SK125099A3 - Combination of ileal bile acid transport inhibiting benzothiepines and hmg co-a reductase inhibitors - Google Patents

Abstract

Provided are novel benzothiepines, derivatives, and analogs thereof; pharmaceutical compositions containing them; and methods of using these compounds and compositions in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions such as those associated with atherosclerosis or hypercholesterolemia, in mammals. Also provided are compositions and methods for combination therapy employing ileal bile acid transport inhibitors and HMG Co-A reductase inhibitors for the treatment of hyperlipidemic conditions.

Description

The invention relates to novel benzotiepines, their derivatives and analogs in combination with HMG CoA reductase inhibitors, pharmaceutical compositions containing them, and the use of these compositions in medicine, particularly in the prophylaxis and treatment of hyperlipidemia associated with atherosclerosis or hypercholesterolemia in mammals.

BACKGROUND OF THE INVENTION

It is well known that hyperlipidemia associated with elevated concentrations of total cholesterol and LDL cholesterol are a major risk factor for coronary heart disease and especially atherosclerosis. Prevention of bile acid circulation within the intestinal tract reduces serum cholesterol levels in a direct relationship. The epidemiological data that are collected suggest that such a reduction leads to an improvement in the health status of atherosclerosis. Stedronsky, in the article "Interaction of bile acids and cholesterol with nonsystemic agents having hypocholesterolemic properties", Biochimica et Biophvsica Acta. 1210 (1994) 255-287, discusses biochemistry, physiology and known active agents related to bile acids and cholesterol.

Pathophysiological changes are associated with the interruption of the enterohepatic bile acid circulation in humans, as shown in Heuby, J. E., et al., "Primary Bile Acid Malabsorption: Defective in Vitro Heal Active Bile Acid Transport", Gastroenterology. 1982; 83: 804-11.

The fact remains that cholestyramine binds bile acid in the intestinal tract, thus preventing its normal inclusion in enterohepatic circulation (Reihnér, E. et al., "Regulation of hepatic cholesterol metabolism in humans; stimulators of cholestyramine effects on HMG-CoA reductase activity and low density" lipoprotein receptor expression in gallstone patients ", Journal of Lipid Research, Volume 31, 1990, 2219-2226 and Suckling et al.," Cholesterol Lowering and White Acid Excretion in the Hamster with Cholestyramine Treatment ", Atherosclerosis. 89 (1991) 183-190 ). This leads to increased hepatic bile acid synthesis by cholesterol-utilizing liver, as well as increased regulation of hepatic LDL receptors, which increase cholesterol secretion and lower serum LDL cholesterol levels

In a further approach to the reduction of bile acid recirculation, the ileal bile acid transport system is an anticipated pharmaceutical target for the treatment of hypercholesterolaemia, based on

- to disrupt enterohepatic circulation by specific transport inhibitors (Kramer, et al., Jntenstinal Bile Acid Absorption, The Journal of Biological Chemistrv. Vol. 268, No. 24, Issue of August 25, pp. 18035-18046, 1993).

In a series of patent applications, Canadian patent application no. 2,025,294; 2,078,588; 2,085,782; and 2,085,830 and EP application no. 0 379,161; 0 549,967; 0 559 064; and 0 563 731, Hoechst Aktiengesellschaft discloses polymers of various naturally occurring components of the enterohepatic circulatory system and derivatives thereof, including bile acids, which inhibit the physiological transport of bile acids to reduce LDL cholesterol levels sufficiently for their use as pharmaceuticals, particularly as hypercholesterol. agent.

In vitro inhibition of bile acid transport showing hypolipidemic activity is shown in "The Wellcome Foundation Limited Disclosure" of International Patent Applications No. WO 93/16055 for "Hypolipidemic Benzothiazepine Compounds".

Selected benzotiepines are described in International Patent Application No. WO 93/321146 for many uses including fatty acid metabolism and coronary vascular disease.

Other selected benzotiepines, known for use as a hypolipaemic and hypocholesterolaemic agent, especially for the treatment or prevention of atherosclerosis are described in patent application no. EP 508425, FR 2661676 and WO 92/18462, each of which is limited to an amide-bonded carbon adjacent to the phenyl ring of the linked bicyclobenzothiepine core.

The references above show an ongoing effort to find a safe, effective agent for the prophylaxis and treatment of hyperlipidemic diseases and their use as a hypocholesterolemic agent.

Other selected benzotiepines are described for use in the treatment of various disease states outside the scope of the invention. These are EP 568 898A listed as an abstract in Derwent Abstract no. 93351589; WO 89/1477 / A disclosed as an abstract in Derwent Abstract no. 89-370688; U.S. 3,520,891 listed as abstract in Derwent Abstract 50701R-B; U.S. 3,287,370, U.S. 3,389,144; U.S. Pat. No. 3,694,446 issued as an abstract in Derwent Abstract no. 65860T-B and WO 92/18462

HMG Co-A reductase inhibitors are 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, the initial and slowest step in cholesterol synthesis.

-3Benzotiepine antihyperlipidemic agents are described 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-A61949 / 94.

The invention is the result of efforts to develop a novel pharmaceutical composition and methods of treating hyperlipidemic conditions.

SUMMARY OF THE INVENTION

The invention provides compounds of formula (I):

g is an integer from 1 to 4; a is an integer from 0 to 2;

R ¹ and R ² 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 are optionally substituted with one or more substituents selected from the group consisting of OR ⁹ , NR ⁹ R ¹⁰ , R ^9, R ⁹ , S ⁹ R ^{9 1 °} and R ', P + r'r'Va; S (O) R ^9, SO 2 R ^9, SO ₃ R ^9, CO 2 R ^9, CN, halogen, oxo, and COR'R ^10, wherein the alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and optionally containing cykolalkyl one or more of the carbons replaced by O, NR ⁹ , N * R ⁹ R ¹⁰ A ', S, SO, SO ₂ , S ^ R'', P ^ R'R' A ', or hairdryer, wherein R ⁹ and R ¹⁰ and R ^w are independently selected from H, alkyl, alkenyl, alkynyl, cykolalkyl, aryl, acyl, heterocycle, heteroaryl, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; the sky

R ¹ and R ² together with the carbon to which they are attached form a C 3 -C 10 cycloalkylidene;

-4R ³ and R ⁴ are independently selected from the group consisting of alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, heteroaryl, OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S (O) R ⁹ , SO ² R ⁹ , and SO ³ R ⁹ wherein R ⁹ and R ¹⁰ are as defined above; or

R ³ and R ⁴ together form = 0, = N0R ^n, = S, = NNR ⁿ R ^12, = NR ^9, or = CR ⁿ R ^12, wherein R ¹¹ and R ¹² are independently selected from H, alkyl, alkenyl, , alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, heteroaryl, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR ^9, NR ⁹ R ^10, SR ^9, S (O) R ^9, SO 2 R ^9, SO 3 R ^9, CO 2 R ^9, CN, halogen, oxo, and CONR ⁹ R ¹⁰ , wherein R ⁹ and R ¹⁰ are as defined above, such that R ³ and R ⁴ cannot be OH, NH 2, and SH or

R ¹¹ and R ¹² together with the nitrogen or carbon atom to which they are attached form a cycle;

R ⁵ and R ⁶ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, SR ⁹ , S (O) R ⁹ , SO a R ⁹ and SO, R ⁹ wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl may be substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ¹³ R ¹³ and SO ³ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ^15, N02, CO 2 R ^13, CN, OM, S0 ₂ 0M, SO ₂ NR ¹³ R ^14, C (O) NR ¹³ R ^14, C (0) 0M, COR ^13, P (O) R ¹³ R ^14, L ⁺ NR ¹³ NR ¹⁴ R ¹⁵ A, P (OR ¹³⁾ OR ^14, SWA; Anfra ^ A;

where:

is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl may be further substituted with one or two substituents selected from OR ⁷ , NR ⁷ R ⁸ , SR ^7, S (O) R ^7, SOzR ^7, SO ₃ R ^7, coire ^7, CN, oxo, CONR ⁷ R ^8, N + R 'R'', alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P (O) R ⁷ R ⁸ , P ⁺ R ⁷ R ⁸ R ⁹ A 'and P (O) (OR ⁷ ) OR ⁸ , and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl may optionally have one or more carbon atoms replaced by O, NR ⁷ , N 4 R ^7a ; S, SO, S0 _2, TFA ", PR ^7, P (0) R ^7, PR ⁷ R ⁸ A; or phenylene and R ¹³ , R ¹⁴ and R ¹⁵ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, quaternary heteroarylalkyl,

-5-where alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, heteroaryl, polyalkyl optionally have one or more carbon atoms replaced by O, NR ⁹ , N ⁹ R ⁹ R ¹⁰ A ', S, SO, SO 2, S 4 R 8', PR ⁹ , P? R'R? A ', P (O) R ⁹ , phenylene, carbohydrate, amino acid, peptide or polypeptide; and

R ¹³ , R ¹⁴ and R ¹⁵ are optionally substituted with one or more substituents selected from the group consisting of sulfoalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR ⁹ , NR ⁹ R ¹⁰ , NW 6, SR ⁹ , S (O) R ⁹ , SO ² R ⁹ , SO ³ R ⁹ , oxo, CO ₂ R ⁹ , CN, halogen, CONR ⁹ R ¹⁰ , SO 2OM, SO ₂ NR ⁹ R ^w , Ρ (Ο) (Ο ^ ⁶ ) Ο ^ ⁷ , PR ⁹ R ¹⁰ R ⁿ A- and SWa 'and C (O) OM, wherein R ¹⁶ AR ¹⁷ are independently selected from the substituents forming R ⁹ and M, or

R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a cycle

R ^{7 and} R ⁸ are independently selected from the group consisting of hydrogen and alkyl, and one or more R ^x is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl , polyether, heterocycle, quaternary heteroaryl, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , S (O) 2 R ¹³ , SO ³ R ¹³ , S 4 RA, NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO2, CO2R ¹³ , cn, om, so2, so ₂ nr ¹³ r ¹⁴ , NR ¹³ C (O) R ¹⁴ , C (O) NR ¹³ R ¹⁴ , NR ¹⁴ C (O) R ¹³ , C ( O) OM, COR ¹³ , OR ¹⁸ , S (O) n R ¹⁸ , nr ¹³ r ¹⁸ , NR ¹⁸ OR ¹⁴ , N + r'r '^' A ', P + R'R ^^ A', amino acid , peptide or polypeptide, carbohydrate wherein alkyl, alkenyl, alkynyl, polyalkyl, heterocycle, heteroaryl, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, quaternary heteroaryl may be further substituted with OR ⁹ , NR ⁹ R ¹⁰ , N 4 R'R ^ ¹ ^ ^12, SR ^9, S (O) R ^9, SO 2 R ^9, SO ₃ R ^9, oxo, CO ^ ^9, CN, halogen, CONR ^10, S020M, SOiNR'R ¹⁰ , P (O) (OR ¹⁶ ) OR ¹⁷ , FIW 6, S 6 R 6 A ', C (O) OM and wherein R ¹⁸ is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle heteroaryl quaternary wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, quaternary heteroaryl may optionally be substituted with one or more substituents selected from the group consisting of OR ⁹ , NR ⁹ R ¹⁰ , N ⁹ R ^9, R ⁹ , SR ^9, S (O) R ^9, SOIR ^9, SO 3 R ^9, oxo, CO 2 R ^9, CN, halogen, CONR ⁹ R ^10, SO ₂ M, SO ₂ NR ⁹ R ^10, P (OXOR ¹⁶⁾ OR ^17, C (O) OM, where in R ^x one or more carbon atoms may optionally be replaced by O, NR ¹³ , N * R ¹³ R ¹⁴ A ·, S, SO, SO ₂ , SV'A *, Ι, ¹³ , Ρ ( Ο) ^{13 13} , P + R R R ¹⁴ ,, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether or polyalkyl,

Anywhere in said polyalkyl, phenylene, peptide, polypeptide, and carbohydrate, one or more carbon atoms may be replaced by O, NR ⁹ , N + R'R 4 A; S, SO, SO 2, SR ⁹ A ', PR ⁹ , P 1 R 1 R 1 A; P (O) a R '.

wherein the quaternary heterocycle and the quaternary heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , S (O) 2R ¹³ , SO ³ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO 2OM, SO ₂ NR ' ³ R ¹⁴ , C (O) NR ¹³ R ¹⁴ , C (O) OM, COR ¹³ , P (O) R ¹³ R ¹⁴ , P + R 6 R 6 R 6 A; P (OR ¹³ ) OR ¹⁴ , S 1 'r'U', N * RWa;

provided that R ⁵ and R ^R may not be hydrogen, OH, or SH, and wherein R ⁵ is OH, R ^1, R ^2, R ^3, R ^4, R ⁷ 'R ⁸ can not all be hydrogen, provided that that when q = 1 and R ^x is a styryl, anilide or anilinocarbonyl group, only one of R ⁵ or R ⁶ is alkyl; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

Preferably R ⁵ and R ⁶ are independently selected from the group consisting of H, aryl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, wherein said aryl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl may be substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , S (O) j R ¹³ , SO 3 R ^13, NR ¹³ OR ^14, NR ¹³ NR ¹⁴ R ^15, NO 2, CO 2 R ^13, CN, OM, SO2OM, SO 2 NR ¹³ R ^14, C (O) NR ^I3 R ^14, C (O) OM, COR ^13, p (0) r ¹³ r ¹⁴ , p 1 'r 1'a; p (or ¹³ ) or ¹⁴ , s ⁺ r ^13, r ¹⁴ a; nW ^ a;

wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl may optionally have one or more carbon atoms replaced by O, NR ⁷ , NW a; S, SO, SO ₂ , sVa; pr ⁷ , pVr'a; P (O) R ⁷ or phenylene, wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl may be further substituted with one or more substituents selected from the group consisting of OR ⁷ , NR ⁷ R ⁸ , SR ^7, S (O) R ^7, SO 2 R ^7, SO 3 R ^7, CO 2 R ^7, CN, oxo, CONR ⁷ R ^8, N + R'r'r'A ', alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, , heteroaryl, quaternary heterocycle, quaternary heteroaryl, P (O) R ⁷ R ⁸ , P 4 R'R '' and P (O) (OR ⁷ ) OR ⁸ .

More preferably, R ⁵ or R ^{6 have the} formula:

-Ar- (R ^y ) t wherein t is an integer from 0 to 5;

-ΊAr is selected from the group consisting of phenyl, thiophenyl, pyridyl, piperazinyl, piperonyl, pyrrolyl, naphthyl, furanyl, anthranyl, quinolinyl, isoquinolinyl, quinoxalinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrimidinyl, thiazolyl, triazolyl, isothiazolol, , benzoxazolyl, benzothiazolyl and benzoisothiasolyl;

one or more R ^y is independently selected from the group consisting of H, alkyl, alkenyl, aryl, alkynyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR ⁹ , SR ⁹ , S (O) R ⁹ , SO ² R ⁹ , SO ³ R ⁹ , wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl may independently be substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl , halogen, oxo, OR ^13, NR ^I3 R ^14, SR ^13, S (O) R ^13, SO 2 R ^13, SO 3 R ^13, NR ¹³ OR ^14, NR ^I3 NR ¹⁴ R ^15, NO 2, COzR ^13, CN, OM, SO2OM, SCfcNA ¹⁴ , C (O) NR ¹³ R ¹⁴ , C (O) OM, COR ¹³ , P (O) R ¹³ R ¹⁴ , p * r ^{, 3} r ¹⁴ r ¹⁵ a; p (Or ¹³ ) or ¹⁴ , s 1, p 1, p 1, p 1, p 1, p 1, p 2, p 2 (p ¹ ); NIWA;

wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl may be further substituted with one or more substituents selected from the group consisting of OR ⁷ , NR ⁷ R ⁸ , SR ⁷ , S (O) R ⁷ , Soar ^7, SO 3 R ^7, CO ₂ R ^7, CN, oxo, R ⁷ C0NR ^8, N @ R'r'r'A, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, heteroaryl quaternary, P (O) R ⁷ R ⁸ , P ⁺ R ⁷ R ⁸ R ⁹ A 'and P (O) (OR ⁷ ) OR ⁸ wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl cycloalkyl, heterocycle, heteroaryl may optionally be replaced by one or more carbon atoms O, NR ⁷ , N ⁺ R ⁷ R ⁸ A ', S, SO, SO 3, S 2 A; PR ⁷ , P ^ R'r'a; P (O) R ⁷ or phenylene.

Most preferably R ⁵ or R ^{6 have the} general formula Π

The invention further relates to compounds selected from the following: R ²⁰ -R ¹⁹ -R ²¹ (Formula D1)

R ²²

I

R ²⁰ -R ¹⁹ -R ²¹ (formula DII),

8a-

R ²²

I

R ²⁰ -R ¹⁹ -R ²¹ (Formula Dffl)

I

R ²³ wherein R ¹⁹ is selected from the group consisting of alkanediyl, alkenediyl, alkindiyl, polyalkanediyl, alkoxydiyl, polyetherdiyl, polyalkoxydiyl, carbohydrate, amino acids, peptide and polypeptide, wherein alkandiyl, alkenediyl, alkindiyl, polyalkoxydiyl, carbohydrate, amino acids, peptide and optionally one or more carbon atoms replaced by O, NR ⁷ , N ⁺ R ⁷ R ⁸ , S, SO, SO 2, S 4 R ⁸ , PR ⁷ , P 4 R ⁸ R ⁸ , phenylene, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl or aryl wherein the alkanediyl, alkenediyl, alkindiyl, polyalkanediyl, alkoxydiyl, polyetherdiyl, polyalkoxydiyl, carbohydrate, amino acid, peptide and polypeptide, wherein the alkanediyl, alkenediyl, alkindiyl, polyalkoxydiyl, carbohydrate, substituent or polypeptide may be a substituent or a polypeptide independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, ha Logen, oxo, OR ^13, NR ¹³ R ^14, SR ^13, S (O) R ^13, SO 2 R ^13, SQjR ^13, NR ¹³ OR ^14, NR ¹³ NR ^I4 R ^15, NO 2, CO 2 R ^13, CN, OM, SO2OM , SO 2 NR ¹³ R ^14, C (O) NR ¹³ R ^14, C (O) OM, COR ^13, P (O) R ¹³ R ^14, R p'r ^ a; P (OR ¹³ ) OR ¹⁴ , s + r '4a;NIWA;

wherein R ¹⁹ further comprises a functional linker that is R ¹⁹ bonded to R ²⁰ , R ²¹ or R ²² in compounds of Formula DII and DIU and R ²³ in compound of Formula DHL Each of R ²⁰ , R ²¹ or R ²² and R ²³ comprises a benzothiepine skeleton as described above, which is therapeutically effective as an inhibitor of ileal bile acid transport.

The invention further relates to compounds selected from those of formula DI, formula DII and formula DID, wherein each of R ²⁰ , R ²¹ , R ²² and R ²³ comprises a benzothiepine skeleton of the formula

(Formula DIV) or

(formula DIVA) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ^x , q and n are the same as in the definition of Formula I above and R ⁵⁵ is either covalently bonded or aiylene.

In the compounds of formula DIV, it is particularly preferred that each of R ²⁰ , R ²¹ , R ²² in the formula DH and DRI and R ²³ in the formula DRI are bonded at their 7- or 8- position to R ¹⁹ .

In compounds of formula DIVA, it is particularly preferred that R ⁵⁵ contains a phenylene moiety bonded on its m- or p-carbon to R ¹⁹ .

Examples of general formulas DI include:

<R%

In any of the dimeric or multimeric structures defined above, the benzothiepine compound of the invention may be used alone or in various combinations.

In any compound of the invention, R ¹ and R ² may be ethyl / butyl or butyl / butyl.

Other compounds used in the invention as ileal bile acid transport inhibitors are shown in Appendix A.

The invention provides pharmaceutical compositions for the prophylaxis or treatment of diseases or conditions in which the need for bile acid transport inhibitors such as hyperlipidemia, for example atherosclerosis, is indicated. Such compositions comprise any of the compounds described above, alone or in combination, with an amount effective to reduce the level of bile acids in the blood, or to reduce their transport through the gastrointestinal membranes, and pharmaceutically acceptable carriers, excipients or solvents.

The invention also provides a method of treating a disease or condition in a mammal, including a human, in need of bile acid transport inhibitors, including

Administering to a patient in need thereof in an effective amount in dosage units or in divided doses.

The invention also provides a process for preparing the compounds of the invention.

The invention encompasses the combination therapy comprising the use of both ileal bile acid transport inhibitors and HMG CO-A reductase inhibitors, useful for the treatment of hyperlipidemic disorders, wherein a plurality of said agents together constitute an effective amount of said agents for the treatment of hyperlipidemic conditions.

The HMG CO-A reductase inhibitor compounds used according to the invention are shown in Appendix B.

Other embodiments of the invention will be apparent from the detailed description below. However, it is to be understood that the following detailed description and examples, although indicating a preferred embodiment of the invention, are given as a way of illustration within the spirit of the invention and will be apparent to those skilled in the art from the detailed description.

The following detailed description of the invention serves to assist those skilled in the art in carrying out the invention. Even this detailed description is not designed to unduly limit the invention. Modifications and variations of the portions discussed herein may be made by those skilled in the art without departing from the spirit of the invention.

The contents of each of the references cited herein, including the contents of references cited within the primary references, are incorporated herein in their entirety.

To assist the reader to understand the following detailed description, the following definitions are provided.

"Alkyl", "alkenyl", and "alkynyl" without further notice are straight or branched hydrocarbon chains of one to twelve carbon atoms for alkyl or two to twelve carbon atoms for alkenyl and alkynyl of the invention and are, for example, methyl, ethyl, propyl, butyl, pentyl or hexyl and ethenyl, propenyl, butenyl, pentenyl or hexenyl and ethynyl, propynyl, butynyl, pentynyl or hexinyl, respectively, and their isomers.

"Aryl" means a fully unsaturated mono- or poly-carbon cycle, including, but not limited to, substituted or unsubstituted phenyl, naphthyl or anthranyl.

"Heterocycle" means a saturated or unsaturated one or more carbon ring, where one or more carbon atoms may be replaced by N, P, S or O. For example, the following structures are included:

- 12ζ

wherein Z, Z ', Z "or Z"' are C, S, P, O or N, provided that one of Z, Z ', Z "or Z"' is other than carbon but carries O or S when bonded to another Z atom by a double bond or when bonded to another atom O or S. In addition, optional substituents are understood to be bonded to Z, Z ', Z "or Z"' only when each is C.

The term "heteroaryl" means a fully unsaturated heterocycle.

For both "heterocycle" and "heteroaryl", the site of attachment to the molecule may be a heteroatom or any ring atom.

The term "quaternary heterocycle" means a heterocycle in which one or more heteroatoms, for example O, N, S or P, have such a plurality of bonds that they contain a positive charge. The point of attachment of the quaternary heterocycle to the target molecule may be a heteroatom or any other atom.

The term "quaternary heteroaryl" means a heteroaryl in which one or more heteroatoms such as O, N, S, or P have such a plurality of bonds that they contain a positive charge. The site of attachment of the quaternary heteroaryl to the target molecule may be a heteroatom or any other atom.

The term "halogen" means a fluoride, chloride, bromide or iodide group.

The term "haloalkyl" means alkyl substituted with one or more halogens.

The term "cycloalkyl" means a one or more membered carbon cycle wherein each ring contains from three to ten carbon atoms, and wherein any ring may contain one or more double or triple bonds.

The term "diyl" means a biradical particle, wherein said particle contains two sites of binding to the target molecule.

The term "oxo" means oxygen bound by a double bond.

The term "polyalkyl" means a branched or straight hydrocarbon chain having a maximum molecular weight of 20000, more preferably 10,000 and most preferably 5000.

The term "polyether" means a polyalkyl wherein one or more carbon atoms are replaced by oxygen, wherein the molecular weight of the polyether is at most 20000, more preferably 10,000 and most preferably 5000

- 13 The term "polyalkoxy" means a polymer of alkylene oxides wherein the polyalkoxy has a molecular weight of at most 20000, more preferably of 10000 and most preferably 5000.

The term "cycloalkylidene" means a one or more membered carbon ring, wherein the carbon inside the ring is bound by a double bond to an atom that is not inside the ring

The term "carbohydrate" means a mono-, di-, tri- or polysaccharide with a maximum molecular weight of 20,000, for example hydroxypropyl methylcellulose or chitosan.

The term "peptide" means a polyamine acid containing up to 100 amino acid units

The term "polypeptide" means a polyamine acid comprising from 100 amino acid units to 1000 amino acid units, more preferably from 100 to 750 amino acid units, and most preferably from 100 to 500 amino acid units.

The term "alkylammonium alkyl" means an amino group NH 2 or a mono-, di- or trisubstituted amino group, any of which is bound to an alkyl, wherein said alkyl is bound to a molecule.

The term "triazolyl" includes all positional isomers. In all other heterocycles and heteroaryls that contain more than one ring heteroatom and for which isomers are possible, these polymers are included in the definition of the so-called heterocycles and heteroaryls.

The term "sulfoalkyl" means an alkyl group to which a sulfonate group is attached, wherein said alkyl is bound to a molecule.

The term "active compound" refers to a compound of the invention that inhibits bile acid transport.

When used in combination, for example, the terms "alkylaryl" or "arylalkyl", the individual terms described above have the same meaning as above.

The term "bile acid transport inhibitor" means a compound capable of inhibiting the absorption of bile acids from the intestine into the circulatory system of a mammal, including a human. This includes increasing fecal excretion of bile acids as well as reducing cholesterol and esterified cholesterol concentrations in blood plasma or serum, and more specifically reducing LDL and VLDL cholesterol. Diseases or diseases that are beneficial for the prophylaxis or treatment of inhibiting bile acid transport include, for example, hyperlipidemic conditions such as atherosclerosis.

The phrase "combination therapy" refers to the administration of bile acid transport inhibitors and HMG Co-A reductase inhibitors in the treatment of hyperlipidemic conditions such as atherosclerosis and hypercholesterolemia. The administration comprises co-administering these inhibitors in substantially simultaneous amounts in the form of a single capsule containing a fixed

14 ratio of active ingredients or more capsules per inhibitory compound. In addition, such administration involves such uses of each type of inhibitor in sequential amounts. In this case, the treatment regimen is carried out with the beneficial effect of the combination of drugs in the treatment of hyperlipidemic conditions.

The phrase "therapeutically effective" refers to the combination of a plurality of inhibitors in combination therapy. These combined amounts achieve the goal of reducing or eliminating hyperlipidemic conditions.

The compounds of the invention may have at least two asymmetric carbon atoms and thus include racemates or stereoisomers, for example diastereoisomers and enantiomers, both in their pure forms and in subsequent mixtures. These stereoisomers can be prepared by standard methods, either by reaction of enantiomeric substances or by separation of isomeric compounds of the invention. Isomers may include geometric isomers such as cis, trans isomers through a double bond. All of these isomers are contemplated for all compounds of the invention.

The compounds of the invention also include tautomers.

Compounds of the invention include salts, solvates and prodrugs thereof.

The starting materials used in the preparation of the compounds of the invention are known or can be prepared by standard methods known to those skilled in the art or by procedures analogous to those described in the art.

In general, the compounds of the invention can be prepared by the procedures described below.

For example, as shown in Scheme I, reaction of aldehyde Π with formaldehyde and sodium hydroxide affords hydroxyaldehyde O, which is converted to mesylate IV by methanesulfonyl and triethylamine, similar to the reaction described in Chem. Ber. 98, 728-734 (1965). Reaction of the mesylate IV with stiophenol V, according to the procedure described in WO 93/16055, in the presence of triethylamine gives the keto-aldehyde VI, which can be cyclized with a reagent prepared from zinc and titanium tetrachloride by refluxing ethylene glycol dimethyl ether (DME). dihydrobenzothiepine VQ and two racemic stereoisomers of benzothiepin- (5H) -4-one V m where R ¹ and R ² are equivalent. Oxidation of VII with three equivalents of m-chloro-perbenzoic acid (MCPBA) affords the isomeric sulfone-epoxides IX, which, by hydrogenation on palladium on carbon as a catalyst, yields mixtures of four racemic 4-hydroxy-2,3,4,5-tetrahydrobenzothiepine- 1,1-dioxide X and the two racemic stereoisomers 2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide XI, unless R ¹ and R ² are equivalent.

Optically active compounds of the invention can be prepared using optically active starting material m or resolving compound X by optical resolution agents well known in the art, as described in J. Org. Chem., 39, 3904 (1974), ibid., 42 , 2781 (1977) and ibid., 44, 4891 (1979).

Scheme 1

Viile

- 17A

Alternatively, ketoaldehyde VI, wherein R is H, can be prepared by reacting thiophenol V with a 2-substituted acrolein.

Benzothiepine- (5H) -4-one VIII can be oxidized by MCPBA to form Benzotiepine- (5H) -4-one-1,1-dioxide ΧΠ, which can be reduced with sodium borohydride to give four racemic stereoisomers of compound X. Two stereoisomers of compound X Xa and XB having an OH group and R ³ on opposite sides of the benzothiepine ring can be converted to the other two isomers of X, Xc and Xd having an OH group and R ³ on the same side of the benzothiepine ring by reaction with 40-50% sodium hydroxide in dichloromethane and phase transfer catalyst (PTC). Transformation can also be performed with potassium t-butoxide in THF.

My * R t- βο, κ ^ β, κ · η, χ · ε · 4 ta> Xa • e «Xe

The «Xd

Compounds of the invention wherein R ⁵ is OR, NRR 'or S (O) n R and R ⁴ is hydroxy can be prepared by reacting epoxide IX, wherein R ⁵ is H, with a thiol, alcohol or amine in the presence of a base.

Another way of obtaining Xc and Xd of the compounds of the invention is shown in Scheme 2. Compound VI is oxidized to compound ΧΠΙ by two equivalents of m-chloro piperbenzoic acid. Hydrogenolysis of compound ΧΙΠ with palladium on carbon gives compound XIV which can be cyclized with either potassium t-butoxide or sodium hydroxide under phase transfer conditions to form a mixture of Xc and Xd. Separation of Xc and Xd can be carried out either by HPLC or by fractional crystallization.

The thiophenols XVHI and V used in the invention can also be prepared according to Scheme 3. By alkylation of phenol XV with arylmethyl chloride in a non-polar solvent according to the procedure of J. Chem. Soc., 2431-2432 (1958) to form the ortho substituted phenol XVI. Phenol XVI can be converted to thiophenol XVm via thiocarbamate XVQ as described in J. Org. Chem., 31, 3980 (1966). Phenol XVI is first reacted with dimethylthiocarbamoyl chloride and triethylamine to form thiocarbamate XVII, which is thermally altered at 200-300 ° C and the altered product is hydrolyzed with sodium hydroxide to give thiophenol XVHL Similarly, thiophenol V can also be prepared from 2-acylphenol XIX via the intermediate thiocarbamate XX.

-21Scheme 3

OH

NaH / toluene * ReCH 2 Cl. , i ¢ 0, w

Scheme 4 shows another route for the formation of the benzotiepine n-1,1-dioxides Xc and Xd. wherein the starting material is thiophenol XVIII. Compound XVIII can be carried out by reaction with an amylate IV to form the sulfide-aldehyde XXI. Oxidation of XXI with two equivalents of MCPBA yields sulfone-aldehyde XIV, which can be cyclized with potassium t-butoxide to form a mixture of benzothiepines XXIIc and XXIId

Scheme 4

Examples of compounds of the invention containing an amine and hydroxylamine groups can be prepared according to the reactions of Schemes 5 and Scheme 6. 2-Chloro-5-nitrobenzophenone is reduced with triethylsilane and trifluoromethanesulfonic acid to 2-chloro-5-nitrodiphenylmethane 32. Reaction of 32 with lithium sulfide followed by reaction of the resulting sulfide with the IV compound to give the sulfide-aldehyde ΧΧΠΙ. Oxidation of ΧΧΠΠ with two equivalents of MCPBA yields sulfone-aldehyde XXIV, which can be reduced by hydrogenation to hydroxylamine XXV. Protection of the hydroxylamine XXV with di-t-butyldicarbonate affords the N, O-di- (t-butoxycarbonyl) hydroxylamino derivative XXVI. Primary derivatives of amines XXXIIIc and ΧΧΧΠΗ can also be prepared by further hydrogenation of XXIV or XXVIIc and XXVIId.

-23Scheme 5

LijS • t .O

NOj ³²

NO.

2-nitro-5-nitrobenzophenone «SN w% i 2MCSBA <?

N (Boc) O (BOC)

3QCVZ

Potassium It-Butoxides 2 pusobenlkyseines

knife

X3QH XXWI c ^ o

XXV (à »

Π ⁰ *** ^{4 i} p _h OH

XXVd

Pd / C-H 26 S 9 kPa, 501

Ph xxvm

Pd / C 4 = 689kPa, 501

Scheme 6 reduction of sulfone-aldehyde XXV with hydrogen followed by reductive alkylation of the resulting amino derivative with hydrogen and palladium-catalyzed aldehyde in the same reaction vessel affords the substituted amino derivative XXVm. Cyclization of XXVIU with potassium t-butoxide affords a mixture of substituted amino derivatives of the invention, XXIXcaXXIXd.

Scheme 6 o

XXIXe o

/ —NH XXVIII

re

KOtBu

THF

XXIXd

Scheme 7 describes one method of introducing a substituent on an aryl ring at the 5-position of benzothiepine. Iodination of the 5-phenyl derivative XXX with iodine affords the iodide derivative XXXI, which is converted to the carboxylate Π by carhonylation on palladium on carbon in an alcohol environment. Hydrolysis of the carboxylate and derivatization of the resulting acid to acid derivatives is well known in the art.

25Scheme 7

The abbreviations used in the above descriptions have the following meanings:

THF tetrahydrofuran

PTC phase transfer catalyst aliquart 336 methyltoctanylammonium chloride

MCPB Am-chloroperbenzoic acid

Celite type diatomaceous earth for filtration

DMF dimethylformamide

DME ethylene glycol dimethyl ether

BOC t-butoxycarbonyl

- 26 R ¹ and R ² may be selected from the group of substituted and unsubstituted C 1 -C 10 alkyls, wherein the substituents may be selected from the group consisting of alkylcarbonyl, alkoxy, hydroxy and a nitrogen containing heterocycle linked to C 1 -C 10 alkyl ether bridges. The substituents on the 3-carbon may include ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, -CH 2 C (= O) C 2 H 5, -CH 2 OC 2 H 5, and -CH 2 O- (4-picoline). Ethyl, n-propyl, n-butyl, npentyl, isobutyl are preferred. In some particularly preferred compounds of the invention, the substituents R ¹ and R ² are identical, for example n-butyl / n-butyl, such that the compound is achiral on 3 carbon. Elimination of optical isomerism at the 3-carbon simplifies the selection, synthesis, separation and quality control of compounds used as an inhibitor of bile acid transport. In both compounds having a chiral 3-carbon and those having an achiral, the substituents (R ^x ) on the benzo ring may include hydrogen, aryl, alkyl, hydroxy, halogen, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkyl, haloalkoxy (N) -hydroxycarbonylalkylamine, haloalkylthio, haloalkylsulfinyl, haloalkylsulfonyl, amino, N-alkylamino,,, Ν-dialkylamino, (N) alkoxycarbamoyl, (N) -aryloxycarbamoyl, (N) -aralkyloxycarbamoyl, especially trialkylammonium), especially trialkylammonium, (N) -amido, (N) -alkylamido, -N-alkylamido, -Ν, Ν-dialkylamido, (N) haloalkylamido, (N) -sulfonamido, (N) -alkylsulfonamido, (N) -haloalkylsulfonamido, carboxyalkylamino, trialkyl ammonium salt, (N) -carbamic acid, alkyl or benzyl ester, Nacylamine, hydroxylamine, haloacylamine, carbohydrate, thiophene, trialkylammonium salt containing a carboxylic acid or hydroxy substituent on one or more alkyl substituents, alkylene bridge containing substituted k a vartemic ammonium salt, [O (CH ₂ ) n] _x -X wherein x is 2 to 12, w is 2 or 3 and X is a halogen or quaternary ammonium salt and a (N) -heterocycle containing heterocycle, wherein the nitrogen of said heterocycle is optionally quaternates. Preferred substituents that may be represented by R ^x include methyl, ethyl, isopropyl, t-butyl, hydroxy, methoxy, ethoxy, isopropoxy, methylthio, iodo, bromo, fluoro, methylsulfinyl, methylsulfonyl, ethylthio, amino, hydroxylamine, N-methylamino , N, N-dimethylamino, Ν, Ν-diethylamino, (N) benzyloxycarbamoyl, trimethylammonium, A ', -NHC (= O) CH 3, - NHC (= O) C 5 Hu, - NHC (= 0) C 6 Hi 3, caiboxyethylamino , (N) -morpholinyl, (N) -azetidinyl, (N) -N-methylazetidinium A ', (N) pyrrolidinyl, pyrrolyl, (N) -N-methylpyridinium A', (N) -N-methylmorpholinium A, NN methylpiperazinesL, (N) -bromomethylamido, (N) -N-hexylamino, thiophene, -N ⁺ (CH3) 2CO2H Γ, NCH3CH2CO2H, - (N) -N'-dimethylpiperazinium (, (N) -t-butyloxycarbamoyl, ( N) methylsulfonamido, (N) N'-methylpyrrolidinium and - (OCH 2 CH 2) 31, wherein A 1 is a pharmaceutically acceptable anion. The benzo ring may be monosubstituted at the 6, 7 or 8 position or disubstituted at the 7- and 8- position. Also included are 6,7,8-trialkoxy compounds, for example, 6,7,8-trimethoxy compounds. The plurality of other substituents may preferably be present in the 6-position,

-277, 8 or or 9 per benzo book, represented, for example, by guanidyl, cycloalkyl, carbohydrate (eg, 5 or 6 carbon monosaccharide), peptide and quaternary ammonium salt bound to books via polyoxyalkylene bridges, for example - (OCH2CH2) _X -NR ¹³ R ¹⁴ R ¹⁵ A ', where x is from 2 to 10. Examples of compounds are shown in Table 1 below.

Table 1

Alternative Compounds # 3 (FFF.xxx yyy) *

prefix (FFF.xxx. compound yyy) R ² = R R ⁵ (R ^X ) q F101.001 01 n-propyl ph 7-methyl 02 n-propyl ph 7-ethyl 03 n-propyl ph 7-isopropyl 04 n-propyl ph 7-t. butyl 05 n-propyl ph 7-OH 06 n-propyl ph 7-OCH 07 n-propyl ph 7-O (iso-propyl) 08 n-propyl ph 7-SCH3 09 n-propyl ph 7- SOCH3 10 n-propyl ph 7- SO2CH3 In the description of the substituents “(N)” indicates that the nitrogen-linked substituent is attached

a ring structure through a nitrogen atom.

Similarly, 2-thiophene refers to a bond at the 2-position of the thiophene ring. A similar concept is used for other heterocyclic substituents. Abbreviations and definitions:

NH-CBZ means -HNC (= O) OCH 2 Ph

11 n-propyl ph 7- SCH2CH3 12 n-propyl ph 7-NHA 13 n-propyl ph 7-NHOH 14 n-propyl ph 7-NHCH3 15 n-propyl ph 7-NH (CH ₃ ) 2

n-propyl ph 7 - ^ (6¾) ^ n-propyl ph 7-NHC (= O) _CH3 n-propyl ph 7-NHCH2CH3 n-propyl ph 7-NMeCH ₂ CO ₂ H n-propyl ph 7 - ^^ 2 2 260211, Γ n-propyl ph 7- (N) -morpholine n-propyl ph 7- (Nyazetidine n-propyl ph 7- (N) -N-methyl-azetidium, 1'-methylbenzyl; n-propyl ph 7- (N) -pyrrolidine n-propyl ph 7- (N) -N-methyl-pyrrolidinium, Γ n-propyl ph 7- (N) - N-methylmorpholinium, Γ n-propyl ph 7- (N) -N'-methylpyperazine n-propyl ph 7- (N) - N'-methylpyperazinium, Γ n-propyl ph 7-NH-CBZ n-propyl ph 7- NH-C (O) C ₅ Hn n-propyl ph 7- NH-C (O) Al 2 Br n-propyl ph 7-NH-C (NH) _NH2 n-propyl ph 7- (2) -thiophene n-propyl ph 8-methyl n-propyl ph 8-ethyl n-propyl ph 8-isopropyl n-propyl ph 8-t. butyl n-propyl ph 8-OH n-propyl ph 8-OCH3 n-propyl ph 8-O (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-NH 2 n-propyl ph 8-NHOH n-propyl ph 8-NHCH3 n-propyl ph 8-NH (CH ₃ ) 2 n-propyl ph 8-Ν * (Οΐ3) 3, Γ

n-propyl ph 8-NHC (= O) _CH3 n-propyl ph 8-NHCH2CH3 n-propyl ph 8-NMeCH ₂ CO ₁ H n-propyl ph S-N-ÍMehCHjCOíHr n-propyl ph 8- (N) -morpholine n-propyl ph 8- (N) -azetidine n-propyl ph 8- (N) -N-Methylazetidium, 1'-N '; n-propyl ph 8- (N) -pyrrolidine n-propyl ph 8- (N) - N-methyl-pyrrolidinium; n-propyl ph 8- (N) - N-methylmorpholinium, Γ n-propyl ph 8- (N) -N'-methylpyperazine n-propyl ph 8- (N) - N'-methylpyperazinium; n-propyl ph 8-NH-CBZ n-propyl ph 8- NH-C (O) C ₅ HH n-propyl ph 8- NH-COCOHjBr 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-isopropyl n-propyl ph 9-t. butyl n-propyl ph 9-OH n-propyl ph 9-OCH ₃ n-propyl ph 9-O (iso-propyl) n-propyl ph 9-SCHj n-propyl ph 9- SOCHj n-propyl ph 9-SO ₂ CH 3 n-propyl ph 9- SCH ₂ CH ₃ n-propyl ph _9-NH2 n-propyl ph 9-NHOH n-propyl ph 9-NHCH ₃ n-propyl ph 9-NH (CH ₃ ) ₃ n-propyl ph 9 - ^ (0 ^, r n-propyl ph 9-NHC (= O) _CH3

n-propyl ph 9-NHCH ₂ CH ₃ n-propyl ph 9-nmech ₂ CO 2 H n-propyl ph 9-Ν * (Μβ) ία «Μ r n-propyl ph 9- (N) -morpholine n-propyl ph 9- (N) -azetidine n-propyl ph 9- (N) -N-Methylazetidium, 1'-N, N'-methylazetidium; n-propyl ph 9- (N) -pyrrolidine n-propyl ph 9- (N) - N-methyl-pyrrolidinium; n-propyl ph 9- (N) - N-methylmorpholinium, Γ n-propyl ph 9- (N) -N'-methylpyperazine n-propyl ph 9- (N) - N'-methylpyperazinium, Γ n-propyl ph 9-NH-CBZ n-propyl ph 9- NH-C (O) C ₅ Hn n-propyl ph 9-NH-C (O) CH ₂ Br n-propyl ph 9-NH-C (NH) _NH2 n-propyl ph 9- (2) -thiophene n-propyl ph 7-OCH ₃ , 8-OCH ₃ n-propyl ph _{7-SCH3, 8-OCH3} n-propyl ph _{7-SCH3, 8-SCH3} n-propyl ph 6-OCH ₃ , 7-OCH ₃ , 8-OCH ₃ compound R ^{1 =} R ² R ⁵ (R '), yyy) 01 n butylPh- 7-methyl 02 n butylPh- 7-ethyl 03 n butylPh- 7-isopropyl 04 n butylPh- 7-t. butyl 05 n butylPh- 7-OH 06 n butylPh- 7-OCH ₃ 07 n butylPh- 7-O (iso-propyl) 08 n butylPh- 7-SCH ₃ 09 n butylPh- 7- SCULPTURE ₃

n-butylPh-7-SO ₂ CH ₃ n-butylPh-7-SCH ₂ CH ₃

n butylPh- _7-NH2 n butylPh- 7-NHOH n butylPh- 7-NHCHj n butylPh- 7-NH (CH ₃ ) 2 n butylPh- 7-1 ^ (013) 3 ^ n butylPh- 7-NHC (= O) _CH3 n butylPh- 7- NHCH ₂ CH ₃ n butylPh- 7-NMeCH ₂ CO ₂ H n butylPh- 7-N ⁺ (Me) ₂ CH ₂ CO ₂ H, r n butylPh- 7- (N) -morpholine n butylPh- 7- (N) -azetidine n butylPh- 7- (N) -N-methyl-azetidium, 1'-methylbenzyl; n butylPh- 7- (N) -pyrrolidine n butylPh- 7- (N) - N-methyl-pyrrolidinium; n butylPh- 7- (N) - N-methyl-morpholinium, Γ n butylPh- 7- (N) -N'-methylpyperazine n butylPh- 7- (N) - N'-methylpyperazinium, Γ n butylPh- 7-NH-CBZ n butylPh- 7- NH-C (O) C ₅ Hn n butylPh- 7-NH-C (O) CH ₂ Br n butylPh- 7-NH-C (NH) _NH2 n butylPh- 7- (2) -thiophene n butylPh- 8-methyl n butylPh- 8-ethyl n butylPh- 8-isopropyl n butylPh- 8-t. butyl n butylPh- 8-OH n butylPh 8-OCH3 n butylPh 8-O (iso-propyl) n butylPh 8-SCH3 n butylPh 8- SOCH3 n butylPh 8- SO ₂ CH 3 n butylPh 8- SCH ₂ CH ₃ n butylPh- _8-NH2

n butylPh- 8-NHOH n butylPh- 8-NHCH3 n butylPh- 8-NH (CH ₃ ) 2 n-butyl Ph- δ-Νγα ^, Γ n butylPh- 8-NHC (= O) _CH3 n butylPh- 8- NHCH2CH3 n butylPh- 8- NMeCHaCO3H n butylPh- 8- (Me 2 CH 3 CO 3 H, δ) n butylPh- 8- (N) -morpholine n butylPh- 8- (N) -azetidine n butylPh- 8- (N) -N-Methylazetidium, 1'-N '; n butylPh- 8- (N) -pyrrolidine n butylPh- 8- (N) - N-methyl-pyrrolidinium; n butylPh- 8- (N) - N-methylmorpholinium, Γ n butyIPh- 8- (N) -N'-methylpyperazine n butylPh- 8- (N) -N'-methylpyperazinium, I n butylPh- 8-NH-CBZ n butylPh- 8- NH-C (O) C ₅ HH n butylPh- 8- NH-QO 3 CH 3 Br n butylPh- 8-NH-C (NH) _NH2 n butylPh- 8- (2) -thiophene n butylPh- 9-methyl- n butylPh- 9-ethyl n butylPh- 9-isopropyl n butylPh- 9-t. butyl n butylPh- 9-OH n butylPh 9-OCH3 n butylPh 9-O (iso-propyl) n butylPh 9-SCH 3 n butylPh 9- SOCH3 n butylPh 9-SO ₂ CH 3 n butylPh 9- SCH ₂ CH ₃ n butylPh- _9-NH2 n butylPh- 9-NHOH

n butylPh- 9-NHCH3 n butylPh- 9-NH (CH ₃ ) 2 n-butyl Ph- 9-N + (CH 3) 3, R n butylPh- 9-NHC (= O) _CH3 n butylPh- 9- NHCH ₂ CH ₃ n butylPh- 9- NMeCH ₂ CO ₂ H n butylPh- g of N-CMe ^ ^ r ^ CHzCO n butylPh- 9- (N) -morpholine n butylPh- 9- (N) -azetidine n butylPh- 9- (N) -N-Methylazetidium, 1'-N, N'-methylazetidium; n butylPh- 9- (N) -pyrrolidine n butylPh- 9- (N) - N-methyl-pyrrolidinium; n butylPh- 9- (N) - N-methylmorpholinium, Γ n butylPh- 9- (N) -N'-methylpyperazine n butylPh- 9- (N) - N'-methylpyperazinium, Γ n butylPh- 9-NH-CBZ n butylPh- 9- NH-C (O) C ₅ Hn n butylPh- 9-NH-C (O) CH 2 Br n butylPh- 9-NH-C (NH) _NH2 n butylPh- 9- (2) -thiophene n butylPh- 7-OCH ₃ , 8-OCH ₃ n butylPh- _{7-SCH3, 8-OCH3} n butylPh- 7-SCH1, 8-SCH3 n butylPh- 6-OCH ₃ , 7-OCH ₃ , 8-OCH ₃

compound R ^{1 =} R ² R ⁵ (R ^x ) _q yyy)

01 n-pentyl ph 7-methyl 02 n-pentyl ph 7-ethyl 03 n-pentyl ph 7-isopropyl 04 n-pentyl ph 7-t. butyl 05 n-pentyl ph 7-OH n-pentyl ph 7-OCH ₃ n-pentyl ph 7-O (iso-propyl)

n-pentyl ph 7-SCH ₃ n-pentyl ph 7- SOCH3 n-pentyl ph 7- SO2CH3 n-pentyl ph 7- SCH2CH3 n-pentyl ph 7-NH 2 n-pentyl ph 7-NHOH n-pentyl ph 7-NHCH3 n-pentyl ph 7-NH (CH ₃ ) 2 n-pentyl ph 7 - ((^ 3) 3, r n-pentyl ph 7-NHC (= O) _CH3 n-pentyl ph 7-NHCH2CH3 n-pentyl ph 7-CO 2 H ₂ nmech n-pentyl ph 7- n-pentyl ph 7- (N) -morpholine n-pentyl ph 7- (N) -azetidine n-pentyl ph 7- (N) -N-methyl-azetidium, 1'-methylbenzyl; n-pentyl ph 7- (N) -pyrrolidine n-pentyl ph 7- (N) -N-methyl-pyrrolidinium, Γ n-pentyl ph 7- (N) - N-methylmorpholinium, Γ n-pentyl ph 7- (N) -N'-methylpyperazine n-pentyl ph 7- (N) - N'-methylpyperazinium; n-pentyl ph 7-NH-CBZ n-pentyl ph 7- NH-C (O) CsH _n n-pentyl ph 7- NH-C (O) CH 2 Br n-pentyl ph 7-NH-C (NH) _NH2 n-pentyl ph 7- (2) -thiophene n-pentyl ph 8-methyl n-pentyl ph 8-ethyl n-pentyl ph 8-isopropyl n-pentyl ph 8-t. butyl n-pentyl ph 8-OH n-pentyl ph 8-OCH3 n-pentyl ph 8-O (iso-propyl) n-pentyl ph 8-SCH3

n-pentyl ph 8- SCULPTURE ₃ n-pentyl ph 8- SO ₂ CH 3 n-pentyl ph 8- SCH ₂ CH ₃ n-pentyl ph _8-NH2 n-pentyl ph 8-NHOH n-pentyl ph 8-NHCH3 n-pentyl ph S-NHÍCHjh n-pentyl ph The N? CHjKľ n-pentyl ph 8-NHC (= O) _CH3 n-pentyl ph 8-NHCH ₂ CH ₃ n-pentyl ph 8-CO2 H ₂ nmech n-pentyl ph 8-ΓΤ (Μβ) € ₂ Η ₂ <; 0 ₂ Η, Γ n-pentyl ph 8- (N) -morphol n-pentyl ph 8- (N) -azetidine n-pentyl ph 8- (N) -N-methylazethidium, Γ n-pentyl ph 8- (N) -pyrrolidine n-pentyl ph 8- (N) - N-methyl-pyrrolidinium; n-pentyl ph 8- (N) - N-methylmorpholinium, Γ n-pentyl ph 8- (N) -N-methylpyperazine n-pentyl ph 8- (N) - N'-methylpyperazinium; n-pentyl ph 8-NH-CBZ n-pentyl ph 8- NH-C (O) C ₅ HH n-pentyl ph 8-NH-R ^ QOjCH 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-isopropyl n-pentyl ph 9-t. butyl n-pentyl ph 9-OH n-pentyl ph 9-OCH3 n-pentyl ph 9-O (iso-propyl) n-pentyl ph 9-SCH 3 n-pentyl ph 9- SOCH3

76 n-pentyl ph 9-SO ₂ CH 3 77 n-pentyl ph 9- SCH2CH3 78 n-pentyl ph 9-NH2 79 n-pentyl ph 9-NHOH 80 n-pentyl ph 9-NHCH3 81 n-pentyl ph 9-NH (CH ₃ ) 2 82 n-pentyl ph 9-N ⁺ _{(CH3) 3,} R 83 n-pentyl ph 9-NHC (= O) _CH3 84 n-pentyl Ph- · 9-NHCH ₂ CH ₃ 85 n-pentyl ph 9-nmech ₂ CO 2 H 86 n-pentyl ph 9-N ⁺ (Me) ₂ CH ₂ CO ₂ H, Γ 87 n-pentyl ph 9- (N) -morpholine 88 n-pentyl ph 9- (N) -azetidine 89 n-pentyl ph 9- (N) -N-methylazetidium, Γ 90 n-pentyl ph 9- (N) -pyrrolidine 91 n-pentyl ph 9- (N) - N-methyl-pyrrolidinium; 92 n-pentyl ph 9- (N) - N-methylmorpholinium, Γ 93 n-pentyl ph 9- (N) -N'-methylpyperazine 94 n-pentyl ph 9- (N) - N'-methylpyperazinium; 95 n-pentyl ph 9-NH-CBZ 96 n-pentyl ph 9-NH-C (O) C 5 H _n 97 n-pentyl ph 9-NH-C (O) CH 2 Br 98 n-pentyl ph 9-NH-C (NH) _NH2 99 n-pentyl ph 9- (2) -thiophene 100 n-pentyl ph 7-OCH ₃ , 8-OCH ₃ 101 n-pentyl ph _{7-SCH3, 8-OCH3} 102 n-pentyl ph 7-SCH _{3 J 8-SCH3} 103 n-pentyl ph 6-OCH ₃ , 7-OCH ₃ , 8-OCH ₃ Prefix compound r ^{1 =} r ² r '(R *)

(FFF.xxx.yyy)

n-hexyl ph 7-methyl n-hexyl ph 7-ethyl n-hexyl ph 7-isopropyl n-hexyl ph 7-t. butyl n-hexyl ph 7-OH n-hexyl ph 7-OCH ₃ n-hexyl ph 7-O (iso-propyl) n-hexyl ph 7-SCH ₃ n-hexyl ph 7- SCULPTURE ₃ n-hexyl ph 7- SO ₂ CH ₃ n-hexyl ph 7- SCH ₂ CH ₃ n-hexyl ph _7-NH2 n-hexyl ph 7-NHOH n-hexyl ph _7-NHCH3 n-hexyl ph 7-NH (CH ₃ ) 2 n-hexyl ph N &apos; CH T n-hexyl ph 7-NHC (= O) _CH3 n-hexyl ph 7-NHCH ₂ CH ₃ n-hexyl ph 7-CO 2 H ₂ nmech n-hexyl ph 7-N ⁺ (Me) ₂ CH ₂ CO ₂ H, Γ n-hexyl ph 7- (N) -morpholine n-hexyl ph 7- (N) -azetidine n-hexyl ph 7- (N) -N-methyl-azetidium, 1'-methylbenzyl; n-hexyl ph 7- (N) -pyrrolidine n-hexyl ph 7- (N) -N-methyl-pyrrolidinium, Γ n-hexyl ph 7- (N) - N-methylmorpholinium, Γ n-hexyl ph 7- (N) -N'-methylpyperazine n-hexyl ph 7- (N) - N'-methylpyperazinium; n-hexyl ph 7-NH-CBZ n-hexyl ph 7-NH-C (O) C _with Hi, n-hexyl ph 7-NH-C (O) CH ₂ Br 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-isopropyl n-hexyl ph 8-t. butyl n-hexyl ph 8-OH n-hexyl ph 8-OCH3 n-hexyl ph 8-O (iso-propyl) n-hexyl ph 8-SCH3 n-hexyl ph 8- SOCH3 n-hexyl ph 8- SO ₂ CH 3 n-hexyl ph 8- SCH ₂ CH ₃ n-hexyl ph _8-NH2 n-hexyl ph 8-NHOH n-hexyl ph 8-NHCH3 n-hexyl ph 8-NH (CH ₃ ) 2 n-hexyl Ph- S-N? CHab,? n-hexyl ph 8-NHC (= O) _CH3 n-hexyl ph 8-NHCH ₂ CH ₃ n-hexyl ph 8-CO2 H ₂ nmech n-hexyl ph e ^ N ^ CMebCH oar n-hexyl ph 8- (N) -morpholine n-hexyl ph 8- (N) -azetidine n-hexyl ph 8- (N) -N-Methylazetidium, 1'-N '; n-hexyl ph 8- (N) -pyrrolidine n-hexyl ph 8- (N) - N-methyl-pyrrolidinium; n-hexyl ph 8- (N) - N-methylmorpholinium, Γ n-hexyl ph 8- (N) -N'-methylpyperazine n-hexyl ph 8- (N) - N'-methylpyperazinium; n-hexyl ph 8-NH-CBZ n-hexyl ph 8- NH-C (O) C ₅ Hn n-hexyl ph 8- NH-C (O) CH 2 Br 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-isopropyl n-hexyl ph 9-t. butyl n-hexyl ph 9-OH n-hexyl ph 9-OCH ₃ n-hexyl ph 9-O (iso-propyl) n-hexyl ph 9-SCHj n-hexyl ph 9- SCULPTURE ₃ n-hexyl ph 9-SO ₂ CH 3 n-hexyl ph 9- SCH2CH3 n-hexyl ph 9-NH2 n-hexyl ph 9-NHOH n-hexyl ph 9-NHCH3 n-hexyl ph 9-NH (CH 3) 2 n-hexyl Ph- 9 - (013) 3, r n-hexyl ph 9-NHC (= O) _CH3 n-hexyl ph 9-NHCH2CH3 n-hexyl ph 9-nmech ₂ CO 2 H n-hexyl ph 9- N ⁺ (Me) 2CH ₂ CO ₂ H, Γ n-hexyl ph 9- (N) -morpholine n-hexyl ph 9- (N) azetidine n-hexyl ph 9- (N) -N-Methylazetidium, 1'-N, N'-methylazetidium; n-hexyl ph 9- (N) -pyrrolidine n-hexyl ph 9- (N) - N-methyl-pyrrolidinium, Γ n-hexyl ph 9- (N) - N-methylmorpholinium, Γ n-hexyl ph 9- (N) -N'-methylpyperazine n-hexyl ph 9- (N) - N'-methylpyperazinium; n-hexyl ph 9-NH-CBZ n-hexyl ph 9- NH-C (O) C _with Hi, n-hexyl ph 9-NH-C (O) CH 2 Br n-hexyl ph 9-NH-C (NH) _NH2 n-hexyl ph 9- (2) -thiophene n-hexyl ph 7-OCH 3, 8-OCH 3 n-hexyl ph 7-OCH3 SCH3,8 n-hexyl ph 7-SCH3, 8-SCH3

103 n-hexyl ph 6-OCH ₃ , 7-OCH ₃ , 8-OCH 3 Prefix compound r '= r ² R ⁵ (R '), (FFF.xxx.yyy) F101.005 01 isopropyl ph 7-methyl 02 isopropyl ph 7-ethyl 03 isopropyl ph 7-isopropyl 04 isopropyl ph 7-t. butyl 05 isopropyl ph 7-OH 06 isopropyl ph 7-OCH 3 07 isopropyl ph 7-O (iso-propyl) 08 isopropyl ph 7-SCH3 09 isopropyl ph 7- SOCH3 10 isopropyl ph 7- SO2CH3 11 isopropyl ph 7- SCH2CH3 12 isopropyl ph 7-NH 2 13 isopropyl ph 7-NHOH 14 isopropyl ph 7-NHCH3 15 isopropyl ph 7-NH (CH3> 2 16 isopropyl ph 7-N + (CH 3) j, r 17 isopropyl ph 7-NHC (= O) _CH3 18 isopropyl ph 7-NHCH2CH3 19 isopropyl ph 7-NMeCH ₂ CO ₂ H 20 isopropyl ph 7- N * (Me) 2 CH 2 CO 2 H, Γ 21 isopropyl ph 7- (N) -morpholine 22 isopropyl ph 7- (N) -azetidine 23 isopropyl ph 7- (N) -N-methyl-azetidium, 1'-methylbenzyl; 24 isopropyl ph 7- (N) -pyrrolidine 25 isopropyl ph 7- (N) - N-methyl-pyrrolidinium; 26 isopropyl ph 7- (N) - N-methylmorpholinium, Γ 27 isopropyl ph 7- (N) -N'-methylpyperazine 28 isopropyl ph 7- (N) - N'-methylpyperazinium, Γ 29 isopropyl ph 7-NH-CBZ

isopropyl ph 7-NH-C (O) C _with Hn isopropyl ph 7-NH-C (O) CH ₂ Br isopropyl ph 7-NH-C (NH) _NH2 isopropyl ph 7- (2) -thiophene isopropyl ph 8-methyl isopropyl ph 8-ethyl isopropyl ph 8-isopropyl isopropyl ph 8-t. butyl. isopropyl ph 8-OH isopropyl ph 8-OCH3 isopropyl ph 8-O (iso-propyl) isopropyl ph 8-SCH3 isopropyl ph 8- SOCH3 isopropyl ph 8- SO ₂ CH 3 isopropyl ph 8- SCH ₂ CH ₃ isopropyl ph _8-NH2 isopropyl ph 8-NHOH isopropyl ph 8-NHCH3 isopropyl ph 8-NH (CH ₃ ) 2 isopropyl ph 8-R (CH ₃₎ 3, R isopropyl ph 8-NHC (= O) _CH3 isopropyl ph 8-NHCH ₂ CH 3 isopropyl ph 8-NMeCH ₂ CO ₂ H isopropyl ph S-N-ÍMehCHjCOÄI ' isopropyl ph 8- (N) -morpholine isopropyl ph 8- (N) -azetidine isopropyl ph 8- (N) -N-Methylazetidium, 1'-N '; isopropyl ph 8- (N) -pyrrolidine isopropyl ph 8- (N) - N-methyl-pyrrolidinium; isopropyl ph 8- (N) - N-methylmorpholinium, Γ isopropyl ph 8- (N) -N'-methylpyperazine isopropyl ph 8- (N) - N'-methylpyperazinium, Γ isopropyl ph 8-NH-CBZ isopropyl ph 8- NH-C (O) C ₅ H _n

isopropyl ph 8- NH-C (O) CH 2 Br isopropyl ph 8-NH-C (NH) _NH2 isopropyl ph 8- (2) -thiophene isopropyl ph 9-methyl- isopropyl ph 9-ethyl isopropyl ph 9-isopropyl isopropyl ph 9-t. butyl isopropyl ph 9-OH isopropyl ph 9-OCH ₃ isopropyl ph 9-O (iso-propyl) isopropyl ph 9-SCHj isopropyl ph 9- SOCH3 isopropyl ph 9-SO ₂ CH 3 isopropyl ph 9- SCH ₂ CH ₃ isopropyl ph _9-NH2 isopropyl ph 9-NHOH isopropyl ph 9-NHCH3 isopropyl ph 9-NH (CH 3) 2 isopropyl ph 9-N + _(CH3) 3, R isopropyl ph 9-NHC (= O) CH isopropyl ph 9-NHCH ₂ CH ₃ isopropyl ph 9-nmech ₂ CO 2 H isopropyl ph g-N + CMe 2 CH 2 Cl 2 CH 2; isopropyl ph 9- (N) -morpholine isopropyl ph 9- (N) -azetidine isopropyl ph 9- (N) -N-Methylazetidium, 1'-N, N'-methylazetidium; isopropyl ph 9- (N) -pyrrolidine isopropyl ph 9- (N) - N-methyl-pyrrolidinium, Γ isopropyl ph 9- (N) - N-methylmorpholinium, Γ isopropyl ph 9- (N) -N'-methylpyperazine isopropyl ph 9- (N> N'-methylpyperazinium, I isopropyl ph 9-NH-CBZ isopropyl ph 9- NH-C (O) C ₅ Hn isopropyl ph 9-NH-C (O) CH ₂ Br

98 isopropyl ph 9-NH-C (NH) _NH2 99 isopropyl ph 9- (2) -thiophene 100 isopropyl ph 7-OCH3, 8-OCH3 101 isopropyl ph 7-SCH 3, 8-OCH 3 102 isopropyl ph 7-SCH3, 8-SCH3 103 isopropyl ph 6-OCH3, 7-OCH3, 8-OCH3 Prefix compound r ^{1 =} r ² r ⁵ (R), (FFF.xxx. Yyy) F101.006 01 isobutyl ph 7-methyl 02 isobutyl ph 7-ethyl 03 isobutyl ph 7-isopropyl 04 isobutyl ph 7-t. butyl 05 isobutyl ph 7-OH 06 isobutyl ph 7-OCH 3 07 isobutyl ph 7-O (iso-propyl) 08 isobutyl ph 7-SCH3 09 isobutyl ph 7- SOCH3 10 isobutyl ph 7- SO2CH3 11 isobutyl ph 7- SCH2CH3 12 isobutyl ph 7-NH 13 isobutyl ph 7-NHOH 14 isobutyl ph 7-NHCH3 15 isobutyl ph 7-NH (CH ₃ ) 2 16 isobutyl ph 7-N \ CH ₃₎ 3, R 17 isobutyl ph 7-NHC (= O) _CH3 18 isobutyl ph 7-NHCH2CH3 19 isobutyl ph 7-NMeCH ₂ CO ₂ H 20 isobutyl ph 7 - ^^) 2 ^ 2002¾ y 21 isobutyl ph 7- (N) -morpholine 22 isobutyl ph 7- (N) -azetidine 23 isobutyl ph 7- (N) -N-methyl-azetidium, 1'-methylbenzyl; 24 isobutyl ph 7- (N) -pyrrolidine

isobutyl ph 7- (N) - N-methyl-pyrrolidinium; isobutyl ph 7- (N) -N-methylmorpholinium, I isobutyl ph 7- (N) -N'-methylpyperazine isobutyl ph 7- (N) - N'-methylpyperazinium; isobutyl ph 7-NH-CBZ isobutyl ph 7-NH-C (O) C ₅ Hi isobutyl ph 7- NH-C (O) CH 2 Br isobutyl ph 7-NH-C (NH) _NH2 isobutyl ph 7- (2) -thiophene isobutyl ph 8-methyl isobutyl ph 8-ethyl isobutyl ph 8-isopropyl isobutyl ph 8-t. butyl isobutyl ph 8-OH isobutyl ph 8-OCH ₃ isobutyl ph 8-O (iso-propyl) isobutyl ph 8-SCH3 isobutyl ph 8- SOCH3 isobutyl ph 8- SO3CH3 isobutyl ph 8- SCH2CH3 isobutyl ph 8-NH 2 isobutyl ph 8-NHOH isobutyl ph 8-NHCH3 isobutyl ph 8-NH (CH ₃ ) 2 isobutyl ph 8-1 ^ (^) 3, Γ isobutyl ph 8-NHC (= O) _CH3 isobutyl ph 8-NHCH2CH3 isobutyl ph 8-NMeCH ₂ CO ₂ H isobutyl ph isobutyl ph 8- (N) -morpholine isobutyl ph 8- (N> azetidine isobutyl ph 8- (N) -N-Methylazetidium, 1'-N '; isobutyl ph 8- (N) -pyrrolidine isobutyl ph 8- (N) -N-methyl-pyrrolidinium, Γ

59 isobutyl ph 8- (N) - N-methylmorpholinium, Γ 60 isobutyl ph 8- (N) -N'-methylpyperazine 61 isobutyl ph 8- (N) - N'-methylpyperazinium; 62 isobutyl ph 8-NH-CBZ 63 isobutyl ph 8- NH-C (O) C ₅ H 7 64 isobutyl ph 8-NH-C (O) CH ₂ Br 65 isobutyl ph 8-NH-C (NH) _NH2 66 isobutyl ph 8- (2) -thiophene 67 isobutyl ph 9-methyl- 68 isobutyl ph 9-ethyl 69 isobutyl ph 9-isopropyl 70 isobutyl ph 9-t. butyl 71 isobutyl ph 9-OH 72 isobutyl ph 9-OCH ₃ 73 isobutyl ph 9-O (iso-propyl) 74 isobutyl ph 9-SCH 3 75 isobutyl ph 9- SCULPTURE ₃ 76 isobutyl ph 9-SO ₂ CH 3 77 isobutyl ph 9- SCH ₂ CH ₃ 78 isobutyl ph _9-NH2 79 isobutyl ph 9-NHOH 80 isobutyl ph 9-NHCH ₃ 81 isobutyl ph 9-NH (CH ₃ ) 2 82 isobutyl ph 9-1 ^ (013) 3, no 83 isobutyl ph 9-NHC (= O) _CH3 84 isobutyl ph 9-NHCH ₂ CH ₃ 85 isobutyl ph 9-NMeCH ₂ CO ₂ H 86 isobutyl ph 9-N (Me) ₂ CH ₂ CO ₂ H, r 87 isobutyl ph 9- (N) -morpholine 88 isobutyl ph 9- (N) -azetidine 89 isobutyl ph 9- (N) -N-Methylazetidium, 1'-N, N'-methylazetidium; 90 isobutyl ph 9- (N) -pyrrolidine 91 isobutyl ph 9- (N) - N-methyl-pyrrolidinium; 92 isobutyl ph 9- (N) - N-methyl-morpholinium;

93 isobutyl ph 9- (N) -N'-methylpyperazine 94 isobutyl ph 9- (N) - N'-methylpyperazinium; 95 isobutyl ph 9-NH-CBZ 96 isobutyl ph 9-NH-C (O) C ₅ Hi 97 isobutyl ph 9-NH-C (O) CH 2 Br 98 isobutyl ph 9-NH-C (NH) _NH2 99 isobutyl ph 9- (2) -thiophene 100 isobutyl ph 7-OCH 3,8-OCH ₃ 101 isobutyl ph 7-SCH 3, 8-OCH 3 102 isobutyl ph 7-SCH3, 8-SCH3 103 isobutyl ph 6-OCH 3, 7-OCH 3, 8-OCH 3 Prefix compound (FFF.xxx.yyy) r * = r ² r ⁵ (R ¹ ), F101.007 01 isopentyl ph 7-methyl 02 isopentyl ph 7-ethyl 03 isopentyl ph 7-isopropyl 04 isopentyl ph 7-t. butyl 05 isopentyl ph 7-OH 06 isopentyl ph 7-OCH 07 isopentyl ph 7-O (iso-propyl) 08 isopentyl ph 7-SCHj 09 isopentyl ph 7- SOCHj 10 isopentyl ph 7- SO ₂ CH ₃ 11 isopentyl ph 7- SCH ₂ CHj 12 isopentyl ph _7-NH2 13 isopentyl ph 7-NHOH 14 isopentyl ph 7-NHCH3 15 isopentyl ph 7-NH (CH 3) 2 16 isopentyl ph 7 - ^ (013) 3,1- 17 isopentyl ph 7-NHC (= O) _CH3 18 isopentyl ph 7-NHCH ₂ CH 3 19 isopentyl ph 7-NMeCH ₂ CO ₂ H

isopentyl ph 7-N * (Me) 3 CH _and CO ₁ H, r isopentyl ph 7- (N) -morpholine isopentyl ph 7- (N) -azetidine isopentyl ph 7- (N) -N-methyl-azetidium, 1'-methylbenzyl; isopentyl ph 7- (N) -pyrrolidine isopentyl ph 7- (N) -N-methylpyrrolidinium, I isopentyl ph 7- (N) - N-methylmorpholinium, Γ isopentyl ph 7- (N) -N'-methylpyperazine isopentyl ph 7- (N) - N'-methylpyperazinium, ' isopentyl ph 7-NH-CBZ isopentyl ph 7-NH-C (O) C ₅ Hn isopentyl ph 7- NH-C (O) CH 2 Br isopentyl ph 7-NH-C (NH) _NH2 isopentyl ph 7- (2) -thiophene isopentyl ph 8-methyl isopentyl ph 8-ethyl isopentyl ph 8-isopropyl isopentyl ph 8-t. butyl isopentyl ph 8-OH isopentyl ph 8-OCH3 isopentyl ph 8-O (iso-propyl) isopentyl ph 8-SCH3 isopentyl ph 8- SÔCH, isopentyl ph 8- SO ₂ CH 3 isopentyl ph 8- SCH ₂ CH ₃ isopentyl ph _8-NH2 isopentyl ph 8-NHOH isopentyl ph 8-NHCH ₃ isopentyl ph 8-NH (CH ₃ ) 2 isopentyl ph p-N ^ CH t isopentyl ph 8-NHC (= O) _CH3 isopentyl ph 8-NHCH ₂ CH ₃ isopentyl ph 8-CO2 H ₂ nmech isopentyl ph 8- ^ (MehCH 3 CO 3 H, Γ)

isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph isopentyl ph

8- (N) -morpholine

8- (N) -azetidine

8- (N) -N-methylazethidium, 1 '8- (N) -pyrrolidine

8- (N) - N-methyl-pyrrolidinium, Γ 8- (N) - N-methyl-morpholinium, Γ 8- (N) - N'-methylpyperazine 8- (N) - N'-methylpyperazinium, I 8- NH-CBZ

8- NH-C (O) C ₅ Hh 8-NH-C (O) CH 2 Br 8-NH-C (NH) NH ₂

8- (2) -thiophene

9-methyl

9-ethyl

9-isopropyl

9-t. butyl

9-OH

9-OCH ₃

9-O (iso-propyl)

9-SCH 3

9- SOCHs

9-SO ₂ CH 3

9- SCH ₂ CH ₃

_9-NH2

9-NHOH

9-NHCH ₃

9-NH (CH ₃ ) ₂

9-1 ^ (0¾) ^

9-NHC (= O) _CH3

9-NHCH ₂ CH ₃

9-NMeCH ₂ CO ₂ H 9-N ⁺ (Me) ₂ CH ₂ CO ₂ H, Γ 9- (N) -morpholine

88 isopentyl ph 9- (N) -azetidine 89 isopentyl ph 9- (N) -N-Methylazetidium, 1'-N, N'-methylazetidium; 90 isopentyl ph 9- (N) -pyrrolidine 91 isopentyl ph 9- (N) - N-methyl-pyrrolidinium, Γ 92 isopentyl ph 9- (N) - N-methylmorpholinium, Γ 93 isopentyl ph 9- (N) -N'-methylpyperazine 94 isopentyl ph 9- (N) - N'-methylpyperazinium, I 95th isopentyl ph 9-NH-CBZ 96 isopentyl ph 9 - NH - C (O) C ₅ Hu 97 isopentyl ph 9-NH-C (O) CH ₂ Br 98 isopentyl ph 9-NH-C (NH) _NH2 99 isopentyl ph 9- (2) -thiophene 100 isopentyl ph 7-OCH ₃ , 8-OCH ₃ 101 isopentyl ph _{7-SCH3, 8-OCH3} 102 isopentyl ph Schat-7, _8-SCH3 103 isopentyl ph 6-OCH ₃ , 7-OCH ₃ , 8-OCH ₃ Prefix compound R = R ² R ⁵ (R *), (FFF.xxx.yyy) F101.008 01 CH ₂ C (= O) C ₂ H ₅ ph 7-methyl 02 CHzCX ^ OjCxH, ph 7-ethyl 03 CH ₂ C (= O) C ₂ H ₅ ph 7-isopropyl 04 CH ₂ C (= O) C ₂ H ₅ ph 7-t. butyl 05 CH ₂ C (= O) C ₂ H ₅ ph 7-OH 06 0 ^ 0 (= 0) (¼¾ ph 7-OCH ₃ 07 CH ₂ C (= O) C ₂ H ₅ ph 7-O (iso-propyl) 08 0 ^ (= 0) (½¾ ph 7-S CH 09 CH ₂ C (= O) C ₂ H ₅ ph 7- SCULPTURE ₃ 10 Chace ^ jCjHj ph 7- SO ₂ CH ₃ 11 CH ₂ C (= O) C ₂ H ₅ ph 7- SCH ₂ CH ₃ 12 CH ₂ C (= O) C ₂ H ₅ ph _7-NH2 13 CHjC ^ CÄ ph 7-NHOH 14 CH ₂ C (= O) C ₂ H ₅ ph _7-NHCH3

CH ₂ C (= O) C 2 H 5 ph 7-NH (CH ₃ ) 2 CH ₂ C (= O) C ₂ H ₅ ph 7 - ^ (0 ^) 3.1- CH ₂ C (= O) C ₂ H ₅ ph 7-NHC (= O) _CH3 CH ₂ C (= O) C ₂ H ₅ ph 7-NHCH ₂ CH ₃ CH ₂ C (= O) C ₂ H ₅ ph 7-NMeCH ₂ CO ₂ H CH ₂ C (= O) C ₂ H ₅ ph 7-N (Me) ₂ CH ₂ CO ₂ H, Γ CH ₂ C (= O) C ₂ H _s ph 7- (N) -morpholine CH ₂ C (= O) C ₂ H ₅ ph 7- (N) -azetidine CH ₂ C (= O) C ₂ H ₃ ph 7- (N) -N-methylazethidium; I ' CH ₂ C (= O) C ₂ H ₅ ph 7- (N) -pyrrolidine CH ₂ C (= O) C ₂ H ₅ ph 7- (N) - N-methyl-pyrrolidinium; CH ₂ C (= O) C ₂ H ₅ ph 7- (N) - N-methylmorpholinium, Γ CH ₂ C (= O) C ₂ H ₅ ph 7- (N) -N'-methylpyperazine CH ₂ C (= O) C ₂ H _s ph 7- (N) - N'-methylpyperazinium, Γ CHjC ^ OjCjH; ph 7-NH-CBZ CH ₂ C (= O) C ₂ H ₅ ph 7- NH-C (O) C ₅ HH CH ₂ C (= O) C ₂ H ₅ ph 7-NH-C (O) CH ₂ Br CH ₂ C (= O) C ₂ H ₃ ph 7-NH-C (NH) _NH2 CH ₂ C (= O) C ₂ H ₅ ph 7- (2) -thiophene CH ₂ C (= O) C ₂ H ₅ ph 8-methyl CH ₂ C (= O) C ₂ H ₃ ph 8-ethyl CH ₂ C (= O) C 2 H 5 ph 8-isopropyl CH ₂ C (= O) C ₂ H ₅ ph 8-t. butyl CH ₂ C (= O) C ₂ H _s ph 8-OH CH ₂ C (= O) C ₂ H _s ph 8-00¾ CH ₂ C (= O) C ₂ H ₅ ph 8-O (iso-propyl) CH ₂ C (= O) C ₂ H ₅ ph 8-SCH ₃ CH ₂ C (= O) C ₂ H ₅ ph 8- SCULPTURE ₃ CH ₂ C (= O) C ₂ H ₅ ph 8- SO ₂ CH 3 CH ₂ C (= O) C ₂ H ₅ ph 8- SCH ₂ CH ₃ CH ₂ C (= O) C ₂ H ₅ ph _8-NH2 CH ₂ C (= O) C ₂ H ₅ ph 8-NHOH CH ₂ C (= O) C ₂ H ₃ ph 8-NHCH3 CH ₂ C (= O) C ₂ H ₃ ph 8-NH (CH ₃ ) 2

CH ₂ C (= O) C ₂ H ₅ ph 8- N 2 CH 3 X 1 CH ₂ C (= O) C ₂ H ₅ ph 8-NHC (= O) _CH3 CH ₂ C (= O) C ₂ H ₅ ph 8- NHCH ₂ CH ₃ CH ₂ C (= O) C ₂ H ₅ ph 8- NMeCH ₂ CO ₂ H CH ₂ C (= O) C ₂ H ₅ ph 8- N * (Me) 2 CH 2 CO 2 H, Γ CH ₂ C (= O) C ₂ H ₅ ph 8- (N) -morpholine CH ₂ C (= O) C ₂ H ₅ ph 8- (N) -azetidine CH ₂ C (= O) C ₂ H 5 ph 8- (N) -N-Methylazetidium, 1'-N '; CH ₂ C (= O) C ₂ H ₅ ph 8- (N) -pyrrolidine CH ₂ C (= O) C ₂ H ₅ ph 8- (N) - N-methyl-pyrrolidinium; CH ₂ C (= O) C 2 H 5 ph 8- (N) - metyl-methyl-morpholinium; CH ₂ C (= O) C 2 H 5 ph 8- (N) -N'-methylpyperazine CH ₂ C (= O) C 2 H 5 ph 8- (N) - N'-methylpyperazinium, Γ CH ₂ C (= O) C 2 H 5 ph 8-NH-CBZ CH ₂ C (= O) C 2 H 5 ph 8- NH-C (O) C 5 H 7 CH ₂ C (= O) C 2 H 5 ph 8- NH-C (O) CH 2 Br CHjQOjCzH. ph 8-NH-C (NH) _NH2 CH ₂ C (= O) C ₂ H ₅ ph 8- (2) -thiophene CH ₂ C (= O) C ₂ H ₅ ph 9-methyl- CH ₂ C (= O) C ₂ H ₅ ph 9-ethyl CH ₂ C (= O) C ₂ H ₅ ph 9-isopropyl CH ₂ C (= O) C ₂ H ₅ ph 9-t. butyl ph 9-0H CH ₂ C (= O) C ₂ H ₅ ph 9-OCH ₃ CH ₂ C (= O) C ₂ H _s ph 9-O (iso-propyl) CH ₂ C (= O) C ₂ H ₅ ph 9-SCH ₃ CH ₂ C (= O) C ₂ H ₅ ph 9- SCULPTURE ₃ CH ₂ C (= O) C ₂ H ₅ ph 9-SO ₂ CH 3 CH ₂ C (= O) C 2 H 5 ph 9- SCH ₂ CH ₃ CH ₂ C (= O) C ₂ H 5 ph _9-NH2 CH ₂ C (= O) C ₂ H ₃ ph 9-NH0H CH ₂ C (= O) C ₂ H ₅ ph 9-NHCH ₃ 0120 (= 0) (¼¾ ph 9-NH (CH ₃ ) 2 CH ₂ C (= O) C ₂ H ₅ ph 9-n7ch ₃ ) ₃ , i-

83 CH ₂ C (= O) C ₂ H ₅ ph 9-NHC (= O) _CH3 84 CH ₂ C (= O) C ₂ H ₅ ph 9-NHCH ₂ CH ₃ 85 CH ₂ C (= O) C ₂ H ₅ ph 9-nmech ₂ CO 2 H 86 CH ₂ C (= O) C 2 H 5 ph 9- N ⁺ (Me) ₂ CH ₂ CO ₂ H; 87 CH ₂ C (= O) C ₂ H _s ph 9- (N) -morpholine 88 CH ₂ C (= O) C ₂ H _s ph 9- (N) -azetidine 89 CH ₂ C (= O) C ₂ H ₅ ph 9- (N) -N-Methylazetidium, 1'-N, N'-methylazetidium; 90 CH ₂ C (= O) C ₂ H ₅ ph 9- (N) -pyrrolidine 91 CH ₂ C (= O) C 2 H 5 ph 9- (N) - N-methyl-pyrrolidinium; 92 CH ₂ C (= O) C ₂ H ₅ ph 9- (N) - N-methylmorpholinium, Γ 93 Chace (= OX ^ Hj ph 9- (N) -N'-methylpyperazine 94 CH ₂ C (= O) C ₂ H ₅ ph 9- (N) - N'-methylpyperazinium, I 95 CH ₂ C (= O) C 2 H 5 ph 9-NH-CBZ 96 CH ₂ C (= O) C ₂ H ₅ ph 9- NH-C (O) C ₅ Hn 97 CH ₂ C (= O) C ₂ H ₅ ph 9-NH-C (O) CH 2 Br 98 CH ₂ C (= O) C ₂ H ₅ ph 9-NH-C (NH) _NH2 99 CHjCÍOX ^ p ph 9- (2) -thiophene 100 CH ₂ C (= O) C ₂ H ₅ ph 7-OCH ₃ , 8-OCH ₃ 101 CH ₂ C (= O) C ₂ H ₅ ph _{7-SCH3, 8-OCH3} 102 CH ₂ C (= O) C ₂ H 3 ph _{7-SCH3, 8-SCH3} 103 CH ₂ C (= O) C ₂ H ₅ ph 6-OCH ₃ , 7-OCH ₃ , 8-OCH ₃ Prefix compound R = R ² R ⁵ (R '), (FFF.xxx.yyy) F101.009 01 CHaOGHs ph 7-methyl 02 CH ₂ OC ₅ ph 7-ethyl 03 ch ₂ oc ₂ h ₅ ph 7-isopropyl 04 ch ₂ oc ₂ h ₅ ph 7-t. butyl 05 CHjOCíHs ph 7-OH 06 CH ₂ OC ₂ H ₅ ph 7-OCH ₃ 07 CH ₂ OC ₂ H ₅ ph 7-O (iso-propyl) 08 CHjOCaHs ph 7-SCH ₃ 09 CHjOCaHs ph 7- SCULPTURE ₃

CHjOCjHs ph 7- SO ₂ CH ₃ CH2OC2H5 ph 7- SCH ₂ CH ₃ CHĺOCaHs ph _7-NH2 CH ₂ OC ₂ H ₅ ph 7-NHOH CHjOCzH. ph 7-NHCH3 CHzOC ^ Hs ph 7-NH (CH ₃ ) ₂ CHzOC ^ Hj ph 7-N + (CH3> 3, r CH ₂ OC ₂ H ₅ ph 7-NHC (= O) _CH3 CH ₂ OC ₂ H _p ph 7-NHCH ₂ CH 3 CHjOcyís ph 7-NMeCH ₂ CO ₂ H CHaOCoHs ph 7-N (Me) ₂ CH ₂ CO ₂ H, Γ OtOCaHj ph 7- (N) -morpholine CH ₂ OC ₂ H, ph 7- (N) -azetidine ch ₂ oc ₂ h ₅ ph 7- (N) -N-methylazethidium, Γ CHzOCaHj ph 7- (N) -pyrrolidine CHaOCaHj ph 7- (N) - N-methyl-pyrrolidinium; chioce ph 7- (N) - N-methylmorpholinium, Γ C ^ OCaHs ph 7- (N) -N'-methylpyperazine CH ₂ OC ₅ ph 7- (N) -N'-methylpyperazinium, I CHjOCiHs ph 7-NH-CBZ CHjOCtHs ph 7-NH-C (O) C ₅ Hn CHjOC ^ Hs ph 7-NH- € (O) CEbBr CHjOCaHs ph 7-NH-C (NH) _NH2 CHjOCÄ ph 7- (2) -thiophene CHaOCaHj ph 8-methyl CKfeOCÄ ph 8-ethyl CH ₂ OC ₂ H ₃ ph 8-isopropyl CHjOC ^ Hs ph 8-t. butyl chioce ph 8-OH chioce ph 8-OCH3 CHjOCÄ ph 8-O (iso-propyl) CHíOCiH. ph 8-SCH3 CHzOC ^ Hj ph 8- SOCH3 CHaOC ^ Hj ph 8- SO ₂ CH 3

CH2OC2H5 ph 8- SCH2CH3 CHjOCíHs ph 8-NH 2 CH2OC2H5 ph 8-NHOH CH2OC2H5 ph 8-NHCH3 CH ₂ OC ₂ H ₃ ph 8-NH (CH ₃ ) 2 CH2OC2H5 ph 8 - ^ (3 ^) 3.1- CH2OC2H5 ph 8-NHC (= O) _CH3 CH2OC2H5 ph 8- NHCH2CH3 CH2OC2H5 ph 8-CO2 H ₂ nmech CH ₂ OC ₂ H ₅ ph 8-N \ Me) 2CH2CO2H, R CH ₂ OC ₂ H ₅ ph 8- (N) -morpholine CH2OC2H5 ph 8- (N) -azetidine CH2OC2H5 ph 8- (N) -N-Methylazetidium, 1'-N '; CH2OC2H5 ph 8- (N) -pyrrolidine CH2OC2H5 ph 8- (N) -N-methyl-pyrrolidinium, Γ CH2OC2H5 ph 8- (N) - N-methylmorpholinium, Γ CH2OC2H5 ph 8- (N) -N'-methylpyperazine CH2OC2H5 ph 8- (N) - N'-methylpyperazinium; CH2OC2H5 ph 8-NH-CBZ CH2OC2H5 ph 8- NH-C (O) C ₅ HH CH2OC2H5 ph 8 -NH-C (O) CH ₂ Br CH2OC2H5 ph 8-NH-C (NH) _NH2 CH2OC2H5 ph 8- (2) -thiophene CH2OC2H5 ph 9-methyl- CH ₂ OC ₂ H ₅ ph 9-ethyl CH ₂ OC ₂ H ₅ ph 9-isopropyl CH2OC2H5 ph 9-t. butyl CH2OC2H5 ph 9-OH CH2OC2H5 ph 9-OCH CH2OC2H5 ph 9-O (iso-propyl) CH2OC2H5 ph 9-SCH 3 CH2OC2H5 ph 9- SOCH3 CH ₂ OC ₂ H ₅ ph 9-SO ₂ CH 3 CH ₂ OC ₂ H 5 ph 9- SCH2CH3

78 ch ₂ oc ₂ h ₅ ph 9-NH2 79 CH2OC2H5 ph 9-NHOH 80 CH2OC2H ₅ ph 9-NHCHj 81 CH2OC2H5 ph 9-NH (CH ₃ ) 2 82 CH2OC2H5 ph 9 - ^ (013) 3,1- 83 CH ₂ OC ₂ H ₅ ph 9-NHC (= O) _CH3 84 CH2OC2H5 ph 9- NHCH2CH3 85 CH ₂ OC ₂ H ₅ ph 9-NMeCH ₂ CO ₂ H 86 CH ₂ OC ₂ H ₅ ph 9- ^ (MehCH 2 CHCl 3, Γ 87 CH ₂ OC ₂ H ₅ ph 9- (N) -morpholine 88 CH2OC2H5 ph 9- (N) -azetidine 89 CH ₂ OC ₂ H ₅ ph 9- (N) -N-Methylazetidium, 1'-N, N'-methylazetidium; 90 CH2OC2H5 ph 9- (N) -pyrrolidine 91 CH2OC2H5 ph 9- (N) - N-methyl-pyrrolidinium, Γ 92 CH2OC2H5 ph 9- (N) - N-methylmorpholinium, Γ 93 CH ₂ OC ₂ H ₅ ph 9- (N) -N'-methylpyperazine 94 CH2OC2H5 ph 9- (N) - N'-methylpyperazinium, Γ 95 CH2OC2H5 ph 9-NH-CBZ 96 CH2OC2HS ph 9- NH-C (O) C ₅ H _n 97 CH2OC2H5 ph 9-NH-C (O) CH 2 Br 98 CH2OC2H5 ph 9-NH-C (NH) _NH2 99 CH2OC2H5 ph 9- (2) -thiophene 100 CH2OC2H5 ph 7-OCH3,8-OCH3 101 CH ₂ OC ₂ H ₅ ph 7-SCH 3, 8-OCH 3 102 CH2OC2H5 ph 7-SCH1, 8-SCH3 103 CH2OC2H3 ph 6-OCH3, 7-OCH3, 8-OCH3

Prefix compound (FFF.xxx. Yyy) r ^{1 =} r ² r ⁵ (R ^X ) q F101.008 01 CH ₂ C (= O) C ₂ H ₅ ph 7-methyl 02 CH ₂ C (= O) C ₂ H ₅ ph 7-ethyl 03 CH ₂ C (= O) C ₂ H ₅ ph 7-isopropyl

CH ₂ C (= O) C ₂ H ₅ ph 7-t. butyl CH ₂ C (= O) C ₂ H ₅ ph 7-OH CH ₂ C (= O) C ₂ H ₅ ph 7-OCH ₃ CH ₂ C (= O) C ₂ H ₅ ph 7-O (iso-propyl) CH ₂ C (= O) C ₂ H ₅ ph 7-SCH3 CH ₂ C (= O) C ₂ H ₅ ph 7- SOCH3 CH ₂ C (= O) C ₂ H _s ph 7- SO2CH3 CH ₂ C (= O) C ₂ H ₅ ph 7- SCH2CH3 CH ₂ C (= O) C ₂ H ₅ ph 7-NH 2 CH ₂ C (= O) C 2 H 5 ph 7-NHOH CH ₂ C (= O) C ₂ H ₅ ph 7-NHCH3 CH ₂ C (= O) C ₂ H ₅ ph 7-NH (CH ₃ ) 2 CH ₂ C (= O) C ₂ H ₅ ph 7-N (CH 3) 3, R CH ₂ C (= O) C ₂ H ₅ ph 7-NHC (= O) _CH3 CH ₂ C (= O) C ₂ H ₅ ph 7-NHCH2CH3 CH ₂ C (= O) C ₂ H ₅ ph 7-CO 2 H ₂ nmech CH ₂ C (= O) C 2 H 5 ph 7-N \ Me) 2CH2CO2H, R CH ₂ C (= O) C ₂ H ₅ ph 7- (N) -morpholine CH ₂ C (= O) C 2 H 5 ph 7- (N) -azetidine CH ₂ C (= O) C ₂ H ₅ ph 7- (Nj-N-methylazetidium) Γ CH ₂ C (= O) C ₂ H _s ph 7- (N) -pyrrolidine CH ₂ C (= O) C ₂ H ₅ ph 7- (N) - N-methyl-pyrrolidinium; CH ₂ C (= O) C ₂ H ₅ ph 7- (N) - N-methylmorpholinium, Γ CH ₂ C (= O) C ₂ H ₅ ph 7- (N) -N'-methylpyperazine CH ₂ C (= O) C ₂ H ₅ ph 7- (N) - N'-methylpyperazinium, Γ CH ₂ C (= O) C ₂ H ₅ ph 7-NH-CBZ CH ₂ C (= O) C ₂ H ₅ ph 7-NH-C (O) C 5 H _n CH ₂ C (= O) C ₂ H ₅ ph 7- NH-C (O) CH 2 Br CH ₂ C (= O) C ₂ H ₅ ph 7-NH-C (NH) _NH2 CH ₂ C (= O) C ₂ H ₅ ph 7- (2) -thiophene CH ₂ C (= O) C ₂ H ₅ ph 8-methyl CH ₂ C (= O) C ₂ H 5 ph 8-ethyl CH ₂ C (= O) C ₂ H 5 ph 8-isopropyl CH 2 C (= O) C ₂ H _s ph 8-t. butyl

CH ₂ C (= O) C ₂ H ₅ ph 8-OH CH ₂ C (= O) C ₂ H ₅ ph 8-OCH ₃ CH ₂ C (= O) C ₂ H ₅ ph 8-O (iso-propyl) CH ₂ C (= O) C ₂ H ₅ ph 8-SCH3 CH ₂ C (= O) C ₂ H ₅ ph 8- SOCHj CH ₂ C (= OK ₂ H ₅ ph 8- SO ₂ CH 3 CH ₂ C (= O) C ₂ H ₅ ph 8- SCH ₂ CH ₃ CH ₂ C (= O) C ₂ H ₅ ph _8-NH2 CH ₂ C ( ⁼ O) C ₂ H 5 ph 8-NHOH CH ₂ C (= O) C ₂ H ₅ ph 8-NHCH3 CH ₂ C (= OK ₂ H ₅ ph 8-NH (CH ₃ ) 2 CH ₂ C (= O) C ₂ H ₅ ph 8-NXCH _{3) 3,} R 0 ^ 0 (= 0) (¼¾ ph 8-NHC (= O) _CH3 CH ₂ C (= O) C ₂ H ₅ ph 8-NHCH ₂ CH ₃ Chace ^ CzHs ph e ^ NMeCHjCO CH ₂ C (= O) C ₂ H ₅ ph 8-N (Me) ₂ CH ₂ CO ₂ H, r CH ₂ C (= ox: 2H 5 ph 8- (N) -morpholine CH ₂ C (= O) C ₂ H ₅ ph 8- (N) -azetidine CH ₂ C (= OX 4 H ₅ ph 8- (N) -N-Methylazetidium, 1'-N '; CH ₂ C (= O) C ₂ H ₅ ph 8- (N) -pyrrolidine CH ₂ C (= O) C ₂ H ₅ ph 8- (N) -N-methyl-pyrrolidinium, Γ CHaCXOjCíHj ph 8- (N) - N-methylmorpholinium, Γ CHizC? X? Hs ph 8- (N) -N'-methylpyperazine CH ₂ C (= O) C ₂ H ₅ ph 8- (N) - N'-methylpyperazinium; GHaCC-OyCzHs ph 8-NH-CBZ CH ₂ C (= O) C ₂ H ₅ ph 8- NH-C (O) C ₅ H _n CH ₂ C (= O) C ₂ H _s ph 8-NH-C (O) CH 2 Br CH ₂ C (= O) C ₂ H ₅ ph 8-NH-C (NH) _NH2 CH ₂ C (= O) C ₂ H ₅ ph 8- (2) -thiophene CH ₂ C (= O) C ₂ H ₅ ph 9-methyl- CH ₂ C (= O) C ₂ H _s ph 9-ethyl CH ₂ C (= O) C ₂ H ₅ ph 9-isopropyl CH ₂ C (= O) C ₂ H ₅ ph 9-t. butyl CH ₂ C (= O) C ₂ H ₅ ph 9-OH

CH ₂ C (= O) C ₂ H ₅ ph 9-00¾ CH ₂ C (= O) C ₂ H _s ph 9-O (iso-propyl) CH ₂ C (= O) C ₂ H ₅ ph 9-SCH 3 CH ₂ C (= O) C ₂ H _s ph 9- SOCH3 CH ₂ C (= O) C ₂ H 5 ph 9-SO ₂ CH 3 CHjCCOjCÄ ph 9- SCH ₂ CH ₃ CH ₂ C (= O) C ₂ H ₅ ph _9-NH2 CH ₂ C (= O) C ₂ H ₅ ph 9-NHOH CH ₂ C (= O) C ₂ H ₅ ph 9-NHCHj CH ₂ C (= O) C ₂ H ₅ ph 9-NH (CH 3) 2 0 ^ 0 (= 0) (¼¾ ph 9 - (013) 3, r CH ₂ C (= O) C ₂ H ₅ ph 9-NHC (= O) _CH3 0 ^ 0 (= 0) (¼¾ ph 9- NHCH ₂ CH ₃ CHjCXOjCjHs ph 9-nmech ₂ CO 2 H CH ₂ C (= O) C ₂ H ₅ ph g-NÁMehCHjCOÄr CH ₂ C (= O) C ₂ H ₅ ph 9- (N) -morpholine 0 ^ 0 (= 0) (¼¾ ph 9- (N) -azetidine 0 ^ 0 (= 0) (¼¾ ph 9- (N) -N-Methylazetidium, 1'-N, N'-methylazetidium; 0120 (= 0) (¼¾ ph 9- (N) -pyrrolidine CH ₂ C (= O) C ₂ H ₅ ph 9- (N) - N-methyl-pyrrolidinium; CH ₂ C (= O) C ₂ H ₅ ph 9- (N) - N-methylmorpholinium, Γ CHaQOjCaHs ph 9- (N) -N'-methylpyperazine CH ₂ C (= O) C ₂ H ₅ ph 9- (N) - N'-methylpyperazinium, Γ CH ₂ C (= O) C ₂ H ₅ ph 9-NH-CBZ CH ₂ C (= O) 0ä ph 9- NH-C (O) CsHn 0 ^ (= 0) (¼¾ ph 9-NH-C (O) CH 2 Br CH ₂ C (= O) C ₂ H ₅ ph 9-NH-C (NH) _NH2 CH ₂ C (= O) C ₂ H ₅ ph 9- (2) -thiophene ΟΗ ₂ Ο (= Ο) Ο2 Η ₅ ph 7-OCH 3, 8-OCH 3 0 ^ (= 0) (¼¾ ph 7-OCH3 SCH3,8 ΟΗ ₂ Ο (= Ο) Ο2 Η ₅ ph 7-SCH1, 8-SCH3 CH ₂ C (= O) C ₂ H ₅ ph 6-OCH 3, 7-OCH 3, 8-OCH 3

-59Predpona compound R ^{1 =} R ² (FFF.xxx.yyy)

R '(R ¹ ),

F101.010 01 CH ₂ CH (OH) C ₂ H ₅ ph 7-methyl 02 CH ₂ CH (OH) C ₂ H ₅ ph 7-ethyl 03 CH ₂ CH (OH) C ₂ H _s ph 7-isopropyl 04 CHjCHtOHjCzHs ph 7-t. butyl 05 CH ₂ CH (OH) C ₂ H ₅ ph 7-OH 06 CH ₂ CH (OH) C ₂ H ₃ ph 7-OCH ₃ 07 CH ₂ CH (OH) C ₂ H ₅ ph 7-O (iso-propyl) 08 OfeCHÍOHJCÄ ph 7-SCH ₃ 09 CH ₂ CH (OH) C ₂ H ₅ ph 7- SCULPTURE ₃ 10 CHĺCHÍOHjCÄ ph 7- SO ₂ CH ₃ 11 CH ₂ CH (OH) C ₂ H 5 ph 7- SCH ₂ CH ₃ 12 CH ₂ CH (OH) C ₂ H ₅ ph _7-NH2 13 CH ₂ CH (OH) C ₂ H 3 ph 7-NHOH 14 CH ₂ CH (OH) C ₂ H ₅ ph 7-NHCH3 15 CHjCHÍOHjCzHs ph 7-NH (CH ₃ ) 2 16 CHjCHÍOWCÄ ph Τ-ΝΧΟΗά, Γ 17 CH ₂ CH (OH) C ₂ H ₅ ph 7-NHC (= O) _CH3 18 CH ₂ CH (OH) C ₂ H 5 ph 7-NHCH ₂ CH ₃ 19 CH ₂ CH (OH) C ₂ H ₅ ph 7-CO 2 H ₂ nmech 20 CH ₂ CH (OH) C ₂ H ₅ ph T-N ^ Me ^ R ^ Chace 21 CH ₂ CH (OH) C ₂ H 5 ph 7- (N) -morpholine 22 CH ₂ CH (OH) C ₂ H ₃ ph 7- (N) -azetidine 23 OfcCHÍOHXiHs ph 7- (N) -N-methyl-azetidium, 1'-methylbenzyl; 24 CHzCHÍOHQCÄ ph 7- (N) -pyrrolidine 25 C ^ CHÍOHjCíHs ph 7- (N) - N-methyl-pyrrolidinium; 26 CH ₂ CH (OH) C ₂ H ₃ ph 7- (N) - N-methylmorpholinium, Γ 27 CH ₂ CH (OH) C ₂ H ₃ ph 7- (N) -N'-methylpyperazine 28 CH ₂ CH (OH) C ₂ H ₃ ph 7- (N) - N'-methylpyperazinium; 29 CHsdKOHX ^ Hs ph 7-NH-CBZ 30 CH ₂ CH (OH) C ₂ H ₃ ph 7- NH-C (O) C ₅ Hn 31 CH ₂ CH (OH) C ₂ H ₃ ph 7- NH-C (O) CH 2 Br

CH ₂ CH (OH) C ₂ H ₅ ph 7-NH-C (NH) _NH2 CH ₂ CH (OH) C ₂ H ₅ ph 7- (2) -thiophene C ^ p ^ CHÍOHjC ph 8-methyl CH ₂ CH (OH) C ₂ H ₅ ph 8-ethyl CH ₂ CH (OH) C ₂ H ₅ ph 8-isopropyl CH ₂ CH (OH) C ₂ H ₅ ph 8-t. butyl CH ₂ CH (OH) C ₂ H ₅ ph 8-OH CH ₂ CH (OH) C ₂ H _s ph 8-OCH CH ₂ CH (OH) C ₂ H ₅ ph 8-O (iso-propyl) CHíCHÍOHJCíHs ph 8-SCH3 CH ₂ CH (OH) C ₂ H ₅ ph 8- SOCHj CH ₂ CH (OH) C ₂ H ₅ ph 8- SO ₂ CH 3 CH ₂ CH (OH) C ₂ H ₅ ph 8- SCH ₂ CH ₃ CH ₂ CH (OH) C ₂ H ₅ ph _8-NH2 CH ₂ CH (OH) C ₂ H ₅ ph 8-NHOH CH ₂ CH (OH) C ₂ H ₅ ph 8-NHCH3 CH ₂ CH (OH) C ₂ H ₅ ph 8-NH (CH 3) 2 CHsCHCOHQCsHs ph 8-N \ CH ₃₎ 3, R CH ₂ CH (OH) C ₂ H ₅ ph 8-NHC (= O) _CH3 CH ₂ CH (OH) C ₂ H ₅ ph 8-NHCH ₂ CH ₃ CHiCHÍOHOCaHs ph much nmech ^ OIH GHbCHCOHJCtfb ph e-lSľíMehCHíCOÄr CH ₂ CH (OH) C ₂ H ₅ ph 8- (N) -morpholine CH ₂ CH (OH) C ₂ H 5 ph 8- (N) -azetidine CHjCHCOHJC ^ Hs ph 8- (N) -N-Methylazetidium, 1'-N '; CHzCHCOHlCaHs ph 8- (N) -pyrrolidine CH ₂ CH (OH) C ₂ H ₅ ph 8- (N) - N-methyl-pyrrolidinium; CH ₂ CH (OH) C ₂ H _s ph 8- (N) - N-methylmorpholinium, Γ CH ₂ CH (OH) C ₂ H ₅ ph 8- (N) -N'-methylpyperazine CH ₂ CH (OH) C ₂ H ₅ ph 8- (N) - N'-methylpyperazinium; CH ₂ CH (OH) C ₂ H ₅ ph 8-NH-CBZ CH ₂ CH (OH) C ₂ H 5 ph 8- NH-C (O) C 5 H _u CH ₂ CH (OH) C ₂ H ₅ ph 8- NH-C (O) CH 2 Br CHjCHÍOHX ^ Hj ph 8-NH-C (NH) _NH2

CH ₂ CH (OH) C ₂ H ₅ ph 8- (2) -thiophene CH ₂ CH (OH) C ₂ H _s ph 9-methyl- CH ₂ CH (OH) C ₂ H 5 ph 9-ethyl CH ₂ CH (OH) C ₂ H 5 ph 9-isopropyl CH ₂ CH (OH) C ₂ H ₅ ph 9-t. butyl CH ₂ CH (OH) C ₂ H ₅ ph 9-OH CHjCHÍOHjCjHs ph 9-OCH ₃ CH ₂ CH (OH) C ₂ H ₅ ph 9-O (iso-propyl) CHaCHÍOHX ^ Hs ph 9-SCH 3 OfeCHCOHJCaHs ph 9- SOCH3 CH ₂ CH (OH) C ₂ H ₅ ph 9-SO ₂ CH 3 CH ₂ CH (OH) C ₂ H ₅ ph 9- SCH ₂ CH ₃ CH ₂ CH (OH) C ₂ H ₅ ph _9-NH2 CH ₂ CH (OH) C ₂ H ₅ ph 9-NHOH CH ₂ CH (OH) C ₂ H ₅ ph 9-NHCH3 CH ₂ CH (OH) CaH ₅ ph 9-NH (CH 3) 2 (Ή £ Η (0Η) ΟΗ5 ph 9-N (CH3) 3; CH ₂ CH (OH) C ₂ H ₅ ph 9-NHC (= O) _CH3 CHgCHCOlQCsHs ph 9-NHCH ₂ CH 3 CHiCHCOH) ^ ph 9-NMeCH ₂ CO ₂ H CH ₂ CH (OH) C ₂ H ₅ ph 9-r ^ NXMehCIfeCO CHjCHtOHjCÄ ph 9- (N) -morpholine CH ₂ CH (OH) C ₂ H ₅ ph 9- (N) -azetidine CH ₂ CH (OH) Cl ₅ ph 9- (N) -N-methylazetidium, Γ CH ₂ CH (OH) C ₂ H ₅ ph 9- (N) -pyrrolidine CHjCHtOHjCjHs ph 9- (N) - N-methyl-pyrrolidinium; CH ₂ CH (OH) C ₂ H ₅ ph 9- (N) - N-methylmorpholinium, Γ ΟΗ ₂ ΟΗ (ΟΗ) (^ Η ₅ ph 9- (N) -N'-methylpyperazine CH ₂ CH (OH) C ₂ H ₅ ph 9- (N) - N'-methylpyperazinium, Γ CH ₂ CH (OH) C ₂ H _s ph 9-NH-CBZ CHaCHCOH) ^ ph 9 - NH - C (O) C ₅ Hh CH ₂ CH (OH) C ₂ H ₅ ph 9-NH-C (O) CH ₂ Br CH HtOHjCsHs ph 9-NH-C (NH) _NH2 CH ₂ CH (OH) C ₂ H ₅ ph 9- (2) -thiophene

100 CH ₂ CH (OH) C ₂ H ₅ ph 7-OCH3, 8-OCH3 101 CH ₂ CH (OH) C ₂ H ₅ ph 7-SCH 3, 8-OCH 3 102 CH ₂ CH (OH) C ₂ H ₅ ph 7-SCH3, 8-SCH3 103 CH ₂ CH (OH) C ₂ H ₅ ph 6-OCH 3, 7-OCH 3, 8-OCH 3

Prefix compound (FFF.xxx.yyy) R ^{1 =} R ² R ⁵ (R ^X ) q F101.011 01 CH ₂ - (4-picoline) ph 7-methyl 02 CH ₂ - (4-picoline) ph 7-ethyl 03 CH ₂ - (4-picoline) ph 7-isopropyl 04 CH ₂ - (4-picoline) ph 7-t. butyl 05 CH ₂ - (4-picoline) ph 7-OH 06 CH ₂ - (4-picoline) ph 7-OCH 3 07 CH ₂ - (4-picoline) ph 7-O (iso-propyl) 08 CH ₂ - (4-picoline) ph 7-SCH3 09 CH ₂ - (4-picolm) ph 7- SOCH3 10 CH ₂ - (4-picoline) ph 7- SO ₂ CH ₃ 11 CH ₂ - (4-picoline) ph 7- SCH ₂ CHj 12 CH ₂ - (4-picoline) ph _7-NH2 13 CH ₂ - (4-picoline) ph 7-NHOH 14 CH ₂ - (4-picoline) ph 7-NHCH3 15 CH ₂ - (4-picoline) ph 7-NH (CH ₃ ) 2 16 CH ₂ - (4-picoline) ph 7-N + (CH) 3, r 17 CH ₂ - (4-picoline) ph 7-NHC (= O) _CH3 18 CH ₂ - (4-picoline) ph 7-NHCH ₂ CH 3 19 CH ₂ - (4-picoline) ph 7-NMeCH ₂ CO ₂ H 20 CH ₂ - (4-picoline) ph 7-N ⁺ (Me) ₂ CH ₂ CO ₂ H, r 21 CH ₂ - (4-picoline) ph 7- (N) -morpholine 22 CH ₂ - (4-picoline) ph 7- (N) -azetidine 23 CH ₂ - (4-picoline) ph 7- (N) -N-methyl-azetidium, 1'-methylbenzyl; 24 CH ₂ - (4-picoline) ph 7- (N) -pyrrolidine 25 CH ₂ - (4-picoline) ph 7- (N) - N-methyl-pyrrolidinium;

CH ₂ - (4-picoline) ph 7- (N) - N-methylmorpholinium, Γ CH ₂ - (4-picoline) ph 7- (N) -N'-methylpyperazine CH2- (4-pikoIín) ph 7- (N) - N'-methylpyperazinium; CH ₂ - (4-picoline) ph 7-NH-CBZ CH ₂ - (4-picoline) ph 7- NH-C (O) C5Hu CH ₂ - (4-picoline) ph 7-NH-C (O) CH ₂ Br CH ₂ - (4-picoline) ph 7-NH-C (NH) _NH2 CH ₂ - (4-picoline) ph 7- (2) -thiophene CH ₂ - (4-picoline) ph 8-methyl CH ₂ - (4-picoline) ph 8-ethyl CH - ^ - picoline) ph 8-isopropyl CH ₂ - (4-picoline) ph 8-t. butyl CH ₂ - (4-picoline) ph 8-OH CH ₂ - (4-picoline) ph 8-OCH CH ₂ - (4-picoline) ph 8-O (iso-propyl) CH ₂ - (4-picoline) ph 8-SCH3 CH ₂ - (4-picoline) ph 8- SOCH3 CH ₂ - (4-picoline) ph 8- SO ₂ CH 3 CH ₂ - (4-picolm) ph 8- SCH ₂ CH ₃ CH ₂ - (4-picoline) ph _8-NH2 CH ₂ - (4-picolm) ph 8-NHOH CH ₂ - (4-picoline) ph 8-NHCH3 CH ₂ - (4-picoline) ph 8-NH (CH ₃ ) 2 CH ₂ - (4-picoline) ph 8-N (CH 3) 3; CH ₂ - (4-picoline) ph 8-NHC (= O) _CH3 CH ₂ - (4-picoline) ph 8-NHCH ₂ CH ₃ CH ₂ - (4-picoline) ph 8-CO2 H ₂ nmech CH ₂ - (4-picoline) ph much írCMe ^ CHaCOÄr CH ₂ - (4-picoline) ph 8- (N) -morpholine CH ₂ - (4-picoline) ph 8- (N) -azetidine CH ₂ - (4-picoline) ph 8- (N) -N-methylazethidium, Γ CH ₂ - (4-picoline) ph 8- (N) -pyrrolidine CH ₂ - (4-picoline) ph 8- (N) -N-methyl-pyrrolidinium, Γ CH ₂ - (4-picolin) ph 8- (N) - N-methylmorpholinium, Γ

CH 2 (4-picoline) ph 8- (N) -N'-methylpyperazine CH 2 (4-picoline) ph 8- (N) - N'-methylpyperazinium; CH 2 (4-picoline) ph 8- NH-CBZ CH 2 (4-picoline) ph 8-NH-C (O) CjHii CH 2 (4-picoline) ph 8 -NH-C (O) CH ₂ Br CH 2 (4-picoline) ph 8-NH-C (NH) _NH2 CH 2 (4-picoline) ph 8- (2) -thiophene CH 2 (4-picoline) ph 9-methyl- CH ₂ - (4-picoline) ph 9-ethyl CH 2 (4-picoline) ph 9-isopropyl CH ₂ - (4-picoline) ph 9-t. butyl CH 2 (4-picoline) ph 9-OH CH 2 (4-picoline) ph 9-OCH ₃ CH2- (4-pikolm) ph 9-O (iso-propyl) CH ₂ - (4-picolm) ph 9-SCH ₃ CH 2 (4-picoline) ph 9- SCULPTURE ₃ CH 2 (4-picoline) ph 9-SO ₂ CH 3 CH 2 (4-picoline) ph 9- SCH2CH3 CH ₂ - (4-picoline) ph 9-NHi CH ₂ - (4-picoline) ph 9-NHOH CH ₂ - (4-picolm) ph 9-NHCHj CH ₂ - (4-picoline) ph 9-NH (CH ₃ ) 2 CH 2 (4-picoline) ph 9-N + (CH 3) j, r CH2- (4-pikoIín) ph 9-NHC (= O) _CH3 CH ₂ - (4-picoline) ph 9-NHCH2CH3 CH 2 (4-picoline) ph 9-nmech ₂ CO 2 H CH ₂ - (4-picoline) ph 9- (Me 2 CH 3 CO 2 H, δ) CH2- (4-pikolm) ph 9- (N) -morpholine CH 2 (4-picoline) ph 9- (N) -azetidine CH 2 (4-picoline) ph 9- (N) -N-Methylazetidium, 1'-N, N'-methylazetidium; CH 2 (4-picoline) ph 9- (N) -pyrrolidine CH ₂ - (4-picoline) ph 9- (N) - N-methyl-pyrrolidinium, Γ CH ₂ - (4-picoline) ph 9- (N) - N-methylmorpholinium, Γ CH ₂ - (4-picoline) ph 9- (N) -N'-methylpyperazine

94 CH 2 (4-picoline) ph 9- (N) - N'-methylpyperazinium; 95 CH 2 (4-picoline) ph 9-NH-CBZ 96 CH ₂ - (4-picoline) ph 9-NH-C (O) C ₃ H ₃ 97 CH 2 (4-picoline) ph 9-NH-C (0) _CH2 Br 98 CH ₂ - (4-picoline) ph 9-NH-C (NH) _NH2 99 CH ₂ - (4-picoline) ph 9- (2) -thiophene 100 CH ₂ - (4-picoline) ph 7-OCH ₃ , 8-OCH ₃ 101 CH 2 (4-picoline) ph _{7-SCH3, 8-OCH3} 102 CH ₂ - (4-picoline) ph _{7-SCH3, 8-SCH3} 103 CH 2 (4-picoline) ph 6-OCH ₃ , 7-OCH ₃ , 8-OCH ₃

Other structures of the invention

τ. bile. R ' R ² R ³ R ⁴ R ⁵ R ⁶ (R ^x ) _q 101 ethyl n-butyl OH H phenyl H in position 7 102 ethyl n-butyl OH H phenyl H 7-trimethylammonium iodide 103 n-butyl ethyl OH H phenyl H 7-trimethylammonium iodide 104 ethyl n-butyl OH H phenyl H 7-dimethylamino 105 ethyl n-butyl OH H phenyl H 7-methanesulfonamido 106 ethyl n-butyl OH H phenyl H 7- (2 '-bromoacetamido) 107 n-butyl ethyl OH H 4- (decyloxy) phenyl H 7-amino 108 ethyl n-butyl OH H phenyl H 7- (hexylamide) 109 ethyl n-butyl OH H 4 <decyloxy) phenyl H 7-amino 110 ethyl n-butyl OH H phenyl H 7-acetamido 111 n-butyl ethyl OH H 4-hydroxyphenyl H 7-amino

112 ethyl n-butyl OH H 0¾. w H 7-amino 113 ethyl n-butyl OH H 4-hydroxyphenyl H 7-amino 114 ethyl n-butyl OH H 4-methoxyphenyl H 7-amino 115 n-butyl ethyl OH H 4-methoxyphenyl H 7- (0-benzylkaibamáto) 116 ethyl n-butyl OH H 4-methoxyphenyl H 7- (0-benzylkaibamáto) 117 n-butyl ethyl OH H phenyl H 7- (0-benzylkaibaináto) 118 ethyl n-butyl OH H phenyl H 7-fO-benzylkaibamáto) 119 ethyl n-butyl OH H phenyl H 7- (O-terc.butylkarbamát0) 120 n-butyl ethyl OH H phenyl H 7 <O-benzyl carbamates) 121 ethyl n-butyl OH H phenyl H 7-amino 122 n-butyl ethyl OH H phenyl H 7-amino 123 ethyl n-butyl OH H phenyl H 7-hexylamino 124 n-butyl ethyl OH H phenyl H 7- (hexylamino) 125 ethyl n-butyl OH H phenyl H in position 8 I 126 n-butyl ethyl OH H 4-fluorophenyl H 7- (0-benzylkaibamáto) 127 n-butyl ethyl OH 4-fluorophenyl H 7-amino 128 ethyl n-butyl OH H 4-fluorophenyl H 7- (O-benzylkaibamáto) 129 ethyl n-butyl OH H 4-fluorophenyl H 7-amino 131 ethyl n-butyl OH H 4-fluorophenyl H in position 7 1 132 ethyl n-butyl OH H phenyl H in position 8 about ' 133 ethyl n-butyl OH H phenyl H 8- (hexyloxy) 134 ethyl n-butyl OH H phenyl H In position 8

135 ethyl n-butyl OH H phenyl H in position 8 1 136 ethyl n-butyl OH H phenyl H 8-hydroxy 137 n-butyl ethyl OH H phenyl H in position 7 138 n-butyl ethyl OH H phenyl H 8-acetoxy- 139 n-butyl ethyl OH H phenyl H in position 7 142 ethyl n-butyl H OH H 3-methoxy-phenyl 7-methylmercapto 143 ethyl n-butyl OH H 3-methoxy-phenyl H 7-methylmercapto 144 ethyl n-butyl OH H 4-fluorophenyl H 7 <L-azetidine) 262 ethyl n-butyl OH H 3-methoxy-phenyl H 7-methoxy 263 ethyl n-butyl H OH H 3-methoxyphenyl 7-methoxy 264 ethyl n-butyl OH H 3-trifluoromethyl phenyl H 7-methoxy 265 ethyl n-butyl H OH H 3-trifluónnetyl- phenyl 7-methoxy 266 ethyl n-butyl OH H 3-hydroxyphenyl H 7-hydroxy 267 ethyl n-butyl OH H 3-hydroxyphenyl H 7-methoxy 268 ethyl n-butyl OH H 4-fluorophenyl H 7-methoxy 269 ethyl n-butyl H OH H 4-fluorophenyl 7-methoxy 270 ethyl n-butyl OH H 4-fluorophenyl H 7-hydroxy 271 ethyl n-butyl OH H 3-methoxyphenyl H 7-bromo 272 ethyl n-butyl H OH H 3-methoxyphenyl 7-bromo 273 ethyl n-butyl H OH H 4-fluorophenyl 7-fluoro 274 ethyl n-butyl OH H 4-fluorophenyl H 7-fluoro 275 ethyl n-butyl H OH H 3-methoxyphenyl 7-fluoro 276 ethyl n-butyl OH H 3-methoxyphenyl H 7-fluoro

277 ethyl n-butyl OH H 3-fluorophenyl H 7-methoxy 278 ethyl n-butyl H OH 2-fluorophenyl H 7-methoxy 279 ethyl n-butyl H OH 3-fluorophenyl H 7-methoxy 280 ethyl n-butyl OH H 2-fluorophenyl H 7-methoxy 281 ethyl n-butyl OH H 4-fluorophenyl H 7-methylmercapto 282 ethyl n-butyl OH H 4-fluorophenyl H 7-methyl 283 ethyl n-butyl H OH H 4-fluorophenyl 7-methyl 284 ethyl n-butyl OH H 4-fluorophenyl H 7- (4'-morpholino) 285 MISSING 286 ethyl ethyl OH H phenyl H 7- (0-benzylkaibamáto) 287 ethyl ethyl OH H phenyl H 7-amino 288 methyl methyl OH H phenyl H 7-amino 289 n-butyl n-butyl OH H phenyl H 7-amino 290 n-butyl n-butyl OH H phenyl H 7-amino 291 n-butyl n-butyl OH H phenyl H 7- (O-benzylkaibamáto) 292 n-butyl n-butyl OH H 4-fluorophenyl H 7-amino 293 n-butyl n-butyl OH H phenyl H 7-benzylamino 294 n-butyl n-butyl OH H phenyl H 7-dimethylamino

295 n-butyl n-butyl OH H H 7-amino 296 ethyl n-butyl OH H H 7-amino 1000 ethyl n-butyl OH H H 7-dimethylamino 1001 ethyl n-butyl OH H you. H 7-dimethylamino 1002 ethyl n-butyl OH H δύο H 7-dimethylamino 1003 ethyl n-butyl OH H H 7-dimethylamino 1004 ethyl n-butyl OH H H 7-dimethylamino

1005 n-butyl n-butyl OH H H 7-dimethylamino 1006 n-butyl n-butyl OH H Br. H 7-dimethylamino 1007 n-butyl n-butyl OH H OK · H 7-dimethylamino 1008 n-butyl n-butyl OH H H 7-dimethylamino 1009 n-butyl n-butyl OH H H 7-dimethylamino 1010 n-butyl n-butyl OH H 3-fluoro-4-methoxyphenyl H 7-dimethylamino 1011 n-butyl n-butyl OH H 3-fluoro-4- (5-trietylamómumpentyloxy) phenyl trifluoroacetate H 7-dimethylamino 1012 n-butyl n-butyl OH H 4-h.ydroxyfenyl H 7-dimethylamino; 9-methoxy 1013 n-butyl n-butyl OH H H 7-dimethylamino 1014 n-butyl n-butyl OH H 4-methoxyphenyl H 7-dimethylamino; 9-methoxy 1015 n-butyl n-butyl OH H H 7-dimethylamino

1016 n-butyl n-butyl OH H you H 7-dimethylamino 1017 n-butyl n-butyl OH H H 7-dimethylamino 1018 n-butyl n-butyl OH H H 7-dimethylamino 1019 n-butyl n-butyl OH H YY M ', «V ABOUT H 7-dimethylamino 1020 n-butyl n-butyl OH H H 7-dimethylamino 1021 n-butyl n-butyl OH H H 7-dimethylamino 1022 n-butyl n-butyl OH H δ ,, λγ- H 7-dimethylamino

1023 n-butyl n-butyl OH H and H 7-dimethylamino 1024 n-butyl n-butyl OH H 11, v ₊ '' L C H 7-dimethylamino 1025 n-butyl n-butyl OH H VY H 7-dimethylamino 1026 n-butyl n-butyl OH H ňu ¹ ϊγΛ H 7-dimethylamino 1027 n-butyl n-butyl OH H H 7-dimethylamino 1028 n-butyl n-butyl OH H *H * cA H 7-dimethylamino

1029 n-butyl n-butyl OH H H 7-dimethylamino 1030 n-butyl n-butyl OH H Ó / «P H 7-dimethylamino 1031 n-butyl n-butyl OH H « + H 7-dimethylamino 1032 n-butyl n-butyl OH H o ^X * ^Sy ^ ^zZ>, Sz ^{zZ> s} ' _N | _C | _W j _H j _i H 7-dunetylamino 1033 n-butyl n-butyl OH H H 7-dimethylamino 1034 n-butyl n-butyl OH H H 7-dimethylamino

1035 n-butyl n-butyl OH H ABOUT. H 7-dňnetylamino 1036 n-butyl n-butyl OH H H 7-dimethylamino 1037 n-butyl n-butyl OH H 4-hydroxyphenyl H 7-dňnetylamino 1038 n-butyl n-butyl OH H No. Ť. about H 7-dimethylamino 1039 n-butyl n-butyl OH H phenyl H 7-dimethylamino 1040 n-butyl n-butyl OH H X H ov® »' o o N (CH, CHJ, + H 7-dimethylamino 1041 n-butyl n-butyl OH H ABOUT, ’U H 7-dimethylamino 1042 n-butyl n-butyl OH H E X '* ^X p _o ^/ ^' J ^ ^Z ' ^Nothing * ^H * ¹ ' H 7-dimethylamino

1043 n-butyl n-butyl OH H H 7-dimethylamino 1044 n-butyl n-butyl OH H cp, what,% _of Aj. _of X @ \ J _x N (CH, CH _3), H 7-dimethylamino 1045 n-butyl n-butyl OH H CF, CO / ° and N (CH »CHJ, H 7-dimethylamino in 1046 n-butyl n-butyl OH H 3-aminophenyl H 7-Dimension Laminate 1047 n-butyl n-butyl OH H Λ H 7-dimethylamino 1048 n-butyl n-butyl OH H Ýl * H 7-dimethylamino 1049 n-butyl n-butyl OH H ΧζχΟ H 7-dimethylamino 1050 n-butyl n-butyl OH H H 7-dimethylamino in 1051 n-butyl n-butyl OH H ^{CF, C} ° ¹ 'C H 7-dimethylamino

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7-dimethylamino 7-dimtylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 35 3! 35 35 35 35 -r j GX ^á T T F ( about J 4 ' 3-fluoro-4-methoxyphenyl about 73 in 7Y <I ' 35 35 35 35 35 35 g g g g 35 ABOUT g n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl T n-butyl n-butyl n-butyl 1058 1059 0901 1061 1062 1063

7-dimethylamino ABOUT and ·? r *. 7-dimethylamino 9-dimethylamino 7-dimethylamino 7-dimethylamino 9-dunetylamino B The B B B B n ? <a 1 ¥ about Ms.? T ABOUT. ó 5 ¹ XII thiophen-3-yl <F phenyl B The B B B B B ABOUT with B ABOUT HO B ABOUT B WITH n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl 1064 1065 1066 1067 1068 1069

T r ~ 7-dimtylamino 7-dimetylanuno 9-dimethylamino [7-dimethylamino | 7-dimetylanuno 9-dimethylamino 7-dimethylamino 17-dimethylamino | The The WITH stí stí IC stí stí hi % with ABOUT Q. T The ť I about L N <5 fa L IX \ <n T à [3-fluoro-4-methoxyphenyl 4-fluorophenyl < <*> F about ♦ 5R s 3-hydroxymethylphenyl 4-hydroxyphenyl The ffi Ä stí WITH stí they they with with with WITH with WITH ABOUT WITH WITH they ABOUT s Έ * s I e ? e 1 e F e F C I s e ? e F and 1 > I F G with No. about r ~ about ^ 4 <a r * about m r * about RM about r> about tS about about 00 r * about

7-dimtylamino 1 7-dimethylamino 9-dimethylamino 7-dimethylamino 7-dimethylamino with The 35 35 33 SL WLF W FROM J . 3 2-pyridyl Qx J WITH 35 35 35 35 with with WITH HO g g n-butyl and n-butyl n-butyl n-butyl n-butyl ethyl n-butyl n-butyl ethyl n-butyl 1079 1080 1081 1082 1083

7-dimtylamino 7-dimethylamino | 9-dimethylamino 7-dimethylamino 17-dimethylamino | 7-dimethylamino B and and B and and b T 4 J x V \ = ± «'| <5 thiophen-3-yl J- s and 3,4-methylenedioxyphenyl 4-methoxyphenyl J a5 and and and and and and and WITH and about with and WITH with δ n-butyl ln-butyl n-butyl n-butyl 1 n-butyl I n-butyl n-butyl | n-butyl n-butyl n-butyl T £ n-butyl TFR 00 ABOUT m 00 ABOUT \about 00 ABOUT r- © 00 00 about about\ 00 about WITH about

Ο ABOUT | about 1 1 Λ g £> F s ε ε ε ε • 9 T 7 t ~ r * r- about\ 35 35 X x ( about .P y ¹ and T ÚQ .r - { - {<l ^x b <F 35 35 WITH X WITH X WITH x Ο ABOUT about WITH Í butyl T butyl C e they e T butyl butyl F C C they C cs m ABOUT\ about\ axis about\ about about ABOUT about rM r "i

7-dimethylamino 7-dimtylamino 7-dimethylamino 9-dimethylamino 7-dimethylamino 17-dimethylamino | 7-dimethylamino 7-dimethylamino WITH SC WITH SC SC SC SC fa -J b r 4 s ABOUT z + / ω \ 1 - \ - 1 4-methoxyphenyl 4-methoxyphenyl ..about S Ť 3-kaiboxYmetylfenyl r> s - Ah p SC SC SC SC SC SC SC SC with WITH g HO g HO HO HO HO n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl 1 n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl ethyl n-butyl | n-butyl n-butyl 1095 1096 1097 1098 1099 11100 I 1101 11102 I 1103

7-dimethylamino 7-dimtylamino 7-dimethylamino 9-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino The WITH The X WITH The X X <5 5-piperonyl 3-hydroxyphenyl Q m \ ^ \ __ Z 3-pyridyl x «Μ ABOUT ABOUT-\ bi 8 * / 1 f 0 0 X p 4-pyridyl X X WITH with The x X WITH g g here WITH The WITH The WITH g The WITH X 0 n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl 1104 1105 1106 1107 1108 1109 1110 1111 1112

7-dimethylamino 7-methylamino 7-dimethylamino 9-dimethylamino | 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 8 WITH WITH WITH WITH 8 8 8 8 3-methoxyphenyl 4-fluorophenyl 13-tolyl | n 2 O + z \ ” 3-fluoro-4-hydroxyphenyl % 3 % 4 . in about 'Ah, in about with WITH The WITH here 8 8 8 8 with WITH WITH g g 8 WITH g 8 ABOUT g n-butyl n-butyl n-butyl | n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl ethyl ethyl ethyl n-butyl n-butyl n-butyl and 1113 1114 1115 1 ¹¹¹⁶ 1117 1118 1119 1120 1121

7-dimethylamino 7-methylamino 7-dimethylamino 9-dimethylamino | 7-dimethylamino 7-dimetylanuno 7-dimethylamino 19-dimethylamino | 7-dimetylanuno 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 53 53 53 53 53 53 53 53 53 53 53 53 53 ΓΓ n £ s about 2 r about r . P, . ) and m < 0 ABOUT about ⁷ \ / J / <5 phenyl 3-methoxyphenyl 13-chloro-4-methoxyphenyl \ = / 3-fluoro-4-hydroxyphenyl 14-fluoro-phenyl 3-chloro-4-fluorophenyl 4-methoxyphenyl 4-cyanomethylphenyl 5i 53 53 53 53 53 53 53 53 53 53 53 with WITH 53 ABOUT g OH g 5! WITH g 53 WITH g and HO | g g n-butyl n-butyl n-butyl N-butyl T and n-butyl n-butyl 1 n-butyl 1 n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl 1 n-butyl ethyl n-butyl n-butyl | n-butyl n-butyl ethyl n-butyl n-butyl ethyl 1122 1123 i 1124 1 ¹¹²⁵ 1126 1127 1128 I 1129 J 1130 1131 1132 1133 1134

7-dimethylamino 7-methylamino 9- (2 ', 2'-dimethylhydrazino) 9-dimethylamino 7-dimethylamino 9- (2 ', 2'-dimethylhydrazino) 7-ethylmethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 17-dimethylamino j 7-dimethylamino p7-dimethylamino | 7-Dimethylsulfonium fluoride salt | [7-dimethylamino, 7-dimethylamino | 7- (ethoxymethyl) matylamino 7-dimethylamino 17-dimethylamino | 17-dimethylamino | ABOUT Q g with and and and and and and and and 3-fluoro-4- methoxyphenyl and and and and and and and and and and and and 3,4-dimethoxyphenyl T 14-fluoro-phenyl 3,4-difluorophenyl 3-methoxyphenyl 4-fluorophenyl D £ £ about J T r and 5-piperonyl 14-methoxyphenyl WHAT about OZ _L £ ABOUT about P 13-methoxyphenyl 14-fluoro-phenyl 14-fluoro-phenyl 3-methoxyphenyl 3-fluoro-4-methoxyphenyl phenyl 14-fluorophenyl, 13-Methoxyphenyl 1 4-fluorophenyl 1 and and and and and and and and and and and and and and and and and and and and and with with g g and about g g g and g g and ABOUT g g HO HO g g g g g g n-butyl n-butyl n-butoxide are preferred n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl 1 n-butyl n-butyl n-butyl | n-butyl I n-butyl 1 n-butyl I ethyl n-butyl n-butyl 1 n-butyl I n-butyl n-butyl n-butyl n-butyl J n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl e n-butyl | n-butyl | | n-butyl | 1 n-butyl 1 n-butyl 1 n-butyl n-butyl n-butyl] n-butyl I n-butyl 1135 1136 1137 1138 1139 1140 1141 1142 1143 1144 ¹¹⁴⁵ 1 1146 r * 00 ABOUT Λ ^ 4 "WITH * Γ Ί • Λ Ti m m

7-fluoro; 9-fluoro 17-Fluoro | 7-fluoro; 9-Fluoro | 7-methyl 7-trimethylammonium iodide | 7-trimethylammonium iodide | 7-bromo | Í F 7-hydroxy | 7-dimethylamino 7-dimethylamino 7- (4-methylpiperazin-1-yl) 7-methoxy 7- (N- dimethylformamide) 7-methoxy X X X X X X X x X X X X X X X 4-fluorophenyl 14-fluoro-phenyl | Phenyl | 4-fluorophenyl 14-methoxyphenyl | 13,4-difluorophenyl | 12-bromophenyl | 14- (dimethylamino) phenyl | 13- (dimethylamino) phenyl] 4- (2- (2-methylpropyl)) phenyl o o are you / r 14-methoxyphenyl ^^ N (CH 3) 3 phenyl 4- (pyridinyl-N-oxide) x X X R3 + R 4 = 0X0 X X X X X X X X X X X X WITH WITH X WITH X WITH g g g g g X WITH g HO g R3 + R 4 = 0X0 HO n-butyl ¹ n-butyl | | n-butyl n-butyl 1 n-butyl n-butyl N-butyl N-butyl 1 n-butyl n-butyl n-butyl 1 n-butyl n-butyl ethyl n-butyl n-butyl | n-butyl n-butyl | n-butyl | n-butyl 1 n-butyl I [n-butyl 1 I n-butyl | n-butyl n-butyl | n-butyl | n-butyl n-butyl n-butyl 00 'C 00 • M \ABOUT 00 fH r * 00 00 00 axis 00 fM ABOUT s Ov fH <a axis Ov WITH 11195 | 1196 1197 1198

7-dimethylamino 17-dimethylamino | 7-methyl 7-methoxy s F § 1 with ft- 7-methoxy 7-demetylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethyl-phenyl 7-dimethylamino 33 phenyl | 33 33 33 33 33 33 33 33 33 33 Xw Á / k 33 33 1 W 5-piperazinyl 4-fluorophenyl n £ about F about - + Z 3,5-diclilórfenyl 4-methoxyphenyl phenyl 12- (Dimethylamino) phenyl J about p with 33 WITH 33 33 33 33 33 33 33 33 33 33 The WITH 33 33 ABOUT WITH WITH § 33 ABOUT 33 WITH WITH 33 ABOUT h 33 ABOUT n-butyl 1 n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl 1 n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl ABOUT n-butyl n-butyl n-butyl 6611 11200 I 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210

7-dimethylamino 9- (4'-morpholino) 7-dimethylamino 7- (N-methylformamido) | 9-methylmercapto | 7-bromo | 7-dimethylamino 9-methylsulfonyl 7-dimethylamino 7-izopropylanuno 7-dimethylamino 7-ethylamino 8-bromo; 7-methylamino 7-fluoro 7-dimethylamino 7-bromo 7- (t-butylamino) 8-bromo; 7-dimethylamino The and 3-fluoro-4- methoxyphenyl The and and and and and and and and and and and and and and V / -XJ ^with l! P 4-methoxyphenyl and 1 phenyl 1 14-methoxyphenyl | 15-piperonyl | } % 4-methoxyphenyl CM about 3-methoxyphenyl 3-methoxyphenyl phenyl 3-nitrophenyl 3-methylphenyl 5-piperonyl 4-fluorophenyl 2-pyrrolyl with WITH OB and and and and and and and and and and and and and and and with The about and and WITH with and WITH with with with g g g g and WITH HO g g and WITH n-butyl n-butyl ethyl 1 n-butyl 1 1 n-butyl 1 | n-butyl | n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl ethyl n-butyl n-butyl | n-butyl ethyl n-butyl n-butyl N-butyl 1 n-butyl 1 ethyl | F e n-butyl n-butyl n-butyl n-butyl T and s G n-butyl n-butyl ethyl n-butyl, n-butyl 1211 1212 1213 L ¹²¹⁴ 1 11215 1 1 ¹²¹⁵ 1 1217 1218 1219 1220 1221 1222 m CM CM 1224 1225 1226 11227 | 1228

7-dimethylamino | 9-dimethylamino; 7-Fluoro | 7-dimethylamino 9-dimethylamino 7-dimethylamino and and and and and 3-chloro-4-hydroxyphenyl phenyl | about- 3-thiophenyl CM s á and and and o a and and ABOUT g and ABOUT and and WITH 1 n-butyl N-butyll n-butyl n-butyl n-butyl n-butyl n-butyl 1 n-butyl n-butyl n-butyl 1229 11230 I 1231 1232 1233

7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino The and and and and WHAT ? about and CHILDREN CN J about from T 4- (Bromomethyl) phenyl n £ _L o i \ ¹ O ó 5 about and and and and and with with g HO and WITH n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl 1234 1235 1236 1237 1238

7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 7- (1-methylhydrazido) 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino WITH E E E E E and E E E E m \ CM 4-methoxy-3-methyl-phenyl 3- (dimethylaminomethyl) phenyl Λ <*> x - o 3-methoxyphenyl <0 _ & 3- (Bromomethyl) phenyl I about ol about in X ABOUT - <o> ”F about \ 7 u. about F F E and E E E E E E and and E with with E ABOUT E ABOUT WITH WITH E ABOUT WITH with with WITH n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl and n-butyl n-butyl n-butyl n-butyl n-butyl i - 1239 1240 1241 1242 1243 1244 1245 1246 1247 1248 1249

, 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 7- (1-methylhydrazido) [7-dimethylamino | ABOUT Ή * 1 r * • * § s 00 19- (t-butylamino) | 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-bromo | 7-dimethylamino | [9-Isopropylamino The 35 3! 35 35 35 35 33 35 phenyl 35 B B B B B s I 1 m l-naphthyl <1> f ¹ o + z 4 o 0 WHAT 1 r f / about \ / ° Q 1— \ m / about | 3-nitrophenyl phenyl 14-fluoro-phenyl 35 3-hydroxyphenyl about 2-thiophenyl 15-piperonyl 14-fluorophenyl | 4-fluorophenyl B 35 35 35 35 33 35 35 35 HO H 35 B B B B B 35 ABOUT g 35 WITH g g g g g g 35 WITH g g g B WITH g n-butyl n-butyl J n-butyl n-butyl n-butyl n-butyl 1 n-butyl n-butyl 1 n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl 1 n-butyl 1 n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl N-butyl J n-butyl N-butyl J ethyl ethyl n-butyl n-butyl n-butyl L n-butyl I n-butyl 1250 1251 1252 1253 1254 1255 11256 J 1257 11258 J 1259 1260 1261 1262 11263 J 11264 | 1265

7-dimethylamino 7-kaiboxymetylester 7-dimethylamino 7-dimethylamino X X X X CN £ 1 f The 5-piperonyl CQ W 2 o - + z \ ¹⁰ "\ IO X about P x X x x HO X with HO HO n-butyl ___ ethyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl 1266 r * with cs 1268 1269

7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino The X X X L_ UL O <5 .Q ° -x > \ n / y WITH i> 'T 4T F £ f o £ o £ T £ f- x x x x WITH with x x about about about about s * £ Σ and and and C Σ ' à Σ · Σ ·? Σ C C C and about CS m I ** · r- r * T cs CS cs cs ^ 4

7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-bromo 7-dimethylamino The The The and and and and C CM F JS o -s f I £ o o o I -s Ϊ I ol ABOUT about J £ £ | F £ S £ f ä f o £ o 04 ABOUT £ P r o £ o JS o -s £ T £ o 1 o in" -from £ r £ o 1 o J5 O £ T £ o 1 o * \ " / < U- p, \ " \ s * \ / ° y / • pp 1 \ O - ¹ < - ( \ / £  <o <5 about about ^p Ä with and and and and and with and with and and and and about about about about about about about n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl 1 n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl 1274 1275 1276 1277 1278 1279 1280

ABOUT

II é ¹ é *

SO «p

CM

- with? -

7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino X WITH The X X X é ΛΛ o \ ₊ Z Úľ / - \ θ / \ o CO CO + 0. \ ^M -ABOUT ABOUT CM £ ABOUT £ about about ύ 7 \ l / i IN:/ ar Q CM ? ' ύτ . \ about Xi about xa in r with X with x x x g HO HO HO HO HO n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl 1291 1292 1293 1294 1295 1296

7-dimethylamino 7-dimethylamino and and CM £ about Sf and Q about > 2 about > <5 and and g g n-butyl n-butyl n-butyl n-butyl 1297 1298

1 T 3 7-dimethylamino | 7-tnmetylamóniumjodid 9-hydroxy | 7-dimethylamino 7-tert-butylamino 9-methylamino 7-dimethylamino 9- (4-morpholino) The 1 phenyl 1 and and and and and and 4 methoxyphenyl M o £ o 3 m ä + <0. \ ^N , 1 h | ho i 3-methoxyphenyl 13-hydroxyphenyl | I- 3-methoxyphenyl 4-fluorophenyl \ __ / uľ - \ ° o = C ° \ about P and ' ¹ > ¹ < and and and and and and and and and WITH and with with and with and WITH and WITH g n-butyl letyl J n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl N-butyl I n-butyl | n-butyl ethyl ethyl n-butyl n-butyl n-butyl 1299 WITH cn 1301 11302] 1303 1304 1305 1306 1307

7-dimethylamino 19-fluoro Π 7-amino 7- (hydroxylamino) 8-hexyloxy 8-ethoxy 7- (hydroxylamino) 7- (hexyloxy) 8-hydroxy 1- 3 7-dimethylamino 7-Fluoro | 7-amino A à at f 0 00 7-dimethylamino and and and and a ' and and and and and and and and and and 0 P 14-Methoxyphenyl 1 phenyl | phenyl | phenyl phenyl phenyl phenyl phenyl phenyl phenyl 13-methoxyphenyl phenyl phenyl Q and and and and and and and and and and and and and and and g and WITH g g and ABOUT g HO HO and WITH g HO g and about g HO n-butyl L n-butyl n-butyl [ethyl 1 ethyl ethyl n-butyl n-butyl ethyl ethyl n-butyl n-butyl n-butyl ethyl n-butyl ethyl J ..... | n-butyl ethyl | n-butyl n-butyl n-butyl ethyl ethyl n-butyl n-butyl ethyl 5 ethyl n-butyl n-butyl 1 1308 11309 1310 f * d 1312 1313 1314 1315 1316 1317 1318 about\ m 1320 1321 1322

100

7-dimethylamino 7-dimethylamino 7-dimethylamino B B B \ x 5 4 - ((diethylamino) methyl) phenyl B B B HO HO HO n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl 1323 1324 1325

7-dimethylamino 7-dimethylamino 7-dimethylamino B B B I ABOUT 3 XJ 3-fluoro-4-hydroxy-5-iodophenyl 'b B B B g B WITH HO n-butyl n-butyl n-butyl e n-butyl n-butyl 1326 1327 1328

101

102

7-dimethylamino 7-dimethylamino 7-dimethylamino WITH the SC Q _ U IN J 7 / J. \ ABOUT _L < about H * - · you -J C with the the with the the about about about à R Ή ' $ ·? C e e s * Ä » s? WITH C C e l at © m ΓΊ m m <*> <**> ^ 4

7-dimethylamino 7- (4´-methylpipetazinyl) | 7-dimethylamino the the the J5 ABOUT - t 4-methoxyphenyl | rt F about with the the the HO Γ ^Η θ HO n-butyl n-butyl | n-butyl n-butyl n-butyl | n-butyl and 1337 | 1338 | 1339

103

7-methyl 7-dimethylamino 7- (4'-fluorophenyl) 7-amino [7-dimethylamino 7-trimetylamóniumjodid in 8. Position 7-dimethylamino 7-dimethylamino 17-dimethylamino 7-trimetylamóniumjodid 7-dimethylamino 7-dimethylamino 7-dimethylamino 8 8 8 WITH 8 8 8 8 8 WITH 8 WITH 8 8 15-piperonyl | 3-methoxyphenyl 5-piperonyl phenyl 13-fluoro-4-methoxyphenyl | 1 phenyl] phenyl 13-fluoro-4-methoxyphenyl | phenyl ]? Ä 3-fluoro-4-methoxyphenyl O / '£ Z s o ¹ »- (-P ΛΛ δ \ / Ai J ° 7 \ o« Ο LL o A á $ about £ £ about <*> about ? U £ θ T 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 WITH § with? 8 ABOUT 8 WITH HO 8 WITH HO WITH HO g 8 ABOUT HO g g 1 ^ 3 1 n-butyl n-butyl n-butyl N-butyl T n-butyl | n-butyl | isobutyl N-butyl I n-butyl n-butyl n-butyl n-butyl 1 and In-ylic n-butyl n-butyl ethyl 1 n-butyl letyl ethyl | n-butyl 1 isobutyl F n-butyl n-butyl n-butyl n-butyl § m 1341 1342 1343 1344 1345 1346 1347 I 00 Tt m ABOUT\ it ABOUT m <*> 1352 1353

104

7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino X X X X L k w Q_! _ \ N 'λ- ¹ m T ( T > the LL θ <F x x x x x x x x about about about about s * B à § C e and e 1 F butyl F they e e and m Ό r * m m m m m ΓΊ <* » m «Μ

105

106

107

108

7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino and and and and and L J3 I ° Λ 4 / \ «xr G á CHILDREN T and and and and and with and WITH g and about g n-butyl n-butyl n-butyl n-butyl n-butyl and n-butyl n-butyl n-butyl n-butyl n-butyl 1371 1372 1373 1374 1375

109

7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimetylanuno 7-dimethylamino 7-dimethylamino X X X X X X \ HJF 2 WHAT 9th x about + 2 \ M WHAT ^ what I about £ about WITH about WHAT £ about £ about z + 4 about WHAT £ about £ about + H pole ¹ ÄX 1 í 1 í  Λ < x x x x x x g OH HO g g HO n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl 1376 1377 1378 1379 1380 1381

110

111

7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino X X X X X X ol ^ε ( ^ε ΗΟ ^ζ θ) Ν ^χ + L s -1 -Φ w Λ \ = / 1- x MD p p yT p p 'A x x x x x x HO HO x about x about HO n-butyl and n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl 1387 1388 1389 1390 1391

112

113

114

115

7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino X X X X X vX 2 X \ / JO T - about F about - S \ <M T CO I O f ¹ o + z 0 U- _K O ΰ X WHAT I o cò Q- "The x y CO of x s ¹ of the gall £ \ 't u- O _(H x x X x x HO HO HO HO HO n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl 1407 1408 1409 1410 1411

116

7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino X X X X X MD ( ^{from =} \ o f = ^ / ⁺ \ q WHAT WHAT x o £ o + 1 * .i. x x x x x x about x about x about x about x about n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl 1412 1413 1414 1415 1416

117

ο about about ABOUT e C 0 .WITH C ε C 53 £ θ ' u ⁴ à ε ε ε ε -σ Ό ie> Ύ r * r- » r * r * E E E E I I about Λ X about _v <> + \ x WHAT . “£ ( ΓΛ 'Z + \ $ \ . \ \ - X -) F ABOUT \ / - / u. z + z x \ ._ (I R-L LL \ about \ // R IN_/ \ - ( -> (V — o-o ) / \ = / \ - / < > 7 E and E E E E E and ABOUT about ABOUT about from" I à No. * X) JD x> and C C C F and l and x> JO X) C No. C C r * · 00 axis 420 T} · Ti *** * · · **

118

119

ο about about about about C .with C C .3 E έ ε Λ 3 from' υ ε dimethyl Σ ε & * ε Σ ε TJ Ό TJ TJ T3 r * · r- t ^ · t4 I I x x x what ? about x £ about about \ z + (in fl X ( _Λ o ) in_·/ 4De % < / ° WHAT 55 X + / Λ No. / \ n WHAT \ , -4 · \ J. Q m. ^ -z) ) / / GQ z + / \ - / \ 1 p. \ x Λ / "Λ z x / 'Á / H -W H? 4 about \ = == / 4 in__/ \ = / 33 X x x x 5 x x x x Ο about about about about Σ » Σ * Σ ' £ Σ ' 3 3 3 3 3 X X x> X X C β 3 s 3 Σ ' à Σ ' Σ · Σ » 3 3 3 3 3 ·? Jä J? X X » e 3 e s 3 VO r- 00 axis ABOUT n (N CM <N what xt ** **

120

121

122

7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino 7-methoxy; 8- methoxy 7-dimethylamino X X X X X X I x \ 0/0 Q. <> —O / Z = 2 WHAT Y-Z + Π3 ¹ co you about about \ « ^z O + \ (Z) what W - ¹ > , \ IN IJ-) m / \ / \ / \ U- O / \ "\ ° / Λ U- O The / \ ) \ y \ from \ - / \ - / \ - / \ - / y \ / IN X x x x x x x x x x x x about about about about about about Σ à Σ à Σ Σ □ 3 3 g 3 3 Ä x> -ABOUT *? X> x e s á e and s Σ Σ ' Σ> > Σ * Σ · WITH 3 3 3 3 3 JD jO •ABOUT J? X3 C C C C C No. CN m TR with C * 5 • 3 · · < NT 5 ** **

123

7-dimethylamino 7-dimethylamino 7-dimethylamino 7-dimethylamino X X X X + 'eo n O ^from W o 0 OO O-, t phenyl about. H X x X x HO HO HO HO n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl 1448 1449 1450 1451

124

PEG = polyethylene glycol having a relative molecular weight of 3400

125

PEG = polyethylene glycol having a relative molecular weight of 3400

126

127

128

129

130

131

132

133

134

135

136

C22 Η 28 02 S 356.529 0 Q Ί S-0 ph - / • et n-Bu

137

-138V other compounds of the invention, R ^a and R @ ⁶ are independently selected from the group consisting of hydrogen and a carbon ring substituted or unsubstituted aryl, thiophene, pyridine, pyrrole, thiazole, imidazole, pyrazole, pyrimidine, morpholine, Nakylpyridíniom, alkylpiperazíniom N, N-alkyl-morpholine or a furan, wherein the substituents are selected from the group consisting of halogen, hydroxyl, trihaloalkyl, alkoxy, amino, N-alkylamino, Ν, Ν-dialkylamino, a quaternary ammonium salt and a C 1 -C 4 alkylene bridge containing a quaternary ammonium salt substituted, alkoxycarbonyl, aryloxy , alkylcarbonyloxy and arylcarbonyloxy, (0,0) -dioxyalkylene, - (O (CH 2) w) x X where x is 2 to 12, w is 2 or 3 and X represents halogen or a quaternary ammonium salt, thiophene, pyridine, pyrrole, thiazole, imidazole, pyrazole or furan. The aryl group of R ⁵ or R ⁶ is preferably phenyl, phenylene or benzene triyl, it may be unsubstituted, mono- or disubstituted. Among the groups that may form aryl ring substituents R ³ or R ⁶ are fluoride, chloride, bromide, methoxy, ethoxy, isopropoxy, trimethylammonium (preferably with an iodide or chloride counterion) methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, propanoyl, (N) - hexyldimethylammonium, hexylenetrimethylammonium, tri (oxyethylene) iodide and tetra (oxyethylene) trimethylammonium iodide, each substituted at the -position, m -position, or both positions of the aryl ring. Other substituents that may be present on phenylene, benzene, triyl or other aromatic rings include 3,4-dioxymethylene (5-membered ring) and 3,4-dioxyethylene (6-membered ring). Among the compounds that are or may be presented as desirable bile acid transport inhibitory effects are those wherein R ³ or R ⁶ are selected from the group consisting of phenyl, p-fluorophenyl, m-fluorophenyl, p-hydroxyphenyl, m-hydroxyphenyl, p-methoxyphenyl, m-methoxyphenyl, pN, N-dimethylaminophenyl, mN, N-dimethylaminophenyl, Γ p- (CH 2) ₃ -N'-phenyl, Γ m- (CH ₂ ) ₃ -N'-phenyl, CH ₂ ) ₃ -N'-CH ₂ CH ₂ (OCH ₂ CH ₂ ) 2 -O-phenyl, β- (CH ₂ ) ₃ -N'-CH ₂ CH ₂ - (OCH ₂ CH ₂ ) ₂ -O-phenyl, Γ m- (N, N-dimethylpiperazinium) - (N ') - CH ₂ - (OCH ₂ CH ₂ ) 2 -O-phenyl, 3-methoxy-4-fluorophenyl, thienyl-2-yl, 5-chlorothienyl-2-yl , 3,4-difluorophenyl,, Γ p (N, N-dimethylpiperazinium) - (N ') - _CH2 - _{(OCH2 CH2) 2} -O-phenyl, 3-fluoro-4-methoxyphenyl, 4-pyridinyl 2-pyridinyl, 3-pyridinyl, N-methyl-4-pyridinium, 1'-N-methyl-3-pyridinium, 3,4-dioxymethylenephenyl, 3,4-dioxyethylenephenyl and pm ethoxycarbonylphenyl. Preferred compounds include 3-ethyl-3-butyl and 3-butyl-3-butyl compounds containing each of the above-mentioned preferred R ³ substituents in combination with the R ^x substituents shown in Table 1. It is particularly preferred that one but not two substituents of R ³ or R ⁶ is hydrogen.

It is particularly preferred that R ⁴ and R ⁶ are hydrogen, R ³ and R ³ are not hydrogen and if R ³ and R ³ are oriented in the same direction with respect to the plane of the molecule, for example, both va and β

- 139configuration. It is further preferred that R ² is butyl and R ¹ is ethyl, then R ³ has the same orientation relative to the plane of the molecule as R ³ and R ⁵ .

R 1 / R ³ , R ^s / R ⁶ and R ^x are shown in Table 1A.

Table 1A

R ¹ . R ² R ³ . R ⁴ R ⁵ IR ^x ) o ethyl OH- ph 7-methyl n-propyl H p-F-Ph- 7-ethyl n-butyl m-F-Ph- 7-isopropyl n-pentyl p-Ph-chjo 7-tert-butyl n-hexyl 7-OH isopropyl _m-CH3 O-Ph- 7-OCH ₃ isobutyl p- (CH ₃ ) ₂ N-Ph 7-O (iso-propyl) isopentyl m- (CH _{3) 2} N-Ph 7-SCH ₃ CH ₂ C (= O) C ₂ H ₅ Γ, p-ICHah-K-Ph- 7-SOCH ₃ CH ₂ OC ₂ H ₅ Γ, m- (CH ₃ ) ₃ -N ^ -Ph- 7-SO ₂ CH ₃ CHjCHÍOHjCiHs Γ, m-CH 2 -jSr-CHaCH 2 - _{7-SCH2 CH3} CH ₂ O- (4-picoline) (OCH ₂ CH ₂ ) ₂ -O-Ph- _7-NH2 Γ, m- (CH ₃ ) ₃ -N ⁺ -CH ₂ CH ₂ - 7-NHOH (OCH ₂ CH ₂ ) ₂ -O-Ph- _7-NHCH3 Γ, p - (N, N- 7-N (CH ₃ ) ₂ dimethyl) - 7 - ^ (0¼) ^ (N 1 -CH 2 OCH 2 H 2 -O- 7-NHC (= O) _CH3 ph 7-N (CH ₂ CH ₃ ) ₂ Γ, m - (N, N- 7-NMeCH ₂ CO ₂ H dimethyl) - 7-N (Me) ₂ CH ₂ CO ₂ H, Γ (N) -CH ₂ - (OCH ₂ CH ₂ ) ₂ -O- 7- (N) -morpholine ph 7- (N) azetidine m-F, p-CH3-Ph- 7- (N) -N-methyl-azetidinium, 1'-methylbenzyl; 3,4-dioxy methylene-Ph 7- (N) -pyrrolidine _m-CH3 O-, pF-Ph 7- (N) -N-methylpyrrolidinium; 4-pyridine 7- (N) -N-methylmorpholinium; N-methyl-4-pyridinium, Γ 7- (N) -N-methylpyperazine 3-pyridine 7- (N) -N-dimethylpyperazidinium, Γ N-methyl-3-pyridyl, Γ 7-NH-CBZ 2-pyridine 7-NHC (= O) C H N _{5 p-CH3 O2} C-Ph- 7-NHC (= O) CH ₂ Br thienyl-2-yl 7-NH-C (NH) _NH2 5-Cl-thienyl-2-yl 7- (2) -thiophene

1403,4-difluoro m-F, p-CH 3 -Ph

8-methyl

8-ethyl

8-isopropyl

8-t-butyl

8-OH

8-OCH3

8-O (iso-propyl)

8-SCH3

8-SOCH3

8-SO2CH3

8-SCH2CH3

8-NH 2

8-NHOH

8-NHCH3

8-N (CH ₃ ) ₂

8-N + (CH 3) 3, R

8-NHC (= O) _CH3

8-N (CH ₂ CH ₃ ) ₂

8-CO2 H ₂ nmech much OlehCHiCOÄ N + Γ

8- (N) -morpholine

8- (N) azetidine

8- (N) -N-methylazetidinium, Γ 8- (N) -pyrrolidine 8- (N) -N-methylpyrrolidinium, Γ 8- (N) -N-methylmorpholinium, Γ 8- (N) -N-methylpyperazine

8- (N) -N-dimethylpyperazidinium, Γ 8-NH-CBZ 8-NHC (= O) C 8 H 8 8- NHC (= O) CH 2 Br 8-NH-C (NH) NH ₂

8- (2) -thiophene

9-methyl 9-ethyl

9-isopropyl

9-t-butyl

9-OH

9-OCH3

9-O (iso-propyl)

9-SCH 3

9-SOCH3

9-SO ₂ CH ₃

_{9-SCH2 CH3}

_9-NH2

9-NHOH

9-NHCH3

9-N (CH3) 2

-1419-N ⁺ _(CH3) 3, I '

9-NHC (= O) _CH3

9-N (CH ₂ CH 3) ₂

9-NMeCH ₂ CO ₂ H

9-N ⁺ (Me) ₂ CH ₂ CO ₂ H;

9- (N) -morpholine

9- (N) azetidine

9- (N) -N-methylazetidinium, Γ 9- (N) -pyrrolidine 9- (N) -N-methylpyrrolidinium, Γ 9- (N) -N-methylmorpholinium, Γ 9- (N) -N-methylpyperazine

9- (N) -N-dimethylpyperazidinium, Γ 9-NH-CBZ 9-NHC (= O) C ₅ Hn 9-NHC (= O) CH ₂ Br 9-NH-C (NH) NH ₂ 9- (2 ) -thiophene 7-OCH 3, 8-OCH 3 7-SCH 3, 8-OCH 3 7-SCH 3, 8-SCH 3 6-OCH 3, 7-OCH 3, 8-OCH 3,

Other preferred compounds of the invention comprise a backbone by two or more pharmaceutically active benzothiepine structures as described above, covalently bound to the backbone by functional bridges. Such active benzothiepine structures preferably comprise:

DIV or

-142

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , x, q andan are as defined above and R ⁵⁵ is either a covalent bond or arylene.

The backbone may comprise an alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyalkoxy diyl, carbohydrate, amino acid and peptide polypeptide wherein the alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyalkoxy diyl, carbohydrate , the amino acid and the peptide, the polypeptide may optionally have one or more carbons replaced by O, NR ⁷ , N ⁺ R ⁷ R ⁹ , S, SO, SO 2, S ⁹ R ⁹ , PR ⁷ , P ⁹ R ⁹ , phenylene, heterocycle, quaternary a heterocycle, a quaternary heteroaryl or an aryl wherein the alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyalkoxy diyl, carbohydrate, amino acid and peptide, polypeptide may be substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ² R ¹³ , SO ³ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO 2, CO a R ¹³ , CN, OM, SO 2OM, SO ₂ NR ¹³ R ^14, C (O) NR ¹³ R ^14, C (O) OM, COR ^13, P (O) NR ¹³ R ^14, F * R ¹³ R ¹⁴ R ¹⁵ A · C (OR ¹³⁾ OR ¹⁴ , ST < ¹³ R ¹⁴ A 'and N + R'r' 4 'A', wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle may be further substituted with one or more substituents selected from the group consisting of OR ^7, NR ⁷ R ^9, SR ^7, S (O) R ^7, SOjR ^7, SO 3 R ^7, COzR ^7, CN, oxo, CONR ⁷ R ^9, N + R'r'r'A ', alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P (O) R ⁷ R ⁹ , P 4 R 6A and P (O) (OR ⁷ ) OR ⁹ and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle can optionally have one or two carbon atoms replaced by O, ^NR7, N + R'r'A, S, SO, SO _2, N, S ', R ^7, P (O) R ^7, or P'R'R'A · phenylene.

Examples of basic skeletons include:

-143-

. ²⁶

BCN

where:

R ²⁵ is selected from the group consisting of C or N, and R ²⁶ and R ²⁷ are independently selected from the group consisting of:

-144-

wherein R ²⁶ , R ²⁹ , R ³⁰ and R ³¹ are independently selected from the group consisting of alkyl, alkenylalkylaryl, aryl, arylalkyl, cycloalkyl, heterocycle and heterocycloalkyl, A is a pharmaceutically acceptable anion when it is from 1 to 10.

In the compounds of formula DIV, R ²⁰ , R ²¹ , R ²² in formulas DH and DHIA R ²³ in formula DHI, they may bind at any of their 6-, 7-, 8- or 9-position to R ¹⁹ . In compounds of formula DIVA, it is preferred that R ⁵⁵ contains a phenylene moiety bound at its m- or position to R ¹⁹ .

In another section, the backbone, R ¹⁹ , as discussed herein in formula DII and DHI, may be substituted by more than four linked active benzothiepine units, for example, R ²⁰ , R ²¹ , R ²² and R ²³ as discussed above, through multiple functional groups within the basic skeleton. The backbone unit, R ¹⁹ , may comprise the backbone unit itself, its multimer, and multimeric mixtures of the various backbone units discussed herein, alone or in combination. The number of discrete skeletal units may range from about 1 to 100, preferably from about 1 to 90, more preferably from about 1 to 50, and most preferably from 1 to 25. The number of attachment sites of similar or different bound active benzothiepine units within the base skeleton unit it may range from about 1 to 100, preferably from about 1 to 90, more preferably from about 1 to 50, and most preferably from 1 to 25. These attachment sites may contain C, S, O, N or P bonds within any structure included in the definition of R ¹⁹ .

More preferably, the benzothiepine unit comprises R ²⁰ , R ²¹ , R ²² , or R ²³ adapted to the preferred structures as outlined above for Formula I. The carbon 3 of each

The -145 benzothiepine unit may be achiral and the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^x may be selected from the preferred groups and combinations of substituents listed above. The base structures may comprise, for example, poly (oxyalkylene) or oligo (oxyalkylene), in particular poly or oligo (oxyethylene) or poly- or oligo (oxypropylene).

Dosage, formulations and routes of administration

The bile acid transport inhibiting compounds of the invention can be administered in the prophylaxis or treatment of hyperlipidemic diseases or conditions by any means, preferably orally, to ensure contact of these compounds with the site of their action in the body, for example in an ileum of a mammal, including a human.

For the prophylaxis or treatment of the conditions described above, the compounds of the invention may be used as compounds per se.

Pharmaceutically acceptable salts are particularly suitable for therapeutic application due to their greater solubility in water relative to the compounds from which they are formed. Such salts must clearly contain a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention include, if possible, inorganic acid salts such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic, sulfuric, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic. fumaric, gluconic, glycolic, isotionic, lactic, lactobionic, maleic, malic, methanesulfonic, amber, toluenesulfonic, wine and trifluoroacetic. Chlorides are particularly preferred for medical purposes. Suitable pharmaceutically acceptable basic salts may include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as magnesium and calcium salts.

Of course, the anions of the invention listed as A * must also be pharmaceutically acceptable and are also selected from those listed above.

The compounds of the invention may be in the form of a pharmaceutical composition together with a suitable carrier. Of course, the carrier must be suitable in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof. The carrier may be solid or liquid, or both, and is preferably formulated with the compound as a unit dosage composition, for example, a tablet containing from 0.05% to 95% by weight of active ingredient. Other pharmaceutically active substances may also be present, including the compounds of the invention. The pharmaceutical compositions of the invention may be

Prepare by any known pharmaceutical technique involving essentially mixing the components.

These compounds can be administered by any conventional means suitable for use, in conjunction with pharmaceuticals, not only as an individual therapeutic compound, but also as a combination of therapeutic compounds.

The amount of compound required to achieve the desired biological effect will of course depend on a number of factors such as the choice of the specific compound, the use for which it is intended, the mode of administration and the clinical condition of the patient.

Generally, the daily dose may range from about 0.3 to 100 mg / kg body weight / day, preferably from about 1 mg to 50 mg / kg body weight / day, more preferably from about 3 to 10 mg / kg body weight. /day. This total daily dose may be administered to the patient in a single dose or several times in multiple smaller doses. These smaller doses may be administered 2 to 6 times daily. Dosages in sustained release form can be effective to obtain the desired results.

Unit dosage formulations for oral administration, such as capsules or tablets, may contain, for example, from about 0.1 to 100 mg of the benzotiepine compound, preferably from about 1 to 75 mg of the compound, more preferably from about 10 to 50 mg of the compound. In the case of a pharmaceutically acceptable salt, the above weight refers to the weight of the benzotiepine ion derived from the salt.

Oral administration of the bile acid transport inhibitors of the invention may include formulations well known in the art to prolong the continuous administration of the drug to the gastrointestinal tract. Such formulations include, but are not limited to, pH-dependent dosage release based on pH change in the small intestine, slow erosion of a tablet or capsule, stomach retention based on physical properties of the formulation, bioadhesion of the dosage form to the mucosal layer of the intestinal tract, enzymatic releasing the active drug from the dosage form. Expectant effect of extending the time period in which the active ingredient of arriving at the site of action (the ileum) _L manipulation of the dosage form. Intestinal coated formulations and controlled release intestinal coated formulations are within the scope of the invention. Suitable substances for coating intestinal formulations are cellulose acetate phthalates, polyvinyl acetate phthalates, hydroxypropylmethylcellulose phthalates and anionic polymers of methacrylic acid and methacrylic acid methyl ester.

For example, when administered intravenously, the dose may be in the range of 0.1 mg / kg body weight to 1 mg / kg body weight, preferably in the range of 0.25

-147 mg / kg body weight to 0.75 mg / kg body weight, more preferably in the range of 0.4 mg / kg body weight to 0.6 mg / kg body weight. This dose may conveniently be administered as an infusion at a rate of from 10 ng / kg body weight to 100 ng / kg body weight per minute. An infusion solution suitable for this purpose may contain, for example, from about 0.1 ng to 10 mg, preferably from about 1 ng to 10 mg per milliliter. For example, a dosage unit may contain from about 1 mg to 10 g of a compound of the invention. The ampoules for injection may contain, for example, from about 1 mg to 100 mg.

Pharmaceutical compositions of the invention include compositions suitable for oral, rectal, topical, buccal (e.g., sublingual) and parenteral (e.g., subcutaneous, intramuscular, intradermal or intravenous) administration, the most appropriate route of administration depending on the origin and severity of the condition being treated and the particular condition. the compound to be used. In most cases, oral administration is preferred.

Pharmaceutical compositions suitable for oral administration may be as discrete units such as capsules, cachets, lozenges or tablets, each containing a determined amount of at least one compound of the invention; such as a powder or granules; as solutions or suspensions in an aqueous or non-aqueous solvent; or as an oil-in-water emulsion or a water-in-oil emulsion. As indicated, these compositions can be prepared by any suitable pharmaceutical method, comprising the step of adding the active agent or agents and the carrier (which may comprise one or more additives). In general, the compositions are prepared by uniformly and substantially adding the active compound to a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, tablets may be prepared by compressing or compressing the powder or granules of the compound, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, by means of a suitable machine, the compounds in a freely administrable form such as a powder or granules, optionally mixed with a binder, an inert solvent, a lubricant or a surface-active or dispersing agent. Compressed tablets may be prepared by compressing, with the aid of suitable equipment, powdered compounds moistened with an inert liquid solvent.

Pharmaceutical compositions suitable for buccal (sublingual) administration include sweets containing a compound of the invention in a flavoring base, usually sucrose and acacia or tragacanth, and lozenges containing the compound in an inert matrix such as gelatin and glycerin or sucrose and acacia.

Pharmaceutical compositions suitable for parenteral administration suitably include sterile aqueous preparations of a compound of the invention. These additions are preferably administered intravenously, though

Administration may also be by subcutaneous, intramuscular or transdermal injection. Such compositions may conveniently be prepared by mixing the compound with water and preparing a sterile and isotonic solution with blood. Injectable compositions of the invention generally contain from 0.1 to 5% by weight. % wt. of the compounds described herein.

Pharmaceutical compositions suitable for rectal administration are preferably prepared as unit dose suppositories. These may be prepared by mixing the compound of the invention with one or more suitable solid carriers, for example coconut butter, and shaping the resulting mixture.

Pharmaceutical compositions suitable for topical application to the skin are preferably in the form of ointments, creams, lotions, pastes, gels, sprays, aerosols or oils. The carriers used may contain petrolatum, lanolin, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound is generally present at a concentration of 0.1 to 15 wt. from 0.5 to 2% by weight.

Such transdermal application is possible. Pharmaceutical compositions suitable for transdermal application may be presented in the form of individual patches adapted to provide intimate contact with the skin of the recipient over an extended period of time. These patches suitably comprise a compound of the invention optionally buffered in its aqueous solution dissolved or dispersed in an adhesive or dispersed in a polymer. A suitable concentration of the active compound is in the range of 1% to 35%, preferably in the range of about 3% to 15%. As a special option, electrotransport of the compound or iontophoresis remains, for example, as described in Pharmaceutical Research, 3 (6), 319 (1996).

In all cases, the amount of active ingredient that may be combined with the carriers to produce a single dosage form for administration will vary depending upon the host treated and the particular mode of administration.

Solid dosage forms for oral administration include the capsules, tablets, dragees, powder and granules mentioned above containing one or more of the compounds of the invention mixed with at least one inert solvent such as sucrose, lactose or starch. These dosage forms may also contain, as is normal practice, additional substances other than inert solvents, for example, lubricating agents such as magnesium stearate. In the case of capsules, tablets and dragees, the dosage form may also contain buffering agents. Tablets and dragees may additionally be prepared with an enteric coating.

Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert solvents commonly used in the art, such as water. These compositions may also contain adjuvants such as

Humectants, emulsifiers and suspending agents, including sweetening, flavoring and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated to the knowledge of the art using suitable dispersing or adjuvanting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic and parenterally acceptable solvent or diluent, for example a solution in 1,3-butanediol. Acceptable solvents and excipients include 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 mono or diglycerides. Fatty acids such as oleic acid also find use in the preparation of injections.

Pharmaceutically acceptable carriers include all of the foregoing and the like.

In combination therapy, administration of bile acid transport inhibitors and HMG CoA reductase inhibitors may be sequentially in individual formulations or may be accomplished by simultaneous administration of single or separate formulations. Administration can be by oral, intravenous, intramuscular, or subcutaneous injection. The formulation may be in the form of a bolus or in the form of an aqueous or non-aqueous isotonic sterile injectable solution or suspension. These solutions and suspensions may be prepared from sterile powder or granules containing one or more pharmaceutically acceptable carriers or diluents or binder such as gelatin or hydroxypropylmethyl cellulose, together with one or more lubricating, preservative, surface-active or dispersing agents.

The pharmaceutical composition for oral administration may be in the form of, for example, tablets, capsules, suspensions, or liquids. Capsules, tablets, etc., can be prepared by conventional methods well known in the art. The pharmaceutical compositions are preferably formulated in dosage units containing a specific amount of the active ingredient or ingredients. Examples of dosage units are tablets or capsules. These may advantageously contain one or more bile acid transport inhibitors in the amount indicated above. In the case of HMG Co-A reductase inhibitors, the dosage may range from 0.01 mg to 500 mg or otherwise, depending on the specific inhibitor as known in the art.

The active ingredients may also be administered by injection, as a composition wherein, for example, sodium chloride, dextrose or water is used as a suitable carrier. Appropriate daily dose of all

The -150 active inhibitors are such as to cause the same blood serum level as when administered orally as described above.

The active inhibitors may also be administered by any dual combination route of administration, such as oral / oral, oral / parenteral or parenteral / parenteral.

The pharmaceutical compositions for use in the methods of treatment of the invention may be administered orally or intravenously. Oral administration is preferred for combination therapy. Dosage for oral administration may be on a single daily dose or a single dose over several days, or multiple divided doses over a day. Inhibitors of the combination therapy may be administered by the simultaneous administration, not only in a combined dosage form, but also in the form of individual dosage forms intended primarily for simultaneous oral administration. Inhibitors that are the essence of combination therapy can also be administered as follows, with each inhibitor administered in a regime called two-step use. The mode of administration may be referred to as sequential administration, wherein the inhibitors are used separately as separate active agents. The time period between multiple use steps may range from several minutes to several hours, depending on the properties of the inhibitor such as potential, solubility, bioavailability, plasma half-life and inhibitor kinetic profile, as well as the age and condition of the patient. When the combination therapy inhibitors are administered simultaneously, especially simultaneously or sequentially, they may include regimens of administering one inhibitor by the oral route and the other inhibitor intravenously. When the combination therapy inhibitors are administered orally or intravenously, separately or together, each such inhibitor will be included in a suitable pharmaceutical formulation of pharmaceutically acceptable excipients, solvents or other formulation components. Examples of suitable pharmaceutically acceptable formulations containing inhibitors for oral administration are listed above.

Treatment regimens

Dosage regimens of the compounds and / or compositions of the invention for preventing, alleviating or ameliorating disease states with hyperlipidemia as part of a disease, for example atherosclerosis, or for protecting or treating high levels of plasma or blood cholesterol are selected with respect to a variety of factors. These include the type, age, weight, sex, diet and medical condition of the patient, degree of disease, route of administration, pharmacological aspects such as activity, efficacy, pharmacokinetics and toxicological profile of the particular compound used, whether a drug delivery system is used and whether the compound is administered as part of the combination

-151liekov. Thus, the dosage regimen employed may deviate greatly and therefore differ from the preferred dosage regimens listed above.

Initial treatment of a patient with hyperlipidemia may begin with the regimen described above. Treatment should generally last as necessary over a period of several weeks to months or years as long as the hyperlipidemic condition is controlled or eliminated. Patients treated with the compounds or compositions described herein can be routinely monitored, for example, by determining serum LDL and total cholesterol levels, by any method known in the art to determine the efficacy of the combination therapy. Continuous analysis of such data permits modification of the treatment regimen during therapy so as to administer an effective amount of each type of inhibitor at any time and to determine the duration of treatment well. In this case, the treatment regimen or dosage schedule may reasonably be modified during therapy to administer a minimum amount of bile acid transport inhibitors and HMG Co-A reductase inhibitors that together have satisfactory efficacy, and that such administration lasts for the necessary time to successfully treat hyperlipidemic conditions.

A potential advantage of the combination therapy described herein may be the reduction in the amount of bile acid transport inhibitors, HMG Co-A reductase inhibitors, or both, effective in the treatment of hyperlipidemic conditions such as atherosclerosis and hypercholesterolemia.

The following examples are not limiting and serve to illustrate various aspects of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Preparation 1:

2-Ethyl-2- (mesyloxymethyl) hexanal (1)

To a cooled solution (10 ° C) of 12.6 g (0.11 mol) of methanesulfonyl chloride and 10.3 g (0.13 mol) of triethylamine is added dropwise 15.8 g of 2-ethyl- (hydroxymethyl) hexanal prepared according to the procedure described in Chem. Ber. 98, 728-734 (1965), maintaining the reaction temperature below 30 ° C. The reaction mixture was stirred at room temperature for 18 hours, neutralized with dilute hydrochloric acid solution and extracted with dichloromethane. The dichloromethane extract was dried over magnesium sulfate and concentrated in vacuo to give 24.4 g of a brown oil.

-152Preparation 2:

2 - ((2-benzoylphenylthio) methyl) -2-ethylhexanal (2)

A mixture of 31 g (0.144 mol) of 2-mercaptobenzophenone, prepared according to the procedure described in WO 93/16055, 24.4 g (0.1 mol) of 2-ethyl-2- (mesyloxymethyl) -hexanal (1), 14.8 g (0.146 mol) triethylamine and 80 ml of 2-methoxyethyl ether were refluxed for 24 hours. The reaction mixture was poured into 3M HCl and extracted with 300 mL of dichloromethane. The dichloromethane layer was extracted with 300 mL of 10% NaOH, dried over magnesium sulfate and concentrated in vacuo to remove the 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-dihydrobenzothiepine- (5H) 4-one (4a) and trans -3-Butyl-3-ethyl-5-phenyl-2,3,3-dihydrobenzothiidin (5H) 4-one (4b)

A mixture of 2.6 g (0.04 mol) of zinc powder, 7.2 g (0.047 mol) of TiCl2 and 80 ml of anhydrous ethylene glycol dimethyl ether (DME) is refluxed for 2 hours. The reaction mixture was cooled to 5 ° C. A solution of 3.54 g (0.01 mol) of 2 in 30 mL of DME was added dropwise over 40 minutes. The reaction mixture was stirred at room temperature for 16 hours and then refluxed for 2 hours, cooled before being poured into brine. The organics were extracted into dichloromethane. The dichloromethane extract was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by HPLC (hexane) to give 1.7 g (43%) of 3 as an oil as the first fraction. The second fraction a is not collected and the third fraction is further purified by HPLC (hexane) to give 0.07 g (2%) of 4a in the first fraction and 0.1 g (3%) of 4b in the later fraction.

Example 2:

cis-3-butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepine- (5H) 4-one-1,1-dioxide (5a) and trans-3-butyl-3-ethyl-5-phenyl-2, 3-dihydrobenzotiepín- (5 H) 4-one-l, l-dioxide (5b)

To a solution of 1.2 g (3.5 mmol) of 50-60% MCPBA in 20 mL of dichloromethane was added 0.59 g (1.75 mmol) of a mixture of 4a and 4b in 10 mL of dichloromethane. The reaction mixture was stirred for 20 hours. To the reaction mixture was further added 1.2 g (1.75 mmol) of 50-60% MAPBA and stirred for an additional 3 hours, then rubbed with 50 mL of 10% NaOH. The insoluble solid was filtered off. The dichloromethane layer of the filtrate was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residual syrup is purified by HPLC (5% EtOAc-hexane)

Formation (30%) of 5a as an oil in the first fraction and 0.17 g (26%) of 5b as an oil in the second fraction.

Example 3 - (3a, 4a, 5b) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (6a), (3a, 4b, 5a) 3-butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-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-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (6d)

A: · reduction of 5a and 5b with sodium borohydride

To a solution of 5b (0.22 g, 0.59 mmol) in ethanol (10 mL) was added sodium borohydride (0.24 g, 6.4 mmol). The reaction mixture was stirred at room temperature for 18 hours and concentrated in vacuo to remove ethanol. The residue was triturated with water and extracted with dichloromethane. The dichloromethane extract was dried over magnesium sulfate and concentrated in vacuo to give 0.2 g syrup. In a separate experiment, 0.45 g of 5a and 0.44 g of sodium borohydride in 10 ml of ethanol are reacted and proceeded as described above to give 0.5 syrup which is identical to the syrup obtained above. The two materials were combined and purified by HPLC using 10% EtOAc-hexane as eluent. The first fraction yielded 0.18 g (27%) of 6a as a syrup. The second fraction gives 0.2 g (30%) of 6b also as a syrup. The column was then washed 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, wash the column 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 by NaOH and PTC

To a solution of 6a (0.29 g, 0.78 mmol) in dichloromethane (10 mL) was added 40% NaOH (9 g). The reaction mixture was stirred for 0.5 hours at room temperature and a drop of Aliquat-336 (methyltrioctanoylammonium chloride) phase transfer catalyst (PTC) was added. The mixture was stirred for half an hour at room temperature, then 25 ml of ice crystals were added and extracted with dichloromethane (3 x 10 ml), dried over magnesium sulfate and concentrated in vacuo to give 0.17 g of a colorless film. The components of this mixture are separated using HPLC (EtOAc-hexane eluent) 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 mg (31%) of 6d in the third fraction.

-154Oxidation of 6a to 5b

To a solution of 6a (0.2 g, 0.52 mmol) in dichloromethane (5 mL) was added pyridinium chlorochromate (0.23 g, 1.0 mmol). The reaction mixture was stirred for 2 hours, then 0.23 g of pyridinium chlorochromate was added and stirred overnight. Pour the dark reaction mixture into a ceramic filter frit containing silica gel and elute with dichloromethane. The filtrate was concentrated in vacuo to give 167 mg (87%) of 5b as a colorless oil.

Example 4:

3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepine-1,1-dioxide (7)

To a solution of 5.13 g (15.9 mmol) of 3 in 50 mL of dichloromethane was added 10 g (31.9 mmol) of 50-60% MCPBA (m-chloroperoxybenzoic acid), a low refluxing amount and a white solid. The reaction mixture was allowed to stir overnight under a nitrogen atmosphere and then rubbed with 25 mL of water followed by 50 mL of 10% NaOH solution. The dichloromethane extract was dried over magnesium sulfate and evaporated to dryness to give 4.9 g (87%) of a matt viscous oil.

Example 5:

(1aa, 2b, 8ba) 2-butyl-2-ethyl-8b-phenyl-1a, 2,3,8b-tetrahydro-benzothiepine (4,5-b) oxirene-4,4-dioxide (8a) and (1aa, 2a (8ba) 2-Butyl-2-ethyl-8b-phenyl-1a, 2,3,8b-tetrahydro-benzothiepine (4,5b) oxirene-4,4-dioxide (8b)

To 1.3 g (4.03 mol) of 3 in 25 mL of chloroform was carefully added 5g (14.1 mmol) of 50-60% MCPBA causing a slight exothermic reaction. The reaction mixture was stirred overnight under nitrogen and then allowed to reflux for 3 hours. The insoluble white suspension is filtered. The filtrate was extracted with 10% potassium carbonate (3 x 50 mL), once with brine, dried over magnesium sulfate and concentrated in vacuo to give 1.37 g of a slightly yellowish oil. Purification by HPLC gave 0.65 g of crystalline material. This material is a mixture of two isomers. Fraction of this crystalline product in hexane gave 141.7 mg (10%) of the crystalline product. This isomer is characterized by NMR and mass spectrometry as the (1aa, 2b, 8ba) isomer 8a. The hexane filtrate was concentrated in vacuo to give 206 mg of a white film which was a mixture of 30% 8a and 70% 8b by 1 H NMR.

EXAMPLE 6 cis-3-butyl-3-ethyl-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (9a), trans-3-butyl-3-ethyl-5-phenyl-2, 3,4,5-tetrahydrobenzothiepine-1,1-dioxide (9b) and 3-butyl-3-ethyl-4-hydroxy-5cyclohexylidine-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (10)

A mixture of 0.15 g (0.4 mmol) of a 3: 7 mixture of 8a and 8b is dissolved in 15 mL of MeOH in a 85.2 g (3 oz) Fisher-Porter vessel, then 0.1 g of 10% Pd / C catalyst. The mixture is hydrogenated at 50 psi for 5 hours and filtered. The filtrate was evaporated to dryness in vacuo to give 0.117 g of a colorless oil. This material was purified by HPLC using EtOAc-hexane as eluent. The first fraction contained 4.2 mg (3%) of 9b. The second fraction, 5.0 mg (4%), was a mixture of 50/550% of 9a and 9b. The third fraction contained 8.8 mg (6%) of 6a. The fourth fraction contained 25.5 mg (18%) of 6b. The fifth fraction contained 9.6 mg (7%) of a mixture of 6b and the product considered 3-butyl-3-ethyl-4,5-dihydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide per mass spectrometry. The sixth fraction contained 7.5 mg of a mixture of 6d and one of the isomers 10 or 10a.

Example 7:

In a further experiment, 3.7 g of the epoxidation product 3 with an excess of MCPBA in chloroform reflux was hydrogenated under an atmosphere of air in 100 ml of methanol in the presence of 1 g of 10% Pd / C catalyst at a hydrogen pressure of 482.3 kPa. 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 of the isomers 10 and 10a and 0.03 g (1%) of the other of the isomers 10 and 10b.

Example 8:

2 - ((2-Benzoylphenylthio) methyl) butyraldehyde (11)

To a solution cooled in an ice bath of 9.76 g (0.116 mol) of 2-ethylacrolein in 40 ml of dry THF was added 24.6 g (0.116 mol) of 2-mercaptobenzophenone in 40 ml of THF followed by 13 g (0.128 mol) of triethylamine. The reaction mixture was stirred at room temperature for 3 days, dissolved in ether, followed by dilute HCl, brine and 1M potassium carbonate. The ether layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by HPLC (10% EtOAc-hexane) to give 2 g (64%) of 11 in the second fraction. Attempting to further purify this material by kugelrohror distillation at 0.5 torr (160-190 ° C) gave a fraction (12.2 g) which contained the starting material, which is a back-reaction during distillation. This material was dissolved in ether (100 mL) and washed with 50 mL of 1M carbonate

-156 potassium three times to give 6.0 g of syrup, which was purified by HPLC (10% EtOAc-hexane) to give 5.6 g of pure 11.

Example 9:

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

To a mixture of 2.61 g (0.04 mol) of zinc powder and 60 ml of DME was added 7.5 g (0.048 mol) of TiCl2. The reaction mixture was refluxed for 2 hours. A solution of 2.98 g (0.01 mol) of 11 is added dropwise over 1 hour. The reaction mixture was refluxed for 18 hours, cooled and poured into water. The organics were extracted with ether. The ether layer was washed with brine and filtered through celite. The filtrate was dried over magnesium sulfate and concentrated. The residual oil (2.5 g) was purified by HPLC to give 2.06 g (77%) of 12 as an oil in the second fraction.

Example 10:

(1aa, 2a, 8ba) 2-ethyl-8b-phenyl-1a, 2,3,8b-tetrahydrobenzothiepine (4,5-b) oxirene-4,4-dioxide (13)

To a solution of 1.5 g (5.64 mmol) of 12 in 25 mL of chloroform was added 6.8 g (19.4 mmol) of 50-60% MCPB, an exothermic process to give a white solid. The mixture was stirred at room temperature overnight, dissolved in 100 mL of dichloromethane and washed in turn with 10% potassium carbonate (4 x 50 mL), water (2 x 25 mL), and brine. The organic layer was then dried over magnesium sulfate and evaporated to dryness to give 1.47 g of a white solid. ^! 1 H NMR shows that only one isomer is present. This solid was suspended in 200 mL of warm ethanol and filtered to give 0.82 g (46%) of 13 as a white solid, mp 185-186.5 ° C.

Example 11:

(3a, 4b, 5a) 3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (14a), (3a, 4b, 5b) 3-ethyl-4 -hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (14b) and cis-3-ethyl-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide ( 15)

A mixture of 0.5 g (1.6 mol) of 13, 50 ml of acetic acid and 0.5 g of a 10% Pd / C catalyst was hydrogenated at 50 psi for 4 hours. The crude reaction suspension is filtered and the filtrate is stirred with 150 ml of saturated NaHCO 3 solution, 89 g of NaHCO 3 powder are added to neutralize the acetic acid residue. The mixture was extracted with dichloromethane (4x25 mL), then the organic layer was dried over magnesium sulfate and concentrated in vacuo to give 0.44 g (87%) of a large white precipitate 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 with

M.p. 142-143.5 ° C in the second fraction and 35 mg (7%) of impure 14b in the third fraction.

Example 12:

2-Ethyl-2 - ((hydroxymethylphenyl) thiomethyl) hexenal (16)

A mixture of 5.0 g (0.036 mol) of 2-mercaptobenzyl alcohol, 6.4 g (0.032 mol) of substance 1, 3.6 g (0.036 mol) of triethylamine and 25 ml of 2-methoxyethyl ether is refluxed for 7 hours. 1.1 g of mercaptobenzyl alcohol and 0.72 g of triethylamine are added and the mixture is refluxed for a further 16 hours. The reaction mixture was cooled and poured into 6M HCl and extracted with dichloromethane. The dichloromethane extract was washed twice with 10% NaOH, dried over magnesium sulfate and concentrated in vacuo to give 9.6 g. Purification by HPLC (20% EtOAc-hexane) gave 3.7 g (41%) of 16 as an oil.

Example 13:

2-Ethyl-2 - ((2-formylphenyl) thiomethyl) hexenal (17)

A mixture of 3.7 g of 16, 5.6 g (0.026 mol) of pyridinium chlorochromate, 2 g of Celite and 30 ml of dichloromethane is stirred for 18 hours and filtered through a silica gel column. The silica gel was eluted with dichloromethane. The eluted dichloromethane fractions were purified by HPLC (20% EtOAc-hexane) to give 2.4 g (66%) as an oil.

Example 14:

3-Butyl-3-ethyl-2,3-dihydrobenzothiepine (18)

A mixture of 2.6 g (0.04 mol) of zinc powder, 7.2 g (0.047 mol) of TiCl2 and 50 ml of DME was refluxed for 2 hours and cooled to room temperature. To this was added 2.4 g (8.6 mmol) of 17 in 20 mL of DME over 10 minutes. The reaction mixture was stirred at room temperature for 2 hours and refluxed for 1 hour, then allowed to stand at room temperature over the weekend. The reaction mixture was poured into dilute HCl and stirred with dichloromethane. The dichloromethane / water mixture was filtered through celite. The dichloromethane layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 3.0 g of a residue. HPLC purification gave 0.41 g (20%) of 18 as an oil in the first fraction.

- 158Example 15- (1aa, 2a, 8ba) 2-butyl-2-ethyl-1α, 2,3,8b-tetrahydrobenzothiepine (4,5-b) oxirene-4,4-dioxide (19a) and (1aa, 2b) (8ba) 2-Butyl-2-ethyl-8b-phenyl-1a, 2,3,8b-tetrahydrobenzothiepine (4,5-b) oxirene-4,4-dioxide (19b)

To a solution of 0.4 g (1.6 mmol) of 18 in 30 mL of dichloromethane was added 2.2 g (3.2 mmol) of 50-60% MCPBA. The reaction mixture was stirred for 2 hours and concentrated in vacuo. The residue was dissolved in 30 ml of chloroform and refluxed for 18 hours under a nitrogen atmosphere. The reaction mixture is stirred with 100 ml of 10% NaOH and 5 g of sodium sulfite. The dichloromethane layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was 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 fraction from the first fraction was mixed with the second fraction and further purified by HPLC to give additional 19a in the first fraction and 60 mg of 19b in the second fraction. Crystallization from hexane gave 56 mg of a white solid.

Example 16:

-butyl-3-ethyl-4,5-dihydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (20)

This product is isolated at the same time as 6b after hydrogenation of mixtures 8a and 8b.

Example 17:

3-butyl-3-ethyl-4-hydroxy-5-phenylthio-2,3,4,5-tetrahydrobenzothiepine-l, l-dioxide (21)

A mixture of 25 mg (0.085 mmol) of 19b, 0.27 g (2.7 mmol) of thiophenol, 0.37 g (2.7 mmol) of potassium carbonate and 4 ml of DMF was stirred at room temperature under nitrogen for 19 hours. The reaction mixture was poured into water and extracted with dichloromethane. The dichloromethane layer was washed in turn with 10% NaOH and brine, dried over magnesium sulfate and concentrated in vacuo to give 0.19 g of a semi-solid which contained a partial amount of diphenyldisulfide. This material was purified by HPLC (5% EtAOc-hexane) to remove the diphenyldisulfide contained in the first fraction. The column is then eluted with 20% EtOAchexane to give 17 mg of the first fraction, 4 mg of the second fraction and 11 mg of the third fraction, which are three different isomers of 21, 21a, 21b and 21c, identified by 1 H NMR and mass spectrometry.

Example 18;

Alternative synthesis of 6c and 6d

-159. Preparation of 2 - ((2-benzoylphenylthio) methyl-2-ethylhexanal (2) step 1. 2 - ((2-benzoylphenylsulfonyl) methyl-2-ethylhexanal (44)

To a solution of 9.0 g (0.025 mol) of 2 in 100 ml of dichloromethane was added portionwise 14.6 g (0.025 mol) of 50-60% MCPBA. The reaction mixture was stirred at room temperature for 64 hours, then stirred with 200 ml of 1M potassium carbonate and filtered through celite. The dichloromethane layer was washed twice with 300 ml of 1M potassium carbonate, once with 10% NaOH and once with brine. The insoluble residue formed during the wash was removed by filtration through celite. The dichloromethane solution was dried and concentrated in vacuo to give 9.2 g (95%) of a semi-solid. 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 - ((2-benzylphenylsulfonyl) methyl-2-ethylhexanal (45)

A solution of 50 g (0.13 mol) of unpurified 44 in 250 mL of dichloromethane was divided into two portions and placed in two Fisher-Porter flasks. 125 ml of methanol and 5 g of 10% Pd / C are added to each vial. The vials are pressurized with hydrogen to 50 psi and the reaction mixture is stirred for 7 hours before the next addition of 5g of 10% Pd / C. The reaction mixture is further hydrogenated at 50 psi for 7 hours. This procedure is repeated once more but only 1 g of Pd / C is added to the reaction mixture. The combined reaction mixtures were filtered and concentrated in vacuo to give 46.8 g of 45 as a brown oil.

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

To a solution of 45 (27.3 g, 73.4 mmol) in anhydrous THF (300 mL) cooled to a 2 ° C ice bath was added 9.7 g (73.4 mmol) of 95% potassium t-butoxide. The reaction mixture was stirred for 20 minutes, neutralized with 300 mL of 10% HCl and extracted with dichloromethane. The dichloromethane layer was dried over magnesium sulfate and concentrated in vacuo to give 24.7 g of a yellow oil. Purification by HPLC (ethyl acetate-hexane) gave 9.4 g of 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.

A. Preparation of 2-hydroxydiphenylmethane

Step 1. 2-Mercaptodiphenylmethane (46)

160 g 16 g (0.33 mol) of an oil dispersion of 60% sodium hydride are added to a 500 ml flask. Wash the sodium hydride twice with 50 ml of hexane. To the reaction flask was added 100 mL of DMF, a solution of 55.2 g (0.3 mol) of 2-hydroxydiphenylmethane in 200 mL of DMF over one hour, maintaining the temperature below 30 ° C using an ice bath. After all the reagent has been added, the mixture is allowed to stir at room temperature for 30 minutes, then cooled in an ice bath. 49.4 g (0.4 mol) of dimethylthiocarbamoyl chloride are added in one portion to the reaction mixture. Remove the ice bath and stir the reaction mixture at room temperature for 18 hours, then pour into 300 mL of water. The organics are extracted into 500 ml of toluene. The toluene layer was washed sequentially with 10% NaOH and brine, concentrated in vacuo to give 78.6 g of a yellow oil, 95% pure dimethyl (O-2-benzylphenylthiocarbamate). The oil was heated to 280-300 ° C in a tubular vessel under local vacuum for 30 minutes. The residue was distilled in a bead tube at 1 torr (180-280 ° C). The distillate (56.3 g) was crystallized from methanol to give 37.3 g (46%) of the altered dimethyl (S-2-benzylphenylthiocarbamate) product as a yellow solid. A mixture of 57 g (0.21 mol) of this yellow solid, 30 g of potassium hydroxide and 150 ml of methanol was stirred overnight and then concentrated in vacuo. The residue was dissolved in 200 ml of water and extracted with ether. The aqueous layer was acidified with concentrated hydrochloric acid. 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 (47)

A mixture of 60 g (0.3 mol) of the yellow solid from Step 1, 70 g (0.3 mol) of Preparation 1, 32.4 g (0.32 mol) of triethylamine, 120 ml of 2-methoxyethyl ether is refluxed for 6 hours and concentrated in vacuo. The residue was triturated with 500 mL of water and 30 mL of concentrated HCl. The organics were extracted into ether. The ether layer was washed sequentially with brine, 10% NaOH and brine, dried over magnesium sulfate and concentrated in vacuo. The residue (98.3 g) was purified by HPLC (ethyl acetate-hexane) to afford 47 as a yellow syrup.

Step 3. 2 - ((2-Benzylphenylsulfonyl) methyl) -2-ethylhexanal (45)

To a solution of 72.8 g (0.21 mol) of the yellow syrup from step 2 in 1 liter of cooled dichloromethane at 10 ° C was added 132 g of 50-60% MCPBA over 40 minutes. The reaction mixture was stirred for 2 hours. An additional 13 g of 50-60% MCPBA was added and allowed to stir again for 2 hours, then filtered through Celite. The dichloromethane solution was washed twice with 1 L of IM

-161 potassium carbonate and once a liter of brine. The dichloromethane layer was dried over magnesium sulfate and concentrated in vacuo to give 76 g of 45 as a syrup.

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

Treatment of 45 with potassium t-butoxide according to Procedure A described in Step 3 affords pure 6c and 6d after HPLC purification.

Example 19:

(3a, 4b, 5b) 3-butyl-3-ethyl-4-hydroxy-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (25) and (3a, 4a, 5a) ) 3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide (26)

Step 1. Preparation of 2 - ((2-benzoyl-4-methoxyphenylthio) methyl) -2-ethylhexanal (22)

2-Hydroxy-4-methoxybenzophenone is converted to dimethyl (O-2-benzoylphenyl thiocarbamate) by the method described in Example 18. The product can be isolated by recrystallization from ethanol. Using this improved isolation procedure, there is no need for chromatography. The temperature conversion is carried out by reacting thiocarbamate (5 g) in diphenyl ether at 260 ° C as described above. An improved isolation procedure that allows the chromatography step to be omitted is described below.

The crude pyrolysis product was heated to 65 ° C in 100 mL of methanol and 100 mL of THF in the presence of 3.5 g of KOH for 4 hours. After removal of THF and methanol by rotary evaporation, the solution was extracted with 5% NaOH and ether. The basic layer was acidified and extracted with ether to give 2.9 g of crude thiophenol product. This product is further purified by titrating the desired mercaptan on a weak KOH basis. Acidification and extraction with ether gave pure 2-mercapto-4-methoxybenzophenone (2.3 g).

2-mercapto-4-methoxybenzophenone can be easily converted to 2 - ((2-benzoyl-4-methoxyphenylthio) methyl) -2-ethylhexanal (22) by reaction with 2-ethyl-2- (mesyloxymethyl) hexanal (1) as described higher.

Step 2.2 - ((2-Benzoyl-5-methoxyphenylsulfonyl) methyl) -2-ethylhexanal (23)

22 is readily oxidized to 2 - ((2-benzoyl-5-methoxyphenylsulfonyl) methyl) -2-ethylhexanal (23) as described in Example 18.

- 162Step 3.2 - ((2-benzyl-5-methoxyphenylsulfonyl) methyl) -2-ethylhexanal (24)

Sulfone 23 is reduced to 2 - ((2-benzyl-5-methoxyphenylsulfonyl) methyl) -2-ethylhexanol (24) as described in Example 18.

Step 4. (3a, 4b, 5b) 3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide (25) and (3a, 4a, 5a) 3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (26)

A three-necked flask equipped with a powder addition funnel, thermostated with nitrogen bubbling, was charged with 19.8 g (0.05 mol) of sulfone 24 in 100 mL of dry THF. The reaction mixture was cooled to an internal temperature of -1.6 ° C with an ice / salt bath. 5.61 g (0.05 mol) of potassium t-butoxide is slowly added via a powder addition funnel. A slightly yellow solution is formed which is maintained at -1.6 ° C. After 30 minutes, 400 mL of cooled ether was added and this solution was extracted with cooled 10% HCl. The acidic layer was then extracted with 300 mL of dichloromethane. The organic layers were combined and dried over magnesium sulfate and, after filtration, evaporated to dryness to give 19.9 g of product. NMR and glpc showed 96% conversion to a 50/50 mixture of 25 and 26. The only other compound observed was the starting sulfone 24 as 4%.

The product was then dissolved in 250 mL of 90/10 hexane / ethyl acetate by heating to 50 ° C. The solution is allowed to cool to room temperature and thus pure substance 26 can be isolated. Crystallization can be accelerated by adding the parent crystal of substance 26. After two crystallizations, the mother liquor, which now contains 85.4% of substance 25 with 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 the parent crystal of 25 and left overnight at 0 ° C.

Example 20:

(3a, 4a, 5a) 3-Butyl-3-ethyl-4,8-dihydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (27)

In a 25 ml round bottom flask, a solution of 1 g of 26 (2.5 mmol) and 10 ml of dichloromethane was cooled to -78 ° C with stirring. While stirring, 0.7 mL of boron tribromide (7.5 mmol) was added. The reaction was allowed to warm slowly to room temperature and stirred for 6 hours. The reaction was then diluted with 50 mL of dichloromethane and washed twice with saturated NaCl solution and then with water. The organic layer was dried over sulfate

-163horečnatým. The product (0.88 g) 27 was characterized by NMR and mass spectrometry.

Example 21:

General alkylation of phenol 27

A 25 mL flask was charged with 0.15 g of 27 (0.38 mmol), 5 mL of anhydrous DMF, 54 mg of potassium carbonate (0.38 mmol) and 140 mg of ethyl iodide (0.9 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was diluted with 50 mL of ethyl ether and washed with water (25 mL), then with 5% NaOH (20 mL) and saturated NaCl solution. Removal of the solvent gave the ethoxylated product, 28, in high yield. The product is characterized by NMR and mass spectrometry. The same product was used to prepare the products listed in Table 1 from the corresponding iodides and bromides. Only one equivalent of the alkyl halides was used for the higher boiling point of alkyl iodides and bromides.

RO

Table 1 Compound no.

R

H

Me

Et hexyl

Ac _(CH2) 6-N-phthalimide

-164Example 22:

(3a, 4a, 5a) 3-butyl-3-ethyl-4-hydroxy-7-hydroxyamino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (37) and (3a, 4b, 5b) ) 3-Butyl-3-ethyl-4-hydroxy-7-hydroxyamino-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide (38)

Step 1. Preparation of 2-chloro-5-nitrodiphenylmethane (32)

Article modification: Synthesis-Stuttgart 9 770-772 (1986) Olah G. et. al

A 3-necked flask filled with 45 g (0.172 mol) of 2-chloro-5-nitrobenzophenone in 345 mL of dichloromethane was cooled in an ice bath under nitrogen. 150 g (0.172 mol) of trifluoromethanesulfonic acid in 345 ml of dichloromethane are added slowly via an addition funnel. 30 g of triethylsilane (0.172 mol) in 345 ml of dichloromethane are then added dropwise to the frozen solution. The two additional steps (trifluoromethanesulfonic acid and triethylsilane) were repeated. After complete addition, the reaction mixture was slowly warmed to room temperature and stirred for 12 hours under a nitrogen atmosphere. The reaction mixture was then poured into 1600 mL of a frozen, stirred saturated sodium bicarbonate solution. Gas evolution is observed. Pour into a 41 separatory funnel and separate the layers. The dichloromethane layers were separated and combined with two 500 mL aqueous phase extracts. The dichloromethane solution was dried over magnesium sulfate and concentrated in vacuo. The residue was recrystallized from hexane to give 39 g of product. Structure 32 was confirmed by mass spectrometry and carbon NMR.

Step 2. Preparation of 2 - ((2-benzyl-4-nitrophenylthio) methyl) -2-ethylhexanal (33)

The previously obtained 2-chloro-5-nitrodiphenylmethane, substance 32 (40 g, 0.156 mol) was placed in a two-liter, two-necked vial with a water condenser. Next, 150 mL of DMSO and 7.18 g (0.156 mol) of lithium sulfide were added and the solution was allowed to stir at 75 ° C for 12 hours. The reaction was cooled to room temperature and then 51.7 g of mesylate IV in 90 mL of DMSO was added. The reaction mixture was heated to 80 ° C under nitrogen. After 12 hours the reaction is checked by thin layer chromatography and additional mesylate is added if necessary. The reaction is continued until complete. The reaction mixture was poured slowly into 1900 ml of 5% acetic acid solution with stirring, extracted with 4 x 700 ml of ether and dried over magnesium sulfate. Removal of the ether gave 82.7 g of product. This material can be further purified using silica gel chromatography using 95% hexane and 5% ethyl acetate. If pure mesylate was used in this step, no further purification is required. Structure 33 was confirmed by mass spectrometry and NMR.

-165Step 3 Oxidation of the nitro product 33 to sulfone 2 - ((2-benzyl-4-nitrophenylsulfonyl) methyl) -2-ethylhexanal (34)

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

Step 4 Reduction of 34 to 2 - ((2-benzyl-4-hydroxyaminophenylsulfonyl) methyl) -2-ethylhexanal (35) g of 34 was dissolved in 230 mL of ethanol and placed in a 500 mL round bottom flask under nitrogen. 1.5 g of 10 wt% Pd / C are added and the solution is bubbled with hydrogen at room temperature until substrate 34 is consumed. The reaction can be easily monitored by thin layer chromatography on silica gel using 80/20 hexane / EtOAc. The product 35 is isolated after filtration of Pd / C and precipitation from EtOH as solvent. Structure 35 was confirmed by mass spectrometry and NMR.

Step 5. Preparation of 2 - ((2-benzyl-4-N, O-di- (t-butoxycarbonyl) hydroxyaminophenylsulfonyl) methyl) -2-ethylhexanal (36)

13.35 g of 35 (0.0344 mol) in 40 ml dry THF was stirred in a 250 ml round bottom flask. 7.52 g (0.0344 mol) of di-t-butyl dicarbonate in 7 ml of THF are added. Heat at 60 ° C overnight. It precipitated from THF and redissolved in dichloromethane. Extract with 1% HCl and then with 5% sodium bicarbonate.

The product was further purified by column chromatography using 90/10 hexane / ethyl acetate and 70/30 hexane / ethyl acetate. The product 36 (4.12 g) which was obtained according to the proton NMR spectrum proved to be mainly the di- (t-butoxycarbonyl) derivative.

Step 6. (3a, 4a, 5a) 3-Butyl-3-ethyl-4-hydroxy-7-hydroxyamino-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide (37) and (3a, 4b, 5b) 3-Butyl-3-ethyl-4-hydroxy-7-hydroxy-amino-5-phenyl-2,3,4,5-tetrahydrobenzothiazepine-1,1-dioxide (38)

A 250 mL round bottom flask was charged with 4 g of 36 (6.8 mmol) and 100 mL of anhydrous THF and cooled to -78 ° C under a nitrogen atmosphere. Slowly add 2.29 g of potassium t-butoxide (20.4 mmol) while stirring and maintaining the temperature at -78 ° C. After one hour at -78 ° C the addition of the base is complete and the temperature is raised to -10 ° C with an ice-salt bath. After 3 hours at -10 ° C, only traces of substance 36 remain in the reaction, as shown

- 166-layer chromatography. 35 ml of deionized water are then added at -10 DEG C. and stirred for 5 minutes. Most of the THF was removed, added to a separatory funnel, and extracted with ether until all the organic material was extracted from the aqueous phase. The combined ether fractions were washed with saturated NaCl solution and then dried over sodium sulfate. According to thin layer chromatography and NMR, the only product is the two BOC protected isomers of 37 and 38. The isomers are separated by silica gel chromatography using 85% hexane and 15% ethyl acetate; BOC-37 (0.71g and BOC-38 (0.78g)).

Further, the BOC protecting groups were removed by reacting 0.87 g of BOC-38 (1.78 mmol) with 8.7 mL of 4 M HCl (34.8 mmol) in dioxane for 30 minutes. Then, 4.74 g of sodium acetate (34.8 mmol) was added to the reaction mixture and 16.5 ml of ether and stirred until the solution became clear. After transfer to a separatory funnel, the ether and aqueous phases are separated, and the ether phase is then dried over sodium sulfate. After removal of the ether, 0.665 g of 38 is obtained. Isomer 37 can be obtained by a similar procedure.

Example 23, (3a, 4a, 5a) 3-Butyl-3-ethyl-7- (n-hexylamino) -4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide ( 40) and (3a, 4b, 5b) 3-butyl-3-ethyl-7- (n-hexylamino) -4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (41)

Step 1. Preparation of 2 - ((2-benzyl-4- (n-hexylamino) phenylsulfonyl) methyl) -2-ethylhexanal (39)

Weigh 0.5 g of 34 (1.2 mmol) into a Fisher-Porter flask and dissolve in 3.8 mL of ethanol under a nitrogen atmosphere. 0.1 g of Pd / C and 3.8 ml of hexanal are then added. The flask is plugged and pressurized to 50 psi with hydrogen. Stir for 48 hours. After filtering off the catalyst and removing the solvent on a rotary evaporator, 39 is obtained, which is further purified by column chromatography (0.16g) using 90/10 hexane / ethyl acetate gradually increasing to 70/30 hexane / ethyl acetate. The product was characterized by NMR and mass spectrometry.

Step 2. (3a, 4a, 5a) 3-Butyl-3-ethyl-7- (n-hexylamino) -4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide ( 40) and (3a, 4b, 5b) 3-butyl-3-ethyl-7- (n-hexylamino) -4-hydroxy-5-phenyl-2,3,3,5,5-tetrahydro-benzothiepine-1,1-dioxide (41) )

A 25 ml two-necked round-bottomed flask with a magnetic stirrer was charged with 0.158 g of 39 (0.335 mmol) and 5 ml of anhydrous THF under a hydrogen atmosphere. Cool to -10 ° C with an ice / salt bath. 0.113 g of potassium t-butoxide (0.335 mmol) was added slowly. After 15 minutes at -10 ° C, all starting material was reacted by TLC and observed

Then, 5 mL of frozen 10% HCl was added and stirred at -10 ° C for 5 minutes. Pour the reaction mixture into a separatory funnel and extract with ether. Dry over sodium sulfate. The proton NMR spectrum of the dried product (0.143 g) shows the presence of only two isomers 40 and 41. The two isomers are separated by silica gel column chromatography using 90/10 hexane / ethyl acetate sequentially increasing to 70/30 hexane / ethyl acetate. 40 (53.2 mg), 41 (58.9 mg).

Example 24 Quaternization of amine substrates 40 and 41

Amine products such as 40 and 41 can be easily alkylated to form quaternary salts. For example, 40 in DMF with 5 equivalents of methyl iodide in the presence of 2,6-dimethyl lutidine gives the dimethylhexylamino quaternary salt.

Example 25:

(3a, 4b, 5b) 3-Butyl-3-ethyl-4-hydroxy-5- (4-iodophenyl) -2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (42)

In a two-necked 25 ml round-bottomed flask, add 0.5 g (1.3 mmol) of 6d, 0.67 g of mercuric triftalate and dissolve in 20 mL of dry dichloromethane with stirring. 0.34 g of iodine is added and the solution is stirred at room temperature for 30 hours. The reaction was diluted with 50 mL of dichloromethane and washed with 10 mL of 1 M sodium thiosulfate, 10 mL of saturated KI solution and dried over sodium sulfate. See Tetrahedron, Vol.50, No.17, p. 5139-5146 (1994) Bachki, F. et al. The mass spectrum shows a mixture of 6d mono-iodide 42 and a diiodide adduct. The mixture can be separated by column chromatography and 42 characterized by mass spectrometry and NMR.

Example 26:

(3a, 4b, 5b) 3-Butyl-5- (4-carbomethoxyphenyl) -3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (43)

Substance 42 0.1 g (0.212 mmol), 2.5 ml dry methanol, 38 μΐ triethylamine (0.275 mmol) 0.3 ml toluene and 37 mg palladium chloride (0.21 mmol) are added to a glass elongated mini reactor at pressure 2,067 MPa of carbon monoxide. The reactor was heated at 100 ° C overnight. The catalyst was filtered off to give the product in high yield. The product was characterized by NMR and mass spectrometry.

It should be noted that the ester function 43 product can be converted to the free acid by hydrolysis

Example 27, (3a, 4a, 5a) 3-butyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (48) and (3a, 4b, 5b) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (49)

Step 1. 2-mercapto-5-methoxybenzophenone (50)

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 of cyclohexane according to the procedure in WO 93/16055 gives 73.2 g of a brown oil which is distilled on a tubular bead apparatus to remove 4-methoxythiophenol to give 43.86 g of crude 50 as a residue in the vessel.

Step 2. 2 - ((2-Benzoyl-4-methoxyphenylthio) methyl) -2-ethylhexanal (51)

Reaction of 10 g (0.04 mol) of crude 50 with 4.8 g (0.02 mol) of mesylate 1 and 3.2 ml (0.23 mol) of triethylamine in 50 ml of diglyme. Following Preparation 2, 10.5 g of crude product 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-ethylhexanal (52)

A solution of 1.2 g (3.1 mmol) of 51 in 25 mL of dichloromethane was treated with 2.0 g (6.2 mmol) of 5060% MCPBA according to the procedure of Step 2 of Procedure A in Example 18 to give 1.16 g ( 90%) 52 as a yellow oil.

Step 4.2 - ((2-Benzyl-4-methoxyphenylsulfonyl) methyl) -2-ethylhexanal (53)

Hydrogenation of 1.1 g of 52 according to the procedure of Step 3 of Procedure A of Example 18 gives 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-1,1-dioxide (48) and ( 3a, 4b, 5b) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide (49)

A solution of 1.1 g of 53, 0.36 g of potassium t-butoxide and 25 ml of anhydrous THF was refluxed for 2 hours and then continued according to Step 4 of Procedure A of Example 18 to give

1.07 g of crude product, which is further purified by HPLC to give 40 mg (4%) of 48 as crystals of m.p. 153-154 ° C and 90 mg (8%) of 49 as a melting point solid; M.p. 136-140 ° C.

Example 28:

5-Phenyl-2,3-dihydrospirobenzothiepine-3,1-cyclohexane (57)

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

To a cooled (0 ° C) mixture of 100 g (0.891 mol) of cyclohexanecarboxaldehyde, 76.5 g of 37% formaldehyde in 225 mL of methanol was added dropwise 90 mL of 1 M sodium hydroxide over one hour. The reaction mixture was stirred at room temperature for 48 hours, then evaporated to remove methanol. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with water, brine and dried over sodium sulfate and concentrated in vacuo to give 75 g (59.7%) of a thick oil. Proton NMR analysis and mass spectrometry are consistent with the product.

Step 2. 1- (Mesyloxymethyl) -cyclohexanecarboxaldehyde (55)

To a cooled (0 ° C) mixture of alcohol 54 (75 g, 0.54 mol) and 65.29 g (0.57 mol) of methanesulfonyl chloride in 80 mL of dichloromethane was added pyridine solution (47.96 g, 0.57 mol). in 40 ml of dichloromethane. The reaction mixture was stirred at room temperature for 18 hours, quenched with water, acidified with concentrated HCl and extracted with dichloromethane. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated in vacuo to give 91.63 g (77.8%) of a thick oil. Proton NMR analysis and mass spectrometry are consistent with the product.

Step 3. 1 - ((2-Benzoylphenylthio) methyl) cyclohexanecarboxaldehyde (56)

A mixture of 69 g (0.303 mol) of 2-mercaptobenzophenone, 82 g (0.303 mol) of mesylate 55, 32 g of triethylamine and 150 ml of diglyme is stirred and refluxed for 24 hours. The mixture was cooled and poured into dilute HCl and extracted with dichloromethane. The organic layer was washed with 10% NaOH, brine, and dried over sodium sulfate, concentrated in vacuo to remove diglyme. The material was further purified through silica gel column chromatography by flash chromatography (5% EtOAc-hexane) to give 18.6 g (75.9%) of a yellow oil. Proton NMR analysis and mass spectrometry correspond to the product.

-170Step 4. 5-phenyl-2,3-dihydrospirobenzothiepine-3,1'-cyclohexane (57)

To a mixture of 6.19 g of zinc powder and 100 mL of dry DME was added TiCl 2 (16.8 g, 0.108 mol). The reaction mixture was heated to reflux and maintained for 2 hours. A solution of 56 (8.3 g, 0.023 mol) in 50 mL of DME was added dropwise to the reaction mixture over one hour and the mixture was refluxed for 18 hours. The mixture was cooled, poured into water and extracted with ether. The organic layer was washed with water, brine, dried over sodium sulfate, filtered through celite, and concentrated in vacuo. The residue was further purified by HPLC (10% EtOAc: hexane) to give 4.6 g (64%) of a white solid, mp 90-91 ° C. Proton NMR analysis and mass spectrometry are consistent with the product.

Example 29:

8b-phenyl-1, 2,3,8b-tetrahydrospiro (benzothiepino (4,5-b) oxirene-2,1'-cyclohexane) -4,4-dioxide (58)

To a solution of 57 (4.6 g, 15 mmol) in 50 mL of chloroform under nitrogen was added 55% MCPBA (16.5 g, 52.6 mmol) portionwise with a spatula. The reaction was refluxed for 18 hours and washed with 10% NaOH (3x), water, brine, dried over sodium sulfate and concentrated in vacuo to give 5 g of crude product. This was recrystallized from hexane / EtOAc to give 4.3 lg (81%) of a yellow solid, mp 154-155 ° C. Proton NMR analysis and mass spectrometry are consistent with the product.

Example 30:

trans-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrospiro (benzothiepine-3,1'-cyclohexane) -1,1-dioxide (59)

A mixture of 0.5 g (1.4 mmol) of 58.20 ml of ethanol, 10 ml of dichloromethane and 0.4 g of a 10% Pd / C catalyst is hydrogenated at 50 psi for 3 hours at room temperature. The crude reaction suspension was filtered through celite and evaporated to dryness. The residue was purified by HPLC (10% EtOAchexane, 25% EtOAc-hexane). The first fraction was 300 mg (60%) of a white solid, mp 99-100 ° C. Proton NMR spectra showed the trans isomer. The second fraction yielded 200 mg of solid, which was the impure cis isomer.

Example 31 cis-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrospiro (benzothiepine-3,1'-cyclohexane) -1,1-dioxide (60)

To a solution of 0.2 g (0.56 mmol) of 59 in 20 mL of dichloromethane was added 8 g of 50% NaOH and one drop of Aliquat-336 (methyltrioctanoylammonium chloride) phase transfer catalyst.

The reaction mixture was then stirred at room temperature for 10 hours. 20 g of ice was added to the mixture, and the mixture was extracted with dichloromethane (3 x 10 mL), washed with water, dried over magnesium sulfate with brine and concentrated in vacuo to give 0.15 g of crude product. This was recrystallized from hexane / EtAOc to give 125 mg of white crystals, mp 209-210 ° C. Proton NMR analysis and mass spectrometry are consistent with the product.

Example 32:

(3a, 4a, 5a) 3-butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine (61) and (3a, 4b, 5b) 3-butyl-3-ethyl -4-Hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine (62)

To a solution of 0.5 g (1.47 mmol) of 47 in 5 mL of anhydrous THF was added 0.17 g (1.47 mmol) of 95% potassium t-butoxide. The reaction mixture was stirred at room temperature for 18 hours and quenched with 10% HCl. The organic layer was extracted into dichloromethane. The dichloromethane extract was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by HPLC (2% EtAOc-hexane) to give 47 mg of 61 in the second fraction and 38 mg of 62 in the third fraction. Proton NMR analysis and mass spectrometry are consistent with the product.

Example 33:

(3a, 4a, 5a) 3-Butyl-3-ethyl-4-hydroxy-7-amino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (63) and (3a, 4b, 5b) ) 3-Butyl-3-ethyl-4-hydroxy-7-amino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (64)

The autoclave was charged with 200 mg of 37 in 40 ml of ethanol and 0.02 g of 10% Pd / C. After purging with nitrogen, the autoclave was pressurized to 689 kPa with hydrogen and heated to 55 ° C. The reaction is monitored by TLC and mass spectrometry, allowing the reaction to continue until all 37 has been consumed. After completion of the reaction, the catalyst is filtered off and the solvent is evaporated off under vacuum. The only product observed is substance 63. The same procedure can be used to prepare substance 64 of 38.

Example 34:

(3a, 4a, 5a) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5- (3'-methoxyphenyl) -2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (65) and (3a, 4b, 5b) 3-butyl-3-ethyl-4-hydroxy-7-methoxy-5- (3'-methoxyphenyl) phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide ( 66)

Alkylation of 4-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.

172This material is converted to 65 with a melting point of 138.5-141.5 ° C and 66 with a melting point of 115.5-117.5 ° C by a procedure similar to that of Example 18, Method B.

Example 35, (3a, 4a, 5a) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5- (3 '- (trifluoromethyl) 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-tetrahydrobenzothiepine-1,1 -dioxide (68)

Alkylation of 4-methoxyphenol with 3- (fluoromethyl) benzyl chloride according to the procedure described in J. Chem. Soc., 2431 (1958) gave 4-methoxy-2- (3 3- (trifluoromethyl) benzyl) phenol. This material was converted to 67 with a melting point of 226.5-228 ° C and 68 with a melting point of 188-190 ° C by a procedure similar to that described in Example 18, Method B.

Example 36:

(3a, 4a, 5a) 3-butyl-3-ethyl-5- (4'-fluorophenyl) -4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (69) and (3a, 4b, 5b) 3-butyl-3-ethyl-5- (3 '- (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) phenol. This material was converted to 69 and 70 by a procedure similar to that described in Example 18, Method B.

Example 37:

(3a, 4a, 5a) 3-butyl-3-ethyl-5- (3'-fluorophenyl) -4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-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 71 and 72 by a procedure similar to that described in Example 18, Method B.

-173Example 38:

(3a, 4a, 5a) 3-Butyl-3-ethyl-5- (2'-fluorophenyl) -4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (73) and (3a, 4b, 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 73 and 74 by a procedure similar to that described in Example 18, Method B.

Example 39:

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

Example 40:

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

Alkylation of 4-fluorophenol with 3-fluorobenzyl chloride according to the procedure described in J. Chem. Soc., 2431 (1958) gave 4-fluoro-2- (4'-fluorobenzyl) phenol. This material is converted to 77 with a melting point of 228-230 ° C and 78 with a melting point of 134.5-139 ° C 18 method B.

Example 41:

(3a, 4a, 5a) 3-Butyl-3-ethyl-7-fluoro-4-hydroxy-5- (3'-methoxyphenyl) -2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (79) and (3a, 4b, 5b) 3-butyl-3-ethyl-7-fluoro-4-hydroxy-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) affords 4-fluoro-2- (4'-methoxybenzyl) phenol. This material was converted to 79 as a solid and 80 with a melting point of 153-155 ° C by a procedure similar to that described in Example 18, Method B.

-174Example 42:

(3a, 4a, 5a) 3-Butyl-3-ethyl-5- (4‘-fluorophenyl) -4-hydroxy-7-methylthio-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (81)

A mixture of 0.68 (1.66 mmol) 77, 0.2 g (5 mmol) sodium methanethiolate and 15 ml of anhydrous DMF was stirred at room temperature for 16 days. The reaction mixture was then diluted with ether and washed with water and brine, and dried over magnesium sulfate. The ethereal solution was concentrated in vacuo. The residue was purified by HPLC (20% ethyl acetate in hexane). The first fraction is impure (3a, 4a, 5a) 3-butyl-3-ethyl-4-hydroxy-7-methylthio-5- (4'-fluorophenyl) -2,3,4,5-tetrahydro-benzothiepine-1,1- dioxide. The second fraction contains a substance with a melting point of 185-186.5 ° C.

Example 43:

(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 78 and 5 ml of pyrrolidine was refluxed for 1 hour. The reaction mixture was diluted with ether and washed with water, then dried over magnesium sulfate. The ethereal solution was concentrated in vacuo. The residue was crystallized from ether-hexane to give 82, mp 174.5-177 ° C.

Example 44:

(3a, 4b, 5b) 3-Butyl-3-ethyl-5- (4'-fluorophenyl) -4-hydroxy-7- (1-morpholinyl) -2,3,4,5-tetrahydrobenzothiepine-1,1- Dioxide (83)

A mixture of 0.4 g (0.98 mmol) of 78 and 5.0 g (56 mmol) of morpholine was refluxed for two hours and concentrated in vacuo. The residue was dissolved in ether (30 mL) and washed with water and brine, and dried over magnesium sulfate. The ethereal solution was concentrated in vacuo and the residue was recrystallized from ether-hexane to give 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-1,1-dioxide (84) and (3a, 4b, 5b) 3-butyl-3-ethyl-5- (4'-fluorophenyl) -4-hydroxy-7-methyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (85)

Alkylation of 4-methylphenol with 4-fluorobenzyl chloride according to the procedure described in J. Chem. Soc., 2431 (1958) gave 4-methyl-2- (4'-fluorobenzyl) phenyl. This material does

-175 was converted to 84 and 85 with a melting point of 153-155 ° C by a procedure similar to that described in Example 18, Method B.

Example 46 (3a, 4b, 5b) 3-Butyl-3-ethyl-4-hydroxy-5- (4'-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) -7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1- Dioxide (87)

To a solution of 66 (0.52 g, 1.2 mmol) in dichloromethane (20 mL) was added boron tribromide (1.7 g, 6.78 mmol). The reaction mixture was cooled to -78 ° C and stirred for 4 minutes. Again, boron tribromide, this time 0.3 ml, was added to the reaction mixture and the reaction mixture was stirred at -78 ° C for 1 hour and quenched with 2M HCl. The organics were extracted into ether. The ether layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue (0.48 g) was purified by HPLC (30% ethyl acetate in hexane). The first fraction contained 0.11 g of 86 as a white solid, mp 171.5-173 ° C. The second fraction was crystallized from chloroform to give 0.04 g of 87 as a white solid, mp 264 ° C (dec.).

Example 47:

(3a, 4b, 5b) 3-Butyl-3-ethyl-4,7-dihydroxy-5- (4‘-hydroxyphenyl) -2,3,4,5-tetrahydrobenzothiazole-1,1-dioxide (88)

Treatment of 70 with an excess of boron tribromide at room temperature and following the procedure of Example 45 gives 88 after HPLC purification.

Example 48:

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

A mixture of 0.2 g (0.49 mmol) of 78 and 2.0 g (35 mmol) of azetidine was refluxed for 3 hours and concentrated in vacuo. The residue was diluted with ether (30 mL), washed with water and brine, and dried over magnesium sulfate. The ethereal solution is concentrated in a steam bath. The separated crystals were filtered to give 0.136 g of 89 as prisms of melting point

196.5-199.5 ° C.

-176Example 49:

(3a, 4a, 5a) 3-Butyl-3-ethyl-5- (3'-methoxyphenyl) -4-hydroxy-7-methylthio-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (90) and (3a, 4b, 5b) 3-butyl-3-ethyl-5- (3'-methoxyphenyl) -4-hydroxy-7-methylthio-2,3,4,5-tetrahydrobenzothiazepine-1,1-dioxide (91)

A mixture of 0.4 g (0.95 mmol) of 79, 0.08 g (1.14 mmol) of sodium methanethiolate and 15 ml of anhydrous DMF was stirred at 60 ° C for 2 hours. An additional 1.4 mmol of sodium methanethiolate was added to the reaction mixture, and the reaction mixture was stirred at 60 ° C for an additional 2 hours. The reaction mixture is then triturated with 100 ml of water and extracted with dichloromethane. The water / dichloromethane mixture was filtered through celite and the dichloromethane layer was dried over magnesium sulfate and concentrated in vacuo. The first fraction (0.1g) is 90 with a melting point of 117-121 ° C. The second fraction (0.16 g) is 91 with a melting point of 68-76 ° C.

Example 50:

Preparation of benzothiepine-derived polyethylene glycol A.

no. 141 No. 136

A 50 ml round bottom flask was charged with 0.54 g of M-Tres-5000 (polyethylene glycol Tresylate (methoxy-PEG-Tres, Mh 5000) purchased from Shearwateer Polymers Inc., 2130 Memorial Parkway, SW, Huntsville, Alabama) under a nitrogen atmosphere. 35801), 0.055 g of 136, 0.326 calcium carbonate and 2 ml of anhydrous acetonitrile. The reaction mixture was stirred at 30 ° C for 5 days and the solution was then filtered to remove salts. Acetonitrile was then removed in vacuo and the product was dissolved in THF and precipitated by the addition of hexane. The polymer precipitate was isolated by filtration from a solvent mixture (THF / hexane). The precipitation process continues until the presence of 136 by TLC on S1O2 in the precipitated product is detected. The precipitated polymer is dissolved in water and filtered and the water-soluble polymer is dialyzed for 48 hours in a cellulose dialysis tube (spectrum® 7, 45 mm x 15.24) cm (0.5

- 177 feet), permeability up to 1000 molecular weight). The polymer solution is then removed from the dialysis tube and lyophilized to dryness. The NMR spectrum corresponds to the desired substance A, and gel permeation chromatography shows the presence of the polymer of 4,500 molecular weight and serves to verify that it does not contain any free substance. assay on IBAT cells

Example 51 '

Preparation of substance No 140

O-O-polyethyleáglykol

ra <2 or

Fill a 50 ml 2-neck round bottom flask with 0.42 g of Tres-3400 (polyethylene glycol Tresylate (methoxy-PEG-Tres, Mh 3400) purchased from Shearwateer Polymers Inc., 2130 Memorial Parkway, SW, Huntsville, Alabama 35801), 0.1 Potassium carbonate, 0.100 g of 111 and 5 ml of anhydrous DMF Stir for 6 days at 27 ° C. The disappearance of the starting material 111 can be monitored by TLC. Transfer the solution to a separatory funnel and dilute with 50 ml of dichloromethane and extract with water. to dryness using a rotary evaporator. The dry weight is 0.4875 g. Then the polymer is dissolved in water and dialyzed for 48 hours at 40 ° C in a cellulose dialysis cell.

- 178 tube (spectrum® 7, 45 mm x 15.24 cm (0.5 feet), permeability up to 1000 molecular weight). The polymer solution was removed from the dialysis tube and lyophilized to dryness (0.341 g). NMR spectra confirm the structure of the desired product B.

Example 52:

no. 134

A 10 mL vial was charged with 0.21 g of 136 (0.5 mmol), 0.17 g (1.3 mmol) of potassium carbonate, 0.6 g (1.5 mmol) of 1,2-bis- (2- iodoethoxy) ethane and 10 ml DMF. The reaction mixture was stirred for 4 days at room temperature and then continued with water and ether. The ether layer was evaporated to dryness and the desired product 134 was isolated on a silica gel column using 80/20 hexane-ethyl acetate.

Example 53:

no. 112

- 179 Example 54:

no. 113

A 25 ml two-necked round-bottomed flask was charged with 0.5 g (1.24 mmol) 69462, 13 ml anhydrous DMF, 0.055 g 60% NaH dispersion and 0.230 g (0.62 mmol) 1.2 bis (2-iodoethoxyethane) at 10 ° C under nitrogen. The reaction mixture was slowly warmed to 40 ° C. After 14 hours, the entire amount of 113 was consumed, the reaction mixture was cooled to room temperature and extracted with ether / water. The ether layer was evaporated to dryness and chromatographed on silica gel (80/20 ethyl acetate / hexane). The isolated compound 112 (0.28g) was characterized by NMR and mass spectroscopy.

Example 55:

no. 135

-180

no. 136

To a 50 mL round bottom flask was added 0.7 g (1.8 mmol) of 136, 0.621 g of potassium carbonate, 6 mL of DMF, and 0.33 g of 2-bis (2-iodoethoxyethane). Stir at 40 ° C under a nitrogen atmosphere for 12 hours. The procedure is the same as for 112.

Examples 56 and 57 (Substances No. 131 and No. 137):

The structure of these substances is shown in Table 3.

The same procedure as in Example 55 was followed except for the use of the corresponding benzothiepine

Example 58 (Substance 139):

The structure of these substances is shown in Table 3.

The same procedure as in Example 55 was followed except for the use of the corresponding benzothiepine 1,6 diiodo-hexane instead of 1,2bis (2-iodoethoxyethane).

No 101

This substance is prepared by condensation of 7-NH2benzothiepine with 1,12-dodecane dicarboxylic acid or acid halide

Example 60 (104):

no. 104

2-Chloro-4-nitrobenzophenone is reduced with triethylsilane and trifluoromethanesulfonic acid to 2-chloro-4-nitrodiphenylmethane 32. Reaction of 32 with lithium sulfide followed by reaction of the resulting sulfide with mesylate IV affords sulfide-aldehyde XXHL to form sulfide-aldehyde XXHL by oxidation of MCP with two equivalents XXIV (see Scheme 5). Reduction of the sulfone-aldehyde XXIV with formaldehyde and hydrogen at 689 kPa at 55 ° C for 12 hours catalysed by palladium on carbon in the same reaction vessel affords the substituted dimethylamine derivative XXVBI. Cyclization of XXVH with potassium t-butoxide affords a mixture of substituted amino derivatives of Compound # 1. 104 of the invention.

-182Scheme 6

Example 61:

no. 102

A 28.4 g (1 oz) Fisher-Porter flask was charged with 0.14 g (0.34 mmol) 70112, 0.97 g (6.8 mmol) methyl iodide and 7 mL anhydrous acetonitrile. Heat at 50 ° C for 4 days.

The 192 salt of compound 192 was isolated by concentration in 1 mL of acetonitrile and then precipitation with diethyl ether.

Example 62:

Γ

no. 125

A 0.1 g (0.159 mmol) sample of 134 was dissolved in 15 mL of anhydrous acetonitrile in a Fisher-Porter vial, bubbled with trimethylamine at 0 ° C for 5 min, and then the vial was capped and warmed to room temperature. The reaction mixture is stirred overnight and the desired product is isolated by removal of the solvent by rotary evaporation.

Example63 (substance 295)

no. 295

-184-

no. 113

60% sodium hydride (11 mg, 0.27 mmol) in 1 mL acetonitrile at 0 ° C was treated with 0.248 mmol (0.10 g) 54 in 2.5 mL acetonitrile at 0 ° C. g (2.48 mmol) of 1,2-bis (2-iodoethoxyethane). After warming to room temperature, it is stirred for 14 hours. The product was isolated by column chromatography.

Example 64 (compound 286):

No. 286

Following a procedure similar to that of Example 86, see below (compound 118), the title compound was prepared and purified as a colorless solid, mp 180181 ° C; 1 H NMR (CDCl 3) 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, 1H), 1.64-1.80 (m, 1H), 2.24-2.38 (m, 1H, 3.15 (AB, Jab = 15Hz, Av = 42Hz) (2H), 4.20 (d, J = 8 Hz, 1H), 5.13 (s, 2H), 5.53 (s, 1H), 6.46 (s, 1H), 6.68 (s, 1 H), 7.29-7.51 (m, 10H), 7.74 (d, J = 8 Hz, 1H, 8.06 (d, J = 8 Hz, 1H). FABMS m / z 494 (M + H) HRMS calcd for (M + H) 494.2001, found 494.1993, calculated for C28H31NO5S: C, 68.13; H, 6.33; N, 2.84. Found: C, 68.19, H N, 2.74.

-185Example 65 ·

no. 287

Following a procedure similar to that of Example 89, below, (Compound No. 121), the title compound was prepared and purified as a colorless solid, mp 245-246 ° C. 1 H NMR (CDCl ₃ ) δ 0.84 (t, J = 6 Hz, 3H), 0.92 (t, J = 6 Hz, 3H), 1.28 (d, J = 8 Hz, 1H), 1.32-1.42 (m, 1H) 1.44-1.60 (m, 1H), 1.64-1.80 (m, 1H), 2.20-2.36 (m, 1H), 3.09 (AB, Jab = 15Hz) Λ av = 42 Hz, 2H), 3.97 (bs, 2H), 4.15 (d, J = 8Hz, 1H), 5.49 (s, 1H), 5.95 (s, 1H), 6 54 (d, J = 7 Hz, 1H), 7.29-7.53 (m, 5H), 7.88 (d, J = 8 Hz, 1H), ESMS 366 (M + Li). Calcd. For C ₂₀ H ₂₅ NO ₃ S: C, 66.82; H, 7.01; N, 3.90. Found: C, 66.54; H, 7.20; N, 3.69

Example 66 (Compound 288):

no. 288

Following a procedure similar to that in Example 89, below (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; 1 H NMR (CDCl ₃ ) δ 1.12 (s, 3H), 1.49 (s, 3H), 3.0 (d, J = 15 Hz, 1H), 3.28 (d, J = 15 Hz) (1H),

-1864.00 (s, 1H), 5.51 (s, 1H), 5.97 (s, 1H), 6.56 (dd, J = 2.1, 8.4 Hz, 1H), 7, 31-7.52 (m, 5H), 7.89 (d, J = 8.4 Hz, 1H) MS (FAB &lt; + &gt;) (M + H) m / z 332.

Example 67 (compound 289).

no. 289

Following a procedure similar to that in Example 89, below (Compound No. 121), the title compound was prepared and purified by silica gel chromatography to give the desired product as a colorless solid, mp 205-206 ° C; 1 H NMR (CDCl 3) δ 0.80-0.95 (m, 6H), 1.10-1.70 (m, 7H), 2.15 (m, 1H), 3.02 (d, J = 15.3 Hz, 2H), 3.15 (d, J = 15.1 Hz, 2H), 3.96 (s, br, 2H), 4.14 (d, J = 7.8 Hz, 1H) 5.51 (s, 1H), 5.94 (d, J = 2.2 1H), 6.54 (dd, J = 8.5, 2.2 Hz, 1H), 7.28-7, 50 (m, 6H), 7.87 (d, J% 8.5 Hz, 1H). MS (FAB): mlz 388 (M + H).

Example 68

no. 290

Following a procedure similar to that in Example 89, below (Compound No. 121), the title compound was prepared and purified as a colorless solid, mp 9698 ° C. 1 H NMR (CDCl 3) δ 0.92 (t, J) = 7Hz, 6H), 1.03-1.70 (m, 11H), 2.21 (J = 8Hz, 1H), 3.09 (AB, Jab = -18Hz, Av = 38Hz, 2H 1.96 (bs, 2H), 4.14 (d, J = 7 Hz, 1H), 5.51 (s, 1H),

1875.94 (s, 1H), 6.56 (d, J = 9 Hz, 1H), 7.41-7.53 (m, 6H), 7.87 (d, J = 8 Hz, 1H); FABMS m / z 416 (M + H) &lt; + &gt;.

Example 69:

no. 291

Following a procedure similar to that described in Example 86, below (Compound No. 118), the title compound was prepared and purified as a colorless solid: 1 H NMR (CDCl 3) δ 0.91 (t, J = 7Hz, 6H); 1.02-1.52 (m, 11H), 1.60-1.70 (m, 1H), 2.23 (t, J = 8Hz, 1H), 3.12 (AB, Jab = 18Hz, ν) = 36 Hz, 2H), 4.18 14 (d, J = 7 Hz, 1H), 5.13 (s, 2H), 5.53 (s, 1H), 6.43 (s, 1H), 6, 65 (s, 1H), 7.29-7.52 (m, 10H), 7.74 (d, J = 9 Hz, 1H), 8.03 (d, J = 8 Hz, 1H); ESMS m / z 556 (M + Li).

Example 70

no. 292

Following a procedure similar to that in Example 89, below (Compound No. 121), the title compound was prepared and purified as a colorless solid, mp 111-112.5 ° C, 1 H NMR (CDCl ₃ ) 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, Jab = 15 Hz, Jf = 45 Hz, 2H), 4.09 (bs, 2H), 5.49 (s, 1H), 5.91 (s, 1H), 6.55 (d) J = 9Hz, 1H), 7.10 (t, J = 7Hz, 2H), 7.46 (t, J = 6Hz, 2H), 7.87 (d, J = 9Hz, 1H)

Example 188

no. 293

During the preparation of substance no. 290 from substance no. 291 by BBr ₃ , the title compound was isolated: 1 H NMR (CDCl ₃ ) δ 0.85 (t, J = 6 Hz, 6H), 0.98-1.60 (m, 10H), 1.50 -1.66 (m, 2H), 2.16 (t, J = 8Hz, 1H), 3.04 (AB, Jab = 15Hz, Av = 41Hz, 2H), 4.08 (s, 1H), 4.12 (s, 1H), 5.44 (s, 1H), 5.84 (s, 1H), 6.42 (d, J = 9Hz, 1H), 7.22 (d, J = 8) Hz, 2H), 7.16-7.26 (m, 10H), 7.83 (d, J = 8Hz, 1H), ESMS m / z 512 (M + Li).

Example 72 (Compound No. 294Y

Following a procedure similar to that in Example 60, below (Compound No. 104), the title compound was prepared and purified as a colorless solid: 1 H NMR (CDCl ₃ ) δ 0.90 (t, J = 6 Hz, 6H) 1.05-1.54 (m, 9H), 1.60-1.70 (m, 1H), 2.24 (J = 8Hz, 1H), 2.80 (s, 6H), 3 .05 (AB, Jab = 15Hz, .delta. = 42 Hz, 2H), 4.05-4.18 (m, 2H), 5.53 (s, 1H), 5.93 (s, 1H), 6, 94 (d, J = 9Hz, 1H), 7.27-7.42 (m, 4H), 7.45 (d, J = 8Hz, 2H), 7.87 (d, J = 9Hz, 1 H); ESMS m / z 444 (M + H) &lt; + &gt;.

The structures of the compounds of Examples 33 to 72 are shown in Tables 3 and 3 A.

Examples 73-79, 87, 88 and 91-102

Using the examples and methods generally described in Examples 1 to 72 corresponding to the substituents introduced, the compounds having the structures shown in Table 3 were prepared. The starting materials shown in the reaction schemes shown above varied according to the principles of organic synthesis well known in the art to introducing said substituents at the 4- and 5- positions (R ³ , R ⁴ , R ⁵ , R ⁶ ) and indicated at the benzo ring position (R *).

The structures of the compounds produced in Examples 73-102 are shown in Tables 3 and 3A.

-189Example in 80-84:

Preparations 115,116, 111,113

Preparation of 4-chloro-3- (4-methoxyphenylmethyl) nitrobenzene

Weigh 68.3 g of phosphorus pentachloride (0.328 mol, 1.1 equivalents) into a 500 ml two-necked round-bottomed flask. 50 ml of chlorobenzene are added. 60 g of 2-chloro-5-nitrobenzoic acid (0.298 mol) was added slowly. Stir at room temperature overnight under a nitrogen atmosphere and then heat at 50 ° C for 1 hour. The chlorobenzene was removed in vacuo, and the residue was washed with hexane. The dry weight is 55.5 g

In the same round-bottom flask, dissolve the acid chloride (55.5 g 0.25 mol) above with 100 ml of anisole (about 3.4 equivalents). Cool the solution in an ice bath and sparge with nitrogen. Slowly add 40.3 g of aluminum chloride (1.2 equivalents, 0.3 mol.) Stir under nitrogen for 24 hours.

After 24 hours, the solution is poured into 300 ml of 1M HCl and cooled. Stir 15 minutes. Extract several times with diethyl ether. Extract the organic layer once with 2% NaOH and then twice with water. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The solid is washed well with ether and then with ethanol before drying. Weight 34.57 g (a mixture of meta, ortho and para derivatives).

element in theory found C 57.65 57.45 H 3.46 5.51 N 4.8 4.8 Cl 12.15 12.16

The next step of reducing the ketone with trifluoromethanesulfonic acid and triethylsilane and crystallizing from ethyl acetate / hexane gives pure 4-chloro-3- (4-methoxyphenylmethyl) nitrobenzene.

4-Chloro-3- (4-methoxy-phenylmethyl) -nitrobenzene was then used as described in the synthesis of 117a18 from 2-chloro-4-nitrophenylmethane. Compounds 115 and 116 can be synthesized according to these procedures. Compounds 111 and 113 can be synthesized according to the procedures described for the preparation of 121.

Compound 114 can be prepared by reacting 116 with ethyl mercaptan and aluminum chloride.

Examples 85 and 86:

Preparation of substances No.117all8

-1902-chloro-4-nitrobenzophenone is reduced with triethylsilane and trifluoromethanesulfonic acid to 2-chloro-4-nitrodiphenylmethane 32. Reaction of 32 with lithium sulfide followed by reaction of the resulting sulfide with mesylate IV affords sulfide-aldehyde XXIII by sulfonating XXIII with two equivalents of XXBA -aldehyde XXIII. Oxidation of XXIII with two equivalents of MCPBA affords 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 of toluene and 100 ml of ethanol and 3.2 g of 10% Pd / C, heated to 55 ° C under pressure The reaction mixture was then filtered to remove the catalyst. The amine product (0.076 mol, 29.5 g) from this reaction is then treated with benzyl chloroformate (27.4 g) in toluene in the presence of 35 g of potassium carbonate, and the mixture is stirred at room temperature overnight. After extraction with water, the CBZ protected amine is further purified by precipitation from toluene / hexane.

The CBZ protected amine product is then reacted with three equivalents of potassium t-butoxide in THF at 0 ° C to give compounds 117 and 118, which are separated by silica gel column chromatography.

Examples 89 and 90:

Preparation of substances 121 or 122

118 (0.013 mol, 6.79 g) was dissolved in 135 mL of dry chloroform and cooled to -78 ° C, then boron tribromide (4.9 g) was added and the reaction mixture was allowed to warm to room temperature. The reaction is complete after an hour and a half. The reaction is quenched by the addition of 10% potassium carbonate at 0 ° C and the reaction mixture is extracted with ether. Removal of the ether yields compound 121. A similar procedure can be used to generate compound 122 from compound 117.

Examples 93-96:

The compounds 126, 127, 128 and 129 are included in Table 3 and were prepared separately as outlined for 115, 116, 111 and 113, respectively, except that fluorobenzene was used as the starting material instead of anisole.

Table 3

Specific Compounds (No. 102-111, 113-130, 132-134, 136,138,142-144,262-296)

-191 Table 3a

Example Comp. R ¹ R ² R ³ R ⁴ R ⁵ R ⁶ IR ^X ) q 61 102 Et-n-Bu- OH- H- ph H Γ, 7- (CH ₃ ) 3 N < 73 103 n-Bu- Et- OH- H- ph H 1,7 (0¾ ^. 60 104 Et-n-Bu- OH- H- ph H 7 (CH ₃₎ 2 N- 74 105 Et-n-Bu- OH- H- ph H 7-CH ₃ SO ₂ NH 75 106 Et-n-Bu- OH- H- ph H _7-Br-CH2 CONH 76 107 n-Bu- Et- OH- H- p-n-CioHíí H _7-NH2 - O-Ph 77 108 Et-n-Bu- OH- H- ph H 7-C ₅ H _n CONH 78 109 Et-n-Bu- OH- H- p-n-CioHíí O-Ph H _7-NH2 - 79 110 Et-n-Bu- OH- H- ph H 7-CH ₃ CONH- 80 111 n-Bu- Et- OH- H- p-HO-Ph H _7-NH2 - 81 112 Et-n-Bu- OH- H- p-HO-Ph H _7-NH2 - 82 114 Et-n-Bu- OH- H- p-Ph-chjo H _7-NH2 - 83 115 n-Bu- Et- OH- H- p-Ph-chjo H 7-NH-CBZ 84 116 Et-n-Bu- OH- H- p-CH ₃ O-Ph H 7-NH-CBZ 85 117 n-Bu- Et- OH- H- ph H 7-NH-CBZ 86 118 Et-n-Bu- OH- H- ph H 7-NH-CBZ 87 119 Et-n-Bu- OH- H- ph H 7-NHCO ₂ -t-Bu 88 120 n-Bu- Et- OH- H- ph H 7-NHCO ₂ -t-Bu 89 121 Et-n-Bu- OH- H- ph H _7-NH2 - 90 122 n-Bu- Et- OH- H- ph H _7-NH2 - 91 123 Et-n-Bu- OH- H- ph H 7-n-CeHn -NH- 92 124 n-Bu- Et- OH- H- ph H L-N-CeHn -NH- 62 125 Et-n-Bu- OH- H- ph H rXCH ^ NXCHjCHjOjj 93 126 n-Bu- Et- OH- H- p-F-Ph- H 7-NH-CBZ 94 127 n-Bu- Et- OH- H- p-F-Ph- H _7-NH2 - 95 128 Et-n-Bu- OH- H- p-F-Ph- H 7-NH-CBZ 96 129 Et-n-Bu- OH- H- p-F-Ph- H _7-NH2 - 97 130 Et-n-Bu- OH- H- ph H rXCHjhbFCeHnO- 98 132 Et-n-Bu- OH- H- ph H 8-naphthalimidyl-C6Hi ₂ O-

-192-

133 et- n-Bu- OH- H ph H 8-11-C10H21- 134 et- n-Bu- OH- H ph H 8-I- (C ₂ H ₄ O) ₃ - 136 et- n-Bu- OH- H ph H 8-HO- 138 n-Bu - Et- OH- H ph H 8-CH ₃ CO ₂ - 90 et- n-Bu- H OH- H- m-CH 3 -Ph- 7-CH ₃ S- 91 et- n-Bu- OH- H m-Ph-chjo H 7-CH ₃ S- 89 et- n-Bu- OH- H p-F-Ph- H 7- (N) azetidine 66 et- n-Bu- OH- H m-CH ₃ O-Ph - H- 7-CH ₃ O- 65 et- n-Bu- H OH- H _m-CH3 O-Ph- 7-CH ₃ O- 68 et- n-Bu- OH- H m-CF ₃ -Ph- H 7-CH ₃ O- 67 et- n-Bu- H OH- H m-CF ₃ -Ph- 7-CH ₃ O- 87 et- n-Bu- OH- H m-OH-Ph H 7-HO- 86 et- n-Bu- OH- H m-OH-Ph H 7-CH ₃ O- 70 et- n-Bu- OH- H p-F-Ph- H 7-CH ₃ O- 69 et- n-Bu- H OH- H p-F-Ph- 7-CH ₃ O- 88 et- n-Bu- OH- H p-F-Ph- H 7-HO- 76 et- n-Bu- OH- H m-CH ₃ O-Ph H 7-Br 75 et- n-Bu- H OH- H _m-CH3 O-Ph- 7-Br 77 et- n-Bu- H OH- H p-F-Ph- 7-F- 78 et- n-Bu- OH- H p-F-Ph- H 7-F- 79 et- n-Bu- H OH- H _m-CH3 O-Ph- 7-F- 80 et- n-Bu- OH- H m-CH ₃ O-Ph - H- 7-F- 72 et- n-Bu- OH- H m-F-Ph- H 7-CH ₃ O- 73 et- n-Bu- H OH- H o-F-Ph 7-CH ₃ O- 71 et- n-Bu- H OH- H m-F-Ph- 7-CH ₃ O- 74 et- n-Bu- OH- H o-F-Ph H 7-CH ₃ O- 81 et- n-Bu- OH- H p-F-Ph- H 7-CH ₃ S- 85 et- n-Bu- OH- H p-F-Ph- H 7-CH ₃ - 84 et- n-Bu- H OH- H p-F-Ph- 7-CH ₃ - 83 et- n-Bu- OH- H p-F-Ph- H 7- (N) -morpholine 82 et- n-Bu- OH- H p-F-Ph- H 7- (N) -pyrrolidine

-193-

286 Et- n-Bu- OH- H ph H 7-NH-CBZ 287 Et- Et- OH- H ph H _7-NH2 - 288 ch ₃ - ch ₃ - OH- H ph H _7-NH2 - 289 n- n- c ₃ hrs ₇ - c ₃ hrs ₇ - OH- H ph H _7-NH2 - 290 n-Bu- OH- H ph H _7-NH2 - 291 n-Bu- OH- H ph H 7-NH-CBZ 292 n-Bu- OH- H p-F-Ph- H _7-NH2 - 293 n-Bu- OH- H ph H 7-PhCH ₂ N- 294 n-Bu- OH- H ph H 7 (CH ₃₎ 2 N- 295 Et- n-Bu- OH- H p-I (CalWhPh- H _7-NH2 - 296 Et- n-Bu- OH- H γ, ρ- H 7-NHí-

(CH ^ C ^ N

H 3 -Phababeta 3 A

Benzothiophenes with bridges (No. 101, 112, 131, 135, 137, 139-141)

-194-

JL ä. 101 (example 5 »)

-195-

no. 135 (example 55)

no. 137 (example 57)

fi. 139 (example 58)

£. 135 (example 55)

X ** 08

£. 137 (example 57)

£. 139 (example 58)

-197-

3400 Mr polyathylengykol aet

Examples 104-231:

Using the examples and methods generally described in Examples 1 to 72 corresponding to the substituents introduced, containing, if necessary, other conventional synthetic procedures well known in the art, compounds having the structures shown in Table 4 were prepared. shown above were different according to the principles of organic synthesis, well known in the art, for introducing said substituents at the 4- and 5- positions (R ³ , R ⁴ , R ⁵ , R ⁶ ) and said positions on the benzo ring (R *) .

Table 4 <u °

-198-

Compound No. R ⁵ (R \ 302 p-F-Ph 7- (l-aziridine) 303 p-F-Ph 7 ETS 304 p-F-Ph _7-CH3 S (O) - 305 p-F-Ph 7-CH ₃ S (O) ₂ - 306 p-F-Ph 7-PhS- 307 p-F-Ph 7-CH ₃ S- 308 p-F-Ph 7-O-CH ₃ 9-CH ₃ O- 309 p-F-Ph 7-eth- 310 p-F-Ph 7-iPr- 311 p-F-Ph 7-t-Bu- 312 p-F-Ph 7- (l-pyrazole) · 314 _m-CH3 O-Ph- 7- (l-azetidine) 315 _m-CH3 O-Ph- 7- (l-aziridine) 316 m-Ph-CHSO ETS-7- 317 m-Ph-chjo _7-CH3 S (O) - 318 _m-CH3 O-Ph- 7-CH ₃ S (O) ₂ - 319 m-Ph-chjo 7-PhS- 320 _m-CH3 O-Ph- _{7-S-CH3 9-CH3} S- 321 _m-CH3 O-Ph- 7-O-CH ₃ 9-CH ₃ O- 322 _m-CH3 O-Ph- 7-eth- 323 _m-CH3 O-Ph- 7-iPr- 324 _m-CH3 O-Ph- 7-t-Bu- 325 p-F-Ph 6- CH ₃ O- 7- CH ₃ O- 326 p-F-Ph- 7- (l-azetidine) _9-CH3 - 327 p-F-Ph- 7-EtS 9-CH ₃ - 328 p-F-Ph- 7-CH ₃ S (O) -9-CH ₃ - 329 p-F-Ph- 7- CH ₃ S (O) ₂ 9-CH ₃ - 330 p-F-Ph- 7-PhS- 9-CH ₃ - 331 p-F-Ph- 7- CH ₃ S 9-CH ₃ - 332 p-F-Ph- 7- CH ₃ O 9-CH ₃ - 333 p-F-Ph- 7- CH ₃ 9-CH ₃ - 334 p-F-Ph- _{7-CH3 CH3} Q9-O-

-199-

335 p-F-Ph- 7- (l-pyrrole) 336 p-F-Ph- 7- (N) -N-methylpiperazine 337 p-F-Ph- ph 338 p-F-Ph- 7-CH ₃ C (= CH ₂ ) - 339 p-F-Ph- 7-Cyclopropyl 340 p-F-Ph- 7- _{(CH3) 2} -NH- 341 p-F-Ph- 7- (N) -azetidine _9-CH3 S- 342 p-F-Ph- 7- (N-pyrrolidine) 9-CH ₃ S- 343 p-F-Ph- 7- (CH ₃ ) 2 N-9-CH ₃ S- 344 _m-CH3 O-Ph- 7- (l-pyrazole) 345 m-Ph-chjo 7- (N) -N-methylpiperazine 346 _m-CH3 O-Ph- ph 347 m-Ph-CHSO 7-CH ₃ C (= CH ₂ ) - 348 _m-CH3 O-Ph- 7-Cyclopropyl 349 _m-CH3 O-Ph- 7- _{(CH3) 2} -NH- 350 _m-CH3 O-Ph- 7- (N) -azetidine _9-CH3 S- 351 _m-CH3 O-Ph- 7- (N-pyrrolidine) 9-CH ₃ S- 352 _m-CH3 O-Ph- 7- (CH 3) ₂ N- 9-CH ₃ S 353 _m-CH3 O-Ph- 6-CH ₃ O 7-CH ₃ O CH ₃ O 8 354 _m-CH3 O-Ph- 7- (l-azetidine) _9-CH3 - 355 _m-CH3 O-Ph- 7-EtS 9-CH ₃ - 356 _m-CH3 O-Ph- 7- CH ₃ S (O) 9-CH ₃ - 357 _m-CH3 O-Ph- 7- CH ₃ S (O) ₂ 9-CH ₃ - 358 _m-CH3 O-Ph- 7-PhS- 9-CH ₃ - 359 _m-CH3 O-Ph- 7- CH ₃ S 9-CH ₃ - 360 _m-CH3 O-Ph- 7- CH ₃ O 9-CH ₃ - 361 _m-CH3 O-Ph- 7- CH ₃ 9-CH ₃ - 362 p-F-Ph- 7- CH ₃ O 9 -CH ₃ O- 363 thien-2-yl 7- (l-aziridine) 364 thien-2-yl 7 ETS 365 thien-2-yl _7-CH3 S (O) - 366 thien-2-yl _7-CH3 S (O) 2- 367 thien-2-yl 7-PhS- 368 thien-2-yl 7-CHjS-

-200-

369 thien-2-yl 7-O-CH ₃ 9-CH ₃ O- 370 thien-2-yl 7-eth- 371 thien-2-yl 7-iPr- 372 thien-2-yl 7-t-Bu- 373 thien-2-yl 7- (l-pyrazole) - 374 thien-2-yl 7-CH ₃ O- 375 thien-2-yl 7-CH ₃ S- 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 ETS-7- 381 5-Cl-thien-2-yl _7-CH3 S (O) - 382 5-Cl-thien-2-yl 7-CH ₃ S (O) ₂ - 383 5-Cl-thien-2-yl 7-PhS- 384 5-Cl-thien-2-yl _{7-S-CH3 9-CH3} S- 385 5-Cl-thien-2-yl 7-O-CH ₃ 9-CH ₃ O- 386 5-Cl-thien-2-yl 7-eth- 387 5-Cl-thien-2-yl 7-iPr- 388 5-Cl-thien-2-yl 7-t-Bu- 389 5-Cl-thien-2-yl 7-CH ₃ O- 390 5-Cl-thien-2-yl 7-CH ₃ S- 391 5-Cl-thien-2-yl 7-Me 392 thien-2-yl 7- (l-azetidine) 9-CHj- 393 thien-2-yl 7-EtS 9-CH ₃ - 394 thien-2-yl 7- CH ₃ S (O) 9-CH ₃ - 395 thien-2-yl 7- CH 3 S (O) ₂ 9-CH ₃ - 396 thien-2-yl PhS9 7 CH ₃ - 397 thien-2-yl 7- CH ₃ S 9-CH ₃ - 398 thien-2-yl 7- CH ₃ O 9-CH ₃ - 399 thien-2-yl 7- CH ₃ 9-CH ₃ - 400 thien-2-yl _{7-CH3 CH3} Q9-O- 401 thien-2-yl 7- (l-pyrazole) 402 thien-2-yl 7- (N) -N-methylpiperazine 403 thien-2-yl ph

-201-

404 thien-2-yl 7-CH ₃ C (= CH ₂ ) - 405 thien-2-yl 7-Cyclopropyl 406 thien-2-yl 7- _{(CH3) 2} -NH- 407 thien-2-yl 7- (N) -azetidine _9-CH3 S- 408 thien-2-yl 7- (N-pyrrolidine) - _9-CH3 S- 409 thien-2-yl 7- (CH ₃ ) ₂ N- 9-CH ₃ S- 411 5-Cl-thien-2-yl 7- (l-pyrazole) 412 5-Cl-thien-2-yl 7- (N) -N'-methylpiperazine 413 5-Cl-thien-2-yl ph 414 5-Cl-thien-2-yl 7-CH ₃ C (= CH ₂ ) - 415 5-Cl-thien-2-yl 7-Cyclopropyl 416 5-Cl-thien-2-yl 7- _{(CH3) 2} -NH- 417 5-Cl-thien-2-yl 7- (N) -azetidine _9-CH3 S- 418 5-Cl-thien-2-yl 7- (N-pyrrolidine) - _9-CH3 S- 419 5-Cl-thien-2-yl 7- (CH ₃ ) ₂ N- 9-CH ₃ S- 420 5-Cl-thien-2-yl 7- (l-azetidine) _9-CH3 - 421 5-Cl-thien-2-yl 7 ETS 9-CHj- 422 5-Cl-thien-2-yl 7- CH ₃ S (O) 9-CH ₃ - 423 5-Cl-thien-2-yl 7- CH ₃ S (O) 29-CH ₃ - 424 5-Cl-thien-2-yl PhS9 7 CH ₃ - 425 5-Cl-thien-2-yl 7- CH ₃ S 9-CH ₃ - 426 5-Cl-thien-2-yl 7- CH ₃ O 9-CH ₃ - 427 5-Cl-thien-2-yl 7- CH ₃ 9-CH ₃ - 428 5-Cl-thien-2-yl _{7-CH3 CH3} Q9-O- 429 thien-2-yl 6-CH ₃ O 7-CH ₃ O CH ₃ O 8 430 5-Cl-thien-2-yl 6-CH ₃ O 7-CH ₃ O CH ₃ O 8

Examples 232 -1394:

Using the examples and methods generally described in Examples 1 to 72 corresponding to the substituents introduced, containing, if necessary, other conventional synthetic

Processes well known in the art, compounds having the structures shown in Table 1 were prepared. The starting materials shown in the reaction schemes shown above varied in accordance with the principles of organic synthesis well known in the art for introducing the said substituents at the 4- and 4- positions. 5- (R ³ , R ⁴ , R ⁵ , R ⁶ ) and the indicated positions 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 room temperature was added 6.2 g (135 mmol) of lithium sulfide (Aldrich). The dark red solution is stirred at 75 ° C for 1.5 hours or until the starting material is completely consumed, and then 34 g (135 mmol) of dibutyl mesylate aldehyde is added at a temperature of about 50 ° C. The reaction mixture is stirred at 75 ° C for three hours or until the starting material is completely consumed. The cooled solution was poured into water and extracted with ethyl acetate. The combined extracts were washed several times with water, dried over magnesium sulfate and concentrated in vacuo. Purification of the crude extract by silica gel chromatography gave 23.6 g (59%) of fluorobenzene dialdehyde as a yellow oil: 1 H NMR (CDCl ₃ ) 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, 1H), 7.5-7.6 ( m, 2H), 9.43 (s, 1H), 10.50 (d, J = 2.62 Hz, 1H).

Step 2: Preparation of dibutyl 4-fluorobenzene alcohol

To a solution of 22.6 g (69.8 mmol) of dialdehyde 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 syringe. The reaction mixture was stirred at -40 ° C for 20 hours. Sufficient ethyl acetate was added to the cooled solution at -40 ° C to quench excess DIBAL and then 3M HCl. The mixture was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and concentrated in vacuo. Purification of the crude product by silica gel chromatography gave 13.5 g (58%) of the starting material and 8.1 g (36%) of the desired fluorobenzyl alcohol as

-203 colorless oil: 1 H NMR (CDCl ₃ ) d 0.88 (ζ J = 7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.5 1.72 (m, 4H), 1.94 (br s, 1H), 3.03 (s, 2H), 4.79 (s, 2H), 6.96 (dt, J = 8.46, 3.02 Hz, 1H) 7.20 (dd, J = 9.47, 2.82 Hz, 1H), 7.42 (dd, J = 8.67, 5.64, 1H), 9.40 (s, 1H).

Step 3: Preparation of Dibutyl 4-fluorobenzyl bromide

To a solution of 8.1 g (25 mmol) of benzyl alcohol from step 2 in 100 mL of DMF at -40 ° C was added 47 g (50 mmol) of bromotrophenylphosphonium bromide (Aldrich). The resulting solution was stirred cold for 30 minutes then allowed to warm to 0 ° C. To the mixture was added 10% sodium sulfite solution and ethyl acetate. The extract was washed several times with water, dried over magnesium sulfate and concentrated in vacuo. The reaction mixture was stirred in a small amount of ethyl acetate / hexane (1: 4) and filtered through a silica gel column eluting with the same mixture of solvents. The combined filtrates are concentrated in vacuo to give 9.5 g (98%) of the desired product as a colorless oil: 1 H NMR (CDCl 3) d 0.88 (ζ J = 7.05 Hz, 6H), 1.0 L, 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, 1H), 7.15 (dd, J = 9.47, 2.82 Hz, 1H), 7.46 (dd, J = 8.67, 5.64, 1H), 9.45 (s, 1 H).

Step 4: Preparation of sulfonyl 4-fluorobenzyl bromide

To a solution of 8.5 g (25 mmol) of the sulfide obtained in step 3 in 200 mL of dichloromethane at 0 ° C was added 15.9 g (60 mmol) of mCPBA (64% peracid). The resulting solution was stirred cold for 10 minutes then stirred at ambient temperature for 5 hours. A 10% solution of sodium sulfite and ethyl acetate was added to the mixture. The extract was washed several times with saturated sodium carbonate solution, dried over magnesium sulfate and concentrated in vacuo to give 10.2 g (98%) of the desired product as a colorless oil: ¹ H NMR (CDCl 3) d 0.91 (t, J = 7) , 05 Hz, 6H), 1.03-1.4 (m, 8H), 1.65-1.82 (m, 2H), 1.90-2.05 (m, 2H), 3.54 ( s, 2H), 5.01 (s, 2H), 7.04-7.23 (m, 1H), 7.30 (dd, J = 8.87, 2.42 Hz, 1H), 8.03 (dd, J = 8.86, 5.64, 1H), 9.49 (s, 1H).

Example 1396

-204-

-205-

Scheme X

1. LijS. DMSO, heat

......—>

2. eeaylate aldehyde, heat

1. BuLi.PMETA -40 ° C.THF

2. DMF

I

PMET; from ^N ^ N

3γΡΙι ₃ ΡΒγ, -40Ύ:

DMF

R ⁵ B (OR) j, heat>

Pd (Ph ₃ P) ₄ , Na ₂ CO 3 EtOH, toluene ηΛο DME or

R ^with SnRj, heat W (Ph ₃ P), roapourant

R = H - alkyl (C1-C6)

Scheme X: Nucleophilic substitution of a suitably substituted 2-fluorobenzaldehyde with lithium sulfide or other nucleophilic sulfide in a polar solvent (e.g. DMF, DMA, DMSO etc.), followed by the addition of dialkyl mesylate aldehyde (x), affords dialkylbenzene dialdehyde Y at reduced dialdehyde temperature. DIBAL will arise

-206benzyl alcohol monoaldehyde Z. Conversion of benzyl alcohol to benzyl bromide followed by oxidation of sulfide to sulfone gives rise to the key intermediate W.

Preparation of N-propylsulfonic acid

To a solution of 51 mg (11 lpm) of substance X in ethanol (400μ1) is added 1,3 propane sulton (19,5 μΐ, 222 μιη). The reaction mixture is stirred in a hermetically sealed vessel at 55 ° C for 25 hours. The sample is concentrated under a stream of nitrogen and purified by reverse phase chromatography using acetonitrile / water (30-45%) as eluent to give the desired compound as an off-white solid. (28.4 mg, 44%): 1 H NMR (CDCl 3) d 0.82 -0.96 (m, 6H), 1.11 - 1.52 (multiplet multiplet, 10H, 1.58 -1.72) (m, 1H), 2.08 - 2.21 (m, 1H), 2.36 - 2.5 (m, 2H), 2.93 (s, 6H), 3.02 - 3.22 (multiplet) multiplet, 5H), 3.58-3.76 (m, 2H), 4.15 (s, 1H), 5.51 (s, 1H), 6.45 - 6.58 (m, 1H), 6 92-7.02 (m, 1H); 7.35-7.41 (m, 1H); 7.41-7.51 (m, 2H); 8.08 (d, J = 8.1 Hz) (1H), 8.12-8.25 (tn, 1H); MS ES MH m / z 579.

Example 1397:

The 7-fluoro, 9-fluoro and 7,9-difluoro analogs of the benzothiepine compounds of the invention can react with sulfur and nitrogen nucleophiles to form the corresponding sulfur and nitrogen substituted analogs. The following example demonstrates the synthesis of these analogs.

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

F

Mixture of 0,4 g of 3,3-dibutyl-7-fluoro-5a- (4'-fluorophenyl) -4a-hydroxy-2,3,4,5-tetrabenzothiepine-1,1-dioxide prepared by the method described above, 0,12 g sodium methanethiolate and 20 mL of DMF were stirred at 50 ° C for three days. Addition of 0.1 g of sodium methanethiolate was added to the reaction mixture, and the reaction mixture was stirred for an additional 20 hours at 50 ° C and then concentrated in vacuo. The residue was rubbed with water and extracted with ether. The ethereal extract was dried over sulfate

And concentrated in vacuo to give 0.44 g of an oil. Purification by HPLC (10% EtOAc in hexane) gave 0.26 g of needles, mp 167-165.5 ° 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-1,1-dioxide

To 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 above, in 20 ml 2M dimethylamine in THF was heated at 160 ° C in a hermetically sealed pan reactor overnight. The reaction mixture was then cooled and concentrated in vacuo. The residue was rubbed with 25 ml of water and extracted with ether. The ether extract was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by HPLC (10% EtOAc in hexane) to give 35 mg of the material in the earlier fraction identified as 3,3-dibutyl-9-dimethylamino-7-fluoro-5a- (4'-fluorophenyl) -4ahydroxy-2,3 4,5-tetrahydrobenzothiepine-1,1-dioxide, MS (CI) m / e 480 (M * +1) and 29 mg of the later fraction identified as 7,9-bis (dimethylamino) -3,3-dibutyl -5α- (4'-fluorophenyl) 4α-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide, MS (CI) m / e 505 (M + +1).

Compounds of the invention can be synthesized using cyclic sulfate (A, below) as reagent as shown in the following scheme. The following examples describe the procedure using a cyclic sulfate reagent

-208

Kotb

-209Cyclic dibutyl sulfite:

Q.

> P.

n

A solution of 2,2-dibutyl-1,3-propanediol (103 g, 0.548 mol) and triethylamine (221 g, 2.19 mol) in anhydrous dichloromethane (500 mL) was stirred at 0 ° C under a nitrogen atmosphere. Thionyl chloride (97.8 g, 0.82 mol) was added dropwise to the mixture, and the solution turned yellow and darkened over a period of 5 hours when the addition was complete. The reaction mixture was then stirred for 3 hours. Gas chromatography shows that the reaction mixture no longer contains any starting material. The reaction mixture was washed twice with ice water and then twice with brine. The organic phase was dried over magnesium sulfate and concentrated in vacuo to give the cyclic sulfite 128g (100%) as a black oil. Mass spectrometry (MS) was consistent with the product.

To a solution of the above compound (127.5 g, 0.54 mol) in 600 mL acetonitrile and 500 mL ice-cooled water under nitrogen atmosphere was added ruthenium chloride (1 g) and sodium periiodate (233 g, 1.08 mol). . The reaction mixture was stirred overnight and the solution turned black. Gas chromatography shows that the reaction mixture no longer contains any starting material. The mixture is extracted with 300 ml of ether and the ether extract is then washed three times with brine. The organic phase is dried over magnesium sulphate and filtered through celite. The filtrate was concentrated in vacuo to give the cyclic sulfate 133 g (97.85) as an oil. Proton and carbon NMR spectra and MS confirm the product.

2 - ((2- (4-fluorobenzyl) -4-methylphenylthio) methyl) -2-butylhexanal

and

F

-210 Sodium hydride (60% oil dispersion), 0.27 g (6.68 mmol) was washed with hexane and the hexane phase was decanted. To the washed sodium hydride was added 20 mL of 2-methoxyethyl ether (diglyme) and the mixture was cooled in an ice bath. A solution of 1.55g (6.68 mmol) of 2- (4'-fluorobenzyl) -4-methylbenzenethiol in 10 mL of 2-methoxyethyl ether was added dropwise over 15 minutes. A mixture of cyclic dibutylsulfate (2.17 g, 8.68 mmol) in 2-methoxyethyl ether (10 ml) was then added in one portion and the reaction mixture was stirred at 0 ° C for 30 minutes, then at room temperature under nitrogen for 1 hour. Gas chromatography shows that the reaction mixture no longer contains any starting material. The solvent was evaporated and triturated with water then extracted twice with ether. The aqueous layer was separated, 20 ml of 10% NaOH was added, boiled for 30 minutes and cooled, acidified with 6M HCl and boiled for 10 minutes. The reaction mixture was cooled and extracted with ether. The organic layer was washed well with water and brine, dried over magnesium sulfate and concentrated in vacuo to give 2.47 g (92.5%) as an oil. Proton and carbon NMR spectra and MS confirm the product.

2 - ((2- (4'-Fluorobenzyl) -4-methylphenylthio) methyl) -2-butylhexanal

F

To a solution of the above product (2 g, 4.9 mmol) in 40 mL of dichloromethane cooled in an ice bath under nitrogen atmosphere was added pyridinium chlorochromate (2.18 g, 9.9 mmol) in one portion. The reaction mixture was stirred for 3 hours and filtered through a silica gel column. The filtrate was concentrated in vacuo to give 1.39 g (70%) as an oil. Proton and carbon NMR spectra and MS confirm the product.

2 - ((2- (4-Fluorobenzyl) -4-methylphenylsulfonyl) methyl) -2-butylhexanal

-211-

h ₃ c

I

F

To a solution of the above product (0.44 g, 1.1 mmol) in 20 mL of dichloromethane cooled in an ice bath under nitrogen atmosphere was added 70% chloroperbenzoic acid (0.54 g, 2.2 mmol) in one portion. The reaction mixture was stirred for 18 hours and filtered. The filtrate was washed well with 10% NaOH (3x), water, brine, and dried over magnesium sulfate and concentrated in vacuo to give 0.42 g (90%) as an oil. Proton and carbon NMR spectra and MS confirm the product.

3,3-Dibutyl-7-methyl-5α- (4'-fluorophenyl) -4α-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide

A mixture of 0.37 g (0.85 mmol) of the above product in 30 mL of anhydrous THF was stirred at 0 ° C. Potassium t-butoxide (102 mg, 0.85 mmol) was then added. After three hours, it can be determined by TLC that the product is present in the reaction mixture and the starting product is consumed. The crude reaction mixture was acidified with 10% HCl and extracted with ether. The ether extract was washed well with water and dried over magnesium sulfate with brine and concentrated in vacuo. The residue was purified by HPLC (10% EtOAc-hexane). The first fraction contained 0.1 g of starting material as an oil and the second fraction a white solid 0.27 g (75%). Proton and carbon NMR spectra and MS (CI) m / e 433 (M + T) confirm the product.

-212Example 1398.

C „H „C1NO, Mrζζ 291.69

In an inert atmosphere, 68.3 g of phosphorus pentachloride (0.328 mol, Aldrich 15, 777-5) are weighed into a 500 ml two-necked round-bottomed flask equipped with a nitrogen inlet and seal. Remove from the inert atmosphere and flush the flask with nitrogen. Add 50 ml of anhydrous chlorobenzene (Aldrich 28, 451-3) via syringe and start stirring with a magnetic stirrer.

Weigh 60 g of 2-chloro-5-nitrobenzoic acid (0.298 mol, Aldrich 12.511-3). Add slowly to the chlorobenzene solution while bubbling nitrogen. Stir at room temperature overnight. After stirring at room temperature for 20 hours, place the flask in an oil bath and heat at 50 ° C for 1 hour. The chlorobenzene is removed under vacuum. The residue was washed with anhydrous hexane. An acid chloride with a dry weight of 61.95 g is formed. It is stored in an inert and dry atmosphere.

Dissolve the acid chloride in an inert atmosphere with 105 ml of anhydrous anisole (0.97 g mol of Aldrich 29,629-5). Place the solution in a 500 ml two-necked round-bottomed flask.

Weigh 45.1 g of aluminum chloride (0.34 mol, Aldrich 29, 471-3) and add to the solid addition flask. The reaction flask was equipped with an addition funnel and nitrogen inlet. Remove from inert atmosphere. The reaction mixture was cooled in an ice bath and purged with nitrogen. Add aluminum chloride slowly until the addition is complete, allow the reaction mixture to warm to room temperature and stir overnight. The reaction was quenched by pouring into a solution of 300 mL of 1M HCl and ice. Stir 15 minutes, extract twice with ether. The combined ether fractions were extracted twice with 2% NaOH and twice with deionized water. They are dried over magnesium sulphate, filtered and concentrated to dryness on a rotary evaporator. Anisole was removed in vacuo, the product crystallized from 90% ethanol and 10% ethyl acetate. Dry under vacuum, m = 35.2 g, yield 41%. NMR and mass spectrum (m / z = 292) are obtained.

-213Step 2.

C _m H _at C1NO, Mr «277.71

Dissolve 38.10g (0.131 mol) of benzophenone from step 1 in 250 mL of anhydrous dichloromethane. Pour into a 3 liter flask equipped with a nitrogen inlet, an additional container and a stopper, and stir with a magnetic stirrer. The solution was cooled in an ice bath.

A solution of 39.32 g of trifluoromethanesulfonic acid (0.262 mol, Aldrich 15.853-4) and 170 ml of anhydrous dichloromethane is prepared. It is placed in an addition funnel and added dropwise to the cooled solution under nitrogen. Stir five minutes until the reaction is complete.

A solution of 22.85 g of triethylsilane (0.197 mol, Aldrich 23, 019-7) and 170 ml of anhydrous dichloromethane is prepared. It is placed in an addition funnel and added dropwise to the cooled solution under nitrogen. Stir five minutes until the reaction is complete.

A second solution of 39.32 g of trifluoromethanesulfonic acid and 170 ml of anhydrous dichloromethane is prepared. It is placed in an addition funnel and added dropwise to the cooled solution under nitrogen. Stir five minutes until the reaction is complete.

A second solution of 22.85 g of triethylsilane and 170 ml of anhydrous dichloromethane is prepared. It is placed in an addition funnel and added dropwise to the cooled solution under nitrogen. After all the additions, the reaction mixture was slowly allowed to warm to room temperature overnight, with stirring and under nitrogen.

Prepare 1300 ml of saturated sodium bicarbonate in a 4 L beaker. Cool in an ice bath. The reaction mixture is added slowly with vigorous stirring, stirred at the bath temperature for 30 minutes. The organic layer was removed and the aqueous was washed twice with dichloromethane. The organic layers were dried over magnesium sulfate. Crystallized from ethanol, concentrated in vacuo. The dry weight is 28.8 g. The structure was confirmed by NMR and mass spectrometry (m / e = 278).

-214Krok3.

C 11 H ₁₁ NO ₄ S Mr = 443.61

10.12 g (0.036 mol) of product 2 are dissolved with 200 ml of anhydrous DMSO. Place in a 500 ml round bottom flask equipped with a magnetic stirrer, water condenser, nitrogen inlet and stopper. 1.84 g of lithium sulfide (0.04 moles of Aldrich 21,324-1) are added. Place the flask in an oil bath and heat to 75 ° C under nitrogen overnight, then cool to room temperature.

Weigh 10.59 g of dibutyl mesylate (0.040 mol). Dissolve in anhydrous DMSO and add to the reaction mixture. The reaction was purged vigorously with nitrogen and heated to 80 ° C overnight.

Cool to room temperature. Prepare 500 ml of 5% acetic acid in a beaker 21. While stirring, slowly add the reaction mixture. Stir for 30 minutes, extract three times with ether. The combined ether fractions were extracted with water and saturated NaCl solution. The organic fraction was dried over magnesium sulfate, filtered and concentrated to dryness on a rotary evaporator. The pure product is obtained by purification by column chromatography using 95% hexane and 5% ethyl acetate as the mobile phase. Dry weight 7.8 g. Obtained NMR mass spectrum (m / z = 444).

Step 4

215-

Ο ,, Η ,, ΝΟ, ε Mr = 475.61

9.33 g (0.021 mol) of product 3 is dissolved in 120 ml of anhydrous dichloromethane. Place in a 250 ml round bottom flask equipped with a magnetic stirrer, water condenser, nitrogen inlet and stopper. The solution was cooled in an ice bath and purged with nitrogen. Slowly add 11.54 g of 3-chlorobenzoic acid (0.0435 mol, Fluka 25800, ~ 65%). After the addition, the reaction mixture was allowed to warm to room temperature and TLC was performed. The sulfoxide intermediate is rapidly formed in the reaction mixture, but the conversion to sulfone takes 8 hours. The solution was frozen in the freezer overnight. Solids were filtered from the reaction mixture and the filtrate was extracted with 10% potassium carbonate. The aqueous phase is extracted twice with dichloromethane. The combined organic fractions were dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. Crystallization from methanol yields pure product, column chromatography may also be used. NMR and mass spectrum (m / z = 476) are obtained.

Step 5.

C 11 H 11 NO ₄ S Mr = 473.68

The reaction was carried out in a 300 ml stirred Parr mini reactor of stainless steel. 9.68 g (00204 mol) of product 4 are placed therein, 160 ml of ethanol are added. For safety reasons, the other two substances are added under a nitrogen atmosphere in a glove bag. In this medium, 15.3 ml of formaldehyde (0.204 mol, Aldrich 25, 54-9, about 37 wt% in water) and 1.45 g of 10% Pd / C (Aldrich 20,569-9) are added. Before removing the glove bag, seal the reactor and flush it three times with hydrogen. In a hydrogen atmosphere, heat the reaction mixture to 55 ° C. The reaction conditions are 14 psi of hydrogen pressure, 55 ° C, and a stirring speed of 250 rpm. Under these conditions, leave the reaction overnight.

Then cool the reactor, remove hydrogen and sparge with nitrogen, evaluate the reaction by TLC. The reaction mixture is a mixture of the desired product and the intermediate. The reaction mixture was filtered through celite and washed well with ether, evaporated in a vacuum evaporator and redissolved in ether. Extract with water. The organic layer was dried over magnesium sulfate, filtered and dried to a rotary evaporator.

Refill the reactor with the same amount of material, seal the reactor and leave under the same conditions overnight. After the second run, all the material is converted to the desired product. Then cool the reactor, remove the hydrogen and sparge with nitrogen. The reaction mixture was filtered through celite and washed well with ether, evaporated in a vacuum evaporator and redissolved in ether. Extract with water. The organic layer was dried over magnesium sulfate, filtered and dried to a rotary evaporator. NMR and mass spectrum (m / z = 474) are obtained.

Step 6.

8.97 g (0.0189 mol) of product 5 is dissolved in 135 ml of anhydrous THF. Place in a 250 ml round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet and stopper.

Cool the solution in an ice / salt bath under a nitrogen atmosphere. 2.55 g of potassium t-butoxide (0.227 mol, Aldrich 15.667-1) are added slowly. After complete addition, stirring was continued while monitoring the reaction mixture by TLC at -10 ° C. When the reaction is complete, it is quenched by the addition of 135 ml of 10% HCl and stirred for 10 minutes. Extract three times with ether, dry the organic layer over magnesium sulfate, filter and concentrate on a rotary evaporator. Crystallize from ether. NMR and mass spectrum (m / z = 474) are obtained.

Step 7.

«ZV

Mr = 459.65

4.67 g (0.01 mol) of product 6 are dissolved in 100 ml of anhydrous chloroform. Place in a 250 ml round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet and stopper. The solution was cooled in a dry ice / acetone bath under a nitrogen atmosphere. 2.84 mL of boron tribromide (0.03 mol, Aldrich 20.220-7) was added slowly via syringe. Stir 15 minutes after addition, allow to warm to room temperature, monitor the reaction by TLC. The reaction is usually complete in 3 hours.

The solution was cooled in an ice bath and quenched with 100 mL of 10% potassium carbonate with rapid stirring. Stir for 10 minutes, then transfer the solution to a separatory funnel and remove the aqueous layer. The organic phase is extracted once with 10% HCl, once with water and once with saturated NaCl solution, dried over magnesium sulphate, filtered and dried on a rotary evaporator. The product is crystallized from ether. NMR and mass spectrum (m / z = 460) are obtained.

-218 Step 8.

C "H, _{f 4} JJO SI Mg70.1,71

Weigh 0.38 g of NaH (9.57 mmol, Aldrich 19, 923-0, 60% dispersion in mineral oil) into a 250 ml round bottom flask equipped with a magnetic stirrer, nitrogen inlet and stopper. The solution was cooled in an ice bath and purged with nitrogen.

4 g (8.7 mmol) of product 7 are dissolved in 60 ml of anhydrous DMF and added to cooled sodium hydride. After stirring for 30 minutes in the cold, 1.33 g of potassium carbonate (9.57 mmol of Fisher P-208) were added.

Dissolve 16.1 g of 1,2-bis- (2-iodoethoxy) ethane (43.5 mmol, Aldrich 33,343-3) in 60 mL of anhydrous DMF. The solution was added to the cooled reaction mixture, warmed to room temperature and then heated to 40 ° C overnight under a nitrogen atmosphere.

The solution was purified by dilution in ether and extraction followed by 5% NaOH, water and saturated NaCl solution. The organic phase is dried over magnesium sulphate, filtered and dried. The pure product is purified by column chromatography using 75% hexane and 25% ethyl acetate as the mobile phase. NMR and mass spectrum (m / z = 702) are obtained.

Step 9.

ε ,, Η. Ν, Ο, ΞΙ _Mr r = 802.90

Dissolve 1 g (1.43 mmol) of product 8 in 10 ml of anhydrous acetonitrile and place in a Fisher-Porter pressure reaction vessel 85.1 g (3 oz) with a magnetic stirrer. 2.9 g of triethylamine (28.6 mmol, Aldrich 23,962-3) dissolved in 10 ml of anhydrous acetonitrile are added. The solution is purged with nitrogen thoroughly before closing the system. The reaction mixture was heated to 45 ° C, monitored by TLC. The reaction is usually complete in 48 hours.

Purification is accomplished by removing acetonitrile in vacuo, redissolving in anhydrous chloroform and precipitating the quaternary ammonium salt with ether. This procedure is repeated several times, then the reaction mixture is concentrated to give a crystalline product. NMR and mass spectrum (m / z = 675) are obtained.

Example 1399:

Step 1. Preparation of substance 1

To a solution of 144 g KOH (2.56 mol) in 1.1 1 DMSO was added 120 g 2-bromobenzyl alcohol (641 mmol) slowly through an addition funnel. Then 182 g of methyl iodide (80 mL, 1282 mmol) was added via an addition funnel. The reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was poured into 1 liter of water and extracted three times with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Purify by silica gel chromatography through a 200 mL column using hexane (100%) as eluent to give 103.2 g (80%) of 1 as a clear colorless liquid. 1 H NMR (CDCl ₃ ) d 3.39 (s, 3H), 4.42 (s, 2H), 7.18-7.27 (m, 2H), 7.12 (d, J = 7.45) Hz, 1 H), 7.50 (s, 1 H).

Step 2. Preparation of the substance 2

To the cooled solution at -78 ° C, 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 reaction mixture was stirred for one hour and then 180 g of zinc iodide (566 mmol) dissolved in 500 ml of THF was added.

-220 minutes, allowed to warm to 5 ° C, cooled to -10 ° C and 6 g of Pd (PPh ₃ ) ₄ (5.2 mmol) and 125 g of 2,5-difluoro-benzoyl chloride (708 mmol) were added. The mixture was stirred at room temperature for 18 hours and then cooled to 10 ° C, quenched with water, partitioned between ethyl acetate and water, and the organic layer was washed with 1M HCl and 1M NaOH. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Purify by silica gel chromatography (Waters Prep-500) using 5% ethyl acetate / hexane as eluent to give 53.6 g (43%) of 2 as an orange oil. ^J 1 HNMR (CDCl ₃₎ d 3.40 (s, 3H), 4.51 (s, 2H), 7.12-7.26 (m, 3H), 7.47 (ζ J = 7.50, 1H), 7.57 (d, J = 7.45, 1H), 7.73 (d, J = 7.454, 1H), 7.8 (s, 1H).

Step 3. Preparation of the substance 3

A solution of 53 g (202.3 mmol) of 2 and 11.2 g of lithium sulfide (242.8 mmol) in 250 mL of DMF was heated at 100 ° C for 18 hours. The reaction mixture was cooled to 0 ° C and 60.7 g of X '(cyclic sulfate of Example 1397) (242.8 mmol) in 50 mL of DMF was added. The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. To the organic residue was added 1 liter of water and extracted twice with diethyl ether. The aqueous layer was acidified to pH 1 and refluxed for two days. It is then cooled to room temperature and extracted with dichloromethane, the organic phase is dried over magnesium sulphate and concentrated in vacuo. Purify by silica gel chromatography (Waters Prep-500) using 10% ethyl acetate / hexane as eluent to give 42.9 g (48%) of 3 as a yellow oil. 1 H NMR (CDCl ₃ ) d 0.86 (t, J = 7.25 Hz, 6H), 1.10-1.26 (m, 12H), 2.83 (s, 2H), 3.32 ( s, 2H), 3.40 (s, 3H), 4.48 (s, 3H), 7.02 (dd, J = 8.26 Hz and 2.82 Hz, 1H), 7.16 (dt, J = 8.19 Hz and 2.82 Hz, 1H), 7.45 (t, J = 7.65 Hz, 1H), 7.56-7.61 (m, 2H), 7.69 (d, J = 7.85 Hz, 1H), 7.74 (s, 1H).

-221

Step 3. Preparation of the substance 3

To a cooled solution (-40 ° C) of 42.9 g (96.2 mmol) of 3 in 200 mL of dichloromethane was added 21.6 g of trifluoromethanesulfonic acid (12.8 mL, 144 mmol) then 22.4 g of triethylsilane ( 30.7 mL, 192.4 mmol). The reaction mixture was stirred at -20 ° C for 2 hours, quenched with water and warmed to room temperature. The reaction mixture was partitioned between dichloromethane and water, the organic layer was dried over magnesium sulfate and concentrated in vacuo. Purify by silica gel chromatography (Waters Prep-500) using 10% ethyl acetate / hexane as eluent to give 24.2 g (60%) of 4 as an oil. NMR (CDCl3) d 0.89 (J = 7.05 Hz, 6H), 1.17-1.40 (m, 12H), 1.46 (t, J = 5.84 Hz, 1H), 2 81 (s, 2H), 3.38 (s, 3H), 3.43 (d, J = 5.23 Hz, 2H), 4.16 (s, 2H), 4.42 (s, 2H) 6.80 (d, J = 9.67 Hz, 1H), 6.90 (t, J = 8.46 Hz, 1H), 7.09 (t, J = 7.45 Hz, 1H), 7 15-7.21 (m, 2H); 7.25-7.32 (m, 2H); 7.42 (m, 1H).

Step 5. Preparation of the substance 5

To a cooled solution (15-18 ° C) of 24.2 g (55.8 mmol) of 4 in 100 mL of DMSO was added 31.2 g of pyridine SO 3 complex (195 mmol). The reaction mixture was stirred at room temperature for 40 minutes. It is then poured into chilled water and extracted three times with ethyl acetate. Wash the organic layer with 5% HCl (300 mL) and brine (300 mL), then dry over magnesium sulfate and concentrate in vacuo to give 23.1 g (96%) of 5 as a brown oil. ^LH NMR (CDCl₃) d 0.87 (t, J = 7.05 Hz, 6H), 1.01 to 1.32 (m, 8 H), 1.53-1.65 (m, 4H), 2 98 (s, 2H), 3.38 (s, 3H), 4.15 (s, 2H), 4.43 (s, 2H), 6.81 (dd, J = 9.66 Hz and 2), 82 Hz, 1H), 6.91 (J = 8.62 Hz, 1H), 7.07 (d, J = 7.46 Hz, 1H), 7.14 (s, 1H), 7.19 07 (d) J = 7.65 Hz, 1H), 7.26-7.32 (m, 1H), 7.42 (dd, J = 8.66 Hz and 5.64 Hz, 1H), 9.40 (s , 1H).

-222Step 6. Fabric Preparation 6

To a cooled solution (0 ° C) of 23.1 g (53.6 mmol) of 5 in 20 mL of dichloromethane was added 28.6 g of m-chloroperoxybenzoic acid (112.6 mmol). The reaction mixture was stirred at room temperature for 24 hours. Quench the reaction with 100 mL of 10% sodium sulfate, partition between water and dichloromethane. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give 24.5 g (98%) of 6 as a pale yellow oil. ¹ H NMR (CDCl 3) d 0.861.29 (m, 14H), 1.58-1.63 (m, 2H), 1.82-1.91 (m, 2H), 3.13 (s, 2H) 3.39 (s, 3H), 4.44 (s, 2H), 4.50 (s, 2H), 6.93 (d, J = 9.07 Hz, 1H), 7.10-7, 33 (m, 5H), 8.05 (s, 1H), 9.38 (s, 1H).

Step 7. Preparation of the substance 7

To a solution of 24.5 g (52.9 mmol) of 6 in 220 mL of THF in a stainless steel reaction vessel was added 100 mL of 2M dimethylamine solution and 20 mL of pure dimethylamine. The reaction vessel was sealed and heated to 110 ° C for 16 hours. The reaction vessel was then cooled to room temperature and the contents concentrated in vacuo. Purify by silica gel chromatography (Waters Prep-500) using 15% ethyl acetate / hexane as eluent to give 21.8 g (84%) of 7 as a clear colorless oil. 1 H NMR (CDCl 3) d 0.85 (t, J = 7.25 Hz, 6H), 0.93-1.29 (m, 8H), 1.49-1.59 (m, 2H), 1 70-1.80 (m, 2H), 2.98 (s, 8H), 3.37 (s, 3H), 4.41 (s, 2H), 4.44 (s, 2H), 6, 42 (s, 1H), 6.58 (dd, J = 9.0 Hz and 2.61 Hz, 1H), 7.13 (d, J = 7.45 Hz, 1H), 7.21 (s, 1H), 7.281, J = 7.85 Hz, 1H), 7.82 (d, J = 9.06 Hz, 1H), 9.36 (s, 1H)

-223Step 8. Preparation of the substance 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 1M potassium t-butoxide solution was added slowly, keeping the temperature below 5 ° C. The reaction mixture was stirred for 30 minutes, then quenched with 50 mL of saturated ammonium chloride solution. The organic layer was partitioned between ethyl acetate and water, the organic layer was dried over magnesium sulfate and concentrated in vacuo. Recrystallization in 10% ethyl acetate / hexane 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 / hexane as eluent to give 3.0 g of 8 as a white solid. MS (FABLi ⁴ ) m / e 494.6 HRMS (EI ⁴ ) calculated for M + H 487.2756, found 487.2746.

Step 9. Preparation of the substance 9

A solution of 2.0 g (4.1 mmol) of 8 in 20 mL of dichloromethane was cooled to -60 ° C, and 4.1 mL of 1 M boron tribromide solution was added. The reaction mixture was stirred at room temperature for 30 minutes. The reaction was cooled to 10 ° C and quenched with 50 mL of water. The oiganic layer was partitioned between dichloromethane and water, dried over magnesium sulfate, and concentrated in vacuo. Recrystallize from 50% ethyl acetate / dichloromethane to give 1.95 g (89%) of 9 as a white solid. MS ⁽ FABLi) ⁴ ) m / e 537 HRMS (FAB) calcd 536.1834, found 536.1822

Step 10. Preparation of the substance 10

-224-

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 room temperature for 18 hours. The reaction was concentrated in vacuo. Recrystallize from methanol / diethyl ether to give 1.9 g (96%) of 10 as a white solid. MS (FAB ⁴ ) m / e 535.5.

Example 1398:

Step 1. Preparation of the substance 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 of 3-nitrobenzeneboronic acid (28.6 mmol), 0.8 g of tetrakis. (triphenylphosphine) palladium (0) (0.7 mmol) and 45 mL of a 2M solution of sodium carbonate in water. The heterogeneous mixture was refluxed for 3 hours, then cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Purify by silica gel chromatography (Waters Prep500) using ethyl acetate / hexane (25/75) as eluent to give 4.8 g (73%) of the title compound as a yellow solid. 1 H NMR (CDCl 3) d 0.88 (t, J = 7.45Hz, 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), 693 (dd, J = 10.5 Hz and 2.4 Hz, 1H), 7, 15 (dt, J = 8.4 and 2.85 Hz, 1H), 7.46-7.59 (m, 2H), 8.05-8.16 (m, 3H), 9.40 (s, 1H).

Step 3. Preparation of the substance 3

-225-

NO 2

A solution of 4.8 g (10.4 mmol) of 2 in 500 mL of THF was cooled to 0 ° C in an ice bath. 20 ml of 1M potassium t-butoxide solution is slowly added to the solution while maintaining a temperature of less than 5 ° C. Stirring is continued for another 30 minutes, then quenched with 100 mL of saturated ammonium chloride solution. The mixture was partitioned between ethyl acetate and water; the organic layer was washed with brine then dried over magnesium sulfate and concentrated in vacuo. Purify by silica gel chromatography through a 100 mL column using dichloromethane as eluent to give 4.3 g (90%) of 3 as a light yellow foam. 1 H NMR (CDCl ₃ ) d 0.93 (t, J = 7.25 Hz, 6H), 1.00-1.55 (m, 8H), 1.59-1.74 (m, 3H), 2.15-2.95 (m, 1H), 3.16 ( _qAB , Jab = 15.0 Hz, AV = 33.2 Hz, 2H), 4.17 (d, J = 6.0 Hz, 1H ), 5.67 (s, 1H), 6.34 (dd, J = 9.6 and 3.0 Hz, 1H), 7.08 (dt, J = 8.5 and 2.9 Hz, 1H) 7.64 (t, J = 8.1 Hz, 1H), 7.81 (d, J = 8.7 Hz, 1H), 8.13 (dd, J = 9.9 and 3.6 Hz), 1H), 8.23-8.30 (m, 1H), 8.44 (s, 1H). MS (FABH ¹ ) m / e (relative intensity) 464.5 (100), 446.6 (65). HRMS calcd for M + H 464.1907, found 464.1905.

Step 4. Preparation of the substance 4

To a cooled solution (0 ° C) of 4.3 g (9.3 mmol) of 3 in 30 mL of THF in a stainless steel reaction vessel was added 8.2 g of dimethylamine (182 mmol). The vial was sealed and heated to 110 ° C for 16 hours. Cool the reaction vessel to room temperature and concentrate the contents in vacuo. Purify by silica gel chromatography (Waters Prep-2000) using a gradient of ethyl acetate / hexane (10-40% ethyl acetate) as eluent to give 4.0 g (88%) of 4 as a yellow solid. 1 H NMR (CDCl 3) d 0.80-2260.95 (m, 6H), 0.96-1.53 (m, 8H), 1.60-1.69 (m, 3H), 2.11- 2.28 (m, 1H), 2.79 (s, 6H), 3.09 (qAB, Jab = 15.0 Hz, AV = 45.6 Hz, 2H), 4.90 (d, J = 9) 0.1 Hz, 1H), 5.65 (s, 1H), 5.75 (d, J = 2.1 Hz, 1H), 6.52 (dd, J = 9.6 and 2.7 Hz, 1H 7.89 (d, J = 9.0 Hz, 1H), 8.20 52 (dd, J = 8.4 and 1.2 Hz, 1H), 8.43 (s, 1H). MS (FABH +) m / e (relative intensity) 489.6 (100), 471.5 (25). HRMS calcd for M + H 489.2423, found 489.2456.

Step 5. Preparation of the substance 5

To a suspension of 1 g (2.1 mmol) of 4 in 100 mL of a stainless steel Parr reactor was added 1 g of 10% palladium on carbon. The vial was sealed, purged twice with hydrogen, then filled with hydrogen at 50 psi and heated to 45 ° C for 6 hours. Cool the reaction vessel to room temperature and filter the contents to remove the catalyst. The filtrate is concentrated in vacuo to give 0.9 g (96 g)

%) Of 5 ^T H NMR (CDCl₃) d 0.80-0.98 (m, 6H), 1.00 to 1.52 (m, 10 H), 1.52 to 169 (m, 1 H), 2 15-2.29 (m, 1H), 2.83 (s, 6H), 3.07 (qAB, Jab = 15.1 Hz, AV = 44.2 Hz, 2H), 3.70 (s, 2H), 4.14 (s, 1H), 5.43 (s, 1H, 6.09 (d, J = 2.4 Hz, 1H), 6.52 (dd, J = 12.2 and 2, 6 Hz, 1H), 6.93 (d, J = 7.50 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.89 (d, J = 8.9 Hz) MS (FABH ⁴ ) m / e (relative intensity) 459.7 (100) HRMS calcd for M + H 459.2681, found 459.2670.

Step 6. Preparation of the substance 6

To a solution of 914 mg (2.0 mmol) of 5 in 50 mL of THF was added 800 mg (4.0 mmol) of 5-bromopentanoyl chloride. 4g (39.6 mmol) of TEA is then added. The reaction mixture was stirred for 10 minutes, partitioned between ethyl acetate and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Purify using silica gel chromatography through a 70 mL MPLC column eluting with a gradient of ethyl acetate (20-50% in hexanes to give 0.9 g 73%) of 6 as a light yellow oil. NMR (CDCl 3) d 0.84-0.95 (m, 6H), 1.02-1.53 (m, 10H), 1.53-1.68 (m, 1H), 1.80-2, Δ (m, 4H), 2.12-2.26 (m, 4H), 2.38 (t, J = 6.9 Hz, 2H), 2.80 (s, 6H), 3.07 ( _qAB) Jab = 15.6 Hz, DV = 40.4 Hz, 2H), 3.43 (t, J = 6.9 Hz, 2H), 4.10 (s,

-2271 °), 5.51 (s, 1H), 5.95 (d, J = 2.4Hz, 1H), 6.51 (dd, J = 9.3 and 2.7Hz, 1H), 7 28 (s, 1H), 7.327.41 (m, 2H), 7.78 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 9.0 Hz, 1H).

Step 7. Preparation of the substance 7

To a solution of 0.9 g (1.45 mmol) of 6 in 25 mL of acetonitrile was added 18 g (178 mmol) of TEA. The reaction mixture was heated at 55 ° C for 16 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. Purify by reverse phase silica gel chromatography (Waters Delta Prep 3000) using an acetonitrile gradient (20-65% acetonitrile / water) containing 0.05% TFA to give 0.8 g (73%) of 7 as a white foam. 1 H NMR (CDCl 3) d 0.80-0.96 (m, 6H), 0.99-1.54 (m, 19H), 1.59-1.84 (m, 3H), 2.09- 2.24 (m, 1H), 2.45-2.58 (m, 2H), 2.81 (s, 6H), 3.09 07 ( _qAB , Jab = 15.6 Hz, AV = 18.5 Hz, 2H), 3.13-3.31 (m, 8H), 4.16 (s, 1H), 5.44 (s, 1H), 6.08 (d, J = 1.8 Hz, 1H 6.57 (dd, J = 9.3 and 2.7 Hz, 1H), 7.24 (t, J = 8.4 Hz, 1H), 7.34 (t, J = 8.4 Hz) 1H, 7.56 (d, J = 8.4Hz, 1H), 7.74 (s, 1H), 7.88 (d, J = 9.0Hz, 1H), 9.22 (s) , 1H). HRMS calcd 642.4304, observed 642.4343.

Example 1400.

Step 1.

^c 14 ^h 13 ° 2 ^f Mr = 232.25

A 12 liter four-necked round-bottomed flask equipped with a reflux condenser, nitrogen inlet, mechanical stirrer, and an additional funnel is required. Nitrogen is bubbled through the system. A suspension of sodium hydride (126.0 g / 4.988 mol) in toluene (2.5 L) was added and the mixture was cooled to 6 ° C. A solution of 4-fluorophenol (560.5 g / 5.000 mol) in toluene (2.5 L) was added via addition funnel over 0.5 h. The reaction mixture was then heated to reflux (100 ° C) and left for 1 hour. A solution of 3-methoxybenzyl chloride (783.0 g / 5.000 mol) in toluene (750 mL) was then added via addition funnel while maintaining reflux. After 15 hours at reflux, the reaction mixture was cooled to room temperature and poured into water (2.5 L). After stirring for 20 minutes, the layers were separated and the organic layer was extracted with a solution of potassium hydroxide (720 g) in methanol (2.5 L). A methanol layer was added to a 20% aqueous potassium hydroxide solution and the reaction mixture was stirred for 30 minutes. The mixture was then washed 5 times with toluene. Toluene fractions were combined and extracted with 20% aqueous KOH. All 20% KOH solutions were combined and acidified with concentrated HCl. The acidic solution was extracted three times with ethyl ether, dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by tubular bead distillation to give a clear colorless oil (449.0 g / 39% yield), mp 120-130 ° C / 50 psi Hg. 1 H NMR and MS ((M + H) ⁺ = 233) confirm the expected structure.

Step 2.

A 12 liter three-necked round-bottomed flask equipped with nitrogen inlet and mechanical stirrer is required. Nitrogen is bubbled through the system. 4-Fluoro-2- (3-methoxybenzyl) -phenol (455.5 g / 1.961 mol) and dimethylformamide were added. The solution was cooled to 6 ° C and sodium hydride (55.5 g / 2.197 mol) was added slowly. After warming to room temperature, dimethylthiocarbamoyl chloride (242.4 g / 1.961 mol) was added. After 15 h, the reaction mixture was poured into water (4 L) and extracted twice with ethyl ether. The combined organic phases are washed with water and saturated NaCl solution, dried over magnesium sulphate, filtered and

Concentrate in vacuo to give the product (605.3 g, 97% yield). 1 H NMR and MS ((M + H) ⁺ = 320) confirm the expected structure.

Step 3

A 12 liter round-bottomed vessel equipped with a reflux condenser, nitrogen inlet and mechanical stirrer is required. Nitrogen is bubbled through the system. 4-Fluoro-2- (3-methoxybenzyl) -phenyldimethylthiocarbamate (605.3 g / 1.895 mol) and phenylether (2.0 kg) were added and the solution was heated to reflux for 2 hours. The reaction mixture was stirred at room temperature for 64 hours. After cooling to room temperature, methanol (2.0 L) and THF (2.0 L) were added and the solution was stirred for 15 hours, and potassium hydroxide (425.9 g / 7.590 mol) was added. After cooling to room temperature, the mixture was concentrated on a rotary evaporator, the residue was dissolved in ethyl ether (1.0 L) and extracted with water, the aqueous extracts were acidified with concentrated hydrochloric acid and extracted with ethyl ether. the ether extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give amber oil (463.0 g, 98% yield). ^H NMR confirmed the desired structure.

Step 4.

230-

^C 25 ^H 35 ° 2 ^FS MpMIiUI

A 5 liter 3-neck round bottom flask equipped with a nitrogen inlet and mechanical stirrer is required. Nitrogen is bubbled through the system. 4-Fluoro-2- (3-methoxybenzyl) -thiophenol (100.0 g / 403.2 mmol) and 2-methoxyethyl ether (1.01) were added and the solution was cooled to 0 ° C. Sodium hydride (9.68 g / 383.2 mmol) was added slowly and the mixture was allowed to warm to room temperature. 2,2-Dibutylpropylene sulfate (110.89 g / 443.6 mmol) was added and the mixture was stirred for 64 hours. The reaction mixture is concentrated on a rotary evaporator and the residue is dissolved in water. The aqueous solution was washed with ethyl ether and concentrated sulfuric acid was added. The aqueous solution was then refluxed for 30 minutes, cooled to room temperature and extracted with ethyl ether. The ether solution was dried over magnesium sulfate, filtered, and concentrated in vacuo to give an amber oil (143.94 g / 85% yield). 1 H NMR and MS ((M + H) ⁺ = 419) confirm the expected structure

Step 5.

A 4-neck, 2-liter round-bottom flask equipped with nitrogen inlet and mechanical stirrer is required. Nitrogen is bubbled through the system. Add the corresponding

-231 alcohol (143.94 g / 343.8 mmol) and dichloromethane (1.0 L) and the solution was cooled to 0 ° C. Pyridinium chlorochromate (140.53 g / 651.6 mmol) was added. After 6 hours, additional dichloromethane was added. After 20 minutes, the reaction mixture was filtered through silica gel and washed with dichloromethane. The filtrate was concentrated in vacuo to give a dark yellow-red oil (110.6 g, 77% yield). 1 H NMR and MS ((M + H) ⁺ = 417) confirm the expected structure.

Step 6.

A 4-neck, 2-liter round-bottom flask equipped with nitrogen inlet and mechanical stirrer is required. Nitrogen is bubbled through the system. The corresponding sulfide (110.6 g / 265.5 mmol) and dichloromethane (1.0 L) were added. The solution was cooled to 0 ° C and then 3-chloroperbenzoic acid (158.21 g / 531.7 mmol) was added portionwise. After 30 minutes the reaction mixture was allowed to warm to room temperature, after 3.5 hours the reaction mixture was cooled to 0 ° C and filtered through a fine frit. The filtrate was washed with 10% aqueous potassium carbonate solution. An emulsion is formed which is extracted with ethyl ether. Combine the organic layers, dry over magnesium sulfate, filter, and concentrate in vacuo to give the product (93.2 g, 78% yield). 'H NMR confirms the expected structure.

-232Krok7

^c 25 ^H 33 ° 4 ^rs: Mr = 448.59

A 2-liter, 4-necked round-bottomed flask is required, equipped with a nitrogen inlet, an additional powder funnel and a mechanical stirrer. Nitrogen is bubbled through the system. The corresponding aldehyde (93.2 g / 208 mmol) and THF (1.01) were added and the mixture was cooled to 0 ° C. Add potassium t-butoxide (23.35 g / 208.1 mmol) via an addition funnel. After 1 hour, the mixture was extracted three times with ethyl ether, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by recrystallization from 80/20 hexane / ethyl acetate to give a white solid (33.60 g / combined yield: 71%). 1 H NMR confirms the expected structure.

Step 8.

A Fisher-Porter vessel equipped with nitrogen inlet and magnetic stirrer was bubbled through nitrogen. The corresponding fluorine compound (28.1 g / 62.6 mmol) was added and the vial was sealed and cooled to -78 ° C. Dimethylamine (17.1 g / 379 mmol) was condensed in a carbon dioxide / acetone bath and added to the reaction vessel. The reaction mixture was allowed to warm to room temperature and then warmed to 60 ° C. After 20 hours the reaction mixture was left

Cool to room temperature and dissolve the residue in ethyl ether. The ether solution was washed with water, saturated aqueous NaCl, dried over magnesium sulfate, filtered and concentrated in vacuo to give a white solid (28.5 g / 96% yield). 1 H NMR confirms the expected structure.

Step 9.

OH ^C 26 ^H 37 ° 4 ^NS Mr = 459.64

A 250 ml three-necked round-bottomed flask equipped with a nitrogen inlet and mechanical stirrer is needed. Nitrogen is bubbled through the system. The corresponding methoxy compound (6.62 g / 14.0 mmol) and chloroform (150 mL) were added. The reaction mixture was cooled to -78 ° C and boron tribromide (10.50 g / 41.9 mmol) was added. The reaction mixture was allowed to warm to room temperature, after 4 hours the reaction mixture was cooled to 0 ° C and quenched by the addition of 10% potassium carbonate (100 mL). After 10 minutes, the layers were separated and the aqueous layer was extracted twice with ethyl ether. Combine the chloroform and ether extracts and wash with saturated aqueous NaCl, dry over magnesium sulfate, filter and concentrate in vacuo to give the product (6.27 g / 98% yield). ^! 1 H NMR confirms the expected structure.

-234-

To a 250 mL one neck and round bottom flask equipped with a magnetic stir bar add 2-diethylaminoethyl chloride hydrochloride (Mr 172.10 g / mol) Aldrich D8, 720-1 (2.4 mmol, 4.12 g), 34 mL anhydrous ether and 34 mL of IM KOH (aqueous solution). The reaction mixture was stirred for 15 minutes and then the ether phase was separated and dried over anhydrous potassium carbonate.

Sodium hydride (60% dispersion in mineral oil, 100 mg, 2.6 mmol) and 34 mL of DMF were added to a second 250 mL round bottom flask with a magnetic stirrer and cooled in an ice bath. Then the phenol product (previous step) 1.1 g (2.4 mmol in 5 ml DMF) and the ether solution prepared above were added. The reaction mixture was heated at 40 ° C for 3 days. TLC-free product was dissolved in ether and extracted once with 5% NaOH, then with water and brine. The ether layer was dried over magnesium sulfate and the ether was evaporated on a rotary evaporator. The crude product (1.3 mg) can be further purified by chromatography (SiO ₂ 99% ethyl acetate / 1% NH 4 OH at 5 mL / minute). 0.78 g ^. 1 H NMR and MS confirm the expected structure.

-235Krokll

The product of Step 10 (0.57 g, 1.02 mmol, Mr 558.83 g / mol) and 1.6 g of iodoethane (10.02 mmol) are added to 5 mL of acetonitrile in a Fisher-Porter vial and heated to temperature 45 ° C for 3 days. The solution is evaporated to dryness and redissolved in 5 ml of chloroform. Ether was then added to the chloroform solution and the resulting mixture was cooled. The desired product is obtained by precipitation of 0.7272 g. MS M-1 = 587.9, 1 H NMR

Example 1401:

: Step.

c ₁₄ h ₁₃ o ₂ p Mr = 232.25

A 12-liter three-necked round-bottomed flask equipped with nitrogen inlet, addition funnel, reflux condenser and mechanical stirrer is required. Nitrogen is bubbled through the system. A suspension of sodium hydride (126.0 g / 4.988 mol) in toluene (2.5 L) was added and the mixture was cooled to 6 ° C. A solution of 4-fluorophenol (560.5 g / 5.000 mol) in toluene was added via an addition funnel. (2.5 L) for 2.5 hours. The reaction mixture was refluxed at 100 ° C for 1 hour. A solution of 3-methoxybenzyl chloride (783.0 g / 5.000 mol) in toluene (750 mL) was added via addition funnel while maintaining reflux. After 15 hours at reflux, the reaction mixture was allowed to cool to room temperature and poured into water (2.5 L). Mon 20

The phases are separated for -236 minutes, the organic layer is extracted with a solution of potassium hydroxide (720 g) in methanol (2.51). The methanol layer was added to 20% aqueous potassium hydroxide and the mixture was stirred for 30 minutes. The mixture was then washed five times with toluene and the toluene extract was washed with 20% aqueous KOH. All 20% KOH solutions were combined and acidified with concentrated HCl. The acidic solution was extracted three times with ether, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by bead tube distillation to give pure colorless oil (449.0 g / 39% yield), mp 120-130 ° C / 50 psi Hg. 1 H NMR and MS ((M + H) ⁺ = 233) confirm the expected structure.

Step 2.

^C 17 ^H 18 ^NO 2 ^FS Mr = 319.39

A 12 liter three-necked round-bottomed flask equipped with nitrogen inlet and mechanical stirrer is required. Nitrogen is bubbled through the system. 4-Fluoro-2- (3-methoxybenzyl) -phenol (455.5 g / 1.961 mol) and dimethylformamide were added. The solution was cooled to 6 ° C and sodium hydride (55.5 g / 2.197 mol) was added slowly. After warming to room temperature, dimethylthiocarbamoyl chloride (242.4 g / 1.961 mol) was added. After 15 h, the reaction mixture was poured into water (4.0 L) and extracted twice with ethyl ether. The combined organic phases were washed with water and saturated NaCl solution, the phases were dried over magnesium sulfate, filtered and concentrated in vacuo to give the product (605.3 g, 97% yield). 1 H NMR and MS ((M + H) ⁺ = 320) confirm the expected structure.

-237Step 3.

ΟΜβ

C14H13OFS Mr = 248.32

A 12 liter round-bottomed vessel equipped with nitrogen inlet, reflux condenser and mechanical stirrer is required. Nitrogen is bubbled through the system. 4-Fluoro-2- (3-methoxybenzyl) -phenyldimethylthiocarbamate (605.3 g / 1.895 mol) and phenylether (2.0 kg) were added and the solution was refluxed for 2 hours. The reaction mixture was then stirred at room temperature for 64 hours and then refluxed for 2 hours. After cooling to room temperature, methanol (2.01) and THF (2.01) were added and the reaction mixture was stirred for 15 hours. KOH (425.9 g / 7.590 mol) was added and the reaction mixture was refluxed for 4 hours. After cooling to room temperature, the reaction mixture was concentrated on a rotary evaporator and the residue was redissolved in ethyl ether (1.01) and extracted with water. The aqueous extracts were combined and acidified with concentrated HCl then extracted with ethyl ether. The ether extract was dried over magnesium sulfate and concentrated in vacuo to give an amber oil (463.0 g, 98% yield). ¹ H NMR confirms the expected structure.

Step 4.

F ^C 25 ^H 35 ° ^FS 2

Mr = 418.61

A 5-liter, 5-liter round-bottom flask equipped with nitrogen inlet, reflux condenser and mechanical stirrer is required. Nitrogen is bubbled through the system. 4-Fluoro-2- (3-methoxybenzyl) thiophenol (100.0 g / 403.2 mmol) and 2-methoxyethyl ether (1.01) were added and the solution was cooled to 0 ° C. Sodium hydride (9.68 g / 383.2 mmol) was added slowly and the reaction was allowed to warm to room temperature, then 2,2-dibutylpropylene sulfate (110.89 g / 443 mmol) was added and the reaction stirred for 64 hours. The reaction mixture is concentrated on a rotary evaporator and the residue is dissolved in water. The aqueous solution was washed with ethyl ether and concentrated sulfuric acid was added. The aqueous solution was then refluxed for 30 minutes, cooled to room temperature and extracted with ethyl ether. The ether solution was dried over magnesium sulfate, filtered and concentrated in vacuo to give an amber yellow oil (143.94 g / 85% yield). 1 H NMR and MS ((M + H) ⁺ = 419) confirm the expected structure.

Step 5.

OMe

A four-necked 2-liter round-bottom flask equipped with a mechanical stirrer inlet of nitrogen is required. Nitrogen is bubbled through the system. The corresponding alcohol (143.94 g / 343.8 mmol) and dichloromethane (1.01) were added and the solution was cooled to 0 ° C. Pyridinium chlorochromate (140.53 g / 651.6 mmol) was added, after 6 hours dichloromethane was added. After 20 minutes, the reaction mixture was filtered through silica gel and washed with dichloromethane. The filtrate was concentrated in vacuo to give a dark yellow-red oil (110.6 g, 77% yield). 1 H NMR and MS ((M + H) ⁺ = 417) confirm the expected structure.

-239Step 6.

A 4-neck, 2-liter round-bottom flask equipped with nitrogen inlet and mechanical stirrer is required. Nitrogen is bubbled through the system. The corresponding sulfide (110.62 g / 265.5 mmol) and dichloromethane (1.01) were added. The solution was cooled to 0 ° C and 3-chloroperbenzoic acid (158.21 g / 531.7 mmol) was added portionwise. After 30 minutes the reaction mixture was allowed to warm to room temperature and after 3.5 hours the reaction mixture was cooled to 0 ° C and filtered through a fine frit. The filtrate was washed with 10% aqueous potassium carbonate solution. An emulsion is formed which is extracted with ethyl ether. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to give the product (93.2 g, 78% yield). 1 H NMR confirms the expected structure.

Step 7.

R 59

A 2-liter, 4-necked round-bottomed flask is required, equipped with a nitrogen inlet, an additional powder funnel and a mechanical stirrer. Nitrogen is bubbled through the system. The corresponding aldehyde (93.2 g / 208 mmol) and THF (1.01) were added and the reaction mixture was cooled to 0 ° C. Add potassium t-butoxide (23.35 g / 208.1 mmol) via an addition funnel. After 1 hour, a 10% aqueous HCl solution (1.0 L) was added and after an additional hour the reaction was added

The mixture was extracted three times with ethyl ether, dried over magnesium sulphate and concentrated in vacuo. The crude product was purified by recrystallization from 80/20 hexane / ethyl acetate to give a white solid (32.18 g). The mother liquor was concentrated in vacuo and recrystallized from 95/5 toluene / ethyl acetate to give a white solid (33.60 g, combined 71% yield). 1 H NMR confirms the expected structure.

Step 8.

^c 27 ^H 39 ° 4 ^NS M = 473.67

Fill the Fisher-Porter vessel equipped with nitrogen inlet and magnetic stirrer. Add the corresponding fluorine compound (28.1 g / 62.6 mmol), seal the vial and cool to -78 ° C. Dimethylamine (17.1 g / 379 mmol) was condensed in a carbon dioxide / acetone bath and added to the reaction vessel. The reaction mixture was allowed to warm to room temperature and heated to 60 ° C. After 20 hours, the reaction mixture was allowed to cool to room temperature and dissolved in ethyl ether. The ether solution was washed with water and saturated aqueous sodium load dried over magnesium sulfate, filtered and concentrated in vacuo to give a white solid (28.5 g / 96% yield. ^H NMR confirmed the desired structure.

-241Krok9.

A 250 ml round bottom flask equipped with a nitrogen inlet and mechanical stirrer is required. Nitrogen is bubbled through the system. The corresponding methoxy compound (6.62 g / 14.0 mmol) and chloroform (150 mL) were added and the reaction mixture was cooled to -78 ° C, and boron tribromide (10.50 g / 41.9 mmol) was added. The reaction mixture was allowed to cool to room temperature, cooled to 0 ° C after 4 hours and quenched with 10% potassium carbonate (100 mL). After 10 minutes, the layers were separated and the aqueous phase was extracted twice with ethyl ether. The chloroform and ether extracts were combined and washed with saturated NaCl solution, dried over magnesium sulfate and concentrated in vacuo to give the product (6.27 g / 98% yield. 1 H NMR confirmed the expected structure).

Step 10.

To a 250 mL one neck and round bottom flask equipped with a magnetic stir bar add 2-diethylaminoethyl chloride hydrochloride (Mr 172.10 g / mol) Aldrich D8, 720-1 (2.4 mmol, 4.12 g), 34 mL anhydrous ether and 34 ml of IM KOH (aqueous solution)

The mixture was stirred for 15 minutes and then the ether phase was separated and dried over anhydrous potassium carbonate.

Sodium hydride (60% dispersion in mineral oil, 100 mg, 2.6 mmol) and 34 mL of DMF were added to a second 250 mL round bottom flask with a magnetic stirrer and cooled in an ice bath. Then the phenol product (previous step) 1.1 g (2.4 mmol in 5 ml DMF) and the ether solution prepared above were added. The reaction mixture was heated at 40 ° C for 3 days. TLC-free product was dissolved in ether and extracted once with 5% NaOH, then with water and brine. The ether layer was dried over magnesium sulfate and the ether was evaporated on a rotary evaporator. The crude product (1.3 g) can be further purified by chromatography (SiO ₂ 99% ethyl acetate / 1% NH 4 OH at 5 mL / minute). 0.78 g. 1 H NMR and MS confirm the expected structure

Step 11.

Step 10 product (0.57 g, 1.02 mmol Mr 558.83 g / mol) and 1.6 g iodoethane (10.02 mmol) are added to 5 mL acetonitrile in a Fisher-Porter vial and heated to 45 ° C for 3 days. The solution was evaporated to dryness and redissolved in 5 mL of chloroform. Ether was then added to the chloroform solution and the resulting mixture was cooled. The desired product is obtained by precipitation of 0.7272 g. MS M-I = 587.9, HNMR.

Biological tests

The utility of the compounds of the invention is shown in the following tests. These assays are performed in vitro and in animal models mainly employing procedures designed to demonstrate the utility of the compounds of the invention.

-243In vitro assay of compounds that inhibit IBAT-mediated absorption of ( ¹⁴ C) taurocholate

H14 cells

Young hamster kidney cells transfected with human IBAT cDNAs (H1 4 cells) were plated at 60,000 cells per dish in 96-well Top-Count tissue culture plates for a 24 hour assay, 30,000 cells per 48 hour assay plate, and 10,000 cells per plate for 72 hours.

On the day of the assay, the cell monolayer is gently washed once with 100 ml assay buffer (Dulbecco's Modified Eagle's medium with 4.5 g per liter glucose + 0.2% (w / v) free fatty acids in bovine serum albumin (FAF) BSA) . To each dish was added 50 mL of twice more concentrated test compound in assay buffer and 50 mL of 6 mM ( ¹⁴ ° C) taurocholate in assay buffer (final concentration of ( ¹⁴ ° C) taurocholate is 3 mM). The cell cultures are incubated for two hours at 37 ° C, then each dish is gently washed twice with 100 ml of Dulbeccco's phosphate-buffered saline (PBS) cooled to 4 ° C containing 0% (w / v) (FAF). BSA. The plates are then gently washed once with 100 ml of PBS at 4 ° C without (FAF) BSA. Add 200 milliliters of liquid scintillation medium to each dish, heat and stir for 30 minutes, then measure the amount of radioactivity in each dish using a Packard Top-Count.

In vitro assay of compounds that inhibit ( ¹⁴ C) -alanine absorption

The alanine absorption test is performed in the same manner as the taurocholate test, except that the labeled taurocholate replaces the labeled alanine.

In vivo test of compounds that inhibit the ileal absorption of ( ¹⁴ C) -taurocholate in the bile in rats (see "Meatabolism of 3α, 7β-dihydroxy-7α-methyl-5β-cholanoic acid and 3α, 7βdihydroxy-7α-methyl-5β-cholanoic") acid in hamsters ”in Biochimica et Biophysica Acta 833 (1985) 196-202 by Une et al.)

Male wistar rats (200-300 g) are anesthetized with inactin @ 100 mg / kg. A 10 'cannula PE10 is inserted into the bile ducts. The small intestine is exposed and placed on a gauze pad. The cannula (1/8 "luer cap, conical outer adapter) is inserted 12 cm from the junction of the small intestine to the caecum. The incision is made 4 cm from the same joint (8 cm intestine is used). The intestinal segment is rinsed with 20 mL of warm Dulbecco's phosphate buffered saline (PBS), pH 6.5. A 20 cm long silicone tube (0.02 "I.D. x 0.037" O.D.) is inserted into the distal opening. The proximal cannula was

Connect to the peristaltic pump and intestine is washed for 20 minutes with warm PBS at a flow rate of 0.25 ml / min. The intestinal segment temperature is continuously monitored. At the start of the experiment, 2.0 ml of control ( ¹⁴ C) taurocholate @ 0.05 ml / ml with 5 mM cold taurocholate) was dosed into the intestinal segment with a 3 ml syringe and bile samples were started. The control is infused at a rate of 0.25 ml / min for 21 minutes. Bile samples are taken every three minutes during the first 27 minutes of the procedure. After 21 minutes of sample infusion, the ileal loop is washed with 20 ml warm PBS (using a 30 ml syringe), then the loop is washed for 21 minutes with warm PBS at a flow rate of 0.25 ml / min. The second perfusion is performed as above, but this time with the test compound administered together (21 minutes of administration followed by a 21 minute wash), and bile samples are taken every 3 minutes for the first 27 minutes. If necessary, a third perfusion is performed in the same manner, which usually contains a control sample.

Measurement of hepatic cholesterol (hepatic chol)

The liver tissue is weighed and homogenized in chloroform: methanol (2: 1). After homogenization and centrifugation, the supernatant is separated and evaporated under a stream of nitrogen. The residue is dissolved in isopropanol and the cholesterol content is determined enzymatically using a combination of cholesterol oxidase and peroxidase, see Allain, C.A., et al. (1974) Clin. Chem. 20,470.

Measurement of hepatic HMG Co-A reductase activity (HMG CO A)

Homogenization of liver samples in phosphate / sucrose buffer followed by centrifugation yields liver microsomes. The final sediment is suspended in buffer and the measured portion is assayed for HMG Co-A reductase activity by incubation for 60 minutes at 37 ° C in the presence of ¹⁴ C-HMG Co-A reductase-CoA (Dupont-NEN). The reaction is terminated by the addition of 6N HCl followed by centrifugation. The measured portion of the supernatant is separated by TLC and the spot corresponding to the product is scraped off the plate, extracted and the radioactivity measured on a scintillator. (See Akerlund, J. and Bjorkhem, I. (1990) J. Lipid Res. 31, 2159)

-245Determination of serum cholesterol (serol. · HDL-chol. TGI and VLDL + LDL)

Total serum cholesterol (ser.chol.) Is determined enzymatically using a commercial kit from Wako Fine Chemicals (Richmond, VA); Cholsterol Cll HDL Cholesterol (HDL-chol) is determined by the same kit after precipitation of VLDL and LDL with Sigma Chemical Co HDL Cholesterol Catalog No. 27664909. 352-3 (dextran sulfate method). Total serum triglycerides (pre-quantified) (TGI) are determined enzymatically by Sigma Chemical Co. GPO-Trinder 337-B. VLDL and LDL (VLDL + LDL) concentrations are calculated as the difference between total and HDL cholesterol.

Determination of hepatic cholesterol 7-α-hydroxylase activity

Homogenization of liver samples in phosphate / sucrose buffer followed by centrifugation yields liver microsomes. The final sediment is suspended in buffer and the measured portion is assayed for cholesterol 7-α-hydroxylase activity, incubating for 5 minutes at 37 ° C in the presence of NADPH. The suspension was then extracted with petroleum ether, the organic solvent was evaporated and the residue redissolved in acetonitrile / methanol. The enzymatic product is quantified by separating a measured dose of the extract by reverse phase HPLC with a C 18 column, using a UV detector at 240 nm. See Horton, J. D., et al. (1994) J. Clin. Invest. 93.2084).

Determination of faecal bile acid concentration (FB A)

The faeces of separately reared hamsters were collected every 24 or 48 hours, dried under a stream of nitrogen, crushed to a powder, and weighed. About 0.1 g was weighed and extracted in an organic solvent (butanol / water). The organic phase was removed and dried, the residue was dissolved in methanol, and the amount of bile acids was determined enzymatically using 3α-hydroxysteroid dehydrogenase by reaction with bile acids reducing NAD. (See Madhige, F., et al. (1981) Clin. Chem. 27, 1352).

-246Rabsorbing ( ³ H) taurocholate in rabbit membrane follicle membrane vesicles

Rabbit ileal membrane brush membranes were prepared from frozen ileal mucosa by the calcium precipitation described by Malathi et al. ((1979) Biochimica Biophysica Acta, 554,259). The method for measuring taurocholate was accurately taken from Kramer et al. ((1992) Biochimica Biophysica Acta, 1111,93) except that 200 μΐ of test sample was used instead of 100 μΐ Briefly, at room temperature 190 μΐ of a solution containing 2 μΜ ( ³ H) of taurocholate (0.75 pCi), 20 mM tris, 100 mM NaCl, 100 mM mannitol pH 7.4 incubated for 5 seconds with 10 μΐ of membrane broth membrane vesicles (60-120 µg protein). Incubation was initiated by addition of BBMV by shaking with voitex and quenched by addition of 5 ml ice-cold buffer ( 20 mM Hepes-tris, 150 mM KCl) and immediately followed by filtration through a nylon filter (0.2 µm pores) and further washing with 5 ml stop buffer.

Acyl-CoA: cholesterol acvl transferase (ACAT)

Hamsters and rat intestinal microsomes were prepared from tissues as described above) (1980) J. Biol. Chem. 255, 9098) and used as a source of ACAT enzyme. The assay consisted of incubating 2 ml containing 24 μΜ of Oleoyl-CoA (0.05 pCi) in 50 mM sodium phosphate, 2 mM DTT pH 7.4 buffer containing 25% BSA and 200 µg microsomal protein. The assay was initiated by the addition of Oleoyl-CoA. The reaction was carried out at 37 ° C for 5 minutes and quenched by addition of 8.0 mL of chloroform / methanol (2: 1). 125 μΐ of cholesterol oleate in chloroform / methanol as carrier were added to the extraction, the organic and aqueous phases were separated by centrifugation of the vortex vigorous shaking emulsion. The chloroform phase was dried, loaded onto silica gel 60. A hexane / ethyl ether (9: 1) mixture was used as mobile phase. The amount of cholesterol ester formed was quantified by measuring the amount of radioactivity incorporated into the spot corresponding to cholesterol oleate on a TLC plate using a Packard instaimager.

Data for each compound in the assays described above are summarized in Tables 5,6,7 and 8:

Table 5

compound IC50 μΜ * In vitro% Inhibition of TC Income @ 100 pM # % Alanine Inhibition Intake @ 100 pM # % control TC transport in rat ileum @ 0.1 mM # benzothiazepine 2 0 45.4 +/- 0.7 12 25 3 0 4a 3

-247-

5a 34 5b 40 0 72.9 +/- 5.4 @ 0.5 mM 4b 9 18 6 14b 18 14 13 13 23 15 60 19 0 19b 15 8a 41 Mixtures 8a and 8b 69 Mixtures 9a and 9b 6 6a 5 6b 85 9a 5 0% (three) 25 mM 53.7 +/- 3.9 Mixtures 6a and 20 13 Mixtures 6d and 10a 0.8 14% @ 25 mM 21 37 21c 52 21b 45 6c 2 58.5 68.8 +/- 5.7 at 0.4 mM 6d 0.6 77.7 16.1 +/- 1.1 @ 0.5 mM 30.2 +/- 0.9 @ 0.15 mM 17 10 7 50 49.3 10a 7 77.6 62.4 = 0.9 0.9 @ 0.2 mM 10b 15 68.6 25 0.1 4% @ 10mM 26.0 +/- 3.3 26 2 31% @ 25 mM 87.9 +/- 1.5 27 5 7% (5) 20 mM 28 8 31% (3) 20 mM 29 88 (3) 50 mM 30 96 (3) 50 mM 31 41 (5) 50 mM 37 3 0% (S) 5 mM 38 0.3 11% @ 5 mM 20.6 +/- 5.7 40 49 (3) 50 mM 41 2 0% (5) 20 mM 42 1.5 43 1.5 16% @ 25 mM 48 2 22% @ 20mM 49 0.15 21% @ 200 mM 21.2 +/- 2.7 57 51 (5) 50 mM 58 20 (5) 50 mM 59 70 60 9 59 61 30 175

-248-

62 10 63 90 @ 6mM 64 100 @ 6 mM

* Absorption of taurocholate by cells in vitro # Unless otherwise stated = Comparative example is example no. 1 of WO 93/16055

Table 6

compound TC-uptake TC-uptake TC-uptake ACAT ACAT (H1 4 cells) Ileál loop (BBMV) (Liver) intestine IC (50) IC (50) IC (50) IC (50) IC (50) compound example 1 mM 74 mM 3 mM 20 mM 20 mM 6d 0.6 mM 31 mM 1.5 mM 25 mM 20 mM 38 0.3 mM 12 mM 2 mM 20 mM N.D. 49 0.1 mM 12 mM N.D. 6 mM N.D. 25 0.1 mM 20 mM 0.8 mM 8 mM 8 mM

Comparative example is example no. 1 of WO 93/16055

Table 7

The activity of compound no. 25 in hamsters fed with cholesterol-containing feed parameter inspection 4% cholestyramine 0.2% of compound no. 25 Weight (g) (mean +/- SEM, * p <0.05, A-Student test, B-Dunette test denli 117 (2) 114 (6) 117 (5) Day 14 127 (2) 127 (2) 132 (3) Liver weight 5.4 (0.3) 4.9 (0.4) 5.8 (0.2) Serum cholesterol (mg%) 143 (6) 119 (4) * A, B 126 (2) A, B HDL-Cholesterol (mg%) 89 (4) 76 (3) A, B 76 (1) A, B VLDL + LDL 54 (7) 42 (3) A, B 50 (3) TGI (mg%) 203 (33) 190 (15) 175 (12) Hepatic cholesterol (Mg / g) 2.5 (0.3) l, 9 (0, L) * A, B l, 9 (0, L) * A, B

-249-

HMG COA (pm / mg / min) 15.6 (7.6) 448.8 (21.6) * Α, Β 312.9 (37.5) * Α, Β 7a-0Hase (pm / mg / min) Fecal weight per 24 hours (g) FBA (mM / 24 hr / 100g) 235.3 (25.1) 2.3 (0.1) 6.2 (0.8) 357.2 (28.3) * Α, Β 2.7 (0.1) * Α, Β 12.3 (1.5) * Α, Β 291.0 (6.0) * A 2.4 (0.04) 11.9 (0.5) * Α, Β

Table 8

The activity of compound no. 25 in a rat model with an Alzet mini pump parameter checks and 20 mpl of compound no. 25 per day Weight (g) (mean +/- SEM, * p <0.05, A-Student test, B- Dunett test denli 307 (3) 307 (2) Day 8 330 (3) 310 (4) * Α, Β Liver weight 15.5 (0.6) 14.6 (0.4) Serum cholesterol (mg%) 85 (3) 84 (3) Hepatic cholesterol (mg / g) 21 (0.03) 2.0 (0.03) HMG COA (pm / mg / min) 75.1 (6.4) 318.0 (40.7) * Α, Β 7a-OHase (pm / mg / min) Weight 281.9 (13.9) 535.2 (35.7) * A, B feces in 24 hours (g) 5.8 (0.1) 5.7 (0.4) FBA (mM / 24 hrs / 100g) 17.9 (0.9) 39.1 (4.5) * Α, Β

Furthermore, taurocholate uptake assays were performed as shown in Table 9.

Table 9

Bioassay data of some compounds of the invention

Compound No. Human TC IC50 (pM) Alanine intake Percentage of inhibition @ μΜ 101 @ o o i 102 0,083 103 13 @ 0.25 104 0.0056 105 0.6 106 0.8 107 14.0 @ 0.063 108 0.3 109 2.0 @ 0.063 110 0.09

-250-

111 2.5 112 3.0 113 ο, ι 114 0.19 115 8.0 116 0.3 117 12.0 @ 0.625 118 0.4 119 1.3 120 34.0 @ 5.0 121 0,068 122 1.07 123 1.67 124 14.0 @ 6.25 125 18.0 126 18 @ 1.25 127 0.55 128 0.7 129 0,035 131 1.28 132 5.4 @ 0.063 133 16.0 134 0.3 135 22.0 136 0.09 137 2.4 138 3.0 139 > 25.0 142 0.5 143 0.03 262 0,053 263 0.7 264 0.2 266 0.5 267 0,073 268 0,029 269 0.08 270 0.12 271 0.07 272 0.7 273 1.9 274 0.18 275 5.0 @ 0.25 276 0.23 277 0.04 278 3.0 279 0.4 280 0.18 281 0,019

-251-

282 0,021 283 0.35 284 0.08 286 19.0 287 4.0 288 10.0 @ 6.25 289 0.23 290 0,054 291 0.6 292 0,046 293 1.9 294 0,013  295 1.3 296 1.6 1005 0.0004 1006 0,001 1007 0,001 1008 0,001 1009 0,001 1010 0,001 1011 0,001 1012 0.0015 1013 0,002 1014 0,002 1015 0,002 1016 0,002 1017 0,002 1018 0,002 1019 0,002 1020 0,002 1021 0,002 1022 0,002 1023 0,002 1024 0,002 1025 0,002 1026 0,002 1027 0,002 1028 0,002 1029 0,002 1030 0,002 1031 0,002 1032 0,002 1033 0,002 1034 0,002 1035 0,002 1036 0,002 1037 0.0022 1038 0.0025 1039 0.0026

-252-

1040 0,003 1041 0,003 1042 0,003 1043 0,003 1044 0,003 1045 0,003 in 1046 0,003 1047 0,003 1048 0,003 1049 0,003 1050 0,003 in 1051 0,003 1052 0,003 1053 0,003 1054 0,003 1055 0,003 1056 0,003 1,057 0,003 1058 0,003 1059 0,003 1060 0.0036 1061 0,004 1062 0,004 1063 0,004 1064 0,004 1065 0,004 1066 0,004 1067 0,004 1068 0,004 1069 0,004 1070 0,004 1071 0,004 1072 0,004 1073 0,004 1074 0,004 1075 0.0043 1076 0.0045 1077 0.0045 1078 0.0045 1079 0,005 1080 0,005 1081 0,005 1082 0,005 1083 0,005 1084 0,005 1085 0,005 1086 0,005 1087 0,005 1088 0.0055

-253-

1089 0.0057 1090 0,006 1091 0,006 1092 0,006 1093 0,006 1094 0,006 1095 0,006 1096 0,006 1097 0,006 1098 0,006 1099 0.0063 1100 0.0068 1101 0,007 1102 0,007 1103 0,007 1104 0,007 1105 0,007 1106 0.0073 1107 0.0075 1108 0.0075 1109 0,008 1110 0,008 1111 0,008 1112 0,008 1113 0,009 1114 0,009 1115 0.0098 1116 0.0093 1117 0.01 1118 0.01 1119 0.01 1120 0.01 1121 0.01 1122 0,011 1123 0,011 1124 0,011 1125 0,012 1126 0,013 1127 0,013 1128 0,017 1129 0,018 1130 0,018 1131 0.02 1132 0.02 1133 0.02 1134 0.02 1135 0,021 1136 0,021 1137 0,021

-254-

1138 0,022 1139 0,022 1140 0,023 1141 0,023 1142 0,024 1143 0,027 1144 0,028 1145 0,029 1146 0,029 1147 0,029 1148 0.03 1149 0.03 1150 0.03 1151 0,031 1152 0,036 1153 0,037 1154 0,037 1155 0,039 1156 0,039 1157 0.04 1158 0.06 1159 0.06 1160 0,062 1161 0,063 1162 0,063 1163 0.09 1164 0,093 1165 ο, ιι 1166 ο, ιι 1167 0.12 1168 0.12 1169 0.12 1170 0.13 1171 0.14 1172 0.14 1173 0.15 1174 0.15 1175 0.17 1176 0.18 1177 0.18 1178 0.19 1179 0.19 1180 0.2 1181 0.22 1182 0.25 1183 0.28 1184 0.28 1185 0.28 1186 0.3

-255-

1187 0.32 1188 0.35 1189 0.35 1190 0.55 1191 0.65 1192 ι, ο 1193 ι, ο 1194 1.6 1195 1.7 1196 2.0 1197 2.2 1198 2.5 1199 4.0 1200 6.1 1201 8.3 1202 40.0 1203 0 @ 0.063 1204 0.05 1205 0,034 1206 0,035 1207 0,068 1208 0,042 1209 0 @ 0.063 1210 0.14 1211 0.28 1212 0.39 1213 1.7 1214 0.75 1215 0.19 1216 0.39 1217 0.32 1218 0.19 1219 0.34 1220 0.2 1221 0,041 1222 0,065 1223 0.28 1224 0.33 1225 0.12 1226 0,046 1227 0.25 1228 0,038 1229 0,049 1230 0,062 1231 0,075 1232 1.2 1233 0.15 1234 0.067 1235 0,045

-256-

1236 0.05 1237 0.07 1238 0.8 1239 0,035 1240 0,016 1241 0,047 1242 0,029 1243 0.63 1244 0,062 1245 0.32 1246 0,018 1247 0,017 '1248 0.33 1249 10.2 1250 0,013 1251 0.62 1252 29 1253 0.3 1254 0.85 1255 0.69 1256 0,011 1257 ο, ι 1258 0.12 1259 16.5 1260 0,012 1261 0,019 1262 0.03 1263 0,079 1264 0.21 1265 0.24 1266 0.2 1267 0.29 1268 0,035 1269 0,024 1270 0,024 1271 0,013 1272 0,047 1273 0,029 1274 0,028 1275 0,024 1276 0,029 1277 0,018 1278 0,017 1279 0,028 1280 0.76 1281 0,055 1282 0.17 1283 0.17 1284 0,011

-257-

1285 0,027 1286 0,068 1287 0,071 1288 0,013 1289 0,026 1290 0,017 1291 0,013 1292 0,025 1293 0,019 1294 0,011 1295 0,014 1296 0,063 1297 0,029 1298 0,018 1299 0,012 1300 1.0 1301 0.15 1302 1.4 1303 0.26 1304 0.25 1305 0.25 1306 1.2 1307 3.1 1308 0.04 1309 0.24 1310 1.16 1311 3.27 1312 5.0 1313 6.1 1314 0.26 1315 1.67 1316 3.9 1317 21.0 1319 11.0 @ 0.25 1321 11.1 @ 5.0 1322 3.0 @ 0.0063 1323 4.0 @ 0.0063 1324 43.0 @ 0.0008 1325 1.0 @ 0.0063 1326 36.0 @ 0.0008 1327 3.0 @ 0.0063 1328 68.0 @ 0.0063 1329 2.0 @ 0.0063 1330 9.0 @ 0.0063 1331 57.0 @ 0.0008 1332 43.0 @ 0.0008 1333 0 @ 0.0063 1334 50.0 @ 0.0008 1335 38.0 @ 0.0008

-258-

1336 45.0 @ 0.0008 1337 0 @ 0.0063 1338 1.0 @ 0.25 1339 b 0 @ 0.0063 1340 9.0 @ 0.0063 1341 1.0 @ 0.0063 1342 1.0 @ 0.0063 1345 13.0 @ 0.25 1347 0.0036 1351 0.44 1352 0.10 1353 0.0015 1354 0,006 1355 0.0015 1356 0.22 1357 0,023 1358 0,008 1359 0,014 1360 0,003 1361 0,004 1362 0,019 1363 0,008 1364 Oh, oo6 1365 0,008 1366 0,015 1367 0,002 1368 0,005 1369 0,005 1370 0,002 1371 0,004 1372 0,004 1373 0,008 1374 0,007 1375 0,002 1449 0,052 1450 0,039 1451 0,014

The examples can be successfully repeated by substituting the generally or specifically described reactants and / or reaction conditions of the invention.

The novel compositions of the invention are further described in the appended Examples A and B. The invention, as described herein, can be practiced in many variations. These variations should not be construed as extending beyond the scope of the invention, each of such modifications and equivalents as will be apparent to those skilled in the art within the scope of the following claims.

Table C2: Alternative compounds # 2 (F101-F 123 families)

Family Cpďà R 1 = R ² R ⁵ (R ^x ) q F 101 Selected from Table D ph Selected from Table D F102 Selected from Table D p-F-Ph- Selected from Table D F103 Selected from Table D m-F-FH- Selected from Table D F104 Selected from Table D p-Ph-chjo Selected from Table D F105 Selected from Table D m-Ph-CHsQ Selected from Table D F106 Selected from Table D p- (CH 3) ₂ N-Fh- Selected from Table D F107 Selected from Table D m- (CH 3) ₂ N-Fh- Selected from Table D F108 Selected from Table D Γ, ρ-ίΟΗ3) ₃ -Ν * -Ρή- Selected from Table D F109 Selected from Table D r, m-starch-M-Ph- Selected from Table D F110 Selected from Table D r, p- (CH 3) ₃ -n * -ch ₂ ch ₂ (OCH ₂ CH ₂ ) ₂ -O-Ph- Selected from Table D Flll Selected from Table D r, m- (CH 3) 3 -N-CH ₂ CH ₂ (OCH 3 CH ₂ -O-Ph- Selected from Table D F112 Selected from Table D Γ, p-N, N-dimethylpiperazine) - Selected from Table D

(N ') - CH ₂ - (OCH ₂ CH ₂ ) 2 -O-PhF113

Selected from Table D

Γ, m-N, N-dimethylpiperazine) - Selected from Table D (N 1 -CH 2 -OCH 3 CH 2 -Z-Ph-

F114 F115 Selected from Table D Selected from Table D m-F-Ph- P-CH 3 O- 3,4-dioxy-methylene-Ph- Selected from Table D Selected from Table D F116 Selected from Table D m-F-FH- Selected from Table D p-F-Ph- F117 Selected from Table D m-CHjO- Selected from Table D p-F-Ph- F118 Selected from Table D 4-pyridine Selected from Table D F119 Selected from Table D N-methyl-4-pyridinium Selected from Table D F120 Selected from Table D 3-pyridine Selected from Table D F121 Selected from Table D N-methyl-4-pyridinium Selected from Table D F122 Selected from Table D 2-pyridine Selected from Table D F123 Selected from Table D D-CH ₃ O, C-Ph- _Λ 2. . i nl n2 n · Selected from Table D . . . -

260

% '7 9 KCH, J, 7 ° ^ * ° '7 "xcx XQ < i OH Č OH ABOUT, NCCH, J, 0 NCCHjDj | - XQC , XQ ~ i OH s oh 9 K .; NCCH, D, j- ♦ 1 // *** 3% _in - £ OH Q jk CH, N-CH ,, -

ι

CH,

CH,

261

-262Annex A

The ileal bile acid transport inhibitors used according to the invention include, for example, the compounds listed in this Annex A.

A-I

Compounds of formula (I)

wherein R ¹ and R ² are the same or different and each is optionally substituted C ₁ -C ₆ alkyl, C ₃ . C ₆ cycloalkyl, or R ¹ and R ² together with the carbon atom to which they are attached, form an optionally substituted C 6 -C 8 spiro-cycloalkyl group.

R ⁴ is C 5 -C 14 aryl, or C 3 -C 13 heteroaryl, each optionally substituted with one to eight substituents which are the same or different and which may be halogen, hydroxy, nitro, phenyl-C 1 -C 6 alkoxy, C 1 -C 6 alkoxy optionally substituted Ci.Có alkyl, S (O) n R ^8, SO 2 nR ⁸ R ^9, COzR ^8, O (CH2CH2O) "R ^8, OSO 2 R ^8, O (CH 2) pSO3R ^8, O (CH 2) p nR ⁹ R ^10, and Η Ο ^ ^ ^ Ν 'Α ¹¹ wherein R ⁸ to R ¹¹ are identical or different and are independently hydrogen or optionally substituted C 1-6 alkyl and wherein p is an integer from I to 4 and n is an integer from 0 to 3;

Each of R ^6a , R ^5b , R ^5c and R ^5d represents atoms or groups that are the same or different and each is hydrogen, halogen, cyano, R ⁸ -acetylide, OR ⁸ , optionally substituted C 1 -C 6 alkyl, COR ⁸ , CH (OH) R ⁸ , S (O) h R ⁸ , SO ² NR ⁸ R ⁹ , P (O) (OR ⁸ ) 2, OCOR ⁸ , OCF 3, OCN, SCN, NHCN, CH ₂ OR ⁸ , CHO, (CH 2) CN, -CONR ¹⁰ (CH 2) _p CO ₂ R ^8, (CHajpNR'R ^10, CO 2 R ^8, NHCOCF 3, NHSO ₂ R ^8, OCH2OR ^8, OCH = CHR ^8, O (CH 2 CH ₂ O) ^'R8, OSO ₂ R ^8, O (CH 2) pSO3R ^8, O (CH 2) p NR ⁹ R ¹⁰ and OÍCHbVí ^ RW ^1, wherein R ⁸ to R ^11, n and p are as defined above, or R ⁵ and R ^sb, R ^Coll and R ^5c, or R ^Sc and ^R are taken together with the ring to which they are attached, form a cyclic group -O (CR ⁹ R ¹⁰⁾ m O- wherein R ⁹ and R ¹⁰ are as defined above and m is 1 or 2;

-263R ⁶ and R ⁷ are the same or different and each is hydrogen, optionally substituted C ₁ -C 6 alkyl, C ₃ -C 6 cycloalkyl, or R ⁶ and R ⁷ together with the carbon atom to which they are attached form an optionally substituted C ₃ -C ⁶ a spiro-cycloalkyl group;

X is CH ₂ , C = O, C = S, or C = NR ⁸ , wherein R ⁸ is as defined above; 1 is an integer from 0 to 2, and salts, solvates or physiologically functional derivatives thereof.

A-2

A compound of formula (I) (see above) wherein

R ¹ is methyl or ethyl;

R ² is methyl, ethyl or n-butyl;

R ⁴ is phenyl;

R ⁵ 'and R ^5d are hydrogen;

R ^5b and R ^8c are the same or different and each is hydrogen, methyl, methoxy, hydroxy, trifluoromethyl or halogen;

R ⁶ and R ⁷ are the same or different and each is hydrogen, methyl, ethyl or i-butyl;

X is CH ₂ or C = O;

lje2;

or a salt, solvate, or physiologically functional derivative thereof.

A-3

A compound of formula (I) selected from the group consisting of (+) - 3-n-butyl-3-ethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one;

(+) - 3-n-butyl-3-ethyl-2,3-dihydro-5-phenyl-l, 5-benzothiazepine-4-one-l, l-dioxide;

(+) - 3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l, 5-benzothiazepine;

(+) - 3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l, 5-benzothiazepine-l, l-dioxide;

(+) - 3-n-butyl-2-isobutyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l, 5-benzothiazepine-l, l-dioxide;

3,3-diethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one;

3,3-diethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one-1,1-dioxide;

3,3-diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine;

3,3-diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-1,1-dioxide;

3,3-dimethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one;

3,3-dimethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one 1,1-dioxide;

3,3-dimethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine;

3,3-dimethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-1,1-dioxide;

(+) - 3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide;

3,3-diethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide;

Or a salt, solvate, or physiologically functional derivative thereof.

(±) -3-n-Butyl-3-ethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one-1,1-dioxide;

(±) -3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l, 5-benzothiazepine;

(+) - 3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-1,1-dioxide, (+) - 3-n-butyl- 2-isobutyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-1,1-dioxide

3,3-diethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one;

3,3-diethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one 1,1-dioxide;

3,3-diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine;

3,3-diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-1,1-dioxide;

3,3-dimethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one;

3,3-dimethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one-1,1-dioxide;

3,3-dimethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine;

3,3-dimethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-1,1-dioxide;

(+) - 3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide;

3,3-diethyl-2,3,4,5-tetrahydro-7,8-dinethoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide; (+) - 3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide;

3,3-diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide;

(+) - 3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l, 5-benzothiazepin-8-ol-l, l-dioxide;

3,3-diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-8-ol-1,1-dioxide;

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

3,3-diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,5-benzothiazepin-8-ol-1,1-dioxide; (+) - 7-Bromo-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide;

7-bromo-3,3-diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l, 5-benzothiazepine-l, l-dioxide;

(+) - 3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l, 5-benzothiazepine-7,8-diol-l, l-dioxide;

3,3-diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-7,8-diol-1,1-dioxide;

(+) - 3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l, 5-benzothiazepine-l-monoxide;

3,3-diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1-monoxide; (+) - 3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l, 5-benzothiazepin-8-ol-l-monoxide;

3,3-diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-8-ol-1-monoxide;

(+) - 3-n-butyl-3-ethyl-2,3-dihydro-8-methoxy-5-phenyl-l, 5-benzothiazepine-4-one;

(+) - 3-n-butyl-3-ethyl -2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l, 5-benzothiazepine;

(+) - 3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide; (+) - 3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-8-hydroxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide;

-266 (+) - 7-bromo-3-n-butyl-3-ethyl-2,3-dihydro-8-methoxy-5-phenyl-1,5-benzothiazepine-4-one; (+) - 7-bromo-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine 1,1-dioxide;

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

(+) - 3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l, 5-benzothiazepine-7,8-diol-l, l-dioxide; (+) - 7-bromo-3-n-butyl-3-ethyl-2,3-dihydro-5-phenyl-l, 5-benzothiazepine-4-one; (+) - 3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide; and (±) -3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-7-ol-1,1-dioxide.

Particularly preferred compounds include:

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

A-5

3,3-Diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yl aspartan. (3 R, 5 R) -3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l, 4-benzothiazepine 1,1-dioxide;

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

(+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l, 4-benzothiazepine l-dioxide;

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

(3 R, 5 R) -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-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepin-4-ol

1,1-dioxide;

(3R, 5R) -3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-7,8-diol-1,1-dioxide; (3 R, 5 R) -3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine-7-ol 1,1-dioxide;

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

-267 (+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l, 4-benzothiazepine l, l-dioxide; Of (±) Trans-3-butyl-3-ethyl-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-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine-7-carbaldehyde-1,1-dioxide;

(+) - trans-2 - ((3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepin-7-yl) methoxy) ethanol-S, S-dioxide;

(+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-hydroxy-5-phenyl-1,4-benzothiazepine-7-carbaldehyde-1,1-dioxide;

(+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l, 4-benzothiazepin-8-thiol-l, l-dioxide; (+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-8-sulfonic acid

1,1-dioxide;

(7R, 9R) -7-Butyl-7-ethyl-6,7,8,9-tetrahydro-9-phenyl-1,3-dioxolo (4,5-HX1,4) -benzothiazepine

5.5- dioxide;

(+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8,9-dimethoxy-5-phenyl-l, 4-benzothiazepine l-dioxide;

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

(+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine-7-methanol-5,5-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-tetrahydro-5-phenyl-1,4-benzothiazepine-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) -benzothiazepine6. 6-dioxide;

(3R, 5R) -3-Butyl-7,8-diethoxy-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide; (+) - trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide; (+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide hydrochloride;

(+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-carbaldehyde 1,1-dioxide;

-2683.3-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-tetrahydro-8-methoxy-1,4-benzothiazepine-1,1-dioxide,

3,3-diets of 1-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide;

3,3-diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-4,8-diol-1,1-dioxide, (RS) -3,3-diethyl-2,3, 4,5-tetrahydro-4-hydroxy-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide, (+) - trans-3-butyl-8-ethoxy-3-ethyl-2, 3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-4-ol-1,1-dioxide; (+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1,4-benzothiazepin-4-ol 1,1-dioxide;

(+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8,9-trimethoxy-5-phenyl-l, 4-benzothiazepin-4-ol1,1-dioxide;

(3R, 5R) -3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-4,7,8-triol-1,1-dioxide; (+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-4,7,8-trimethoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide;

(+) - Trans-3-butyl-3-ethyl-5-phenyl-2,3,4,5-tetrahydro-7,8-dimethoxy-1,4-benzothiazepin-4-yl acetate-S, S-dioxide ;

3,3-diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol-1,1-dioxide;

3,3-diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-8-ol-1,1-dioxide;

3,3-dibutyl-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-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yl hydrogen sulphate (+) - trans- 3-butyl-3-ethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yl dihydrogen phosphate;

3,3-diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yl hydrogen sulphate;

3,3-diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yl dihydrogen phosphate; (±) -trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yl aspartan; and (+) - trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine-7-methanol S, S-dioxide, m.p. 122-123 ° C (3R, 5R) -3-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-7-nitro-5-phenyl-1,4-benzothiazepine-1,1 Dioxide 0.40 hydrate, m.p. 122-123 ° C (±) -trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-7- (methoxymethyl) -5-phenyl -1,4-benzothiazepine-1,1-dioxide, m.p. 118-119 ° C

-269 (±) -trans-7-bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol-1,1-dioxide 0 M.p. 137-138 ° C (+) - trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8,9-trimethoxy-5-phenyl-1,4 -benzothiazepine-1,1-dioxide, m.p. 169-170 ° C (3R, 5R) -3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-7, 8-diyl diacetate-1,1-dioxide, m.p. 79-81 ° C (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, m.p. 82 ° C (3R, 5R) -3-butyl-7,8-diethoxy-2,3,4,5-tetrahydro -5-phenyl-1,4-benzothiazepine-1,1-dioxide 0.20 hydrate, m.p. 110-111 ° C (+) - trans-3-butyl-8-ethoxy-3-ethyl-2,3, 4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide, m.p. 45-54 ° C (+) - trans-3-butyl-3-ethyl-2,3,4,5 -tetrahydro-8- (methylthio) -5-phenyl-1,4-benzothiazepine-1,1-dioxide hydrochloride, m.p. 194-197 ° C (+) - trans-3-butyl-3-ethyl-2,3 , 4,5-tetrahydro-8-isopropoxy-5-phenyl-l, 4-benzothiazepine l-dioxo id hydrochloride, m.p. 178-181 ° C (±) -trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-8-carbaldehyde-1, m.p. 165-170 ° C

3,3-Diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazazin-8-yl aspartan

3,3-diethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide, m.p. 163-164 ° C

3.3-diethyl-5- (4-fluorophenyl) -2,3,4,5-tetrahydro-8-methoxy-1,4-benzothiazepine-1,1-dioxide, m.p. 101-103 ° C

3,3-diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide, m.p. 132-133 ° C

3.3-diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-4,8-diol-1,1-dioxide, mp 225-227 ° C (RS) -3,3 -diethyl-2,3,4,5-tetrahydro-4-hydroxy-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide, m.p. 205-206 ° C (+) - trans- 3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-4-ol-1,1-dioxide, m.p. 149-150 ° C ( ±) -trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1,4-benzothiazepin-4-ol-1,1-dioxide, m.p. 109-115 ° C

-270 (±) Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8,9-trimethoxy-5-phenyl-l, 4-benzothiazepine-4-ol1,1- Dioxide, m.p. 84-96 ° C (3R, 5R) -3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-4,7,8-triol -1,1-dioxide, mp 215-220 ° C (+) - trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-4,7,8-trimethoxy-5-phenyl- 1,4-benzothiazepine-1,1-dioxide, m.p. 169-187 ° C (±) -trans-3-butyl-3-ethyl-5-phenyl-2,3,4,5-tetrahydro-7,8-dimethoxy -1,4-benzothiazepin-4-yl acetate-S, S-dioxide, m.p. 154-156 ° C

3,3-diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol-1,1-dioxide, m.p. 177-178 ° C

3,3-Diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-8-ol-1,1-dioxide

(+) - Trans-3-butyl-3-ethyl-2,3-dibutyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol-1,1-dioxide 4,5,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yl hydrogen sulphate, m.p. 196.5-200 ° C (+) - trans-3-butyl-3-ethyl -2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yl dihydrogen phosphate

3,3-Diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yl hydrogen sulphate

3,3-Diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yl dihydrogen phosphate (+) - trans-3-butyl-3-ethyl- 2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yl aspartan

A-6

Compounds of formula (I):

wherein R ¹ is a straight chain C 1 -C 6 alkyl group; R ² is a straight chain C 1 -C 6 alkyl group; R ³ is hydrogen or OR ¹¹ in which R ¹¹ is hydrogen, optionally substituted C 1 -C 6 alkyl or C 1 -C 6 alkylcarbonyl; R ⁴ is pyridyl or optionally substituted phenyl; R ^5, R ^6, R ⁷ and R ⁸ are the same or different and each is hydrogen, halogen, cyano, R ^ls -acetylid, OR ^15, optionally substituted C -C alkyl, COR ^15, CH (OH) R ^15, S (O) n R ¹⁵ , P (OXOR ¹⁵ ) 2, OCOR ¹⁵ , OCF 3, OCN, SCN, NHCN, CH ² OR ¹³ , CHO, (CH 2) p CN,

-271 CONR ¹² R ^13, (CHĺjpCOíR ^15, (CH 2) p NR ¹² R ^13, CO 2 R ^15, NHCOCF 3, NHSO 2 R ^15, OCH2OR ^15, OCH = CHR ^15, O (CH2CH2O) "R ^15, O (CH 2) ₃ PSO R ¹⁵ , O (CH ₂ ) p NR ¹² R ¹³ or wherein p is an integer from 1 to 4, n is an integer from 0 to 3 and R ¹² , R ¹³ , R ¹⁴ and

R ¹⁵ are independently hydrogen or optionally substituted C 1 -C 6 alkyl; or R ⁶ and R ⁷ are joined to form a group

-O (CR ¹ R ¹³ ) _m

Where R ¹² and R ¹³ are as defined above and m is 1 or 2; and R ⁹ and R ¹⁰ are the same or different and each is hydrogen or C 1 -C 6 alkyl; with the proviso that when R ^{3 is} hydrogen, then either R ⁷ is not

C 6 O hydrogen, or at least two of R, R, R and R are not hydrogen; and salts, solvates and physiologically functional derivatives thereof.

A-7

Compounds described in A-6 having the general formula (Π)

wherein R ¹ to R ¹⁰ are as defined above and R ⁷ 'is halogen, cyano, R ¹⁵ -acetylide, OR ¹⁵ , optionally substituted C 1-6 alkyl, COR ¹⁵ , CH (OH) R ¹⁵ , S (O) n' R ^15, P (OXOR ¹⁵⁾ 2, OCOR ^15, OCF 3, OCN, SCN, HNCN, _CH2 ^OR15, CHO, (CH 2) p CN, CONR ¹² R ^n, (CH ^ CO ^ ^15, (CH 2) p ^{NR. 2} R ^13, CO 2 R ^15, NHCOCF5, NHSO 2 R ^15, OCH2OR ^{1 s,} OCH = CHR ^15, O (CH 2 CH ₂ O) hR ^15, O (CH 2) pSO3R ^15, O (CH 2) p NR ¹² R ¹³ andlor O _{(CH2) P} N ⁺ R ¹² R ¹³ R ¹⁴ , wherein n, p and R ¹² to R ¹⁵ are as defined above, and salts, solvates or physiologically functional derivatives thereof.

A-8

Compounds described in A-6 of general formula (ΠΙ):

-272-

(ΠΙ) wherein R ¹ -R ¹⁰ are described in A-6; and salts, solvates and physiologically functional derivatives thereof.

A-9

Compounds described in A-6 of formula (IV)

(IV) wherein R ¹ -R ¹⁰ are described in A-6; and salts, solvates and physiologically functional derivatives thereof.

A-10

Compounds described in A-6 of formula (IVa)

(IVa) wherein R 1 -R ¹⁰ are described in A-6; and salts, solvates and physiologically functional derivatives thereof.

A-II

The compounds described in A-6, wherein:

R ¹ and R ² are straight chain C 1 -C 6 alkyl;

R ³ is hydrogen or hydroxy;

R ⁴ is unsubstituted phenyl,

R ⁵ is hydrogen;

R ⁹ and R ¹⁰ are both hydrogen; and either

-273R ⁷ is halogen, hydroxy, Ci.Ce alkoxy, optionally substituted Ci.Ce alkyl, -S (O) n R ¹⁵ or CH ₂ OR ¹⁵ wherein R ¹⁵ is hydrogen or alkyl Ci.Ce; and

R ⁶ and R ⁸ are independently hydrogen or one of the groups given in the definition of R ⁷ ; or R ⁸ is hydrogen and R ⁶ and R ⁷ are joined to form -O- (CH ₂ ) n -, - O-, wherein m is 1 or 2, and salts, solvates and physiologically functional derivatives thereof.

A-12

A compound according to any one of A-6 to A1, wherein R ⁶ and R ⁷ are both methoxy.

A-13

A compound selected from the group consisting of:

3,3-diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yl aspartan.

(3R, 5R) -3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide;

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

(+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide;

(±) Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l, 4-benzothiazepin-4-ol, l-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-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepin-4-ol

1,1-dioxide;

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

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

(±) Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l, 4-benzothiazepine l, l-dioxide; (+) - Trans-3-butyl-3-ethyl-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;

-274 (+) - trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine-7-carbaldehyde-1,1-dioxide;

(+) - trans-2 - ((3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepin-7-yl) methoxy) ethanol-S, S-dioxide;

(±) -trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-hydroxy-5-phenyl-1,4-benzothiazepine-7-carbaldehyde-1,1-dioxide;

(+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-8-thiol-1,1-dioxide; (+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-8-sulfonic acid 1,1-dioxide;

(7R, 9R) -7-Butyl-7-ethyl-6,7,8,9-tetrahydro-9-phenyl-1,3-dioxolo (4,5-HX1,4) -benzothiazepine5,5-dioxide;

(+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8,9-dimethoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide;

(3R, 5R) -3-Butyl-3-ethyl-5- (4-fluorophenyl) -2,3,4,5-tetrahydro-7,8-dimethoxy-1,4-benzothiazepin-4-ol-1,1- dioxide;

(+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine-7-methanol-5,5-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-tetrahydro-5-phenyl-1,4-benzothiazepine-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;

(3R, 5R) -3-Butyl-7,8-diethoxy-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide; (+) - Trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide; (+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide hydrochloride;

(+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-carbaldehyde 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-tetrahydro-8-methoxy-1,4-benzothiazepine-1,1-dioxide;

-Β53,3-Diets 1-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide;

3,3-diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-4,8-diol-1,1-dioxide;

(RS) -3,3-Diethyl-2,3,4,5-tetrahydro-4-hydroxy-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide;

(±) -trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-4-ol-1,1-dioxide;

(+) - trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1,4-benzothiazepine-4-ol-1,1-dioxide, (+) trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8,9-trimethoxy-5-phenyl-l, 4-benzothiazepin-4-ol1,1-dioxide;

(3R, 5R) -3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-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 l-dioxide;

(±) -trans-3-butyl-3-ethyl-5-phenyl-2,3,4,5-tetrahydro-7,8-dimethoxy-1,4-benzothiazepin-4-yl acetate-S, S-dioxide ;

3,3-diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol-1,1-dioxide;

3,3-diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-8-ol-1,1-dioxide;

3,3-dibutyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-8-OH, 1-dioxide;

(±) -trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yl hydrogen sulfate;

(+) - trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yl dihydrogen phosphate;

3,3-diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yl hydrogen sulphate;

3,3-diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yl dihydrogen phosphate; (±) -trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yl aspartan; and

3,3-Diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yl aspartan.

(3R, 5R) -3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide, or a salt, solvate, or a physiologically functional derivative thereof.

A-14

Compounds having particular hypolipidemic properties include:

-276 (±) -trans-3-ethyl-2,3,4,5-tetrahydro-3 - ((2 R) -2-hydroxy-butyl) -5-phenyl-l, 4-benzothiazepine l-dioxide;

(±) -trans-l- (3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l, 4-benzothiazepine-3-yl) -2 (R) S--2butanol , S-dioxide;

(±) -trans-l- (3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l, 4-benzothiazepine-3-yl -) - 3-BUTANOLS, S-dioxide ;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-l, 4-benzothiazepine-3-yl) -2 (R) S--2butanol , S-dioxide;

(±) -trans-1- (3-ethyl-5- (4-fluorophenyl) -2,3,4,5-tetrahydro-7-methoxy-1,4-benzothiazepin-3-yl) 2 (R) - 2-butanol S, S-dioxide;

(+) - trans-l- (3-Ethyl-5- (4-hydroxyphenyl) -2,3,4,5-tetrahydro-l, 4-benzothiazepine-3-yl) -2 (R) S--2butanol S-dioxide 0.5 hydrate;

(+) - trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5- (4-hydroxyphenyl) -1,4-benzothiazepine-1,1-dioxide hydrochloride (+) - cis- 3-ethyl-2,3,4,5-tetrahydro-3- (4-hydroxybutyl) -5-phenyl-1,4,4-benzothiazepine-1,1-dioxide hydrochloride;

(+) - Trans-3-ethyl-2,3,4,5-tetrahydro-3- (4-hydroxybutyl) -5-phenyl-l, 4-benzothiazepine l, l-dioxide;

(±) Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7-hydroxy-5-phenyl-l, 4-benzothiazepine l, l-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l, 4-benzothiazepine-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-butanol S, S-dioxide;

(±) -trans-3-ethyl-2,3,4,5-tetrahydro-3- (3-hydroxybutyl) -5-phenyl-1,4-benzothiazepine-1,1-dioxide; (+) - trans-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-1,4-benzothiazepin-3-yl) -2 (R) -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-2 ( S) -2-butanol S, S-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l, 4-benzothiazepine-3-yl) -4,4,4trifluór-2 ( S) -butanol S, S-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l, 4-benzothiazepine-3-yl-2 (R) -2butanol- S, S-dioxide;

-N (+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l, 4-benzothiazepine-3-yl) -4,4, 4trifluór-2-butanol S, S-dioxide;

(±) -trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l, 4-benzothiazepine-3-yl) -3,3,4, 4,4-pentafluoro-2-butanol-S, S-dioxide, (+) - trans-3 - ((3-ethyl-2,3,4,5-tetrahydro-5-phenyl-3-) 4-trifluoro-2-hydroxybutyl) -1,4-benzothiazepin-8-yl) oxy) propanesulfonic acid-1,1-dioxide; (+) - trans-3 - ((3-ethyl-2,3,4,5-tetrahydro-3- (2-hydroxybutyl) -5-phenyl-l, 4-benzothiazepin-8-yl) oxy) etyltrimetylamóniumjodid-1, 1-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-diethoxy-5-phenyl-l, 4-benzothiazepine-3-yl) -4,4,4trifIuór- 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-benzothiazepine-8-) yl) oxy) ethyltrimethylammonium iodide-1,1-dioxide; (±) -trans-3 - ((3-ethyl-2,3,4,5-tetrahydro-3- (2-hydroxybutyl) -5-phenyl-1,4-benzothiazepin-8-yl) oxy) propanesulfonic acid-1 1,1-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-diethoxy-5-phenyl-l, 4-benzothiazepine-3-yl) -2-BUTANOLS, S dioxide;

(+) - trans-l- (3- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-4-benzotiazepín3-yl) - 4,4,4-trifluoro-2-butanol S, S-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dihydroxy-5-phenyl-l, 4-benzothiazepine-3-yl) -4,4,4trifluór- 2-butanol S, S-dioxide;

(+) - trans-1- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepin-3-yl) -1-butanol-S, S dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dihydroxy-5-phenyl-l, 4-benzothiazepine-3-yl) -2butanol-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-1- butanol S, S-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dihydroxy-5-phenyl-l, 4-benzothiazepine-3-yl) -2-butanone S, S dioxide;

Of the above, the following are preferred:

(+) - trans-l- (3-Ethyl-5- (4-fluorophenyl) -2,3,4,5-tetrahydro-7-methoxy-l, 4-benzothiazepine-3-yl) -2 (R) - 2-butanol S, S-dioxide;

(±) -trans-l- (3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l, 4-benzothiazepine-3-yl) -4,4,4-trifluoro- (2S) - 2-butanol S, S-dioxide;

-278 (+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-l, 4-benzothiazepine-3-yl) -4,4,4trifluór- (2 S) -2-butanol S, S-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l, 4-benzothiazepine-3-yl) -4,4,4trifluór-2 ( S) -butanol S, S-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l, 4-henzotiazepín-3-yl-2 (R) -2butanol- S, S-dioxide;

(+) - trans-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1,4-benzothiazepine-3-methanol-1,1-dioxide, m.p. 79-80 ° C;

(+) - ds-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1,4-benzothiazepine-3-methanol-1,1-dioxide hydrochloride 0.25 hydrate, m.p. 222-224 C;

(+) - trans-4- (3-butyl-3-ethyl-2,3,4,5-tetrahydro-4 _{J-benzothiazepine-5-yl)} phenol hydrochloride, mp 234-235 DEG C. (dec);

(+) - trans-544-Benzyloxyphenyl-3-ethyl-2,3-4,5-tetrahydro-1,4-benzothiazepine-3-methanol, m.p. 138-143 ° C;

(+) - trans-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-3-methanol-1,1-dioxide, m.p. 134-137 ° C;

(+) - trans-3-ethyl-2,3,4,5-tetrahydro-3- (3-hydroxybutyl) -5-phenyl-1,4-benzothiazepine-1,1-dioxide, m.p. 151-155 ° C;

(+) - cis-3-ethyl-2,3,4,5-tetrahydro-3-butyl-4-hydroxy-5- (3-pyridyl) -1,4-benzothiazepine-1,1-dioxide, m.p. 205 ° C;

(+) - cis-4- (3-butyl-3-ethyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-5-yl) phenol hydrochloride, m.p. 236-237 ° C (dec.);

(+) - cis-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5- (4-hydroxyphenyl) -1,4-benzothiazepine-1,1-dioxide, m.p. 163-165 ° C ;

(+) - cis-3-ethyl-2,3,4,5-tetrahydro-3- (3-hydroxybutyl) -5-phenyl-1,4-benzothiazepine-1,1-dioxide hydrochloride, m.p. 206-209 C;

(+) - trans-3-ethyl-2,3,4,5-tetrahydro-3- (2 (R) -2-hydroxybutyl) -5- (4-hydroxyphenyl) -1,4-benzothiazepine-1,1-dioxide mp 197-198 ° C;

(+) - trans-3-ethyl-2,3,4,5-tetrahydro-3- (2 (S) -2-hydroxybutyl) -5- (4-hydroxyphenyl) -1 _; 4-benzothiazepine-1,1-dioxide, m.p. 178-179 ° C;

(+) - trans-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-3-methanol, mp 104106 ° C;

- (-) - cis-5- (4-benzyloxyphenyl) -3-ethyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-3-methanol, mp 123-128 ° C;

(+) - trans-1- (3-ethyl-5- (4-fluorophenyl) -2,3,4,5-tetrahydro-1,4-benzothiazepin-3-yl) -2 (R) -2-butanol-S S-dioxide, m.p. 130-132 ° C;

(±) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-3-yl) _-4-T 4.4 trifluoro-2 (R) -2butanol-S, S-dioxide mp 140-145 ° C;

(+) - trans-1- (3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-3-yl) -4-fluoro-2 (RS) -2-butanol-S, S-dioxide 0, 50 hydrate, m.p. 130-147 ° C, (±) -trans-1- (3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-3-yl) -4 4,4-trifluoro-2 (S) -2-butanol-S-oxide, m.p. 159-161 ° C;

(+) - trans-1- (3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-3-yl) -4,4,4-trifluoro-2 ( S) -2-butanol-S, S-dioxide, m.p. 168-170 ° C; (+ ~) -Trans-l-r3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepin-3-yl) -4.4.4trifluór-2 (S) -2-butanol S S-dioxide, m.p. 175-179 ° C;

(+) - trans-1- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepin-3-yl) -2 (R) -2-butanol-S, S-dioxide, temperature mp 156-157 ° C;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l, 4-benzothiazepin-3-yl) -4,4,4trifluór- 2-butanol S, S-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l, 4-benzothiazepin-3-yl) -3,3,4,4, 4pentafluór-2-butanol S, S-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l, 4-benzothiazepin-3-yl) -3,3,4, 4,4pentafluór-2-butanol S, S-dioxide;

(+) - trans-3 - ((3-ethyl-2,3,4,5-tetrahydro-5-phenyl-3- (4,4-trifluoro-2-hydroxybutyl-1,4-benzothiazepin-7-yl) oxy) propanesulfonic acid-1, 1-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) propanesulfonic acid-1,1-dioxide;

(+) - trans-3 - ((3-ethyl-2,3,4,5-tetrahydro-3- (2-hydroxybutyl) -5-phenyl-l, 4-benzothiazepine-7-yl) oxy) etyltrimetylamóniumjodid-1, 1-dioxide;

(+) - trans-3 - ((3-ethyl-2,3,4,5-tetrahydro-3- (2-hydroxybutyl) -5-phenyl-1,4-benzothiazepin-8-yloxy) ethyltrimethylammonium iodide-1,1-dioxide;

(+) - trans-l-f3-ethyl-2,3,4,5-tetrahydro-7,8-dietoxv-5-phenyl-1,4-benzothiazepin-3-yl) -4.4.4trifluór-2-butanol S, S-dioxide,

-280 (+) - trans-3 - ((3-ethyl-2-3-4-5-tetrahydro-5-phenyl-3 (4-4-4-trifluoro-2-hvdroxybutyl) -1.4benzotiazepin-7 -yl) oxy) ethyltrimethylammonium iodide-1,1-dioxide, (+) - trans-3 - ((3-ethyl-2,3,4.5-tetrahydro-5-phenyl-3- (4,4,4-trifluoro-2-hydroxybutyl)) _T 4benzotiazepin -l-8-yl) oxy) etyltrimetylamóniumjodid-l, l-dioxide; (±) -trans-3 - ((3-ethyl-2,3,4,5-tetrahydro-3- (2-hydroxybutyl) -5-phenyl-1,4-benzothiazepin-8-yl) oxy) propanesulfonic acid-1 1,1-dioxide;

(+) - trans-3 - ((3-ethyl-2,3,4,5-tetrahydro-3- (2-hydroxybutyl) _-5-phenyl-S 4-benzothiazepin-7-yl) oxy) propanesulfonic acid 1,1-dioxide ;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7 8 _{T-diethoxy-5-phenyl-4 T-benzothiazepin-3-yl)} -2-butanol ·

S, S-dioxide;

(+) - trans-l- (3- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l, 4-benzothiazepine

3-yl) -4,4,4-trifluoro-2-butanol S, S-dioxide;

(+) - trans-1- (3- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-8-methoxy-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-9-methoxy-5-phenyl-1,4-benzothiazepin-3-yl) -4,4,4-trifluoro-2- butanol S, S-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-9-methoxy-5-phenyl-l, 4-benzothiazepin-3-yl) -2-BUTANOLS, S-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dihydroxy-5-phenyl-1,4-benzothiazepin-3-yl) _-4-J 4,4trifluór 2-butanol S, S dioxide;

(+) - trans-1- (3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepin-3-yl) -1-butanol S, S-dioxide;

(+) - trans-1- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepin-3-yl) -1 butanol-S, S-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dihydroxy-5-phenyl-1,4-benzothiazepin-3-yl) -2butanol-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-1- butanol S, S-dioxide;

(+) - trans-1- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepin-3-yl) -4,4,4-trifluoro- 1-butanol-S, S-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dihydroxy-5-phenyl-l, 4-benzothiazepin-3-yl) -2-butanone S, S dioxide;

A-15

Compound of Formula (I) *

-281-

wherein the integer is from 0 to 4;

n is an integer from 0 to 2;

R is an atom or a group selected from:

halogen, cyano, hadroxy, nitro, alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, aralkyl, alkaryl, -OCH 2 SO 2 R ¹¹ , -O (CH 2) p NR ¹¹ R ¹² , - (XCH 4 W 'R 4 R ¹⁴⁾ , -COR ^11, -COzR ^11, CONR ¹² R ^{n, the} -CH 2 oR, -NR ⁿ R ^12, -NHCOR ^11, -NHSO 2 R, -SR ^11, -SO 2 R ', -SO ₂ NR ^h R ^12, and SO 3 R ^11, or R is -OCH ₂ O-, which forms another ring attached to X, wherein p is an integer from 1 to 4, R ¹¹ , R ¹² are independently hydrogen, C 1 -C 6 alkyl or phenyl, and R ¹⁴ is hydrogen or C 1-6. C 6 alkyl, wherein said alkyl, alkoxy, aryl, heteroaryl aryloxy, arylalkoxy, aralkyl and alkaryl groups are optionally substituted with one or more atoms or groups selected from halogen, hydroxy, nitro, nitrile, alkyl, alkoxy, -COR ¹¹ , -CO 3; ¹¹ , -SO ³ R ¹¹ , wherein R ¹¹ is as defined above, and -NR ¹⁴ R ¹⁵ , wherein R ¹⁴ is as defined above, and R ¹⁵ is hydrogen or C 1-6 alkyl;

R ¹ is hydrogen or C 1 -C 6 alkyl;

R ² is an atom or a group selected from: hydrogen, C 1 -C 6 alkyl (including cycloalkyl and cycloalkylalkyl), C 1 -C 4 alkoxy, pyryl, thienyl, pyridyl, 1,3-benzodioxolo, phenyl and naphthyl, wherein the groups are optionally substituted with one or more atoms or groups independently chosen from halogen, cyano, hydroxyl, nitro, carboxyl, phenyl, phenoxy, benzyloxy, COR ^11, -COitR ^11, -CONR ⁿ R ^12, -CH 2 oR ^n, -NR ⁿ R ^12, -NHCOR ¹¹ , -NHSO ^11, -SR ^11, SO ^ ^11, -SOjR ¹¹ (wherein R ¹¹ and R ¹² are defined as above), -O (CH 2) _p NR ¹² R ^1I, leading to their N ^ R ^ ¹ ^ ¹ ^ ¹³ and -OCH 2 SO 3 R ¹¹ (wherein p, R ¹¹ and R ¹² are as defined above and R ¹³ is hydrogen or C 1 -C 6 alkyl);

-282R ³ is hydrogen, hydroxy, C 1 -C 6 alkyl, alkoxy or-OC 1 -C 6 acyl;

R ⁴ is independently selected from: C 1 -C 6 alkyl (including cycloalkyl and cycloalkylalkyl), C 2 -C 6 alkenyl, and C 2 -C 8 alkynyl, wherein the groups are optionally substituted with one or more atoms or groups independently selected from: halogen, oxo, -OR ¹⁴ , -CO ² R ¹⁴ , NR ¹⁴ R ¹⁵ , -SR ¹⁴ , -S (O) C 1-6 alkyl, -SO ² R ¹⁴ and -SO ³ R ¹⁴ (wherein R ¹⁴ and R ¹⁵ are as defined above), or R ⁴ and R ⁵ together with the carbon atom to which they are attached form a C 3 -C 7 spirocycloalkyl group which is optionally substituted with one or more atoms or groups independently selected from: halogen, -OR ¹⁴ , -CO ² R ¹⁴ , -SO ³ R ¹⁴ and -NR ¹⁴ R ¹⁵ (wherein R ¹⁴ and R ¹⁵ are as defined above);

R ⁶ and R ⁷ are independently hydrogen or C 1 -C 6 alkyl; and

X is an aromatic or non-aromatic monocyclic or bicyclic ring system having from 5 to 10 carbon atoms (including those two carbon atoms that form part of the thiazepine ring) wherein optionally one or more carbon atoms are replaced by heteroatom (s) independently selected (i) between nitrogen, oxygen and sulfur;

with the proviso that at least one of R, R ² , R ⁴ and R ⁵ is hydroxy or a hydroxy group;

and salts, solvates and physiologically functional derivatives thereof.

A-16

A compound as described in A-15, wherein:

1 is 0, 1, or 2;

n is 1 or 2; and

R ¹ , R ⁶ and R ⁷ are all hydrogen; and

R ³ is hydrogen or hydroxy.

A-17

A compound as in A-15 which is a trans isomer wherein:

(a) 1 is 0 or 1; n is 2; and

R ⁴ and R ⁵ are independently selected from: C 1 -C 6 alkyl (including cycloalkyl and cycloalkylalkyl), C 1 -C 6 alkenyl and C ₂ -C 6 alkynyl, wherein said alkyl, alkenyl, or

-283alkynyl may be substituted with one or more hydroxy groups, or R ⁴ and R ⁵ together with the carbon atom to which they are attached form a C 3 -C 7 spirocycloalkyl group which may be substituted with one or more hydroxy groups; or (b) 1 is 0 or 1; n is 2;

R ² is a phenyl group which may be substituted by one or more atoms or groups independently chosen from halogen, cyano, hydroxyl, nitro, carboxyl, phenyl, phenoxy, benzyloxy, -COR ^11, -CO 2 R ^11, -CONR ¹² R ^{U, n} -CH 2 oR, -NR ⁿ R ^12, -NHCOR ^11, NHSO 2 R ^n, -SR ^11, -SO ^ ^11, -SO 3 R ¹¹ (wherein R ¹¹ and R ¹² are independently hydrogen, alkyl or phenyl Ci.Ce), -O _(CH2), NR ⁿ R ^12, -0 (¾ 0¾ ^^. ^ ¾ ^{11 13} -0 and (0¾ ^ SO 3 R ¹¹ (wherein p is an integer from 1 to 4, R ¹¹ and R ¹² are defined as above and R ¹³ is hydrogen or C 1 -C 6 alkyl);

R ⁴ and R ⁵ are independently selected from: C 1 -C 8 alkyl (including cycloalkyl and cycloalkylalkyl), C 2 -C 6 alkenyl and C 2 -C 6 alkynyl, wherein said alkyl, alkenyl, or alkynyl group may be substituted with one or more hydroxy groups, or R ⁴ and R ⁵ together with the carbon atom to which they are attached form a C 3 -C 7 spirocycloalkyl group which may be substituted by one or more hydroxy groups; or (c) 1 is 0 or 1; n is 2;

R ² is a phenyl group which may be substituted by one or more atoms or groups independently selected from halogen, cyano, hydroxyl, nitro, carboxyl, phenyl, phenoxy, benzyloxy, -COR ^11, -CO 2 ^H, -CONR ⁿ R ^12, -CH 2 OR ^h, -NR ^L1 R ^12, -NHCOR ^11, -NHSO 2 R ^1? , SR ^11, -SOtR ^11, -SO 3 R ¹¹ (wherein R ¹¹ and R ¹² are independently hydrogen, alkyl or phenyl cj.com), OÍCHjjpNR ¹¹ ^ ^2, -OÍCftjXR'VR ¹³ and -O (CH 2) ⁿ pSO3R (wherein p is an integer from 1 to 4, R ¹¹ and R ¹² are as defined above and R ¹³ is hydrogen or C 1 -C 6 alkyl);

R ⁴ and R ⁵ are independently selected from: C 1 -C 6 alkyl (including cycloalkyl and cycloalkylalkyl), C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl, wherein the groups may be substituted with one or more hydroxy groups; and

X is a fused phenyl, naphthyl, pyridyl, thienyl, or pyridyl group;

-284Α-18

A compound as in A-15 which is:

(+) - trans-3-ethyl-2,3,4,5-tetrahydro-3 - ((2R) -2-hydroxybutyl) -5-phenyl-1,4-benzothiazepine-1,1-dioxide, (+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l, 4-benzothiazepin-3-yl) -2 (R) -2butanol-S, S-dioxide ;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l, 4-benzothiazepin-3-yl -) - 3-BUTANOLS, S-dioxide ;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-l, 4-benzothiazepin-3-yl) -2 (R) S--2butanol , S-dioxide;

(+) - trans-l- (3-Ethyl-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-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) -1,4-benzothiazepine-1,1-dioxide hydrochloride (+) - cis- 3-ethyl-2,3,4,5-tetrahydro-3- (4-hydroxybutyl) -5-phenyl-1,4-benzothiazepine-1,1-dioxide hydrochloride;

(T) -trans-3-ethyl-2,3,4,5-tetrahydro-3- (4-hydroxybutyl) -5-phenyl-l, 4-benzothiazepine l, l-dioxide;

(±) Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7-hydroxy-5-phenyl-l, 4-benzothiazepine l, l-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l, 4-benzothiazepine-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-butanol S, S-dioxide;

(±) -trans-3-ethyl-2,3,4,5-tetrahydro-3- (3-hydroxybutyl) -5-phenyl-1,4-benzothiazepine-1,1-dioxide;

(+) - trans-3-ethyl-2,3,4,5-tetrahydro-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-benzothiazepine-3-yl) -2 (R) S--2butanol , S-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-l, 4-benzothiazepine-3-yl) -4,4,4trifluór-2 ( S) -2-butanol S, S-dioxide;

(±) -trans-l- (3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l, 4-benzothiazepine-3-yl) -4,4,4trifluór-2 ( S) -butanol S, S-dioxide;

-285 (±) -trans-1- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepin-3-yl 1-2-R) -2butanol-S, S-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l, 4-benzothiazepine-3-yl) -4,4,4trifluór- 2-butanol S, S-dioxide;

(±) -trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l, 4-benzothiazepine-3-yl) -3,3,4, 4,4pentafluór-2-butanol S, S-dioxide;

(+) - trans-3 - ((3-ethyl-2,3,4,5-tetrahydro-5-phenyl-3- (4,4,4-trifluoro-2-hydroxy-butyl) -l, 8-4benzotiazepín yl) oxy) propanesulfonic acid-1,1-dioxide; (+) - trans-3 - ((3-ethyl-2,3,4,5-tetrahydro-3- (2-hydroxybutyl) -5-phenyl-4-benzotia2epín-8-yl) oxy) etyltrímetylamóniumjodid-1, 1-dioxide;

(+) - trans-1- (3-ethyl-2,3,4,5-tetrahydro-7,8-diethoxy-5-phenyl-1,4-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-hydroxy-butyl) -l, 8-4benzotiazepin yl) oxy) ethyltrimethylammonium iodide-1,1-dioxide; (+) - trans-3 - ((3-ethyl-2,3,4,5-tetrahydro-3- (2-hydroxybutyl) -5-phenyl-l, 4-benzothiazepin-8-yl) oxy) propánsulfónovákyselina-l, l-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-diethoxy-5-phenyl-l, 4-benzothiazepin-3-yl) -2-BUTANOLS, S dioxide;

(+) - trans-1- (3- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazazin-3-yl) - 4,4,4-trifluoro-2-butanol S, S-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dihydroxy-5-phenyl-l, 4-benzothiazepin-3-yl) -4,4,4trifluór- 2-butanol S, S-dioxide;

(+) - trans-1- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepin-3-yl) -1-butanol-S, S dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dihydroxy-5-phenyl-l, 4-benzothiazepin-3-yl) -2butanol-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-1- butanol-S, S-dioxide;

-286-

R ² R ³ • R ⁵

R ⁴ (Ia) wherein the integer is from 0 to 4;

n is an integer from 0 to 2;

R is an atom or group selected from halogen, cyano, hydroxyl, nitro, alkyl, alkoxy, aryl, heteroaryl, aryloxy, aralkyl, alkaryl, -COR ^11, -CO 2 R ^11, -CONR ¹² R ^{n, n} -CH 2 OR, -NR ⁿ R ¹² , NHCOR ¹¹ , -NHSO ² R ¹¹ , -SR ¹¹ , -SO ² R ¹¹ , -SO ² NR ⁿ R ¹² and -SO ³ R ¹¹ , wherein R ¹¹ and R ¹² are independently selected from: hydrogen, C 1 -C 6 alkyl and phenyl, wherein said alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, aralkyl and alkaryl groups are optionally substituted with one or more atoms or groups independently selected from halogen, hydroxy, nitro, nitrile, alkyl, alkoxy, COR ¹¹ , -CO ² R ¹¹ , -SO 3 R ¹¹ , wherein R ¹¹ is as defined above, and -NR ¹⁴ R ¹⁵ , wherein R ¹⁴ and R ¹⁵ are as defined above;

R ¹ is hydrogen or C 1 -C 6 alkyl;

R ² is an atom or a group selected from: hydrogen, C 1 -C 6 alkyl (including cycloalkyl and cycloalkylalkyl), C 1 -C 4 alkoxy, pyryl, thienyl, pyridyl, 1,3-benzodioxolo, phenyl and naphthyl, wherein the groups are optionally substituted with one or more atoms or groups independently selected from halogen, cyano, hydroxyl, nitro, carboxyl, phenyl, phenoxy, benzyloxy, -COR ^11, CO 2 R ^n, -CONR ⁿ R ^12, -CH 2 oR ', NR ⁿ R ^12, -NHCOR ¹¹ , -NHSO ² R ¹¹ , -SR ¹¹ , -SO ¹ R ¹¹ , SO ³ R ¹¹ (wherein R ¹¹ and R ¹² are independently selected from: hydrogen, C 1 -C 6 alkyl and phenyl), -O (CH ₂ ) _P NR ¹¹ R ¹² , OCH ^{2 and} R ^{11 13} and -OCH 2 SO 3 R ¹¹ (wherein p is an integer from 1 to 4, R ¹¹ and R ¹² are as defined above and R ¹³ is hydrogen or C 1 -C 6 alkyl);

R ³ is hydrogen, hydroxy, C 1 -C 6 alkyl;

R ⁴ is independently selected from: C 1 -C 6 alkyl (including cycloalkyl and cycloalkylalkyl), C ₂ -C 6 alkenyl and C 1 -C 6 alkynyl, wherein the groups are optionally substituted with one or more atoms or groups independently selected from: halogen, -OR ¹⁴ -CO 2 R ¹⁴ , -NR ¹⁴ R ¹⁵ , -SO ³ R ¹⁴ (wherein R ¹⁴ and R ¹⁵ are independently selected from H or C 1 -C 6 alkyl);

R ⁵ is independently selected from C 1 -C 6 alkyl (including cycloalkyl and cycloalkylalkyl), C 1 -C 6 alkenyl and C 1 -C 6 alkynyl, wherein the groups are optionally substituted with one or more atoms

-287 or groups independently selected from: halogen, -OR ¹⁴ , -CO 2 R ¹⁴ , -NR ¹⁴ R ¹⁵ , -SO ³ R ¹⁴ (wherein R ¹⁴ and R ¹⁵ are independently selected from H or C 1 -C 6 alkyl);

or R ⁴ and R ⁵ together with the carbon atom to which they are attached form a C 3 -C 7 spirocycloalkyl group which is optionally substituted with one or more atoms or groups independently selected from: halogen, -OR ¹⁴ , -CO ² R ¹⁴ , -SO ³ R ¹⁴ and -NR ¹⁴ R ¹⁵ (wherein R ¹⁴ and R ¹³ are as defined above),

R and R are independently selected from hydrogen and C 1 -C 6 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 carbon atoms are replaced by heteroatom (s) independently selected (i) between nitrogen, oxygen and sulfur; with the proviso that at least one of R, R ² , R ⁴ and R ³ is hydroxy and a hydroxy group; salts, solvates and physiologically functional derivatives thereof.

A-20

Compound of formula (I):

wherein the integer is from 0 to 4;

n is an integer from 0 to 2;

R is an atom or a group selected from: halogen, cyano, hydroxy, nitro, alkyl, alkoxy, aryl, heteroaryl, aryloxy, aralkyl, alkaryl, -O (CH ₂ ) _p SO ³ R ¹¹ , -O (CH ₂ ) _p NR ¹¹ R ¹² ,

0 (0¼ ^] ^ ¹¹ ^ ¾. ^14th -COR ^11, -COAr ^11, -C0NR ⁿ R ^12, -CH20R ^n, -NR ⁿ R ^12, -NHCOR ^11, NHS02R ^n, -SR ^11, -SO 2 R ¹¹ , -SO 2 nR ⁿ R ^12, and -SO 3 R ^11, or R is a group -0CH20- which forms a further ring attached to X wherein p is an integer from 1 to 4, R ¹¹ and R ¹² are independently selected from hydrogen, Ci. C 6 alkyl and phenyl and R ¹⁴ is hydrogen or C 1 -C 6 alkyl, wherein said alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, aralkyl and alkaryl groups are optionally substituted with one or more atoms or groups independently selected from halogen, hydroxy,

-288 nitro, nitrile, alkyl, alkoxy, -COR ¹¹ , -CO 2 R ¹¹ , -SC 4 R ¹¹ , wherein R ¹¹ is as defined above, and NR ¹⁴ R ¹⁵ , wherein R ¹⁴ is as defined above, and R ¹⁵ is hydrogen or C 1 -C 6 alkyl;

R ¹ is hydrogen or C 1 -C 6 alkyl;

R ² is an atom or a group selected from: hydrogen, C 1 -C 6 alkyl (including cycloalkyl and cycloalkylalkyl), C 1 -C 4 alkoxy, pyryl, thienyl, pyridyl, 1,3-benzodioxolo, phenyl and naphthyl, wherein the groups are optionally substituted with one or more atoms or groups independently selected from halogen, cyano, hydroxyl, nitro, carboxyl, phenyl, phenoxy, benzyloxy ,, -COR ^11, CO 2 R ^n, -CONR ⁿ R ^12, -CHíOR ^11, -NR ¹² R ^U, -NHCOR ^11, -NHSO 2 R ^h, -SR ^11, -SO ^11, SO 3 R ¹¹ (wherein R ¹¹ and R ¹² are independently selected from hydrogen, alkyl and phenyl Ci.Ce), -O (CH _2)> ⁿ NR ¹² R (ΧΟ ^ ^ Ν 'Ά ¹³ and -OÍCH Sosro ^ ¹¹ (wherein p is an integer from 1 to 4, R ¹¹ and R ¹² are as defined above and R ¹³ is hydrogen or C-Q-alkyl);

R is hydrogen, hydroxy, C 1 -C 6 alkyl, alkoxy or -O-C 1 -C 6 acyl;

R ⁴ is independently selected from: C 1 -C 6 alkyl (including cycloalkyl and cycloalkylalkyl), C 3 -C 6 alkenyl and C 3 -C 6 alkynyl, wherein the groups are optionally substituted with one or more atoms or groups independently selected from: halogen, oxo, -OR ¹⁴ , -CO ¹⁴ , -NR ¹⁴ R ¹⁵ , -SR ¹⁴ , S (O) C 1 -C 6 alkyl, -SO 4 ¹⁴ and -SO 3 R ¹⁴ (wherein R ¹⁴ and R ¹⁵ are as defined above);

or R ⁴ and R ⁵ together with the carbon atom to which they are attached form a C 3 -C 7 spirocycloalkyl group which is optionally substituted with one or more atoms or groups independently selected from: halogen, -OR ¹⁴ , -CCbR ¹⁴ , -SO ³ R ¹⁴ and -NR ¹⁴ R ¹⁵ (wherein R ¹⁴ and R ¹⁵ are as defined above);

R ⁶ and R ⁷ are independently selected from hydrogen and C 1 -C 6 alkyl; and

X is an aromatic or non-aromatic monocyclic or bicyclic ring system having from 5 to 10 carbon atoms (including those two carbon atoms that form part of the thiazepine ring) wherein optionally one or more carbon atoms are replaced by heteroatom (s) independently selected (i) between nitrogen, oxygen and sulfur; with the proviso that at least one of R, R ² , R ⁴ and R ⁵ is hydroxy or a hydroxy group; and salts, malts and physiologically functional derivatives thereof, for use in the prophylaxis or treatment of clinical conditions for which a bile acid absorption inhibitor is indicated.

A-21

Compounds of formula (1) having significant hypolipidemic properties include. (-) - (RR) -3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l, 4-benzothiazepine l, l-dioxide; (+) - trans-3 - ((E) -2-butenyl) -3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide;

-289 (+) - trans-3-ethyl-2,3,4,5-tetrahydro-3- (3-methoxypropyl) -5-phenyl-1,4-benzothiazepine-1,1-dioxide; (+) - trans-1- (3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-3-yl) -2-butanone-S, S-dioxide, (+) trans-1- (3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepin-3-yl) -2-butanone S, S-dioxide hydrochloride 1, 1 hydrate;

(±) -trans-3- (1-butenyl) -3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide hydrochloride 0.4 hydrate;

(+) - trans-3- (ethoxyethyl) -3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide hydrochloride hemihydrate;

(+) - trans-3- (ethoxymethyl) -3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide hydrochloride;

(+) - trans-ethyl 3- (3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l, 4-benzothiazepin-3-yl) propionate l-dioxide;

(+) - trans- (E) -4- (3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l, 4-benzothiazepin-3-yl) -3-buten-2-one- l-dioxide;

(+) - 2,3,4,5-tetrahydro-8-methoxy-5-phenylspiro (l, 4-benzothiazepine-3, l-cyclohexane) -l, l-dioxide; (+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5- (4-pyridyl) -1,4-benzothiazepine-1,1-dioxide; (+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-4-hydroxy-5- (4-pyridyl) -l, 4-benzothiazepine l-dioxide;

(+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5- (2-thienyl) -l, 4-benzothiazepine l, l-dioxide; (+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5- (lH-pyrrol-l-yl) -l, 4-benzothiazepine-l, l-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-tetrahydro-5-phenyl-2H-pyrrolo [3,4-F] -1,4-benzothiazepine-1,1-dioxide 0, 1 hydrate;

(+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenylthieno (2,3-F) -1,4-benzothiazepine-1,1-dioxide; (+) - trans-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-3- (4,4,4-trifluorobutyl) -1,4-benzothiazepine-1,1-dioxide;

(+) - trans-2,3,4,5-tetrahydro-3-isopropyl-3-methyl-5-phenyl-l, 4-benzothiazepine l, l-dioxide 0.25 _H2O;

(+) - trans-3 - ((E) -2-butenyl) -3-ethyl-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-l, 1-dioxide 0.66 H ₂ O;

(±) trans -3- (3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l, 4-benzothiazepine-3-yl) propane-l, l-dioxide; (+) - trans-3-ethyl-5- (4-fluorophenyl) -2,3,4,5-tetrahydro-7-methoxy-3- (3-methoxypropyl) -1,4-benzothiazepine-1,1-dioxide hydrochloride;

-290 (+) - 2,3,4,5-tetrahydro-7-methoxy-5-phenylspiro [1,4-benzothiazepine-3,1-cyclohexane] -1,1-dioxide; (±) -trans-1- (3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-3-yl) -2-butanone 5,5-dioxide hydrochloride ;

(±) Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-fenylnafto (3,2-F) -l, 4-benzothiazepine l, l-dioxide; (±) -trans-1- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepin-3-yl) -2-butanone-S, S- dioxide;

(+) - trans-3- (1-butenyl) -3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l, 4-benzothiazepin-3-yl) -3butanón-S, S Dioxide, (+) - trans-1- (3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepin-3-yl) -1-butanone dioxide;

(+) - trans-1- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepin-3-yl) -1-butanone-S, S dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-5-Phenyl-l, 4-benzothiazepin-3-yl) -4,4,4trifluór- l-butanone S, S-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l, 4-benzothiazepin-3-yl) -3,3,4, 4,4pentafluór-2-butanone S, S-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l, 4-benzothiazepin-3-yl) -4,4,4trifluór- 2-butanone S, S-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-3- (4,4,4-trifluorobutyl) -l, 1-4benzotiazepín 1,1-dioxide;

(+) - trans-l- (3- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-4-benzotiazepin3-yl) - 2-butanone S, S-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-diethoxy-5-phenyl-l, 4-benzothiazepin-3-yl) -2-butanónS, S dioxide;

(+) - trans-3 - ((3-ethyl-2,3,4,5-tetrahydro-3- (2-oxobutyl) -5-phenyl-1,4-benzothiazepin-8-yl) oxy) propanesulfonic acid 1, 1-dioxide;

(±) - trans-3 - ((3-ethyl-2,3,4,5-tetrahydro-3- (2-oxo-butyl) -5-phenyl-l, 4-benzothiazepin-8-yl) oxy) etyltrimetylamóniumjodid-1, 1-dioxide;

(-) - (RR) -3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide;

-291 (+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l, 4-benzothiazepine-3-yl) -2-butanónS, S Dioxide Hydrochloride 1.1 Hydrate;

(+) - cis-2,3,4,5-tetrahydro-3-isopropyl-3-methyl-5-phenyl-1,4-benzothiazepine 1,1-dioxide 0.66 H ₂ O;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l, 4-benzothiazepin-3-yl) -2-butanone S, S dioxide;

A-22 (+) - 2,3,4,5-tetrahydro-5-phenylspiro (1,4-benzothiazepine-3,1-cyclohexane) -1,1-dioxide, m.p. 177-179 ° C;

(+) - trans-2,3,4,5-Tetrahydro-3-isopropyl-3-methyl-5-phenyl-1,4-benzothiazepine-1,1-dioxide 0,25

H ₂ O, mp 130-132 ° C;

(+) - (S) -2,3,4,5-tetrahydro-5-phenylspiro (1,4-benzothiazepine-3,1'-cyclohexane) -1,1-dioxide, mp 210-211 ° C;

(+) - (R) -2,3,4,5-tetrahydro-5-phenylspiro (1,4-benzothiazepine-3,1'-cyldohexane) -1,1-dioxide, m.p. 210-211 ° C;

(+) - trans-2,3,4,5-tetrahydro-3-isopropyl-3-methyl-5-phenyl-1,4-benzothiazepine hydrochloride, m.p. 211-213 ° C;

(+) - cis-2,3,4,5-tetrahydro-3-isopropyl-3-methyl-5-phenyl-1,4-benzothiazepine hydrochloride, m.p. 268-270 ° C;

(+) - 3-sec-butyl-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1,4-benzothiazepine hydrochloride, m.p. 202-205 ° C;

(+) - 4,5-dihydro-5-phenylspiro (1,4-benzothiazepine-3- (2H), 1'-cyclopentane) hydrochloride 0.25 H ₂ O, mp 224-226 ° C;

(+) - 2,3,4,5-tetrahydro-5-phenylspiro (1,4-benzothiazepine-3,1'-cyclohexane) -hydrochloride H ₂ O, mp 167-169 ° C (ef.);

(+) - 5- (2-fluorophenyl) -2,3,4,5-tetrahydrospiro (1,4-benzothiazepine-3,1'-cyclohexane) -1,1-dioxide, m.p. 160-161 ° C;

(+) - cis-3- (2,3,4,5-tetrahydro-3-methyl-5-phenyl-1,4-benzothiazepin-3-yl) propionic acid 1,1-dioxide 0,5 H ₂ O, mp 132-133 C;

(+) - trans-ethyl-3- (2,3,4,5-tetrahydro-3-methyl-5-phenyl-1,4-benzothiazepin-3-yl) propionate-1,1-dioxide, m.p. 143-148 ° C;

-293 (±) -cis-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5- (1H-pyrrol-1-yl) -1,4-benzothiazepine-1,1-dioxide mp 50-52 ° C;

(+) - cis-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-7H-pyrrolo [3,4-F] -1,4-thiazepine-1,1-dioxide 0.125 H ₂ O, mp 75-77 ° C;

(+) - 2,3,4,5-tetrahydro-7-methoxy-5-phenylspiro (1,4-benzothiazepine-3,1-cyclohexane) -1,1-dioxide, m.p. 142-143 ° C;

(+) - trans-l- (3-ethyl-5 2.3.4 _{T-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-3-yl)} -2-butanón5.5- dioxide hydrochloride, mp 175 -176 ° C;

(+) - trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenylnaphtho (3,2-F) -1,4-benzothiazepine-1,1-dioxide, m.p. 128 -131 ° C;

(+) - trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5- (2-pyridyl) -1,4-benzothiazepine-1,1-dioxide, m.p. 50-53 ° C;

(+) - trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5- (3-pyridyl) -1,4-benzothiazepine-1,1-dioxide 0.25 hydrate, m.p. 153-155 [deg.] C .;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l, 4-benzothiazepin-3-yl) -2-butanone S, S dioxide, m.p. 142-146 ° C;

(+) - trans-3- (1-butenyl) -3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide;

(+) - trans-3- (1-butenyl) -3-ethyl-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-8-methoxy-5-phenyl-1,4-benzothiazepin-3-yl) -3-butanone 5,5-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepin-3-yl) -3butanón-S, S-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-8-inetoxy-5-phenyl-l, 4-benzothiazepin-3-yl) -l-butanónS, S-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l, 4-benzothiazepin-3-yl) -3butanón-S, S dioxide (+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepin-3-yl) 4 4 _{J J} 4trifluór-1-butanone S, S dioxide;

(+) - trans-1- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepin-3-yl) -4,4,4-trifluoro- 1-butanone-S, S-dioxide;

(±) -trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l, 4-benzothiazepin-3-yl) -3,3,4, 4,4pentafluór-2-butanone S, S-dioxide;

-294 (±) -trans-l- (3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l, 4-benzothiazepin-3-yl) -3,3,4, 4,4pentafluór-2-butanone S, S-dioxide;

(+) - trans-l- _{(3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l,} 4-benzothiazepin-3-yl) -4,4,4trifluór-2-butanone S, S-dioxide;

(+) - trans-l- (3-ethyl-2.3 4.5 _{T-tetrahydro-8-methoxy-5-phenyl-4 T-benzothiazepin-3-yl)} -4,4 4trifluór _J-2-butanone S, S-dioxide;

(+) - trans-1- (3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-3- (4,4,4-trifluorobutyl) -1,4-benzothiazepine-1,1 dioxide;

(+) - trans-l- (3-ethyl-2, 3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-3- (4,4,4-trifluorobutyl) -l, 1-4benzotiazepín 1,1-dioxide;

(+) - trans-1- (3- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepin-3-yl) -2- butanone S, S-dioxide;

(+) - trans-l- (3- (2,2,2-trifluoroethyl) -2,3 _PART 4,5-tetrahydro-7,8-dimethoxy-5-phenyl-4-benzothiazepin _J

3-yl) -2-butanone S, S-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-9-methoxy-5-phenyl-1,4-benzothiazepin-3-yl) -2-butanónS, S-dioxide;

(±) -trans-3 - ((3-ethyl-2,3,4,5-tetrahydro-3- (2-oxobutyl) -5-phenyl-1,4-benzothiazepin-7-yl) oxy) propanesulfonic acid 1, 1-dioxide, (+) - trans-1- (3-ethyl-2,3,4,5-tetrahydro-7,8-diethoxy-5-phenyl-1,4-benzothiazazin-3-yl) -2- butanone

S, S-dioxide;

(+) - trans-1- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-4-hydroxy-5-phenyl-1,4-benzothiazepin-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) propanesulfonic acid 1,1-dioxide;

(+) - trans-2 - ((3-ethyl-2,3,4,5-tetrahydro-3- (2-oxobutyl) -5-phenyl-1,4-benzothiazepin-7-yl) oxy) ethyltrimethylammonium iodide 1,1 dioxide;

(+) - trans-2 - ((3-ethyl-2,3.4.5-tetrahydro-3- (2-oxobutyl-5-phenyl-1,4-benzothiazepin-8-yl) oxy) ethyltrimethylammonium iodide 1,1-dioxide

A-23

Compound of formula (I):

-295 (°) ^{η η} 7 (rji

* N

VL

R ² R ^J (I) wherein the integer is from 0 to 4;

n is an integer from 0 to 2;

R is an atom or a group selected from: halogen, cyano, nitro, alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, aralkyl, alkaryl, -O (CH ₂ ) _p SO ³ R ¹¹ , -O (CH ₂ ) _p NR ¹¹ R ¹² ,

Ο (ΟΗ ₂₎ ρΝ ^η ^ ^ ^14, -COR ^11, -CO 2 R ^11, -CONR ⁿ R ^12, -CH 2 OR ^11, -NR ⁿ R ^12, -NHCOR ^11, NHSO 2 R ^11, -SR ^11, -SO 2 R ^11, -SO 1 N ¹² R ¹² and -SO ³ R ¹¹ wherein p is an integer from 1 to 4, R ¹¹ and R ¹² are independently selected from: hydrogen, C 1 -C 6 alkyl and phenyl, and R ¹⁴ is hydrogen or C 1 -C 6 alkyl , or R is -OCH ₂ O-, which forms an additional ring attached to X, wherein said alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, aralkyl and alkaryl groups are optionally substituted with one or more atoms or groups selected from: halogen , nitro, nitrile, alkyl, alkoxy, -COR ¹¹ , -CO ² R ¹¹ , -SO ³ R ¹¹ , where R ¹¹ is as defined above, and -NR ¹⁴ R ¹⁵ , wherein R ¹⁴ is as defined above, and R ¹⁵ is hydrogen or C 1 C1-6 alkyl;

R ¹ is hydrogen or C 1 -C 6 alkyl;

R ² is an atom or a group selected from: hydrogen, C 1 -C 6 alkyl (including cycloalkyl and cycloalkylalkyl), C 1 -C 4 alkoxy, pyryl, thienyl, pyridyl, 1,3-benzodioxolo, phenyl and naphthyl, wherein the groups are optionally substituted with one or more atoms or groups independently selected from halogen, cyano, nitro, carboxyl, phenyl, phenoxy, benzyloxy, -COR ^11, -CO 2 R ^11, CONR ¹² R ^n, -CH 2 oR ^11, -NR ¹¹ R ^12, -NHCOR ^11, - NHSO ² R ¹¹ , -SR ¹¹ , -SO ² R ¹¹ (wherein R ¹¹ and R ¹² are as defined above), O (CH 2) PN ⁴ R ¹¹ R ¹² R ¹³ and -O (CH 2) _P SO ₃ R ¹¹ (wherein p, R ¹¹ and R ¹² are as defined above and R ¹³ is hydrogen or C 1 -C 6 alkyl);

R ³ is hydrogen, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or -OC 1 -C 6 acyl;

R ⁴ is independently selected from: C 1 -C 6 alkyl (including cycloalkyl and cycloalkylalkyl), C 2 -C 6 alkenyl and C 2 -C 6 alkynyl, wherein the groups are optionally substituted with one or more atoms or groups independently selected from: halogen, oxo, C1. C 4 alkoxy, -CO 2 R ¹⁴ , -NR ¹⁴ R ¹⁵ , SR ¹⁴ , -S (O) C 1-6 alkyl, -SO ² R ¹⁴ , -SO ² R ¹⁴ (wherein R ¹⁴ and R ¹⁵ are as defined above);

-296or R ⁴ and R ⁵ together with the carbon atom to which they are attached form a C 3 -C 7 spirocycloalkyl group which is optionally substituted by one or more atoms or groups independently selected from: halogen, C 1 -C 6 alkoxy, -CO ² R ¹⁴ , - SO ³ R ¹⁴ and -NR ¹⁴ R ¹⁵ (wherein R ¹⁴ and R ¹⁵ are as defined above);

A 7

R and R are independently hydrogen or C 1 -C 6 alkyl; and

X is an aromatic or non-aromatic monocyclic or bicyclic ring system having from 5 to 10 carbon atoms (including those two carbon atoms forming part of the thiazepine ring), wherein optionally one or more carbon atoms are replaced by heteroatom (s) independently selected (s) (i) between nitrogen, oxygen and sulfur; with the proviso that when 1 is an integer from 0 to 4, R ^{1 =} R ⁶ = R ⁷ = H, R ³ = H or OH, R ² = unsubstituted phenyl or phenyl substituted with one or more atoms or groups independently selected from: halogen, nitro, phenylalkoxy, C 1 -C ⁴ alkoxy, C 1 -C ⁶ alkyl and O 4 H 4 SO 5 R ¹¹ , wherein p and R ¹¹ are as defined above, wherein said phenylalkoxy, alkoxy and alkyl groups are optionally substituted with one or more halogen atoms, and X is a fused phenyl ring then R ⁴ is different from a C 1 -C ⁶ unbranched alkyl group and R ⁵ is different from a C 2 -C 3 unbranched alkyl group; and salts, sovates and physiologically active derivatives thereof.

A-24

A compound as in A-23 which is the trans isomer wherein it is 0,1 or 2;

n is 1 or 2;

R ¹ , R ⁶ and R ⁷ are all hydrogen;

<1

R is hydrogen or hydroxy; and

X is a phenyl, naphthyl, pyryl, thienyl or pyridyl group attached.

A-25

A compound as in A-23 or A-24, wherein 0 or 1;

n is 2; and

R ² is pyryl, thienyl, pyridyl, phenyl or naphthyl, these groups may optionally be substituted with one or more atoms or groups independently selected from: halogen, cyano, nitro, carboxyl, phenyl, phenoxy, benzyloxy, -COR ¹¹ , -CO ³ R ¹¹ , -CONR ⁿ R ^12, -CH ₂ OR ^n, -NR ⁿ R ^12, NHCOR ^11, -NHSOjR ^11, -SR ^11, -SOjR ^11, -SO 3 R ¹¹ (wherein R ¹¹ and R ¹² are independently selected from:

-297hydrogen, C 1-4 alkyl and phenyl), -O (O½) ^ ¹¹ ^ ² , O (O¾) ^ ¹ ^ ¾ ¹³ and -CKCH ³ J p SO ³ R ¹¹ (where p is an integer from 1 to 4, R ¹¹ and R ¹² are defined as above and R ¹³ is hydrogen or C 1 -C 6 alkyl). A-26

A compound as in A-23 which is:

(-) - (RR) -3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide;

(+) - trans-3 - ((E) -2-butenyl) -3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide; (+) - Trans-3-ethyl-2,3,4,5-tetrahydro-3- (3-methoxypropyl) -5-phenyl-l, 4-benzothiazepine l, l-dioxide; (+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l, 4-benzothiazepin-3-yl) -2-butanone S, S-dioxide; (+) - trans-1- (3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepin-3-yl) -2-butanone S, S-dioxide hydrochloride 1.1 hydrate;

(+) - trans-3- (1-butenyl) 3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide hydrochloride 0.4 hydrate;

(+) - trans-3- (ethoxyethyl) -3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide hemihydrate hydrochloride;

(+) - trans-3- (ethoxymethyl) -3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide hydrochloride;

(+) - trans-ethyl 3- (3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l, 4-benzothiazepin-3-yl) propionate l-dioxide;

(+) - trans- (E) -4- (3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l, 4-benzothiazepin-3-yl) -3-buten-2-one- l-dioxide;

(+) - 2,3,4,5-tetrahydro-8-methoxy-5-phenylspiro (1,4-benzothiazepine-3,1-cyclohexane) -1,1-dioxide; (+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5- (4-pyridyl) -l, 4-benzothiazepine l, l-dioxide; (+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-4-hydroxy-5- (4-pyridyl) -l, 4-benzothiazepine l-dioxide;

(+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5- (2-thienyl) -1,4-benzothiazepine-1,1-dioxide; (+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5- (lH-pyrrol-l-yl) -l, 4-benzothiazepine l, l-dioxide; (+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-pyrido (4,3-F) -l, 4-benzothiazepine l, l-dioxide; (+) - trans-3-butyl-3-ethyl-3,4,5,7-tetrahydro-5-phenyl-2H-pyrrolo [3,4-F] -1,4-benzothiazepine-1,1-dioxide 0, 1 hydrate;

(+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-thieno (2,3-F) -l, 4-benzothiazepine l, l-dioxide; (+) - trans-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-3- (4,4,4-trifluorobutyl) -1,4-benzothiazepine-1,1-dioxide;

(+) - trans-2,3,4,5-tetrahydro-3-isopropyl-3-methyl-5-phenyl-l, 4-benzothiazepine l, l-dioxide 0.25 H ₂ 0;

-298 (+) - trans-3 - ((E) -2-butenyl) -3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l, 4-benzothiazepine;

(+) - cis-2,3,4,5-tetrahydro-3-isopropyl-3-methyl-5-phenyl-1,4-benzothiazepine-1,1-dioxide 0,66

H ₂ O;

(±) -trans-3- (3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-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 ;

(±) -2,3,4,5-tetrahydro-7-methoxy-5-phenylspiro [1,4-benzothiazepine-3,1-cyclohexane] -1,1-dioxide; (+) - trans-1- (3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-3-yl) -2-butanone 5,5-dioxide hydrochloride ;

(+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-fenylnafto (3,2-F) -l, 4-benzothiazepine l, l-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l, 4-benzothiazepine-3-yl) -2-butanone S, S dioxide;

(+) - trans-3- (1-butenyl) -3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dinietoxy-5-phenyl-l, 4-benzothiazepin-3-yl) -3butanón-S, S dioxide;

(+) - trans-1- (3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepin-3-yl) -1-butanone 5,5-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l, 4-benzothiazepin-3-yl) -lbutanón-S, S dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l, 4-benzothiazepin-3-yl) -4,4,4trifluór- 1-butanone-S, S-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dinietoxy-5-phenyl-l, 4-benzothiazepin-3-yl) -3,3,4, 4,4pentafluór-2-butanone S, S-dioxide;

(+) - trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l, 4-benzothiazepin-3-yl) -4,4,4trifluór- 2-butanone S, S-dioxide;

(+) - trans-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-3- (4,4,4-trifluoroibutyl) -1,4-benzothiazepine-1,1- dioxide;

(+) - trans-l- (3- (2,2,2-trifluoroethyl) -2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-4-benzotiazepin3-yl) - 2-butanone S, S-dioxide;

(±) -trans-l- (3-ethyl-2,3,4,5-tetrahydro-7,8-diethoxy-5-phenyl-l, 4-benzothiazepin-3-yl) -2-butanónS, S dioxide;

(±) -trans-3 - ((3-ethyl-2,3,4,5-tetrahydro-3- (2-oxobutyl) -5-phenyl-1,4-benzothiazepin-8-yl) oxy) propanesulfonic acid 1, 1-dioxide;

-299 (±) -trans-2 - ((3-ethyl-2,3,4,5-tetrahydro-3- (2-oxo-butyl) -5-phenyl-l, 4-benzothiazepin-8-yl) oxy) etyltrimetylamóniumjodid- 1,1-dioxide;

A-27

Compound as in A-23 of formula (Ia):

(Ia) wherein the integer is from 0 to 4;

n is an integer from 0 to 2;

R is an atom or group selected from halogen, cyano, nitro, alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, aralkyl, alkaryl, -COR ^11, -COAr ^11, -CONR ¹¹ R ^12, -CH 2 ^N, -NR ^h R ^12, -NHCOR ^11, -NHSO ^11, -SR ^11, -SO ^ ^11, -SO 3 R ⁿ wherein R ¹¹ and R ¹² are independently selected from hydrogen, alkyl and phenyl cj.com, wherein said alkyl, alkoxy, , aryl, heteroaryl, aryloxy, arylacloxy, aralyl and alkaryl are optionally substituted with one or more atoms or groups selected from: halogen, nitro, nitryl, alkyl, alkoxy, -COR ¹¹ , -CO 4 ¹¹ , SO ⁵ R ¹¹ , wherein R ¹¹ is as defined above, and -NR ¹⁴ R ¹⁵ , wherein R ¹⁴ and R ¹⁵ are as defined above;

R ¹ and R ³ are independently selected from: hydrogen and C 1 -C 6 alkyl;

R ² is an atom or a group selected from: hydrogen, C 1 -C 6 alkyl (including cycloalkyl and cycloalkylalkyl), C 1 -C 4 alkoxy, pyryl, thienyl, pyridyl, 1,3-benzodioxolo, phenyl and naphthyl, wherein the groups are optionally substituted with one or more atoms or groups independently selected from halogen, cyano, nitro, carboxyl, phenyl, phenoxy, benzyloxy, -COR ^11, -CO ^11, CONR ¹² R ^{n, n} -CH 2 oR, -NR ⁿ R ^12, -NHCOR ^11, -NHSO ² R ^H , -SR ¹¹ , -SO ² R ^H , -SO ³ R ¹¹ (wherein R ¹¹ and R ¹² are independently selected from hydrogen, C 1 -C 6 alkyl and phenyl), -O (CH 2) p SO ₃ R ⁿ (where p is an integer the number from 1 to 4, R ¹¹ and R ¹² are as defined above and R ¹³ is hydrogen or C 1 -C 6 alkyl); R ⁴ is independently selected from: C 1 -C 6 alkyl (including cycloalkyl and cycloalkylalkyl), C 1 -C 6 alkenyl and C 1 -C 6 alkynyl, wherein the groups are optionally substituted with one or more atoms or groups independently selected from: halogen, C 1 -C 4 alkoxy , -CO 3 ¹⁴ , -NR ¹⁴ R ¹⁵ , -SO ₃ R ¹⁴

-300 (wherein R ¹⁴ and R ¹⁵ are independently selected from hydrogen and C 1 -C 6 alkyl) and R ¹⁶ COR ¹⁷ wherein R ¹⁶ is C 1 -C 4 alkylene and R ¹⁷ is C 1 -C 4 alkyl;

R ⁵ is independently selected from: C 2 -C 6 alkyl (including cycloalkyl and cycloalkylalkyl), C 2 -C 6 alkenyl and C 2 -C 6 alkynyl, wherein the groups are optionally substituted with one or more atoms or groups independently selected from: halogen, C 1 -C 4 alkoxy , -CO 2 R ¹⁴ , -NR ¹⁴ R ¹⁵ , -SO ³ R ¹⁴ (where R ¹⁴ and R ¹⁵ are independently selected from hydrogen and a C 1 -C 6 alkyl group) and R ¹⁶ COR ¹⁷ , wherein R ¹⁶ is a C 1 -C ⁴ alkylene group and R ^{16 17} is C 1 -C 4 alkyl; or R ⁴ and R ⁵ together with the carbon atom to which they are attached form a C 3 -C 7 spirocycloalkyl group which is optionally substituted with one or more atoms or groups independently selected from: halogen, C 1 -C 6 alkoxy, -CO ² R ¹⁴ , -SO 3 R ¹⁴ and -NR ¹⁴ R ¹⁵ (wherein R ¹⁴ and R ¹⁵ are as defined above);

R ⁶ and R ⁷ are independently selected from hydrogen and C 1 -C 6 alkyl; and

X is an aromatic or non-aromatic monocyclic or bicyclic ring system having 5 to 10 carbon atoms (including those two carbon atoms forming part of the thiazepine ring) wherein one or more carbon atoms are / are optionally replaced with heteroatom (s) independently selected from nitrogen, oxygen and sulfur; with the proviso that when 1 is an integer from 0 to 4, R ^{1 =} R ³ = R ⁶ = R ⁷ = H, R ² = unsubstituted phenyl or phenyl substituted with one or more atoms or groups independently selected from: halogen, nitro, phenylalkoxy, C 1 -C 4 alkoxy, C 1 -C 6 alkyl, and -OCH ² p R ¹¹ , wherein p and R ¹¹ are as defined above, wherein said phenylalkoxy, alkoxy and alkyl groups are optionally substituted with one or more halogen atoms, and X is a phenyl ring attached then R ⁴ is different from C 1 -C ⁶ unbranched alkyl and R ⁵ is different from C 2 -C 5 unbranched alkyl, and salts, solvates and physiologically functional derivatives thereof.

A-28

Compound of formula (I):

is an integer from 0 to 4;

(I)

-301n is an integer from 0 to 2;

R is an atom or a group selected from:

halogen, cyano, hadroxy, nitro, alkyl, alkoxy, aryl, heteroaryl, aryloxy, arylalkoxy, aralkyl, alkaryl, -COR ^11, -CO 2 R ^{n, n} -C0NR R ^12, -CH 2 OR ^n, -NR ⁿ R ^12, -NHCOR ^11, -NHSO 2 R ^U, SR ^11, -SO ^ ^11, and -SO 3 R ¹¹ wherein R ¹¹ and R ¹² are independently selected from hydrogen, alkyl and Ci.Ce phenyl, wherein said alkyl, alkoxy, aryl, heteroaryl, aryloxy, , arylalkoxy, aralkyl and alkaryl are optionally substituted by one or more atoms or groups selected from halogen, hydroxy, nitro, nitrile, alkyl, alkoxy, -COR ^11, -CO 2 R ^n, -SO 3 R ', wherein R ¹¹ is as defined above, and -NR ¹⁴ R ¹⁵ , wherein R ¹⁴ and R ¹⁵ are as defined above;

R ¹ is hydrogen or C 1 -C 6 alkyl;

R ² is an atom or a group selected from: C 1 -C 6 alkyl (including cycloalkyl and cycloalkylalkyl), C 1 -C 4 alkoxy, pyryl, thienyl, pyridyl, 1,3-benzodioxolo, phenyl and naphthyl, wherein the groups are optionally substituted with one or more atoms or groups independently selected from halogen, cyano, hydroxyl, nitro, carboxyl, phenyl, phenoxy, benzyloxy, -COR ^11, -CO ^11, -CONR ⁿ R ^12, CH 2 OR ^n, -NR ⁿ R ^12, -NHCOR ^11, -NHSO ^ ^11, -SR ^11, -SO ^ ^11, and -SO 3 R ¹¹ (wherein R ¹¹ and R ¹² are independently hydrogen, alkyl or phenyl cj.com), -OÍCH NR ^ ¹¹ ^ ^2, -0 (ΟΪ2) ρΝ ^ ^π R ¹³ and OCH 2 SO 5 R ¹¹ (where p is an integer from 1 to 4, R ¹¹ and R ¹² are as defined above and R ¹³ is hydrogen or C 1 -C 6 alkyl);

R ³ is hydrogen, hydroxy or C 1 -C 6 alkyl;

R ⁴ is independently selected from: C ₁ -C 6 alkyl (including cycloalkyl and cycloalkylalkyl), C ₂ -C 6 alkenyl and C ₂ -C 6 alkynyl, wherein the groups are optionally substituted with one or more atoms or groups independently selected from: halogen, -OR ¹⁴ , -CO 2 R ¹⁴ , -NR ¹⁴ R ^15, and -SO ³ R ¹⁴ (wherein R ¹⁴ and R ¹⁵ are independently hydrogen or C 1 -C 6 alkyl);

R ⁵ is independently selected from: C ₂ -C 6 alkyl (including cycloalkyl and cycloalkylalkyl), C ₂ -C 6 alkenyl and C ₂ -C ₆ alkynyl, wherein the groups are optionally substituted with one or more atoms or groups independently selected from ^- halogen , -OR ¹⁴ , -CO 4 R ¹⁴ , -NR ¹⁴ R ^15, and -SO ³ R ¹⁴ (wherein R ¹⁴ and R ¹⁵ are independently selected from hydrogen and C 1 -C 6 alkyl);

or R ⁴ and R ^s taken together with the carbon atom to which they are attached, they form a C 3 -C 7 spiro radical, which is optionally substituted by one or more atoms or groups independently selected from halogen, -OR ^14, -CO ^14, -SO 3 R ¹⁴ and -NR ¹⁴ R ¹⁵ (wherein R ¹⁴ and R ¹⁵ are as defined above);

R ⁶ and R ⁷ are independently selected from hydrogen and C 1 -C 6 alkyl; and

X is an aromatic or non-aromatic monocyclic or bicyclic ring system having from 5 to 10 carbon atoms (including those two carbon atoms that form part of

-302thazepine ring), wherein optionally one or more carbon atoms are replaced by heteroatom (s) independently selected (i) between nitrogen, oxygen and sulfur;

with the proviso that when 1 is an integer from 0 to 4, R ^{1 =} R ⁶ = R ⁷ = H, R ³ = H or OH,

A

R = unsubstituted phenyl or phenyl substituted with one or more atoms or groups independently selected from halogen, nitro, phenylalkoxy, C 1 -C 4 alkoxy, C 1 -C 6 alkyl and O (CH ₂ ) _p SO ₃ R ¹¹ , where p and R ¹¹ are defined as above, wherein said phenylalkoxy, alkoxy and alkyl groups are optionally substituted with one or more halogen atoms, and X is a phenyl ring attached thereto, then R ⁴ is different from a C 1 -C ⁶ unbranched alkyl group and R ⁵ is different from a C ₂ -C 5 unbranched alkyl group and salts, solvates and physiologically functional derivatives thereof for use in therapy

A-29

3-ethyl-3-methyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine, mp 124-125 ° C; (+) - 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide, mp 100102 ° C;

3-butyl-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1,4-benzothiazepine-1,1-dioxide, mp 103104 ° C;

3-methyl-3-propyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide, m.p.

120-121 [deg.] C .;

3,3-diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide, m.p. 115-116 ° C;

(+) - trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide, m.p. 101 ° C;

(+) - trans-2,3,4,5-tetrahydro-3-methyl-5-phenyl-3-propyl-1,4-benzothiazepine-1,1-dioxide, m.p. 129-130 ° C;

(-) - 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide, m.p. 101103 ° C;

3-ethyl-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1,4-benzothiazepine, m.p. 110-112 ° C; 3-ethyl-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1,4-benzothiazepine hydrochloride 0.25 H ₂ O, mp 162-164 ° C (ef.);

3-ethyl-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1,4-benzothiazepine-1,1-dioxide, mp 128129 ° C;

-3033.3-diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine hydrochloride, m.p. 211-214 ° C, (+) - 2,3,4,5-tetrahydro-3- methyl 5-phenyl-3-propyl-1,4-benzothiazepine, m.p. 101-103 ° C;

2.3.4.5-tetrahydro-3-methyl-5-phenyl-3-propyl-1,4-benzothiazepine, mp 72-74 ° C; 3-ethyl-2,3,4,5-tetrahydro-5-phenyl-3-propyl-1,4-benzothiazepine hydrochloride 0.25 H ₂ O, mp 205-207 ° C;

3-ethyl-2,3,4,5-tetrahydro-5-phenyl-3-propyl-1,4-benzothiazepine-1,1-dioxide 0.25 H ₂ O, mp 115-118 ° C;

2.3.4.5-tetrahydro-5-phenyl-3,3-dipropyl-1,4-benzothiazepine hydrochloride, 209-211 ° C; 3-ethyl-2,3,4,5-tetrahydro-5-phenyl-3-propyl-1,4-benzothiazepine-1,1-dioxide hydrochloride 0.33 H ₂ O, 206-209 ° C;

2.3.4.5-tetrahydro-5-phenyl-3,3-dipropyl-1,4-benzothiazepine-1,1-dioxide, m.p. 104-106 ° C;

3,3-dibutyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine hydrochloride, b. 209-212 [deg.] C .; 3-butyl-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1,4-benzothiazepine hydrochloride, m.p. 203-205 ° C;

3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine hydrochloride, m.p. 205207 ° C;

3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide hydrochloride, m.p. 209-212 ° C;

2.3.4.5-tetrahydro-3-methyl-3-pentyl-5-phenyl-1,4-benzothiazepine maleate, m.p. 182183 ° C;

3-ethyl-2,3,4,5-tetrahydro-5-phenyl-3-propyl-1,4-benzothiazepine hydrochloride, m.p. 198-200 ° C;

(+) - cis-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methyl-5-phenyl-1,4-benzothiazepine-1,1-dioxide, m.p. 138-140 ° C;

(+) - cis-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepine, light yellow oil; (+) - trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepine, light yellow oil;

(+) - cis-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide, m.p. 113-115 C;

-304 (+) - cis-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepine-1-oxide, mp 103-105 ° C;

(+) - trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide hydrochloride, m.p. 201 [deg.] C .;

(+) - trans-3-butyl-3-ethyl-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxide, m.p. 98-101 ° C;

(+) - trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1-oxide, m.p. 133-136 ° C;

(+) - cis-7-chloro-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine 0.4 toluene, light yellow oil;

(+) - trans-7-chloro-3-butyl-3-ethyl-2-3-4-5-tetrahydro-5-phenyl-1,4-benzothiazepine 0.3 toluene, light yellow oil;

(+) - Trans-3-butyl-7-chloro-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-l, l-dioxide. mp 100-102 ° C;

(+) - trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5- (4-methoxyphenyl) -1,4-benzothiazepine-1,1-dioxide hydrochloride, m.p. 194-196 C;

(±) -trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5- (4-tolyl) -1,4-benzothiazepine-1,1-dioxide hydrochloride, m.p. 204-206 C;

(+) - cis-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5- (4-tolyl) -1,4-benzothiazepine-1,1-dioxide, m.p. 155-156 ° C;

(+) - cis-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5- (4-methoxyphenyl) -1,4-benzothiazepine, m.p.

75-77 [deg.] C .;

(+) - cis-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5- (4-methoxyphenyl) -1,4-benzothiazepine-1,1-dioxide, mp 109-111 ° C;

(+) - cis-3-butyl-3-ethyl-5- (4-fluorophenyl) -2,3,4,5-tetrahydro-1,4-benzothiazepine, m.p.

76-78 [deg.] C .;

(+) - trans-3-butyl-5- (3,4-dichlorophenyl) -3-ethyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, m.p. 98-100 ° C;

(+) - Trans-3-butyl-5- (4-chlorophenyl-3-ethyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-1,1-dioxide hydrochloride 0,3H2O, mp 178-180 ° C) ;

(+) - cis-3-butyl-5- (4-chlorophenyl) -5-ethyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-1,1-dioxide hydrochloride, m.p. 186-188 C;

-305 (+) - trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5- (3-nitrophenyl) -1,4-benzothiazepine-1,1-dioxide, m.p. 139-142 ° C;

(+) - trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5- (4-nitrophenyl) -1,4-benzothiazepine-1,1-dioxide, m.p. 139-142 ° C;

(+) - trans-5- (4-benzyloxyphenyl) -3-butyl-3-ethyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-1,1-dioxide, m.p. 94-95 ° C;

(±) -cis-5- (4-benzyloxyphenyl) -3-butyl-3-ethyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-1,1-dioxide, m.p. 137-138 ° C;

(±) -trans-5- (4-benzyloxyphenyl) -3-butyl-3-ethyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, m.p. 97-98 ° C;

(+) - trans -3- [4- (3-Butyl-3-ethyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-5-yl) phenoxy] propanesulfonic acid 1,1-dioxide, m.p. 270 DEG C. (decomposition);

(+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5- (2-fluorophenyl) -1,4-benzothiazepine-1,1-dioxide hydrochloride, m.p. 194-196 C;

(+) - Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5- (3-fluorophenyl) -1,4-benzothiazepine l, l-dioxide. mp 143-145 ° C;

(+) - cis-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5- (4-pyridyl) -1,4-benzothiazepine-1,1-dioxide, m.p. 121-123 ° C;

(+) - trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5- (4-pyridyl) -1,4-benzothiazepine-1,1-dioxide, m.p. 110-111 ° C;

(+) - cis-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5- (4-trifluoromethylphenyl) -1,4-benzothiazepine-1,1-dioxide, m.p. 64-65 ° C;

(+) - trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5- (4-trifluoromethylphenyl) -1,4-benzothiazepine-1,1-dioxide, m.p. 110-112 ° C;

(+) - trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5- (3,4-difluorophenyl) -1,4-benzothiazepine-1,1-dioxide, m.p. 215 [deg.] C .;

(+) - trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5- (2,4-difluorophenyl) -1,4-benzothiazepine-1,1-dioxide, m.p. 97-99 ° C;

(+) - trans-3-isopentyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide, m.p. 86-87 ° C; and (+) - cis-3-isopentyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide, m.p. 123-125 ° C (- (R) -3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide hydrochloride

-306 (+) - trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide, m.p. 98-100 ° C, (-) - trans-3-methyl-3-propyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide, mp 129-130 ° C;

A-30

Compound of Formula (I) (R) j

(I) wherein the integer is from 0 to 4;

m is an integer from 0 to 5;

n is an integer from 0 to 2;

R and R 'are atoms or groups independently selected from: halogen, nitro, phenylalkoxy, C 1 -C 4 alkoxy, C 1 -C 6 alkyl and -OfC 1-6 SChR, wherein p is an integer from 1 to 4 and R 1 is hydrogen or C 1-6. C 6 alkyl, wherein said phenylalkoxy, alkoxy and alkyl groups are optionally substituted with one or more halogen atoms;

R ⁴ is C 1 -C 6 unbranched alkyl; and

R ⁵ is a C 2 -C 6 unbranched alkyl group;

and salts, sovates and physiologically functional derivatives thereof.

A-31

A compound of formula (1) as in A-30, wherein n is 2;

-307R ⁴ is methyl, ethyl, n-propyl, or n-butyl; and

R ⁵ is ethyl, n-propyl, or n-butyl;

and salts, solvates and physiologically functional derivatives thereof.

A-33

A compound of formula (I) as in A-31, wherein the compound is in a trans configuration, as defined herein, or a salt solvate, or a physiologically functional derivative thereof.

A-34

A compound of formula (I) as in A-32, wherein the 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 a physiologically functional derivative thereof.

A-35

The compound of formula (I) described in A-33, wherein the compound is in the form of (RR) -, (SS) -, or (RR, SS) -, or is a salt, solvate, or physiologically functional derivative thereof. (-) - (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 thereof compound.

(-) - (RR) -3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide (+) - (RR, SS) -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.

(+) - (RR, SS) -3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide

A-36

Polymeric or oligomeric bile acid, prepared by polymerizing a monomeric bile acid of formula I

G-X-A (I) wherein

G is a free bile acid or a basic metal salt thereof, or a bile acid having rings A, B, C, D esterified on ring D and which is bonded via ring A, B or C to group X,

X is a bridge and

-308A is a polymerizable, ethylenically unsaturated group, or unsaturated by copolymerization with a monomer comprising a polymerizable, ethylenically unsaturated double bond, or unsaturated by copolymerization with N-vinylpyrrolidone or derivatives thereof, and / or copolymerization with ethylenically unsaturated dicides and ethylene unsaturated dicides, each containing 2 to 6 carbon atoms; esters or polyesters thereof, esters understood as alkyl esters having 1-6 carbon atoms, cycloalkyl esters having 5 to 8 carbon atoms, benzyl esters or phenyl esters.

A-37

A polymer or oligomer as in A-36, wherein

G is a free bile acid or a basic metal salt or bile acid esterified on ring D which is bonded through its ring A, B or C to a group X to which the formula Π (Y)) - (Z) _P OO applies, in which

Y is adjacent to G and is -O-, -NR'-,

O O

I II

-Ο-C-, or -NR'-CZ is (C 1 -C 12) -alkylene or (C 7 -C 13) -aralkylene, wherein the individual methylene groups in the alkylene chain of the alkylene or aralkylene radical may be replaced by one or more groups selected from:

-O-, -NR-, -NR'-C-, -O-C- and -NR'-C-NR''-.

n i u

0 o o and p are independently zero or one, where o λ p are not zero at the same time,

A is an ethylenically unsaturated group of the formula

-3090 tl

N— or

R

CH ₂ = C R -.

II

About where

R ¹ is hydrogen or CH 3 and R ² is

O O u n

-NR-C-, -O-C-. -O-, -NR'or single bond, wherein the carbonyl groups are adjacent to a C-C double bond, R 'and R are independently hydrogen or (C 1 -C 6) alkyl.

A-38

A polymer or oligomer as in A-37, wherein

G corresponds to the general formula ΙΠ

in which

-310R ³ to R ⁸ are independently hydrogen, OH, NH ₂ or OH group protected by a protective group of OH and one of the radicals R ³ to R ⁶ is a bond to the group X, where this bond starts from the positions 3 ^(R3 or R ⁴ ) or 7 (R ⁵ or R ⁶ ), and the second remaining position 7 or 3 in each case carries an OH group or a protected OH group,

B is -OH, -O-alkali metal, -O-alkaline earth metal, -O- (C 1 -C ₁₂ ) -alkyl, -O-allyl or -O-benzyl, wherein the alkyl is either n-alkyl or iso- alkyl and wherein the ester group is formed

ABOUT

is an ester that can be saponified with both acid and base,

Y is -O-, -NR'-,

O O n u

-Ο-C-, or-NR'-CZ is (C 1 -C ₁₂ ) -alkylene, (C 7 -C 11) -aralkylene wherein 1-3 of the methylene groups in the alkylene chain are replaced by -O-, -NR ', -NR'-C-, -O-C-,

O O or -NR'-C-NR 10

and o and p are independently zero or one, where o and p are not simultaneously zero,

And it is

O n

C I

N - or CH ₂ = C - R ¹ -.

II

Wherein R ¹ is hydrogen or CH ₃ and R ² is

ABOUT

II

-NR'-C-311-NR'- or a single bond, wherein R 'and R are independently hydrogen or (C 1 -C 6) alkyl

A-39

The polymeric or oligomeric bile acid of A-36, wherein said monomer comprising a polymerizable, ethylenically unsaturated double bond is a monomer of Formula IV

R ⁹

H ₂ C = CR ¹⁰ (IV)

R ⁹ is hydrogen or methyl;

R ¹⁰ is

O O O

II 'II ₁₂ π II H

-COR ¹¹ , -C-NR ¹² R ¹³ , -OCR ¹⁴ ,

-CN, -OR ¹⁵ , hydrogen, halogen, -SO 3 H, or -O- (CH ₂ -CH ₂ -O) n R ¹⁶ , wherein

R ¹¹ is hydrogen, (C 1 -C 10) -alkyl, (C 1 -C 10) -monohydroxyalkyl or - (CH ₂ CH ₂ -O-) R ¹⁶ ,

R ¹² , R ¹³ , R ¹⁵ , and R ¹⁶ are identical or different and are (C 1 -C 10) -alkyl, R ¹⁴ is (C 1 -C ₁₈ ) -alkyl and is 1 to 50.

A-40

A polymer or oligomer as in A-36, wherein the average molecular weight is up to 250,000 g / mol.

A-41

A polymer or oligomer as in A-36, wherein in the case of copolymers the molar ratio of bile acid units to units of copolymerized monomers is between 300-1 and 1: 300

-312Α-42

A polymer or oligomer as in A-36, wherein the cross bridges are formed by copolymerization with ethylene polyunsaturated monomers.

A-43

A polymer or oligomer as in A-42, wherein the cross bridges are formed by ethylene polyunsaturated derivatives of acrylic acid and methacrylic acid.

A-44

A polymer or oligomer as in A-42, wherein the cross bridges are formed by the acid amides of formula V

R ⁹ OOR ⁹

I II II I h ₂ c = c-nh-d-nh-cc = ch ₂ (V) in which

R ⁹ is hydrogen or methyl and D is - (CHE) _m -, wherein m is 1 to 10 a

E is hydrogen or OH.

A-45

A pharmaceutical composition comprising the compound of A-36 and a pharmaceutically acceptable carrier.

A-46

A polymer or oligomer as in A-40, wherein the average molecular weight is between 2,000 and 100,000 g / mol.

A-47

The polymer or oligomer described in A-47, wherein the average molecular weight is between 3,000 and 60,000 g / mol.

A-48

A polymer or oligomer as in A-38, wherein B is -OH, -O-alkali metal, -O- (C 1 -C 6) -alkyl, -Olyl or -O-benzyl.

A-49

A polymer or oligomer as in A-38, wherein R ³ to R ⁸ are independently hydrogen, OH, NH 2 or an OH group protected by an OH protecting group and one of the radicals R to R is a bond to the X group where the bond begins from 3 (R ³ or R ⁴ ) or 7 (R ⁵ or R ⁶ ) in the β-position and the remaining position 7 or 3 in each case carry an OH group or a protected OH group.

A-50

A polymer or oligomer as in A-37, wherein G is a free bile acid or an alkali metal salt thereof, or a bile acid esterified on ring D, which is linked via ring A to group X.

A-51

A polymer or oligomer as in A-39, wherein the monomers are compounds of formula IV and are (meth) acrylic acid, esters of (meth) acrylic acid, acrylamide and its derivatives, vinyl esters of carboxylic acids having 3-20 carbon atoms or N-vinylpyrrolidone and its derivatives.

A-52

The polymeric or oligomeric bile acid of A-39, wherein said halogen is chlorine, bromine, or iodine.

EXAMPLE 1

g (122 mmol) of 3a, 7a, 12a-trihydroxy-24-nor-23-cholanic acid (= norcholic acid), 200 ml of formic acid and 1 ml of perchloric acid (60%) are stirred at 50 ° C for 1.5 hours hours, the mixture is cooled to room temperature, 160 ml of acetic anhydride are added and the mixture is stirred for a further 15 minutes. It is poured into 1.5 l of water and the solids are filtered off with suction and rinsed with 1 l of water. The precipitate is dissolved in 700 ml of ether and washed three times with water. The organic phase was dried (MgSO4) and concentrated. Yield 52 g (89%) of Example 1.

MS (FAB, 3-NBA / LiCl) Ο ₂₆ Η ₃₈ Η ₈ (478), 485 (m + Li ⁺ )

-315Example 2

g (10.4 mmol) of the compound of Example 1 was dissolved in 20 ml of trifluoroacetic acid / 5 ml of trifluoroacetic anhydride at 0 ° C. 840 mg (12 mmol) of sodium nitrite are added in portions over one hour. The mixture was then stirred at 0 ° C for an additional hour, then at 40 ° C for two hours. The solution was recooled to 0 ° C, neutralized with 5M NaOH and extracted with dichloromethane. The organic phase was dried (MgSO 4) and concentrated. Example 2 gives a precipitate on silica gel (cyclohexane / ethyl acetate = 2: 1) 3.1 g (67%).

MS (FAB, 3-NBA / LiCl) C ₂₅ H ₃₅ NO ₆ (445), 452 (M + Li ⁴ )

Example 3

H

OH

-3161.5 g (3.37 mmol) of the compound of Example 2 and 5 g of KOH are dissolved in 50 ml of ethanol / water (= 1: 1) and the solution is heated to reflux. When the reaction is complete (TLC monitoring), the ethanol is distilled off and the residue is washed with ether. The aqueous phase was acidified with 2M HCl and extracted three times with ethyl acetate. The combined organic phases were dried (MgSO 4) and concentrated. 1.25 g (97%) of Example 3 was obtained.

MS (FAB, 3-NBA / LiCl) C ₂ 2H 36 O ₅ (380), 387 (M + Li ⁺ )

Example 4

500 mg (12.87 mmol) of 3a, 7a, 12a-trihydroxy-24-nor-23-cholanic acid and 370 mg (36 mmol) of N-methylmorpholine are dissolved in 20 ml of THF. Ethyl chloroformate (0.34 mL, 36 mmol) was added at 10 ° C. After 15 minutes a solution of 270 mg (36 mmol) of glycine in 5 mL of 1M NaOH was added dropwise. The mixture was then stirred at room temperature for 18 hours. The reaction mixture was concentrated and the precipitate was chromatographed on silica gel (dichloromethane / methanol = 8: 2). 320 mg (56%) of Example 4 were obtained.

MS (FAB / 3-NBA) C ₂₅ H ₄ NO ₆ (451), 452 (M + H ⁺ )

-317- the main frame

340 mg (53%) of Example 5 was obtained from 500 mg (12.67 mmol) of norcholic acid and 450 mg (836 mmol) of taurine in the process described in Example 4.

MS (FAB, 3-NBA) C25I143NO7S (501), 502 (M + H ⁴⁾

Example 6

g (25.3 mmol) of norcholic acid are dissolved in 50 ml of pyridine. Methanesulfonyl chloride (2.6 mL) was added dropwise at 0 ° C. The reaction mixture is then stirred at RT

-318 room temperature for 3 hours. Pour into ice water and extract three times with ethyl acetate. The organic phase was dried (MgSO 4) and concentrated. The crude product was crystallized from diisopropyl ether, filtered off with suction and dried in vacuo. 11.2 g (93%) of the compound of Example 6 are obtained.

MS (FAB, 3-NBA / LiCl) Cm H w O 5 S (472), 485 (M + 2 Li ⁺ -H ⁺ )

Example 7

38.7 g (81.9 mmol) of the compound of Example 6 and 6.9 g (106 mmol) of sodium azide are stirred

2.5 hours in 350 ml of dimethylformamide at 130 ° C. After cooling, the mixture was poured into 1.5 L of ice-water and extracted three times with ethyl acetate. The organic phase was dried (MgSO 4) and concentrated. The crude product was esterified in a methanolic hydrochloric acid solution prepared from 100 ml of methanol and 14 ml of acetyl chloride at room temperature for 2 hours. For work-up, the mixture was partially concentrated and the product was poured into 1 L of water and extracted three times with ethyl acetate. After drying and concentration of the organic phase, the crude product is chromatographed on silica gel (cyclohexane / ethyl acetate = 6: 4). 9.0 g (25%) of Example 7 were obtained.

MS (FAB, 3-NBA / LiCl) C 24 H 39 N 3 O 4 (433), 440 (M + Li ⁺ )

Example 8

-319-

8.0 g (18.5 mmol) of the compound of Example 7 was hydrogenated with hydrogen in 220 mL of ethyl acetate in the presence of about 50 mg of 10% Pd / C. When the reaction is complete, the catalyst is filtered off and the filtrate is concentrated. Chromatography of the residue (methanol / triethylamine = 95: 5) gives 6.0 g (80%) of Example 8.

MS (FAB, 3-NBA / LiCl) C 24 H 41 NO 4 (407), 414 (M + Li ⁺ )

The -3204.3 g (8.6 mmol) mesylate (cf. EP-A-0 489 423) are heated to 100 to 110 ° C in 80 ml dry DMF with 0.42 g (8.6 mmol) sodium cyanide to 3 ° C. hours. The mixture was poured into ice water and extracted with ethyl acetate, and the residue from the organic phase was filtered through silica gel (ethyl acetate / heptane = 2: 1). 890 mg (25%) of the nitrile was obtained

MS (FAB, 3-NBA / LiCl) C 26 H 41 NO 4 (431), 438 (M + Li ⁺ )

1.5 g (3.48 mmol) of the nitrile of Example 9 was hydrogenated in 100 ml of methanol with the addition of 10 ml of concentrated ammonia solution and 1 g of a 5 percent nitrate on Al 2 O 3 under 140 bar at 50 ° C for 24 hours. The catalyst was filtered off with suction, the filtrate was concentrated and the precipitate was purified over silica gel (CH ₂ Cl 2 / MeOH / conc. NH 3 solution = 100: 15: 2). 1.1 g (73%) of the amine are obtained (Example 10).

MS (FAB, 3-NBA / LiCl) C 26 H 45 NO 4 (435), 442 (M + Li ⁴ )

-321-

270 mg of dry zinc iodide was added to 9 g (21.4 mmol) of the ketone (see equation 4) under argon in 50 mL of dry dichloromethane and 10 mL (3.5 equivalents) of trimethylsilyl cyanide was added portionwise while cooling with ice. After about 1.5 hours, the reaction is complete. The precipitate remaining after concentration is purified by n-heptane / ethyl acetate = 10: 1 over silica gel. 12.1 g (85%) of a colorless oil are obtained, which mainly comprises (> 9: 1) one stereoisomer.

MS (FAB, 3-NBA / LiCl) Cl 2 H 4 NO 3 Si (664), 671 (M + Li ⁺ )

-322-

First, 2.1 mL (27.4 mmol) of trifluoroacetic acid was added to a suspension of 1.036 g (827.4 mmol) of sodium borohydride in dry THF, stirred for 15 minutes, and then 12.1 g (18.2 mmol) was added. of the nitrile from Example 11A in 40 mL of dry THF while cooling with ice. After 24 hours at room temperature, the mixture is treated with water and ether, the organic phase is extracted by shaking with a hydrogen carbonate solution and the precipitate is purified by chromatography with CH 2 Cl 2 / CH 3 OH / conc. NH 3 solution = 100: 10: 1.5. 7.83 g (48%) of the amine is obtained.

MS (FAB, 3-NBA / LiCl) Cl 2 NO 3 S 2 (596), 603 (M + Li ⁺ )

-323Example 12A

The OH g (42 mmol) of methyl ketone (compare to equation 2) is dissolved in 400 ml of methanol, 2.48 g (64 mmol) of sodium borohydride are added and the mixture is stirred at room temperature for 45 minutes. After addition of 400 ml of water, 2M HCl is carefully added until the pH reaches 3. The mixture is concentrated, water is again added and the mixture is extracted with EA. The organic phase was dried and concentrated, and the precipitate was subjected to silica gel chromatography (cyclohexane / ethyl acetate 1: 1). Yield: 15.1 g (75%)

MS (FAB, 3-NBA / LiCl) C 27 H 42 O 7 (478), 485 (M + Li ⁺ )

-324Example 12B

15.1 g (31.5 mmol) of the alcohol (Example 12A) are dissolved in 250 ml of dichloromethane / 250 ml of pyridine, 4 g (35 mmol) of methanesulfonyl chloride are added at 0 ° C and the mixture is stirred at room temperature for 2 hours. For working up, water was added and the mixture was extracted.

325-

2.0 g (5.01 mmol) of 3α, 7α, 12α-trihydroxy-24-nor-23-cholanoic acid, 2.1 g (4.98 mmol) of methyl 3β-amino-7α, 12α-dihydroxy-24 -cholateate (cf. EP-A-0 417 725), 1.36 g (10 mmol) of hydroxybenzotriazole and 1.04 g (5.4 mmol) of dicyclohexylcarbdiimide are stirred in 100 ml of dry THF at room temperature for 24 hours. and the residue is chromatographed on silica gel (chloroform / methanol = 85:15).

3.0 g (75%) of Example 13 were obtained.

MS (FAB, 3-NBA / LiCl) C4gH _TO NO ₈ (798), 805 (M + Li ⁺⁾

Examples 14 to 31 of Tables 1 to 3 are obtained similar to Example 13 (reactive -X-G2 derivatives are described in EP-A-0 489 423 or EP-A-0 417 725)

326

TABLE 1

Example_-X-G2_MS (FAB, 3NBA / LiCl 3)

C ₅ oH ₈₃ N09

849 (M + H +)

H

327

C48H77NO7 (783)

789 (M + Li ⁺ )

C49H81NO8 (811)

819 (M + Li ⁺ )

328

C ₅₅ H97NO ₉ Si ₂

979 (M + Li ⁺ )

TABLE 2

OH

329

Example -X-G2

NBA / LiCl)

MS (FAB, 3C47H77NO8)

791 (M + Li ⁺ )

(828)

C49H87NO7

835 (M + Li ⁺ )

(872)

C51H85NO10

879 (M + Li ⁺ )

330

C53H87NO9 (885)

891 (M + Li ⁺ )

C47H77NO7 (768)

775 (M + Li ⁺ )

H

- 331 25

C49H81NO8

819 (M + Li ⁺ )

(814)

C43H79NO9

821 (M + Li ⁺ )

TABLE 3

332

Example _-X-G2_MSIFAB, 3NBA / LiCl)

C45H73NO8 (757)

763 (M + Li ⁺ )

C47H77NO8 (800)

807 (M + Li ⁺ )

H

333 (844)

C49H81NO10

(740)

C45H73NO7

747 (M + Li ⁺ )

C46H75NO7

H

761 (M + Li ⁺ )

334

3.0 g (3.76 mmol) of the compound of Example 13 are dissolved in 80 ml of ethanol, 30 mol of 1M aqueous NaOH solution are added and the mixture is stirred at room temperature for 16 hours. For working up, 30 ml of water are added and the alcohol is distilled off completely. After acidification with 1M-HCl, the precipitate is filtered off with suction, rinsed with water and dried under vacuum. 2.5 g (85%) of Example 32 were obtained.

MS (FAB, 3-NBA / LiCl) C 47 H 77 NO 8 (784), 791 (M + Li ⁺ )

Examples 33 to 50 of Tables 4 to 6 are obtained analogously to Example 32 from methyl esters (Tables 1-3).

- 33Β TABLE 4

Example-X-G2_MSfFAB, 3NBA / LiCn

C49H81NO8 (828)

835 (M + Li ⁺ )

C51H83NO10 (873)

879 (M + Li ⁺ )

336 ( ₊ H + W) SLL (89i)

£ 9

( ₊ H + W) 168

- 337 37

C44H79NO8

805 (M + Li ⁺ )

C48H79NO9

821 (M + Li ⁺ )

TABLE 5

338

Example_z2GG2_MS (FAB, 3NBA / LiCn

C ₄ 6H ₇₅ NO ₈

777 (M + Li ⁺ )

C48H79NO9 (813)

821 (M + Li ⁺ )

H

339 (857)

C50H83NO10

865 (M + Li ⁺ )

(870)

C52H87NO9

877 (M + Li ⁺ )

(754)

C46H75NO7

755 (M + Li ⁺ )

340

(798)

C48H79NO8

805 (M + Li ⁺ )

(800)

C47H77NO9

807 (M + Li ⁺ )

341

TABLE 6

EXAMPLE-X-G2_MS (FAB, 3NBA / LiCn

C ^ HviNOg (741)

749 (M + Li ⁺ )

C46H ₇₅ NO ₉

793 (M + Li ⁺ )

H

342

C48H79NO10 (832)

837 (M + Li ⁺ )

C44H71NO7 (727)

733 (M + Li ⁺ )

C45H73NO7 (740)

747 (M + Li ⁺ )

343

Examples 51-54 of Table 7 are obtained analogously to Example 5 from the acids described above.

TABLE 4

Príklad_-X-G2_MSŕFAB. 3-NBA / LiCl)

C ₄ 9H ₈ 2N ₂ OioS

892 (M + H ⁴⁾

ChHwNíOhS (935) 942 (M + H ⁴⁾

344

C ₄ 9H ₈ 2N ₂ O ₉ S (875) 920 (M + H ⁺ )

345

C49H80N2O9

842 (Μ + Η ⁺⁾

C51H84N2O10

892 (M + Li ⁺ )

C53H88N2O11

Examples 58 to 63 of Table 9 are obtained as in Example 13.

346

TABLE 9

(in the following formula, the free G 1 bond is not shown).

Example Gb_MS (FAB, 3NBA / LiCn

C48H79NO8

805 (M + Li ⁺ )

C48H79NO7 (783)

789 (M + Li ⁺ )

347

C48H79NO8 (783)

782 (M + Li ⁺ )

C48H79NO8

805 (M + Li ⁺ )

OH

348

C47H77NO8 (785)

791 (M + Li + ⁴ )

(770)

777 (M + Li ⁴⁾

Examples 64 to 69 are obtained as in Example 32.

TABLE 10

349

(in the following formula, the free Gi binding is not shown).

Example G1-MS (FAB, 3NBA / LiCn

C ₄₇ H77NO ₈ (785)

791 (M + Li ⁺ )

H

350

C47H77NO7 (768)

775 (M + Li ⁺ )

C47H77NO8 (785)

791 (M + Li ⁺ )

C ₄ 6H ₇₅ NO ₈

H

351

C45H73NO8

The sodium salts of Example 32 and all examples of Tables 4 to 8 and 10 can be prepared. The compound was dissolved in methanol, an equimolar amount of 1M aqueous NaOH solution was added, and the mixture was evaporated in vacuo.

A-54

Bile acid derivative of the formula I

G, -XG ₂ wherein G ₁ binds through the side chain at atom no. 17 with a binding member X to the 3rd atom G ₂ ; G 1 is a radical of formula II

in which

Z is one of the following radicals

352 h ₃ c \

CH — CH j — CH j—,

H,

CH — CHi-, I

HJC

CH—, or a single bond,

R (1) is H, an alkyl radical of 1 to 10 carbon atoms or an alkenyl radical of 2 to 10 carbon atoms

R (2), R (3), R (4), R (5) are independently H, OH or

R (2) and R (3), or R (4) and R (5) together form the oxygen of the carbonyl group, X is a single bond or a bridge of formula 111

O O

II 11

-e (N), -A-N-C-CCH 2 -CJrN- (B) _f L (1J 2) L (3) wherein

A is an alkylene chain which is branched or unbranched and which is optionally interrupted by -O-, -S-, or phenylene, wherein the phenyl ring bond is in the ortho-, meta- or para- position and the chain comprises 2 to 12 members,

B is an alkylene chain which is branched or unbranched and which is optionally interrupted by -O-, -S-, or phenylene, wherein the phenyl ring bond is in the ortho-, meta- or para- position and the chain comprises 2 to 12 members,

L (1), L (2) and L (3) are identical or different and may be: H, an alkyl radical or alkenyl radical having up to ten carbon atoms, a cycloalkyl radical having up to 8 carbon atoms, a phenyl radical which is unsubstituted or is

353 mono- to trisubstituted by F, Cl, Br, (C | _-C4) -alkyl or (C 1 -C 4) alkoxy group, or a benzyl which is unsubstituted or mono- to trisubstituted by F, Cl, Br, (C -C 4) -alkyl or (C 1 -C ₄ ) -alkoxy, q is 0 to 5; r is 0 or 1; s is 0 or 1; whether 0 or 1,

G 2 is a radical of formula IV

wherein Z is one of the following radicals

HjC ^ HjC \

CH-CH 1 -CK 3 -, CH-CH ₂ -,

HJC

CH - or a single bond, with the proviso that Z may be

354

to ties

CH ₂ -CHilen CK of one of the formulas II and IV; V is -O- or when W is H, or

V is -CH ₂ - or -CH ₂ -CH ₂ - when W is H or OH,

Y is -OL, NHL,

L /

—N \

L or an amino acid or an amino sulfonic acid linked via an amino group selected from the group consisting of -NH-CH ₂ -COOH, -NH-CH ₂ -CH ₂ -,

SO ₃ H,

-N-CH ₂ -COOH and -N-CH ₂ -CH ₂ -SO ₃ H,

II CH ₃ CH ₃ wherein L is H, an alkyl radical or alkenyl radical having up to ten carbon atoms, cykloalkylradikál having 3 to 8 carbon atoms, a phenyl radical which is unsubstituted or mono- to trisubstituted by F, Cl, Br, (C ^ C - alkyl or (C 1 -C 4) -alkoxy, or a benzyl radical which is unsubstituted or mono- to trisubstituted by F, Cl, Br, (C 1 -C 4) 355 alkyl or (C 1 -C 6 -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 oxygen of the carbonyl group. -55

A bile acid derivative of the Formula I as described in A-54, wherein L is an alkenyl radical having 2 to 10 carbon atoms.

A-56

A bile acid derivative of the Formula I as described in A-54, wherein one or more of L (1), L (2) or L (3) is an alkenyl radical having 2 to 10 carbon atoms.

Non-absorbable, insoluble, basic, cross-linked polymers have been therapeutically used for bile acid binding for many years.

The bile acid derivatives described in patent application EP-A-0 489 423 have a high affinity for the intestinal bile acid transport system, allowing specific inhibition of enterohepatic circulation.

A-58 dimeme bile acid derivatives of formula

G1-X-G2 wherein G1 and G2 are linked at positions 3,7 or 12, respectively by a linker X. Bile acid derivatives in which G1 binds to X by positions 7 or 12, or G2 by positions 3,7, 12, or lateral chain are not described in the examples given in said patent application.

A-59 Bile Acid Derivatives of Formula I

G 1 -X-G 2 wherein G 1 is a radical of formula II

(Π)

356 in which

Y denotes the following: OKa, where Ka is an alkali metal, an alkaline earth metal, or a quaternary ammonium ion, -OL, -NHL, -NL2 denotes an amino acid, or an amino sulfonic acid bonded via an amino group, such as

-nhch ₂ cooh, -nhch ₂ ch ₂ Sat ₃ hr. -nch ₂ cooh, -nch ₂ ch ₂ with ₃ h ch ₃ ch ₃ a (C 1 -C 4) -alkyl esters, alkali metal salts, alkaline earth metals and quaternary ammonium salts and wherein L represents H, an alkyl or alkenyl radical having a maximum of 10 carbon atoms, both branched and unbranched, a cycloalkyl radical having from three to eight carbon atoms, or a phenyl radical or a benzyl radical, which is unsubstituted or mono- or trisubstituted with F, Cl, Br, (C1) -C4) -alkyl, or (C1-C4) -alkoxy,

R ¹ is H, an alkyl or alkenyl radical having a maximum of 10 carbon atoms, whether or not branched, a cycloalkyl radical having from 3 to 8 carbon atoms, a benzyl radical, a biphenylmethyl or triphenylmethyl radical whose nuclei are unsubstituted or mono- or trisubstituted F,

Cl, Br, (C--C4) -aJkylom. or radicals 0 0 II II or 0 -P-OL. S-OL 1 II 1 C-L 0 0

wherein L denotes the above.

R @ ² to R @ ⁵ , R @ ² and R @ ³ , or R @ ⁴ and R @ ⁵ , in both cases, may together represent oxygen of the carbonyl group, optionally individually and in each case independently

357

can pose one from the following structures 0 0 0 OL 0 D B B 1 U H, -OT. -ST. -NH 7, O-C-T. S-C-T. -NH-C-T. -0-P-07, B 0 O-S-OT. -T B 0

in which T has the meaning of either the same as L or is a free electron binding pair to bind the X group, and wherein only a total of one binding electron pair exits on G1 to bind X.

X is a single bond, or a group of formula III

O 0

B II

-I- (N) _of -ANC- _{(CH2) q} -O-] _r N _(t PU L ¹ L ² L ³ wherein

A and B are branched or linear alkylene chains. Alternatively, these chains are interrupted by -O- or -S-,

L ¹ , L ² and L ³ may be the same or different and take the meaning L aq is from zero to 5, r is zero or 1, s is zero or 5 and t is zero or 5, and

358

(IV) in which

Z is a free valence binding group X, optionally having the meaning described as Y

R ⁶ is a free valency binding group X, optionally having the meaning described as R ¹

R ⁷ -R ¹⁰ have the same meaning as described for R ² -R ⁵ , in which only one free valence is directed from G 2 to group X.

Particularly preferred compounds of formula I are those containing as the G 1 radical of formula II

(II) in which

Y

OH. O- (C 1 -C ₄ ) -alkyl. -NHCH ₂ COOH, • NCHjCOOH, -NHCH ₂ CH ₂ SO ₃ hours. -nch ₂ ch ₂ Sat ₃ hr

1

CH, CH,

359

R ¹ represents H, benzyl, biphenylmethyl, formyl, or acetyl,

R ² -R ⁵ R ² and R 3, respectively R 4 and R 5 together in each case represent the oxygen of the carbonyl group, or each separately represents one of the following groups

O O

II II

H. -OT, -NHT, -O-C-T, -NH-C-T, -T wherein T represents

H, a branched or linear (C1-C4) -alkyl radical, a free valency bridging the group X, and from which there is only one valence starting from G1 to bind the group X,

X is a bond,

-NH-CH ₂ CH ₂ NH • ch ₂ ch ₂ ch ₂ nh ·

O O

- (CH _{2) n} -NC- _{(CH2) fn} -CN _{(CH2) 0} HH wherein n has the value 2 or 3, m is 1-4 and the value 2 or 3 and

360

(IV) in which

Z is a free valence for the bond of group X, or is as described above for group Y,

R ⁶ is a free valence for the bond of group X, optionally having the meaning described above for group R ^1a

R ⁷ is as described above for R 2 and R 5 and wherein G 2 has only one free valency binding group X.

A process for preparing a compound of formula I comprises:

(a) in cases where X is a single bond, the mutual reaction of the appropriate forms of G1; and

G2 in principle by a known method, or

(b) in cases where X is a linking group, a reaction with each other

(a) reactive forms of G1-X with G2; or

(b) reactive forms of G2-X with G1 in principle by known procedures; or

c) preparing compounds of formula I (G1-X-G2) from G1-X1 and X2-G2 by known processes and, where known, by the processes detailed below. In these processes, X is formed from X 1 and X 2 by forming a covalent bond, in particular a condensation or substitution reaction.

a) X is a single bond

Bile acids are included herein either free or in a form protected by a protecting group. After reaction with G 2, which is also present in free or protected form, the protecting groups are cleaved and, if necessary, the carboxy group C-24 is derivatized. Suitable hydroxy protecting groups are formyl, acetyl,

361 tetrahydropyranyl, or t-butyldimethylsilyl. Suitable carboxy groups for C24 are various alkyl or benzyl esters and also, for example, orthoesters.

Bile acid, for example, preferably reacts with activated forms of carboxylic acids, such as acid chlorides mixed with anhydrides, in the 3-position but also 7, in the presence of bases such as trialkylamine, pyridine and also NaOH at room temperature in suitable solvents such as tetrahydrofuran, dichloromethane , or ethyl acetate, but also dimethylformamide (DMF) or dimethoxyethane (DME).

The different isomers can then be separated by chromatography. The reactions can be carried out selectively using different protecting groups.

Analogously, they can be converted by bile acid amino derivatives into the corresponding amides. Bile acid forms with or without protecting groups can also be used in these reactions.

Other compounds may be bound analogously to known processes,

b) X is a linking group

The procedures described in a) are also applicable to the binding of G1-X with G2, or G1 with G2X. Also here, the individual forms of bile acids are used in protected or unprotected form.

A preferred preparation process involves reacting the reactive forms of G1 with the reactive form of G2-X. If the situation so requires, this reaction is followed by a process of cleavage of the protecting groups, optionally by derivatisation of the C-24 carboxyl.

The preparation of reactive bile acid derivatives G1-X and X-G2 is described by the following equation.

(in)

362

363

R = H, formyl or acetyl, R '= H or OH, R = formyl or acetyl

(XII)

(XIV)

(Xv)

about

(XY I I)

R = H, formyl or acetyl, R '= H or OH, n = 2 or 3

364

Type V compounds having the 3-protected position react with allyl bromide / Hunig's base or triethylamine. Alkylation is unambiguous when Compound V has only one OH group; when two OH groups are present, the alkylation proceeds at approximately the same rate at the 7 and 12 positions to form the monoalkyl derivatives, while only trace amounts of the dialkyl derivative are formed. The protecting group at the 3-position can either be cleaved with sodium methylate or used for further reactions. The monoalkyl derivatives of compounds VI and VII can be cleaved by ozone or OsO4 / NaIO4 to give aldehydes VIII and IX. Of these, 7- and 12-hydroxyethyl derivatives of compounds X and XI are sometimes available by simple reaction, for example with Na BH ₄ . The corresponding 7- and 12-hydroxypropyl derivatives XII and XIII can be synthesized from the allyl compounds VI and VII by hydroboration. Aminoalkyl derivatives XIV and XV can be prepared from hydroxyalkyl derivatives of compounds of type X-XIII by a sequence of principally known reactions (mesylation of the primary OH group with methanesulfonyl chloride / pyridine, azide exchange with sNaN3 in dimethylformamide, reduction of azide functionality with hydrogen). Further reaction of the amino groups of these compounds with succinic anhydride yields bile acid compounds of types XVI and XVII. Suitable bile acid compounds are additionally disclosed in EP-A-0 489 423.

A-60 Examples 1 and 2

Example 1 Example2

150 g (0.32 mol) of methyl 1-3-acetylcholate, 500 ml of dimethylformamide, 125 ml of N-diethyl diisopropylamine and 70 ml of allyl bromide were heated at reflux for 16 hours. New (25 mL) allyl bromide was added every two hours. The reaction solution was evaporated on a rotary evaporator. The residue was partitioned in a water / dichloromethane system. The organic phase was separated

365 and dried over magnesium sulfate. Column chromatography fractions (ethyl acetate / cyclohexane 1: 2, silica gel 70-200 μσι) were evaporated on a rotary evaporator. Yield = 92.2 g of a mixture of 7- and 12-allyl compounds.

C ₃ oH480 ₆ (504), MS 511 (M + Li ⁺⁾

The mixture was separated by fractional crystallization with n-heptane.

Example 3

0 '

First, 50 g (0.1 mol) of the compound of Example 1, 250 ml of diethyl ether and 250 ml of water were charged into the reaction vessel while stirring. 503 mg (0.002 mol) of osmium tetroxide was added. The mixture was stirred at room temperature for 15 minutes. 53 g (0.25 mol) of sodium periodate was added portionwise over one hour and the mixture was stirred vigorously for 8 hours. The organic phase was separated, dried over magnesium sulfate and evaporated on a rotary evaporator.

Yield: 47 g of crude (506) MS 513 (M + Li ⁺ )

The reaction product of Example 3 was used without further purification.

Example 4

366

4.2 g (0.11 mol) of sodium borohydride were added to 47 g (0.093 mol) of the product of Example 3 and 250 ml of methanol at 0 ° C. After two hours at 0 ° C, the reaction mixture was poured into saturated ammonium chloride solution. The mixture was extracted three times with ethyl acetate. The organic phase was dried over magnesium sulphate and evaporated on a rotary evaporator. The fractions with the product after column chromatography (ethyl acetate / cyclohexane 1.5: 1, silica gel 35-70 μΜ) were evaporated on a rotary evaporator and the product was crystallized with diisopropyl ether. Yield: 25 g of C 29 H 48 O 7, MS 515 (M + Li ⁺ ).

Example 5

g (0.02 mol) of the product of Example 1 and 250 ml of tetrahydrofuran were added to the reaction vessel at room temperature. 40 ml (0.04 mol) of borane-tetrahydrofuran complex (1 mol solution) were added dropwise at the same temperature. Then the mixture was stirred for two hours at room temperature. Subsequently, 25 ml of water, 25 ml of 2M sodium hydroxide solution and 25 ml of 35% hydrogen peroxide solution were added dropwise. The mixture was stirred for an additional 15 min at room temperature. The reaction product was poured into water and the mixture was extracted three times with diethyl ether. The organic phases were combined, dried with magnesium sulfate and evaporated on a rotary evaporator.

Yield: 8.5 g of C 30 H 50 O 7 (522), MS 529, (M + Li ⁺ ).

The product of Example 5 was further used without further purification.

Example 6

367

g (0.02 mol) of the product of Example 4 and 100 ml of pyridine were first charged to the reaction vessel at 0 ° C. While stirring, 1.7 mL (0.022 mol) of methanesulfonyl chloride was added dropwise at 0 ° C. Next, the mixture was stirred for an additional 30 min at 0 ° C and further for 2 h at room temperature. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and evaporated on a rotary evaporator. The product was dissolved in 100 ml of dimethylformamide. 1.4 g (0.022 mol) of sodium azide was added and the mixture was stirred at 80 ° C for two hours. The reaction solution was poured into water and worked up as described above. The product was dissolved in 100 mL of methanol. Hydrogenation was carried out under normal pressure for 2 hours with 100 ml of 10% palladium on charcoal. The catalyst was filtered off and the eluate was evaporated on a rotary evaporator. The reaction product of Example 6 was obtained after column chromatography (ethyl acetate / MeOH / Et 3 N 10: 1: 1, silica gel 70-200 gm). Yield = 7.3 g of C 29 H 49 NO 6 (507), MS 514 (M + Li ⁺ ).

Example 7

98.6 g (0.001 mol) of succinic anhydride were added to 500 g (0.001 mol) of the amino compound, 20 ml of tetrahydrofuran and 4 ml of triethylamine at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction solution was poured into a 25% sodium dihydrogen phosphate solution. The mixture was extracted three times

368 with ethyl acetate and the combined organic phases were evaporated on a rotary evaporator after drying over magnesium sulfate.

Yield: 580 mg of C 33 H 53 NO 9 (607), MS 614 (M + Li ⁺ ). The reaction product of Example 7 was further used without further purification.

The products of Examples 8-12 were prepared analogously to Example 3-7.

Examples 8-12

Example R ¹¹ MS 8 --CH2 CHO 513 (M + Li ⁺ ) 9 -CH ₂ CH ₂ OH 515 (M + Li ⁺ ) 10 -CH2CH2CH2OH 529 (M + Li ⁺ ) 11 -CH2CH2NH2 514 (M + Li ⁺ ) 12 -CH2CH2NHCOCH2CH2COOH 614 (M + Li ⁺ )

Example 13

369

300 g (0.73 mmol) of cholic acid, 330 mg (0.78 mmol) of methyl 7β-amino3α, 12α-dihydroxy-5β-cholateate (Redel, Bull.Soc.Chim.Fr., p. 877, 1949) 240 mg (0.97 mmol) of EEDQ and 0.25 ml of diisopropylethylamine were stirred in 20 ml of DMF at 90 ° C for 4 hours. After cooling, the reaction mixture was concentrated and the resulting mixture was chromatographed on silica gel (CH 2 Cl 2 / MeOH 8.2). C 49 H 81 NO 9 (812) 819 (M + Li ⁺ ). The two bile acids may also be linked by triethylamine in dichloromethane, or dicyclohexylcarbodiimide, hydroxybenzotriazole, or triethylamine in tetrahydrofuran.

The compounds in Table 1 were prepared analogously to Example 13.

Table 1

370

Example T ⁷ R ^lj R ¹⁴ MS (FAB, 3-NBA) 14 a-OH H OH C49H81NO7 (796) 803 (M + Li ⁺ ) 15 β-ΟΗ H OH C49H81NO7 (796) 803 (M + Li ⁺ ) 16 H H -Oh CsoHeiNO? (808.5) 809.5 (M + H ⁺ )

The compounds listed in Table 2 were obtained analogously to the product of Example 13 of Examples 7 and 8.

Table 2

Example X ³ R MS (FAB, 3-NBA) 17 NH H C ₃ H ₈ iNOio (898) 905 (M + Li ⁺ ) 18 NH diphenylmethyl C ₆₆ H _{9 7} NO, o (1064) 1071 (M + Li ⁺ ) 19 -NHCO (CH ₂ ) ₂ CONH (CH ₂ ) ₃ NH- H C ₆ H ₉ N ₃ O 12 (1054) 1061 (M + Li ⁺ ) 20 -NHCO (CH ₂ ) ₂ CONH (CH 2) ₃ NH- diphenylmethyl C ₇₃ Hio9N ₃ 0 | ₂ (1220) 1227 (M + Li ⁺ )

The examples in Tables 3 and 4 were obtained analogously to Example 13.

Table 3

-371 Table 3

Example JU * MS (FAB, 3 NBA / LiCl) 21 vC hT H h - The C ₆ 2H ₁₀ N ₂ O ₁₄ (1097) 1104 (M + L ⁺ ) 22 = ° ^^ ° ^u · H C ₆ H 98 N ₂ O 13 (1055) 1104 (M + L ⁺ )

-372Tabuľka4

Example R ¹⁷ MS (FAB, 3 NBA / LiCl) 23 0 H _o \ '* C / h * o H H C ₅₃ H87NO, α (898) 905 (M + L ⁺ ) 24 0 H 0 Aap 1 e O '' ^ ^X T ^ ^? Ú n M C ₆ 2H ₁₀ N ₂ O ₁₄ (1097) 1104 (M + L ⁺ ) 25 0 e C ₆ o _{9 9} NO, 3 (1055) 1062 (M + L ⁺ )

Example 26

250 mg (0.31 mmol) of the product of Example 13 was dissolved in 20 mL of ethanol. After addition of 2 ml of 1M NaOH solution, the mixture was stirred at room temperature for 16 hours. The mixture was then concentrated, dissolved in H 2 O, adjusted to pH 1-2 with 2M HCl solution and concentrated again. The result was chromatographed on silica gel (CHCl 3 / MeOH 8: 2). 220 mg of free acid (90%) was prepared.

MS (FAB, 3-NBA / LiCl) C ₄₈ H 9 NO _{7 8} (798) 805 (M + Li ^4).

The examples in Tables 5-8 were obtained analogously to Example 26.

-374-

Example R ¹² R ¹³ MS 27 a-OH H C48H79NO7 (782) 789 (M + Li ⁺ ) 28 β-ΟΗ H C48H79NO7 (782) 789 (M + Li ⁺ ) 29 H H C48H79NO7 (766) 773 (M + Li ⁺ )

Table 6

Example X ³ R MS 30 NH H C 50 H 50 NO 10 (860) 867 (M + Li ⁺ ) 31 NH diphenylmethyl C ₆₃ H ₉₅ NOio (1026) 1033 (M + Li ⁺ ) 32 -NHCO (CH ₂ ) ₂ CONH (CH ₂ ) ₃ NH- H C ₅₇ H9 ₇ N ₃ O ₂ (1016) 1023 (M + Li ⁺ ) 33 -NHCO (CH ₂ ) ₂ CONH (CH ₂ ) ₃ NH- diphenylmethyl C ₇ oH _{1 ()} 7 N ₃ O ₁₂ (1182) 1189 (M + Li ⁺ )

-375 Table 7

Example R ¹⁶ MS 34 0 HO  -4 ^ ' "^ O ^ CPX - H C ₅₆ H92N ₂ Oi ₂ (985) 992 (M + Li ⁺⁾ 35 0 H_O .JJ5 H ΓιηΓ H H C58H96N2O12 (985) 992 (M + Li *)

-376Tabuľka8

Example R17 MS (FAB, 3 NBA / LiCl) 36 0 HO ΗΟ ^^ Γ ^ 'Ο H H C50H83NO9 (842) 849 (M + Li ⁺ ) 37 OH 0 ° ^^ jp H0 4 H ^7, C 0H C ₅₆ H ₉₂ N ₂ O ₁₂ (985) 992 (M + Li ⁺ ) 38 0 ho> - £ -¾ 0 ^M 1 C ₅₆ H ₉₂ N ₂ Oi ₂ (985) 992 (M + Li ⁺⁾

The following glycine-taurine conjugates were obtained by analogous synthesis processes as described (EP 489 423).

Table 9

Example R ¹² Ŕ ¹³ MS (FAB, 3 NBA / LiCl) 39 a-OH a-OH C 50 H 55 N 2 O 10 S (905) 918 (M + 2 Li ⁺ - H ⁺ ) 40 a-OH H C 6 H 11 N 2 O 2 S (889) 890 (M + H ⁺ ) 41 β-ΟΗ H C50H84N2O9S (889) 912 (M + Na ^&lt; ^{+ &gt;} ) 42 H H C50H84N2O8S (872.5) 895.5 (M + Na ⁺ )

-378Table 10

Pr. X ³ R ¹⁵ MS (FAB, 3 NBA / LiCl) 43 NH H C ₅₂ H ₉₀ N ₂ S ₂ Oi (967) 974 (M + Li ⁺⁾ 44 NH diphenylmethyl C6 ₅ HiooN ₂ Oi ₂ S (1133) 1140 (M + Li ⁺ ) 45 -NHCO (CH ₂ ) ₂ CONH (CH 2) ₃ NH- H C55HHBN4O14S (1123) 1130 (M + Li ⁺ ) 46 -NHCO (CH ₂ ) ₂ CONH (CH ₂ ) ₃ NH- diphenylmethyl C ₇₂ Hio ₂ N ₄ O ₁₄ S (1289) 1296 (M + Li ⁺ )

Example 47

MS (FAB, 3-NBA / LiCl) C 60 H 101 N 3 O 14 S (1092) 1099 (M + Li ⁺ )

-379Example 48:

MS (FAB, 3-NBA / LiCl) C 72 H 110 N 4 O 13 (1239) 1246 (M + Li ⁺ )

Table 11 shows the measured inhibition values of vesicular vesicle transport of [ ³ H] taurocholate from the rabbit gut membrane membrane. IC 50 and IC 50 values of the reference substance taurochenodeoxycholate (TCDC) and the test substance are shown.

Table 11

Example compound IOn-TCDC follicle IC50 - substance [pmol] ICsnNa - TCDC luminal IC 50 Na - substance [pmol] 20 0.00 0.12 26 0.00 0.29 27 0.64 0.44 28 0.54 0.43 29 0.23 0.17 30 0.93 0.85 32 1.00 0.80 39 0.92 1.05 40 0.54 0.52 43 1.18 0.96 47 0.35 0.26 48 0.75 0.71

-380Α-61 Bile acid derivatives of formula I G1-X-G2 (I) in which G1 denotes a group of formula II

(Π) in which

Y has the following meaning: OKa, where Ka is an alkali metal, an alkaline earth metal, or a quaternary ammonium ion,

-OL, -NHL, -NL, amino acid, or amine sulfonic acid linked via an amino group such as

-NHCH ₃ COOH, -NHCH ₂ CH ₂ SO ₃ H, - (NCH ₃ ) CH ₂ COOH, - (NCH ₃ ) CH ₂ CH ₂ SO ₃ H and (C 1 -C 4) -alkyl esters, alkali metal, alkaline earth metal and quaternary ammonium salts in which L denotes H, alkyl, or alkenyl radical having up to 10 carbon atoms, which is a branched or unbranched cycloalkyl radical having from 3 to 8 carbon atoms, or a phenyl or a phenyl group, respectively. a benzyl radical unsubstituted or mono- to trisubstituted with substituents such as F, Cl, Br, (C 1 -C 4) -alkyl or (C 1 -C 4) -alkoxy,

R &lt; ¹ &gt; H, alkyl, or alkenyl radical having up to 10 carbon atoms, which is a branched or unbranched cycloalkyl radical having from 3 to 8 carbon atoms or a benzyl, biphenyl or triphenyl radical with unsubstituted or mono- to trisubstituted substituents such as F , Cl, Br, (C1-C4) -alkyl or (C1-C4) -alkoxy, or a radical

-381 -P-OL. -S-OL or

II I ο ο ο

they

-C-L wherein L is as defined above,

R @ ² to R @ ⁵ , R @ ² and R @ ^3, or R @ ⁴ and R @ ⁵ are in each case taken together with the oxygen of the carbonyl group or, in particular, one of the following groups:

O O O OL O

Children I B

H. -OT. -ST. -NH 7, O-C-T. S-C-T. -NH-C-T. O-P-OT. O-S-OT. -T

K o o where T has the same meaning as L, or is a free valency to the bond of the X group, and wherein at the same time only one valency points from G1 to X.

X is a single bond, or a group of formula III

O O u

-l- (N) ,. NC- | _{CH2) q} N _r -CJ (B) _t L ¹ L ² L ³ (ΠΙ) wherein

A and B are branched or unbranched alkylene chains which may optionally be interrupted

-O- or -S-.

L, L ² and L ³ are identical or different, have the meaning of L where q has a value of 0 to 5 r has a value of 0 to 1

-382s has a value of 0 to 1 and t has a value of 0 to 1 a

G 2 is a radical of formula IV

in which

Z is a free valence to group X, or has the meaning ascribed to group Y.

R ⁶ is a free valence to the group X, or assumes the meaning assigned to the group R ¹ R ⁷ -R ¹⁰ have the meaning described for R ² to R ⁵ and where only one valency to the group X is derived from G 2.

A-62 Bile Acid Derivatives of Formula I as described in A-61, wherein G 1 is a radical of Formula II

(Π) in which

Y is OH, O- (C 1 -C ₄ ) -alkyl, -NHCH ₂ COOH, - (NCH ₃ ) CH ₂ COOH, NHCH ₂ CH ₂ SO ₃ H, - (NCH ₃ ) CH ₂ CH ₂ SO ₃ H

R ¹ is H, benzyl, biphenylmethyl, formyl, or acetyl

-383 R ² to R ⁵ , R ² and R ^3, or R ⁴ and R ⁵ , in each case, are together oxygen of the carbonyl group, or each separately one of the following groups

H, -OT, -NHT, -OCOT, -NHCOT, -T where T is

H, branched or unbranched (C 1 -C 4) -alkyl radical, or by a free valence to the linking group X and wherein only one valency to the group X is derived from G1 at a time,

X is a bond, -NH-, -CH ₂ CH ₂ NH-, -CH ₂ CH ₂ CH ₂ NH-,

- (CH ₂ ) n NHCO (CH ₂ ) _m CONH (CH ₂ ) _o wherein n is 2 or 3, m is from 1 to 4 and from 2 to 3, and

G 2 is a radical of formula IV

(IV) in which

Z is a free valence to the group X or has the meaning of Y

R 6 is a free valence to the group X, or has the meaning of R 1

R 7 -R 9 are as described for R 2 -R 5, where only one valency is from G2 to X.

A-63 monomeric bile acid derivatives of formula I

Z-X-GS

-384kde

GS is a bile acid residue having a side chain substituted with an acid function, or a salt of such a residue.

X is a covalent bond, or a linking group of formula (CH 2) n, wherein n = 1 to 10 and wherein the alkylene chain may contain 1 to 3 oxygen atoms, NH or NHCO groups, and wherein GS is bound by X and

eats

HO-, CH ₃ -O-, HO-CH ₂ -CH = CH-CH ₂ -, (C ₆ H ₅ ) 2 -CH ₂ -O-, Alkali-O-SO ₃ -, H ₂ PO ₄ -,

O o

H II

KO -? - o-. about-.

OH o

II

0 <QHj)

O II

Gii the CH = C-NH. TSD-C-NH-.

About NH

If II

HN-C-NH. HJX-C-NH-,

C * Hj

-N (R) ₂ or -N (R) ₃ wherein R is in all cases C 1 -C 7 alkyl, or H ₂ N- (CH ₂ ) 6-

(CrCid-ADcyl-C-NH.

-385 where the alkyl is optionally substituted with COOH

wherein A is in all cases OH or NH (C 1 -C 10) alkyl.

Preferred compounds of formula I are those wherein GS is linked to X at the 3-position in both the α and β orientations.

As used herein, an acidic functional group is a carboxyl group or a sulfone group. The alkyl radicals may be branched or unbranched. The compounds of formula I, as understood in this patent application, have a high affinity for a specific bile acid transport system in the colon and inhibit the absorption of bile acids in a concentration-dependent, competitive manner.

Due to competitive inhibition, it is possible to increase the selectivity of interventions in enterohepatic circulation. Avitaminoses are not anticipated and a qualitative change in bile acid composition is also unlikely. Controlled cholesterol lowering can be achieved by the compounds described herein without a known side effect. Due to their high affinity for the bile acid transport system, much lower doses than commercially available polymers are required. This leads, among other things, to greater tolerance for patients and doctors.

These substances have valuable pharmacological properties which rank them among hypolipidemic agents.

The invention therefore also relates to medicaments based on formula I, for the use of these substances as medicaments, in particular cholesterol-lowering agents.

The compounds of this invention were biologically tested to determine their inhibitory activity of [3H] taurocholate transport on vesicles from the rabbit gut membrane membrane. The inhibition study was performed as follows:

1. Preparation of vesicles from the rabbit gut membrane membrane

Brush hem membrane vesicles were prepared from colon cells by the so-called Mg ²⁺ precipitation method. Male New Zealand rabbit (body weight: 2-2.5 kg) was sacrificed by intravenous injection of 0.5 ml aqueous solution

2.5 mg tetracaine HCl, 100 T 61 ^Å and 25 mg mebezonium iodide. The colon was dissected and rinsed with ice-cold saline. The last 7/10 colon (measured in the direction of the oral-rectal end), ie the rectum containing the active Na ⁺ -dependent bile acid transport system, was used to prepare the membrane vesicles of the brush border membrane. The material was frozen in plastic bags in liquid nitrogen to -80 ° C. To prepare membrane vesicles, the material was thawed in a 30 ° C water bath. The mucosa was scraped and suspended in 60 ml of ice-cold 12 mM TrisCl buffer (pH 7.1) / 300 mM mannitol, 5 mM EGTA, 10 mg / l phenylmethylsulfonyl fluoride, 1 mM

-387mg / l trypsin inhibitor from soybean (32 U / mg), 5mg / l bacitracin. After dilution to 300 ml with distilled water, the mixture was homogenized under ice cooling for 3 min, at 75% Ultraturax performance (tip 18, IKA Werk Staufen, FRG). After the addition of 3 ml of 1 M MgCl ₂ solution (to a final concentration of 10 mM), the mixture was left at 0 ° C for 1 minute. Cell membranes, in addition to the brush border membrane, aggregate and precipitate in the presence of Mg ²⁺ . The suspension was centrifuged at 3000xg (5000 rpm, SS-34 rotor) for 15 minutes. The precipitate was scanned and the supernatant containing the brush border membranes was centrifuged at 267,000xg (15,000 rpm, SS-34) for 30 minutes. The supernatant was discarded and the pellet was resuspended in 60 ml of 12 mM TrisCl buffer (pH 7.1) / 60 mM mannitol, 5 mM EGTA using a Potter-Ehejhem homogenizer (Braun, Melsungen, 900 rpm, 10 shocks). After adding 0.1 ml of 1M MgCl ₂ and 15 minutes at 0 ° C, the mixture was again centrifuged at 3000xg for 15 minutes. The supernatant was then centrifuged again at 46000xg (15000 rpm, SS-34) for 30 minutes. The precipitate was suspended in 30 ml of 10 mM Tris / Hepes buffer (pH 7.4) / 300 mM mannitol, a 20 stroke Potter-Elvejhem homogenizer at 1000 rpm. After centrifugation at 48,000xg (20000 rpm, SS-34) for 30 minutes, the precipitate was suspended in 0.5-2 ml of Tris / Hepes buffer (pH 7.4) / 280 mM mannitol (final concentration 20 mg / ml) using tuberculin syringes and needles no. The vesicles were either used immediately for inhibition studies or stored at -169 ° C in a 4 mg aliquot in liquid nitrogen.

2. Inhibition of [ ³ H] -taurocholate transport in membrane vesicles from intestinal brush rim.

The transport of substrate to the vesicles from the brush border membrane described above was determined by the so-called membrane filtration technique. 10 μΐ of the vesicle suspension (100 µg protein) was pipetted as a drop into a polystyrene incubation tube (11x70 mm) containing the incubation medium with the corresponding ligands (90 μΐ). The incubation medium contained 0.75 μΐ = 0.75 pCi of [ ³ H (G)] taurocholate (specific activity: 2.1 Ci / mmol), 0.5 μΐ 10 mM taurocholate, 8.75 μΐ sodium transport buffer (10 mM Tris) / Hepes pH 7.4; 100 mM mannitol; 100 mM NaCl) (Na-TP) or 8.75 μΐ potassium transport buffer (10 mM Tris / Hepes pH 7.4; 100 mM mannitol; 100 mM KCl) (KTP) and 80 μΐ of the test inhibitor solution dissolved in Na-T or KT buffer, depending on the experiment. The medium was filtered through a polyvinylidene fluoride membrane filter (SYHV LO

-388 4NS; 0,45 μιη; 4 mm²; Millipore, Eschbom, FRG). The transport measurement itself was started by mixing the vesicles with the incubation medium. The concentration of taurocholate in the incubation medium was 50 μΜ. At the end of the incubation period (usually 1 minute), the process was stopped by the addition of 1 ml ice stop solution (10 mM Tris / Hepes pH 7.4; 150 mM KCl).

The resulting mixture was immediately filtered through a nitrocellulose filter (ME 25;

O, 45 μιη; 25 mm in diameter; Schleicher & SchuelI, Dassell, FRG) under a pressure of 25 30 mbar. The filter was rinsed with 5 ml of stop solution. Transport of radiolabeled taurocholate was measured by dissolving the membrane filter in 4 ml of Quicksyint 361 scintillator (Zinsser Analytik GmbH, Frankfurt, FRG) and radioactivity was measured by liquid scintillation counting with a TriCarb 2500 meter (Canberra Packard GmbH, Frankfurt, FRG). After calibration of the instrument with standard solutions and correction for the chemiluminescence present, the values were measured in dpm (decomposition per minute).

Control values for each measurement were determined on Na-TP and K-TP, respectively. Na ⁺ -dependent transport was determined as the difference between Na-TP and KTP transport. Inhibitor concentration at which Na ⁺ -dependent transport was 50% inhibited - relative to control - was reported as IC 50 Na + - The table shows the inhibition values of [3 H] -taurocholate transport to vesicles from the rabbit gut membrane membrane. The IC 50 and IC 50 Na + taurochenodezoxycholate (TCDC) values measured for each membrane vesicle preparation as a standard and the values measured for the test substances are shown.

Example substance IC ™ ICsom (TCDC) IC50 (substances) ICsove (fabrics) 3 0.4 0.35 4 0.77 0.69 18 0.47 0.42 21 0.34 0.33 33 0.33 0.35 35 1.0 1.02 36 0.19 0.20 38 0.49 0.41 40 0.52 0.50 43 0.78 0.73

The invention further relates these substances directly to their use in the preparation of medicaments.

In this case, the compounds of formula I are dissolved in a suitable pharmacologically acceptable organic solvent, such as mono- or polyhydrated alcohols, such as ethanol or glycerol, optionally in triacetin, in oils such as sunflower or cod liver, in ethers such as diethylene glycol diethyl ether or in polyethers. such as polyethylene glycol, or also in the presence of other pharmacologically acceptable polymeric carriers, such as polyvinylpyrrolidone, or other pharmacologically acceptable additives such as starch, cyclodextrins, and the like. polysaccharides. The compounds may also be administered in combination with other drugs in the context of the present invention.

The compounds of formula I may be administered in various dosage forms, preferably orally in the form of tablets, capsules, or liquid. The daily dose ranges from 3 to 5000 mg, but preferably from 10 to 1000 mg, depending on the body weight and the constitution of the patient.

Particularly calculated non-isotopic molecular weights are shown in the following examples.

Unless otherwise indicated, mass spectra are recorded by FAB technique with addition of LiCl and 3-nitrobenzaldehyde (3-NBA).

The starting compounds characterized by the structure of bile acids have already been described in some cases (e.g. EP-A-0 417 725, EP-A-0 489 423 and EP-A-0 548 793).

R * is as defined in Example 6.

Example 39

η · J g (1.96 mmol) of the methyl ester was dissolved in 15 mL of tetrahydrofuran (THF) or 1,4-dioxane and the solution was vigorously stirred with 10 mL of 2N NaOH solution overnight at room temperature. Then the solution was diluted with plenty of water and acidified with hydrochloric acid (1: 1 with water) while cooling on ice. The precipitation was completed by stirring on ice for 1 hour. The precipitate was filtered off under vacuum and washed with cold water. Recrystallization from ethanol / water and drying in vacuo gave 940 mg (96%) of the product of Example 1.

C29H50O6 (494) MS: 501 (M + Li ^&lt; ^{+ &gt;} )

The following Examples 2-7 were prepared analogously to Example 1 from the corresponding bile acid esters:

Example number n = empirical formula MW MS 2 6 C30H52O6 508 515 (M + Li ⁺ ) 3 8 C32H56O6 536 543 (M + Li ⁺ ) 4 9 C33H58O6 550 557 (M + Li ⁺ ) 5 10 C34H60O6 564 571 (M + Li ⁺ )

Example 6

C28H48O7 (496) MS: 503 (M + Li ^&lt; ^{+ &gt;} )

Example 7

C30H52O7 (540) MS: 547 (M + Li ^&lt; ^{+ &gt;} )

Example 8

The -392100 mg (0.2 mmol) of the methyl ester was dissolved in 10 mL of dioxane and the solution was stirred with 3 mL half-times concentrated NaOH at room temperature for 6 hours. The mixture was diluted with water and acidified half-concentrated HCl. Filtration and washing gave the acid-product of Example 8 (50 mg 51%).

C 29 H ₄₇ NO ₅ (489) MS: 496 (M + Li ⁺⁾

The following compounds were prepared as in Example 8:

Example 9

C29H47NO6 (506)

MS: 512 (M + Li ^&lt; ^{+ &gt;} )

Example 10

C ₃ H ₅₃ NO 6 (547) n = 5

MS: 554 (M + Li ^&lt; ^{+ &gt;} )

Example 11

C ₃₃ H ₅₅ NO ₆ (561) n = 6

MS: 568 (M + Li ^&lt; ^{+ &gt;} )

Example 13

ABOUT

NH- (CH ₂ ) n R ¹ n = 6

C34H59NO7 (593) MS-600 (M + Li ⁺ )

Example 14

ABOUT

-NH- (CH _{2) n} -R 5 n = ¹

C33H57NO7 (579) MS: 586 (M + Li ^&lt; ^{+ &gt;} )

Example 15

ABOUT

Á

H ₃ C-O ^ \ ^N, N NH (CH _{2) n} -R ¹ n = 2

C ₃ H ₅₁ NO ₇ (537) MS: 544 (M + H +)

Example 16

H

-394-

0.84 ml of triethylamine was added to 3.14 g (6 mmol) of the primary alcohol and (n = 6) in 100 ml of dry dichloromethane and the mixture was cooled to -10 ° C. 0.4 ml (6 mmol) of chlorosulfonic acid in 20 ml of dry dichloromethane was added to this solution. After one hour at 0 ° C and one hour at room temperature, water was added. The organic phase was separated and the aqueous phase was extracted several times with ethyl acetate. The combined organic phases were dried and concentrated. The mixture was purified by chromatography (SiO 2, ethyl acetate / methanol = 3: 1). 1.45 g (40%) of the product of Example 16 were obtained.

C31H54O9S (602) MS: 631 (M-H &lt; ⁺ &gt; Li ⁺ + Na &lt; ⁺ &gt;) 615 (M-H &lt; ^{+ &gt;} + 2Li *)

Example 17

Example compound 16 -> Na-O-SO 2 -O- (CH 2) 6 -R '

0.5 g (0.83 mmol) of the product of Example 16 was stirred in 20 mL dioxane with 7 mL half-concentrated NaOH at room temperature for 6 hours. The mixture was then acidified half-concentrated HCl and concentrated in vacuo. The mixture was purified by column chromatography (SiO 2, ethyl acetate / methanol = 3: 1). 254 mg (52%) of the product of Example 17 were obtained.

C30H51O9S (610) MS: 617 (M + Li ^&lt; ^{+ &gt;} ) 601 (M-Na ⁺ + 2Li ⁺ )

Example 39

ml of diphenylphosphoric acid ester was added dropwise to a solution of 2.6 g (5.12 mmol) of the product of Example 2 in 20 ml of pyridine at 0-5 ° C. The mixture was stirred at room temperature for two hours. It was poured into 200 ml of ice water. 15 ml of concentrated sulfuric acid was added with stirring and cooling. The mixture was extracted several times into ethyl acetate. The organic phase was concentrated by evaporation and purified by chromatography (SiO 2, CH 2 Cl 2 / CH 3 OH = 10: 1). 1.78 g (47%) of the product of Example 18 were obtained.

C ₄₂ H ₆ O ₉ P (740) MS: 747 (M + Li ⁺ )

Example 19

ABOUT

II

HO -? - O- _(CH) t-R I

The OH 1g (1.35 mmol) of the product of Example 18 was hydrogenated in 50 mL of glacial acetic acid with platinum on activated carbon (spatula tip) on a shaker. After completion of the reaction (4 hours), the catalyst was filtered off under vacuum and concentrated. The residue was purified by column filtration (SiO 2, ethyl acetate / CH ₃ OH = 2: 1). 270 mg (34%) of the product of Example 19 were obtained.

C30H53O9P (588) MS: 601 (M-H &lt; ⁺ &gt; 2L &lt; ^{+ &gt;} ) 595 (M + Li ^&lt; ^{+ &gt;} )

Example 39

The amine (2.24 g, 4 mmol) and potassium cyanide (324 mg, 4 mmol) were suspended in 60 ml of water and the suspension was heated to boiling. A solution was formed from which a solid precipitate precipitated in a short time. The mixture was stirred at boiling point for 30 minutes and then cooled. Water (40 ml) was added and the mixture was acidified with dilute hydrochloric acid. The mixture was extracted several times with ethyl acetate. The organic phase was dried and concentrated and then purified by chromatography (SiO 2, ethyl acetate / CH 2 OH = 10: 1). 520 mg (23%) of the product of Example 20 were obtained. C32H56N2O5 (564) MS: 571 (M + Li ⁺ )

EXAMPLE 21

450 mg (0.1 mmol) of the product of Example 20 are stirred in 10 mL of dioxane with 5 mL of 0.5 times concentrated NaOH at room temperature for 6 hours. After finishing

The reaction was diluted with water, acidified with hydrochloric acid and stirred in an ice bath for 1 hour. The precipitate was filtered off in vacuo, rinsed with water and dried in vacuo. 430 mg (97%) of the product of Example 21 were obtained.

C33H54N2O6 (550) MS: 557 (M + Li ^&lt; ^{+ &gt;} )

Example 22

mmol of phenylisocyanate in 5 mL of dichloromethane was added to 1.04 g (2 mmol) of amine b (Example 20) in 50 mL of dry dichloromethane and 28 mL of triethylamine at 0 ° C. The mixture was stirred at room temperature for 6 hours and worked up as described in Example 16 by acidifying the aqueous phase. After column filtration (CH 2 Cl 2 / CH 3 OH = 10: 1) 6540 mg (51%) of the product of Example 22 were obtained.

C ₃₈ H ₆ N ₂ O ₆ (640) MS: 647 (M + Li ⁺ )

Example 23

ABOUT

NH-R-tCHjk

C ₃₇ H 58 N ₂ O ₆ MS: 633 (M + Li ⁺ )

Example 39

2.08 g (4 mmol) of amine b, 10 ml of triisobutylamine and 5 ml of iodomethane were heated to boiling point in 50 ml of acetonitrile for 2 hours. All volatile components were evaporated in vacuo and the residue purified by chromatography (SiO 2, CH 2 Cl 2 / CH 3 OH = 10: 1). 1.2 g (43%) of the product of Example 24 were obtained.

C34H62INO5 (691) MS (FAB, 3-NBA): 564 (M &lt; + &gt;)

Example 25 ((H, Qj, N'-fCH, J'-R ¹

Cl

The product of Example 25 was prepared from the product of Example 24, analogously to Example 21. The crude product was purified by medium pressure chromatography on RP8 silica gel (CH ₃ OH / H ₂ O = 7: 3).

C ₃₃ H ₆₀ ClNO ₃ (585) MS (FAB, 3-NBA): 550 (M - Cl)

-399Example 26

xHBr

1.04 g (2 mmol) of amine b and 276 mg (2 mmol) of pyrazole c were heated under reflux in 40 ml of dry acetonitrile for 10 hours. Upon cooling and addition of ether, a precipitate formed, which was filtered off and rinsed with dry ether. After drying, 450 mg of the product of Example 26 were obtained.

C 6 H 8 B Br Na 2 O (643) MS: 570 (M - HCl + Li ⁺ ) 550 (M - Cl)

Example 27

NH

NH-CCH 2 -R ¹ xHCl

It is prepared analogously to "Example 21".

CaiHseCIN 3 O 5 (585) MS: 556 (M - HCl + Li ⁺ ) 550 (M - Cl)

-400Example 28

1.0 g (1.9 mmol of amine b, 265 mg of NaBH ₃ CN and 610 mg of heptanal were stirred in 10 ml of methanol at room temperature for 48 hours. The mixture was concentrated in vacuo and partitioned between ethyl acetate and saturated bicarbonate solution. In addition to a small amount of the monoheptyl amino derivative, 650 mg (49%) of the product of Example 28 was obtained.

C ₄ H ₈₃ NOs (718) MS: 725 (M + Li ⁺ )

Example 29

N- (CH 3 -R ¹¹ n-C 3 H ₃ 3 xHCl)

The material was prepared similarly to Example 21. After acidification, the aqueous phase was decanted from the oily crude product. The residue was mixed with ethyl acetate, filtered and dried.

C _{4 4} H ₈₂ ClNO ₅ (740) MS: 711 (M-HCl + Li ⁺ ) 705 (M-Cl)

401

Example 30

The compound was prepared analogously to Examples 28 and 29 by reductive amination of anthracene-9-carbaldehyde with methyl 3α- (aminoethyl) -7α, 12α-dihydroxy-24-cholate (d) followed by alkaline hydrolysis.

C41H55NO4 (625) MS: 632 (M + Li ^&lt; ^{+ &gt;} )

Example 31

The compound was prepared similarly to Example 30 using cyclododecanone as carbonyl.

₃ C 8 H ₈₇ NO4 (602) MS: 609 (M + Li ⁺⁾

-402Example 32

Fffl C-CH-CH. "

CQOR

R = CH3

H

0.38 g (2 mmol) of naphthyl chloride in 5 ml of CH 2 Cl 2 was added to 0.9 g (2 mmol) of amine b and 0.6 ml of triethylamine in 20 ml of dry CH 2 Cl 2, while cooling on ice. The mixture was stirred on ice for one hour and allowed to stand overnight. Water was added, the mixture was acidified and extracted several times with CH 2 Cl 2. The organic phase was purified by chromatography (SiO 2, EtOAc / cyclohexane = 3: 1). 1 g (83%) of the product of Example 32 was obtained.

C38H53NO5 (603) MS: 610 (M + Li ^&lt; ^{+ &gt;} )

Example 33

The compound was prepared in analogy to Example 21. C37H51NO5 (589) MS: 596 (M + Li ⁺ )

Example 34

The compound was prepared in analogy to Examples 32 and 35 using anthracene-9-carbonyl chloride.

C41H53NO5 (639) MS: 646 (M + Li ^&lt; ^{+ &gt;} )

Example 35

HjC // \

The compound was prepared in analogy to Example 34 using p-toluenesulfonyl chloride and amine b.

C37H59NO7S (661) MS: 668 (M + Li &lt; + &gt;)

Example 36

H, C — VSO SON- (CHi), -R>

The compound was prepared in analogy to Example 35. The methyl ester obtained as an intermediate was methylated in dimethylformamide after deprotonation with sodium hydride,

-404 with iodomethane at room temperature. The product was then subjected to basic hydrolysis in analogy to Example 35.

₃ C 8 H ₆₁ NO ₇ S (675) MS: 688 (M - H ⁺ + 2LF) 682 (M + Li ⁺⁾

Example 37

The compound was prepared analogously to Example 34 using o-phthalic anhydride and amine b.

C ₃₈ H ₅₇ NO ₈ (655) MS: 668 (M ⁺ H ⁺ + Li ⁺ ) 662 (M + Li ⁺ )

Example 38

ABOUT

II c-xH- (CKaä-a ¹

The compound was prepared in analogy to Example 32/33 using amine b. C41H59NO5 (661) MS: 668 (M + Li &^lt; ⁴ &gt;)

Example 39

C-NH-CH, -CH,

ABOUT

OCH

426 mg (1 mmol) of urethane and 782 mg (15 mmol) of amine b were heated under reflux in 50 ml of dioxane for 4 hours. The mixture was concentrated and the residue purified by chromatography (SiCl 2, CH 2 Cl 2 / CH 3 OH = 10: 1). 540 mg (59%) of the product of Example 39 were obtained.

C48H70ClN3O10S (915) MS: 922 (M + Li ^&lt; ^{+ &gt;} )

Example 40

The compound was prepared in analogy to Example 21. C ₄ 7H ₆₈ ClN ₃ O ₁₀ S (901) MS (electrospray): 902 (M + H ⁺ )

Example 41

750 mg (3.6 mmol) of dicyclohexylcarbodiimide was added to a solution of 1.56 g (3 mmol) of amine b, 576 mg (3 mmol) of Chinese acid and 490 mg (83.6 mmol of hydroxybenzotriazole in 100 ml of THF). stirred at room temperature. the formed urea was filtered off, the residue was separated with ethyl acetate. the solution was washed with saturated _NaHCO3, 2N citric acid, and water. the residue of the organic phase was purified by chromatography (SiC> 2 _with ethyl acetate / CH ₃ OH = 5: 1). 1.2 g (58%) of the product were obtained.

C ₃₈ H 65 NO 10 (695) MS: 702 (M + Li ⁺ )

Example 42

The compound was prepared as in Example 21. C ₃₇ H ₆₃ NO, δ (681) MS (FAB, 3-NBA): 682 (M + H ⁺ )

-407Example 43 / NH-CH2CH2-R »

C

I

H — C — OH I

HO-C — H I

H — C — OH I

H-C-OH

CHiOH

The compound was prepared as in Example 41/42 using gluconic acid. CaóHeaNO! i (685) MS: 714 (M-H ^@ + + Li ^@ + + Na ^{@ +} )

Example 44

1.04 g (4 mmol) of acid chloride e, 2.1 g (4 mmol) of amine b and a spatula tip of 4-dimethylaminopyridine were stirred in 40 ml of dry pyridine at room temperature for 6 hours. After standing overnight at room temperature, the mixture was concentrated in vacuo. Chromatographic purification (SiO 2, CH 2 Cl 2 / CH 3 OH = 20: 1) gave the product of Example 44.

C4 ₃ H ₆₉ NO ₉ (743) MS: 750 (M + Li ⁺ )

-408Example 45

The compound was prepared as in Example 21.

C42H67NO9 (729) MS: 742 (M-H &lt; ⁺ &^gt; + Li &lt; ^{+ &gt;} ) 736 (M + Li ^&lt; ^{+ &gt;} )

Example 46

2.6 g (5 mmol) of amine b in CH 2 Cl 2 was added to 1.3 g (5 mmol) of acid chloride e and 0.8 ml of triethylamine in 50 ml of dry CH 2 Cl 2 with cooling. The mixture was stirred at 0 ° C for 1 hour. Excess methanol was added, the mixture was warmed to room temperature and water was added. The mixture was acidified with dilute hydrochloric acid. The aqueous phase was extracted several times into CFLCl 2 - Chromatographic purification (SiO 2, CH 2 Cl 2 / CH 3 OH = 10: 1) gave the product of Example 46.

C44H73NO10 (775) MS: 783 (M + H +)

-409-

Example 47

COOH

COOH-CO-NH-CCKi-R ¹

The compound was prepared as in Example 2.1.

C ₄₂ H 69 NO ₁₀ (747) MS: 760 (M-H ⁺ + 2 Li ⁺ ) 754 (M + Li ⁺ )

Example 48

3.14 g (6 mmol) of alcohol and (n = 6) were heated at 100 ° C with 3 ml of ethyldiisopropylamine and 1.5 g of diphenylmethyl bromide in 50 ml of DMF for 8 hours. After working up with water and chromatographic purification (SiO 2, CH 2 Cl 2 / CH 3 OH = 10: 1), the product of Example 48 was obtained.

C ^ HHmOô (688) MS: 695 (M + Li ⁺ )

-410-

O- (CH Os — R ¹

The compound was prepared analogously to Example 21.

C43H62O6 (674) MS: 681 (M + Li &lt; + &gt;)

The following compounds were prepared analogously to Example 1 from the following bile acid esters by alkaline hydrolysis:

Example 50

MS (H + O) (478) MS: 485 (M + Li ⁺ )

Example 51

C ₂₈ H ₄₆ O ₅ (462) MS: 469 (M + Li ⁺ )

411

Example 52

C30H53NO4 (491) MS: 498 (M + H &lt; ^{+ &gt;} )

Example 53

The compound was prepared from the product of Example 44 and n-hexylamine in analogy to the product of Example 41 with a reaction time of about 25 hours.

C49H82N2O8 (827) MS: 834 (M + Li ^&lt; ^{+ &gt;} )

Example 54

-412

C-NH- _(CH2) * - R a COOH

II

C-NH- (CH-CHjJj

170 mg of the product of Example 53 was dissolved in 5 mL of dioxane, 1.5 mL of 0.5 times concentrated NaOH and 25 mL of water. The mixture was stirred at room temperature for 12 hours. The suspension was filtered and the filtrate was acidified with dilute hydrochloric acid. The mixture was stirred for one hour and then vacuum filtered. After drying, 154 mg of the product was obtained.

C ₄₈ H 82 N ₂ O ₉ (831) MS: 838 (M + Li ⁺ )

Example 55

The compound was prepared analogously to Examples 53 and 54 from fluorescine and amine b. C 50 H 63 NO 9 (821) MS: 828 (M + Li ⁺ )

Example 56

The compound was prepared analogously to Example 55 from pivalic acid and amine b.

-413C ₃₅ H ₆₁ NO ₆ (591) MS: 598 (M + Li ⁺ )

The compound was prepared analogously to Example 55 from 2-ethylhexanoic acid and amine b.

MS (633) MS: 640 (M + Li ⁺ )

Example 58

The compound was prepared analogously to Example 55 from clofibric acid and amine b. C ₄ H ₆₂ ClNO 7 (703) MS: 710 (M + Li ⁺ )

Example 59

The compound was prepared analogously to Example 55 from gemfibrocil and amine b.

-414C45H73NO7 (740) MS: 747 (M + Li ^&lt; ^{+ &gt;} )

Example 60

The material was prepared from 522 mg of amine b and 94.1 mg of bis-n-propylmalonic acid in THF in the presence of DCC / HOBT. It was isolated after 54 hours. The yield was 69%.

MS (690) MS: 697 (M + Li ⁺ )

Example 61

250 mg of the product of Example 60 was hydrolyzed with 2N NaOH in dioxane. After working up with water and purification by column chromatography (EtOAc / CH ₃ OH 10: 1). 160 mg of compound were obtained

C ₃ 9 H ₆₇ NO ₈ (676) MS: 677 (M + 1).

A-64 Bile Acid Derivatives of Formula IA

415-

where

R is H, CH ₃ or M and M is a metal capable of forming a salt

X is a linking group of formula (CH 2) _n , sn = 1 to 3 in which 1-3 CH 2 groups may be replaced by -NH-, or -NHCO-, or a linking group of formula (CH 2) _n , sn = 4 to 10 in which 1-3 of the CH 2 groups may be replaced by oxygen, NH or -NHCO-, provided that no adjacent CH 2 groups can be replaced by oxygen and in which GS is bonded to X as described.

Z is HO-, CH 3 O-, HOCH ₂ CH = CHCH ₂ -, (C ₆ H ₅ ) ₂ CH-O-, AlkaL-O-SO ₂ -O-, H ₂ PO _{4 -} , (C ₆ H ₅ ) ₂ PO ₄ -, CH ₂ = CHCONH-, H 2 N-CO-NH-, C ₆ H ₅ -NH-CO-NH-, guanidine, -N (R) 2, or -N * (R) ₃ wherein

R is in each case C 1 -C 7 alkyl, or H ₂ N (CH 2) 6

II (C 1 -C 10) .alpha.-C-NH-.

Wherein the alkyl is sometimes substituted with a COOH group

-417-

to ties

CW; ζ

ABOUT

II

C — NH -

COOH

-418-

wherein A is in each case OH or NH (C 1 -C 10) alkyl

A-65 A bile acid derivative of the Formula I as described in A-64 wherein GS bound to X at position 3 in the α or β orientations.

Annex B

Compound and classes of compounds CAS numbers for specific and representative compounds link benfluorex 23602-78-0 ES 474498 fluvastatin 93957-54-1 EP 244364 Lavostatín 75330-75-5 EP 22478 pravastatin 81093-37-0 DE 3122499 simvastatin 79902-63-9 EP 33538 atorvastatin 134523-00-5 EP 409281 cerivastatin 145599-86-6 JP 08073432 Bervastatin and relatives 132017-01-7 Network, Parker, Motorcycle, Han, benzopyrans Bala-subramanian, Catt, Brown, Harte, Thompson, and Wright, J. Med. Chem. (1990), 33 (11), 2982-99 NK-104 141750-63-2 Takano, Kamikubo, Suglhara, Suz Ogasawara, Tetrahedron: Assymetry (1993), 4 (2) (Karboxydihydroxyheptenyl) sulfonyl 201-4 onylpyrroles including S-4522 148966-78-3, 139993-

-419-

Boron analogs of di- and tripeptides Zaragozic acid Seco-oxysterol analogues including U-88156 Pyridopyrimidines including acitemate BMY 22566 44-5 139993-45-6 139993-46-7, 13999347-8, 139993-48-9 139993-49-0, 13999351-4, 139993-52-5 139993-53-6, 13999354-7, 139993-55-8 139993-56-9, 13999357-0, 139993-58-1 139993-59-2, 13999360-5, 139993-61-6 139993-62-7, 13999363-7, 139993-64-9, 139993-65-0, 13999366-1, 139993-67-2 139993-68-3, 13999369-4, 139993-70-7 139993-71-8, 13999372-9, 139993-73-0, 139993-74-1, 13999375-2, 139993-76-3 139993-77-4, 13999378-5, 139993-79-6 139993-80-9, 14011063-0, 140128-98-9 140128-99-0, 14015762-6 125894-01-1, 12589402-2, 125894-03-3 125894-04-4, 12589440-5, 125894-08-8, 125894-09-9, 12591496-7 157058-13-4, 15705814-5, 157058-15-6 157058-16-7, 15705817-8, 157058-18-9 157058-19-0 157555-28-7, 15755529-8 64405-40-9, 10119799-3 129829-03-4 Sood, Sood, Spielyogel, Hall, Eur. Med Chem. (1990), 25 (4), 301-8 GB 2270312 Larsen, Spilman, Yagy, Dish, Hart, and Hess, J. Med. Chem. (1994), 37 (15). 2343-51 Larsen, Meszaros, VasvariDebreczy, Horvath, Virag and Sipos, Hung, ArzneimForsch (1979), 29 (12), 1833-5 Network, Parker, Motorcycle, Han, Balasubramanian, Catt, Brown, Harte, and Thompson

-420-

Colestolón 50673-97-7 Wright, J. Med. Chem. (1990), 33 (11), 2982-99. Raulston, Mishaw, Parish and CP-83101 130746-82-6, 130778- Schroepfer, Biochem. Biophys. Res. Commun. (1976) 71 (4): 984-9. Wint and McCarthy, J. 27-7 Labeled Compd. dalvastatin 132100-55-1 Padiopharm. (1988), 25 (11), 1289-97. Kumar, Windisch, Trived Dihydromevinolín 77517-29-4 and Golebiowski, J. Chromatogr., A (1994), 678 (2), 259-63. Falck and Yang, Tetrahedron DMP-565 Lett. (1984) 25 (33) 356366 Ko, Trzaskos, Abstr. Papers pyridyl 122254-45-9 Am. Chem. Soc. (207. National Meeting, Part 1, MEDI 10.1994) Beck, Kesseler, Baader and Pyrimidinylethenyldesmethyl- Bartmann, Bergmann mevalonates including glenvastine Granzer, Jendralla, Von GR 95030 157243-22-6 Kerekjarto, Krause et al. J. Med. Chem. (1990), 33 (1), 52-60. US 5316765 Izoxazolpyridylmevalonáty. 130581-42-9, 130581- carboxylic acids and esters 43-0, 130581-44-1 Lactones 6-phenoxy-3,5-dihydroxy 130581-45-2, 13058146-3, 130581-47-3, 130581-48-5, 13058149-7, 130581-50-9, 130581-51-0, 13058152-1, 13619-07-7, 13619-08-8, 13619- 09-9 127502-48-1, 136006- Jenderella, Granzer, Von hexanoic acid 66-1,136034-04-3 Kerekjarto, Krause L659699 29066-42-0 Schacht, Baader, Bartmann, Beck, Bergmann et al. J. Med. Chem. (1991), 34 (10), 2962-83. Chiang, Yang, Heck, L669262 130468-11-0 Chabala and Chang J. Org. Chem. (1989) 54 (24) 570812. Stokker, J. Org. Chem. mevastatin 73573-88-3 (1994) 59 (20) 5983-6 JP 56051992

-421 -

Pannorín Rawson RP 61969 Bile acid derived from HMG CoA reductase inhibitors including Na S-2467 a 5- 2468 SC 32561 SC 45355 phosphorus-containing HMG CoA reductase inhibitors including SQ 33600 6-Aryloxymethyl-4-hydroxy-tetrahydro-pyran-2-one, carboxylic acid and salts Atorvastine calcium (CI 981) Fenofobrat bezafibrate etofibrate Analogs of Mevinoline Pyranone derivatives 1,2,4-triazolidine-3,5-dione Isoazolidine-3,5-dione CS-514 1,10-bis (carboxymethylthio) -decan analogues of α-, β-, and γalkylaminophenone including Nphenylpiperazinopropiophenone 3-Amino-1- (2,3,4-mononitro, mono- or dihalophenyl) propan-1-ones including 3-morpholino or piperidin-1- (3-nitrophenyl) propan-1-ones Substituted isoxazolo 137023-88-5 125111-69-5 126059-69-6 76752-41-5 125793-76-2 133983-25-2 1350-71-6, 136215- 82-2, 136215-83-3 136215-84-4, 13621585-5, 136315-18-9 136315-19-0, 13631520-3, 136315-21-4 136316-20-6 134523-03-8 49562-28-9 41859-67-0 31637-97-5 16044-43-2 124756-24-7 81181-70-6 32827-49-9 Ogawa, Hasumi, Sakai, Murakawa, and Endo, J. Antibiot. (1991) 44 (7) 762. Charte, Troupe, Khan, Westley and Faulkner, Phytochemistry (1989) 28 (11): 2917-19 EP 326386 Kramer, Wess, Enhsen, Bock, Falk, Hoffman, Neckermann, Gantz, Shul et al., Biochim. Biophys. Acta D (1994), 1227 (3), 137-54. US 4230626 EP 329124 US 5274155 EP 418648 Baumann, Butler, Deering, Mennen, Millar, Nanning, Palmer and Roth, Tetrahedron Lett. (1992), 33 (17), 22834. DE 2250327 DE 2149070 US 3723446 EP 245003 US 4937259 WO 9000897 EP 321090 DE 3122499 DE 2038835 Huang and Halí, Eur. J. Med. Chem. (1996) 31 (4) 28190

-422pyridinóny

Biphenyl derivatives

4- (1- (substituted phenyl) -2-oxo-pyrrolidin-4-yl) methoxybenzoic acid

Dihydroxy (tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl, or hexahydrocycloheptapyrazole derivatives) hepteoate.

benfluorex

fluvastatin

lovastatin

pravastatin

simvastatin

atorvastatin

cerivastatin

bervastatin

BMS-180431

NK-104

S-4522

Boron analogs

HMG-CoA reductase inhibitors

HMG-CoA reductase inhibitors

U-88156

A-1233

acitemate

BAY-w-9533

BB-476

BMS-180436

BMY-22566

Colestolón

CP-83101

dalvastatin

Dihydromevonolín

DMP-565

glenvastatin

GR-95030

HMG-CoA reductase inhibitors HMG-CoA reductase inhibitors HMG-CoA reductase inhibitors, chiral

HMG-CoA reductase inhibitors, isoxazolopyridine HMG-CoA reductase inhibitors, sec. oxysterol

64769-68

US 4049813

JP 07089898

Watanabe, Ogawa, Ohno, Yano, Yamada and Shirasaka, Eur. J. Med. Chem. (1994) 29 (9): 675-86.

US 5134155

Servier

Sandoz

Merck & Co

Sankyo

Merck & Co

Warner-Lambert

Bayer

Merck KgaA Bristol-Myers Squibb Nissan Chemical Shionogi

Boron Biologicals

British Biotech & Japan

Tabacco

Merck & Co Pharmacia & Upjohn Kitasato University of Mitsubishi Chemical Bayer

British Biotech Bristol-Myers Squibb

American Home Products Pfizer

Rhone-Poulenc Rorer Merck & DuPont Merck Hoechst Marion Roussel Glaxo Wellcome Bristol-Myers Squibb Ono

Chiroscience

Nissan Chemical

Pharmacia & Upjohn

-423 HMG-CoA reductase inhibitors, Thiophene

HMG-CoA reductase inhibitors, 5-phenoxy-3,5dohydroxyhexanoic acid

Hypolipaemics

L-659699

L-669262

mevastatin

N - ((1-methylpropyl) carbonyl) -8 (2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl) ethyl perhydroisoquinoline

N- (1-oxododecyl) -4alpha, 10-dimethyl-8-aza-trans-decal-3betaol

P-882222 Pannorin Rawsonol RP 61969 S-2468

5- 853758A (S) -4 - ((2- (4- (4-Fluorophenyl) -5-methyl-2- (1-methylethyl) -6-phenyl-3-pyridinyl) ethenyl) hydroxyphosphinyl) -3-hydroxybutyric acid, dibasic sodium

SC-32561

SC-45355

SDZ-265859 (4R- (4alpha, 6beta (E)))) - 6- (2- (5 (4-fluorophenyl) -3- (1-years ago)) -1 (2-pyridinyl-H-pyrazole- 4-yl) ethenyl) tetrahydro-4-hydroxy-2H-pyran-2-one 5-beta-aminoethylthiopentanoic acid derivatives

6-Amino-2-mercapto-5-methylpyridine-4-carboxylic acid 6-phenoxymethyl-6-phenylethylene- (4-hydroxytetrahydropyran-2-one) atorvastine (4R- (4alpha, 6beta (E))) - 6- (2- (5- (4-Fluorophenyl) -3- (1-methylethyl) -1- (2-pyridinyl-4-pyrazol-4-yl) ethenyl) tetrahydro-4-hydroxy-2H-pyran-2-one)

Sandoz

Hoechst, Marion, Roussel

Warner-Lambert

Merck & Co

Merck & Co

Sankyo

Sandoz

Hoechst, Marion, Roussel

Nissan chemical Tokyo Noko University SmithKline Beecham Rhone-Poulenc Rorer Hoechst, Marion, Roussel Hoechst, Marion, Roussel Bristol-Myers Squibb

Monsanto non-industrial source Sandoz

Bristol-Myers Squibb Warner Lambert

Boehringer Mennheim, North Carolina University

IN//

424

Claims (17)

A composition comprising an ileal bile acid transport inhibitor and an HMG Co-A reductase inhibitor. 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 dose which is an amount of an ileal bile acid transport inhibitor, a second dose which is an amount of an HMG Co-A reductase inhibitor, both of which together form an effective amount of an antihyperlipidemic agent, and a pharmaceutically acceptable support. 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. Composition according to claims 1, 2, 3 or 4, characterized in that the ileal bile acid transport inhibitor is a compound of formula I: clay) 425 where: q is an integer from 1 to 4; n is an integer from 1 to 2; R ¹ and R ² are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino and alkylthio, (polyalkyl) aryl and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino and alkylthio, (polyalkyl) aryl and cycloalkyl, are optionally substituted with one or two substituents selected from the group consisting of OR ⁹ , NR ⁹ R ¹⁰ , N ⁺ R ⁹ R ¹⁰ R ^w a ·, SR ^9, S ⁺ R ⁹ R ¹⁰ N-, P ⁺ R ⁹ R ¹⁰ R ¹¹ N-, S (O) R ^9, SO 2 R ^9, SO 3 R ^9, CO 2 R ^9, CN, halo, oxo and CONR ⁹ R ^10, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl containing optionally one or more carbon atoms are replaced by O, NR ^9, N ⁺ R ⁹ R ¹⁰ R ^w A ', S, SO, SO ₂ , S ⁺ R ⁹ A', P * R ⁹ R ¹⁰ A ', or phenylene wherein R ⁹ , R ¹⁰ , and R ^w are independently selected from the group consisting of consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, heteroaryl, ammonium alkyl, alkylammonium alkyl and arylalkyl; or R ¹ and R ² together with the carbon atom to which they are attached form a C ₃ -C ₁₀ cycloalkylidene; R ³ and R ⁴ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, heteroaryl, OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S (O) R ⁹ , SO ² R ⁹ and SO ³ R ⁹ , wherein R ⁹ and R ¹⁰ are as defined above; or R ³ and R ⁴ together form = 0, = N0R ^11, = S, = NNR ¹¹ R ^12, = NR ^9, or = CR ⁿ R ^12, wherein R ¹¹ and R ¹² are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, arylalkyl, alkenylalkyl, alkynylalkyl heterocycle, heteroaryl, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR ^9, NR ⁹ R ^10, SR ^9, S (O) R ^9, SO 2 R ^9, and SO 3 R ⁹ CO 2 R ⁹ , CN, halide, oxo, and CONR ⁹ R ¹⁰ , wherein R ⁹ and R ¹⁰ are as defined above, provided that R ³ and R ⁴ cannot be simultaneously OH, NH ₂ or SH or R ¹¹ and R ¹² together with the nitrogen or carbon atom to which they are attached form a cycle; 426 R ⁵ and R ⁶ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, SR ⁹ , S (O) R ⁹ , SO ² R ⁹ and SO ³ R ⁹ , wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle and quaternary heteroaryl may be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halide, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ² R ¹³ , SO ³ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ^15, NO 2, CO 2 R ^13, CN, OM, SO2OM, SO ₂ NR ¹³ R ^14, C (O) NR ¹³ R ^14, C (O) OM, COR ^13, P (O) R ¹³ R ¹⁴ P ⁺ R ¹³ R ¹⁴ R ¹⁵ A ', P (OR ¹³ ) OR ¹⁴ , S ⁺ R ¹³ R ¹⁴ A' and N ⁺ R ⁹ R ¹¹ R ¹² A ', where: A 'is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl may be further substituted with one or more substituent groups selected from the group consisting of OR ⁷ , NR ⁷ R ⁸ , SR ⁷ , S (O) R ⁷ , SO ² R ⁷ , SO ³ R ⁷ , CO ₂ R ⁷ , CN, oxo, CONR ⁷ R ⁸ , N ⁺ R ⁷ R ⁸ R ⁹ A ', alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle and heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P (O) R ⁷ R ⁸ , P * R ⁷ R ⁸ R ⁹ A 'and P (O) (OR ⁷ ) OR ⁸ and S ⁺ R ¹³ R ¹⁴ A 'and N ⁺ R ⁹ R ¹¹ R ¹² A, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, quaternary heteroaryl, P (O) R ⁷ R ⁸ , P * R ⁷ R ⁸ R ⁹ A 'and P (O) (OR ⁷ ) OR ⁸ and wherein alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl may optionally have one or more carbon atoms replaced ch O, NR ⁷ , N ⁺ R ⁷ R ⁸ A ', S, SO, SO ₂ , S ⁺ R ⁷ A', PR ⁷ , P (O) R ⁷ , P ⁺ R ⁷ R ⁸ A 'or phenylene; and R ¹³ , R ¹⁴ and R ¹⁵ are independently selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl and quaternary heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, heteroaryl and polyalkyl optionally have one or more carbon atoms replaced by O, NR ⁹ , N ⁺ R ⁹ R ¹⁰ A ', S, SO, SO ₂ S * R ⁹ A', PR ⁹ , P ⁺ R ⁹ R ¹⁰ A ', P (O) R ⁹ , phenylene, carbohydrate, amino acid, peptide or polypeptide; and 427 R ¹³ , R ¹⁴ and R ¹⁵ are optionally substituted with one or more groups selected from the group consisting of: sulfoalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR ⁹ , NR ⁹ R ¹⁰ , N * R ⁹ R ¹¹ R ¹² A SR ⁹ S (O) R ^9, SO 2 R ^9, SO 3 R ^9, oxo, CO 2 R ^9, CN, halo, CONR ⁹ R @ ^10, S020M, SO ₂ NR ⁹ R ^10, PO (OR ¹⁶⁾ OR ^17, P ⁺ R ⁹ R ¹ ° R ¹¹ R, S ⁺ R ⁹ R ^1o N- and C (0) 0M, wherein R ¹⁶ and R ¹⁷ are independently selected R ⁹ and M; or R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a cycle; R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen and alkyl; and one or more R ^x is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halide, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , S (O) 2 R ¹³ , SO ³ R ¹³ , S ⁺ R ¹³ R ¹⁴ A ', NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO 2, CO2R ¹³ , CN, OM, S020M, SO ₂ NR ¹³ R ^14, NR ¹⁴ C (O) ^R13, C (0) NR ¹³ R ^14, NR ¹⁴ C (0) ^R13, C (0) 0M, COR ^13, OR ¹⁸ , S (O) n NR ¹⁸ , NR ¹³ R ¹⁸ , NR ¹⁸ OR ¹⁴ , N ⁺ R ⁹ R ¹¹ R ¹² A ', P ⁺ R ⁹ R ¹¹ R ¹² A', amino acid, peptide, polypeptide and carbohydrate wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, heteroaryl, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle and quaternary heteroaryl may be further substituted with OR ⁹ , NR ⁹ R ¹⁰ , N ⁺ R ⁹ R ¹¹ R ¹² A ', SR ^9, S (0) R ^9, SO 2 R, SO 3 R ^9, oxo, CO 2 R ^9, CN, halides, CONR ⁹ R ^10, S0 ₂ 0M, SO ₂ NR ⁹ R ¹⁰ , PO (OR ¹⁶⁾ OR ^17, P ⁺ R ⁹ R ¹¹ R ¹² N-, S ⁺ R ⁹ R ^1o N- or C (0) 0M, 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, alkyl, quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more substituents selected from the group consisting of OR ⁹ , NR ⁹ R ⁹ _n * r ⁹ r ¹¹ r ¹² a; SR ^9, S (O) R ^9, SO 2 R ^9, SO 3 R ^9, oxo, CO ₂ R ^9, CN, a halide, CONR ⁹ R ^10, SO 3 R ^9, S020M SO ₂ NR ⁹ R ^w, PO (OR ¹⁶⁾ OR ¹⁷ and C (O) 0M, wherein in R ^x , one or more carbon atoms are optionally replaced by O, NR ¹³ , N ⁺ R ¹³ R ¹⁴ A; S, SO, S0 _2, S ⁺ R ¹³ A; PR ¹³ , P (O) R ¹³ , P ⁺ R ¹³ R ¹⁴ A ', phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether or polyalkyl, 428 wherein one or more of the carbon atoms optionally substituted with O, NR ⁹ , N ⁺ R ⁹ R ¹⁰ A ', S, SO, SO ₂ , S ⁺ R ⁹ A is present for the polyalkyl, the linen, the amino acid, the peptide, the polypeptide and the carbohydrate ', PR ^9, P ⁺ R ⁹ R ^1o N- or P (O) R ^9; wherein the quaternary heterocycle and the quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, halide, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , S (O) 2R ¹³ , SO ³ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO 2i CO2R ¹³ , CN, OM, SO2OM, SO ₂ NR ¹³ R ¹⁴ , C (O) NR ^13, R ( ¹⁴⁾ , C (O) OM, COR ¹³ , P (O) R ^13, R ¹⁴ , P ⁺ R ^13, R ^14, R ¹⁵ A ', P (OR ¹³ ) OR ¹⁴ , S ⁺ R ¹³ R ¹⁴ A 'and N ⁺ R ⁹ R ¹¹ R ¹² A', provided that R ⁵ and R ⁶ cannot be simultaneously hydrogen, OH or SH, and that R ⁵ is OH, R ¹ , R ² , R ³ , R ⁴ , R ⁷ and R ⁸ cannot all be hydrogen; provided that R ⁵ or R ⁶ is phenyl, only one of R ¹ or R ² is H, provided that when q = 1 and R ^x is styryl, anilide or aniline carbonyl, only one of R ⁵ or R ⁶ is alkyl; or a pharmaceutically acceptable salt, solvate or prodrug thereof. The composition of claim 5, wherein R ⁵ and R ⁶ are independently selected from the group consisting of H, aryl, heterocycle, heteroaryl, quaternary heterocycle and quaternary heteroaryl, wherein aryl, heterocycle, heteroaryl, quaternary heterocycle and quaternary heteroaryl may 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, halide, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ^13, S (O) R ^13, SO 2 R ^13, SO 3 R ^13, NR ¹³ OR ^14, NR ¹³ NR ¹⁴ R ^15, NO 2, CO 2 R ^13, CN, OM, SOzOM, SO 2 NR ¹³ R ^14, C (O) NR ¹³ R ¹⁴ , C (O) OM, COR ¹³ , P (O) R ¹³ R ¹⁴ , P ⁺ R ¹³ R ¹⁴ A ¹⁵ , P (OR ¹³ ) OR ¹⁴ , s * r ¹³ r ¹⁴ a'an ⁺ r ⁹ r ¹¹ r ¹² a; wherein alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl may optionally have one or more carbon atoms optionally replaced with O, NR ⁷ , N ⁺ R ⁷ R ⁸ A ', S, SO, SO 2, S ⁺ R ⁷ A ', P (O) R ⁷ O, NR ⁹ , N ⁺ R ⁹ R ^w A ·, S, SO, SO 2, S ⁺ R ⁷ A', PR ⁷ , PA ⁷ , P ⁺ R ⁷ R ⁸ A 'or phenylene wherein alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl may be substituted with one or more 429 substituent groups selected from the group consisting of OR ⁷ , NR ⁷ R ⁸ , SR ⁷ , S (O) R ⁷ , SO ² R ⁷ , SO ³ R ⁷ , CO ₂ R ⁷ , CN, oxo groups, CONR ⁷ R ⁸ , N ⁺ R ⁹ R ¹¹ R ¹² A ', alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P (O) R ⁷ R ⁸ , P ⁺ R ⁷ R ⁸ R ⁹ A' and P (O) (OR ⁷⁾ OR ^eighth Composition according to claim 6, characterized in that R ⁵ and R ⁶ have the general formula: -Ar- (R ^y ) 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, pyrimidinyl, thiazolyl, triazolyl, indoliazolyl, indole, , benzoxazolyl, benzothiazolyl and benzoisothiazolyl; and one or more R ^y is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR ⁹ , SR ⁹ , S (O) R ⁹ , SO ² R ⁹ and SO ³ R ⁹ , wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl may be substituted with one or more substituent groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl , arylalkyl, halide, oxo groups, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ² R ¹³ , SO ³ R ¹³ , NR ¹³ OR ¹³ , NR ¹³ NR ¹⁴ R ¹⁵ , NO 2 CO2R ¹³ , CN, OM, SO2OM, SO ₂ NR ¹³ NR ¹⁴ , C (O) NR ¹³ R ¹⁴ , C (O) OM, COR ¹³ , P (O) R ¹³ R ¹⁴ , P ⁺ R ¹³ R ¹⁴ R ¹⁵ A ', P (OR ¹³ ) OR ¹⁴ , S ⁺ R ¹³ R ¹⁴ A 'and N ⁺ R ⁹ R ¹¹ R ¹² A', wherein alkyl, alkenyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl may be further substituted with one or more substituent groups selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, halide, oxo, OR ⁷ , NR ⁷ R ⁸ , SR ⁷ , S (O) R ⁷ , SO ² R ⁷ , SO ³ R ⁷ , CO ₂ R ⁷ , CN, oxo, CONR ⁷ R ⁸ , N * R ⁷ R ⁸ R ⁹ A ', alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, 430 quaternary heterocycle, quaternary heteroaryl, P (O) R ⁷ R ⁸ , P ⁺ R ⁷ R ⁸ R ⁹ A 'and P (O) (OR ⁷ ) OR ⁸ , and wherein alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl may optionally have one or more carbon atoms replaced by O, NR ⁷ , N ⁺ R ⁷ R ⁸ A ', S, SO, SO ₂ , S ⁺ R ⁷ A', PR ⁷ , P (O) R ⁷ , P ⁺ R ⁷ R ⁸ A 'or phenylene. Composition according to claim 6, characterized in that R ⁵ or R ⁶ has the general formula II: 9. A method of combination therapy for the prevention or treatment of a hyperlipidemic condition in a mammal, comprising administering to a patient a first dose of an ileal bile acid transport inhibitor, and administering a second dose of an HMG Co-A reductase inhibitor, wherein the first a the second dose of inhibitors together represent an effective amount of inhibitors for the anti-hyperlipidemic condition. The combination therapy method of claim 9, wherein the HMG Co-A reductase inhibitor is selected from the group consisting of lovastatin, simvastatin, pravastatin and fluvastatin. The method of claim 9 or 10, wherein the ileal bile acid transport inhibitor is a compound of Formula I: 431 q is an integer from 1 to 4; n is an integer from 0 to 2; R ¹ and R ² are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamine, alkylthio, (polyalkyl) aryl and cycloalkyl wherein alkyl, alkenyl, alkynyl, haloalkyl , alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamine, alkylthio, (polyalkyl) aryl and cycloalkyl are optionally substituted with one or two substituents selected from the group consisting of OR ⁹ , NR ⁹ R ¹⁰ , N ⁺ R ⁹ R ¹⁰ R ^w A , SR ⁹ , S ⁺ R ⁹ R ¹⁰ A ', P ⁺ R ^e R ¹⁰ R ¹¹ A', S (O) R ⁹ , SO ² R ⁹ , SO ³ R ⁹ , CO ₂ R ⁹ , CN, halide, oxo groups and CONR ⁹ R ¹⁰ , wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl and cycloalkyl optionally have one or more carbon atoms replaced by O, NR ⁹ , N ⁺ R ⁹ R ¹⁰ A ', S, SO SO ₂₎ S ⁺ R ⁹ A; P ⁺ R ⁹ R ^1o A 'or phenylene, wherein R ^9, R ^10, 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 R ¹ and R ² together with the carbon atom to which they are attached form a C ₃ -C ₆ cycloalkylidene; R ³ and R ⁴ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, heteroaryl, OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S (O) R ⁹ , SO ² R ⁹ and SO ³ R ⁹ , wherein R ⁹ and R ¹⁰ are as defined above, or R ³ and R ⁴ together form = O, = NO ¹¹ , = S, = NR ¹¹ R ¹² , = NR ⁹ or = CR ¹¹ R ¹² , wherein R ¹¹ and R ¹² are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, heteroaryl, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S (O) R ⁹ , SO ² R ⁹ , SO ³ R ⁹ , CO ₂ R ⁹ , CN, halide, oxo, and CONR ⁹ R ¹⁰ , wherein R ⁹ and R ¹⁰ are 432 quaternary heterocycle, quaternary heteroaryl, P (O) R ⁷ R ⁸ , P ⁺ R ⁷ R ⁸ R ⁹ A 'and P (O) (OR ⁷ ) OR ⁸ , and wherein alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl may optionally have one or more carbon atoms replaced by O, NR ⁷ , N ⁺ R ⁷ R ⁸ A ', S, SO, SO ₂ , S ⁺ R ⁷ A', PR ⁷ , P (O) R ⁷ , P ⁺ R ⁷ R ⁸ A 'or phenylene. Composition according to claim 6, characterized in that R ⁵ or R ⁶ has the general formula II: (II) 9. A method of combination therapy for the prevention or treatment of a hyperlipidemic condition in a mammal, comprising administering to a patient a first dose of an ileal bile acid transport inhibitor, and administering a second dose of an HMG Co-A reductase inhibitor, wherein the first a the second dose of inhibitors together represent an effective amount of inhibitors for the anti-hyperlipidemic condition. The combination therapy method of claim 9, wherein the HMG Co-A reductase inhibitor is selected from the group consisting of lovastatin, simvastatin, pravastatin and fluvastatin. The method of claim 9 or 10, wherein the ileal bile acid transport inhibitor is a compound of Formula I: 433 as defined above, provided that R ³ and R ⁴ cannot be simultaneously OH, NH ₂ or SH or R ¹¹ and R ¹² together with the nitrogen or carbon atom to which they are attached form a cycle; R ⁵ and R ⁶ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, SR ⁹ , S (O) R ⁹ , SO ² R ⁹ , SO ³ R ⁹ , wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle and quaternary heteroaryl may be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halide, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ² R ¹³ , SO ³ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ^15, NO 2, CO 2 R ^13, CN, OM, SO2OM, SO ₂ NR ¹³ R ^14, C (O) NR ¹³ R ^14, C (O) OM, COR ^13, P (O) R ¹³ R ¹⁴ P ⁺ R ¹³ R ¹⁴ R ¹⁵ A ', P (OR ¹³ ) OR ¹⁴ , S ⁺ R ¹³ R ¹⁴ A and N ⁺ R ⁹ R ¹¹ R ¹² A, where A * is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable the cation, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl may be further substituted with one or two substituent groups selected from the group consisting of OR ⁷ , NR ⁷ R ⁸ , SR ⁷ , S (O R ⁷ , SO ² R ⁷ , SO ³ R ⁷ , CO ₂ R ⁷ , CN, oxo, CONR ⁷ R ⁸ , N ⁺ R ⁷ R ⁸ R ⁹ A ', alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl P (O) R ⁷ R ⁸ , P ⁺ R ⁷ R ⁸ R ⁹ A 'and P (O) (OR ⁷ ) OR ⁸ and wherein alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl , haloalkyl, cycloalkyl, heterocycle and heteroaryl may optionally have one or more carbon atoms replaced by O, NR ⁷ , N ⁺ R ⁷ R ⁸ A ', S, SO, SO ₂ , S ⁺ R ⁷ A', PR ⁷ , P ( O) R ⁷ , P * R ⁷ R ⁸ A 'or phenylene and R ¹³ , R ¹⁴ and R ¹⁵ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl , quartem y heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle and heteroaryl may optionally have one or more carbon atoms replaced by O, NR ⁹ , N ⁺ R ⁹ R ¹⁰ A ', S, SO, SO ₂ , S ⁺ R ⁹ A ', PR ⁹ , P ⁺ R ⁷ R ⁸ A', P (O) R ⁹ , phenylene, carbohydrate, amino acid, peptide or polypeptide; and 434 R ¹³ , R ¹⁴ and R ¹⁵ are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR ⁹ , NR ⁹ R ¹⁰ , N * R ⁹ R ¹¹ R ¹² A, SR ⁹ , S (O) R ⁹ , SO ² R ⁹ , SO ³ R ⁹ , oxo groups, CO ₂ R ⁹ , CN, halide, CONR ⁹ R ¹⁰ , SO 2OM, SO ₂ NR ⁹ R ¹⁰ , PO (OR ¹⁶ ) OR ¹⁷ , P ⁺ R ⁷ R ⁸ R ⁹ A, S ⁺ R ¹³ R ¹⁴ A 'and C (O) OM, wherein R ¹⁶ and R ¹⁷ are independently selected from the substituents consisting of R ⁹ and M; or R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a cycle; R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen and alkyl; and one or more R * is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halide, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , S (O) 2R ¹³ , SO ³ R ¹³ , S ⁺ R ⁹ R ¹⁰ A ·, NR ¹³ OR ¹⁴ , NR ¹³ R ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ^13, CN, OM, SO2OM, SO 2 NR ¹³ R ^14, NR ¹⁴ C (O) R ^13, C (O) NR ¹³ R ^14, NR ¹⁴ C (O) R ^13, C (O) OM, COR ^13, OR ¹⁸ , S (O) n NR ¹⁸ , NR ¹³ R ¹⁸ , NR ¹⁸ OR ¹⁴ , N ⁺ R ⁹ R ¹¹ R ¹² A; P ⁺ R ⁹ R ¹¹ R ¹² A ', amino acids, peptide, polypeptide and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, heteroaryl, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle and quaternary heteroaryl can be further substituted by OR ⁹ , NR ⁹ R ¹⁰ , N ⁺ R ⁹ R ¹¹ R ¹² A ', SR ⁹ , S (O) R ⁹ , SO ² R ⁹ , SO ³ R ⁹ , oxo, CO ² R ⁹ , CN, halide, CONR ⁹ R ^10, SO ₂ M, SO ₂ NR ⁹ R ^10, PO (oR ¹⁶⁾ oR ^17, P ⁺ R ⁹ R ¹¹ R ¹² N-, S ⁺ R ⁹ R ^1o N- or C (O) 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, alkyl, quaternary heterocycle and quaternary heteroaryl are optionally substituents selected from the group consisting of OR ⁹ , NR ⁹ R ¹⁰ , n, R ^9, R ^11, R ^12, and; SR ⁹ , S (O) R ⁹ , SO ² R ⁹ , SO ³ R ⁹ , oxo group, CO ₂ R ⁹ , CN, halide, CONR ⁹ R ¹⁰ , SO 2OM, SO ₂ NR ⁹ R ^w , PO (OR ¹⁶ ) OR ¹⁷ and C ( O) OM wherein in R ^x one or more carbon atoms are optionally replaced by O, NR ¹³ , N ⁺ R ¹³ R ¹⁴ A ', S, SO, SO ₂ , S ⁺ R ¹³ a; PR ¹³ , P (O) R ¹³ , P * R ^13, R ¹⁴ A; phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether or polyalkyl, 435 wherein for polyalkyl, phenylene, amino acid, peptide, polypeptide and carbohydrate, one or more carbons is optionally replaced by O, NR ⁹ , N ⁺ R ⁹ R ¹⁰ A ', S, SO, SO ₂ , S ⁺ R ⁹ A; PR ^9, P ⁺ R ⁹ R ^1o N- or P (O) R ^9; wherein the quaternary heterocycle and the quaternary heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, halide, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO2R ¹³ , so3r ¹³ , nr ¹³ or ¹⁴ , nr ¹³ nr ¹⁴ r ¹⁵ , no2, co2r ¹³ , CN, OM, so2, SO ₂ NR ¹³ R ¹⁴ , C (O) NR ¹³ R ^14, C (O) OM, COR ^13, P (O) R ¹³ R ^14, P ⁺ R ¹³ R ¹⁴ R ¹⁵ A; P (OR ¹³ ) OR ¹⁴ R ¹³ R ¹⁴ A and N ⁺ R ⁹ R ¹¹ R ¹² A, provided that neither R ⁵ nor R ⁶ can be simultaneously hydrogen, OH or SH and when R ⁵ is OH, R ¹ , R ² , R ³ , R ⁴ , R ⁷ or R ⁸ cannot be hydrogen; provided that when R ⁵ or R ⁶ is phenyl, only R ¹ or R ² is H; provided that when q = 1 and R ^x is styryl, anilide or aniline carbonyl, only R ⁵ and R ⁶ is alkyl; or a pharmaceutically acceptable salt, solvate or prodrug thereof. 12. A method according to claim 11, characterized in that R ⁵ and R ⁶ are independently selected from the group consisting of H, aryl, heterocycle, heteroaryl, quaternary heterocycle, and quaternary heteroaryl, wherein the aryl, heterocycle, heteroaryl, quaternary heterocycle, and quaternary heteroaryl, may 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, halide, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ² R ¹³ , SO ³ R ¹³ , NR ¹³ 0 R ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO 2 CO ² R ¹³ , CN, OM, S020M, SO ₂ NR ¹³ R ¹⁴ , C (O) NR ¹³ R ¹⁴ , C (0) 0M, COR ¹³ , P (O) R ¹³ R ¹⁴ , P-R ¹³ R ¹⁴ R ¹⁵ a, P (OR ¹³⁾ OR ^14, S * R ¹³ R ¹⁴ N- and N ⁺ R ⁹ R ⁿ R ^12, and • wherein the alkyl, alkenyl, alkynyl, polyalkyl, polyether , aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl may further have one or more carbon atoms replaced by O, NR ⁷ , N ⁺ R ⁷ R ⁸ A ', S, SO, SO ₂ , S ⁺ R ⁷ A', PR ⁷ , P (O) R ⁷ , P * R ⁷ R ⁸ A 'or phenylene wherein alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl may be substituted with one or more 436 substituent groups selected from the group consisting of OR ⁷ , NR ⁷ R ⁸ , SR ⁷ , S (O) R ⁷ , SO ² R ⁷ , SO ³ R ⁷ , CO ₂ R ⁷ , CN, oxo CONR ⁷ R ⁸ , N ⁺ R ⁷ R ⁸ R ⁹ A ', alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P (O) R ⁷ R ⁸ , P ⁺ R ⁷ R ⁸ R ⁹ A 'and P (O) (OR ⁷ ) OR ⁸ . A method according to claim 12, characterized in that R ⁵ and R ⁶ have the general formula: -Ar- (R ^y ) _t where: 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, pyrimidinyl, thiazolyl, triazolyl, indoliazolyl, indole, , benzoxazolyl, benzothiazolyl and benzoisothiazolyl; and one or more R ^y is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR ⁹ , SR ⁹ , S (O) R ⁹ , SO ² R ⁹ and SO ³ R ⁹ , wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, and heteroaryl may be substituted with one or more substituent groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl , arylalkyl, halide, oxo groups, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ² R ¹³ , SO ³ R ¹³ , NR ¹³ OR ¹³ , NR ¹³ NR ¹⁴ R ¹⁵ , NO 21 CO2R ¹³ , CN, OM, SO2OM, SO ₂ NR ¹³ NR ¹⁴ , C (O) NR ¹³ R ¹⁴ , C (O) OM ¹³ , P (O) R ¹³ R ¹⁴ , p ⁺ r ¹³ r ¹⁴ r ¹⁵ a; P (OR ¹³ ) OR ¹⁴ , $ ⁺ R ¹³ R ¹⁴ A 'an ⁺ r ⁹ r ¹¹ r ¹² a; wherein the alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl may be further substituted by one or more substituent groups selected from the group consisting of OR ⁷ , NR ⁷ R ⁸ , SR ⁷ , S (O) R ⁷ , SO ₂ R ⁷ , SO ₃ R ⁷ , CO ₂ R ⁷ , CN, oxo, CONR ⁷ R ⁸ , N ⁺ R ⁷ R ⁸ R ⁹ A ', alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle and heteroaryl, arylalkyl, heterocyclic quaternary, heteroaryl quaternary, P (O) R ⁷ R ⁸ , P * R ⁷ R ⁸ R ⁹ A 'and P (O) (OR ⁷ ) OR ⁸ ; and wherein alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl may optionally have one or more carbon atoms 437 replaced by O, NR ⁷ , N ⁺ R ⁷ R ⁸ A ', S, SO, SO ₂ , S ⁺ R ⁷ A', PR ⁷ , P (O) R ⁷ , P ⁺ R ⁷ R ⁸ A 'or phenylene . The method of claim 13, wherein R ⁵ and R ⁶ have the formula II: The composition of claim 1, wherein the HMG Co-A reductase inhibitor is atorvastatin. The pharmaceutical composition of claim 3, wherein the HMG Co-A reductase inhibitor is atorvastatin. The combination therapy method of claim 9, wherein the HMG Co-A reductase inhibitor is atorvastatin.