ in Formula Dili can be bonded at any of their 6-, 1- , 8-, or 9- positions to R¹'. In compounds of Formula DIVA, it is preferred that R comprises a phenylene moiety bonded at a m- or p- position thereof to R^XΪ.

In another embodiment, a core moiety backbone, R¹', as discussed herein in Formulas DII and Dili can be multiply substituted with more than four pendant active benzothiepine units, i.e., R²¹, R", and R^H as discussed above, through multiple functional groups within the core moiety backbone. The core moiety backbone unit, R , can comprise a single core moiety unit, multimers thereof, and multimeric mixtures of the 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 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 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 comprising R²⁰, R²¹, R²² and/or R²³ 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, R², R³, R⁴, R⁵ and R^x can be selected from the preferred groups an combinations of substituents as discussed above. The core structures can comprise, for example, poly(oxyalkylene) or oligo (oxyalkylene) , especially poly- or oligo (oxyethylene) or poly- or oligo (oxypropylene) .

Dosages, Formulations, and Routes of Administration

The ileal bile acid transport inhibitor compounds 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 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 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 compounds of the present invention when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic, and sulf ric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids. The chloride salt is

6 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 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. 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 not be deleterious to the recipient. The carrier can be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from 0.05% to 95% by weight of the active compound. Other pharmacologically active substances can also be present, 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 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. 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 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, 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 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 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 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 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 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

\^ 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 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 an 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 inert base such as gelatin and glycerin or sucrose and acacia.

Pharmaceutical compositions suitable for parenteral administration conveniently comprise sterile 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 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 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 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 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, from 0.5 to 2%.

Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal administration can be presented as discrete patches 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

iS3 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

< 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 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 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 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 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 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 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 components. Examples of suitable pharmaceutically- acceptable formulations containing the inhibitors for oral administration are given above. 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 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 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 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 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.

ι6> -

2-Ethyl-2-(mesyloxyιnethyl)hexanal (1) ^M 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 30 °C. The reaction mixture was stirred at room temperature for 18 h, quenched with dilute HCI 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_. moi) 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 HCI and extracted

Ko with 300 mL of methylene chloride. The methylene chloride layer was washed with 300 mL of 10% NaOH, dried over MgS0₄ and concentrated in vacuo to remove 2- methoxyethyl ether. The residue was purified by HPLC (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- (5H) 4-one (4a) and trans-3-Butyl-3-ethyl-5-phenyl-2, 3- dihydro-benzothiepin- (5ff) 4-one

A mixture of 2.6 g (0.04 mole) (0.047 mole) of TiCl. and 80 L 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 30 mL of DME in 40 min. The reaction mixture was stirred at room temperature for 16 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 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.

Example 2 cis-3-Butyl-3-ethyl-5-phenyl-2/3-dihydrobenzothiepin- (5H)4-one-l,l-dioxide (5a) and trans-3-Butyl-3-ethyl-5- phenyl-2,3-dihydro-benzothiepin- (5H)4-one-l, 1-dioxide

in

20 mL of methylene chloride was added 0.59 g (1.75

\ <o(o 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 MgS0₄, 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

tetrahydrobenzothiepine-1, 1-dioxidθ (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 ethyl-4-hydroxy-5-phenyl-2,3,4,5- tetrahydrobenzothiepine-1, 1-dioxide (6c), and (3a, 4b, 5b) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2, 3, 4, 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 (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 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.

B. Conversion of 6a to 6c and 6d with NaOH and PTC

To a solution of 0.29 g (0.78 mmole) of 6a in 10 mL CH.C1. , was added 9 g of 40% NaOH. The reaction mixture was stirred for 0.5 h at room temperature and was added one drop of Aliquat-336 (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 CH.Cl. (3x10 ml), dried over MgS0₄ and concentrated 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 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

CH_jCl. was added 0.23 g (1.0 mmole) of pyridinium 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 CH.Cl.. The filtrate was concentrated in vacuo to recover 167 mg (87%) of 5b as a colorless oil.

Ifcfc Example 4

3-Butyl-3-ethyl-5 drobenzothiepine-l,l- dioxide (7)

To a solution of le) of 3 in 50 L of

CH.C1. was 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 N. and was triturated with 25 mL of water followed by 50 mL of 10% NaOH solution. The organic was extracted into CH.C1. (4x20 mL) . The CH.Cl. extract was dried over MgS0₄ and evaporated to dryness to recover 4.9 g (87%) of an opaque viscous oil.

Example 5

( laa, 2b, 8ba ) 2-Butyl-2 -ethyl- 8b-phenyl-la, 2 , 3 , 8b- tetrahydro-benzothiepino [4 , 5 -Jb] oxirene-4 , 4 -dioxide ( 8a) ( laa, 2a, 8ba) 2 -Butyl-2 -ethyl- 8b-phenyl-la, 2 , 3 , 8b- tetrahydro-benzothiepino [4 , 5 -Jb] oxirene-4 , 4-dioxide

CHCl ",3 was added portionwise 5 g (14.1 mmole) of 50-60 % MCPBA causing a 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 MgS0₄, and concentrated in vacuo 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 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 *H NMR. cis-3-Butyl-3-ethyl-5-phenyl-2,3^<7^,5-tetrahydro benzothiepine-1, 1-dioxide (9a), trans-3-Butyl-3-ethyl- 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 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 70 psi H. for 5 h and filtered. The filtrate was evaporated to dryness in vacuo to recover 0.117 g of a colorless oil. 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 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, 10a.

Example 7

In another experiment, a product (3.7 g) from epoxidation of 3 with excess MCPBA in refluxing CHC1. 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, 10a and 0.03 g (1%) of another isomer of 10, 10b.

116 Example 8

2- ( (2-Benzoylphenylthio)methyl)butyraldehydβ (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 HCI, brine, and 1 M potassium carbonate. The ether layer was dried over MgS0₄ 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.

Example 9

3-Ethyl-5-phenyl-2,3-dihydrobenzothiepine (12)

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 MgS0₄ 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.

m Exam^ple 10

(laa,2a,8ba) benzothiepino- [4, 5-Jb]oxirene- ,4-dioxide (13)

To a solution of 1.5 g (5.64 mmole) of 12 in 25 ml of CHC1. 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 washed successively with 10% K_jC0₃ (4x50 ml), water (twice with 25 ml) and brine. The organic layer was then dried over MgS0₄ 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 slurried in 200 ml of warm Et.O and filtered to give 0.82 g (46%) of 13 as a white solid, mp 185-186.5 °C.

Example 11

(3a, b, 5a)- 3-Ethyl-4-hydroxy-5-phenyl-2, 3,4, 5- tetrahydro-benzothiepine-l,l-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,l- dioxide (15)

A mixture of of ace 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 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 MgS0₄ and concentrated in vacuo to give 0.44 g (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-

[n x 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

A mixture of 5.0 g (0.0 c3s6cmπole)rofo2-omercaptobenzyl 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 at reflux for additional 16 h. The reaction mixture was cooled and poured into 6N HCI 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. Purification by HPLC (20% EtOAc-hexane) gave 3.7 g

2-Ethyl-2-( (2-formylphenyl) thiomethyl) exenal (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 with methylene chloride. The combined methylene chloride eluant was purified by HPLC (20% ETOAc-hexane) to give 2.4 g (66%) of an oil.

Example 14 3-Butyl-3-ethyl-2,

A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047 mole) of TiCl., and 50 mL of DME was held at

n3 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 let standing at room temperature over weekend. The reaction mixture was poured into dilute HCI and was stirred with methylene chloride. The methylene chloride-water mixture was filtered through Celite. The methylene chloride layer was washed with brine, dried 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

( laa, 2a, 8ba ) 2-Butyl-2-ethyl-la, 2 , 3 , 8b-tetrahydro- benzothiepino [4 , 5 -Jb] oxirene- , 4-dioxidβ ( 19a) and ( laa, 2b, 8ba) 2-Butyl-2-ethyl-8b-phenyl-la, 2 , 3 , 8b- tetrahydro-benzothiepino [4 , 5 -Jb] oxirene-4, 4-dioxide

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 30 mL of CHC1₃ and was held at reflux for 18 h under N.. 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 (20% EtOAc-hexane) to give a third fraction which 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 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- Crystallization from hexane gave 56 mg of a white solid.

Example 16

3-Butyl-3-ethyl-4, 5-dihydroxy-5-phenyl-2, 3,4,5- tetrahydro-benzothiepine-l, 1-dioxide (20)

This product was isolated along with 6b from hydrogenation of a mixture of 8a and 8b.

Example 17

3-Butyl-3-ethyl-4-hydroxy-5-phenylthio-2, tetrahydro-benzothiepine-1, 1-dioxide (21)

A mixture of 25 mg (0.085 mmole) of 19b, mmole) of thiophenol, 0.37 g (2.7 mmole) of potassium carbonate, and 4 mL of DMF was stirred at room temperature under N. for 19 h. The reaction mixture was poured into water and extracted with methylene chloride. The methylene chloride layer was washed successively with 10% NaOH and brine, dried over MgS0₄, 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% 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 21c, respectively, by *H NMR and mass spectra.

Example 18

Alternative Synthesis of 6c and 6d

A. Preparation from 2- ( (2-Benzoylphenylthio)methyl) -2- ethylhexanal (2)

Step 1. 2-( (2-Benzoylphenylsulfonyl)methyl)-2- e hylhexanal (44)

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 moi) of 50-60% MCPBA portionwise. The reaction mixture was stirred at room temperature for 64 h then was 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 removed by filtration through Celite. The methylene

■chloride solution was dried and concentrated in vacuo to give 9.2 g (95%) of εemisolid. 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

Step 2. 2- ( ( -Benzylphenylsulfonyl)methyl) -2- _β, ethylhexanal

A solution of 50 g (0.13 mole) of crude 44 in 250 ml of 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 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 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, 1-dioxide (6c), and (3a, 4b, 5b) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4, 5- tetrahydrobenzothiepine-1, 1-dioxide (6d)

πfe 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% HCI 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.

B. Preparation from 2-hydroxydiphenylmethane

Step 1. 2-mercaptodiphenylmethane (46)

To a 500 ml flask was charged 16 g (0.33 moi) 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 moi) of 2- hydroxydiphenylme hane in 200 ml of DMF in 1 h while temperature was maintained below 30 °C by an ice-water bath. After complete addition of the reagent, the mixture was stirred at room temperature for 30 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 O-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

m 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 HCI, 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 HCI. 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- ethylhexanal 47 as a yellow syrup.

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 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- ethylhexanal 45 as a syrup.

Step 4. (3a, a, 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.

Example 19 <^* 7/ )

( 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) ethyl) -2-ethylhexanal (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 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 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 converted to the 2- ( (2-benzoyl-4- methoxyphenylthio)methyl) -2-ethylhexanal (22) by reaction with 2-ethyl-2- (mesyloxymethyl)hexanal (1) as previously described.

Step 2. 2- ( (2-Benzoyl-5-methoxyphenylsulfonyl) ethyl) -

Substrate 22 was readily oxidized to 2- ( (2-benzoyl-5- methoxyphenyl-sulfonyl)methyl) -2-ethylhexanal (23) as

Step 3 . 2- ( (2-benzyl-5-methoxyphenylsulfonyl)met y - - ethylhexanal (24 )

Sulf one 23 was then reduced to 2- ( ( 2-benzyl-5- methoxyphenyl-sulfonyl)methyl) -2-ethylhexanal (24 ) as

Step 4 . (3a, 4 , 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-tetrahydrobenziDthiepine-l, 1-

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

1*2.0 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 reaction 400 ml of cold ether was added and this solution was extracted with cold 10 % HCI. 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 dryness to obtain 19.9 g of product. *H 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.

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 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

2,3,4, 5-tetrahydrobenzothiepinθ-l, 1-dioxide (27)

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 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 sulfate. The product (0.88g) 27 was characterized by NMR and mass spectra.

Example 21 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 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. 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.

ι^<y. Table 1

Compound No. R

27 H

26 Me

28 Et

29 hexyl

30 Ac

31 (CH2 ) 6-N-pthalimide

Example 22

(3a, 4a, 5a) 3-Butyl-3-ethyl-4-hydroxy-7-hydroxyamino-5- phenyl-2, 3,4, 5-tetrahydrobenzothiepine-l, 1-dioxide (37) and (3a, b, 5b) 3-Butyl-3-ethyl-4-hydroxy-7- hydrox amino-5-phenyl-2, 3,4, 5-tetrahydrobenzothiepine- 1, 1-dioxide (38)

Procedure adapted from reference : Synthesis -Stuttgart 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 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 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 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

⁽S3 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

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 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. 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 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.

Step 3. Oxidation of the nitro product 33 to the sulfone 2- ( (2-benzyl-4-nitrophenylsulfonyl) ethyl) -2- ethylhexanal (34)

The procedure used to oxidize the sulfide 33 to the sulfone 34 has been previously described.

Step 4. Reduction of 34 to 2- ( (2-benzyl-4- hydroxyaminophenylsulfonyl) ethyl) -2-ethylhexanal (35)

A 15 g sample of 34 was dissolved in 230 ml of ethanol 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 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-IV, O-di- (t-

i i fl k added 7.52 g (0.0344 mole) of di-t-butyl dicarbonate in 7 ml THF. Heated at 60 °C overnight. Striped off THF and redissolved in methylene chloride. Extracted with

1 % HCI; and then 5% sodium bicarbonate.

The product was further purified by column chromatography using 90/10 hexane/ethyl acetate and then 70/30 hexane/ethyl acetate. The product 36 was obtained (4.12 g) which appeared to be mainly the di-

1, 1-dioxide (37) and (3a,4b,5b) 3-Butyl-3-ethyl-4-

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

1*5^" 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 HCI (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 procedure.

Example 23 (!> )

(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) ethyl) -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

1*86 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 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.

Step 2. (3a, 4a, 5a) 3-Butyl-3-ethyl-7- (n-hex l mino) -4- hydroxy-5-phenyl-2, 3,4, 5-tetrahydrobenzothiepine-l, 1- dioxide (40) and (3a, 4b, 5b) 3-Butyl-3-ethyl-7- (n- hexy1amino) -4-hydroxy-5-phenyl-2, 3,4, 5- 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 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% HCI and stirred at -10 °C for 5 min. Transferred to a separatory funnel and extract with 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 mobile phase to 70/30 hexane/ethyl acetate. 40 ( 53.2

Quaternization 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 methyl iodide in the presence of 2,6 dimethyl lutidine

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 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 Kl ; and 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 spectra.

Example 26

(3a,4b,5b) 3-Butyl-5- 4-carbomethoxyp enyl) -3-ethyl-4- hydroxy-2,3,4, 5-tetrahydrobenzothiepine-l, 1-dioxide (43)

A 0.1 g sample of 42 ( 0.212 mmole), 2.5 ml dry methanol, 38 μl triethylamine (0.275 mmole) , 0.3 ml toluene and 37 mg of palladium chloride (0.21 mmole) 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.

Note the ester functionalized product 43 can be converted to the free acid by hydrolysis.

I<δτ3 Example 27

(3a, 4a, 5a) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5- phenyl-2,3,4, 5-tetrahydrobenzothiepine-l, 1-dioxidβ (48), and (3a, b, 5b) 3-Butyl-3-ethyl-4-hydroxy-7- methoxy-5-phenyl-2, 3, 4, 5-tetrahydrobenzothiepine-l, 1-

Reaction of 66.2 g of 4-methoxythiophenol with 360 ml 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 g of crude 50 in the pot residue.

Step 2. 2- ( (2-Benzoyl-4-methoxyphenylthio)methyl) -2- ethylhexanal (51) 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- hexane) to give 1.7 g (22%) of 51.

Step 3. 2-( (2-Benzoyl-4-methoxyphenylsulfonyl)methyl)- 2-ethyl-hexanal (52) ✓ 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.

Step 4. 2-( (2-Benzyl-4-methoxyphenylsulfonyl) ethyl)- 2-ethylhexanal (53)

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 ⁽49⁾

A solution of 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, mo 136-140

Example 28 T5&o<.-⁵ _Λ ^4") 5-Phenyl-2, 3-dihydrospirobenzothiepine-3, 1' -cyclohexane (57)

Step 1. 1- (Hydroxymethyl) -cyclohexanecarboxaldehyde (54)

To a cold (0 ^"C¹ 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

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 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 cone. HCI and extracted with methylene chloride. The organic layer was washed with water, 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

Benzoylphenylthio) ethyl)cyclohexanecarboxaldehyde (56)

A mixture of 69 g (0.303 mole) of 2- mercaptobenzophenone, 82 g (0.303 mole) of mesylate 55, 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. HCI and extracted with methylene chloride. The organic layer was washed with 10% NaOH, water, brine, and dried over sodium sulfate 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.

Step 4. 5-Phenyl-2,3-dihydrospirobenzothiepine-3,l'- cyclohexane ⁽57) STrf' κ ~Λ \

To a mixture of 6.19 g of zinc dust and 100 ml of dry DME was added TiCl. (16.8 g, 0.108 mole) . The reaction 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

1 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

8b-Phenyl-la, 2,3, 8b-tetrahydrospiro (benzothiepino [4, 5- b]oxirene-2,l' -cyclohexane) -4,4-dioxide (58)

To a solution of 57 (4.6 g, 15 mmole) in 50 ml 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, 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 product .

Example 30 trans-4-Hydroxy-5-phenyl-2,3,4, 5-1etrahydro spiro(benzothiepine-3,l' -cyclohexane) -1, 1-dioxide (59)

A mixture of 0.5 g (1.4 mmoles) of 58 , 20 ml of 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% 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.

h* Example 31 cis-4-Hydroxy-5-phenyl-2,3,4,5-tetrahydro spiro(benzothiepine-3,l' -cyclohexane) -1, 1-dioxide (60)

To a solution of 0.2 g (0.56 mmole) of 59 in 20 ml of CH.C1., 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 CH.C1. (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

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% HCI. 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.

Example 33

(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)

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 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 ^O * US Q ^(fe* )

(3a, 4a, 5a) 3-Butyl-3-et^Jhyl-4-hydroxy-7-methoxy-5- (3 ' - me hoxyphenyl) -2,3,4, 5-tetrahydrobenzothiepine-l, 1- 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. Chem. Soc, 2431 (1958) gave 4-methoxy-2- (3 ' - methoxybenzyl) phenol in 35% yield. This material was converted to compound 65, mp 138.5-141.5 °C, and compound 66, mp 115.5-117.5 °C, by the procedure similar to that in Example 18 method B.

Example 35

(3a, 4a, 5a) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5- (3 ' - (trifluoromethyl) phenyl) -2,3,4,5- tetrahydrobenzothiepine-1, 1-dioxide (67), and (3a, 4b, 5b) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-_5- (3 ' - (trifluoromethyl) phenyl) -2,3,4,5- tetrahydrobenzothiepi

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 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. _jc^--

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) .

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) henol. This material was converted to compound 69 and compound 70 by the procedure similar to

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) .

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 that in Example 18 method B.

(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, b, 5b) 3-Butyl-3-ethyl-5- (2 ^■ - fluorophenyl) -4-hydroxy-7-methoxy-2, 3,4,5- 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 ^■ - fluorobenzyl) phenol. This material was converted to

methoxyphenyl ) -2 , 3 , 4 , 5-tetrahydrobenzothiepine-l , 1- dioxide (75 ) , and ( 3a, b, 5b) 3 -Butyl-7-bromo-3 -ethyl-4- hydroxy-5- ( 3 ' -methoxyphenyl ) -2 , 3 , 4 , 5- tetrahydrobenzothiepine-1 , 1-dioxide ( 76 ) .

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 compound 75, mp 97-101.5 °C, and compound 76, mp 102-

fluorophenyl) -4-hydroxy-2 ,3,4,5-^' tetrahydrobenzothiepine-1, 1-dioxide (77), and (3a, 4b, 5b) 3-Butyl-3-ethyl-7-fluoro-5- (4 ^■ - fluorophenyl) -4-hydroxy-2 ,3,4,5- . tetrahydrobenzothiepine-1, 1-dioxide (78).

Alkylation of 4-fluorophenol with 4-fluorobenzyl chloride according to the procedure described in J.

1 6 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

methoxyphenyl) -2,3,4, 5-tetrahydrobenzothiepine-l, 1- 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 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

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 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 M_eS0₄. The ether solution was concentrated in vacuo. The residue was purified by HPLC (20% ethyl acetate in hexanes) . The 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. Example 3 ¹ on ₍ i)

(3a, 4b, 5b) 3-Butyl-3-ethyl-5- (4 ' -fluorophenyl) -4- hydroxy-7- (1-pyrrolidinyl) -2,3,4,5- 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 water and brine and dried over M SO, . The ether solution was concentrated in vacuo. The residue was crystallized from ether-hexanes to give compound 82, mp

(56 mmol) of morpholine was held at reflux for 2 h and concentrated in vacuo. The residue was diluted with ether (30 ml) and washed with water and brine and dried over M_gS0₄. The ether solution was concentrated in vacuo. The residue was recrystallized from ether- hexanes to give compound 83, mp 176.5-187.5 °C.

Example 45

(3a, 4a, 5a) 3-Butyl-3-ethyl-5- (4 ' -fluorophenyl) -4- hydroxy-7-methyl-2, 3, 4, 5-tetrahydrobenzothiepine-l, 1- dioxide (84), and (3a, b, 5b) 3-Butyl-3-ethyl-5- (4 ^• - fluorophenyl) -4-hydroxy-7-methyl-2, 3 , 4, 5- ^~" tetrahydrobenzothiepine-1, 1-dioxide (85) .

Alkylation of 4-methylphenol with 4-fluorobenzyl^' chloride according to the procedure described in J.

Chem. Soc, 2431 (1958) gave -methyl-2- (4 ' - fluorobenzyl)phenol) . This material was converted to ompound 84 and compound 85 by the procedure similar to

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 ββ 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 HCI. The organic was extracted into ether. The ether layer was washed with brine, dried over M_gS0₄, 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 room temperature and worked up as in Example 46 gave compound 88 after an HPLC purification.

Example 48

(3a, 4b, 5b) 3-Butyl-3-ethyl-5- (4 ' -fluorophenyl) -4- hydroxy-7- (1-azetidinyl) -2,3,4,5- tetrahydrobenzothiepine-1, 1-dioxide (89) .

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 steam bath. The separated crystals were filtered to ^■

7 hydroxy-7-methyl hio-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) .

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 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 M_βS0₄ and concentrated in vacuo. 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.

3-oo

Example 50

Preparation of polyethyleneglycol functionalized benzothiepine A.

A 50 ml rb flash under a nitrogen atmosphere was charged with 0.54 g of M-Tres-5000 (Polyethyleneglycol 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_tCO. and 2cc anhydrous acetonitrile. The 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 filtration from the solvent mixture (THF/hexane) . This precipitation procedure was continued until no Compound No. 136 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 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 permeation chromatography indicated the presence of a

4500 MW polymer and also verified that no free Compound No. 136 was present. This material was active in the IBAT in vitro cell assay.

loX Example 51

Preparation of Compound 140

No. 140

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 Inc., 2130 Memorial Parkway, SW, Huntsville, Alabama 35801), 0.1 potassium carbonate, O.lOOg of Compound No, 111 and 5 ml anhydrous DMF Stir for 6 days at 27 °C. TLC indicated the disappearance of the starting Compound No. 111. The solution was transferred to a 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 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 (0.5mmoles), 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.

no* Example 53

No. 112

Example 54

uoS 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 (80/20 ethyl acetate/hexane) . Isolated Compound No. 112 (0.28 g) was characterized by NMR and mass spec.

Example 55

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.

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.

Example 58 (Compound No. 139)

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] .

Example 59 (Compound No. 101)

This compound is prepared by condensing the 7-NH. benzothiepine with the 1, 12-dodecane dicarboxylic acid or acid halide.

SLOT Example 60 (Compound No . 104 )

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 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 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 Compound No. 104.

2LO Scheme 6

Example 61

A 1 oz. Fisner-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

o \ isolated by concentrating to 1 cc acetonitrile and then precipitating with diethyl ether.

ςϋo Example 62

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)

λU

Sodium Hydride 60% (11 mg, 0.27 mmoles) in 1 cc of 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 chromatography.

Example 64 (Compound 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 solid; mp 180-181 °C; ^*H NMR (CHC1.) δ 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, IH) , 1.64-1.80 (m, IH) , 2.24-2.38 (m, IH) , 3.15 (AB, J_^ = 15 Hz, Δv = 42 Hz, 2H) , 4.20 (d, J

O = 8 Hz, IH) , 5.13 (s, 2H) , 5.53 (s, IH) , 6.46 (s, IH) , 6.68 (s, IH) , 7.29-7.51 (m, 10H) , 7.74 (d, J = 8 Hz, IH) , 8.06 (d, J = 8 Hz, IH) . FABMS m/z 494 (M+H) , HRMS calcd for (M+H) 494.2001, found 494.1993. Anal. Calcd. for C₂,H₃₁N0₅S: C, 68.13; H, 6.33; N, 2.84. Found: C, 68.19; H, 6.56; N, 2.74.

Example 65 (Compound 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, *H NMR (CDC1.) 5 0.84 (t, J = 6 Hz, 3H) , 0.92 (t, J = 6 Hz, 3H) , 1.28, (d, J = 8 Hz, IH) , 1.32-1.42 (m, IH) , 1.48-1.60 ( , IH) , 1.64-1.80 (m, IH) , 2.20-2.36 (m, IH) , 3.09 (AB, J^, = 15 Hz, Δv = 42 Hz, 2H) , 3.97 (bs, 2H) , 4.15 (d, J = 8 Hz, IH) , 5.49 (s, IH) , 5.95 (s, IH) , 6.54 (d, J = 7 Hz, IH) , 7.29- 7.53 (m, 5H) , 7.88 (d, J = 8 Hz , IH) ; ESMS 366 (M+Li) . Anal. Calcd. for C₂₀H.₅NO₃S : C, 66.82; H, 7.01; N, 3.90. Found: C, 66.54; H, 7.20; N, 3.69.

Example 66 (Compound No. 288)

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 (CDCl,) δl .12 (s, 3H) , 1.49 (s, 3H) , 3.00 (d, J = 15 Hz, IH) , 3.28 (d, J = 15 Hz, IH) , 4.00 (s, IH) , 5.30 (s, IH) , 5.51 (s, IH) , 5.97 (s, IH) , 6.56 (dd, J = 2.1, 8.4 Hz, IH) , 7.31-7.52 (m, 5H) , 7.89 (d, J = 8.4 Hz, IH) . 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; *H NMR (CDCl.) δ 0.80-0.95 (m, 6H) , 1.10-1.70 (m, 7H) , 2.15 (m, IH) , 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, IH) , 5.51 (s, IH) , 5.94 (d, J = 2.2, IH) , 6.54 (dd, J = 8.5, 2.2 Hz, IH) , 7.28-7.50 (m, 6H) , 7.87 (d, J = 8.5 Hz, IH) . MS (FAB): m/z 388 (M+H).

Example 68 (Compound No. 290)

No. 290

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, *H NMR (CDCl,) δ 0.92 (t, J = 7 Hz, 6H) , 1.03-1.70 (m, 11H) , 2.21 (t, J = 8 Hz, IH) , 3.09 (AB, J_M =- 18 Hz, Δv = 38 Hz, 2H) , 3.96 (bs, 2H) , 4.14 (d, J = 7 Hz, IH) , 5.51 (s, IH) , 5.94 (s, IH) , 6.56 (d, J = 9 Hz, IH) , 7.41-7.53 (m, 6H) , 7.87 (d, J = 8 Hz, IH) ; FABMS m/z 416 (M+H).

Example 69

No. 291

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: ^lH NMR (CDCl,) δ 0.91 (t, J = 7 Hz, 6H) , 1.02- 1.52 (m, 11H) , 1.60-1.70 ( , IH) , 2.23 (t, J = 8 Hz, IH) , 3.12 (AB, J_M = 18 Hz, Δv = 36 Hz, 2H) , 4.18 (d, J = 7 Hz, IH) , 5.13 (s, 2H) , 5.53 (s, IH) , 6.43 (s, IH) , 6.65 (s, IH) , 7.29-7.52 (m, 10H) , 7.74 (d, J = 9 Hz, IH) , 8.03 (d, J = 8 Hz, IH) ; ESMS m/z 556 (M+Li) .

Example 70 (Compound No. 292)

No. 292

Following a procedure similar to 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 (CDCl,) δ 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, J_M = 15 Hz, Δv = 45 Hz, 2H) , 4.09 (bs, 2H) , 5.49 (s, IH) , 5.91 (s, IH) , 6.55 (d, J = 9 Hz, IH) , 7.10 (t, J = 7 Hz, 2H) , 7.46 (t, J = 6 Hz, 2H) , 7.87 (d, J = 9 Hz, IH) .

Example 71 (Compound No. 293)

No. 293

During the preparation of Compound No. 290 from Compound No. 291 using BBr,, the title compound was isolated: ^XH NMR (CDCl,) δ 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, IH) , 3.04 (AB, J_M = 15 Hz, Δv = 41 Hz, 2H) , 4.08 (s, IH) , 4.12 (s, IH) , 5.44 (s, IH) , 5.84 (s, IH) , 6.42 (d, J = 9 Hz, IH) , 7.12 (d, J = 8 Hz, 2H) , 7.16-7.26 (m, 10H) , 7.83 (d, J = 8 Hz, IH) ; 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: ^XH NMR (CDCl,) δ 0.90 (t, J = 6 Hz, 6H) , 1.05-1.54 (m, 9H) , 1.60-1.70 (m, IH) , 2.24 (t, J = 8 Hz, IH) , 2.80 (s, 6H) , 3.05 (AB, J_M = 15 Hz, Δv = 42 Hz, 2H) , 4.05-4.18

(m, 2H) , 5.53 (s, IH) , 5.93 (s, IH) , 6.94 (d, J = 9 Hz, IH) , 7.27-7.42 (m, 4H) , 7.45 (d, J = 8 Hz, 2H) , 7.87 (d, J = 9 Hz, IH) ; 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 (R³, R⁴, R⁵, R*) and in the indicated position on the benzo ring (R^x) .

UT 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 N. for 24 hrs. After 24 hrs, the solution was poured into 300 mis

IN HCI 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 found

C 57.65 57.45

H 3.46 5.51

N 4.8 4.8

Cl 12.15 12.16

Q.3Λ 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. 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 to prepare compound 121.

Compound 114 can be prepared by reaction of 116 with ethyl mercaptan and aluminum trichloride.

Examples 85 and 86 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 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) . 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 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 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 0 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.

O C TABLE 3

Specific compounds (§102-111,113-130,132- 134, 136, 138, 142-144, 262-296)

Ex. Cp§ R^l R² R³ R< R5 R^β (R^∑)q

61 102 Et- n-Bu- HO- H- Ph- E- I-, 7- (CE₃) ₃N+-

73 103 n-Bu- Et- KO- E- Ph- E- I-, 7- (CE₃ ) ₃N⁺-

60 104 Et- n-Bu- EO- E- Ph- . . E- 7- (CE₃) 2N-

'7".

74 • 105 Et- n-Ξu- EO- E- ?h- E- 7-

CH₃S0 NE-

75 106 Et- n-3u- EO- E- ?h- E- 7-3r-CH₂- CONE-

76 107 n-3u- Et- EO- E- p-.n-CioE_∑r E- 7-NΞ2-

-O-Ph-

77 108 Et- n-Bu- EO- E- Ph- H- 7-

C5E₁₁CONE-

78 109 Et- n-Bu- EO- E- p-n-Ci₀E₂i- H- 7-NH2- -O-Ph-

79 110 Et- n-Bu- EO- H- Ph- H- 7-CE₃CONE-

80 111 n-Bu- Et- EO- E- p-EO-Ph- E- 7-NE2-

81 113 Et- n-Bu- EO- H- p-EO-Ph- H- 7-NΞ2-

82 11 Et- n-Bu- EO- E- p-CΞ₃0-Ph- H- 7-NH2-

83 115 n-3u- Et- EO- H- p-CE₃0-?h- H- 7-NE-CBZ

84 116 Et- n-Bu- HO- H- p-CE₃0-Ph- H- 7-NH-CBZ

a.3 85 117 n-Bu- Et- EO- E- Ph- E- 7-NE-CBZ

86 118 Et- n-Bu- EO- E- Ph- H- 7-NE-C3Z

87 119 Et- n-Bu- EO- E- Ph- E- 7-NEC0₂-t-

Bu

88 120 n-Bu- Et- EO- E- Ph- E- 7-NHCθ2"t-

Bu

89 121 Et- n-Bu- EO- E- Ph- E- 7-NH₂-

90 122 n-Bu- Et-.^!'EO- E- Ph- H- 7-NE₂-

91 123 Et- n-Bu- EO- E- Ph- E- 7-n-C_eEι₃-

NE-

92 124 n-Bu- Et- EO- E- Ph- E- 7-n-CsHι₃-

NE-

62 125 Et- n-Bu- EO- E- Ph*- E- I", 8-

(CE₃)₃ N+( CH₂CE₂0) ₃-

93 126 n-Bu- Et- EO- E- p-F-Ph- E- 7-NE-C3Z

94 127 n-Bu- Et- EO- E- p-F-?h- E- 7-NE₂-

95 128 Et- n-Bu- EO- E- p-F-?h- E- 7-NE-C3Z

96 129 Et- n-Su- EO- E- p-F-?h- E- 7-NΞ₂-

97 130 Et- n-Bu- EO- E- Ph- E- I", 8-

(CE₃)₃N+ C₆E₁₂0-

98 132 Et- n-Bu- EO- E- Ph- E- 8-phthal- imidyl- C₆Hι₂0-

99 133 Et- n-Bu- EO- E- Ph- E- 8-n-CioH2i- 52 134 Et- n-Bu- EO- E- Ph- E- 8- I- (C₂H₄0) ₃-

100 136 Et- n-Bu- EO- E- Ph- E- 8- EO- 101 138 n-Bu- Et- EO- E- Ph- K- 8- CH₃C0₂-

49 90 Et- n-Bu- E- EO- E- m-CH₃0-Ph- 7-CH₃S-

49 91 Et- n-Bu- BO- E- m-CB₃0-Ph- E- 7-CH₃S-

48 89 Et- n-Bu- EO- _ E- p-F-Ph- E- 7-(N)- azetidine

34 66 Et- n-Bu- EO- E- m-CE0-?h- E- 7-CE₃O-

34 65 Et- n-Bu- H- EO- E- m-c:-:₃o-?h- 7-CH₃O-

35 68 Et- n-Bu- EO- E- m-CF₃-Ph- E- 7-CH₃O-

35 67 Et- n-3u- E- EO- E- - -CF₃-Ph- 7-c:-:₃o-

46 87 Et- n-3u- EO- E- m-EO-?h- E- 7-EO-

46 86 Et- n-3u- EO- E- κι-EO-?h- E- 7-CE3O-

36 70 Et- n-3u- EO- E- p-F-?h- E- 7-CE₃O-

36 69 Et- n-Bu- E- EO- E- p-F-?h- 7-CS₃O-

47 88 Et- n-Bu- EO- E- p-F-Ph- E- 7-EO-

39 76 Et- n-Bu- EO- H- m-CH0-Ph- E- 7-3r-

39 75 Et- n-3u- E- EO- E- m-CE₃0-Ph- 7-Br-

40 77 Et- n-3u- E- EO- E- p-F-Ph- 7-F-

40 78 Et- n-Bu- EO- E- p-F-?h- E- 7-F-

41 79 Et- n-Bu- E- EO- E- m-CE0-Ph- 7-F-

41 80 Et- n-Bu- EO- E- m-CH₃0-Ph- E- 7-F-

37 72 Et- n-Bu- EO- E- m-F-Ph- H- 7-CE₃0-

38 73 Et- n-Bu- E- EO- E- o-F-Ph- 7-CE₃0-

37 71 Et- n-Bu- E- EO- K- m-F-Ph- 7-CE₃0-

2.^5^" 7744 EEtt-- n-Bu- EO- E- o-F-Ph- E- 7-CH₃0-

81 Et- n-Bu- EO- E- p-F-Ph- H- 7-CB3S-

85 Et- n-Bu- EO- E- p-F-Ph- H- 7-CH₃-

84 Et- n-Bu- E- EO- H- p-F-Ph- 7-CB₃-

83 . ^■ Et- n-Bu- EO- E- p-F-Ph- H- 7- (N) - morpholine 82 Et- n-Bu- EO- H- p-F-Ph- H- 7- (N) - pyrroli- dine 286 Et- ^• Et- EO- E- Ph- H- 7-NB-C3Z

287 Et- Et- EO- E- Ph- H- 7-NB2-

288 CH₃- CE₃- EO- E- Ph- E- 7-NE2-

289 n- n- EO- E- Ph- K- 7-NE2-

C₃E₇- C₃E - 290 n-3u- n-3u- EO- E- Ph- H- 7-NE2-

291 n-3u- n-3u- EO- E- Ph- E- 7-NB-C3Z

292 n-3u- n-Bu- EO- E- p-F-Ph- H- 7-NE2-

293 n-Bu- n-Bu- EO- E- Ph- H- 7-PhCΞ₂N-

294 n-3u- n-Bu- HO- H- Ph- H- 7- (CB₃) ₂N-

295 Et- n-Bu- HO- E- p-I- H- 7-NE2-

(C₂H₄0) ₃- Ph-

296 Et- n-Bu- EO- B- i-, p- H- 7-NΞ₂-

(CB₃) ₃N+ (C₂ B4O) ₃-Ph-

aλ6 TABLE 3A Bridged Ben∑othiephenes (§101,112,131,135,137,139-141)

CPD #112 (Ex. 53)

a XI

CPD #137 (Ex. 57)

CPD #139 (Ex. 58)

a ?

\ 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 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 organic synthesis well known to the art in order to introduce the indicated substituents in the 4- and 5- positions (R^J, R⁴, R⁵, R^s) and in the indicated position on the benzo ring (R^x) .

2. 0 TABLE 4 Alternative compounds §1 (§302-312, 314-430)

Cpd# R5 (R*)q

302 p-F-Ph 7-(l-aziridine)

303 p-F-Ph 7-EtS-

304 p-F-Ph 7-CH₃S(0)-

305 p-F-Ph' 7-CE₃S(0)₂-

306 p-F-Ph' %- 7-PhS- ^•

307 p-F-Ph 7-CB3S-

9-CS3S-

308 p-F-Ph- 7-CH3O- 9-CE3O-

309 p-F-Ph- 7-Et- 310 p-F-Ph- 7-iPr- 311 p-F-Ph- 7-t-Bu- 312 p-F-Ph- 7-(l-pyrazole)-

314 m-CB₃0-Ph 7-(l-azetidine) 315 m-CB O-Ph- -(l-aziridine) 316 m-CH₃0-Ph- 7-EtS- 317 m-CH₃0-Ph- 7-CH₃S(0)- 318 m-CB₃0-Ph- 7-CB₃S(0)2- 319 m-CB₃0-Ph- 7-PhS- 320 m-CB₃0-Ph 7-CB₃S- 9-CB₃S-

321 m-CB₃0-Ph 7-CB₃0- 9-CH₃0-

322 m-CB₃0-Ph 7-Et-

323 m-CB₃0-Ph 7-iPr-

324 m-CB₃0-Ph 7-t-Bu-

325 p-F-Ph- 6-CB3O- 7-CH3O- 8-CH3O-

326 p-F-Ph- 7- (l-azetidine) 9-CH₃-

327 p-F-Ph- 7-ΞtS- . 9-CE3-

328 p-F-Ph- 7-CH₃S (0) - 9-CB₃-

329 p-F-Ph- 7-CH₃S (0) ₂- 9-CB3-

330 p-F-Ph- 7-PhS- 9-CB₃-

331 p-F-Ph- 7-CE3S-

9-CB₃-

332 p-F-Ph- 7-CB₃0- 9-CE3-

333 p-F-Ph- 7-CB3-

9-CB3-

334 p-F-Ph- ^" -^"CB3θ-

9-ca₃o-

335 p-F-Ph- 7- (1-pyrrole) 336 p-F-Ph- 7- (N)-N' -methylpiperazine

^ 337 p-F-Ph- Ph-

338 p-F-Ph- 7-CH₃C(=CB2)-

339 p-F-Ph- 7-cyclproρyl

340 p-F-Ph- 7-(CB₃)₂NB -

341 p-F-Ph- 7- (N) -azetidine 9-CB₃S-

342 p-F-Ph- 7- (N-pyrrolidine) 9-CH₃S-

343 p-F-Ph- 7-(CB₃)₂N- 9-CE3S-

344 m-CH3θ-Ph- 7- (1-pyrazole)

345 m-CH₃θ-Ph- 7- (N)^' -methylDiDerazine

346 m-CB3θ-Ph- Ph-

347 m-CB₃0-Ph- 7-CH3C(=CE₂)-

348 m-CH3θ-Ph- 7-cycloρropyl

349 m-CB3θ-Ph- 7-(CB₃)₂NB -

350 m-CH3θ-Ph- 7- (N) -azetidine 9-CH₃S-

351 m-CB₃0-Ph- 7- (N-pyrrolidine) - 9-CB₃S-

352 m-CB₃0-Ph- 7- (CB₃) ₂N-

9-CB₃S-

353 m-CB₃0-Ph- 6-CB3O-

7-CB3O-

8-ca₃o-

354 m-CB₃0-Ph- 7- (1-azetidine)

9-CH3-

1 355 m-CB₃0-Ph- 7-EtS- 9-CH₃-

356 m-CB₃0-Ph- 7-CB₃S (0) -

9-CB3-

357 m-CB₃0-Ph- 7-CB₃S (0) 2-

9-CB3-

358 m-CB₃0-Ph- 7-PhS- 9-CB3-

359 m-CB₃0-Ph- 7-CB₃S- 9-CB₃-

360 m-CB₃0-Ph- 7-CB₃0- 9-CH₃-

361 m-CB₃0-Ph- 7-Cfi₃- 9-CB₃-

362 m-CH₃0-Ph- 7-CB₃0- .. 9-CB3O-

363 thien-2-yl 7- (1-aziridine)

364 thien-2-yl 7-EtS-

365 thien-2-yl 7-CH₃S (0) -

366 thien-2-yl 7-CH₃S ⁽0⁾ ₂-

367 thien-2-yl 7-PhS-

368 thien-2-yl 7-ca₃s-

9-CB₃S-

369 thien-2-yl 7-ca₃o- 9-ca₃o-

370 thien-2-yl 7-Et-

371 thien-2-yl 7-iPr-

372 thien-2-yl 7-t-Bu-

373 thien-2-yl 7- (1-pyrrole) -

374 thien-2-yl 7-CH3O-

5- - 375 thien-2-yl 7-CB₃S-

376 thien-2-yl 7-(l-azetidine)

377 thien-2-yl 7-Me-

378 5-Cl-thien-2-yl 7-(l-azetidine)

379 5-Cl-thien-2-yl 7-(l-aziridine)

380 5-Cl-thien-2-yl 7-EtS-

381 5-Cl-thien-2-yl 7-CB₃S(0)-

382 5-Cl-thien-2-yl 7-CH₃S(0)₂-

383 5-Cl-thien-2-yl 7-PhS-

384 5-Cl-thien-2-yl 7-CB₃S- 9-CB₃S-

385 5-Cl-thien-2-yl 7-CB₃0- 9-CB₃0-

386 5-Cl-thien-2-yl 7-Et-

387 5-Cl-thien-2-yl 7-iPr-

388 5-Cl-thien-2-yl 7-t-3u-

389 5-Cl-thien-2-yi 7-CB₃0-

390 5-Cl-thien-2-yl 7-CB₃S-

391 5-Cl-thien-2-yl 7-Me

392 thien-2-yl 7-(l-azetidine) 9-CB₃-

393 thien-2-yl 7-EtS- 9-CB₃-

394 thien-2-yl 7-CH₃S(0)- 9-CB3-

395 thien-2-yl 7-CB₃S (0)2- 9-CH3-

Ab 396 thien-2-yl 7-PhS- 9-CB₃-

397. thien-2-yl 7-CB₃S- 9-CB₃-

398 thien-2-yl 7-CB₃0- 9-CB₃-

399 thien-2-yl 7-CB3-

9-ca₃-

400 thien-2-yl 7-CB₃0-

9-ca₃o-

401 thien-2-yl 7- (1-pyrazrole) 402 thien-2-yl 7- (N>- ' -methylpiperazine 403 thien-2-yl Ph- 404 thien-2-yl 7-CH₃C(=Ca₂)- 405 thien-2-yl 7-cyclpropyl 406 thien-2-yl 7-(CB₃)₂NB - 407 thien-2-yl 7- (N) -azetidine 9-CB3S-

408 thien-2-yl 7- (N-pyrrolidine) 9-CB3S-

409 thien-2-yl 7-(ca₃)₂N-

9-CB3S-

411 S-Cl-thien-2-yl 7- (1-pyrazrole)

412 ^~5-:i-th en-2-yl^" 7- (N)-N' -methylpiperazine

413 5-Cl-th^'ien-2-yl Ph-

414 S-Cl-t ien-2-yl

415 5-Cl-thien-2-yl 7-cyclopropyl

416 5-Cl-thien-2-yl 7- (CB₃) ₂NK -

Λ5C 417 5-Cl-thien-2-yl 7- (N) -azetidine 9-CS₃S-

418 5-Cl-thien-2-yl 7- (N-pyrrolidine)

9-Cfi₃S-

419 5-Cl-thien-2-yl 7-(CB₃)₂N-

9-ca₃s-

420 5-Cl-thien-2-yl 7-(l-azetidine) 9-CB₃-

421 5-Cl-thien-2-yl 7-EtS-

9-ca₃-

422 5-Cl-thien-2-yl 7-CK₃S(0)-

9-ca₃-

423 5-Cl-thien-2-yl ^'7-CB₃S (0) 2-

9-ca₃-

424 5-Cl-thien-2-yl 7-PhS- 9-CB₃-

425 5-Cl-thien-2-yl 7-CB₃S- 9-CB₃-

426 5-Cl-thien-2-yl 7-CB₃0- 9-CB₃-

427 5-Cl-thien-2-yl 7-CB₃- 9-CB₃-

428 5-Cl-thien-2-yl 7-CB3O-

9-ca₃o-

429 thien-2-yl 6-CB₃0- 7-CB₃0- 8-CS₃0-^~

430 5-Cl-thien-2-yl 6-CB₃0-

7-ca₃o- 8-ca₃o-

bl 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 (R¹, R⁴, R⁵, R^s) and in the indicated position on the benzo ring (R^x) .

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 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

£3* 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) , 1.5-1.78 (m, 4H) , 3.09 (s, 2H) , 7.2-7.35 (m, IH) , 7.5- 7.6 (m, 2H) , 9.43 (s, IH) , 10.50 (d, J = 2.62 Hz, IH) .

Step 2 : Preparation of dibutyl 4-fluorobenzyl alcohol To a solution of 22.6 g (69.8 mmol) of the dialdehyde 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 of DIBAL, followed by 3 N HCI. 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 (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 (br s, IH) , 3.03 (s, 2H) , 4.79 (s, 2H) , 6.96 (dt, J = 8.46, 3.02 Hz, IH) , 7.20 (dd, J = 9.47, 2.82 Hz, IH) , 7.42 (dd, -J = 8.67, 5.64, IH) , 9.40 (s, IH) .

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 added 47 g (50 mmol) of bromotriphenyphosphonium bromide (Aldrich) . The resulting solution was stirred cold for 30 min, then was1 allowed^" to- arm to 0^~C.^~TcT the mixture was added 10% solution of sodium sulfite and ethyl acetate. The extract was .washed a few times 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.

Zl^<\ 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) , 7.02 (dt, J= 8.46, 3.02 Hz, IH) , 7.15 (dd, J = 9.47, 2.82 Hz, IH) , 7.46 (dd, J = 8.67, 5.64, IH) , 9.45 (s, IH) .

Ste^p 4 : Preparation of sulfonyl 4-fluorobenzyl bromide

To a solution of 8.5 g (25 mmol) of sulfide obtained from Step 3 in 200 mL of CH.Cl. at 0 °C was added 15.9 g (60 mmol) of mCPBA (64% peracid) . The resulting solution was stirred cold for 10 min, then was allowed 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 Na.CO., dried (MgSO , and concentrated in vacuo to give 10.2 g (98%) of the desired product as 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, IH) , 7.30 (dd, J = 8.87, 2.42 Hz, IH) , 8.03 (dd, J = 8.86, 5.64, IH) , 9.49 (s, IH) .

Λ4-0 Example 1396

** » Generic Scheme X

C CHO

THF

mCPBA

base; e.g. KOtBu

Generic Scheme X: The nucleophilic substitution of an appropriately substituted 2-fluorobenzaldehyde with

P-4 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 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 .

Preparation of N-propylsulfonic acid

To a solution of 51 mg (111 μm) Compound X in ethanol

(400 μl) was added 1,3 propane sultone (19.5 μl, 222 μm) . 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 (28.4 mg, 44%): Η NMR (CDCL.) d 0.82-0.96 (m, 6H) ,

1.11-1.52 (m of m, 10H) , 1.58-1.72 (m, IH) , 2.08-2.21 (m, IH) , 2.36-2.50 (m, 2H) , 2.93 (s, 6H) , 3.02-3.22 ( of m, 5H) , 3.58-3.76 (m, 2H) , 4.15 (s, IH) , 5.51 (s, IH) , 6.45-6.58 (m, IH) , 6.92-7.02 (m, IH) , 7.35-7.41 (m, IH) , 7.41-7.51 (m, 2H) , 8.08 (d, J = 8.1 Hz, IH) , 8.12-8.25 (m, IH) ; MS ES- M-H m/z 579.

Fxamole 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 analogs. The following example demonstrates the synthesis of these analogs.

3, 3-Dibutyl-5a- ( ' -fluorophenyl) -4a-hydroxy-7- methylthio-2, 3, , 5-tetrahydrobenzothiepine-l, 1-dioxide.

*«3

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 gSO 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 %C.

3, 3-Dibutyl-9-dimethylamino-7-fluoro-5a- (4'- fluorophenyl) -4a-hydroxy-2,3,4,5- tetrahydrobenzothiepine-1, 1-dioxide and 7,9- Bis (dimethylamino) -3 , 3-dibutyl-5a- (4 ' -fluorophenyl) -4a- hydroxy-2,3, 4, 5-tetrahydrobenzothiepine-l, 1-dioxide.

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 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 extract was dried over MgSθ 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- tetrahydrobenzothiepine-1, 1-dioxide, MS (CD 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 (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 example describes a procedure for using the cyclic sulfate as the reagent.

S $

3. H₂S0₄

Dibutyl cyclic sulfite:

n4.t,

A solution of 2, 2-dibutyl-l , 3-propandiol

(103g, 0.548 moi) and triethylamine (221g, 2.19 moi) 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 moi) was added dropwise 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 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.

To a solution of the above compound (127.5g , 0.54 moi) 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 moi). The reaction was stirred overnight and the color of the solution turned black. GC showed that there was no starting material left. The mixture was extracted with 300 ml of ether and the ether extract was washed three times with brine. The_ organic phas_e_ was dried_over magnesium sulfate and passed through celite. The 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- methylphenylthio)methyl] -2-butylhexanol:

λ 7

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-me hoxyethyl ether (diglyme) and the mixture was 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- 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 separated, treated with 20 ml of 10% NaOH then was boiled for 30 min and cooled, acidified with 6N HCI 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 ^{^} 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- ( ' -Fluorobenzyl) -4- methylphenylthio) ethyl] -2-butylhexanal:

3.4-**

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

10 consistent with the product.

2- [ (2- (4 ' -Fluorobenzyl) -4- methylpheny1sulfonyl)methyl] -2-butylhexanal

-15-

To a solution of the above product (0.44 g ,1.1 mmole) in 20 ml methylene chloride solution cooled in

20 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.

74<\ 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 the product.

3, 3-Dibutyl-7-mβthyl-5a- (4 ' -fluorophenyl) -4a- hydroxy-2,3,4, 5-tetrahydrobenzothiepine-l, 1-dioxidβ:

A mixture of 0.37 g (0.85 mmol) of the above product in 30 ml of anhydrous THF was stirred at 0 %C . Then potassium t-butoxide (102 mg, 0.85 mmol) was added. After 3 hrs, TLC showed that there was a product and some starting material left. The crude reaction mixture was acidified with 10% HCI and extracted with ether. The ether extract was washed successively with water and brine, dried with MgS0 and concentrated 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) also confirmed the product, m/e 433 (M⁺ 1) .

SLS Example 1398

Step 1

C₁₄H_l0C 1N0₄ f w= 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 with a N. inlet adapter and suba seal. Remove from inert atmosphere and begin N₂ purge. Add 50mls anhydrous chlorobenzene (Aldrich 28,451-3) to the PCI, via syringe and begin stirring with magnetic stir bar.

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 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). Place solution in_ja 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 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 Quench reaction by pouring into a solution of 300 mis IN HCI and ice. Stir 15 min. Extract twice with ether. Combine organic layers and extract twice with 2% NaOH, then twice with deionized H₂0. Dry with MgS0₄, 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) .

Step 2

C_MH_ιaClNO, fw=277.71

Dissolve 38.10gms (0.131 moles) of the 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 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 N₂- Stir 5 minutes after addition is complete.

Prepare a solution of 22.85 gms triethyl silane (0.197mole Aldrich 23,019-7) and 170mls anhydrous methylene ^"chloride. ^~ Place in addition funnel^~and add dropwise to chilled solution under N.. Stir 5 minutes after addition is complete.

Prepare a second solution of 39.32 gms trifluoromethane sulfonic acid and 170mls anhydrous methylene chloride. Place in addition funnel and add dropwise to chilled solution under N.. Stir 5 minutes after addition is complete.

&z- 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 N₂. After all additions are made allow to slowly warm to room temperature overnight. Stir under N. overnight .

Prepare 1300 mis saturated NaHCO, in a 4 liter beaker. Chill with ice bath. While stirring vigorously, slowly add reaction mixture. Stir at 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 MgS0₄. Crystallize from ethanol. Dry on vacuum line. Dry wt=28.8gms. Confirm by NMR and mass spec (m/z=278) .

Step 3

C_2sH_J3N0₄S fw=443.61

Dissolve 10.12 gms (0.036 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 condenser, N₂ inlet, and stopper. Add 1.84 gms Li₂S (0.040 moles Aldrich 21,324-1). Place flask in oil bath and heat at 75°C under N₂ overnight then cool to room temperature.

Weigh out 10.59 gms dibutyl mesylate (0.040 moles) . Dissolve with anhydrous DMSO and add to reaction solution. Purge well with N₂, heat overnight

λS3 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 with ether 3 times. Combine organic layers and extract with water and sat'd NaCl. Dry organic layer with MgS0₄, 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 phase. Dry wt=7.8 gms. Obtain NMR and mass spec (m/z=444) .

Step 4

C„H₃₃N0₆S fw=475 . 61

Dissolve 9.33 gms (0.021 moles) of product 3 with 120 mis anhydrous methylene chloride. Place in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N₂ inlet and stopper. Chill solution with ice bath under N. purge. Slowly add 11.54 gms 3- chloroperbenzoic acid (0.0435 moles, Fluka 25800, -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 filtrate with 10% K.C0₃. Extract aqueous layer twice with methylene choride. Combine organic layers and dry

&S«- 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=476) .

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 N₂ 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 H₂. Heat to 55°C under H-. Run reaction at 200 psig H₂, 55^βC, and a stir rate of 250 rpm. Run overnight under these conditions.

Cool reactor and vent H₂. Purge with N₂. Check progress of run by TLC. Reaction is a mixture of desired product and intermediate. Filter reaction 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 reactor and run overnight under same conditions.

Λ ^" After second run all of the material has been converted to the desired product. Cool and vent H₂ pressure. Purge with N₂. Filter over a bed of celite, washing well with ether. Rotovap to dryness. Dissolve with ether and extract with water. Dry organic layer with MgS0₄, filter and rotovap to dryness. Dry on vacuum line. Obtain NMR and mass spec (m/z=474) .

Step 6

C.,H₃₉N0₄S fw=473.68

Dissolve 8.97 gms (0.0189 mole) of product 5 with 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 N₂ purge. Slowly add 2.55 gms potassium t-butoxide (0.227 mole Aldrich 15,667-1). After addition is complete, continue to stir at -10^βC monitoring by TLC.

Once reaction is complete, quench by adding 135 mis 10% HCI stirring 10 min. Extract three times with ether. Dry organic layer with MgS0₄, filter and rotovap to dryness. Crystallize from ether. Obtain NMR and mass spec (m/z=474) .

Step 7

C..H..NO.S fw=459.65

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 N₂ purge. Slowly add, via 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.

Chill solution with ice bath. Quench with 100 mis 10% K₂C0₃ 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 H₂0, and once with saturated NaCl solution. Dry organic layer with MgS0₄, filter and rotovap to dryness. Crystallize product from ether. Obtain NMR and mass spec (m/z=460) .

Step 8

C₃₂H₄,NO,SI fw=701.71

Weigh 0.38 gms NaH (9.57 mmoles Aldrich 19,923-0 60% disp. in mineral oil) in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N. inlet and stopper. Chill NaH with ice bath and begin N₂ purge .

Dissolve 4.0 gms (8.7 mmoles) of product 7 with 60 mis anhydrous DMF. Add to the cold NaH. Stir at cold temperature for 30 min. Add 1.33 gms K.CO. (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 DMF. Add to cold reaction mixture. Warm to room temperature then heat to 40^βC overnight under N..

Cleanup by diluting with ether and extracting sequentially with 5% NaOH, H_sO, and saturated NaCl. Dry organic layer with MgS0₄, filter and dry. Obtain 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

Q.58

C₃,H„N₂0,SI fw=802.90

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 tri^'ethyl amine (28.6 mmoles Aldrich 23,962-3) dissolved in 10 mis anhydrous acetonitrile. Purge well with N₂ then close system . Heat at 45^CC. 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) .

λS^«ϊ Example 1399

Step 1. Preparation of 1

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. Poured reaction contents into 1.0 L of water and extracted three times with ethyl acetate. The organic layer was dried over MgS0₄ and concentrated in vacuo . Purified by silica-gel chromatography through a 200 mL plug using hexanes (100%) as elutant yielded 103.2 g (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, IH) , 7.50 (s, IH) .

Step 2. Preparation of 2

To a cooled (-78 ^βC) 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 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(PPh₃)₄ (5.2 mmol) and 125 g 2,5-difluorobenzoyl chloride (708 mmol). The 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

S o 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 elutant gave 53.6 g (43 %) of 2 as an orange oil. ^lH NMR (CDC1₃) d 3.40 (s, 3H) , 4.51 (s, 2H) , 7.12-7.26 (m, 3H) , 7.47 (t, J = 7.50, IH) , 7.57 (d, J = 7.45, IH) , 7.73 (d, J = 7.45, IH) , 7.80 (s, IH) .

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 ^βC for 18 hours. The reaction was cooled (0 ^βC) and 60.7 g of X^' (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 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 %) of 3 as a yellow oil. *H NMR (CDCl.) 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, IH) , 7.16 (dt, J = 8.19 Hz and 2.82 Hz, IH) , 7.45 (t, J = 7.65 Hz, IH) , 7.56-7.61 (m, 2H) , 7.69 (d, J = 7.85 Hz, IH) , 7.74 (s, IH) ,

Step 4. Preparation of 4

To a cooled (-40 ^βC) 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 MgS0₄ 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 (CDC1₃) d 0.89 (t, J = 7.05 Hz, 6H) , 1.17 - 1.40 (m, 12H) , 1.46

(t, J = 5.84 Hz, IH) , 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, IH) , 6.90 (t, J = 8.46 Hz, IH) , 7.09

(d, J = 7.45 Hz, IH) , 7.15 - 7.21 (m, 2H) , 7.25 - 7.32

(m, 2H) , 7.42 (m, IH) .

Step 5. Preparation of 5

To a cooled (15-18 ^βC) 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 MgS0₄ and condensed in vacuo to give 23.1 g (96 %) of 5 as a light brown oil. *H NMR

Wl (CDCl,) 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, IH) , 6.91 (t, J = 8.62 Hz, IH) , 7.07 (d, J = 7.46 Hz, IH) , 7.14 (s, IH) , 7.19 (d, J = 7.65 Hz, IH) , 7.26 - 7.32 (m, IH) , 7.42 (dd, J = 8.66 Hz and 5.64 Hz, IH) , 9.40 (s, IH) .

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 L 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. ^XH NMR (CDC1₃) 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, IH) , 7.10 - 7.33 (m, 5H) . 8.05 (s, IH) , 9.38 (s, IH) .

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 20 mL of neat dimethyl amine. The vessel was sealed and heated to 110 ^βC 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 (CDCl,) 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, IH) , 6.58 (dd, J = 9.0 Hz and

2.61 Hz, IH) , 7.13 (d, J = 7.45 Hz, IH) , 7.21 (s, IH) , 7.28 (t, J = 7.85 Hz, IH) , 7.82 (d, J = 9.06 Hz, IH) , 9.36 (s, IH) .

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 30 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 recryεtalization 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 (El^*) calculated for M+H 487.2756. Found 487.2746.

a&^ Step 9. Preparation of 9

A solution of 2.0 g (4.1 mmol) of 8 in 20 mL of methylene chloride was cooled to -60 ^βC. 4.1 mL of a 1M solution of boron tribromide was added. Stirred at ambient temperature for thirty minutes. Cooled reaction to -10 ^CC and quenched with 50 mL of water. The organic layer was partitioned between methylene chloride and water, dried over MgS0₄ 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.

SLC 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 MgS0₄ 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. ^*H NMR (CDCl,) 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, IH) , 7.15 (dt, J = 8.4 and 2.85 Hz, IH) , 7.46-7.59 (m, 2H) , 8.05- 8.16 (m, 3H) , 9.40 <s, IH, .

α&& 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 30 minutes, then the reaction was quenched with 100 L of saturated ammonium chloride. The mixture was partitioned between ethyl acetate and water; the organic layer was washed with brine, then dried (MgS0₄) and concentrated in vacuo. Purification by silica gel chromatography through a 100 ml plug using CH.Cl, as eluent yielded 4.3 g (90%) of 3 as a pale yellow foam. ^*H NMR (CDCl,) 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, IH) , 3.16 (q_AB, J_AB = 15.0 Hz, ΔV = 33.2 Hz, 2H) , 4.17 (d, J =

6.0 Hz, IH) , 5.67 (s, IH) , 6.34 (dd, J=9.6 and 3.0 Hz, IH) , 7.08 (dt, J = 8.5 and 2.9 Hz,^' IH) , 7.64 (t, J =

8.1 Hz, IH) , 7.81 (d, J = 8.7 Hz, IH) , 8.13 (dd, J = 9.9 and 3.6 Hz, IH) , 8.23-8.30 (m, IH) , 8.44 (s, IH) .

MS(FABH⁺) m/e (relative intensity) 464.5 (100), 446.6 (65). HRMS calculated for M+H 464.1907. Found 464.19057

2 1 Step 4 . Preparation of 4

To a cooled (0 ^βC) 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 ^CC for 16 hours. The reaction vessel was cooled to ambient temperature 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. ^*H NMR (CDCl.) d 0.80-0.95 (m, 6H) , 0.96-1.53 (m, 8H) , 1.60-1.69 (m, 3H) , 2.11-2.28 (m, IH) , 2.79 (s, 6H) ,

3.09 (q_AB, = 15.0 Hz, DV= 45.6 Hz, 2H) , 4.90 (d, J

= 9.0 Hz, IH) , 5.65 (s, IH) , 5.75 (d, J = 2.1 Hz, IH) , 6.52 (dd, J = 9.6 and 2.7 Hz, IH) , 7.59 (t, J = 8.4 Hz, IH) , 7.85 (d, J = 7.80 Hz, IH) , 7.89 (d, J = 9.0 Hz, IH) , 8.20 (dd, J = 8.4 and 1.2 Hz, IH) , 8.43 (s, IH) .

MS(FABH⁺) m/e (relative intensity) 489.6 (100), 471.5 (25). HRMS calculated for M+H 489.2423. Found 489.2456. 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 H₂, then charged with H₂ (100 psi) and heated to 45 ^βC 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 (CDCl,) d 0.80-0.98 (m, 6H) , 1.00-1.52 (m, 10H) , 1.52-1.69 (m, IH) , 2.15-2.29 (m, IH) , 2.83 (s, 6H) ,

3.07 (q^, JAB = 15.1 Hz, DV = 44.2 Hz, 2H) , 3.70 (s,

2H) , 4.14 (s, IH) , 5.43 (s, IH) , 6.09 (d, J = 2.4 Hz, IH) , 6.52 (dd, J = 12.2 and 2.6 Hz, IH) , 6.65 (dd, J =

7.8 and 1.8 Hz, IH) , 6.83 (s, IH) , 6.93 (d, J = 7.50 Hz, IH) , 7.19 (t, J = 7.6 Hz, IH) , 7.89 (d, J = 8.9 Hz,

IH) . MS(FABH⁺) m/e (relative intensity) 459.7 (100). HRMS calculated for M+H 459.2681. Found 459.2670.

SL > 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. Η NMR (CDCl,) d 0.84-0.95 (m, 6H) , 1.02-1.53 (m, 10H) , 1.53-1.68 (m, IH) , 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^, j^ = 15.6 Hz, DV = 40.4 Hz, 2H) , 3.43 (t, J = 6.9 Hz,

2H) , 4.10 (s, IH) , 5.51 (s, IH) , 5.95 (d, J = 2.4 Hz,

IH) , 6.51 (dd, J = 9.3 and 2.7 Hz, IH) , 7.28 (s, IH) ,

7.32-7.41 (m, 2H) , 7.78 (d, J = 8.1 Hz, IH) , 7.90 (d, J

= 9.0 Hz, IH) .

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)

aτ?o gave 0.8 g (73%) of 7 as a white foam. ^*H NMR (CDCl,) d 0.80-0.96 (m, 6H) , 0.99-1.54 (m, 19H) , 1.59-1.84 (m, 3H) , 2.09-2.24 (m, IH) , 2.45-2.58 (m, 2H) , 2.81 (s, 6H) , 3.09 (q_AB, J^ = 15.6 Hz, DV = 18.5 Hz, 2H) , 3.13- 3.31 (m, 8H) , 4.16 (s, IH) , 5.44 (s, IH) , 6.08 (d, J = 1.8 Hz, IH) , 6.57 (dd, J = 9.3 and 2.7 Hz, IH) , 7.24 (t, J = 7.5 Hz, IH) , 7.34 (t, J = 8.4 Hz, IH) , 7.56 (d, J = 8.4 Hz, IH), 7.74 (s, IH) , 7.88 (d, J = 9.0 Hz, IH) , 9.22 (s, IH) . HRMS calcd 642.4304; observed 642.4343.

Example 1400 Step 1

^C14^H13°2^F fw=232.25

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 2 •

A slurry of sodium hydride (126.0g/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 ,0g/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 H2O (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

λn( 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 acidic solution was extracted three times with ethyl ether, dried (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. ^XH NMR and MS [ (M + H)⁺ = 233] confirmed desired structure.

Step 2

C₁₇H₁₈N0₂FS fw=319.39

A 12-liter, 3-neck round-bottom flask was fitted with mechanical stirrer and N 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/2.197mol) was added slowly. After warming to room temperature, dimethylthiocarbamoyl chloride

(242.4g/1.961mol) was added. After 15 h, the reaction mixture was poured into H2O (4.0 L) , and extracted two times with ethyl ether. The combined organic layers were washed with H2O and saturated aqueous NaCl, dried

(MgSO^ , filtered, and concentrated in vacuo to give the product (605.3g, 97% yield). ¹H NMR and MS [(M+H)⁺ = 320] confirm desired structure.

313- Step 3

C₁₄H₁₃OFS fw=248.32

A 12-liter, round-bottom flask was equipped with N gas adaptor, mechanical stirrer, and reflux condenser. The system was purged with N2. 4-Fluoro-2- (3- methoxybenzyl) -phenyldimethylthiocarbamate (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, 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 H2O. The aqueous extracts were combined, acidified with concentrated 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) . H NMR confirmed desired structure.

Step 4

a.13

^C25^H35°2^FS fw=418.61

A 5-liter, 3-neck, round-bottom flask was equipped with ₂ gas adaptor and mechanical stirrer. The system was purged with N2. 4-Fluoro-2- (3-methoxybenzyl) - thiophenol (100. Og/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 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 ethyl ether, and concentrated H2SO 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) ' fϋ^tereά, and conc'd in vacuo to give an amber oil (143.94g/85% yield). ²H NMR and MS [ (M + H)⁺ = 419] confirm the desired structure.

Step 5

n

^C25^H33°2^FS fw=416.59

A 2-liter, 4-neck, round-bottom flask was equipped with N gas adaptor, and mechanical εtirrer. The system was purged with N2. The corresponding alcohol

(143.94g/343.8mmol) and CH₂Cl₂ (1.0 L) were added and cooled to 0 C . Pyridinium chlorochromate (140.53g/651.6mmol) was added. After 6 h. , CH₂C1₂ was added. After 20 min, the mixture was filtered through silica gel, washing with CH2CI2. The filtrate was concentrated in vacuo to give a dark yellow-red oil

(110.6g, 77% yield). ^-H NMR and MS [ (M + H)⁺ = 417] confirm the desired structure.

Step 6

^C25^H33°4^FS fw=448.59

A 2-liter, 4-neck, round-bottom flask was equipped with N2 gas adaptor and mechanical εtirrer. The system was purged with N2. The corresponding sulfide (110.6g/265.5mmol) and CH₂C1₂ d-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 (M S0 ) , filtered, and concentrated in vacuo to give the product (93.2g, 78% yield). ^-H NMR confirmed the desired structure.

21 Step 7

^C25^H33°4^FS *w*4^4β.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/208mπ»ol) and THF (1.0 ) 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 (MgS0₄), 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%) . ^"^H NMR confirmed the desϊrea product.

Step 8

A Fisher porter bottle was fitted with N₂ line and magnetic εtirrer. The system was purged with ₂ • The corresponding fluoro-compound (28. lg/62. βmmol) was added, and the vessel was sealed and cooled to -78 C. Dimethylamine (17. lg/379mmol) was condensed via a C0₂ /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). ¹H NMR confirmed the desired structure.

;ns Step 9

^C26^H37°4^NS f =459.64

A 250-mL, 3-neck, round-bottom flask was equipped with N₂ gas adaptor and magnetic εtirrer. The system was purged with N₂. The corresponding methoxy-compound

(6.62g/14.0mmol) and CHCI3 (150 L) 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% K₂C0₃ (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 (MgSC^) , filtered, and concentrated in vacuo to give the product (6.27g/98% yield). ¹H NMR confirmed the desired structure.

Step 10

In a 250 ml single neck round bottom Flask with stir bar place 2- diethylamineoethyl chloride hydochloride (fw 172.10g/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)

SO Step 11

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).

Example 1401

Step 1

C₁₄H₁₃0₂F fw=232.25

A 12-liter, 4-neck round-bottom flask was equipped with

ASI reflux condenser, N gas adaptor, mechanical εtirrer, and an addition funnel. The system was purged with N₂.

A slurry of sodium hydride (126.0g/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 (783.0g/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 MgSO^, 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

363-

C₁ H₁₈N0₂FS fw=319 .39

A 12-liter, 3-neck round-bottom flask was fitted with mechanical εtirrer and N 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/2.197mol) 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 H 0 (4.0 L) , and extracted two times with ethyl ether. The combined organic layers were washed with H 0 and saturated aqueous NaCl, dried over MgSO^, filtered, and concentrated in vacuo to give the product (605.3g, 97% yield). ¹H NMR and MS [(M+H)⁺ = 320] confirm desired structure.

Step 3

C₁₄H₁₃OFS fw=248.32

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/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 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 H₂0. The aqueous extracts were combined, acidified with cone. 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) . ^H NMR confirmed desired structure.

Step 4

^C25^H35°2^FS f =418.^'61

A 5-liter, 3-neck, round-bottom flask was equipped with N₂ gas adaptor and mechanical stirrer. The system

7 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 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 H 0. The aqueous solution was washed with ethyl ether, and cone. H₂S0₄ 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 (MgS0₄) , filtered, and concentrated in vacuo to give an amber oil (143.94g/85% yield). ¹H NMR and MS [ (M + H)⁺ = 419] confirm the desired structure.

Step 5

C₂₅H₃₃0₂FS fw=416.59

A 2-liter, 4-neck,^' round-bottom flask was equipped with N₂ gas adaptor, and mechanical εtirrer...The system was purged with N₂. The corresponding -alcohol

(143.94 g/343.8 mmol) and CH₂Cl (1.0 L) were added and cooled to 0 C. Pyridinium chlorochromate (140.53g/651.6mmol) was added. After 6 h. , CH₂Cl was

W& added. After 20 min, the mixture was filtered through silica gel, washing with CH₂Cl₂. 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.

-λSk Step 6

C₂₅H₃₃0₄FS 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 CH₂Cl₂ (1.0 L) were added. The εolution 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 K₂C0₃. 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). ¹H NMR confirmed the desired structure.

3-11 Step 7

C₂₅H₃₃0₄FS 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 (MgS0₄) , 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.

^«δ«r Step 8

C₂ H₃₉0 NS fw=473.67

A Fisher porter bottle was fitted with N₂ line and magnetic stirrer. The εystem was purged with N₂. The corresponding fluoro-compound (28. lg/62.6mmol) was added, and the vesεel waε sealed and cooled to -78 C. Dimethylamine (17. lg/379mmol) was condensed via a C0₂/acetone bath and added to the reaction vesεel. 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 over MgS0₄, filtered, and concentrated in vacuo to give a white solid (28.5g/96% yield) ^LH NMR confirmed the desired structure.

7 <\ Step 9

C₂₆H₃₇0₄NS" fw=459.64

A 250-mL, 3-neck, round-bottom flaεk was equipped with N₂ gas adaptor and magnetic stirrer. The system was purged with N₂. The corresponding methoxy-compound

(6.62g/14.0mmol) and CHC1₃ (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% K₂C0₃ (100 mL) . After 10 min, the layers were separated, and the aqueous layer was extracted two times with ethyl ether. The CHC1 and ether extracts were combined, washed with saturated aqueous NaCl, dried over MgS0₄, filtered, and concentrated in vacuo to give the product (6.27g/98% yield). ¹H NMR confirmed the desired structure.

^O Step 10

In a 250 ml εingle neck round bottom flask with stir bar place 2- diethylamineoethyl chloride hydochloride (fw 172. lOg/ ole) 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 extraction and dry over anhydrous potassium carbonate.

In a separate 2-necked 250 ml round bottom flask with stir bar add εodiu hydride (60% diεperεion 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 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% NaOH, followed by water and then brine. The ether layer waε 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.). Isolated yield: 0.78 g (mass spec , and HI NMR)

Step 11

3>^«U

The product from step 10 (0.57gmε, 1.02 millimole 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 solution and the resulting mixture was chilled. The desired product is isolated as a precipitate 0.7272 gms. Masε εpec M-I = 587.9, 'H NMR).

BIOLOGICAL ASSAYS

The utility of the compounds of the present invention is shown by the following assays. These assayε are performed in vi tro and in animal models essentially using a procedure recognized to εhow the utility of the present invention.

In Vitro Assay of compounds that inhibit IBAT-mediated uptake of ."cl -Taurocholate (TO in H14 Cells

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, 30,000

a^a- cells/well for assays run within 48 hours, and 10,000 cells/well for aεsays run within 72 hours.

On the day of aεεay, 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 [^l4C] -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^β 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 εhaken for 30 minutes at room temperature prior to measuring the amount of radioactivity in each well on a Packard Top-Count instrument.

λ-33 Jπ Vitro Assay of compounds that inhibit uptake of ("CI -Alanine

The alanine uptake assay is performed in an identical fashion to the taurocholate assay, with the exception that labeled alanine is subεtituted for the labeled taurocholate.

In Vivo Assay of compounds that inhibit Rat Ileal uptake of ["cl -Taurocholate into Bile (See"Metaboliεm 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 ratε (200-300 g) are aneεthetized with inactin @100 mg/kg. Bile ductε 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. 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 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 of control sample ( [¹⁴C] -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 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

λ<H perfusion is initiated aε 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 necesεary, a third perfusion is performed as above that typically contains the control sample.

Measurement of Hepatic Cholesterol Concentration (HEPATIC CHOP Liver tisεue 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 peroxidaεe, aε deεcribed by Allain, C. A., et al . (1974) Clin . Chem. 20, 470.

Measurement of Hepatic HMG CoA-Reductase Activity (HMG COA)

Hepatic microsomes were prepared by homogenizing liver samples in a phosphate/εucroεe buffer, followed by centrifugal separation. The final pelleted material waε reεuεpended in buffer and an aliquot waε assayed for HMG CoA reductase activity by incubating for 60 minutes at 37° C in the presence of ¹⁴C-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. HDL-CHOL, TGI and VLDL + LDL)

Total serum cholesterol (SER.CHOL) was measured enzymatically using a commercial kit from ako Fine

ms Chemicals (Richmond, VA) ; Cholesterol Cll, Catalog No. 276-64909. HDL cholesterol (HDL-CHOL) was asεayed 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 aεεayed 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-Hvdroxylase Activity (7a-OHase)

Hepatic microsomes were prepared by homogenizing liver samples in a phoεphate/εucroεe buffer, followed by centrifugal εeparation. The final pelleted material waε resuεpended in buffer and an aliquot waε aεsayed for cholesterol 7-a-hydroxylase activity by incubating for 5 minutes at 37° C in the preεence of NADPH. Following extraction into petroleum ether, the organic εolvent waε evaporated and the reεidue was dissolved in acetonitrile/ methanol. The enzymatic product was separated by injecting an aliquot of the extract onto a C_1B 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 εeparation and drying, the reεidue was dissolved in methanol and the amount of bile acid preεent was eaεured enzymatically uεing the 3a-hydroxysteroid steroid dehydrogenase reaction with bile acids to reduce NAD. (Reference: Maεhige, F., et al . (1981)

3^& Clin . Chem. 27, 1352) .

['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 μl instead of 100 μl . Briefly, at room temperature a 190 μl solution containing 2μM [³H] -taurocholate (0.75 μCi) , 20 mM tris, 100 mM NaCl, 100 mM mannitol pH 7.4 waε incubated for 5 sec with 10 μl of brush border membrane vesicles (60-120 μg 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 Hepeε-tris, 150 mM KCl) followed immediately by filtration through a nylon filter (0.2 μm pore) and an additional 5 ml wash with stop buffer.

Acyl-CoA; cholesterol Acyl Transferase (ACAT) Hamster liver and rat intestinal microsomes were prepared from tisεue as described previouεly (Reference: (1980) J. Biol . Chem. 255, 9098) and uεed as a source of ACAT enzyme. The asεay consiεted of a 2.0 ml incubation containing 24 μM Oleoyl-CoA (0.05 μCi) in a 50 mM εodium phoεphate, 2 mM DTT ph 7.4 buffer containing 0.25 % BSA and 200 μg of microsomal protein. The aεsay 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 μg 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 dryneεε and then εpotted on a εilica gel 60 TLC plate and developed in hexane/ethyl ether (9:1). The amount of choleεterol eεter 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 compoundε in the aεεays deεcribed above iε as εet forth in TABLES 5, 6, 7, and 8 as follows:

*-^■-? TABLE 5

1<\

' oD

* In vitro Taurocholate Cell Uptake

# Unless otherwise noted

= Comparative Example is Example No. 1 in WO 93/16055

2>o[ TABLE 6

Comparative Example is Example No. 1 in WO 93/16055

o .

>0

Additional taurocholate uptake teεts were conducted in the following compounds listed in Table 9.

TA T

Biological Assay Data for Some Compounds of the Present Invention

3oζT

^*3θ£

3ofc

3o<

3io

3W

2.

5'4

3»S- The examples herein can be repeated with similar succesε by εubεtituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples. Novel compositionε of the invention are further illuεtrated 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 preεent 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.

3^ Table C2 : Alternative compounds #2 (Families F101-F123)

Family Cpd# !=R2 R5 <R*)q

F101 CEOSEN FROM. Ph- CHOSEN FROM TABLE D * TABLE D

F102 CHOSEN FROM p-F-Ph- CHOSEN FROM TABLE D TABLE D

F103 CHOSEN FROM m-F-Ph- CHOSEN FROM TABLE D TA3LE D

F104 CHOSEN FROM p-CK₃0-Ph- CEOSEN FROM TABLE D TABLE D

F105 CEOSEN FROM m-CH3θ-Ph- CHOSEN FROM TABLE D TA3LE D

F106 CHOSEN FROM p-(CK₃)₂N-Ph- CHOSEN FROM TABLE D TABLE D

F107 CHOSEN FROM m-(CK3)2N-Ph CHOSEN FROM TABLE D TABLE D

F108 CHOSEN FROM I", p-(CH₃)₃-N⁺-Ph- CHOSEN FROM TA3LE D TABLE D

F109 CHOSEN FROM I-, m-(CH3)3-N⁺-Ph- CHOSEN FROM TABLE D TABLE D

F110 CHOSEN FROM I^", p-(CH₃)3-N⁺-CH₂CH2- CHOSEN FROM TABLE D (OCH2CH2)2~0-Ph- TABLE D

Fill CHOSEN FROM I~, m- (CHJ) 3-N⁺-CH₂CH2- CHOSEN FROM- TABLE D (OCH₂CH₂) 2-O-Ph- TABLE D

F112 CHOSEN FROM I", p-(N,N- CHOSEN FROM ^■TABLE D dimethylpiperazine) - (N' ) - •TABLE D

CH₂- (OCH₂CH₂) 2-O-Ph-

H Exhibit A F113 CHOSEN FROM 1", m-(N,N- CHOSEN FROM TABLE D dimet ylpiperazine) - (N' ) - TABLE D

CH₂- (OCH₂CH2) 2-O-Ph-

F114 CHOSEN FROM m-F-?h- CHOSEN FROM TABLE D P-CH3O- TABLE D

F115 CHOSEN FROM 3, 4,dioxy-methylene-Ph- CHOSEN FROM TABLE D TABLE D

F116 CHOSEN FROM m-F-Ph- CHOSEN FROM TABLE D p-F-Ph- TABLE D

F117 CHOSEN FROM m-CH₃0- CHOSEN FROM TABLE D p-F-Ph- TABLE D

F118 CHOSEN FROM 4-pyridine CHOSEN FROM TABLE D TABLE D

F119 CHOSEN FROM N-methyl- -pyridinium CHOSEN FROM TABLE D TABLE D

F120 CHOSEN FROM 3-pyridine CHOSEN FROM TABLE D TABLE D

F121 CHOSEN FROM N-methyl-3-pyridinium CEOSEN FROM TABLE D TABLE D

F122 CHOSEN FROM 2-pyridine CHOSEN FROM TABLE D TABLE D

F123 CEOSEN FROM p-CE₃0₂C-Ph- CEOSEN FROM TABLE D TABLE D

Similar families can be generated where R¹<>R², such as R¹ = Et and R2 = n-Bu, but (R^x)q is chosen from table CI.

Exhibit B \<\

λo

33Λ APPENDIX A

The ileal bile acid transport inhibitors used in the present invention include, for example, those compounds disclosed in this Appendix A.

1) The compounds ofthe formula (I)

wherein ^ and R^ are the same or different and each is optionally substituted C\^ alkyl, C3.5 cycloalkyl, or R and K- together with the carbon atom to which they are attached form an optionally substituted C3.5 spiro-cycloalkyl group;

R is a Cg.i4 aryl, or a C3.13 heteroaryl group each optionally substituted with one to eight substituents which are the same or different and are each selected from halogen, hydroxy, nitro, phenyl-C j.₀ alkoxy, C g alkoxy, optionally substituted C\^ alkyl, S(0)_nR⁸, S0₂NR⁸R⁹ C0₂R⁸, 0(CH2CH₂O)_πR⁸, OS0₂R⁸, 0(CH₂)_pS03R⁸, O CH^pNR^¹⁰ and O(CH₂)_pN⁺R⁹R¹⁰R^{1 1} wherein R⁸ to R^{1 1} are the same or different and are independently selected from hydrogen or optionally substituted C\. alkyl , and wherein p is an integer from 1-4 and n is an integer from 0-3;

R-^$a, R5b_f R5c_t and R5d g^jj _rep_rcsem atoms or groups which are the same or different and each is hydrogen, halogen, cyano, R⁸-acetylide, OR⁸, optionally substituted C ^ alkyl,..COR⁸._CH(OH)R⁸. S(0)_nR⁸. SQ₂NR⁸R⁹. P(OXOR )₂. . OCOR⁸, OCF3, OCN, SCN, NHCN, CH₂OR⁸, CHO, (CU^CN, C0NR9R1°, (CH^pCO^⁸, (CH^pNR^¹⁰, C0₂R⁸, NHCOCF3, NHS0₂R⁸, OCH₂OR⁸, OCH-CHR⁸, 0(CH₂CH₂0)_nR⁸, 0SO₂R⁸, Of H^pSOsR⁸, OCCH^pNR^^⁰ and O(CH₂)_pN⁺R⁹R¹⁰R^{1 1} wherein R⁸ to R¹1, n, and p are as hereinbefore defined; or R^5a and R^5b, R⁵*³ and R^5c, or R^5c and R^5d together with the ring to which they are attached form a cyclic group -O(CR9R¹⁰)_mO- wherein R⁹ and R¹⁰ are as hereinbefore defined and m is 1 or 2;

33 -2- /40375

R^β and R? are the same or different and each is hydrogen, optionally substituted C\.,$ alkyl, C3.6 cycloalkyl, or R^ and R? together with the carbon atom to which they are attached form an optionally substituted C3.6 spiro-cycloalkyl group;

X is CH₂, C=0, C=S, or C=NR⁸ wherein R⁸ is as hereinbefore defined; and

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

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

R2 is methyl, ethyl or n-butyl;

R⁴ is phenyl;

R5a and R5d are hydrogen;

R5b and R?^c are the same or different and are each hydrogen, methyl, methoxy, hydroxy, trifluoromethyl or halo;

Rδ and R are the same or different and are each hydrogen, methyl, ethyl or i-butyl;

X is CH₂ or C-O;

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

3) A compound of formula (I) selected from the group consisting of

(±)-3-n-Butyl-3-ethyJ-2,3-dihydro-5-phenyl- 1 ,5-benzothiazepin-4-one; (± 3-n-Butyl-3-emyl-2,3-dihydro-5-phenyl-l,5-berttθthiazepin-4-one-l, 1-dioxide; (±)-3-n-ButyI-3-ethyl-2,3,4_>5-tetrahydro-5-phenyl-l,5-benzothiazepine; (±)-3-n-Butyl-3-ethyl-2,3,4,5-tetr--hydro-5-phenyl- 1 ,5-benzothiazepine- 1 , 1 -dioxide; (±)-3-n-Butyl-2-isobutyl-3-ethyI-2,3,4,5-tetr-ιhydro-5-phenyl-l,5-ber-zotJτiazep-ne- 1, 1-dioxide;

3,3-DiethyI-2,3-dihydro-5-phenyI-l,5-ber-zothiazepin-4-one; 3,3-Diethyl-2,3-dihydro-5-phenyl- ] ,5-benzothi--zepin-4-one 1 , 1 -dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl- 1 ,5-benzothiazepine; 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-l,5-benzothiazepine-l, 1-dioxide;

32 J 3,3-Dimethyl-2,3-dihydro-5-phenyl-l,5-benzothiazepin-4-one; 3,3-DimethyI-2,3-dihydro-5-phenyl-l,5-benzothiazeptn-4-one-l, 1-dioxide; 3,3-Dimethyl-2,3,4,5-tetrahydro-5-phenyl-l,5-ber-zothiazepine; 3 ,3-Dimethyl-2,3 ,4,5-tetrahydro-5-phenyl- 1 ,5-benzothiazepine- 1 , 1 -dioxide; (±)-3-n-ButyI-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l ,5- benzothiazepine- 1 , 1 -dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl- 1 ,5-benzothiazepine- 1 , 1 - dioxide; (-i:)-3-n-ButyI-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l,5-benzothiazepine-

1, 1-dioxide;

3,3-Diethyl-2,3,4,5-te ahydro-8-methoxy-5-phenyl-l,5-benzothiazepine-l, 1-dioxide;

(=)-3-n-Buryl-3-ethyl-2,3,4,5-tetrahydro-5-pheπyl- 1 ,5-benzothiazepin-8-ol- 1 , 1 - dioxide;

3,3-DiethyI-2,3,4,5-tetrahydro-5-phenyl-l,5-benzothiazepin-8-oI-l, 1-dioxide;

(±)-3-n-ButyI-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-l,5-benzothiazepin-8- ol- 1, 1-dioxide;

3,3-Diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-l,5-benzothiazepiπ-8-ol-l,l- dioxide;

(±)-7-bromo-3-n-Butyl-3-ethyl-2,3,4,5-teιrahydro-8-methoxy-5-phenyI-l,5- benzothi-Lzepinc- 1 , 1-dioxide;

7-bromo-3,3-DiethyI-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l,5-benzothiazepine-

1,1 -dioxide;

(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl- 1 ,5-benzothiazepin-7,8-diol- 1,1- dioxide;

3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyI-l,5-benzothiazepin-7,8-diol-l, 1-dioxide;

(-k)-3-n-Butyl-3-ethyl-2,3,4,5-tetr-ώydro-8-methoxy-5-phenyl-l,5-benzothiazepine-l- monoxide;

3,3-Diethyl-2,3,4,5-tetrahydro-8-rnethoxy-5-phenyl-l,5-benzothiazepine-l-monoxide;

(±)-3-n-Butyl-3-etlτyl-2,3,4,5-tetrώyclro-5-phenyl-l,5-ber-zothiazepin-8-ol-l- monoxide;

3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-l,5-benzothiazepin-8-ol-l-monoxide;

(±)-3-n-Butyl-3-ethyl-2,3-dihydrc^8-methoxy-5-phenyl-l,5-benzothiazep-n-4-one;

(±)-3-n-Butyl-3-e yl-2,3,4,5-tetτ-ώydro-8-methoxy-5-phenyl-l,5-beι-zothiazepine;

(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetr-ώydro-8-rnethoxy-5-phenyl-l,5-benzothiazepine-

1, 1-dioxide;

(±)-3-n-Bulyl-3-ethyI-2,3,4₁5-tetnώydro-8-hydroxy-5-phenyl-l,5-ber-zothiazepine-

1,1 -dioxide;

37( (i)-7-Bromo-3-n-butyI-3-ethyl-2,3-dihydro-8-methoxy-5-phenyl-l,5-benzothiazepin- 4-one;

(±)-7-Bromo-3-n-butyl-3-ethyl-2,j,4,5-tetrahydro-8-methoxy-5-phenyl-l,5- benzothiazepine 1, 1-dioxide;

(i)-7-Bromo-3-π-butyl-3-ethyl-2,j, ,5-tetrahydro-5-phenyl-l,5-benzothiazepin-8- ol 1,1 -dioxide;

(-t)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-l,5-benzothiazepin-8-ol 1, 1-dioxide;

(--)-3-n-butyI-3-ethyI-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l,5-benzothiazepine 1, 1-dioxide;

(±)-3-n-butyl-3-ethyI-2,3,4,5-tetrahydro-5-phenyl-l,5-benzothiazεpine-7,8-diol 1,1- dioxide;

(=)-7-Bromo-3-n-butyl-3-ethyl-2,3-dihydro-5-phenyl-l_t5-benzothiazepin-4-one; (=)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-l,5-benzothiazepiπe 1,1 -dioxide; and

(±)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-I,5-benzothiazepin-7-ol 1,1- dioxide.

4) A compound of formula (I) selected from:

(-k)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-l,5-benzothiazepin-8- ol 1,1 -dioxide; and

(±)-3-n-ButyI-3-ethyl-2, ,4,5-tetr-Lhydro-8-hydroxy-5-pheπyl-l,5-benzothiazepine-

1, 1-dioxide or a salt, solvate, or physiologically functional derivative thereof.

37 (±)-3-n-Butyl-3-€thyI-2,3-dihydro-5-phenyM,5-benzothiazepin-4-one-l, 1-dioxide; (±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,5-benzothiazepine; (-fc)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl- 1 ,5-benzothiazepine- 1 , 1 -dioxide; (-fc 3-n-Butyl-2-isobutyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,5-benzothiazepine-l,I- dioxide;

3,3-Diethyl-2,3-dihydro-5-phenyl-l,5-benzothiazepin-4-one; 3,3-DiethyI-2,3-dihydro-5-phenyl-l,5-benzothiazcpin-4-one 1, 1-dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-l,5-benzothiazepine; 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl- 1,5-benzothiazepiπe- 1 , 1 -dioxide; 3,3-DimethyI-2,3-dihydro-5-phenyl-l,5-benzothiazepin-4-one; 3,3-Dimethyl-2,3-dihydro-5-phenyl- 1 ,5-benzothiazepin-4-one- 1 , 1 -dioxide; 3,3-Dimethyl-2,3,4,5-tetr--hydro-5-phenyl-l,5-benzothiazepine; 3,3-DimethyI-2,3,4,5-tetrahydro-5-phenyl- 1 ,5-benzothiazepine- 1.1 -dioxide; (±)-3-n-ButyI-3-ethyl-2,3,4,5-tetrahydro-7_J8-dimethoxy-5-phenyl-l,5-benzothiazepine-l, l- dioxide;

3 ,3-Diethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl- 1 ,5-benzothiazepine- 1 , 1 -dioxide; (i)-3-n-ButyI-3-ethyl-2,3,4,5-tetr--hydro-8-methoxy-5-phenyl-l,5-benzothiazepine-l, l- dioxide;

3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l,5-benzothiazepine-l, 1-dioxide; (-fc)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl- 1 ,5-benzothiazepin-8-ol- 1 , 1-dioxide; 3,3-DiethyI-2,3,4,5-tetrahydro-5-phenyl-l,5-benzothiazepin-8-ol-l, 1-dioxide; (- )-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-l,5-benzothiazepin-8-oI-l, l- dioxide;

3, -Diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-l,5-benzothiazepin-8-ol-l, 1-dioxide; (- )-7-bromo-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l,5- benzothiazepine- 1 , 1 -dioxide;

7-bromo-3,3-Diethyl---,3,4,5-te-r-ώydro-8-me-hoxy-5-phenyl-l,5-benzothiazepine-l,I- dioxide;

(±)-3-n-ButyI-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-I,5-benzothiazepin-7,8-diol-l, 1-dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-l,5-benzothiazepin-7,8-diol-l, 1-dioxide; (± 3-n-ButyI-3^thyI-2,3 4,5-tetrah dro^τ8-methoxy-5^"-pTϊeήy^ monoxide;

3, 3-Diemyl-2,3,4,5-tetr-ώydro-8-methoxy-5-phenyl-l,5-benzothiazep-ne-l -monoxide; (±J-S-n-Butyl-S-ethyW.S^.S-tetrahydro-S-phenyl-l.S-benzothiazepin-S-ol-l-monoxide; 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-l,5-benzothiazepin-8-ol-l-monoxide; (±>3-n-Butyl-3-ethyl-2,3-dihydro-8-mεmoxy-5-phenyl-l,5-benzothiazepin-4-one; (± 3-n-Butyl-3-ethyl-2,3,4,5-tetr--hydro-8-methoxy-5-phenyl-l,5-benzothiazεpine;

31 1° (±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl- 1 ,5-benzothiazepine- 1 , 1 - dioxide;

(±)-3-n-Butyl-3-ethyI-2,3,4,5-tetrahydro-8-hydroxy-5-phenyl-l,5-benzothiazepine-l,l- dioxide; (-b)-7-Bromo-3-n-butyl-3-ethyl-2,3-dihydro-8-methoxy-5-phenyi-l,5-benzothiazepin-4-one;

(±)-7-Bromo-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-pheπyl-l,5- benzothiazepine 1 , 1 -dioxide;

(±)-7-Bromo-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,5-benzothiazepin-8-ol 1,1- dioxide;

(±)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyI-l,5-benzothiazepin-8-ol 1, 1- dioxide;

(±)-3-n-butyl-3-ethyI-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l ,5-benzothiazepine 1.1- dioxide:

(=)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5_:phenyl-l,5-benzothiazepine-7,8-diol 1 , 1 -dioxide; (±)-7-Bromo-3-n-butyl-3-ethyl-2,3-dihydro-5-phenyI-l,5-benzothiazepin-4-one; (-t)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7-mcthoxy-5-phenyl-I,5-benzothiazepine 1, 1- dioxide; and (±)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,5-benzothiazepin-7-ol 1,1 -dioxide.

Paπicularly preferred compounds include:

(-fc)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyI-l,5-benzothiazepiπ-8-ol 1,1- dioxide; and

(-t)-3-n-Buryl-3-ethyl-2,3,4,5-tetrahydro-8-hydroxy-5-phenyi-l,5-benzothiazepine-l,l- dioxide.

321

3,3-Diethyl-2,3,4,5-tetrahydro- 1 , 1 -dioxo-5-phenyl- 1 ,4-benzothiazepin-8-yI aspartate.

(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetradhydro-7,8-dimethoxy-5-phenyl-l,4-ber othiazepine- 1,1 -dioxide;

(3R,5R)-3-Butyl-3-ethyl-2,3,4_>5-tetr--hydro-7,8-dimethoxy-5-phenyl-l,4-benzothi--zepin-4- ol 1, 1-dioxide;

(+-VTrans-3- utyl-3-€thy!-2,3,4,5-tetrahydτ^ 1,1 -dioxide;

(+- Tracns-3-butyl-3-€thyl-2,3,4₎5-tetrahydro-7,8-dimethoxy-5-phenyl-l,4,-benzot-ιiazepin- 4-ol 1, 1-dioxide;

(3R,5R>7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl- 1 ,4- benzothiazepine 1,1 -dioxide;

(3R,5R)-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetr--hydro-8-methoxy-5-phenyl-l_f4- benzothiazepin-4-ol 1, 1-dioxide;

(3R,5R 3-Butyl-3-ethyl-2,3,4,5-tetr--hydrc 5-phenyl-l,4-benzothi--zepine-7,8-dioll,l- dioxide;

(SR^RH-Butyl-S-ethyl-Z^AS-tetr-mydro-S-metho y- -pheny^^^ 1, 1-dioxide;

zn (3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-l,4-benzothiazepin-8-ol 1, 1-dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-pheπyl- 1 ,4-benzothiazepine 1,1- dioxide;

(+-)-Tr--ns-3-butyl-3-ethyI-2,3,4,5-tetrahydro-5-phenyl- 1 ,4-benzothiazepin-8-ol 1 , 1 -dioxide;

(+-)-Trans-3-butyl-3-ethyl-2₎3,4,5-tetrahydro-5-phenyl-l,4-benzothiazepine-4,8-diol;

(+-)-Trans-3-butyl-3-€thyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l,4-benzothi--zepine-7- carbaldehyde 1,1 -dioxide;

(+-)-Trans-2-{(3-butyl-3-ethyl-2,3,4₎5-tetrahydro-8-methoxy-5-phenyl-l₎4-benzothiazepin- 7-yl)methoxy) ethanol S,S-dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-hydroxy-5-phenyl-I,4-benzothiazepine-7- carbaldehyde 1, 1-dioxide;

(+-)-Trans-3-butyI-3-e-hyl-2,3,4,5-tetrahydro-5-phenyI- 1 ,4-benzothiazepin-8-thiol 1 , 1 - dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazepin-8-sulfonic acid- 1, 1-dioxide;

(7R,9R)-7-Butyl-7-ethyl-6,7,8,9-tetrahydro-9-phenyl-l,3-dioxolo(4,5-H (l,4)- benzothiazepme 5,5-dioxide;

(+-)-Trans-3-butyl-3-€thyl-2,3,4,5-tetrahydro-8,9-dimethoxy-5-phenyl-l,4-beniothJazepine- 1,1 -dioxide;

(3R,5R)-3-butyl-3-ethyl-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-7,8-dimethoxy-l,4- benzothiazpin-4-ol 1, 1-dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l,4-benzothiazepine-7- methanol S,S-dioxide; (3R,5R)-3-butyI-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-7-nitro-5-phenyl-l,4- benzothiazepine- 1 , 1 -dioxide;

(+-)-Trar-s-3-butyl-3-ethyI-2,3,4,5-tetrahydro-8-rnethoxy-7-(rnethoxymethyl)-5-pheπyl-l,4- benzothiazepine 1,1 -dioxide;

(3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetτ-mydro-5-phenyl-l,4-benzothiazepin-7,8-diyl diacetate- 1,1 -dioxide;

(8R, 10R)-8-ButyI-8-ethyl-2,3,7,8,9, 10-hexahydro- 10- 1 ,4-dioxono(2,3-H)( 1 ,4)- benzothiazepine 6,6-dioxide;

(3R,5R)-3-butyl-7,8-diethoxy-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazepine 1, 1-dioxide;

(+-)-Tr-ms-3-butyl-8-ethoxy-3-«hyl-2,3,4,5-tet-^ydro-5-phenyl-l,4-benzothiazepine-l,l- dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-l,4- benzothiazepine 1 , 1 -dioxide hydrochloride;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazepin-8-carbaIdehyde- 1, 1-dioxide;

3,3-Diethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl- 1 ,4-benzothiazepine 1 , 1 -dioxide;

3,3-Diethyl-5-(4-fluorophenyl)-2,3,4,5-tetπ-hydro-8-methoxy-l,4-benzothi-ιzepine 1,1- dioxide;

3 ,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl- 1 ,4-benzothiazepine 1 , 1 -dioxide;

3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazpin-4,8-dioll,^"l-dioxide

(-^)-3,3-Diethyl-2,3,4,5-tet-^ydro-4-hydroxy-7,8-dimethoxy-5-phenyl-l,4- beπzothiazepine 1,1 -dioxide;

(+->Tr-ms-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetnϋιydro-5-phenyl-l,4-benzothiazepin-4-ol- 1, 1-dioxide;

23* (+-)-Trans-3-butyI-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-l,4-benzothiazepin-4- ol 1, 1-dioxide;

(+-)-Trans-3-bu-yl-3-ethyl-2,3,4,5-terrahydro-7,8,9-trimethoxy-5-phenyl-l,4- benzothiazepin-4-oI 1, 1-dioxide;

(3R,5R>3-butyI-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazpin-4,7,8-triol 1,1- dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-4,7,8-trimethoxy-5-phenyl-l,4- benzothiazepine 1,1 -dioxide;

(+-)-Trans-3-butyl-3-ethyl-5-phenyl-2,3,4,5-tetrahydro-7,8-dimethoxy-l,4-benzothiazepin- 4-yI acetate S,S-dioxide;

3,3-Die-hyl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazepin-8-ol 1, 1-dioxide;

3,3-Diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-l,4-beπzothiazepin-8-ol 1, 1-dioxide;

3,3-Dibutyl-2,3,4,5-tetrahydro-5-pheπyl-l,4-benzothiazepin-8-ol 1,1 -dioxide;

(+-)-Tr-ms-3-Butyl-3-ethyl-2,3₎4,5-tetraJ-ydro-l₎l-dioxo-5-phenyi-l,4-beri20thiazepin-8-yl hydrogen sulfate;

(+- Trans-3-Butyl-3-ethyl-2,3,4₎5-tetr-ώydro-I,l-dioxo-5-phenyl-I,4-benzoUuazep-π-8-yI dthydrogen phosphate;

S.S-Diethyl^.S^. -tetrahydro-l.l-dioxo-S-phenyl-l^-benzothiazepin-δ-yl hydrogen sulfate;

3,3-DiethyI-2,3,4,5-tetrahydro- 1 , 1 -dioxo-5-phenyl- 1 ,4-benzothiazepin-8-yl- dihydrogen phosphate;

(+->Trans-3-ButyI-3-ethyl-2,3,4,5-tetrahydro-l_tl-dioxo-5-phenyl-I,4- benzothiazepin-8-yI aspartate; and

(22) (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl- 1 ,4- benzothiazepine-7-methanol S,S-dioxide, mp 122-123° C

(23) (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-7-nitro-5-phenyl-l,4- benzothiazepine 1, 1-dioxide 0.40 hydrate, mp 122-123° C

(24) (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-7-(methoxymethyl)-5- phenyl-l,4-benzothiazepine 1, 1-dioxide, mp 118-119° C

(25) (+- Trans-7-bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,4- benzothiazepin-8-ol 1, 1-dioxide 0.40 hydrate, mp 137-138° C

(26) (+-)-Tr-ιns-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8,9-trimethoxy-5-phenyl-l,4- benzothiazepine 1,1 -dioxide, mp 169-170° C

(27) (3R,5R 3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazep-n-7_I8-diyl diacetate 1, 1-dioxide, mp 79-81° C

(28) (8R, 10R)-8-Butyl-8-ethyI-2,3,7,8,9, 10-hexahydro- 10- l,4-dioxono(2,3-H)( 1 ,4)-- benzothiazepine 6,6-dioxide, mp 82° C

(29) (3R,5R 3-bιrtyl-7,8-diethoxv-2,3,4,5-tetrahydι^5-phenyl-l,4-be-ιzothiazepine 1,1 dioxide 0.20 hydrate, mp 110-111° C (30) (+-)-Tr-u s-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,4- benzothiazepine 1,1 -dioxide, mp 45-54° C

(31) (+-)-Traπs-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-(methylthio)-5-phenyl-l,4- benzothiazepinel, 1-dioxide hydrochloride, mp 194-197° C

(32) (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-I,4- behzothiazepine 1, 1-dioxide hydrochloride, mp 178-181° C

(33) (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazepin-8- carbaldehyde 1, 1-dioxide, mp 165-170° C

(34) 3,3-Diethyl-2,3,4,5-tetrahydro-l,l-dioxo-5-phenyl-l,4-bεnzothiazεpin-8-yl aspaπate

(35) 3 ,3-Die-hyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl- 1 ,4-benzothiazepine- 1,1- dioxide, mp 163-164° C

(36) 3,3-Diethyl-5-(4-fluorophenyl)-2,3,4₁5-tetrahydro-8-methoxy-l ,4-benzothiazepine- 1, 1-dioxide mp 101-103° C

(37) 3,3-Diethyl-2,3,4,5-tetrahydro-8-rncthoxy-5-phenyl-l,4-benzothiazepine-l,l- dioxide, mp 132-133° C

(38) 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazepin-4,8-diol- 1, 1-dioxide, mp 225-227° C

(39) (RS)-3,3-Diethyl-2,3,4,5-tet-^ydro-4-hydroxy-7,8-dimethoxy-5-phenyl-l,4- benzothiazep-ne 1,1 -dioxide, mp 205-206° C

(40) (+-)-Trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,4- benzothiazepin-4-ol 1,1 -dioxide, mp 149-150° C

(41) (+-)-Tr--ns-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-l,4- bermrthiazepin-4-ol 1,1-dioxJde, mp 109-115° C

(42) (+- Trans-3-butyl-3-ethyl-2,3,4_f5-tetrahydro-7,8,9-trimethoxy-5-phenyl-l,4- benzothiazepin-4-ol 1, 1-dioxide, mp 84-96° C (43) (3R-5R)-3-butyl-3-ethyI-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazpin-4,7,8-triol- 1,1 -dioxide, mp 215-220° C

(44) (+-)-Tr-ins-3-butyI-3-ethyl-2,3,4,5-tetrahydro-4,7,8-trimethoxy-5-phenyl-l,4- benzothiazepine 1, 1-dioxide, mp 169-187° C

(45) (+-)-Trans-3-butyl-3-€thyl-5-phenyl-2,3,4,5-tetrahydro-7,8-dimethoxy-l,4- benzothiazepin-4-yl acetate S,S-dioxide, mp 154-156° C

(46) 3,3-Diethyl-2,3,4,5-tetr--hydro-5-phenyl-l,4-benzothiazepin-8-oll, 1-dioxide, mp 177-178° C

(47) 3,3-Diethyl-2,3,4,5-tetrahydro-7-mεthoxy-5-phenyl-l,4-benzothi--zepin-8-ol 1,1- dioxide

(48) 3,3-Dibutyl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazepin-8-ol 1,1 -dioxide

(49) (+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro- 1 , 1 -dioxo-5-phenyl- 1 ,4- benzothiazepin-8-yl hydrogen sulfate, mp 196.5-200°C

(50) (+->Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro- 1 , 1 -dioxo-5-phenyl- 1 ,4- benzot ^'azepin-8-yl dihydrogen phosphate

(51) 3,3-Diethyl-2,3,4,5-tetrahydro-l,l-dioxo-5-phenyl-l,4-benzothiazepin-8-ylhydrogen sulfate

(52) S.S-Diethyl^.S^.S-tetrahydro-l.l-dioxo-S-phenyl-l^-benzothiazepin-S- yldihydrogen phosphate

(53) (+->Trans-3-ButyI-3-ethyl-2,3,4,5-tetrahydro-l,l-dioxo-5-phenyl-l,4- benzothiazepin-8-yl aspartate

33 The compounds of the formula (I)

wherein Rl is a straight chained C\.ζ alkyl group; R² is a straight chained Cj.g alkyl group; R³ is hydrogen or a group OR* 1 in which R^ is hydrogen, optionally substituted C\.-_$ alkyl or a C\.Q alkylcarbonyl group; R⁴ is pyridyl or optionally substituted phenyl; R⁵, R », R7 and R8 ^f^, _tjj_{e Sime or} dif erent and each is selected from hydrogen, halogen, cyano, R^-acetylide, OR¹⁵, optionally substituted C\„-$ alkyl, COR¹⁵, CH(OH)R¹⁵, S(0)_nR¹⁵, P(0)(OR^{I 5})_2> OCOR¹⁵, OCF₃, OCN,

optionally substituted Cj^ alkyl; or R*> and 1\ are linked to form a group

wherein R ² and R¹³ are as hereinbefore defined and m is 1 or 2; and R⁹ and R¹⁰ are the same or different and each is hydrogen or C\.Q alkyl; with the proviso that when R³ is hydrogen either R⁷ is not hydrogen or at least two of R⁵, R⁶, R⁷ and R⁸ are not hydrogen; and salts, solvates and physiologically functional derivatives thereof.

237 2. The compounds as claimed in claim 1 which arε of the formula (I)

wherein R* to R^ are as hereinbefore defined and R^7a is selected from halogen, cyano, R¹⁵-acetylide, OR¹⁵, optionally substituted C\.ζ alkyl, COR¹⁵, CH(OH)R¹⁵, S(0)_nR¹⁵, P(0)(0R^J5)_2l OCORl⁵, OCF₃, OCN, SCN, HNCN, CH₂ K¹⁵, CHO, (CH₂)_pCN, CONRI2R13₎ (CH₂)_pC0₂R¹⁵, (CH₂)_pNRl2_RI3₍ C0₂R¹⁵, NHCOCF_3> NHS0₂R¹⁵, 0CH₂0R^Ϊ5, OCH=CHR¹⁵, 0(CH₂CH₂0)_nRl5, 0(CH₂)_pS0₃Rl5_> 0(CH2)pNR¹²R¹³ and

0(CH )pN⁺H¹ R¹³R¹⁴ wherein n, p and R¹² to R¹⁵ are as hereinbefore defined; and salts, solvates or physiologically functional derivatives thereof.

3. The compounds as claimed in claim 1 which are of the formula (HI) :

wherein R'-R¹" are as defined in claim 1; and salts, solvates and physiologically functional derivatives thereof.

The compounds as claimed in claim 1 which are of the formula (TV)

wherein R^J-R¹⁰ are as defined in claim 1; and salts, solvates and physiologically functional derivatives thereof!

3-^ 5. The compounds as claimed in claim 1 which are of the formula (IVa)

wherein R^-R^ are as defined in claim 1; and salts, solvates and physiologically functional derivatives thereof.

6. The compounds as claimed in claim 1 wherein: R* and R² are straight chained Cι_5 alkyl; R³ is hydrogen or hydroxy,

R⁴ is unsubstituted phenyl;

R⁵ is hydrogen;

R⁹ and R^ are both hydrogen; and either

R⁷ is selected from halogen, hydroxy, C\.§ alkoxy, optionally substituted

Cι_6 alkyl, -S(0)_nR¹⁵, -OC(0)R¹⁵, and -CH₂OR¹⁵ wherein R¹⁵ is hydrogen or

Cj.6 alkyl; and

R*> and R⁸ are independently selected from hydrogen and those groups listed in the definition of R⁷; or

R⁸ is hydrogen and R^ and R⁷ are linked to form a group -0-(CH2)_m-0- wherein m is 1 or 2; and salts, solvates, and physiologically functional derivatives thereof

7. A compound according to any of claims 1 to 6 wherein R^ and R⁷ are both methoxy.

8. A compound selected from the group consisting of :

(3R,5R 3-Butyi-3-e l-2,3,4,5-tetrahy*:o-7,8-dimethoxy-5-phenyl-l,4- benzothiazepine 1,1 -dioxide;

33 ? (3R,5R)-3-ButyI-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-pheπyi-l,4- benzothiazepin-4-oI 1, 1-dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyI-l,4- berizothiazepine 1,1 -dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l,4,- benzothiazepin-4-ol 1 , 1 -dioxide;

(3R,5R 7-Bromo-3-butyl-3-ethyI-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l,4- benzothiazepine 1, 1-dioxide;

(3R,5R)-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l,4- benzothiazepin-4-ol 1,1 -dioxide;

(3R,5R 3-Butyl-3-ethyl-2,3,4,5-tetπώydro-5-phenyl-l,4-benzothiazepine-7.8-diol 1, 1-dioxide;

(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l,4- benzothiazepin-7-ol 1,1 -dioxide;

(3R,5R 3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-l,4- benzothiazepin-8-ol 1, 1-dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l,4- benzothiazepine 1,1 -dioxide;

(+-)-Tr-ms-3-butyl-3-€thyl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothi--zepin-8-ol 1, 1-dioxide;

(^-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetπ ydro-5-phenyl-l,4-beπzgtMazepine-4,8^ dϊoT;

(+-)-Trans-3-butyl-3-ethyI-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l,4- benzothiazepine-7-carbaIdehyde 1, 1-dioxide;

23$ (+-)-Trans-2-((3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l,4- benzothiazepin-7-yl) ethoxy) ethanol S.S-dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-hydroxy-5-phenyl-l,4- benzothiazepine-7-carbaldehyde 1 , 1 -dioxide;

(+- Ti^ns-3-butyl-3-ethyl-2,3,4,5-tetr-ihydro-5-phenyl-l,4-be-uothiazepin-8--hiol 1, 1-dioxide;

(+-)-Trans-3-butyI-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazepin-8- sulfonic acid 1, 1-dioxide;

(7R,9R)-7-Butyl-7-ethyI-6,7,8,9-tetrahydro-9-phenyl-l,3-dioxolo(4,5-H)(l,4)- benzothiazepine 5,5-dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8,9-dimethoxy-5-phenyl-l,4- benzothiazepine 1,1 -dioxide;

(3R,5R 3-butyl-3-ethyl-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-7,8-d-methoxy-l,4- benzothiazpin-4-ol 1,1 -dioxide;

(+->Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l,4- benzotbiazepine-7-methanol S,S-dioxide;

(3R,5R 3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-7-nitro-5-phenyl- 1 ,4- benzothiazepine 1,1 -dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-7-(methoxymethyl)-5- phenyl- 1 ,4-benzothiazepine 1 , 1 -dioxide;

(3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetτ--hydro-5-phenyl-l,4-benzothiazepin-7,8-diyl diacetate 1, 1-dioxide;

(8R, 10R)-8-Butyl-8-ethyl-2,3,7,8,9, 10-hexahydro- 10- 1 ,4-dioxono(2,3-H)( 1 ,4)- benzothiazepine 6,6-dioxide;

33 η (3R,5R)-3-butyl-7,8-diethoxy-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazepine 1,1- dioxide;

(+-)-Trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,4- benzothiazepine 1 , 1 -dioxide;

(+- Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-l,4- benzothiazeptne 1,1 -dioxide hydrochloride;

(+-)-Tr--ns-3-butyl-3-€thyl-2,3,4,5-tetrahydro-5-ρhenyl-l,4-benzothiazepin-8- carbaldehyde 1, 1-dioxide;

3,3-Diethyl-2,3,4,5-tetrahydro-7,8-dime oxy-5-phenyl-l,4-benzothiazepine 1,1- dioxide;

3,3-Diethyl-5-(4-£luorophenyl)-2,3,4,5-tetrahydro-8-rnethoxy-l,4-benzothiazepine 1,1 -dioxide;

3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l,4-benzothiazepine 1,1- dioxide;

3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-l,4-beπzothiazpin-4,8-dioI 1, 1-dioxide;

(RS)-3,3-Diethyl-2,3,4,5-tetrahydro-4-hydroxy-7,8-dimethoxy-5-phenyl-l,4- benzothiazepine 1, 1-dioxide;

(+-)-Trarιs-3-buryl-8-ethoxy-3-e l-2,3,4,5-tetrahydro-5-phenyl-l,4- benzothiazepin-4-ol 1 , 1 -dioxide;

(+- Trar-s-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyI- 1 ,4- ber-zothiazepin-4-ol 1 , 1 -dioxide;

(+-)-Trar-s-3-butyl-3-€thyl-2,3,4,5-tetrahydro-7,8,9-trimethoxy-5-phenyl-l,4- benzothiazepin-4-ol 1, 1-dioxide;

(3R,5R)-3-butyl-3-ethyl-2,3,4,5-tet-^ydro-5-phenyl-l,4-bei-zothiazpin-4,7,8-triol 1,1 -dioxide;

3 Y0 (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-4,7,8-trimethoxy-5-phenyl-l,4- benzothiazepine 1 , 1 -dioxide;

(+-)-Trans-3-butyl-3-ethyl-5-phenyl-2,3,4,5-tεtrahydro-7,8-dimethoxy-l,4- benzothiazepin-4-yl acetate S,S-dioxide;

3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyI- 1 ,4-benzothiazepin-8-ol 1 , 1 -dioxide;

3,3-Diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-l,4-benzothiazepin-8-ol 1,1- dioxide;

3,3-Dibutyl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazepin-8-ol 1, 1-dioxide;

(+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-l,l-dioxo-5-phenyl-l,4- benzothiazepin-8-yl hydrogen sulfate;

(+- Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-l,l-dioxo-5-phenyl-l,4- benzothiazepin-8-yl dihydrogen phosphate;

3,3-Diethyl-2,3,4,5-tetrahydro- 1 , 1 -dioxo-5-phenyl- 1 ,4-benzothiazepin-8-yl hydrogen sulfate;

3,3 -Diethyl-2,3 ,4,5-tetτahydro- 1 , 1 -dioxo-5-phenyl- 1 ,4-benzothiazepin-8-yl dihydrogen phosphate;

(+-)-Traiw-3- utyl-3-e l-2,3,4,5-tetrahydYo-l,l-dioxo-5-phenyl-l,4- benzothiazepin-8-yl aspartate; and

3,3-Diethyl-2,3,4,5-tetrahydro-l,l-dioxo-5-phenyl-l,4-benzothiazepin-8-yl aspartate.

9. (3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7, 8-dimethoxy-5-phenyI-l ,4- benzothiazepine 1,1 -dioxide, or a salt, solvate, or physiologically functional derivative thereof

Compounds ) having exceptional hypolipidaemic propeπies include:-

(+-)-trans-3-ethyl-2,3,4,5-tetr--hydro-3-((2R)-2-hydroxybutyl)-5-phenyl-l,4- benzothiazepine 1,1 -dioxide;

(+-)-n^ns-l-(3-ethyl-2,3,4,5-tetrahydro-8-memoxy-5-phenyl-l,4-bex-zotWazepm-3- yl-2(R)-2-butanol S,S-dioxide;

(+-)-tr--ns-l-(3-ethyl-2,3,4,5-tetrahydro-8-memoxy-5-phenyl-l,4-benzothiazepin-3- yl)-3-butanol S,S-dioxide;

(+-)-tτans-l-(3-e yl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-l₎4-benzothi--zcpin-3- yl)-2(R)-2-butanoI S,S-dioxide;

(+-)-trans- 1 -(3-ethyl-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-7-methoxy- 1 ,4- bεnzothiazεpin-3-yl)-2(R)-2-butanol S,S-dioxide;

(+-)-tr-uιs-l-(3-ethyl-5-(4-hydroxyphenyl)-2,3,4,5-tetr--hydro-I,4-benzothiazepin-3- yl)-2(R)-2-butanol S,S-dioxide 0.5 hydrate; (÷-)-trans-3-butyl-3-ethyl-2₎3,4₎5-tetrahydro-5-(4-hydroxyphenyl)-l,4- benzothiazepine 1,1 -dioxide hydrochloride;

(+-)-cis-3-eΛyl-2,3,4,5-tetrahydro-3-(4-hydroxybutyl)-5-phenyl-l,4-ben2othi--zepine 1 , 1 -dioxide hydrochloride;

(+-)-trans-3-ethyl-2,3 ,4,5-tetrahydro-3-(4-hydroxybutyl)-5-phenyl- 1 ,4- benzothiazepine 1,1 -dioxide;

(+-)-trans-3-butyl-3-e-hyl-2,3,4,5-tetrahydro-7-hydroxy-5-phenyl-l,4- benzothiazepine 1,1 dioxide;

(+-)-trans- 1 -(3-emyl-2,3,4,5-tetrahydro-5-phenyl- 1 ,4-benzotlιiazepin-3-yl)-4,4,4- trifluoro-(2S)-2-butanol- S,S-dioxide;

(+-)-trans-l-(3-ethyl-2,3,4,5-tetrahydro-7-me±oxy-5-phenyl-l,4-benzothiazepin-3- yl)-4,4,4-trifluoro-(2S)-2-butanol-S,S-dioxide; (+-)-trans-3-Ethyl-2_;3,4,5-tetrahydro-3-(3-hydroxybutyl)-5-phenyl-l,4- benzothiazepine 1,1 -dioxide;

(+-)-trans-3-Ethyl-2,3,4,5-tetr--hydro-3-(2(R)-2-hydroxybutyl)-5-(4- hydroxyphenyl)- 1 ,4-benzothiazepine 1 , 1 -dioxide; (+-)-trans-l-(3-Ethyl-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-l,4- benzothiazepin-3-yl)-2(R)-2-butanol S,S-dioxide; (+-)-trans-l-(3-Ethyl-2,3,4,5-te-rahydro-7-methoxy-5-phenyl-l,4 benzothiazepin-3-yl)-4,4,4-trifluoro-2(S)-2-butanol S,S-dioxide; (+-)-trans-l-(3-Ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l,4- benzot--iazepin-3-yl)-4,4,4-trifluoro-2(S)-bu-anol S,S-dioxide; (+-)-trans- 1 -(3-ethyI-2,3,4,5-tetrahydro-7.8-dimethoxy-5-phenyl- 1 ,4-benzothiazepin- 3-yl-2(R)-2-butanol S,S dioxide;

(+-)-trans-l-(3-Ethyl-2,3,4,5-tetrahydro-7.8-dimethoxy-5-phenyl-l,4- benzo-hiazεpin-3-yl)-4,4,4-trifluoro-2-but--nol S,S-dioxide; (+-)-tι--rιs-l-(3-Emyl-2^,4,5-te-rahydro-7,8-dimethoxy-5-phenyl-l,4- benzothiazepin-3-yI)-3,3,4,4,4-pentafluoro-2-butanol S,S-dioxide; (+-)- trans-3-((3-ethyl-2,3,4,5-tetrahydro-5-phenyl-3-(4,4,4-trifluoro-2- hydroxybutyl)-l, 4-ber-zothiazep -8-yl)oxy)propanesulfonic acid 1, 1-dioxide; (+-)-trans -((j^yl-2_;3,4,5-tetrahydro-3-(2-hydroxybutyl)-5-phenylrl,4- benzothiazepin-8-yl)oxy)ethyltrimethylammonium iodide 1, 1-dioxide; (+-)-trans-l-(3-Ethyl-2,3,4,5-tetrahydro-7,8-diethoxy-5-phenyl-l,4- benzothi--zepin-3-yl)-4,4,4-trifluoro-2-butanol S.S-dioxide; (+-)-trans-3-((3-ethyl-2,3.4,5-tetrahydro-5-phenyl-3(4,4,4-trifluoro-2- hydroxybutyl)- 1 ,4-benzothiazepin-8-yl)oxy)ethyltrimeώylammonium iodide 1.1 -dioxide;

j VJ (+-)-trans-3-((3-ethyl-2,3,4,5-tεtrahydro-3-(2-hydroxybutyl)-5-phenyl-l,4- benzothiazepin-8-yl)oxy)propancsulfonic acid 1,1 -dioxide; (+-)-trans- 1 -(3-ethyl-2, ,4,5-tetr--hydro-7,8-diethoxy-5-phenyl- 1 ,4- benzothiazepin-3-yI)-2-butanol S,S-dioxide;

(+-)-traris-l-(3-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-7,8-dimethoxy-5- phenyl- 1 ,4-benzothiazepin-3-yl)-4,4,4-trifluoro-2-butanol S,S-dioxide; (+-)-trans- 1 -(3-Ethyl-2,3,4,5-tetrahydro-7,8-dihydroxy-5-phenyl-l ,4- benzothiazepin-3-yl)-4,4,4-trifluoro-2-butanol S,S-dioxide; (+-)-trans- 1 -(3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l ,4- bεnzothiazepin-3-yl)-l-butanol S,S-dioxide; (+-)-trans- 1 -(3-Ethyl-2,3 ,4,5-tetrahydro-7,8-dihydroxy-5-pheπyl- 1 ,4- benzothiazepin-3-yl)-2-butanol S,S-dioxide; (+-)-trans-l-(3-e-hyl-2,3,4,5-te-rahydro-8-methoxy-5-phenyl-l,4- benzothiazepin-S-y ^^^trifluoro-l -butanol S,S-dioxide; (+-)-trans-l-(3-ethyl-2i3,4,5-tetrahydro-7,8-dihydroxy-5-phenyl-l,4- benzothiazepin-3-yl)-2-butanone S,S-dioxide;

Of the above the following compounds are most prefened:-

(+-)-tr--r-s-l-(3-ethyl-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-7-methoxy-l,4- benzothiazepin-3-yI)-2(R)-2-butanol S,S-dioxide;

(+-)-trans-l-(3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothi-ιzepin-3-yl)-4,4,4- trifluoro-(2S)-2-butanol- S,S-dioxide;

(+-)-trans- 1 -(3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl- 1 ,4-benzothiazepin-3- yl)-4,4,4-trifluoro-(2S)-2-butanoI-S,S-dioxide;

(+-)-trans-l-(3-Ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l,4- benzothi-ιzep -3-yl)-4,4,4-trifluoro-2(S)-butanol S,S-dioxide

(+-)-trans- 1 -(3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l ,4-benzothiazepin-

3-yl-2(R)-2-butanol S,S dioxide;

7

13) (+- Jjai-S-2,3,4,5-Tetrahydro-3-methyl-5-phenyl-l ,4-benzothiazepine-3- methanol 1,1 -dioxide, mp 79-80°C;

14) (+-)-£is-2,3,4,5-Tetrahydro-3-methyl-5-phenyl-l ,4-benzothiazepine-3- methanol 1,1 -dioxide hydrochloride 0.25 hydrate mp 222-224°C;

15) (+-)-1^2l--.-4-(3-Butyl-3-ethyl-2_!3,4,5-te-rahydro-l ,4-benzothi--zepin-5- yl)phenol hydrochloride, mp 234-235°cC(dec);

16) (+-)-lQ--S-5-(4-Berιzyloxypheπyl)-3-ethyl-2,3,4,5-tetrahydro-l,4- benzothiazepine-3-methanol, mp 138-143°C;

17) (+-)-l^-3Jis-3-E±yl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiapzepine-3- methanol 1.1 -dioxide, mp 134-137°C;

18) (÷-)-Ir£i)s-3-E l-2,3,4,5-tetr--hydro-3-(3-hydroxybutyl)-5-phenyl-l ,4- benzothiazcpine 1, 1 -dioxide, mp 151-155°C;

19) (+-)-Cis-3-E±yl-2,3,4,5-tet-^ydro-3-butyl-4-hydroxy-5-(3-pyridyl)-l,4- benzothiazepine 1,1 -dioxide, mp 202-205°C;

20) (+-)-CJs-4-(3-Butyl-3-emyl-2,3,4,5-tetrahydro-l,4-benzothiazepin-5- yl)phenol hydrochloride, mp 236-237°C(dec);

21 ) (+-)-Cjs-3-B utyl-3-ethyl-2,3 ,4.5-tetrahydro-5-(4-hydτoxyphenyl)- 1 ,4- benzothiazepine 1, 1 -dioxide, mp 163-165°C;

22) (+-)-Cjs-3-Ethyl-2.3,4,5-tetrahydro-3-(3-hydroxybutyl))-5-phenyl-l,4- benzothiazepine 1,1 -dioxide hydrochloride. mp 206-209°C;

23) (÷-)-l^ιn-i-3-Ethyl-2.3.4,5-tetrahydro-3-(2(R)-2-hydroxybutyl)-5-(4- hydroxyphεnyl)-I.4-benzothiazepine 1.1 -dioxide, mp 197-198°C;

24) (+-)-Ir-ans-3-Ethyl-2,3,4,5-tetrahydro-3-(2(S)-2-hydroxybutyl)-5-(4- hydroxyphenyl)-l,4-benzothiazepine 1.1 -dioxide, mp 178-179°C;

25) (+-)-X^2ns-3-Ethyl-2,3,4,5-te-r-ιhydro-5-phenyl-l,4-ber-zothiazepine-3- methanol. mp 104-106°C;

26) (+-)-CJs-5-(4-BenzyioxyphenyI)-3-ethyl-2,3,4,5-tetr--hydro- 1 ,4- benzothiazepine-3-methanol, mp 123-128^CC;

27) (+-)-Irans- 1 -(3-Ethyl-5-(4-fluorophenyl)-2,3,4,5-tetrahydro- 1 ,4- benzothiazepin-3-yl)-2(R)-2-butanol S,S-dioxide, mp 130-132°C;

28) (+->Ia-----l-(3-E yl-2,3,4,5-tetrahydro-5-phenyl-l,4-beriZothiazepm-3- yl)-4,4,4-trifluoro-2(R)-2-butanol S,S-dioxide, mp 140-145°C;

29) (+-)-IJQns-l-(3-Eώyl-2,3,4,5-tetrahydro-5-phenyl-l,4-bεnzomi--zεpin-3- yl)-4-fluoro-2-(RS)-2-butanol S,S-dioxide 0.50 hydrate, mp 130-I47°C;

30) (+-)-l^cani-l-(3-EΛyl-2,3,4,5-tetrahydro-5-phenyl-l,4-beιτzothi--zepm-3- yl)-4,4,4-trifluoro-2(S)-2-butanol S.oxide, mp 159-161°C;

31) (+-)--I-r-3r-£-l-(3-Ethyl-2,3,4,5-tetr-ιhydro-7-methoxy-5-phenyl-l,4- ber-zotm^epin-3-yl)-4,4,4-trifluoro-2(S)-2-butanol S,S-dioxide, mp 168- 170°C;

32) (+-)-l^-ailS-l-(3-EΛyl-2,3,4,5-tetr--hydro-8-me-hoxy-5-phenyl-l,4- benzothiazepin-3-y])-4,4,4-trifluoro-2(S)-2-but--nol S,S-dioxidε, mp 175-179°C;

33) (+-)-Trans-l-(3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l,4- bεnzothiazepin-3-yl-2(R)-2-butanol S,S-dioxide, mp 156-157°C;

34) (+-)-Icaris-l -(3-E-hyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l ,4- bεnzothiazepin-3-yl)-4,4,4-trifluoro-2-butanoI S,S-dioxide;

35) (- -Trans- 1 -(3-Ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl- 1 ,4- bεnzothiazepin-3-yl)-3 ,3 ,4,4,4-pentafluoro-2-butanol S,S-dioxide;

36) (+-)-l^-3ii5-l-(3-Ethyl-2.3,4,5-tetr--hydro-7.8-dime-hoxy-5-phenyl-l,4- benzothiazepin-3-yl)-3,3,4,4,4-pentafluoro-2-butanol S,S-dioxide;

37) (÷-)-1^3i-_i-3-((3-ethyl-2,3_?4,5-tetrahydro-5-phenyl-3-(4,4,4-trifluoro-2- hydroxybutyl)- 1.4-benzothiazepin-7-yl)oxy)prop--nesulfonic acid 1 , 1 -dioxide;

38) (+-)-Irjarj&3-((3-ethyl-2.3.4.5-tetrahydro-5-phenyl-3-(4,4,4-trifluoro-2-

3 hydroxybutyl)- 1 ,4-benzothiazepin-8-yl)oxy)propanεsulfonic acid 1 , 1 -dioxide;

39) (+-)-IraDS-3-((3-emyl-2,3.4,5-tetnmydro-3-(2-hydroxybutyl)-5-phenyl-l,4- benzotlιi--zepin-7-yl)oxy)e yltrimemylammonium iodide 1,1 -dioxide;

40) (+-)-1^2r--i-3-((3-e yl-2,3,4,5-tetr--hydro-3-(2-hydroxybutyl)-5-phenyl-l,4- benzo iazepin-8-yl)oxy)emyl-rimemyl--ιnmonium iodide 1,1 -dioxide;

41 ) (+-)-Ir_ans- 1 -(3-Ethyl-2,3 ,4,5- tetrahydro-7,8-diethoxy-5-phenyl-l ,4- benzothiazepin-3-yl)-4,4,4-trifluoro-2-butanol S,S-dioxide;

42) (^•f-)-Tr- s-3-tf3-emvl-2.3.4.5-tetrahydro-5-phenyl-3(4,4_t4--rifluoro-2- hydroxybutyl)- 1 ,4-benzo iazepm-7-yl)oxy)emyltrimeώyl-ιmmonium iodide 1,1 -dioxide

43) (+-)-Trans-3-f(3-eωyl-2.3.4.5-tetrahydro-5-phenyl-3(4_r4_τ4-trifluoro-2- hydroxybutyl)- 1 ,4-ber-zothi--zepm-8-yl)oxy)emyltιτmeώyl--ιnmoniι-m iodide 1,1 -dioxide;

44) (+-)-Tj2--S-3-((3-ethyl-2,3,4,5-tetrahydro-3-(2-hydroxybutyl)-5-phenyl-l,4- benzothiazepin-8-yl)oxy)propaπesulfonic acid 1,1 -dioxide;

45) (+-)-l^aιιs-3-((3-emyl-2,3,4,5-tetrahydro-3-(2-hydroxybutyl)-5-phenyl-l,4- benzothiazepin-7-yl)oxy)propanesulfonic acid 1,1 -dioxide;

46) (+-)-Irans- 1 -(3-ethyl-2,3 ,4,5-tetrahydro-7,8-diethoxy-5-phenyl- 1 ,4- benzothiazepin-3-yl)-2-butanoI S,S-dioxide;

47) (+-)-Tj2jιs-l-(3-(2.2,2--rifluoroe±yl)-2,3,4,5-tetr--hydro-7,8-dimethoxy-5- phenyl- 1 ,4-benzothiazepin-3-yl)-4,4,4-trifluoro-2-butanol S,S-dioxide;

48) (+-)-Irjg _5-l-(3-(2,2^-trifluoroemyl)-2,3,4,5-tetr-ώyclro-8-mε ^ phenyl- l,4-benzothiazepin-3-yl)-4,4,4-trifluoro-2-butanol S,S-dioxide;

49) (+-)-Tj2ns-l-(3-Ethyl-2,3,4,5-tetrahydro-9-methoxy-5-phenyl-l,4- beπzothiazepin-3-yl)-4_J4,4-trifluoro-2-butanol S,S-dioxide;

50) (+-)-l^ajι-i-l-(3-ethyl-2,3,4,5-tetrahydro-9-me-hoxy-5-phεnyl-l,4- benzothiazcpin-3-yl)-2-butanol S,S-dioxide;

51 ) (+-)-Irans- 1 -(3 -EthyI-2,3 ,4,5-tetrahydro-7,8-dihydroxy-5-phenyl- 1 ,4- benzothiazepin-3-yl)-4,4,4-trifluoro-2-butanol S,S-dioxide;

52) (+-)-Jjj3r--.-l-(3-ethyI-2.3.4.5-tetr--hydro-8-rnethoxy-5-phenyl-l,4- benzothiazepin-3-yI)- 1 -butanol S.S-dioxide;

3 V 53) (+->Ii ns- 1 -(3-ethyl-2^,4,5-tetrahydro-7,8-dimethoxy-5-phenyl- 1 ,4- benzothiazepin-3-yl)-l-butanol S,S-dioxide;

54) (+-)-Iαns-l-(3-EΛyl-2,3,4,5-teϋ^ydro-7,8-dihydroxy-5-phenyl-l,4- benzothiazepin-3-yl)-2-butanol S,S-dioxide;

55) (+-)-Trans-l-(3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l ,4- be---Mt iazepin-3-yl)-4,4,4-trifluoro-l-butanol S,S-dioxide;

56) (+- Tra-ιs-l-(3-ethyl-2 ,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l,4- benzot--ia2ep-n-3-yl)-4_J4,4-t-ifluoro-l-butanol S,S-dioxide

57) (+-)-Irjajis-l-(3-E-hyl-2,3,4,5-tetrahydro-7,8-dihydroxy-5-phenyl-l,4- benzothiazepin-3-yl)-2-butanone S,S-dioxide

3Y A compound of formula (I):

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, nitro, alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, aralkyl, alkaryl, -0(CH2)_pS03R¹ , -O CH^pNR¹ lR¹², -©(CH^pN+R¹ !R¹ R¹⁴ -COR¹1, -CO2R¹1, -CONRl ^ΪR , -CH2ORI 1, -NR^{1 1} , -NHCOR¹1, -NHSO2R^{1 1}, -SR¹ K -SO2R^{1 !} , -SO2NR^{1 !}R¹² and -SO3R^{1 !} or R is a group -OCH₂0- which forms a further ring attached to X wherein p is an integer of from 1 to 4, R ! Ri2 are independently selεcted from hydrogen, C\. alkyl and phenyl and R ⁴ is hydrogen or C 1-6 alkyl, wherein said alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, aralkyl and alkaryl groups are optionally substituted by one or more atoms or groups selected from halogen, hydroxy, nitro, nitrile, alkyl, alkoxy, -COR¹ , -CO2R *, -SO3R^{1 1} wherein R^{1 !} is as hereinbefore defined and -NR¹⁴R¹⁵ wherein R¹⁴ is as hereinbefore defined and ^ is hydrogen or C\.β alkyl

R¹ is hydrogen or C\. alkyl;

R2 is an atom or group selected from hydrogen, Ci-g alkyl (including- cycloalkyl and cycloalkylalkyl), C\^ alkoxy, pyrryl, thienyl, pyridyl, 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, phenoxy, benzyloxy, -COR¹1, -CO2R^{1 !}, -CONR¹ iR¹ , -CH2OR 1, . -NR^πR¹². -NHCOR^{1 1}, -NHS0₂Rⁿ, -SR^{1 1}, -S0₂R^π, -SO3R^{1 1} (wherein R^{1 1} and R¹² are as hereinbefore defined), -OCH₂)_pNR^{1 !}R¹², -0(CH₂) N+R¹1R12R13

3 it and -0(CH₂) SO3R^{1 1} (wherein p, R^{1 1} and R¹² are as hereinbefore defined and R¹ is hydrogen or Cj.β alkyl);

R is hydrogen, hydroxy C\. alkyl, alkoxy or -O-Cj.β Acyl;

R⁴ is a group independently selected from C\.ζ alkyl (including cycloalkyl and cycloalkylalkyl), C .β alkenyl, and C₂.(5 alkynyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, oxo, -OR¹⁴, -C0₂R¹⁴, -NR¹⁴R¹⁵, -SR¹⁴, -StO)^ alkyl, -S0₂R¹⁴ and -SO3R¹⁴ (wherein R ⁴ and R¹⁵ are as hereinbefore defined );

R⁵ is a group independently selected from C .g alkyl (including cycloalkyl and cycloalkylalkyl), C2.6 alkenyl and C₂-6 alkynyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, oxo, -OR¹⁴, -C0₂R¹⁴ _? -NR¹⁴R¹⁵, -SR¹⁴, -S(0)Cj.₆ alkyl, -S0₂R¹⁴ and -SO3R¹⁴ (wherein R¹⁴ and R 5 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 -NR^R¹^ (wherein R¹⁴ and R¹⁵ are as hereinbefore defined);

R > and R⁷ are independently selected from hydrogen and Cj.g alkyl; and

X is an aromatic or non-aromatic monocyclic or bicyclic 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 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 derivatives thereof.

2. A compound as claimed in Claim 1 wherein:

_D o 1 is 0, 1, or 2;

n is I or 2; and

R¹, R and R? are all hydrogen; and

R is hydrogen or hydroxy

3. A compound as claimed i Claim 2 which is a trans isomer wherein:

(a) l is O or l;

n is 2; and

R⁴ and Rβ are groups independently selected from C . alkyl (including cycloalkyl and cycloalkylalkyl), C2-6 alkenyl and ^2-6 alkyn l. wherein said alkyl, alkenyl, or alkynyl group may be substituted by one or more hydroxy groups, or R⁴ and R⁵, together with the carbon atom to which they are attached, form a C3.7 spiro cycloalkyl group which can be substituted by one or more hydroxy groups; or

(b) l is O or l;

n is 2;

R² is a phenyl group which may be substituted by one or more atoms or groups independently selected from halogen, cyano, hydroxy, nitro, carboxyl, phenyl, phenoxy, bεnzyloxy, -COR¹1, -C0₂R! 1, -CONR^{1 J}R¹², -CH2OR¹1, -NR^Ϊ JR ², -NHCOR^{1 1}, -NHSO2R^{1 1}, -SR^{1 1}, -S02R ¹, -SO3R^{1 1} (wherein R^{1 1} and R ² are independently selected from hydrogen, Cμg alkyl and phenyl), -0(CH₂) NR^πR¹², -0(CH₂) NR⁺ UR12R13 and -0(CH₂) SO3R^{1 1} (wherein p is an integer of from 1 to 4, R^{1 1} and R¹² are as hereinbefore defiήεd^~and R¹³ is hydrogen or Cj.β alkyl);

R⁴ and R^ are groups independently selected from Cj.β alkyl (including cycloalkyl and cycloalkylalkyl), C₂.g alkenyl and C₂-6 alkynyl, wherein said alkyl, alkenyl, or alkynyl group may be substituted by one or more hydroxy groups, or R⁴ and R^,

3 I together with the carbon atom to which they are attached, form a C3.7 spiro cycloalkyl group which can be substituted by one or more hydroxy groups; or

(c) l is O or l:

n is 2;

R² is a phenyl group which may be substituted by one or more atoms or groups independently selected from halogen, cyano, hydroxy, nitro, carboxyl, phenyl, phenoxy, benzyloxy, -COR¹1, -CO2R 1, -CONR^{1 J}R¹², -CH2OR 1, -NR^R¹², -NHCOR^{1 1}, -NHS02R^{1 1}, -SR^{1 1}, -S0₂R^π, -SO3R^{1 1} (wherein R¹¹ and R¹² are independently selected from hydrogen, Cι_6 alkyl and phenyl), - 0(CH₂) NR^{1 ]}R¹² ₍ -0(CH₂) NR^{+ l ]}R¹²R¹³ and -0(CH₂) SO3R¹1 (wherein p is an integer of from 1 to 4, K^{1 1} and R¹² are as hereinbefore defined and R¹³ is hydrogen or C\. alkyl);

R⁴ and R^ are groups independently selected from C\.ζ alkyl (including cycloalkyl and cycloalkylalkyl), C₂.g alkenyl and C₂.β alkynyl, which groups can be substituted by one or more hydroxy groups; and

X is a fused phenyl, naphthyl, pyrryl, thienyl, or pyridyl group;

4. A compound as claimed in Claim 1 which is:

(+-)-trans-3-ethyl-2,3,4,5-tetrahydro-3-((2R)-2-hydroxybutyl)-5-phenyl-l,4- benzothiazepine 1,1 -dioxide;

(+-)-trar-s-l-(3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l,4-^"benzothiazepin-3- yl-2(R)-2-butanoI S.S-dioxide;

(+-)-trans-l-(3-emyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l,4-benzothi--zepin-3- yl)-3-butanol S.S-dioxide;

(+-)-trans- 1 -(3-ethyI-2,3,4,5-tetrahydro-7-methoxy-5-phenyl- 1 ,4-benzothiazepin-3- yl)-2(R)-2-butanol S.S-dioxide;

(+-)-tτans-l-(3-eΛyI-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-7-methoxy-l,4- benzothiazepin-3-yl)-2(R)-2-butanol S,S-dioxide;

(+-)-trans- 1 -(3-ethyl-5-(4-hydroxyphenyl)-2,3 ,4,5-tetrahydro- 1 ,4-benzothiazεpin-3- yl)-2(R)-2-but--nol S.S-dioxide 0.5 hydrate;

(+-)-trans-3-butyl-3-ethyl-2.3,4.5-tetrahydro-5-(4-hydroxyphenyl)-l,4- benzothiazepine 1,1 -dioxide hydrochloride;

(+-)-cis-3-ethyl-2,3,4,5-tetrahydro-3-(4-hydroxybutyl)-5-phenyl-l,4- benzothiazepine 1,1 -dioxide hydrochloride;

(+-)-trans-3-ethyl-2,3,4,5-tetrahydro-3-(4-hydroxybutyl)-5-phenyl-l,4- benzothiazepine 1,1 -dioxide;

(+-)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7-hydroxy-5-phenyI-l,4- benzothiazepine 1,1 dioxide;

(+-)-trans- 1 -(3-ethyl-2,3,4.5-tetrahydro-5-phenyl-l ,4-benzothiazepin-3-yl)-4,4,4- trifluoro-(2S)-2-butanol- S,S-dioxide;

(+-)-trans-l-(3-e yl-2,3,4,5-tetτahydro-7-meώoxy-5-phenyl-l,4-benzothiazepin-3- yl)-4,4,4-trifluoro-(2S)-2-butanol-S,S-dioxide;

(+-)-trans-3-Ethyl-2,3,4,5-tetrahydro-3-(3-hydroxybutyl)-5-phenyl-l,4- benzothiazepine 1,1 -dioxide;

(+-)-traιιs-3-Ethyl-2,3,4,5-tetrahydro-3-(2(R)-2-hydroxybutyl)-5-(4- hydroxyphenyl)- 1 ,4-benzothiazepine 1 , 1 -dioxide;

(+-)-trans- 1 -(3-Ethyl-5-(4-fluorophenyl)-2.3,4,5-tetrahydro-l ,4- ber_zothiazepin-3-yl)-2(R)-2-butanol S.S-dioxide;

(+-)-trans-l-(3-Ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyI-l,4 berιzothiazepin-3-yl)-4,4₁4-trifluoro-2(S)-2-butanol S,S-dioxide;

(+-)-trans- 1 -(3-Ethyl-2,3 ,4,5-tetrahydro-8-methoxy-5-phenyl- 1 ,4- benzothiazepin-3-yl)-4,4,4-trifluoro-2(S)-butanol S,S-dioxide;

(+-)-trans-l-(3-ethyl-23,4,5-tetrahydro-7.8-dimethoxy-5-phenyl-l, 4- benzothiazepin-3-yl-2(R)-2-butanol S,S dioxide;

(+-)-trans-l-(3-Ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l,4- benzothiazepin-3-yl)-4,4,4-trifluoro-2-butanol S.S-dioxide;

(+-)-tr-ιr-s-l-(3-Eώyl-2,3,4,5-tetrahydro-7,8-dime-hoxy-5-phenyl-l,4- benzothiazepin-3-yl)-3,3,4,4,4-pentafluoro-2-butanoI S.S-dioxide;

(+-)- trans-3-((3-ethyl-2,3,4,5-tetrahydro-5-phenyl-3-(4,4,4-trifluoro-2- hydroxy butyl)- 1, 4-benzothiazepin-8-yl)oxy)prop--nesulfonic acid 1, 1-dioxide;

(+-)-trans-3-((3-ethyl-2,3,4,5-tetrahydro-3-(2-hydroxybutyl)-5-phenyl-l,4- benzoΛiazepin-8-yl)oxy)eώylι_rimeΛylarnmonium iodide 1, 1-dioxide;

(+-)-trans- 1 -(3-Ethyl-2,3,4,5-tetrahydro-7.8-diethoxy-5-phenyl-l ,4- benzothiazepin-3-yl)-4,4,4-trifluoro-2-butanol S,S-dioxide;

(+-)-trans-3-((3-ethyl-2.3,4.5-tetrahydro-5-phenyl-3(4,4,4-trifluoro-2- hydroxybutyl)- 1 ,4-benzothi-ιzepin-8-yl)o\ )ethyltrimethyl--π-monium iodide

1.1 -dioxide:

3^3 (+-)-trans-3-((3-ethyl-2,3 ,4,5-tetrahydro-3-(2-hydroxybutyl)-5-phenyl- 1 ,4- benzothiazepin-8-yl)oxy)propanesulfonic acid 1,1 -dioxide; (+-)-trans-l-(3-ethyl-2,3₎4,5-tetrahydro-7,8-diethoxy-5-phenyl-l,4- benzothiazepin-3-yl)-2-butanol S.S-dioxide;

(+-)-trans-l-(3-(2,2,2-trifluoroeώyl)-2,3,4,5-terrahydro-7,8-dimethoxy-5- phenyl-1 ,4-benzothiazepin-3-yl)-4,4,4-trifluoro-2-butanol S,S-dioxide; (+-)-trans- 1 -(3-E-hyl-2,3,4,5-tetrahydro-7,8-dihydroxy-5-phenyl-l ,4- benzothiazepin-3-yl)-4,4,4-trifluoro-2-butanol S.S-dioxide; (+-)-trans- 1 -(3-ethyI-2,3 ,4,5-tetrahydro-7, 8-dimethoxy-5-phenyl- 1 ,4- benzothiazepin-3-yl)-l-butanol S,S-dioxide; (+-)-trans-l-(3-Ethyl-2,3,4,5-tetrahydro-7,8-dihydroxy-5-phenyl-l,4- benzothiazepin-3-yl)-2-butanol S.S-dioxide; (+-)-trans- 1 -(3 -ethyl-2 ,3 ,4 ,5-tetrahydro-8-methoxy-5-phenyl- 1 ,4- beriZθthiazeρin-3-yl)-4,4,4-trifluoro-l-but--nol S.S-dioxide; or (+- tr-ms-l-(3-emyl-2,3,4,5-tefrahydro-7,8-dihydroxy-5-phenyl-l,4- benzothiazepin-3-yl)-2-butanone S.S-dioxide

A compound, as claimed in claim 1 of 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, hydroxy, nitro, alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, aralkyl, alkaryl, -COR¹ ϊ, -CO2R¹ ^ -CONR^R¹², -CH2OR^{1 1}, -NR^R¹², -NHCOR^{1 1}, -NHSO2R^{1 1}, -SR^{1 1}, -S0₂Rⁿ and -SO3R¹ J wherein R¹ ^ and R¹² are independently selected from hydrogen, C_j-β alkyl and phenyl, wherein said alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, aralkyl and alkaryl groups are optionally substituted by one or more atoms or groups selected from halogen, hydroxy, nitro, nitrile, alkyl, alkoxy, -COR^{1 1}, -CO2R^{1 1}, -

SO3R^{1 1} wherein R^{1 1} is as hereinbefore defined and -NR¹⁴R¹⁵ wherein R¹⁴ and R¹5 are as hereinbefore defined;

R¹ is hydrogen or C 1.5 alkyl;

R² is an atom or group selected from hydrogen, Cj.g alkyl (including cycloalkyl and cycloalkylalkyl), C1-4 alkoxy, pyrryl, thienyl, pyridyl, 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, phenoxy, benzyloxy, -COR^{1 1}, -CO2R^{1 1}, -CONR^R¹², -CH2OR¹1, -NR¹ ΪR¹², -NHCOR^{1 1}, -NHS02R^{1 1}, -SR^{1 1}, -S02R^{1 1}, -SO3R^{1 1} (wherein R^{1 1} and R¹² re independently selected from hydrogen, Cj.g alkyl and phenyl), -0(CH2) NR¹ R¹², -0(CH₂) N⁺R^πR¹²R¹³ and -0(CH₂) SO3R^{1 1} (wherein p is an integer of from 1 to 4, R^{1 1} and R ² are as hereinbefore defined and R^ is hydrogen or C\.ζ alkyl);

R³ is selected from hydrogen, hydroxy and \.ζ alkyl;

R⁴ is a group independently selected from Cj.g alkyl (including cycloalkyl and cycloalkylalkyl), C2-6 alkenyl and C2-6 alkynyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, -OR¹⁴, -C0₂R¹⁴, -NR ⁴RΪ5 and -SO3R¹⁴ (wherein R¹⁴ and RΪ5 are independently selected from hydrogen and Cj.g alkyl);

R5 is a group independently selected from C₂.β alkyl (including cycloalkyl and cycloalkylalkyl), C₂.g alkenyl and C₂.g alkynyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, -OR¹⁴, -C0₂R¹⁴, -NR¹ R*5 and -SO3R¹⁴ (wherein R¹⁴ and R¹^ are independently selected from hydrogen and Cj.β alkyl);

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 independently selected from halogen, -OR¹⁴, -C0₂R¹⁴, -SO3R¹⁴ and -NR¹⁴R¹⁵ (where R¹⁴ and R¹^ are as hereinbefore defined;

R^ and R⁷ are independently selected from hydrogen and Cj.g alkyl; and

X is an aromatic or non-aromatic monocyclic or bicyclic ring system

3^^ 8/40375

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 derivatives thereof.

6. A compound of formula (I):

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, nitro, alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, aralkyl, alkaryl, -0(CH₂)_pSθ3R¹ ϊ, -0(CH₂)pNR^{1 !}R¹², -0(CH₂)_pN⁺R¹1R12R14 -COR¹ Ϊ, -CO2R^{1 1}, -CONR¹ *R¹², -CH70R 1, -NR¹ ΪR¹², -NHCOR 1, -NHSO2R^{1 !}, -SR¹1, -SO2R^{1 ]} -SO2NR^{1 J}R¹² and -SO3R^{1 ]} or R is a group -OCH2O- which forms a further ring attachεd to X wherein p is an integer of from 1 to 4, R ^_1_and R¹² are independently selected from hydrogen, Cj.β alkyl and phenyl and R¹⁴ is hydrogen or C -6 alkyl, wherein said alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, aralkyl and alkaryl groups are optionally substituted by one or more atoms or groups independently selected from halogen, hydroxy, nitro, nitrile, alkyl, alkoxy, -COR¹ , -CO2R¹ ', -SO3R^{1 !} wherein R¹ I is as hereinbefore defined and -NR¹⁴R!5 wherein R¹⁴ is as hereinbeforε defind and R¹³ is hydrogen or C].g alkyl;

3 ^~ζ R¹ is hydrogen or Cj.g alkyl;

R² i_s an atom or group selected from hydrogen, Cj.g alkyl (including cycloalkyl and cycloalkylalkyl), C]_ alkoxy, pyrryl, thienyl, pyridyl, 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, phenoxy, benzyloxy, -COR¹ ϊ, -C0₂R^{1 J}, -CONR ! R ², -O^OR 1, -NR^πR¹², -NHCOR^{1 1}, -NHSO2R^{1 1}, -SR^{1 1}, -S02R^{1 1}, -SO3R^{1 1} (wherein R^{1 1} and R ² are independently selected from hydrogen, C\.^ alkyl and phenyl), -0(CH₂) NR ¹R¹ , -0(CH₂) N⁺R^πR¹²R¹³ and -0(CH₂) SO3R¹1 (wherein p is an integer of from 1 to 4, R^ and R¹² are as hereinbefore denned and R!3 is hydrogen or C\. alkyl);

R is hydrogen, hydroxy C g alkyl, alkoxy or -O-Cμg Acyl;

R⁴ is a group independently selected from Cj.g alkyl (including cycloalkyl and cycloalkylalkyl), C₂.β alkenyl and C₂.g alkynyl, which groups are optionally substi selected from halogen, oxo, - alkyl, -S0₂R¹⁴ and -SO3R¹⁴ (wher

R5 is a group independently selected from C₂.g alkyl (including cycloalkyl and cycloalkylalkyl), C₂.g alkenyl and C2-6 alkynyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, oxo, -OR¹⁴, -C0₂R¹⁴, -NR^RΪS, -SR¹⁴,-S(0)Cμ₆ alkyl, -S0₂R¹⁴ and -SO3R¹⁴ (wherein R¹ and R¹^ are as hereinbefore defined);

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 independently selected from halogen, -OR¹⁴, -CO2R¹⁴, -SO3R¹⁴ and -NR¹⁴R^ (where R¹⁴ and R¹^ are as hereinbefore defined;

R6 and R? are independently selected from hydrogen and C\.₍, alkyl; and

X is an aromatic or non-aromatic monocyclic or bicyclic ring system

3± ^~> 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 derivatives thereof, for use in the prophylaxis or treatment of clinical conditions for which a bile acid uptake inhibitor in indicated.

Compounds of formula (I) having exceptional hypolipidaemic properties include:-

(-)-(RR)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazepine 1, 1-dioxide; (+-)-trans-3-((E)-2-butenyl)-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazepinel,l- dioxide;

(- -)-trans-3-e-hyl-2.3,4,5-terr--hydro-3-(3-methoxypropyl)-5-phenyl-l,4-benzothiazepine 1,1 -dioxide;

(+-)-trans- 1 -(3 -ethyl-2,3 ,4,5-tetrahydro-5-phenyl- 1 ,4-benzothiazepin-3 -yl)-2-butanoneS,S- dioxide;

(+-)-trans-l-(3-emyl-2,3,4,5-tetr-ιhydro-8-meΛoxy-5-phenyl-l,4-benzothi--zepin-3-yl)-2- butanone S,S-dioxide hydrochloride 1.1 hydrate;

(+-)-trans-3-(l-butenyl)-3-emyl-2.3,4,5-tetrahydro-5-phenyl-l,4-benzothiazepinel, 1-dioxide hydrochloride 0.4 hydrate;

(+-)-trans-3-(ethoxyethyl)-3-ethyl-2,3,4,5-tetrahy-uO-5-pheny dioxide hydrochloride hemihydrate;

(+-)-trans-3-(ethoxyme yl)-3-e yl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzotWa2£pinel,l- dioxide hydrochloride;

(+-)-trans-ethyl 3-(3-emyl-2,3,4,5-te-r--hydro-5-phenyl-l,4-benzothiazepin-3-yl)propionate 1,1 -dioxide;

(+-)-ϋ^ns-(E)-4-(3-eΛyl-2,3,4,5-tetr-ιhydro-5-phenyl-l,4-benzothiazepin-3-yl)-3-buten-2- one 1,1 -dioxide;

(+-)-2,3,4,5-tetrahydro-8-memoxy-5-phenylspiro(l,4-benzothiazepine-3,l-cyclohexane) 1,1 -dioxide;

(+-)-trans-3-butyl-3-eΛyl-2,3,4,5-tetrahydro-5-(4-pyridyl)-l,4-benzothia--epine 1, 1-dioxide; (+-)-trans-3-butyl-3-emyl-2,3A5-tetr--hydro-4-hydroxy-5-(4-py^ 1, 1-dioxide;

(+-)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-(2-thienyI)-l,4-benzothiazepine 1,1-dioxide; (+-)-tr--ns-3-butyl-3-eώyl-2,3,4,5-tetι^ydro-5-(lH^^ dioxide;

(+^■)- trans-3 -butyl-3 -ethyl-2,3 ,4,5-tetrahydro- 5 -phenylpyrido(4,3 -F)- 1 ,4-benzothiazepine 1,1-dioxide;

(+-)-trans-3-butyl-3-ethyl-3.4,5,7-te-rahydro-5-phenyl-2H-pynolo(3,4-F)-l,4- benzothiazepine 1.1 -dioxide 0.1 hydrate;

(+-)-tτans-3-butyl-3-eΛyl-2.3,4,5-tetrahydro-5-phenylthieno(2,3-F)-l,4-ben.^thiazepinel,l- dioxide;

331 (+-)-trans-3-ethyI-2,3,4,5-tetrahydro-5-phenyl-3-(4,4,4-trifluorobutyl)-l,4-benzothiazepine

1,1-dioxide;

(+-)--r- s-2.3,4,5-tetj--hydro-3-isopropyl-3-memyl-5-phenyl-1.4-benzothiazepine 1,1- dioxide 0.25 H₂0;

(+-)-tr-ms-3-((E)-2-Butenyl)-3-ethyl-2,3,4.5-tetr--hydro-5-phenyl-l,4-benzothiazepine;

(+-)-Cis-2,3,4,5-Tetrahydro-3-isopropyl-3-methyl-5-phenyl-l ,4-benzothiazepine 1,1-dioxide

0.66 H₂0;

(+-)-trans-3-(3-E-hyl-2,3,4,5-tetr-ώydro-5-phenyl-l,4-benzothiazepin-3-yl)propanoI 1,1 dioxide;

(+-)-tr- s-3-E-hyl-5-(4-Fluorophenyl)-2,3,4,5-tetrahydro-7-methoxy-3-(3-methoxypropyl)-

1,4-benzothiazepine 1,1-dioxide hydrochloride;

(+-)-2,3,4.5-Tetrahydro-7-methoxy-5-phenylspiro( 1 ,4-benzothiazepine-3 , 1 -cyclohexane)

1,1-dioxide;

(+-)-trans-l-(3-Emyl-2,3,4,5-tetr-ihydjo-7-memoxy-5-phenyl-l,4-benzothi--zepin-3-yl)-2- butanone S.S-dioxide hydrochloride;

(+-)- ans-3-butyI-3-emyl-2,3,4,5-tetrahyclro-5-phenybaphmo(3,2-F)-l,4-benzot-nazepine

1,1-dioxide;

(+-)-trans-l-(3-Emyl-2,3,4,5-tetr--hydro-7,8-dime oxy-5-phenyl-l,4-benzothi--zepin-3-yI)- 2-butanonε S,S-dioxide;

(+-)-trans-3-(l -butenyl)-3-emyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl -1 ,4- benzothiazepine 1,1-dioxide;

(+-)-trans- 1 -(3-Ethyl-2,3 ,4,5-tetrahydro-7.8-dimethoxy-5-phe yl- 1 ,4-benzothiazepin-3-yl)- 3-butanone S,S-dioxide;

(+-)-trans- 1 -(3-Ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl- 1 ,4-benzothiazepin-3-yl)-l - butanone S.S-dioxide;

(+-)-trans-l-(3-EΛyl-2,3,4,5-tetr- ycfro-7,8-dime&^^ 1 -butanone S,S-dioxide;

(+-)-trans-l-(3-emyl-2,3,4,5-ter^jahydro-7,8-dimemoxy-5-phenyl-l,4-benzotluazepin-3-yl)- 4,4,4-trifluoro-l -butanone S,S-dioxide;

(+-)-trans- 1 -(3-ethyl-2,3 ,4,5-tetrahydro-7,8-dimethoxy-5-phenyl- 1 ,4-benzothiazepin-3-yl)- 3,3,4,4,4-pentafluoro-2-butangne S,S-dioxide;

(+-)-rrans-l-(3-eώyl-2,3,4,5-tet-^ydro-7.8-dimeώoxy-5-phenyl-l,4-benzotlιi-ιzepin-3-yl)- 4,4,4-trifluoro-2-butanone S,S-dioxide;

(+-)-tr- s-3-emyl-2.3,4,5-tetr--hydro-7,8-dimethoxy-5-phenyl-3-(4,4,4-trifluorobutyl)-l,4- benzothiazepine 1,1-dioxide;

(+-)-tr--ns-l-(3-(2,2.2-trifluoroemyl)-2,3,4,5-te-r--hy-ho-7.8-dimemoxy-5-phenyl-l,4^ benzothiazepin-3-yl)-2-butanone S.S-dioxide;

? _o 0 (+-)-trans-l-(3-Ethyl-2,3,4.5-tetrahydro-7,8-diethoxy-5-phenyl-l,4-benzothiazepin-3-yl)-2- butanone S.S-dioxide;

(+- trans-3-((3-ethyl-2, ,4,5-tetrahydro-3-(2-oxobutyl)-5-phenyl- 1 ,4-bεnzothiazepin-8- yl)oxy)propanesulfonic acid 1,1-dioxide;

(+-)-trans-2-((3-e yl-2,3,4,5-tetrahycho-3-(2-oxobutyl)-5-phenyl-l,4-benzothiazep-n-8- yl)oxy)ethyltrimethylammonium iodide 1,1-dioxide;

(-)-(RR)-3-butyl-3-e yl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazepine 1,1-dioxide; (+-)-trans-l-(3-eΛyl-2,3,4,5-tetτahydro-8-meΛoxy-5-phenyl-l,4-benzothiazepin-3-yl)-2- butanone S,S-dioxide hydrochloride 1.1 hydrate;

(+-)-Cis-2,3,4,5-Tetrahydro-3-isopropyl-3-memyl-5-phenyl-l,4-berιzothiazepine 1,1-dioxide 0.66 H₂0;

(+-)-tr--ns-l-(3-Emyl-2,3,4,5-tetrahydro-7,8-dimemoxy-5-phenyl-l,4-benzothiazepin-3-yl)- 2-butanone S,S-dioxide;

3 i l

20) (+-)-2,3 ,4,5-Tetrahydro-5-phenylspiro(l ,4-benzothiazepine-3 , 1 '- cyclohexane) 1,1-dioxide, mp 177-179°C;

21 ) (+-)-T_ranS-2,3 ,4.5-te tτ-ιhydro-3-isopropyI-3-methyl-5-phenyl- 1 ,4- benzothiazepine 1,1-dioxide 0.25 H₂0, mp 130-132°C;

22) (+)-(S)-2,3,4,5-Tetrahydro-5-phenylspiro( 1 ,4-benzothiazepine-3 , 1 '- cyclohexane) 1,1-dioxide, mp 210-211°C;

23) (-)-(R)-2,3 ,4,5-Tetrahydro-5-phenylspiro( 1 ,4-benzothiazepine-3, 1 '- cyclohexane) 1,1-dioxide, mp 210-211°C;

24) (+-VTj2rj-5-2,3,4,5-te jahydro-3-isopropyI-3-methyl-5-phenyl-l,4- benzothiazepine hydrochloride, mp 211-213°C;

25) (÷-)-Cis-2,3,4,5-tetrahydro-3-isopropyl-3-methyl-5-phenyl-l ,4- benzothiazepine hydrochloride, mp 268-270°C;

26) (+-)-3-<iei.-Bmyl-2 ,4,5-tetrahydro-3-methyl-5-phenyl-l,4- benzothiazepiπe hydrochloride, mp 202-205°C;

27) (+-)-4,5-Dihydro-5-phenylspiro(l ,4-benzothiazepine-3-(2H), - cyclopentane) hydrochloride 0.25 H₂0, mp 224-226°C;

28) (+- 2,3 ,4,5-Tetr--hydro-5-phenylspiro( 1 ,4-benzothiazepine-3 , 1 '- cyclohexane) hydrochloride H 0.-mp 167-169°C (eff.);

29) (÷-)-5-(2-Fluorophenyl)-2.3,4,5-tetrahydrospiro(l .4-benzothiazepine- 3.1'-cyclohexane) 1.1 -dioxide, mp 160-161°C;

30) (÷-)-CJLs-3-(2,3.4,5-tetπ-hydro-3-memyl-5-phenyl-1.4-benzothiazepin-3- yl)propionic acid 1.1-dioxide 0.5 H₂0, mp 132-133°C;

-3 -i 31) I— )-Trans-Ethyl 3-(2.3,4,5)-tetrahydro-3-methyl-5-phenyl-l,4- beι_zothiazepin-3-yl)propioniate 1.1 -dioxide, mp 143-148°C;

32) (— )-Cis-Ethyl 5-(2,3,4,5-tetrahydro-3-methyl-5-phenyl-l,4- benzothiazepin-3-yl)valerate 1.1 -dioxide, mp 121-122°C;

33) (--)-Iιans-3-((E)-2-Butenyl)-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,4- benzothiazepine, mp 69-74°C;

34) ' f--)-Trans-3-Ethyl-2.3.4.5-tetrahydro-3-isopropyl-5-phenyl-l,4- benzothiazepinε 1,1-dioxide, mp 116-118°C;

35) (--)-Cis-3-i2Q-Butyl-3-ethyl-2.3,4.5-tetrahydro-5-phenyl-1.4- benzothiazepine 1 -oxide, mp 91-93°C;

36) (--)-Cis-3-iso-Buryl-3-ethyl-2.3.4.5-tetrahydro-5-phenyl-1.4- benzothiazepine 1,1-dioxide, mp 149-151°C;

37) (--VTrans-3 -iso.-B uty 1-3 -ethyl-2.3.4,5-tetrahydro- 5-pheny 1- 1 ,4- benzothiazepine 1 -oxide, mp 92-93°C;

38) (--)-1^2ns-3-jifl-Butyl-3-emyl-2.3.4,5-tetrahydro-5-phenyl-l,4- benzothiazepine 1,1-dioxide, mp 101-103°C;

39) (- -)-CJ5-3-Butyl-3-e-hyl-2,3,4,5-tetrahydro-5-(3-pyridyl)-l,4- benzothiazepine 1,1-dioxide, mp 60-61°C;

40) (*-)-Cis-EΛyl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazepine-3- carbaldεhyde 1,1-dioxide, mp 162-164°C;

41 ) (~-)-Cis-2, ,4,5-Tetrahydro-3-isopropyl-3-methyl-5-phenyl- 1 ,4- benzothiazepine 1,1-dioxide 0.66 H₂0, mp 119-120°C;

42) (^-J-Ir-ans-S-Ethyl-^.S^^-tetrahydro-S-isopropyl-S-phenyl- 1 ,4- benzothiazepine 1,1-dioxide, mp 121-124°C;

43) (÷-)-Cjs-3-Ethyl-2,3,4,5-tetrahydro-3-isopropyl-5-phenyl-l,4- bεnzothiazepine 1,1-dioxide, mp 150-152°C;

M) (--)-CJ£-3-Buty 3_-_ethyl-2.3 ,4,5-tetr--hydro-4-hydroxy-5-(3 -pyridyl)-l ,4- benzothiazepine 1,1-dioxide, mp 02-205°C;

45) (--)-J ail-.-3-(3-Emyl-2.3.4,5-tetr-Lhydro-5-phenyl-l .4-benzothiazepin-3- Opropanol 1,1-dioxide mp 164-165°C;

46) (^'--)-Ir--n≤-3-Ethyl-5-(4-Fluorophenyπ-2.3.4.5-tetπιhydro-7-methoxy-3-

j n (3-methoxypropyl)-1.4-benzodιiazepine 1,1-dioxide hydrochloride. mp I79-181°C;

47) (÷-)-Cis-3-Bun-I-3-emyl-2.3,4,5-tetr--hydro-5-phenylpyrido(4,3-F)-l,4- thiazepine 1,1-dioxide 0.333 H 0, mp 111-112°C;

48) (+-)-Cis-3-But>-l-3-e-hyl-2,3,4,5-tetrahydro-5-(lH-pynol-l-yl)-l,4- benzothiazepine 1.1 -dioxide, mp 50-52°C;

49) (÷-)-Ci5-3-Butyl-3-ethyl-2,3,4.5-tetrahydro-5-phenyl-7H-pynolo(3,4-F)- 1,4-thiazepine 1.1 -dioxide 0.125 H₂0, mp 75-77°C;

50) (+-)-2,3,4,5-Tetrahydro-7-memoxy-5-phenylspiro(1.4-ber-zothiazepiπe- 3,1-cyclohexanε) 1,1-dioxide, mp 142-143°C;

51) (+-)-Tj2ns-l-(3-Ethyl-2.3,4,5-tetrahydro-7-methoxy-5-phεnyl-l,4- benzothiazepm-3-yl)-2-butanone S.S-dioxide hydrochloride, mp 175- 176°C;

52) (+-)- Trans-3-butyI-3-ethyl-2,3,4,5-tetrahydro-5-phenylnaphtho(3,2-F)- 1,4-benzothiazepinε 1,1-dioxide, mp 128-131°C;

53) (+-)-1^3iis-3-Butyl-3-emyl-2,3,4,5-tetrahydro-5-(2-pyridyl)-l,4- benzothiazepine 1,1-dioxidε, mp 50-53°C;

55) (+-)-Irans- 1 -(3-Ethyl-2.3 ,4,5-tetrahydro-7,8-dimethoxy-5-phenyl- 1 ,4- benzothiazepin-3-yl)-2-butanone S.S-dioxide, mp 142-146° C;

56) (+-)-Tjans-3-(l-butenyl)-3-e yl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl -1,4-benzothiazepine 1,1-dioxide

58) (÷-)-Tjans-l-(3-Ethyl-2.3,4.5-tetrahydro-8-methoxy-5-phenyl-l,4- benzothiazepin-3-yl)-3-butanone S,S-dioxide

59) (+-)-Irans-l -(3-Ethyl-2.3.4,5-tetr--hydro-7,8-dimε-hoxy-5-phenyl-l,4- benzothiazepin-3-yl)-3-butanone S.S-dioxide

60) (+-)-1^2rJLS-l-(3-Eώyl-2.3.4.5-tetr--hydro-8-methoxy-5-phenyl-l,4- benzothiazepin-3-yl)-l -butanone S.S-dioxide

61) (+-)-i_--rj-i-l-(3-Ethyl-2.3.4,5-tetr--hydro-7,8-dimethoxy-5-phenyl-1.4-

7i benzo thiazepin-3-yl)- 1 -butanone S.S-dioxide

62) (+-)-Trans- 1 -(3-ethyl-2,3.4,5-tetrahydro-8-methoxy-5-pheny 1- 1 ,4- bειιzothiazεpin-3-yl)-4.4,4-trifluoro- 1 -butanonε S.S-dioxide

63) (÷-)-Trans-l-(3-ethyl-2.3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l,4- benzothiazepin-3-yl)-4,4.4-trifluoro-l -butanone S.S-dioxide

64) (+-)-Trans-l-(3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l,4- ber-zothiazepin-3-yl)-3,3,4,4,4-pentafluoro-2-butanone S,S-dioxide

/

65) (+-)-Traris-l-(3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l₎4- benzothiazepin-3-yl)-3,3,4,4.4-pentafluoro-2-butanone S,S-dioxide

66) (÷-)-Trans- 1 -(3-ethyl-2,3 ,4,5-tetr--hydro-7,8-dimethoxy-5-phenyl- 1 ,4- btπιzothi-ιzepm-3-yl)-4.4,4-rrifluoro-2-but--none S.S-dioxide

67) (+-)-Trans-l-(3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l,4- benzothiazepin-3-yl)-4,4,4-trifluoro-2-butanone S,S-dioxide

68) (+-)-Trans-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-3-(4,4, 4-trifluorobutyl)- 1,4-benzothiazepine 1,1-dioxide

69) (+-)-Trans-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-3-(4,4, 4-trifluorobutyl)-l,4-ber-zothiazepine 1,1-dioxide

70) (+-)-1^3ns-l-(3-(2^ -πifluoroe yl)-2^,4,5-tetι^ydro-8-methoxy-5- phenyl-1,4- benzothiazepin-3-yl)-2-butanonε S,S-dioxide

71) (-r-)-Tj2n5-l-(3-(2^,2-trifluoroemyl)-2,3,4,5-tetrahydro-7,8-dimethoxy-5- phεnyl-1,4- bεnzothiazepin-3-yl)-2-butanone S.S-dioxide

72) (+-)-J 2H-i- 1 -(3-Ethyl-2,3 ,4,5-tetr--hydro-9-mεthoxy-5-phenyl- 1 ,4- bε--zothiazεpin-3-yl 2-butanonε S,S-dioxide

73) (+-)-Tr-ms-3-((3-ethyl-2,3,4,5-tetrahydro-3-(2-oxobutyl)-5-phenyl-l,4- bcnzothiazepin-7-yl)oxy)propanesulfonic acid 1,1-dioxide

74) (+-)-χ sa---i-l-(3-E l-2_?3₎4,5-tetrahydro-7,8-diethoxy-5-phεnyl-1.4- benzothiazepin-3-yl)-2-butanone S.S-dioxide

75) (+-)-J 3ns-l-(3-Emyl-2.3.4,5-tetrahydro-7,8-dimethoxy-4-hydroxy-5-phenyl- 1.4-benzothiazepin-3-yl)-2-butanone S.S-dioxide

76) (+-)-Trans-3-((3-ethyl-2.3.4,5-te-rahydro-3-{2-oxobutyl)-5-phenyl-l,4- benzothiazepin-8-yl)oxy)propanesulfonic acid 1.1 -dioxide

2t≤ 77) (--)-Trans-2-((3-e-hyl-2,3.4.5-tetr--hydro-3-(2-oxobut 'l)-5-phenyl-1.4- ber-zothiazepm-7-yl)oxy)e yltrimethyl-immonium iodide 1.1 -dioxide

78) (+-)-Trar-s-2- (3-ethyl-2,3,4,5-tetrahydro-3-(2-oxobutyl)-5-phεnyl-l,4- beιιzomi--zepin-8-yl)oxy)e ylrτime ylammor-ium iodide 1,1-dioxide

A compound of formula (I) :

wherein

1 is an integεr of from 0 to 4;

n is an intεger of from 0 to 2;

R is an atom or group selected from halogen, cyano, nitro, alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, aralkyl, alkaryl, -0(CH₂)_pS03R¹ *, -0(CH₂)pNR^{1 J}R¹², -O CH^pN+R¹ iR¹²R¹⁴, COR¹1, -C0₂R^{! l}, -CONR¹ ΪR¹², -CH2ORH, -NR¹ ^¹², -NHCOR^{1 1}, -NHSO2R^{1 1}, -SR^{1 1}, -S0₂Rⁿ, -S0₂NR^{1 1}R¹², -SO3R^{1 1}, wherein p is an integer from 1 to 4, R ¹ and R¹² are independently selεctcd from hydrogen. Cμg alkyl and phenyl, and R¹⁴ is hydrogen or C 1-6 alkyl, or R is a group -OCH₂0- which forms a further ring attached to X, wherein said alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, aralkyl and alkaryl groups are optionally substituted by one or more atoms or groups selεctcd from halogen, nitro, nitrile, alkyl, alkoxy, -COR^{1 1}, -CO2R^{1 1}, -SO3R^{1 1} whεrein R^{1 1} is as herεmbεforε dεfined and - ^R^ wherein R ⁴ is as hereinbefore defined and R¹^ is hydrogen or Cj- alkyl;

R¹ is hydrogen or C - alkyl;

R² is an atom or group selected from hydrogen. C\. alkyl (including cycloalkyl and cycloalkylalkyl), Cι_4 alkoxy. pyrryl, thienyl. pyridyl, 1,3-benzodioxolo, phenyl and naphthyl, which groups are optionally substituted by one or more atoms or groups indepεndently selεctcd from halogen, cyano. nitro, carboxyl, phenyl, phenoxy, benzyloxy, -COR¹1, -CO^R¹1. -CONR¹ 1R12, -CHoOR^{1 1}. -NR^{1 J}R¹²,

?n -NHCOR¹ -NHSO R^{1 ]} , -SR^{1 ]}, -S0₂Rl -SO3R^{1 ]} (wherein R^{1 ]} and R¹² are as herεinbεfore defined). -OCCH^pNR^{1 ]}R¹². -0(CH₂)_pN⁺R^{1 Ϊ} R^R^ and -0(CH₂)_pS03R¹ (wherein p, R¹ ' and R¹² are as hereinbefore defined and R is hydrogεn or C]_ alkyl);

R³ is hydrogen, OH, C_j.β alkyl. Cj-6 alkoxy or -OCj.g acyl;

R⁴ is a group independently selected from C\_β alkyl (including cycloalkyl and cycloalkylalkyl), C2-6 alkenyl and C₂_6 alkynyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, oxo, Cι_ alkoxy, -C0₂R¹⁴, -NR¹⁴R¹⁵, -SR¹⁴, -S(0)Ci-₆ alkyl, -S0₂R¹⁴ -SO3R¹⁴ (wherein R¹⁴ and R¹⁵ are hereinbefore defined);

R^D is a group independently selected from C₂-6 alkyl (including cycloalkyl and cycloalkylalkyl), C _6 alkenyl, and C₂-6 alkynyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, oxo, C alkoxy, -C0₂R¹⁴, -NR¹⁴R¹⁵, -SR¹⁴, -S(O) Ci-₆ alkyl, -S0₂ R¹⁴, -SO3R¹⁴ (wherein R¹⁴ and R¹* are hereinbefore defined);

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 independently selected from halogen, Cj.g alkoxy, -C0₂R¹⁴, -SO3R¹⁴ and -NR^R¹^ (wherε R¹⁴ and R¹^ are as hereinbefore defined);

R" and R? are independently selected from hydrogen and C 1 _ alkyl; and

X is an aromatic or non-aromatic monocyclic or bicyclic ring system having from 5 to 10 carbon atoms (including the two carbon atoms fom-ing 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 when 1 is an integer of from 0 to 4, R¹ = R .= R = H, R3 = H or OH, R² = unsubstituted phenyl or phenyl substituted by one or more atoms or groups independently selected from halogen, nitro. phenylalkoxy, Cj_4 alkoxy, C_j- alkyl and -0(CH₂)_pSθ3R¹ * wherein p and R¹ ' are as hereinbeforε defined, wherein said phenylalkoxy, alkoxy and alkyl groups are optionally substituted by one or more halogen atoms, and X is a fused phenyl ring, then R⁴ is other than a Ci-

sc straight alkyl group and R^ is other than a C₂_5 straight alkyl group, and salts, solvates and physiologically functional derivatives thereof.

2. A compound as claimed in claim 1 which is a trans isomer wherein

1 is 0, 1 or 2:

n is 1 or 2;

R¹, R⁶ and R⁷ are all hydrogen;

R³ is hydrogen or hydroxy; and

X is a fused phenyl, naphthyl, pyrryl, thienyl or pyridyl, group.

3. A compound as claimed in claim 1 or claim 2 wherein

1 is 0 or 1;

n is 2; and

R² is pyrrj'l, thienyl, pyridyl, phenyl or naphthyl, .such groups being optionally substituted by one or more atoms or groups independεntly sεlεctcd from halogen, cyano, nitro, carboxyl, phenyl, phenoxy, benzyloxy, -COR¹ !,

-CO2R¹ -CONR¹ *R¹², -CH2OR¹1, -NR¹ !R ², -NHCOR¹1,

-NHSO2R^{1 1}, -SR^{1 1}, -SO2R^{1 1}, -SO3R^{1 1} (wherεin R^{1 1} and R¹² are independεntly sεlected from hydrogεn, Cj- alkyl andphεnyl),

-0(CH₂)pNRⁿR¹², -0(CH₂)N+R ¹R¹ R 3 and -0(CH₂)_pS0₃R 1 (whεrein p is an integer of from 1 to 4, R^{1 1} and R¹² are as hereinbefore definεd and R¹³ is hydrogεn or C .ζ alkyl).

3 ⁽ 1 A compound as claimed in Claim 1 which is :

(-)-(RR)-3-butyl-3-ethyl-2.3,4.5-tetrahydro-5-phenyl- 1,4-benzothiazepine 1,1- dioxide:

(+-)-trans-3-((E)-2-butεnyl)-3-εthyl-2,3,4.5-tεtrahydro-5-phεnyI-l,4- benzothiazepine 1 , 1 -dioxidε;

(+-)-trans-3-ethyl-2,3,4,5-tetrahydro-3-(3-methoxypropyl)-5-phenyl-l,4- bεnzothiazepine 1,1-dioxide;

(+-)-trans-l-(3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazepin-3-yl)-2- butanoneS.S-dioxide;

(+-)-trans-l-(3-ethyl-2,3,4.5-tetrahydro-8-memoxy-5-phenyl-l,4-benzothiazepin-3- yl)-2-butanone S.S-dioxide hydrochloride 1.1 hydrate;

(+-)-trans-3-(l -butenyl)-3-ethyl-2.3,4,5-tetr-ihydro-5-phenyl-l ,4-benzothiazepinεl ,1- dioxidε hydrochloride 0.4 hydrate;

(+-)-trans-3-(ethoxyethyl)-3-ethyl-2.3,4,5-tetτahydro-5-phenyl-l,4- bεnzothiazepine 1,1 -dioxide hydrochloride hemihydrate;

(+-)-trans-3-(ethoxymethyl)-3-ethyl-2,3,4.5-tetrahydro-5-phenyl-l,4- benzothiazepinε 1 , 1 -dioxidε hydrochloride;

(+-)-trans-ethyl 3-(3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazepin-3- yl)propionatε 1,1 -dioxidε;

(+-)-trans-(E)-4-(3-ethyl-2,3 ,4,5-tetrahydro-5-phenyl- 1 ,4-benzothiazepin-3-yl)-3- buten-2-one 1,1 -dioxidε;

(+-)-2,3,4.5-teιir-Λydro-8-meώoxy-5-phenylspiro(l,4-benzothiazεpinε-3,l- cyclohexane) 1,1-dioxide;

(+-)-tι -s-3-butyl-3-eώyl-2,3,4.5-tetrahydro-5-(4-pyridyl)-l,4-bεr-zothiazepine 1,1- dioxide;

(+- t- ιs-3-butyl-3-ethyl-2,3,4,5-tetr--hydro-4-hydroxy-5-(4-pyridyl)-l,4- benzothiazεpine 1 , 1 -dioxide;

(+-)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-(2-tm^nyl)-l,4-bεnzoι-hiazεpinε 1,1- dioxide;

(+-Hrans 3^^yl-3-e yl-2,3,4,5-tetrahydro-5-(IH-pynol-l-yl)-l,4- benzothiazepine 1 , 1 -dioxide;

(+-)-trans-3-butyl-3-ethyl-2.3,4,5-tetrahydro-5-phenyipyrido(4,3-F)-l,4- benzothiazεpine 1,1-dioxide;

(+-)-trans-3-butyl-3-ethyl-3,4.5,7-tetrahydro-5-phenyl-2H-pynolo(3,4-F)-l,4- benzothiazepine 1.1 -dioxide 0.1 hydrate:

J? ? 0 (+-)-trans-3-butyl-3-ethyl-2.3,4.5-tetrahydro-5-phenylthieno(2,3-F)-l,4- benzothiazepine 1 ,1 -dioxide:

(+-)-tr--ns-3-ethyl-2.3,4₎5-tetrahydro-5-phenyl-3-(4,4,4-trifluorobutyl)-l,4- benzothiazepine 1 ,1-dioxide;

(+-)-trans-2,3,4,5-tetrahydro-3-isopropyl-3-methyl-5-phenyl- 1 ,4-benzothiazepine 1,1-dioxide 0.25 H₂0;

(+-)-trans-3-((E)-2-Butenyl)-3-εthyl-2,3,4,5-tetrahydro-5-phenyl-l,4- benzothiazepine;

(+-)-Cis-2,3,4,5-Tetrahydro-3-isopropyl-3-methyl-5-phenyl-l,4-benzothiazepine 1,1- dioxide 0.66 H 0;

(+-)-trans-3-(3-Ethyl-2,3,4.5-tetrahydro-5-phenyl-l ,4-benzothiazepin-3-yl)propanol 1.1 dioxide;

(+-)-trans-3-Ethyl-5-(4-Fluorophenyl)-2,3,4,5-tetrahydro-7-methoxy-3-(3- methoxypropyl)- 1,4-benzothiazepine 1.1 -dioxide hydrochloride; (-t-)-2,3,4,5-Tetrahydro-7-methoxy-5-phenylspiro(l,4-benzoUιiazepinε-3,l- cyclohexane) 1,1-dioxide;

(+-)-trans- 1 -(3-Ethy 1-2,3 ,4,5-tetrahydro-7-methoxy-5-phenyl- 1 ,4-benzothiazepin-3- yl)-2 -butanone S.S-dioxide hydrochloride;

(+-)- trans-3-butyl-3-ethyl-2,3,4.5-tetrahydro-5-phenylnaphtho(3_J2-F)-l,4- benzothiazepine 1,1 -dioxidε;

(+-)-trans-l-(3-Ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l,4- benzothiazepin-3-yl)-2-butanone S.S-dioxidε;

(+-)-trans-3-(l -butenyl)-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl -1 ,4- benzothiazepinε 1,1 -dioxidε;

(+-)-trans-l-(3-Ethyl-2,3,4,5-tεtrahydro-7,8-dimethoxy-5-phenyl-l,4- benzothiazεpin-3-yl)-3-butanone S,S-dioxide; (- )-trans-l-(3-E yl-2,3,4,5-tetrahycjO-8-meΛoxy-5-pte yl)-l -butanone S.S-dioxide;

(+-)-trans-l-(3-Ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l,4- bεnzothiazepin-3-yl)- 1 -butanone S,S-dioxide; (+-)-trans-l-(3-ethyl-2,3 ,4,5-tetrahydro-7,8-dimethoxy-5-phεnyl-l ,4- bεnzothiazepin-3-yI)-4.4,4-trifluoro- 1 -butanonε S.S-dioxide; (+-)-trans-l-(3-ethyl-2.3.4.5-tetrahydro-7,8-dimethoxy-5-phenyl-l,4- benzothi-izepin-3-yl)-3.3.4.4,4-pentafluoro-2 -butanone S.S-dioxide; (÷-)-trans-l-(3-ethyl-2,3.4.5-tetrahydro-7,8-dimethoxy-5-phenyl-l,4- bεnzothiazεpin-3-y])-4,4.4-trifluoro-2 -butanonε S,S-dioxide;

3 (+-)-trans-3-ethyl-2.3.4.5-tetrahydro-7.8-dimethoxy-5-phenyl-3-(4,4,4- trifluorobutyl)- 1 ,4-benzothiazepinε 1 , 1 -dioxide;

(÷-)-traris-l-(3-(2.2,2-trifluoroemyl)-2,3,4,5-tetr--hycii'θ-7,8-dimethoxy-5-phenyl- 1,4- benzothiazepin-3-yl)-2-butanone S.S-dioxide;

(+-)- trans- 1 -(3-Ethyl-2,3,4.5-tetrahydro-7,8-diεthoxy-5-phenyl- 1 ,4-benzothiazεpin- 3-yl)-2-butanone S,S-dioxide;

(+-)-trans-3-((3-ethyl-2,3,4,5-tetrahydro-3-(2-oxobutyl)-5-phenyl- 1 ,4- benzothiazepin-8-yl)oxy)propanesuIfonic acid 1,1-dioxide; (+-)-tra--≤-2-((3-eΛyl-2,3,4,5-tetrahydro-3-(2-oxoburyl)-5-phεnyl-l,4- benzotm^'a--epm-8-yl)oxy)eώyltrimeώylammonium iodide 1,1-dioxide;

A compound as claimed in claim 1 of the formula (la):

wherεin

1 is an intεgεr of from 0 to 4;

n is an intεgεr of from 0 to 2;

R is an atom or group selected from halogen, cyano, nitro, alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, aralkyl, alkaryl, -COR^1"1, -CO2R^{1 1}, -CONR¹ ΪR¹², -CH₂ORⁿ, -NR ^JR¹², -NHCOR^{1 1}, -NHS0 Rⁿ, -SR^{1 1}, -SO^R^{1 1}, -SO3R^{1 1} wherein R ¹ and R¹² are indεpεndεntly sεlεctcd from hydrogen, Cι_6 alkyl and phenyl, wherεin said alkyl, alkoxy, aryl, hεtεroaryl, aryloxy, arylalkoxy, aralyl and alkaryl groups are^'^-φtib ϊ-dly^{^} ϋbsntutεd by one or ore atoms or groups sεlεcted from halogen, nitro. nitrile. alkyl, alkoxy, -COR^{1 !}, -CO7R¹¹, -SO3R¹ i whεrεin R^{1 1} is as hεrεinbεfore dεfinεd and -NR^R¹^ whεrεin R¹⁴ and R¹^ arε as hεrεinbεfore defined

R¹ and R³ are indεpendently selected from hydrogen and Ci- alkyl:

31»L R is an atom or group selected from hydrogen, Cj.g alkyl (including cycloalkyl and cycloalkylalkyl), C_j-4 alkoxy, pyrryl, thienyl, pyridyl, 1,3-benzodioxolo, phenyl and naphthyl, which groups are optionally substituted by one or more atoms or groups independently selεcted from halogen, cyano, nitro, carboxyl, phenyl, phenoxy, bεnzyloxy, -COR^{1 ]}, -O R¹ -CONR^R¹², -O^OR ¹, -NR^{1 J}R¹², -NHCOR^{1 1}, -NHS0₂R! 1, -SR¹ !, -S0₂R^] 1, -SO3R^{1 ]} (wherein R^{1 J} and R¹² are independently selected from hydrogen, C]_6 alkyl and phenyl), -0(CH₂) NR¹ R¹², -0(CH₂) N+R^R^R^ and -0(CH ) SO3R^{1 1} (wherein p is an integer of from 1 to 4, R^{1 1} and R¹² are as hereinbefore defined and R¹³ is hydrogen or C\.(, alkyl);

R⁴ is a group independently selected from C\. alkyl (including cycloalkyl and cycloalkylalkyl), C .g alkenyl and C _6 alkynyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, C -4 alkoxy, -C0₂R¹⁴, -NR¹⁴R!5, -SO3R¹⁴ (wherεin R¹⁴ and R^Ϊ5 are indepεndεntly selected from hydrogen and C\.ζ alkyl) and R^COR ⁷ where R¹^ is a Cι_4 alkylenε group and R ⁷ is a Cι_4 alkyl group;

R5 is a group indεpεndεntly selεctcd from C₂_6 alkyl (including cycloalkyl and cycloalkylalkyl), C₂.g alkεnyl and C .β alkynyl, which groups arc optionally substitutεd by one or more atoms or groups independεntly sεlected from halogεn, C1-4 alkoxy, -C0₂R¹⁴, -NR¹⁴Rl5, -SO3R¹⁴ (wherεin R¹⁴ and R¹⁵ are independently selected from hydrogen and C\. alkyl) and -R^COR¹⁷ where R¹^ is a C}_4 alkylenε group and R¹⁷ is a C1.4 alkyl 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 morε atoms or groups independently selected from halogen, Cι_ alkoxy, -C0₂R¹⁴, -SO3R¹⁴ and -NR¹⁴R¹⁵ (where R¹⁴ and R¹⁵ are as hereinbεfore defined;

R6 and R? are indepεndεntly selected from hydrogen and C\. alkyl; and

X is an aromatic or non-aromatic monocyclic or bicyclic ring system having from 5 to 10 carbon atoms (including the two carbon atoms forming part of the thiazepinε ring) whεrein optionally one or morε of thε carbon atoms is/arc rεplacεd by hεtεroatom(s) indεpεndεntly sεlectεd from nitrogen, oxygen and sulphur; with the proviso that when 1 is an intεger of from 0 to 4, R¹ = R = R = R7 = j-j, R²

= unsubstitutεd phεnyl or phenyl substituted by one or more atoms or groups independεntly selected from halogen, nitro, phenylalkoxy, Cι_4 alkoxy, C - alkyl and -0(CH₂) SO3R¹ * wherein p and R¹ * arε as hereinbeforε defined, wherein said

" p phεnylalkoxy, alkoxy and alkyl groups arε optionally substitutεd by one or more halogen atoms, and X is a fused phenyl ring, then R⁴ is other than a C_j.β straight alkyl group and R³ is other than a C₂-5 straight alkyl group; and

salts, solvates and physiologically functional derivatives thereof.

6. A compound of formula (I) :

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 selεctcd from halogen, cyano, nitro, alkyl, alkoxy, aryl, hctεroaryl, aryloxy, arylalkoxy, aralkyl, alkaryl, -0(CH2 Sθ3R¹¹, -0(CH₂)P^{NR1 1R12}. -0(CH2)pN⁺ R¹¹R¹²R¹⁴, -COR^{1 1}, -C0₂Rⁿ, -CONR¹ iR¹², -CH2OR¹1, -NR¹ ΪR¹², -NHCOR¹1, -NHSO2R¹1, -SR¹1, -SO2R¹ *, "S^NR¹ JR¹², -SO3R¹ ϊ whεrein p is an integer of from 1 to 4, R¹1 and RΪ2 are indεpendently selεctεd from hydrogen, C\.£ alkyl and phenyl, and R ⁴ is hydrogen or C\^ alkyl, or R is a group -OCH2O- whicrrfόrrns a furtheT^~πng attached to X, wherεin said alkyl, alkoxy, aryl, hεtεroaryl, aryloxy, arylalkoxy, aralkyl and alkaryl groups arε optionally substitutεd by onε or morε atoms or groups sεlεcted from halogen, nitro, nitrile. alkyl, alkoxy. -COR¹ , -CO2R¹¹, -SO3R¹¹ wherεin R¹ is as hεreinbεfore dεfinεd and -NR^R¹^ wherein R¹⁴ is as hereinbεforε defined and R¹³ is hydrogen or C\^ alkyl;

3? R¹ is hydrogen or C g alkyl;

R² is an atom or group selected from hydrogen, C]_ alkyl (including cycloalkyl and cycloalkylalkyl), Cj- alkoxy, pyrryl, thienyl, pyridyl, 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, phenoxy, benzyloxy, -COR 1, -C0₂R^{] ]}, -CONR¹ JR¹², -CH2OR¹1, -NR^{1 !}R¹², -NHCOR^{1 1}, -NHS0₂R^{1 1}, -SR^{1 1}, -S0₂R^{1 1} -S03R^{1 1} (wherεin R^{1 1} and R¹² arε as hereinbefore defined), -0(CH₂)_pNR^{1 l}Rⁿ, -OfCH^pN+R¹ ! R¹²R^{1 3} and -0(CH₂)_pSθ3R^{1 ]} (wherein p, R^{1 !} and R¹² are as hereinbefore defined and R¹³ is hydrogen or C\.(. alkyl);

R³ is hydrogen, OH, Cj.β alkyl, alkoxy or -OCj-6 acyl;

R⁴ is a group independently selected from Cι_6 alkyl (including cycloalkyl and cycloalkylalkyl), C₂_ alkenyl and C₂-6 alkynyl, which groups are optionally substituted by onε or morε atoms or groups indεpendently selεctcd from halogen, oxo, C1- alkoxy, -C0₂R¹⁴, -NR¹⁴R¹⁵, -SR¹⁴, -S(0)Cι.₆ alkyl, -S0₂R¹⁴, -SO3R¹⁴ (wherein R¹⁴ and R¹^ are as hεreinbeforε described);

R^ is a group independently selected from C2- alkyl (including cycloalkyl and cycloalkylalkyl), C2- alkenyl, and C2. alkynyl, which groups are optionally substituted by onε or more atoms or groups indεpεndεntly sεlected from halogεn, oxo, C1-4 alkoxy, -C0₂R¹⁴, -NR¹⁴R¹⁵, -SR¹⁴, -S(0)Cι.₆ alkyl, -S0 R¹⁴ -SO3R¹⁴ (wherein R¹ and R¹5 are as hεrεinbεfore defined);

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 independently sεlεctcd from halogen, C\. alkoxy, -C0₂R¹4, -SO3R¹⁴ and -NR^R¹^ (where R¹⁴ and R¹5 are as hereinbεforε dεfinεd;

Ro and R⁷ arε independently selεctεd from hydrogεn and^'Cj. alkyl; and

X is an aromatic or non-aromatic monocyclic or bicyclic ring system having from 5 to 10 carbon atoms (including the nvo carbon atoms forming part of the thiazepine ring) wherein optionally one or more of the carbon atoms is/are replaced by hetεroatom(s) independently selected from nitrogen, oxygen and sulphur,

313 with thε proviso that whεn 1 is an intεgεr of from 0 to 4, R¹ = R^ = R7 = H, R3 = H or OH, R² = unsubstituted phenyl or phenyl substituted by one or more atoms or groups independently selected from halogen, nitro, phenylalkoxy, C1.4 alkoxy, Cι_ alkyl and -0(CH₂)pSO3R¹1 wherεin p and R¹ J are as hereinbefore definεd, whεrεin said phenylalkoxy, alkoxy and alkyl groups are optionally substituted by one or more halogen atoms, and X is a fused phenyl ring, then R⁴ is other than a Cι_6 straight alkyl group and R^ is other than a C9.5 straight alkyl group, and

salts, solvates and physiologically functional derivatives thereof for use in therapy,

:?? 4) 3- Ethyl-3-methyl-2, 3,4, 5- tetrahydro- 5 -phenyl -1 ,4-benzothiazepine, mp 124-125°C;

5) (+)- 3, 3 -Die hyl -2, 3, , 5 -tetrahydro -5 -phen l -1,4-benzothiazepine 1,1-dioxide, mp 100-102°C;

6) 3 -Butyl- 2, 3, , 5 -tetrahydro -3 -methyl -5 -phenyl -1,4-benzothiazepine

1,1-dioxide, mp 103-104°C;

7) 3 -Methyl- 3 -propyl-2, 3 ,4, 5-te rahydro-5-phenyl-1 ,4-benzothiazepine

1,1-dioxide, mp 120-121°C;

8) 3, 3-Diethyl-2, 3,4,5-tetrahydro-5-phenyl-1 ,4-benzothiazepine 1,1-dioxide, mp 115-116°C;

9) (+)-IraQS-3-Butyl-3-ethyl-2, 3.4, 5-tetrahydro-5-phenyl-1,4-benzothiazepine 1,1-dioxide, mp 101 C;

10) (+) -J_r_ar--i-2,3,4, 5-Tetrahydro- 3-methyl-5-phenyl- 3 -propyl-1,4- benzothiazepine 1,1-dioxide, mp 129-130°C;

11) (-) -3,3-Diethyl- 2,3,4, 5- etrahydro- 5-phenyl- 1,4-benzothiazepine 1,1-dioxide, mp 101-103°C;

12) 3-Ethyl-2, 3,4, 5-tetrahydro-3-methyl-5-phenyl-1,4-benzothiazepine, mp 110-112°C;

13) 3-Ethyl-2 ,3,4,5-tetrahydro- 3-methyl-5-phenyl- 1 ,4-benzothiazepine hydrochloride 0.25H-0, mp 162-164°C (eff.);

14) 3 -Ethyl-2,3,4,5- tetrahydro- 3 -meth l-5 -phen l -1,4-benzothiaze ine 1,1-dioxide, mp 128-129°C;

15) 3,3-Die h l-2,3,4,5- etrahydro- 5-phenyl-1,4-benzothiazepine hydrochloride, mp 211-214°C;

311 16) (+-) -2,3,4, 5 -Tetrahydro- 3 -me thyl -5 -phenyl -3 -propyl- 1,4-benzothiazepine, mp 101-103 C;

17) 2,3,4,5-Tetrahydro-3-methyl-5-phenyl-3-propyl-l ,4-benzothiazepine, mp 72-74 C;

18) 3-Ethyl-2, 3,4, 5 -tetrahydro- 5-phenyl-3-propyl- 1,4-benzothiazepine hydrochloride 0.25H.O, mp 205-207°C;

19) -Eth l-2, 3, , 5-tetrahydro-5-phenyl-3-propyl- 1 ,4-benzothiazepine 1,1-dioxide 0.25H₂O, mp 115-118°C;

20) 2, 3, 4, 5-Tetrahydro-5-phenyl-3, 3-dipropyl- 1, -benzo hiazepine hydrochloride, 209-211°C;

21) 3-Ethyl-2, 3 ,4, 5-tetrahydro-5-phenyl- 3 -propyl- 1, -benzothiazepine 1,1-dioxide hydrochloride 0.33H.O, 206-209°C;

22) 2, 3,4, 5 -Te rahydro-5 -phen l-3.3-diprop l -1, -benzothiazepine 1,1-dioxide, mp 104-106°C;

23) 3, 3 -Dibutyl-2, 3 ,4, 5 -tetrahydro- 5-phenyl -1 ,4-benzo hiazeυine hydrochloride, mp 209-212°C;

24) 3-Butyl-2, 3 ,4, 5-tetrahydro-3-methyl-5 -phenyl- 1,4-benzothiazepine hydrochloride, mp 203-205°C;

25) 3-Butyl-3-ethyl-2,3,4,5-tetrahydro- 5-phenyl-1,4-benzo hiazepine hydrochloride, mp 205-207°C;

26) 3-Butyl-3-eth 1-2, 3,4 ,5- tetrahydro-5-p^'nen 1-1,4-benzo hiazepine 1,1-dioxide hydrochloride. mp 209-212°C;

27) 2,3,4, 5 -Te rahydro- 3 -methyl- 3-pentyl - 5 -phenyl - 1. -benzo hiazepine maleate. mp 182-183°C;

318 28) 3 -Ethyl-2, 3,4,5-tetrahydro-5 -phenyl-3-propyl-1,4-benzothiazepine hydrochloride, mp 198-200°C;

29) (+- )-Cl£-3-Butyl-3-ethyl-2, 3,4,5 -tetrahydro-7-me hyl-5 -phenyl- 1,4-benzothiazepine 1,1-dioxide, mp 138-140°C;

30) (+-)-C_is_-3-Butyl-3-ethyl-2, 3, 4, 5-tetrahydro- 7-methoxy-5-phenyl- 1,4-benzothiazepine, light yellow oil;

31) (+-)-Trans-3-Butvl-3-ethyl-2.3.4.5-tetrahydro-7-mechoxy-5-phenyl- 1,4-benzothiazepine, light yellow oil;

32) (+-)-C_is.-3-Butyl- 3-ethyl- 2, 3,4,5- etrahydro-7 -methoxy- 5 -phenyl- 1,4-benzothiazepine 1,1-dioxide, mp 113-115 C;

33) (+-)-C_is-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl- 1,4-benzothiazepine 1-oxide, mp 103-105°C;

34) (+-) -Trans- 3-Butyl- 3 -ethyl-2, 3,4, 5-tetrahydro-7-methoxy- 5-phenyl- 1,4-benzothiazepine 1,1-dioxide hydrochloride, mp 199-201°C;

35) (+-)-T£ans -3 -Butyl- 3-ethyl-5-phenyl-2 , 3,4, 5-tetrahydro- 1,4- benzothiazepine 1-oxide, mp 98-101°C;

36) (+-) -Trans.- 3-Butyl-3-ethyl- 2, 3, 4, 5-tetrahydro- 5-phenyl-1,4- benzothiazepine 1-oxide, mp 133-136 C;

37) (+-)-Cis-7-Chloro- 3 -butyl- 3-ethyl- 2, 3,4,5- tetrahydro-5-phenyl- 1,4-benzothiazepine 0.4 toluene, light yellow oil;

38) (+- ) -Trans- 7-Chloro- 3 -butyl - 3 -ethyl - 2,3,4,5- tetrahydro- 5 -pheny1- 1,4-benzothiazepine 0.3 toluene, light yellow oil:

39) ⁽+-) -Trans-3-Butyl-7 -Chloro- 3-ethyl-2,3,4, 5- etrahydro-5-phenyl- 1,4-benzothiazepine 1.1-dioxide. mp 100-102 C;

31 °i 40) (+-) - rans - 3-Butyl- 3-ethyl-2.3 , , 5- etrahydro -5- (-»-me hoxyphenyl) -1 ,4-benzothiazepine 1,1-dioxide hydrochloride, mp 194-196 C;

41) (+-)-T_rans-3-Butyl-3-ethyl-2, 3,4,5- tetrahydro- 5-(«- Colyl) - 1, - benzothiazepine 1,1-dioxide hydrochloride, mp 204-206°C:

42) (+-)-Cis-3-Butyl-3-ethyl- 2, 3,4 ,5- tetrahydro- 5- (4- tolyl)- 1,4- benzothiazepine 1,1-dioxide, mp 155-156C;

43) (+- )-£is- 3 -Butyl -3-ethyl -2, 3,4,5 -tetrahydro- 5- (4-methoxypnenyl) - 1,4-benzothiazepine, mp 75-77 C;

4 ) (+- ) -Cis- 3-But l- 3-eth l -2,3,4,5- tetrahydro- 5 - (4 -mecnoxyphen 1) - 1,4-benzothiazepine 1,1-dioxide, mp 109-111°C;

45) (+- )-C_is-3-Butyl-3-ethyl -5- (4- fluorophenyl) -2, 3,4,5 - cetrahydro- 1,4-benzothiazepine, mp 76-78 C;

46) (+-)-Trans-3-Butyl-5-(3,4-dichlorophenyl)-3-ethyl-2,3,4,5-tetra- hydro-l,4-benzothiazepine, p 98-100°C;

47) (+-) -Trans -3 -Butyl- 5- (4-chlorophenyl) -3-ethyl -2, ,4.5 - tecrahydro- 1,4-benzothiazepine 1,1-dioxide hydrochloride 0.3 H 0. mp 178-180°C;

48) (+-) -Cis.- 3-Butyl-5- (4-chlorophenyl) -5-ethyl-2, 3,4,5- tetrahydro- 1,4-benzothiazepine 1,1-dioxide hydrochloride, mp 186-188°C;

49) Trans- 3-Butyl-3 -ethyl- 2, 3 ,4, 5 -tetrahydro- 5- (3 -nitropnenyl) - 1,4- benzothiazepine 1.1-dioxide, mp 139-142°C;

50) Trans- 3 -But l- 3 -ethyl -2.3,4,5- tetrahydro - 5- (4 - nitropheny1) -1,4- benzothiazepine 1,1-dioxide, mp 139-142°C;

3$0 51) (+-)-Trans-5-(4-Benzvloxvt>henvl)-3-butvl-3-ethvl-2.3.4.5- tetrahydro-l,4-benzothiazepine 1,1-dioxide, p 94-95 C;

52) (+- )-Cis-5- (4-Benzyloxyphenyl)-3-but 1-3 -ethyl-2, 3,4,5-tetra- hydro-1 ,4-benzothiazepine 1,1-dioxide, mp 137-138 C;

53) (+-)-Trans-5-(4-Benzvloxvτ>henvl)-3-butyl-3-ethvl-2.3.4.5-tetra- hydro-l,4-benzothiazepine, mp 97-98 C;

54) (+-)-Trans-3-f4-(3-Butyl-3-ethyl-2.3.4.5-tetrahvdro-1.4-ber-zo- thiazepin-5-yl)phenoxy]propanesulphonic acid 1,1-dioxide, mp 270°C (dec);

55) (+-) -Trans -3 -Butyl-3-ethyl-2, 3, 4, 5 -tetrahydro-5- (2 -fluorophenyl) - 1,4-benzothiazepine 1,1-dioxide hydrochloride, mp 194-196 C;

56) (+-) -Trans-3-Butyl-3-ethyl-2.3.4.5-tetrahydro-5- (3-fluorophenyl) - 1,4-benzothiazepine 1,1-dioxide, mp 143-145 C;

57) (+-)-Cis-3-Butyl-3-ethyl-2, 3, 4, 5-tetrahydro- 5-(4-pyridyl) -1,4- benzothiazepine 1,1-dioxide, mp 121-123 C;

58) (+-)-ϊians- -Butyl-3-ethyl-2.3, 4, 5 -tetrahydro- 5-(4-pyridyl) -1,4- benzothiazepine 1,1-dioxide, mp 110-111 C;

59) (+-)-Cis-3-Butyl- 3-ethyl-2, 3,4, 5 -tetrahydro- 5- (4-trifluoromethylphenyl) -1,4-benzothiazepine 1,1-dioxide, mp 64-65 C;

60) (+- ) -Trans-3-Buty - 3-ethyl-2 , 3 , 4 , 5-tetrahydro-5- (3- trifluoro- methylphenyl) -1,4-benzothiazepine 1.1-dioxide, mp 110-112 C;

61) (+- -Trans-3-Butvl-3-ethyl-2.3,4.5-tetrahvdro-5-(3.4-difluoro- phenyl)-l,4-benzothiazepine 1.1-dioxice. mp 205-215 C; 62) (+-) -Trans-3 -Butyl- 3-ethyl -2, 3,4, 5- tetrahydro-5- (2,4 -difluorophenyl) -1 ,4-benzothiazepine 1,1-dioxide, mp 97-99 C;

63) (+-) -Trans -3-isoρentyl-3-ethyl -2, 3, 4, 5-tetrahydro- 5-phenyl-1,4- benzothiazepine 1,1-dioxide, mp 86-87 C; and

64) (+-)-C_is- 3- isopentyl- 3 -ethyl- 2, 3,4,5- tetrahydro-5-phenyl- 1,4- benzothiazepine 1,1-dioxide, mp 123-125 C.

( ■ ) - (RR) - 3 -butyl - 3 -ethyl -2.3.4.5- tetrahvdro- ■ phenyl-1 ,4-benzothiazepine 1.1-dioxide hydrochloride

2) (+-) -Trans -3 -Butyl -3 -ethyl- 2, 3,4, 5 -tetrahydro- 5 -phenyl-1,4-benzothiazepine 1,1-dioxide, mp 98-100 C;

3) (-) -Trans-3-Methyl-3-propyl-2, 3 ,4, 5-tetrahydro-5-phenyl-1,4- benzothiazepine 1,1-dioxide, mp 129-130 C;

3$^ A compound of formula (I)

wherein

1 is an integer of from 0 to 4;

m is an integer of from 0 to 5;

n is an integer of from 0 to 2 ;

R and R' are atoms or groups independently selected from halogen, nitro, phenylalkoxy, C^ alkoxy, C alkyl and -0(CH ) SO.R" wherein p is an integer of from 1 to 4 and R" is hydrogen or C. alkyl, wherein said phenylalkoxy, alkoxy and alkyl groups are optionally substituted by one or more halogen atoms;

?7 is a C- , straight alkyl group; and

R is a Cm . straight alkyl group;

and salts, solvates and physiologically functional derivatives thereof.

33 A compound of formula (I) as claimed in Claim 1 , wherein

n is 2 ;

is methyl, ethyl, n-propyl, or n-butyl; and

is ethyl, n-propyl, or -butyl;

and salts, solvates and physiologically functional derivatives thereof.

3. A compound of formula (I) as claimed in Claim 2. which compound is in the trans configuration as herein defined, or a salt, solvate. or physiologically functional derivative thereof.

4. A compound of formula (I) as claimed in Claim 3, which compound is trans -3-butyl -3 -ethyl-2 ,3,4, 5- tetrahydro- 5 -phenyl-1 ,4-benzothiazepine 1,1-dioxide, or a salt, solvate, or physiologically functional derivative thereof.

5. The compound of formula (I) claimed in Claim 4, which compound is in the (RR) - , (SS)-, or (RR.SS) - form, or is a salt, solvate. or physiologically functional derivative of any thereof.

6. (-)-(RR)-3 -Butyl -3-ethyl-2, 3,4, 5 -tetrahydro-5 -phenyl-1,4-benzothiazepine 1,1-dioxide or a salt, solvate, or physiologically functional derivative thereof.

7. (-)-(RR) -3-Butyl-3-ethyl-2, 3,4, 5-tetrahydro-5-phenyl-1,4-benzothiazepine 1,1-dioxide

8. (+-)-(RR,SS)-3- Butyl - 3-ethyl -2,3.4.5- etrahydro- 5 -phenyl-1,4- benzothia∑epine 1,1-dioxide or a salt, solvate. or physiologically functional thereof. (+-)-(RR,SS)-3-Butyl- 3-ethyl- 2, 3, 4, 5- tetrahydro- 5-phenyl -1,4- benzothiazepine 1,1-dioxide

38

1. A polymeric or oligomeric bile acid, prepared by polymerization of a monomeric bile acid of the formula I

G— X— A (I) in 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-vinylpyrrolidone or its derivatives.

?»i and/or by copolymerization with ethylenically unsaturated dicarboxylic anhydrides and ethylenically (HI) unsaturated dicarboxylic acids each having 2 to 6 carbon atoms; their esters or 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.

2. A polymer or oligomer as claimed in claim 1, 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 forin which mula II applies 15 R³ to R⁸ independently of one another are hydrogen, OH, NH or an OH group protected by an OH

(YV-<Z» (ID protective group and one of the radicals R³to R⁶is a bond to the group X, where this bond starts from the positions 3 (R³ or R⁴) or 7 (R⁵ or Re), and the in which 20 other position 7 or 3 in each case carries an OH Y is adjacent to G and is — O — , — NR' — , group or a protected OH group,

B is —OH, — O-alkali metal, — O-alkaline earth o O metal, — O— (Cι-Cι₂)-alkyl, — O-allyl or — O-ben-

11 II o— c— . '— C— . zyl where alkyl is either n-alkyl or iso-alkyl and or — NR 25 where the ester group formed is (Cι-ci₂)-^a-kylene or (C7-Ci₃)-aralkylene, where individual methylene groups in the alkylene chain of the alkylene or aralkylene radical can be re- ,₀ placed by one or more groups selected from — O-, -NR'— , is an ester which can be saponified both by acid and by base, Y is — O— , — NR'— ,

'— C— . — o— c- and — NR'— C— NR"— , 35

II II

0 o o O

II II

— o— c— . or — NR'— C— , o and p independently of one another are zero or 1, where o and p are not simultaneously zero, ._ Z is (Cι-Cπ)-alkylene, (C7-Cπ)-aralkylene, where 1

A is an ethylenically unsaturated group of the forto 3 methylene groups in the alkylene chain are replaced by the groups — O— , — NR', mula

or 1,

groups are adjacent to the C — C double bond,

R' and R" independently of one another are hydroO gen or (Cι-C6)-alkyl. II

65 -NR'- -c— ,

3. A polymer or oligomer as claimed in claim 2, wherein — NR'— or a single bond, in which R' and R" indepen¬

G corresponds to the formula III dently of one another are hydrogen or (C|-C₆)-alkyl. 98/40375

4. The polymeric or oligomeric bile acid of claim 1, wherein said monomer containing a polmerizable, ethR« o O ' ylenically unsaturated double bond is a monomer of I II II I formula IV H₂C=C— C— NH— D— NH— C— C=CH₂

R» (TV) in which ,„ R⁹ is hydrogen or methyl and H₂C=C ¹ — R¹⁰, D is -(CHEV-, where in which 10 m is 1 to 10 and R⁹ is hydrogen or methyl and E is hydrogen or OH. R"> is 10. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable o o o carrier.

15 11. The polymer or oligomer as claimed in claim 5,

— C— O— R", -C-NR^I2R¹³, — O— C— R , wherein the weight-average molecular weight is between 2,000 and 100,000 g mol.

— CN, — O— R¹⁵, hydrogen halogen — SO₃H, or 12. The polymer or oligomer as claimed in claim 12, — O— (CH₂— CH₂0)_ΛR¹⁶, wherein the weight-average molecular weight is bein which 20 tween 3,000 and 60,000 g mol. R¹¹ is hydrogen, (Cι-Cιo)-alkyl, (Cι-C|₀>monohy- 13. The polymer or oligomer as claimed in claim 3, droxyalkyl or — <CH CH₂— O— )_ΛR"⁶, wherein B is —OH, — O-alkali metal, — O— (Cι-C_)- R¹², R¹³, R¹⁵, and R¹⁶ are identical or different and alkyl, — O-allyl or — O-benzyl. are (Cι-Cιo)-aΙkyΙ, 14. The polymer or oligomer as claimed in claim 3, R¹⁴ is (Cι-Cι₈)-alkyl and 25 wherein R³ to R⁸ independently of one another are n is 1 to 50. hydrogen, OH, NH₂ or an OH group protected by an

5. A polymer or oligomer as claimed in claim 1, OH protective group and one of the radicals R³ to R⁶ is wherein the weight-average molecular weight is up a bond to the group X, where this bond starts from the 250,000 g/mol. positions 3 (R³ or R⁴) or 7 (R⁵ or R⁶) in the ^-position,

6. A polymer or oligomer as claimed in claim 1, r_j and the other position 7 or 3 in each case carries an OH wherein in the case of copolymers the molar ratio of group or a protected OH group. bile acid units to copolymerized monomer units is be15. The polymer or oligomer as claimed in claim 2, tween 300:1 and 1:300. wherein G is a free bile acid or its alkali metal salt or a

7. A polymer or oligomer as claimed in claim 1, bile acid esterfied on ring D which is bonded via its ring wherein the crosslinking is carried out by means of ₃₅ A to the group X. copolymerization with ethylenically polyunsaturated 16. A polymer or oligomer as claimed in claim 4, monomers. wherein the monomers are compounds according to the

8. A polymer or oligomer as claimed in claim 7, formula IV (meth)acrylic acid, (meth)acrylic acid eswherein the crosslinking is carried out with ethyleniters, acrylamide and its derivatives, carboxylic acid cally polyunsaturated acrylic acid and methacrylic acid -10 vinyl esters having 3-20 carbon atoms or N-vinylpyr- derivatives. rolidone and its derivatives.

9. A polymer or oligomer as claimed in claim 7, 17. The polymeric or oligomeric bile acid of claim 4, wherein the crosslinking is carried out with acid amides wherein said halogen is chlorine, bromine, or iodine. of the formula V

45

50

55

60

65

gS EXAMPLE 1

48 g (122 mmol) of 3α,7α,I2α-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 arc added and the mixture is stirred for a further 15 minutes. It is poured onto 1.5 1 of water and the solid constituents are filtered off with suction and washed with 11 of water. The residue is dissolved in 700 ml of ether and washed three times with water. The organic phase is dried (MgSOJ and concentrated. Yield 52 g (89%) of Example 1.

MS (FAB, 3-NBA/LiCl) C^sO,,^), 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 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 (MgSO and concentrated. Chromatography of the residue over silica gel (cyclohexane ethyl acctate=2:l) gives

3S °l 98/40375

then stirred at It is poured onto ice-water with ethyl acetate. The organic concentrated. The crude product ether, filtered off with suc11 2 g (93%) of Example 6 are

3 ° MS (FAB, 3-NBA LiCl) C^H^O-S (472), 485 (M+2Li⁺ 8.0 g (18.5 mmol) of Example 7 are hydrogenated with hydrogen in 220 ml of ethyl acetate in the presence of about 50 mg of 10% Pd C. When the reaction has ended, the

EXAMPLE 7 catalyst is filtered off and the filtrate is concentrated. Chromatography of the residue 95:5)

45 EXAMPLE 10

EXAMPLE 8

MS (FAB, 3-NBA/LiCl) C_2βH₄₃N0₄ (435), 442 (M+I-T) EXAMPLE 11A are obtained.

(Example 12A) are dissolved ml of pyridine, 4 g (35 chloride are added at 0° C. and temperature for 2 hours. For added and the mixture is extracted with

j ^ , ethyl acetate. After drying and concentration of the ethyl dimethyl sulfide is added. The reaction mixture is concenacetate phase, 17.5 g of (quaternary) mesyl compound, trated and the residue is chromatographed over silica gel which can be reacted without further purification, are (cyclohexane ethyl acetate=7.3). 5.8 g (44%) of aldehyde obtained. are obtained MS (FAB, 3-NBA/LiCl) (462), 469 (M+Li*)

EXAMPLE 12E

EXAMPLE 12C

J O 98/40375

2.0 g (5.01 mmol) of 3α,7α,12α-trihydroxy-24-nor-23- 30 matographed over silica gel (chloroform methanol=85:15). cholanic acid, 2.1 g (4.98 mmol) of methyl 3β-amino- 3.0 g (75%) of Example 13 are obtained. 7α,12α-dihydroxy-24-cholanate (cf. EP-A-0417 725), 1.36 g (10 mmol) of hydroxybenzotriazole and 1.04 g (5.4 mmol) MS (FAB, 3-NBA LiCl) C₄₈H₇₉N0₈ (798), 805 (M+Li⁺) of dicyclohexylcarbodiimide are stirred in 100 ml of dry Examples 14 to 31 of Tables 1 to 3 are obtained analotetrahydrofuran at room temperature for 24 hours. The 35 gously to Example 13 (reactive — X — G2 derivatives are reaction mixture is concentrated and the residue is chro- described in EP-A-0 489 423 or EP-A-0 417 725).

TABLE 1

MS (FAB, 3-NBAΛJC.)

TABLE 1 -continued

Ex. MS (FAB.3-NBAΛjO)

^ 98/40375

TABLE 2

Ex. MS (FAB, 3-NBAΛiQ)

₃9(° TABLE 2-continued

MS (FAB, 3-NBA/LiCl)

TABLE 3

MS (FAB.-3-JVJBA/L.C1)

3O 98/40375

TABLE 3-continued

Ex. MS (FAB, 3-NBAΛid)

3^ttS 0375

3.0 g (3.76mmol) of Example 13 are dissolved in 80 ml MS (FAB, 3-NBA/LiCl) (784), 791 (M+Li⁺) of ethanol, 30 moi of IN aqueous NaOH are added and the mixture is stirred at room temperature for 16 hours. For ₄₀ Examples 33 to 50 of Tables 4 to 6 are obtained analoworking up, 30 ml of water are added and the alcohol is gously to Example 32 from the methyl esters (Tables 1-3). 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.

311 O 98/40375

TABLE 4

TABLE 4-continued

TABLE 5

39 C«H₇₃NO, (770), 777 (M+U*)

40 C_4iH„N0₉ (814), 821 (M+U*)

o I 8/40375

TABLE 5-coιιtiπued

TABLE 6

Ex. MS (FAB, 3-NBA UQ)

46 C..H_7INO, (742). 749 (M+U*)

47 C«H₇₃NO, (786), 793 (M+U*)

48 C,,H„NOιo (830), 837 (M+U*)

49 C-. .NO, (726), 733 (M+U*)

SO CjH-jNO, (740), 747 (M+U*)

Examples 51 to 54 from Table 7 are obtained analogously Example S from the adds described above.

y O TABLE 7

Examples 55 to 57 of Table 8 are obtained analogously to Example 4. •

yo γ TABLE 8

Examples 58 to 63 of Table 9 are obtained analogously to Example 13.

TABLE 9

(in the following foπππlir, the free valency of Gl it not iho π).

Ex. 01 - MS (FAB, 3-NBAΛJCI)

TABLE 9-continued

(in the following ferulae, the free valency of Gl is not shown).

Ex. Gl - MS (FAB, 3-NBA UQ)

Examples 64 to 69 of Table 10 are obtained analogously Example 32.

TABLE 10

(The tree valency of Gl is not shown in the following formulae)

Ex. Gl - MS (FAB, 3-NBA/UC1)

y° ? TABLE 10-continued

(The free valency of Gl is not shown in the following formulae)

Ex. Gl- MS (FAB. 3-NBA UCl)

The sodium salts of Example 32 and all the examples of Tables 4 to 8 and 10 can be prepared. The compound is dissolved in methanol, an equimolar amount of IN aqueous NaOH is added and the mixture is then evaporated in vacuo.

ya* 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 atoms, a phenyl radical, which is unsubstituted or mono- to trisubstituted by F, CI, Br, (C,-C₄-alkyl or (C,-C₄-alkoxy, or a benzyl radical, which is unsubstituted or mono- to trisubstituted by F, CL Br, (Cι-C₄)-alkyl or (C_j-CJ-alkoxy,

10 q is 0 to 5; r is 0 or 1;

1. A bile add derivative of the formula I s is 0 or 1; and

15 G₂ is a radical of the formula IV wherein G, is linked via the side chain on atom No. 17 with the bonding member X to atom No. 3 of G₂, and G_t is a radical of the formula II

in which Z is one of the following radicals

H₃C, in which 30 \ Z is one of the following radicals

CH- I

H₃C,

\

CH— , or a single bond, with the proviso that Z may be

40

or a single bond, R(l) is H, an alkyl radical having 1 to 10 carbon atoms or an alkenyl radical having 2 to 10 carbon atoms, ⁴

R(2), R(3), R(4), R(5) are independendy H, OH or in only one of formulas II and IV; R(2) and R(3), or R(4) and 1.(5) together form the oxygen V is — O — or of a carbonyl group, X is a single bond or a bridge member of the formula TH JQ

- -(N).-A-N-C-(CHι)_f-C_7rN-(B)₍- Ul) (2) U3) when

55 W is H or, in which ^~ — V is — CH₂— or — CH₂— CH₂— when W is H or OH,

A is an alkylenε chain, which is branched or unbranched, Y is — OL, NHL, and which is optionally interrupted by — O — , — S — , or phen lene, the linkage of the phenyl ring being in the _w ortho-, meta- or para-position and the chain comprising -N / 2 to 12 chain members, \ ^'

L B is an alkylene chain which is branched or unbranched, and which is optionally interrupted by — O — , — S — , or phenylene, the linkage of the phenyl ring being in the 65 or an amino add or amino-sulfonic add bonded via the ortho-, meta- or para-position and the chain comprising amino group, selected from the group consisting of 2 to 12 chain members. — NH— CH₂— COOH, —NH— CH_j— CH₂— , S0₃H, 2. The bile add derivative of the formula I, as claimed in

— N— CH2-COOH and - -N-CHi- CHj-SOjH. claim 1, wherein L is an alkenyl radical having 2 to 10 CH. CH₃ carbon atoms.

3. The bile add derivative of formula I, as claimed in in which L is H, an alkyl radical or alkenyl radical claim 1, wherein one or more of L(l), L(2) or L(3) is an having up to 10 carbon atoms, a cycloalkyl radical alkenyl radical having 2 to 10 carbon atoms. having 3 to 8 carbon atoms, a phenyl radical, which is unsubstituted or mono- to trisubstituted by F, CL Br, (C_j-C^alkyl or (Cj-C₄)-alkoxy, or a benzyl radical, which is unsubstituted or mono- to trisubstituted by F, 10 Q, Br, (C,-C₄)-alkyl or (Cj-CJ-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.

γ/o Description

Bile acid derivatives, processes for their preparation and the use of these compounds as medicaments

The invention relates to novel bile acid derivatives, processes for their preparation, pharmaceutical preparations based on these compounds and the use of the bile acid derivatives as medicaments-

Bile acids have an important physiological function in lipolysis, for example as cofactors of pancreatic Upases and as natural detergents for solubilizing fats and fat- soluble vitamins. As the end product of cholesterol metabolism, they are synthesized in the liver, stored in the gall bladder and secreted from this by contraction into the small intestine, where they display their physiological action. The greatest proportion of the bile acids secreted is recovered via the enterohepatic circulation. They return to the liver via the mesenterial veins of the small intestine and the portal vein system. Both active and passive transportation processes play a role in reabsorption in the intestine. Most of the bile acids is reabsorbed at the end of the small intestine, the terminal ileum, by a specific Na*-dependent transportation system, and returns to the liver with the mesenterial vein blood via the portal vein, _ to * secreted by the liver cells again into the bile. The bixe acids appear in the enterohepatic circulation both as free acids and in the form of glycine conjugates and taurine conjugates.

Non-absorba le, insoluble- ^asic, ctosslin ed polymers have been used for many years or binding bile acids and utilized therapeutically on the basis of these properties. Bile acid derivatives described in Patent Application EP-A-0 489 423 have a high affinity for the intestinal bile acid transportation system and therefore allow specific inhibition of the enterohepatic circulation. All diseases in which inhibition of bile acid resorption in the intestine, in particular in the small intestine, seems desirable are regarded as the therapeutic object. For example, the biligenic diarrhea following ileum resection or increased blood cholesterol levels are treated in this manner. In the case of increased blood cholesterol level, a reduction in this level can be achieved by intervention in the enterohepatic circulation. The corresponding new synthesis of bile acids from cholesterol in the liver is caused by lowering the bile acid pool in the enterohepatic circulation. The LDL-cholesterol in the blood circulation is resorted to in order to meet the cholesterol requirement in the liver, the hepatic LDL receptors increasingly being used. The acceleration of LDL metabolism which has thus occurred takes effect by reducing the atherogenic cholesterol content in the blood.

The object was to discover novel medicaments which are capable of reducing the atherogenic cholesterol content in the blood or of influencing the enterohepatic circul^¬ ation in respect of increased excretion of bile acid and consequent reduction in the cholesterol level.

This object is achieved by the bile acid derivatives according to the invention.

EP-_A-0 489 423 relates to di eric bile acid derivatives of the formula

G1-X-G2

in which _Gl and G2 are linked in positions 3, 7 or 12 or by the side chain via the linker X. Bile acid derivatives in which Gl 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 yt²- are not described in the examples of the European Patent Application cited.

The invention therefore relates to bile acid derivatives of the formula I

Gl - X - G2 I

in which Gl is a radical of the formula II

in which

Y has the following meaning: OKa, in which Ka is an alkali metal, alkaline earth metal or quaternary ammonium ion, an amino acid or aminosulfonic acid bonded via the amino group, such as, for example

-NHCH₂COOH. -NHCH₂CH₂SO₃H, -NCH₂COOH, -NCH₂CH₂S0₃H

CH₃ CH₃

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, CI, Br, (C--C₄) -alkyl / or (C.-C₄) -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 benzyl radical, a biphenylmethyl or a triphenyl- ethyl radical, in which the nuclei are unsubstituted or mono- to trisubstituted by F, Cl, Br, (C_α-C₄) -alkyl or (C.-C₄) -alkoxy, or a radical

0 O

II II o

-P-OL . -S-OL or I

-C-L

O O

in which L has the abovementioned meaning, R² to R^s, R² and R³ or R⁴ and R^s in each case together being the oxygen of a carbonyl group, or indi- vidually and in each case independently of one another being

0 0 O OL O

H. -OT. -ST. -NHT, O-C I-T. -S-C i-T. -NH-C I-T. -0-P I-OT. -O-S II-OT. -T ii i

0 0

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 Gl for bonding the group X,

X is a single bond or a group of the formula III

0 0

II II

-HN),-A-N-C-|CH₂) -C.]_r-N-(Bl_t- (Ill),

_L1 L² l³

in which if l _A and B are alkylene chains, which are branched or unbranched, it being possible for the chains to be optionally interrupted by -0- or -S-, L¹, L² and L³ are identical or different and 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

in which

Z is a free valency to the group X or has the meaning given under Y, R^β 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 R⁵, and in which in total only one free valency starts from G2 to the group X.

The compounds 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. The compounds according to the invention furthermore are not themselves absorbed and thus do not enter the blood circulation. The enterohepatic circulation can be interrupted very specifically and efficiently by application of this principle of action.

By using the compounds according to the invention, it is possible to reduce the amount of bile acids in the enterohepatic circulation such that a reduction of the cholesterol level in the serum occurs. Avitaminoses are just as unlikely during their use as effects on the absorption of other medicaments or an adverse effect on the intestinal flora. Furthermore, the side-effects known of polymers (constipation, steratorrhea) are not found, i.e. lipolysi3 is not adversely influenced. Because of the high affinity for the specific bile acid transportation system of the small intestine, low daily doses are sufficient, so that acceptance of such medicaments by the doctor and patient will be very high.

Particularly preferred compounds of the formula I are those in which Gl is a radical of the formula II

in which

Y OH, 0-(C_rC₄)-A!kyl. -NHCH₂C00H,

-NCH₂C00H, -NHCH₂CH₂S0₃H, -NCH₂CH₂S0₃H

I I

CH CH₃

R¹ is H, benzyl, biphenylmethyl, formyl or acetyl,

R² to R^s, R² and R^J or R⁴ and R^s in each case together being the oxygen of a carbonyl group, or individually and in each case independently of one another being Q Q o 1

H. -OT, -NHT, -0-C-T, -NH-C-T, -T

in which T is

H, a branched or unbranched (C.-C ) -alkyl radical or a free valency to bridge group X, and in which a total of one free valency starts from Gl for bonding the group X,

is a bond,

-N-. H

-CH₂CH₂NH-

-CH₂CH₂CH₂NH.

(CH₂)_n.N-C-(CH₂)_m-C-N-{CH₂)_t 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

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 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 group X.

The invention furthermore relates to a process for the preparation of compounds of the formula I, which comprises a) in the case where X is a single bond, reacting suitable forms of Gl and G2 with one another by processes which are known in principle, or b) in the case where X is a bridge group, reacting α) reactive forms of Gl-X with G2 or β) reactive forms of G2-X with Gl by processes which are known in principle, or c) preparing compounds of the formula I (G1-X-G2) from 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 bcr.d, in particular within a condensation or substitution reaction.

a) X is a single bond

The bile acids Gl 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 for yl, acetyl, tetrahydropyranyl or t-butyldimethylsilyl. 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 dimethylforma ide (DMF) or diinethoxyethane (DME) . y/f The various isomers can be separated, for example by chromatography. The reaction can be carried out selectively by using suitable protective groups.

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 according to the invention can be linked analogously by known standard processes.

b) X is a bridge group

The processes specified under a) are also used to carry out the linking of Gl-X with G2 or Gl with X-G2. Here also, the bile acid portion is expediently employed either in protected or in unprotected form.

A preferred preparation process comprises reacting reactive forms of Gl with reactive forms of X-G2. If appropriate, the linking reaction is followed by splitting-off 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.

t

va° «

(X) (X I )

R = H, formyl or acetyl, R' - H or OH, R" = formyl or acetyl

(XI I) (XI I I)

z\ t

( x i v ) ( x v )

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 protected are reacted with allyl bromide/Hϋnig base or triethylamine. If the compound V has one OH group, the alkylation is unambiguous; if two free OH groups are present, onoalkylation takes place at positions 7 and 12 in approximately equal proportions and only traces of the dialkylated product are formed. The protective group in the 3-position can either be split off with sodium methyiate or retained for further reactions. The monoalkylated compounds VI and VII can be split with ozone. or with Os0₄/NaI0₄ 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 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 reaction sequence which is known in principle (mesylation of the primary OH group with methanesulfonyl chloride/ pyridine, azide exchange with NaN₃ in dimethylformamide, reduction of the azide function with hydrogen under catalytic conditions). Further reaction of the amino 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.

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 triacetin, oils, such as, for example, sunflower oil or cod-liver oil, ethers, such as, for example, diethyl- ene glycol dimethyl ether, or also polyethers, such as, for example, polyethylene glycol, or also in 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 in combination with other medicaments .

The compounds of the formula I are administered in various dosage forms, preferably orally in the form of tablets, capsules or liquids. The daily dose varies in the range from 3 mg to 5000 mg, but preferably in the dose range from 10 to 1000 mg, depending on the body weight and constitution of the patient.

On the basis of their pharmacological properties, the compounds are particularly suitable as hypolipidemic agents.

The invention therefore also relates to medicaments based on the compounds of the formula (I) and to the use of the compounds as medicaments, in particular for lowering the cholesterol level.

The compounds according to the invention were tested biologically by determination of the inhibition of [³H]- taurocholate uptake in brush border membrane vesicles of the ileum in rabbits. The inhibition test was carried out as follows:

1. Preparation of brush border membrane vesicles from the ileum of rabbits

The brush border membrane vesicles from the intestinal cells of the small intestine were prepared by the so-called Mg²⁺ precipitation method. Male New Zealand rabbits (2 to 2.5 kg body weight) were sacrificed by intravenous injection of 0.5 ml of an aqueous solution of 2.5 mg of tetracaine HCl, 100 T 61^R and 25 mg of mebezonium iodide. The small intestine was removed and flushed with ice-cold physiological saline solution. The terminal 7/10 of the small intestine (measured in the oral-rectal direction, i_^"e7 the terminal^-" ileum which contains the active Na⁺-dependent bile acid transportation system) was used for preparation of the brush border membrane vesicles. The intestines were frozen in plastic bags under nitrogen at -80°C. To prepare the membrane vesicles, the frozen intestines were thawed at 30°C in a water-bath. The mucosa was scraped off and suspended in 60 ml of ice-cold 12 mM Tris/HCl buffer (pH 7.1)/300 mM mannitol, 5 mM EGTA/10 mg/1 of phenylmethyl- sulfonyl fluoride/1 mg/1 of trypsin inhibitor from soybeans (32 U/mg)/0.5 mg/1 of trypsin inhibitor from bovine lung (193 U/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 1 M MgCl₂ solution (final concentration 10 mM) , the 0 mixture was left to stand at 0°C for exactly 1 minute. By addition of Mg²⁺, the cell membranes aggregate and precipitate with the exception of the brush border membranes. After centrifugation at 3000 x g (5000 rpm, SS-34 rotor) for 15 minutes, the precipitate is discarded 5 and the supernatant, which contains the brush border membranes, is centrifuged at 267000 x g (15000 rpm, SS-34 rotor) for 30 minutes. The supernatant was discarded and the precipitate was rehomogenized in 60 ml of 12 mM Tris/HCl buffer (pH 7.1)/60 mM mannitol, 5 mM EGTA using 0 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 3000 x g for 15 minutes. The supernatant was then centrifuged again at 46000 x g 5 (15000 rpm, SS-34 rotor) for 30 minutes. The precipitate was taken up in 30 ml of 10 mM Tris/Hepes buffer (pH 7.4J/300 mM mannitol and resuspended homogeneously by 20 strokes in a Potter Elvejhem homogenizer at 1000 rpm. After centrifugation at 48000 x g (20000 rpm, SS-34 G rotor) for 30 minutes,_ the_ precipitate was taken up in 0.5 to 2 ml of Tris/Hepes buffer (pH 7.4)/280 mM mannitol (final concentration 20 mg/ l) and resuspended with the aid of a tuberculin syringe with a 27 gauge needle. The vesicles were either used for transportation studies 5 immediately after preparation or stored in 4 mg portions in liquid nitrogen at -196°C.

2. Inhibition of Na*-dependent uptake of [³H]-taurocholate in the brush border membrane vesicles of the ileum

The uptake of substrates in the brush border membrane vesicles described above was determined by means of the so-called membrane filtration technique. 10 μl of the vesicle suspension (100 μg of protein) were pipetted as drops onto the wall of a polystyrene incubation tube (11 x 70 mm) which contained the incubation medium with the corresponding ligands (90 μl) . The incubation medium contained 0.75 μl - 0.75 μCi [³H(G) ]-taurocholate (specific activity: 2.1 Ci/mmol)/0.5 μl of 10 mM tauro- cholate/8.75 μl of sodium transportation buffer (10 mM Tris/Hepes (pH7.4)/100 mM mannitol/100 mM NaCl) (Na-T-P) or 8.75 μl of potassium transportation buffer (10 mM Tris/Hepes (pH 7.4)/100 mM mannitol/100 mM KCl) (K-T-P) and 80 μl of the inhibitor solution in question as a solution in Na-T buffer or K-T buffer, depending on the experiment. The incubation medium was filtered through a polyvinylidene fluoride membrane filter (SYHV LO 4NS, 0.45 μm, 4 mm 0, Millipore, Eschborn, FRG). The transpor- tion measurement was started by mixing the vesicles with the incubation medium. The concentration of taurocholate in the incubation batch was 50 μM. 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 KCl).

The mixture formed was immediately filtered off with suction over a r.embrane filter of cellulose nitrate (ME 25, 0.45 μm, 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 radioactively labeled taurocholate, the membrane filter was dissolved with 4 ml of the scintillator Quickszint 361 (Zinssdr Analytik GmbH, Frankfurt, FRG) and the radioactivity was measured by liquid scintillation measurement in a TriCarb 2500 measuring instrument (Canberra Packard GmbH, Frankfurt,

H*L <o FRG) . After calibration of the instrument with the aid of standard samples and after correction for any chemi- luminescence present, the values measured were obtained as dpm (decompositions per minute).

The control values were determined in each case in Na-T-P and K-T-P. The difference between the uptake in Na-T-P and K-T-P gave the Na*-dependent transportation content. The concentration of inhibitor at which the Na*-dependent transportation content was inhibited by 50% - based on the control - was designated the IC₅₀ Na*.

The pharmacological data include a test series in which the interaction of the compounds according to the invention with the intestinal bile acid transportation system in the terminal small intestine was investigated. The results are summarized in Table 11.

Examples 1 and 2

150 g (0.32 moi) of methyl 3-acetyl-cholate, 500 ml of dimethylformamide, 125 ml of N-ethyl-diisopropylamine and 70 ml of allyl bromide are heated under reflux for 16 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 (ethyl acetate/cyclohexane 1:2, silica* gel 70-200 μm) , the product fractions are evaporated on a rotary evaporator. Yield - 92.2 g of 7-/12-allyl mixture. C₃₀HβO« (504), MS 511 (M + Li⁺)

The mixture was separated by fractional crystallization with n-heptane.

Example 3

50 g (0.1 moi) 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 oi) of osmium tetroxide are added. The mixture is stirred at room temperature for 15 minutes. 53 g (0.25 moi) 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. Yield: 47 g of crude C„H_4β0₇ (506), MS 513 (M + Li*)

Example 3 is further reacted without additional purification.

Example 4

4.2 g (0.11 moi) of sodium borohydride are added in portions to 47 g (0.093 oi) of Example 3 and 250 ml of methanol at 0^βC. After 2 hours at 0^βC, 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 μm) , the product fractions are evaporated on a rotary evaporator and the residue is crystallized with diisopropyl ether. Yield: 25 g of C„H_4t0₇ (508), MS 515 (M + Li⁺)

β

10 g (0.02 moi) of Example 1 and 250 ml of tetrahydro- furan were initially introduced into a reaction vessel at room temperature, and 40 ml (0.04 moi) of borane-tetra- 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 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 on a rotary evaporator.

Yield: 8.5 g of C₃₀H₅₀O₇ (522), MS 529. (M + Li*) Example 5 was further reacted without additional purification.

U1 Example 6

10 g (0.02 moi) of Example 4 and 100 ml of pyridine are initially introduced into a reaction vessel at 0^βC. 1.7 ml (0.022 oi) of methanesulfonyl chloride are added dropwise at 0^βC 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 sulfate and evaporated on a rotary evaporator. The residue is dissolved in 100 ml of dimethylformamide, 1.4 g (0.022 oi) 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 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 column chromatography (ethyl acetate/ MeOH/Et₃N 10:1:1, silica gel 70-200 μm) , Example 6 is obtained. Yield - 7.3 g of C₂,H₄₉N0₆ (507), MS 514 (M + Li*)

Example 7

98.6 mg (0.001 oi) of succinic anhydride are added to 500 mg (J3.001 moi) 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

3 [ cholic

300 mg (0.73 mmol) of cholic acid, 330 mg (0.78 mmol) of methyl 7β-amino-3α , 12α-dihydroxy-5β-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). C₄₉H₈₁N0₈ (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

^

The examples of Table 2 were obtained analogously to Example 13 from Examples 7 and 8.

Ϊ32 Table 2

The examples of Tables 3 and 4 were likewise obtained analogously to Example 13.

Table 3

3 Table 4

Example 26

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 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%). MS (FAB, 3-NBA/LiCl) C₄,H₇₉N0, (798) 805 (M + Li*)

The examples of Tables 5 to 8 are obtained analogously to Example 26.

Table 5

<3# Table 6

Table 7

H

yvo Table 8

Example R 17 MS (FAB, 3-NBA/LiCl)

36 C₅₀H₈₃NO, (842) 849 (M+Li^*)

37 C_5tH,₂N₂0₁₂ (985) 992 (M+Li^*)

38 C₅,H₉₂N₂0₁₂ (985) 992 (M+Li*)

The following glycine conjugates and taurine conjugates were obtained analogously to synthesis processes which have already been described (EP 489 423). Table 9

Table 10

Example 47

MS (FAB, 3-NBA/LiCl) C₄₀H N₃O₁₄S (1092) 1099 (M + Li^*)

MS (FAB, 3-NBA/LiCl) C₇₂H₁₁₀N₄O₁₃ (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 IC₅₀ and IC₅₀ Na values of the reference substance tauro- chenodeoxycholate (TCDC) and of the particular test substance are stated.

ιτl Table 11

yyi.^" 1. A bile acid derivative of the formula I

Gl - X - G2 I

in which Gl is a radical of the formula II

in which

Y has the following meaning: OKa, in which Ka is an alkali metal, alkaline earth metal or quaternary ammonium ion, -OL, -NHL, -NL₂, an amino acid or aminosulfonic acid bonded via the amino group, such as, for example

-NHCH₂COOH. .NHCH₂CH₂S0₃H, -NCH₂COOH. -NCH₂CH₂S0₃H

CH₃ CH₃

and (C₁-C₄) -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 unsubsti- tuted or mono- to trisubstituted by F, Cl, Br,

(C_-C₄) -alkyl or (C₃-C₄) -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 vvfc benzyl radical, a biphenylmethyl or a triphenyl- ethyl radical, in which the nuclei are unsubstituted or ono-to trisubstituted by F, Cl, Br, (C₃-C₄) -alkyl or

(C_x-C₄) -alkoxy, or a radical

0 0

11 ii 0

P-OL . -S-OL or II

D 1 -C-L

0 0

in which L has the abovementioned meaning, R^J to R⁵, R² and R³ or R* and R^s in each case together being the oxygen of a carbonyl group, or individually and in each case independently of one another being

0 0 0 OL O

H. -OT. -ST. -NHT. 0-C i-T. -S-Ci-T. -NH-C i-T, -O-Pi-OT. -0-S II-OT. -T

0 o

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 Gl for bonding the group X, X is a single bond or a group of the formula III

0 0

1 I

-HN)_s-A-N-C-(CH₂)_q-C-]_r-N-lB)_t- (III),

in which

A and B are alkylene chains, which are branched or unbranched, it being possible for the chains to be optionally interrupted by -O- or -S-, L¹, L^s and L³ are identical or different and w7 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

in which

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 R⁵, 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 claimed in claim 1, in which Gl is a radical of the formula II

vv* in which

Y is OH, 0-(C_rC₄)-Alkγl. -NHCH₂COOH,

-NCH₂COOH, -NHCH₂CH₂S0₃H, -NCH₂CH₂S0₃H

CH₃ ^CH3

R¹ is E. benzyl, biphenylmethyl, formyl or acetyl,

R² to R⁵, R² and R³ or R⁴ and R⁵ in each case together being the oxygen of a carbonyl group, or individually and in each case independently of one another being

O O

H. -OT, -NHT. -O-C n-T. -NH-C fl-T, -T

in which T is H, a branched or unbranched (C_x-C₄) -alkyl radical or a free valency to bridge group X, and in which a total of one free valency starts from Gl for bonding the group X,

X is a bond,

-N- . H

-CH₂CH₂NH-

-CH₂CH₂CH₂NH-

0 0

1 U

•₍CH₂ϊ_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 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 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 group X.

3. Process for the preparation of a bile acid deriva- tive of the formula I as claimed in claim 1, which comprises a) in the case where X is a single bond, reacting suitable forms of Gl and G2 with one another by processes which are known in principle, or b) in the case where X is a bridge group, reacting α) reactive forms of Gl-X with G2 or P) reactive forms of G2-X with Gl by processes which are known in principle, or c) preparing compounds of the formula I (G1-X-G2) from 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 bond, in particular within a condensa- tion or substitution reaction.

4. A medicament comprising a bile acid derivative as claimed in claim 1.

5. A hypolipidemic agent comprising a bile acid MONOMERIC BILE ACID DERIVATIVES,

PROCESSES FOR THEIR PREPARATION NHC-

II

AND THE USE OF THESE COMPOUNDS AS O

MEDICAMENTS

5

Bile acids arc synthesized in the liver from cholesterol in groups, and in which GS is bonded via X as desired, several enzymatic steps. They are stored in the gall bladder, and from which they are secreted with the bile into the small intestine. They fulfill important physiological functions Z is there during the digestion process, for example as cofactors 10 HO-. CH,-0-. HO-CH_I-CH = CH-CH.-. or pancreatic lipases and as natural detergents for absorption of fats and fat-soluble vitamins. The greatest proportion of 0 bile acids returns to the liver from the small intestine via the II

<C-H.)j— CH— O— . Alltali-O— S— O— . portal vein blood by active and passive transportation proII cesses. 15 o

Polymers which bind bile acids have been employed as o o

in which where the alkyl moiety is optionally substituted by a CS is a bile acid radical having an acid function in the side chain or a salt thereof, SO COOH group,

X is a covalent bond or a bridge group of the formula (CHJ_n, where n=l to 10, in which the alkylene chain can contain 1 to 3 oxygen atoms, NH or

/ l

whcrc A is in each case OH or NH(C,-C₁₀)alkyI. ^3J from the ileum of rabbits. The inhibition test was carried out

Preferred compounds of the formula I are those in which as follows: GS is linked to X in the 3-position, linking taking place in 1. Preparation of brush border membrane vesicles from the the α- or β-position. ileum of rabbits

An acid function is understood as meaning, in particular, Brush border membrane vesicles were prepared from the the COOH group or the sulfonic acid group. 0 intestinal cells of the small intestine by the so-called Mg²*

Alkyl radicals arc straight-chain or branched. precipitation method. Male New Zealand rabbits (2 to 2.5 kg

The compounds of thε formula (I) according to thε body weight) were sacrificed by intravenous injection of 0.5 invention havε a high affinity for the specific bile acid ml of an aqueous solution of 2.5 mg of tetracaine HCl, 100 transportation system of the small intestine and inhibit bile T 61^s and 25 mg of mcbczonium iodide. The small intestine acid absorption in a concentration-dependent and competi- 45 was removed and rinsed with ice-cold physiological saline tive manner. solution. The terminal 7/10 of the small intestine (measured

By competitive inhibition, intervention in the enterohein the oral-rectal direction, i.e. the temώial ileum, which patic circulation can be considerably more selective. Avitacontains the active Na*-dependent bile acid transportation minoses arc not to be expected, and a qualitative change in system) was used for preparation of the brush border memthe bile acid composition in the bile is just as unlikely. A 50 brane vesicle. The intestines were frozen in plastic bags controlled reduction in the serum cholesterol level can be under nitrogen at -80° C. For preparation of the membrane achieved with compounds according to the invention, withvesicles, the frozen intestines were thawed at 30° C. in a out the known side effects being observed. Because of their water bath. Thε mucosa was scraped off and suspended in 60 high affinity for the bile acid transportation system, very ml of ice-cold 12 mM Tris/HCl buffer (pH 7.1)/300 mM much lower daily doses than with the commercially avail- 55 mannitol, 5 mM EGTA/10 mg/1 of phenylmethylsulfonyl able polymers are sufficient; this also leads to a high fluoride/1 mg 1 of trypsin inhibitor from soybeans (32 acceptance by patient and doctor. U/mg)/0.5 mg 1 of trypsin inhibitor from bovine lung (193

The compounds have valuable pharmacological properU/mg)/5 mg/1 of bacitracin. After dilution to 300 ml with ties and are therefore particularly suitable as hypolipidemic ice-cold distilled water, the mixture was homogenized with agents. 60 an Ultraturrax (18-rod, IKA Werk Staufen, FRG) for 3

The invention thus also relates to medicaments based on minutes at 75% of the maximum output, while cooling with the compounds of the formula (I) and to the use of the ice. After addition of 3 ml of 1M MgQ_a solution (final compounds as medicaments, in particular for reducing the concentration 10 mM), the mixture was left to stand at 0° C. cholesterol level. for exactly 1 minute. The cell membranes aggregate by

The compounds according to the invention were tested 65 addition of Mg²* and precipitate, with the exception of the biologically by determination of the inhibition of [³H] brush border membranes. After centrifugation at 3000X g taurocholate uptake in the brush border membrane vesicles (5000 rpm, SS-34 rotor) for 15 minutes, the precipitate was

y d discarded, and the supernatant, which contained the brush present, the values measured were obtained as dpm (decomborder membranes, was centrifuged at 267000X g (15000 positions per minute). rpm, SS-34 rotor) for 30 minutes. The supernatant was The control values were in each case determined in discarded and the precipitate was rchomogcnizcd in 60 ml of Na— T— P and K — T— P. The difference between the uptake 12 M Tris/HCl buffer (pH 7.1)/60 M mannitol, 5 mM 5 in Na— T— P and K— T— P was the Na*-dependent transEGTA using a Potter Elvejhem homogenizer (Braun, Mel- portation contenL The concentration of inhibitor at which sungcn, 900 rpm, 10 strokes). After addition of 0.1 ml of 1 the Na*-dependent transportation content was inhibited by M MgCl₂ solution and an incubation time of 15 minutes at 50% — based on the control — was designated as the 0° G, the mixture was centrifuged again at 3000x g for 15 IC^Na*. minutes. The supernatant was then centrifuged again at 10 The table shows the measurement values of the inhibition 46000X g (15000 rpm, SS-34 rotor) for 30 minutes. The precipitate was taken up in 30 ml of 10 mM Tris Hepes of the [³H]-taurocholate uptake in brush border membrane buffer (pH 7.4) 300 mM mannitol and resuspended homovesicles from the ileum of rabbits. The quotients of the IC_JQ geneously by 20 strokes in a Potter Elvejhem homogenizer and lC_S0Na values of the taurochenodesoxycholate (TCDC) at 1000 rpm. After centrifugation at 48000x g (20000 rpm, 15 investigated as the standard in each vesicle preparation and SS-34 rotor) for 30 minutes, the precipitate was taken up in the particular substance are stated. 0.5 to 2 ml of Tris Hepes buffer (pH 7.4)/280 mM mannitol (final concentration 20 mg/ml) and resuspended with the aid of a tuberculin syringe with a 27 gauge needlε. The vesicles Substance IC» σCDO ICsart fTCDC) were either used immediately for transportation studies after 20 from Example: ICso (Subsume-) ICjαv. (Substas-c) preparation, or stored at -196° C. in portions of 4 mg in 3 0.4 0.35 liquid nitrogen. 4 0.77 0.69

2. Inhibition of Na*-dependent [³H]-taurocholatε uptake in 18 0.47 0.42 the brush border membrane vesicles of the ileum 21 0.34 0.33

The uptake of substrates into the brush border membrane 25 33 0.33 0-35

35 1.0 1.02 vesicles described above was determined by means of the 36 0.19 0-20 so-called membrane filtration technique. 10 ul of the vesicle 38 0.49 0.41 suspension (100 μg of protein) were pipetted as drops onto 40 0.52 0J0 the wall of a polystyrene incubation tube (11 x70 mm) which 43 0.78 0.73 contained the incubation medium with the corresponding 30 ligands (90 μl). The incubation medium contained 0.75 The invention furthermore relates to the use of the com- μl=0.75 μCi of [³H(G)]-taurocholate (specific activity: 2.1 pounds according to the invention for the preparation of a Ci/mmol)/0.5 μl of 10 mM taurocholate/8.75 μl of sodium medicine. transportation buffer (10 mM Tris/Hepes (pH 7.4)/100 mM For this, the compounds of the formula I are dissolved or mannilol/100 mM NaCl) (Na— T— P) or 8.75 μl of potas- 35 suspended in pharmacologically acceptable organic solsium transportation buffer (10 mM Tris/Hepes (pH 7.4)/100 vents, such as mono- or polyhydric alcohols, such as, for mM mannitol/100 mM KCl) (K— T— P) and 80 μl of the example, ethanol or glycerol, or in triacetin, oils, for inhibitor solution in question, dissolved in Na-T buffer or example sunflower oil or cod-liver oil, ethers, such as, for K-T buffer, depending on the experiment The incubation example, diethylene glycol dimethyl ether, or also poly- medium was filtered through a polyviπylidene fluoride 40 ethers, for example polyethylene glycol, or also in the membrane filter (SYHV LO 4NS, 0.45 μm, 4 mm φ, Milli- presence of other pharmacologically acceptable polymeric porc, Eschbom. FRG). The transportation measurement was carriers, such as, for example, polyvinylpyrrolidone, or other started by mixing the vesicles with the incubation medium. pharmaceutically acceptable additives, such as starch, cycio- The concentration of taurocholate in the incubation batch dextriπ or polysaccharides. The compounds according to the was 50 μM. After the desired incubation time (usually 1 45 invention furthermore can be -u-.τ-inistεred in combination minute), the transportation was stopped by addition of 1 ml with other medicaments. of ice-cold stopping solution (10 mM Tris/Hepes (pH 7.4)/ The compounds of the formula I are administered in 150 mM KCl). various dosage forms, preferably orally in the form of

The mixture formed was immediately filtered off with tablets, capsules or liquids. The daily dose varies in the suction over a membrane filter of cellulose nitrate (ME 25, 50 range from 3 mg to 5000 mg, but preferably in the dose 0.45 μm, 25 mm diameter, Schleicher & Schuell, Dassell, range of 10 to 1000 mg, depending on the body weight and FRG) under a vacuum of 25 to 35 mbar. The filter was rinsed constitution of the patient with 5 ml of ice-cold stopping solution. The particular monoisotopic molecular weights calculated

To measure the uptake of the radioactively labeled tauare stated in the following examples. rocholate, the membrane filter was dissolved with 4 ml of 55 Unless stated otherwise, mass spectra were recorded by the scintillator Quickszint 361 (Zinsser Analytik GmbH, the FAB technique with addition of LiCl and 3-nitrobenzal- Frankfurt, FRG) and the radioactivity was measured by dehyde[3-NBA]. ^~ liquid scintillation measurement in a TriCarb 2500 measurStarting compounds which have the bile acid structure ing instrument (Canberra Packard GmbH, Frankfurt, FRG). have already been described in some cases (cf„ for example, After calibration of the instrument with the aid of standard 60 EP-A-0 417 725, EP-A-0 489 423 and EP-A-0 548 793. samples and after correction for any chemuuminescence R¹ is defined in Example 6. EXAMPLE 1

C₃ιιHj2θι (540) MS: 547 (M ♦ ._^"♦)

1 g (1.96 mmol) of the methyl ester a is dissolved in 15 ml of tetrahydrofuran (THF) or 1,4-dioxanc and the solution is stirred intensively with 10 ml of 2N NaOH overnight at ₃₀ 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 35 suction and rinsed with cold water. Recrystallization from ethanol water and drying in vacuo give 940 mg (96%) of Example 1.

C₂₉H_5n0₆(494) MS: 501 (M+Li⁺).

The following Examples 2 to 7 are prepared analogously 40 to "Example 1" from the corresponding bile acid esters:

Example as "Example 1" Empirical No. where n =^; fσπnula MW MS

45

2 6 CsoHs-O, 508 515 (M + U*) 3 8 C ₂H₃₆O_β 536 543 (M + U*) 4 9 C.,H_s.0₆ 550 557 (M + W) 5 10 C«H„0. 564 571 ( + UT

50

EXAMPLE 6

C-|H-ιθ7 <496) MS: 503 (M + U*)

65

EXAMPLE 8

100 mg (0.2 mmol) of the methyl ester are dissolved in 10 EXAMPLE 12 ml of dioxane and the solution is stirred with 3 ml of 25 O 0 half-concentrated sodium hydroxide solution at room temperature for 6 hours. The mixture is diluted with water and "'^^INH^^^^NR^^ *' acidified with half-concentrated hydrochloric acid to give, C3iHnN.θ7<576) MS: 583 (M + U^») after filtration with suction and washing, the acid "Example ₃₀ 8" (50 mg, 51%).

C-.₉H₄-.N0₅ (489) MS: 496 (M+U*)

The following substance examples were prepared as for EXAMPLE 13 "Example 8":

EXAMPLE 9 C₃4H₅,Nθ7(593) MS: 600 (M + U»)

40

H,C.

^:^^ N

^* R' EXAMPLE 14

C₂₉H.₇NO.(505) MS: 512 (M + Li') C₃₃Hj₇ θ (57 ) MS: 586 (M + U*)

EXAMPLE 10

EXAMPLE 15

H.C. ⁽CH.).-R¹ 50 0 n = 5

HjC :--00' \ \-^""^ N NHH--((ιCHj),-R' n »2

CJJHJJNO«<547) MS: 554 (M + U*)

55 C3oHjιNθ7 (537) MS: 544 (M + U*)

EXAMPLE 11 EXAMPLE 16

γs5 dropwise to a solution of 2.6 g (5.12 mmol) of "Example 2" in 20 ml of pyridine at 0 to 5° C. and the mixture is 450 mg (O.mmol) of "Example 20" are stirred in 10 ml of subsequently stirred at room temperature for 2 hours. It is dioxane with 5 ml of half-conccntratcd sodium hydroxide poured onto 200 ml of ice-water, about 15 ml of concen60 solution at room temperature for 6 hours. When the reaction trated sulfuric acid are added, while stirring and cooling, and has ended, the mixture is diluted with water, acidified with the mixture is extracted several times with ethyl acetate. The hydrochloric acid and subsequently stirred in an ice-bath for organic phase is dried and concentrated and thε residue is 1 hour. The precipitate is filtered off with suction and rinsed purified by chromatography (Siθ₂, CH₂C1₂/CH₃OH=10:1). 65 with water to give, after drying in vacuo, 430 mg (97%) of 1.78 g (47%) of "Example 18" arc obtained. "Example 21". C.iH_βiCy (740) MS: 747 (M+U*) C₃₁H₅₄N₂0₆ (550) MS: 557 (M+Li*)

£ EXAMPLE 22 raphy (Si0₂, CH₂C1₂/CH₃OH=10: 1). 1.2 g (43%) of

2 mmol of phenyl isocyanate in 5 ml of methylene chloride 15 "Example 24" are obtained. are added to 1.04 g (2 mmol) of amine b (Example 20) in 50 Cj.HβjINO, (691) MS (FAB, 3-NBA): 564 (M-P³) ml of dry methylene chloride and 28 ml of -riethylamine 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 filtra20 EXAMPLE 25 tion (CH₂C1₂ CH₃OH=10:1), 6540 mg (51%) of "Example 22" are obtained. (HjQ3)3N-(CH₂)_β-R' C-_βH_βoN- _a (6-10) MS: 647 (M+Li*) Clθ

EXAMPLE 23 25 prepared from Example 24 analoThe crude product is purified by atogτaphy over RP-8 silica gel S (FAB, 3-NBA): 550 (M-Cl^®)

C₃₇H₃₈N₂0₆ MS: 633 (M+U*)

EXAMPLE 24 EXAMPLE 26

2.08 g (4 mmol) of amine b. 10 ml of tr-isobutyl-uπώ-e and 5 ml of iodomethane are heated at boiling point in 50 ml of _M acetonitrile for 2 hours. All the volatile constituents are removed in vacuo and the residue is purified by chromatog-

71 1.04 g (2 mmol) of amine b and 276 mg (2 mmol) of EXAMPLE 29 pyrazole c are heated under reflux in 40 ml of dry acetonitrile for 10 hours. After cooling and addition of ether, a precipitate is formed, and is filtered off with suction and rinsed with dry ether. After drying, 450 mg of "Example 26" arc obtained.

C₃₂H₃₈BrN₃O_s (643) MS: 570 (M-HBr+U*) 564 xHCl (M-Brθ) is prepared analogously to "Example 21". The aqueous

EXAMPLE 27 10 phase is decanted off from the oily crude product after

NH acidification, and the residue is extracted by stirring with

H₂i ^NH- <CHj),-R' ethyl acetate and then filtered off with suction and dried. -.H₈₂C1N0₃ (740) MS: 711 (M-HCl+Li^*) 705 xHCl (M-C1^Θ) is prepared analogously to "Example 21".

C_3IH_3βClN₃θ_j (585) MS: 556 (M-HCl+Li*) 550 (M-C1^Θ) EXAMPLE 30

20

EXAMPLE 28

1.0 g (1.9 mmol) of amine b, 265 mg of NaBH₃CN and 610 35 mg of heptanal arc stirred in 10 ml of dry methanol at room temperature for 48 hours. The mixture is concentrated in vacuo, the residue is partitioned between ethyl acetate and

55

60 saturated bicarbonate solution and the residue of the organic is prepared analogously to "Example 28" and 'Εxample 29" phase is purified by chromatography. In addition to a small by reductive amination of anthracene-9-carbaldehyde with amount of monoheptylamino derivative, 650 mg (49%) of methyl 3α-(-jninoethyl)-7α, 12α-dihydroxy-24-cholanate

65 "Example 28" arc obtained. (d) and subsequent alkaline hydrolysis. C,₃H_β3N0₃ (718) MS: 725 (M+Li*) C_4IH₃₃N0₄ (625) MS: 632 (M+Li*)

-i EXAMPLE 31

is prepared analogously to "Example 30" using cyclodode- canonc as the carbonyl component. C_3βHg₇N0₄ (602) MS: 609 (M+Li*)

EXAMPLE 32

0.38 g (2 mmol) of naphthoyl chloride in 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 CH₂C1₂, while cooling with ice. The mixture is subsequently stirred at 0° C. for 1 hour and left 40 to stand overnight. Water is added, and the mixture is acidified and extracted several times with CH₂C1₂. The residue from the organic phase is purified by chromatography (Si0₂, EtOAc/cyclohexane=3:l). 1 g (83%) of "Example 32" is obtained. 45

C₃₈H₃₃N0₃ (603) MS: 610 (M+U*)

EXAMPLE 33

is prepared analogously to "Example 21" 65 C₃₇H₃₁NO_s (589 ) MS: 596 (M+Li*)

ϊϊ°l EXAMPLE 34

is prepared ι---logαuly to "Example 32" and "Example 33" EXAMPLE 37 using ---ιta-cι-πc-9-cϊrbonyl rhlπridr, C_MHJJ O, (639) MS: 646 tM+U^*)

EXAMPLE 35 is prepared a-u-logoutly to "E-u-πrpIc 34" using o-p-trnajtc

HΛ- V- SOj-WI-d-Hili-R' anhydride and snine b. CβHj-NO. <65S) MS: 668 CM-1T+21J') 662 M+LT) is prepared analogojtly to "Example 34" using p-toluenc-

3-rΛExample 33" c-hylfmTnimide. iftcr depratβnittcw by tedium hydride, with iodftitie-hwe at worn temperature The praauα it -ben iiibjectcd to --taline Taytkni ύt ail-tgoαsty lo Tot ample _M -3-Λ---PLB39 35". C_uH.,NO,S (675) MS: 688 ( -W+ r) 682 (M+LT)

y. o 426 mg (1 mmol) of urethane and 782 mg (15 mmol) of amine b arc heated under reflux in 50 ml of dioxane for 4 hours. The mixture is then concentrated and the residue is purified by chromatography (Si0₂, CH₂C1_J CH₃OH=10:1). 540 g (59%) of "Example 39" are obtained. C_4SH₇₀C1N₃0₁₀S (915) MS: 922 (M+Li*)

EXAMPLE 40

is prepared analogously to "Example 21". CcHβgClN_jO -S (901) MS (electrospray): 902 (M+H*) _∞

EXAMPLE 41

750 mg (3.6 mmol) of dicyclohεxylcarbodiimide are added to a solution of 1.56 g (3 mmol) of amine b, 576 mg (3

40 mmol) of China acid and 490 mg (83.6 mmol) of hydroxy- bcnzotriazolc in 100 ml of THF. The mixture is stirred at room temperature for 40 hours. The urea formed is filtered off, the solution is concentrated and the residue is taken up 45 in ethyl acetate. The solution is washed with saturated NaHCO, solution, 2N citric acid, saturated NaHC0₃ solution and water. The residue from the organic phase is purified by chromaιogτaphy (Si0₂, ethyl acetate/CH₃OH= ₀ 5:1). 1.2 g (58%) of "Example 41" are obtained. EXAMPLE 43

is prepared analogously to "Example 41"/"Example 42"

63 is prepared analogously to "Example 21". using gluconic acid.

C₃₇H₆₃NO_]0 (681) MS (FAB, 3-NBA): 682 (M+H*) C_stμ_aNO (685) MS: 714 (M-H*+Li*+Na*)

Y7 EXAMPLE 44

is prepared analogously to "Example 21".

C₄₂H_6SNO₁₀ (747) MS: 760 (M-H*+2Li*) 754 ((M+Li*)

is prepared analogously to "Example 21". 35

C₄₂H₆₇N0₉ (729) MS: 742 (M-H*+2Li*) 736 (M+U*)

EXAMPLE 46

SO

2.6 g (5 mmol) of amine b in CH₂C1₂ are added to 1.3 g (5 mmol) of acid chloride e and 0.8 ml of triethylamine in 50 ^5ϊ ml of dry CH₂C1₂, 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 temperamrc, 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

C₄₄H₇₃N0_I0 (775) MS: 783 (M+Li*)

< EXAMPLE 48

3.14 g (6 mmol) of alcohol a (n=6) are heated at 100° C. with 3 ml of cthyldiisopropylamine and 1.5 g of diphenylmethyl bromide in 50 ml of DMF for 8 hours. After aqueous working up and purification by chromatography (Si0₂, 20 CH₂C1₂/CH₃OH=10:1), "Example 48" is obtained.

EXAMPLE 49

is prepared analogously to "Example 21". 35

C._jH_β-O_β (674) MS: 681 (M+U*)

The following compounds are prepared analogously to Example 1 from the corresponding bile acid esters by alkaline ester hydrolysis:

40

EXAMPLE 50

aH₄.0.

55

60

65

U3 EXAMPLE 51

MW: 462 MS: 469 (M+Li*) hour, and the precipitate formed is filtered off with suction. After drying, 154 mg of "Example 54" are obtained. EXAMPLE 52 C₄.H„N,Oo

EXAMPLE 55

C₃₀H₅₃NO₄₄ MW: 491 MS: 498 (M+H*) EXAMPLE 53

45 is prepared from Example 44 and n-hεxylamine analogously to Example 41 with a reaction time of 25 hours. C₄₉H_B2N₂0₈ (827) MS: 834 (M+Li*)

50 Prepared analogously to "Example 53" and "Example 54"

EXAMPLE 54 from fluoresceine and amine b.

" from pivalic acid

n EXAMPLE 57

is prepared analogously to 'Εxample 55" from 2-ethylhex- anoic acid and amine b. 10 C₃₈H₆₇N0₆ (633) MS: 640 (M+U*)

EXAMPLE 58

is prepared analogously to 'Εxample 55" from clofibric acid 20 and amine b. C₄₀H₆₂CIN0₇ (703) MS: 710 (M+U*)

EXAMPLE 59

is prepared analogously to Εxample 55" from gemfibrocil 35 and amine b. C₄₃H₇₃N0₇ (740) MS: 747 (M+U*)

EXAMPLE 60

Prepared from 522 mg of amine b and 94.1 mg of di-n-pTopylmalonic acid in THF in the presence of DCC/ ^5S HOBT. Isolated after 54 h. The yield is 69%. (690) MS: 697 (M+U*)

60

65

y^ EXAMPLE 61

250 mg of "Example 60" arc hydrolyzed in dioxane using 2N NaOH. After aqueous work-up and purification by column chromatography (EtOAc/CH₃OH 10:1), 160 mg of compound 61 are obtained.

20 -continued

C₃₉H_β7N0₈ (676) MS: 677 (M+1)

We claim:

1. A monomeric bile acid derivative of the formula IA NH— ,

w al '. or H₂— N— <CH₂)_β

by a COOH

-

where A is in each case OH or NH (C_j-C,,,) alkyl.

2. A bile acid derivative of the formula I as claimed in claim 1, in which GS is linked to X in the 3-position, linking taking place in the α- or β-position.

3. A medicament comprising a bile acid derivative as claimed in claim 1.

4. A hypolipidemic agent comprising a bile acid derivative as claimed in claim 1.

Hti APPENDIX B

HMG CoA Reductase Inhibitors

COMPOUNDS CAS NUMBERS REFERENCE and for SPECIFIC and

COMPOUND CLASSES REPRESENTATIVE

COMPOUNDS

Benfluorex 23602-78-0 ES 474498 Ruvastarin 93957-54-1 EP 244364

L0V--.t3t.Tl 75330-75-5 EP 22478

Prav-Lsiaπn 81093-37-0 DE 3122499

Simvastariπ 79902-63-9 EP 33538

Atorvastatin 134523-00-5 EP 409281

Ccrivastarjn 145599-86-6 JP 08073432

Bervas atin and re-aied benzcpyτans 132017-01-7 EP 3S0392

BMS 180431 129S29-03-4 Sit, Parker, Mctoc, Has, Balasubra- manian, Cart, Brown, Haπe, Thompson, and Wright, J.Med. Cher (1990).33(11), 2982-99.

NK-104 141750-63-2 Takano, Kamikubo, Sugihara. Suzu : Ogasawara, Tecahei-oπ:Ass τ etry (1993).4(2), 201-4

(C--rboxyd-hydroxyhcptcnyl)sul cnylpvπo 14S966-78-3. 13999344-5, 139993- EP 464S45 les including S4522 45-6, 139993-46-7. 13999347-8,

13999348-9, 13999349-0. 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; 139993-694, 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, 1401KW3-0, 140128-98-9, 140128-99-0, 140157-62-6

Boron Analogs of di- and tripcpύdcs 125894-01-1, 125894-02-2, 125894- Sood, Sood, Spielvogel, Hall, Eur. J. 03-3, 125894-044, 125894-05-5, M«L Chem. (1990).25(4), 301-8. 125894-08-8, 125894-09-9, 125914- 96-7

Zaragozic acids 157058-13-4, 157058-14-5. 157058- GB 2270312 6 15-6, 157058-16-7, 157058-17-8. 157058-18-9. 157058-19-0

Seco-oxysterol analogs including 157555-28-7, 157555-29-8 Larsen, Spilman, Yεgi, Diπh, Haπ, and U-88156 Hess, J. Med. Chem. (1994), 37(15), 2343-51.

Pyridopyrirnidines including arite ate 6440540-9, 101197-99-3 Hermecz, Meszaros, Vasvari-Debreczy, Horvath, Virag, and Sipos. Hung. Arzneim-Forsch. (1979), 29(12), 1833-5

BMY 22566 129829-034 Sit, Parker, Motoc, Han, B-Jasubra- canian, Cart, Brown, Hane, Thompson, and Wright, J.Med. Chem. (19S0), 33(11), 2982-99.

Colestolone 50673-97-7 Raulston, Mishaw, Parish ^d Schroepfer, Biochem. Biophys. Res. Commun. (1976), 71(4), 9S4-9.

CP-83101 130746-S2-6. 130778-27-7 Wat and McCarthy, J. Labelled Compd. R2dioph--rm. (1SSS), 25(11), 1289-97.

Dalvastaπn 132100-55-1 urcar, Windisch, Trive i and Golebiowski, J. Chrcmatogr., A (1994). 678(2), 259-63.

DihydromeYinolin 77517-294 Falck and Yang. Tetrahedron Lett. (1984), 25(33).3563-66. DMP-565 Ko.Trz-iskos, Chen, Hausύer, Brosz, and Srivastava, Absσ. Papers Am. Chem. Soc. (207th Nanonal Meedng. Part 1, MEDI 10, 1994)

Pyridyl and Pyrimidinylethenyldesmethyl- 12225445-9 Beck, esseler, Baader, Bartrnann, evalonates including glenvastin Bergmann, Granzer, Jendral-a, Von Kerekjaπo, Krause, et al, J. Med. Chem. (1990), 33(1).52-60.

GR 95030 157243-22-6 US 5316765

--»xa--oIopyridylιnevalonates, carboxylic 13058142-9, 13058143-0, 130581- EP 369323 a ids and esters 44-1, 13058145-2, 13058146-3,- 130581474, 13058148-5, 130581- 49-6, 130581-50-9, 130581-51-0. 130581-52-1, 130619-07-7, 130619- 08-8, 130619-09-9

Laαonα of 6-phenoxy-3,5-dihydroxy- 12750248-1. 136006-66-1, 136034- Jenderella, Granzer, Von Kerekjaπo, hexanotc adds 04-3 Krause, Schacht, Baader, Bar-π-ar-n,

W Beck, Bergmann, et al., J. Med. Chem. (1991).34(10).2962-83.

L 659699 2906642-0 Chiang. Yang, Heck, Ctabal--, and Chang, J. Org. Chem. (1989), 54(24). 5708-12.

L 669262 130468-11-0 Stokker, J. Org. Chem. (1994). 59(2.0). 5983-6.

Mevastarjn 73573-88-3 JP 56051992

Pa-morin 137023-81-5 Ogawa, Hasumi, Sakai, Mur--V.-.wa and Endo. J. Antibiot. (1991), 44(7).762-7

Rawsonol 125111-69-5 Carte, Troupe, Chan, Westley and Faulkner, Phytoche istr/ (1989). 28(11).2917-19

RP 61969 126059-69-6 EP 326386

Eile add derived HMG CoA reductase Kramer, Wess, Ed-sea, Eock, Falk, inhibitors including Na S-2 67 and Hof mann, Neckeπr-ai-r-, Ganrz, Schulz, S-2468 et al., Bio-tiro. Eiophys. Acta D (1994), 1227(3). 137-54.

SC 32561 7675241-5 US 4230626

SC 45355 125793-76-2 EP 329124

Phosphorus containing HMG CoA 133983-25-2 US 5274155 reductase inhibitors including SQ 33600

6-A-yioxymemyl-4-hyd-Oxyxetrahydro- 135054-71-6, 136215-82-2, 136215- EP 418643 pyran-2-ones, carboxylic adds and salts 83-3. 136215-844, 136215-85-5, 136315-18-9. 136315-19-0, 136315- 20-3, 136315-214. 136316-20-6

Atorvastadn calάum (CT 981) 154523-03-S Baumann, Butler, Deering, Mermen, Millar, Nanninga, Palmer and Roth, Tetrahedron Lea. (1992).33(17), 2283-

Fenof-br-L-e 49562-28-9 DE 2250327

Ben---£bra-ε 41859-67-0 DE 2149070

• Etofibrate 31637-97-5 US 3723446

Mevinolin analogs EP 245003

Pyranone derivarives US 4937259

lA4-Triazolidinc-3 -<Jion^β 16044-43-2 WO 9000897

Y?o Isoazolidine-3,5-diones 124756-24-7 EP 321090

CS-514 81181-70-6 DE 3122499 l,10-bU(carbox>ττιe-hylthio)decane 3282749-9 DE 2038835 α-, β-, and γ -alkylaminophenone analogs Huang and Hall, Eur. J. Med. Chem. including N-phenylpiperarinopropio- (1996), 31(4), 281-90. phencne

3-Amir,o-l-(2,3,4-moπonitro-, mono-, or Huang and Hall, Arch. Ph-irπ. (1 96). dihalophenyl)pπ.pan-l-cαes including 3- 329(7).339-346. mo holino or piperidino-l-O- nitrophenyl)propan-l-ones

Substituted isoxazclo pyridinones 64769-68-2 US 4049813

Biphenyl derivatives JP 07089898

4-[l-(Subsrituted phenyl>2-oxo- Wareπabe, Oga a, Ohno, Yano, pyrro-idin-4-yrjmethoxybe--zoic adds Ya ada and Shirasaka, Eur. J. Med. Chem. (1994), 29(9). 675-86.

DΛydroxy(tetrahydroind--zolyl, US 5134155 tetrahydrocyclopentapyra2olyl, or he-ft-ahydrocy-clohepDp>τa2θle)heptencate derivatives

V7 / benf luorex Servier f luvastatin Sandoz lovastati Merc & Co ^■ pravastatin Sankyo sirr-vastatin Merck & Co atorvastatin Warner-Lambert cerivastatin Bayer bervastatin Merck KGaA

BMS-180431 Bristol-Myers Squibb

NK-10 Nissan. Chemical

S-4522 Shionogi

Eoron Analogs Eoron Biologicals

KMG-CoA Reductase Inhibitors British Biotech £.

Japan Tobacco

KMG-Ccλ Reductase Inhibitors Merck S. Co U-88156 Pharmacia £. Upjohn.

A-1233 Kitasato University acitemate Mitsubishi Chemical

BAY-w-9533 Eayer

EB-476 British Eiotech

BMS-1S043S Eristol-Myers Squibb

BMY-22566 colestolone American Kome Products

CP-83101 Pfizer dalvastatin Rhone-Poulenc Rorer dihydrcmevinolin Merck & Co

DMP-565 DuPont Merck glenvastatin Koechst Marion Roussel

GR-95030 Glaxo Wellcome

KMG-CoA Reductase Inhibitors Bristol-Myers Squibb

HMG-CoA Reductase Inhibitors Ono

KMG-CoA Reductase Inhibitors, Chiral Chiroscience

KMG-CoA Reductase Inhibitors, isoxazolo- Nissan Chemical pyridine KMG-CoA Reductase Inhibitors, εeco-oxysterol Pharmacia & Upjohn KMG-CoA Reductase Inhibitors, thiophene Sandoz KMG-CoA Reductase Inhibitors, 6-phenoxy- Koechst Marion Roussel

3,5-dihydoxyhexanoic acids hypolipaemics, Warner-Lambert Warner-Lambert L-65S699 Merck & ^'Co L-669262 Merck & Co evastatin Sankyo N- ( (1-methylpropyl) carbonyl} - Sandoz

8-(2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-

2-yl) ethyl) -perhydro-isoquinoline

?<^ N- (1-cxococecyl) -4alpha, 10-dimethyl-8- Koechst Marion Roussel aza- rans-decal-3beta-ol^• P-882222 Nissan Chemical pannorin Tokyo Noko University rawsonol SmithKline Beechara RP 61969 Rhone-Poulenc Rorer S-2468 Koechst Marion Roussel S-853758A Koechst Marion Roussel (S) -4- ( (2- (4- (4-fluorophenyl) -5-me hyl- Eristol-Myers Squibb

2- (1-methylethyl) -6-phenyl-3-pyridinyl) ethenyl ) hydroxyphosphinyl) -

3-hydroxybutanoic acid, disodium salt SC-32561 Monsanto sc-45355 Ncn-industrial source SDZ-265859 Sandoz SQ-33600 Eris tol-Myers Squibb (4R-(4alpha,6beta(E)))-6-(2-(5-(4- Warner Lambert fluorophenyl) -3- (1-methyl-ethyl) -1-

(2-pyridinyK-pyrazol-4 -yl) ethenyl) tetrahydro-4-hydroxy-2H-pyran-2-one 5-beta-amino-ethylthiopentanoic Eoehringer Mannheiia acid derivatives 6-amino-2-mercapto-5-methylpyri idine North Carolina Univers it

-4-carboxylic acid 6-phencxy e hyl- & 6-phenylethylen- Koechst Marion Roussel

( -hydroxy-tetrahydrcpyran-2-one) analogues atorvas tatin

(4R- ( 4alpha, βbeta (E) ) ) -6- (2- (5- (4-fluorophenyl) -3-

( 1-methyl-ethyl ) -1- ( 2 -py idinyK-pyrazol-4-yl) ethenyl) tetrahydro- -hydroxy-2H-pyran-2 -one

γ73

Claims (6)

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. 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.

4. The pharmaceutical composition of claim 3 wherein the HMG Co-A reductase inhibitor is selected from the group consisting of lovastatin, simvastatin, pravastatin and fluvastatin.

5. A combination therapy method for the prophylaxis or treatment of a hyperlipidemic condition in a mammal, comprising: administering to said patient a first amount of an ilea! bile-acid transport- inhibitor, and_, administering to said patient 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.

6. The combination therapy method of claim 5 wherein the HMG Co-A reductase inhibitor is selected from the group consisting of lovastatin, simvastatin, pravastatin and fluvastatin.

V7^~