AU3694600A - Novel 1,2-benzothiazepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake - Google Patents

Novel 1,2-benzothiazepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake Download PDF

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AU3694600A
AU3694600A AU36946/00A AU3694600A AU3694600A AU 3694600 A AU3694600 A AU 3694600A AU 36946/00 A AU36946/00 A AU 36946/00A AU 3694600 A AU3694600 A AU 3694600A AU 3694600 A AU3694600 A AU 3694600A
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alkyl
cio
heterocyclyl
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aryl
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Steve A. Kolodziej
David B. Reitz
Michael B. Tollefson
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GD Searle LLC
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids R2P(=O)(OH); Thiophosphinic acids, i.e. R2P(=X)(XH) (X = S, Se)
    • C07F9/36—Amides thereof
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    • C07—ORGANIC CHEMISTRY
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
    • C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/54—Quaternary phosphonium compounds
    • C07F9/5407—Acyclic saturated phosphonium compounds

Description

WO 00/47568 PCT/USOO/02503 1 NOVEL 1,2-BENZOTHIAZEPINES HAVING ACTIVITY AS INHIBITORS OF ILEAL BILE ACID TRANSPORT AND TAUROCHOLATE UPTAKE Field of the Invention 5 The present invention relates to novel 1,2-benzothiazepines, derivatives and analogs thereof, pharmaceutical compositions containing them, and their use in medicine, particularly in the prophylaxis and/or treatment of hyperlipidemic diseases, conditions and/or disorders, such as those associated with atherosclerosis and/or hypercholesterolemia, in 10 mammals. Description of Related Art It is well-settled that hyperlipidemic conditions associated with elevated concentrations of total cholesterol and low-density lipoprotein 15 ("LDL") cholesterol are major risk factors for coronary heart disease and particularly atherosclerosis. Interfering with the circulation of bile acids within the lumen of the intestinal tract is found to reduce the levels of serum cholesterol in a causal relationship. Epidemiological data has accumulated which indicates such reduction leads to an improvement in the disease state of 20 atherosclerosis. Stedronsky, "Interaction Of Bile Acids And Cholesterol With Nonsystemic Agents Having Hypocholesterolemic Properties," Biochimica et Biophysica Acta, 1210 (1994) 255-287, discusses the biochemistry, physiology and known active agents relating to bile acids and cholesterol. Pathophysiologic alterations are shown to be consistent with 25 interruption of the enterohepatic circulation of bile acids in humans in Heubi, J.E., et al., "Primary Bile Acid Malabsorption: Defective In Vitro Ileal Active Bile Acid Transport", Gastroenteroloay, 1982:83:804-11.
WO 00/47568 PCT/USOO/02503 2 In fact, cholestyramine binds the bile acids in the intestinal tract, thereby interfering with their normal enterohepatic circulation. Reihn6r, E. et al, in "Regulation of Hepatic Cholesterol Metabolism In Humans: Stimulatory Effects Of Cholestyramine On HMG-CoA Reductase Activity And Low 5 Density Lipoprotein Receptor Expression In Gallstone Patients", Journal of Lipid Research, Volume 31, 1990, 2219-2226. This results in an increase in liver bile acid synthesis by the liver using cholesterol as well as an upregulation of the liver LDL receptors which enhances clearance of cholesterol and decreases serum LDL cholesterol levels. Suckling el al, 10 "Cholesterol Lowering And Bile Acid Excretion In The Hamster With Cholestyramine Treatment", Atherosclerosis, 89(1991) 183-190), also discloses the results of cholestyramine treatment to lower serum cholesterol levels. In another approach to the reduction of recirculation of bile acids, the 15 ileal bile acid transport system is a putative pharmaceutical target for the treatment of hypercholesterolemia based on an interruption of the enterohepatic circulation with specific transport inhibitors. Kramer, et al, "Intestinal Bile Acid Absorption", The Journal of Biological Chemistry, Vol. 268, No. 24, Issue of August 25, pp. 18035-18046, 1993. 20 In a series of patent applications, Hoechst Aktiengesellschaft discloses polymers of various naturally occurring constituents of the enterohepatic circulation system and their derivatives, including bile acid, which inhibit the physiological bile acid transport with the goal of reducing the LDL cholesterol level sufficiently to be effective as pharmaceuticals and, in particular for use 25 as hypocholesterolemic agents. See, e.g., Canadian Patent Application Nos. 2,025,294; 2,078,588; 2,085,782; and 2,085,830; and EP Application Nos. 0 379 161; 0 549 967; 0 559 064; and 0 563 731. In vitro bile acid transport inhibition is disclosed to show hypolipidemic activity in The Wellcome Foundation Limited disclosure of the WO 00/47568 PCT/USOO/02503 3 world patent application number WO 93/16055 for "Hypolipidemic Benzothiepine Compounds". Selected benzothiepines are disclosed in world patent application number W093/321146 for numerous uses including fatty acid metabolism and 5 coronary vascular diseases. Additional benzothiepines for use as hypolipidemic agents are disclosed in W097/33882 and U.S. Patent 5,994,391. Other selected benzothiepines are known for use as hypolipaemic and hypocholesterolaemic agents, especially for the treatment or prevention of 10 atherosclerosis as disclosed by application Nos. EP 508425, FR 2661676, and WO 92/18462, each of which is limited by an amide bonded to the carbon adjacent the phenyl ring of the fused bicyclo benzothiepine ring. W096/16051 published May 30, 1996 describes certain 1,5 benzothiazepines as useful in the treatment of hyperlipidemic conditions. 15 W096/05188 published February 22, 1996 describes certain 1,4 benzothiazepines as useful in the treatment of hyperlipidemic conditions. Additional benzothiazepines are discussed in the references set forth below. These references either do not disclose a specific utility or disclose a different utility than the present invention. 20 Orahovats et al., "A Ring Enlargement From Seven- To Ten Membered-Ring Sulfonamide Derivatives", Helv. Chim. Acta, vol. 79, pp. 1121-1128 (1996) describes 4,5-dihydro-7,8-dimethoxy-1,2-benzothiazepine 3-one-1, 1-dioxide. Katrizky et al., "Preparation Of 6-, 7- and 8-Membered Sultams By 25 Friedel-Crafts Cyclization Of Z-Phenylalkanesulfamoyl Chlorides", Org. Prep. Proced. Int., vol. 24(4), pp. 463-467 (1992) describes 2,3,4,5-tetrahydro 1,2-benzothiazepine- 1,1-dioxide and 2,3,4,5-tetrahydro-2-butyl- 1,2 benzothiazepine- 1,1-dioxide for possible use as an anticonvulsant, diuretic or sedative.
WO 00/47568 PCT/USOO/02503 4 Beckwith et al., "Iododediazoniation Of Arenediazonium Salts Accompanied By Aryl Radical Ring Closure", J. Org. Chem., vol. 52, pp. 1922-1930 (1987) describes 2,3,4,5-tetrahydro-2-allyl-1,2-benzothiazepine 1,1-dioxide. 5 Stassinopolou et al., "' 3 C NMR Spectra Of Benzothiazepine, Benzothiazone and Benzosulphonamide N-substituted Derivatives", Org Magn. Reson., vol. 21(3), pp. 187-189 (1983), describes certain N-substituted 4,5 -dihydro-7,8-dimethoxy- 1,2-benzothiazepine-3-one- 1,1-dioxides. Tamura et al., "Novel Conversions Of Benzo[b]thiophen-3(2H)-ones 10 Into 1,2-Benzisothiazole And Tetrahydro- 1,2-benzothiazepin-5-One Systems Via Sulphimide Intermediates", J. Chem. Soc., Perkin Trans. I, vol. 12, pp. 2830-2834 (1980) describes 2,3,4,5-tetrahydro-2-tosyl-4-methyl-1,2 benzothiazepine-5-one- 1,1-dioxide. Catsoulacos et al., "Synthesis Of Some N-Substituted 4,5-Dihydro-7,8 15 dimethoxybenzothiazepin-3-one 1,1-Dioxides, J. Hetero. Chem., vol. 13(6), pp. 1309-1314 (1976) describes 4,5-dihydro-7,8-dimethoxy-1,2 benzothiazepine-3-one- 1,1-dioxide and certain 4,5-dihydro-2-(phenyl, substituted phenyl or pyridyl)-7, 8-dimethoxy- 1,2-benzothiazepine-3-one- 1,1 dioxides having anti-inflammatory and central nervous system activity. 20 Pangiotopoulos et al., "N(p-Bromophenyl)-4,5-Dihydro-7,8 Dimethoxy Benzothiazepine-3 -One 1,1-Dioxide C I 7
H
16 BrNO 5 S", Cryst. Struct. Comm., vol. 9, pp. 313-320 (1980) describes 4,5-dihydro-2-(4-bromo phenyl)-7,8-dimethoxy- 1,2-benzothiazepine-3-one- 1,1-dioxide. Catsoulacos et al., "Thiazo Compounds. Derivatives Of 4,5-Dihydro 25 7,8-Dimethoxybenzothiazepin-3-one 11-Dioxides", J. Chem. Eng. Data, vol. 22(3), pp. 353-354 (1977) describes 4,5-dihydro-2-(ethyl, n-propyl or isopropyl)-7,8-dimethoxy- 1,2-benzothiazepine-3-one- 1,1-dioxide. Camoutsis et al., "N-Substituted 4,5-Dihydro- 1,2-benzothiaepin-3-one 1,1-Dioxide", J. Hetero. Chem., vol. 17(5), pp. 1135-1136 (1980) describes WO 00/47568 PCT/USOO/02503 5 certain 4,5-dihydro-2-(3- or 5-pyridyl)-7,8-dimethoxy-1,2-benzothiazepine-3 one-1, 1-dioxides. U.S. Patent No. 5,350,761 describes hydroxylamine derivatives that generically encompass certain benzothiazepine compounds. These derivatives 5 are described as lipoxygenase inhibitors useful in the treatment of inflammatory and allergic conditions. W098/02432 published January 22, 1998 describes certain 5-(aryl-(N containing-heterocyclyl)alkyl)benzothiazepines and aralkyl-(N-containing heterocyclyl)alkyl)-benzothiazepines as useful for controlling micturition. 10 W097/03953 published February 6, 1997 describes certain sulfonylamino-substituted benzothiazepines as inhibitors of the enzyme cyclooxygenase II. W095/21843 published August 17, 1995 describes certain benzothiazepines substituted with azacyclic condensed piperazines. These 15 compounds are identified as kappa receptor agonists useful as analgesics and diuretics and for the treatment of cerebral ischaemia. EP338331 published October 25, 1989 describes certain 2 benzothiazepine-5-ones useful as muscle relaxants. Summary of the Invention 20 A first aspect of the invention comprises novel 1,2- benzothiazepines that are effective agents for the prophylaxis and/or treatment of hyperlipidemic diseases, conditions and/or disorders. A second aspect of the invention comprises pharmaceutical compositions comprising the novel 1,2- benzothiazepines that are suitable for 25 the prophylaxis and/or treatment of hyperlipidemic diseases, conditions and/or disorders. A third aspect of the invention comprises methods for the prophylaxis and/or treatment of hyperlipidemic diseases, conditions and/or disorders WO 00/47568 PCT/US0O/02503 6 comprising administering to a subject a prophylactically or therapeutically effective amount of one of the novel 1,2- benzothiazepines. A fourth aspect of the invention comprises methods of making the novel 1,2-benzothiazepines of the present invention. 5 Additional aspects of the invention are discussed throughout the specification of this application. Detailed Description of the Invention The following detailed description is provided to aid those skilled in the art in practicing the present invention. This detailed description, 10 however, should not be construed to unduly limit the present invention as modifications and variations in the embodiments discussed herein can be made by those of ordinary skill in the art without departing from the spirit or scope of the present inventive discovery. The contents of each of the references cited herein, including the contents of the references cited within 15 these primary references, are herein incorporated by reference in their entirety. Accordingly, the present invention provides compounds corresponding to the structure of Formula (I): 0 0 11 R N ( R )s *2 R O RR 3R R (I) 20 wherein: WO 00/47568 PCT/USOO/02503 7 q is an integer from 1 to 4; R I and R2 are independently selected from the group consisting of hydrogen and hydrocarbyl, wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, 5 and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; R3 and R4 are independently selected from the group consisting of hydrogen; hydrocarbyl; -OR 9 ; -NR 9
R
1 0; -SR 9 ; -S(O)R 9 ; -S02R 9 ; and 10 SO3R9; or R3 and R 4 together form =0; =NOR 9 ; =S;=NNR 9
R
10 ; =NR9; or =CR IR12 wherein R 9 and R 10 are independently selected from the group consisting of hydrogen; hydrocarbyl; amino; and hydrocarbylamino; wherein 15 said hydrocarbyl moieties may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl moieties optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; and 20 wherein R I and R 12 are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; hydrocarbyl; -OR 9 ; -NR 9
R
10 _
SR
9 ; -S(O)R 9 ; -S02R 9 ; and -S03R 9 ; wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more 25 carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; or R I and R 12 together with the carbon atom to which they are attached form a cyclic ring; and
R
5 and R 6 are independently selected from the group consisting of WO 00/47568 PCT/USOO/02503 8 hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; -OR 9 ; -SR 9 ; -S(O)R 9 ; -S02R 9 ; and -S03R 9 ; wherein the R5 and R6 radicals optionally may be substituted with one or more radicals independently selected from the group consisting of 5 halogen; -N02; -CN; oxo; hydrocarbyl; -OR 13 ; -NR 13
R
14 ; -SR 1 3 . S(O)R 13 ; -S02R 1 3 ; -S03R 1 3 ; -NR 13
OR
14 ; -NR 13
NR
14
R
1 5 ; -C02R 13 . OM; -SO2OM; -S02NR 13
R
14 ; -C(O)NR 13
R
14 ; -C(O)OM; -COR 13
NR'
3 C(O)R; -NR'C(O)NR' 4
R"
5 ; -NR CO 2 R"; -OC(O)R; OC(O)NR1 3 R1 4 ; -NRSOR1 4 ; -NR 3
SO
2
R
4 ; -NR1 3 SONRR; 10 NRBSO 2 NR1 4 R1 5 ; -PR 13
R
14 ; -P(O)R 13
R
14 ; -P+R 13
R
14
R
15 A~; P(OR 13
)OR
1 4 ; -S+R 13 R 14 A-; and -N+R 13 R 4R15A-; wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more 15 heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; and wherein R1 3 , R 4 , and R" are independently selected from hydrogen and hydrocarbyl, wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein 20 said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; or wherein R1 3 and R 4 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally 25 substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R 1 and R15 together with the nitrogen atom to which they are attached form a cyclic ring; and wherein A~ is a pharmaceutically acceptable anion, and M is a WO 00/47568 PCT/USOO/02503 9 pharmaceutically acceptable cation; and wherein R 9 is as defined above; or
R
4 and R 6 together represent a bond; and RN is selected from the group consisting of hydrogen and 5 hydrocarbyl, wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; 10 one or more RX radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -N02; hydrocarbyl; -OR 13 ; NRD13R ; -SR13; -S(O)R 1 3 ; -S(0)2R13; -SO3R13 _+R 13
R
1 4 A-; NR 13
OR
1 4 ; -NR 13
NR
4
R
1 5 ; -C02R 13 ; -OM; -S020M; -S02NR 1 3
R
1 4 - NR' 4 C(O)R1 3 ; -C(O)NR 13
R
1 4 ; -C(O)OM; -COR 13 ; -S(O)nNR 13 R14; 15 N+R 13 Rl 4
R
15 A~; -PR1 3 R1 4 ; -P(O)R 1 3
R
1 4 ; -P+R 13 Rl 4
R
15 A~; amino acid residue; peptide residue; polypeptide residue; and carbohydrate residue, wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more 20 heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; and wherein n is 0, 1 or 2; and wherein R1 3 , R 14 , R", A~, and M are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and 25 provided that at least one of R , R 2 , R 3 , R , R 5 , and R 6 is a radical other than hydrogen or alkyl; and provided that when R 5 or R 6 is aryl, the other of R 5 and R 6 is a radical other than heterocycylalkyl.
WO 00/47568 PCT/USO0/02503 10 A preferred class of compounds comprises those compounds of Formula I wherein: q is an integer from 1 to 4; RI and R2 are independently selected from the group consisting of 5 hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl; or 10 R and R2 taken together with the carbon to which they are attached form C 3
-CI
0 cycloalkyl or C 3 -Cio cycloalkenyl; wherein the R and R 2 alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; 15 aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may be substituted with one or more radicals selected from the group consisting of -CN; halogen; oxo; -OR 9 ; -NR 9
R
10 ; -N+R 9 R'ORwA~; -SR 9 -S*R 9
R
0 A-; -PR 9
R
10 - -P+R9R10RwA~; -S(O)R 9 ; -SO2R9; -S03R9; 20 C02R 9 ; and -CONR 9
R
1 0 ; and wherein the R 1 and R 2 alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl; 25 heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may have one or more carbons replaced by -0-; -NR 9 -; -N+R 9
R
1 OA--; -S-; SO-; -S02-; -S+R 9 A--; -PR 9 -; -P(O)R 9 -; -P+R 9
R
10 A--; or phenylene; and wherein R , R 10 , and Rw are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; WO 00/47568 PCTIUSO0/02503 11 heterocyclyl; alkylammoniumalkyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl; carboalkoxyalkyl; carboxyaryl; carboxyheterocyclyl; amino; alkylamino; carboxyalkylamino; alkoxyalkylamino; and acyl; or 5 wherein A~ is a pharmaceutically acceptable anion; and R3 and R are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; -OR 9 ; -NR 9
R
10 - SR 9 ; -S(O)R 9 ; -S02R 9 ; and -S03R 9 ; or R3 and R 4 together form =0; =NOR 9 ; =S; =NNR 9
R
10 ; =NR 9 ; or 10 =CRIIR12. wherein R 1 and R 12 are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl; carboalkoxyalkyl; cycloalkyl; cycloalkenyl; haloalkyl; hydroxyalkyl; 15 cyanoalkyl; -OR 9 ; -NR 9 R10; -SR 9 ; -S(O)R 9 ; -S02R 9 ; -S03R 9 ; -C02R 9 ; and -CONR 9
R
10 ; or R 1 and R 12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R 9 and R' 0 are as defined above; and 20 R5 and R6 are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl;
-OR
9 ; -SR 9 ; -S(O)R9; -SO2R9; and -SO3R9 wherein the R 5 and R 6 alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; and quaternary heterocyclyl radicals optionally may be 25 substituted with one or more radicals independently selected from the group consisting of halogen; -CN; -N02; oxo; alkyl; polyalkyl; haloalkyl; hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR 13 ; -NR 1 3
R'
4 SR 13 ; -S(O)R 13 ; -S02R 13 ; -S03R 13 ; -NR 13
OR
14 ; -NR 13NR1R15- WO 00/47568 PCT/USOO/02503 12 C02R 13 ; -OM; -SO2OM; -S02NR 13
R
14 ; -C(O)NR 13 R 14 ; -C(O)OM; COR 13 ; -NR'C(O)R1 4 ; -NR"C(O)NR 4
R
5 ; -NR"C0 2 R"; -OC(O)R"; OC(O)NR 3 R 1 4 ; -NR1 3
SOR
14 ; -NR'S0 2 R1 4 ; -NR"SONR1 4 R1 5 ; NR"S0 2
NR
1 4 R"; -PR 13
R
1 4 ; -P(O)R 1 3
R
14 ; -P+R 13
R
14
R
15 A~; 5 P(OR 13
)OR
1 4 ; -S+R 13
R
1 4 A~; and -N+R 13
R
14
R
15 A~; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the R 5 and R 6 radicals optionally may be further substituted with one or more radicals selected 10 from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR 7 ; -NR7R 8 ; -SR 7 ; -S(O)R 7 ; -S02R 7 ; -S03R 7 ;- C02R 7 - CON R 7
R
8 ; -N+R 7
R
8
R
9 A-; -P(O)R 7
R
8 ; -R 8 +R 7
R
8
R
9 A~; and P(O)(OR 7
)OR
8 ; and 15 wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the R' and R 6 radicals optionally may have one or more carbons replaced by -0-; -NRi-; N+R 7
R
8 A--; -S-; -SO-; -S02-; -S+R 7 A--; -PR 7 -; -P(O)R 7 -; -P+R 7
R
8 A--; or 20 phenylene; and wherein R 7 and R 8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R 1 3 , R 14 , and R 1 5 are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; 25 alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminoalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or WO 00/47568 PCT/USOO/02503 13 wherein R" and R" together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or 5 wherein R and R15 together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R 1 3 , R 14 , and R 1 5 alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; 10 alkylheterocyclylalkyl; alkylammoniumalkyl; aminoalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl; hydroxyalkyl; sulfoalkyl; 15 alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl; -OR 1 6; -NR 9
R
1 0. N+R9R10RwA~; -SR16; -S(O)R9; -SO2R9; -SO3R 16; -CO2R16 _
CONR
9
R
1 0 ; -SO2NR 9
R
1 0; -PO(OR 16 )OR 1 7; -P 9
R
10
-P+R
9
R
1 0 R1 1 A-; S+R 9
R
10 A-; and carbohydrate residue; and 20 wherein the R 1 , R , and R 1 5 alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminoalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; 25 carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -0-; -NR 9 -; -N+R 9
R
1 0 A--; -S-; -SO-;
-SO
2 -; -S+R 9 A--; -PR 9 -; -P+R 9
R
1 OA--; -P(O)R 9 -; phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R 16 and R 17 are independently selected from the group WO 00/47568 PCT/USOO/02503 14 consisting of R 9 and M; and wherein M is a pharmaceutically acceptable cation; and wherein R 9 , R 1 0 , R 1 , R", Rw, and A~ are as defined above; and RN is selected from the group consisting of hydrogen; alkyl; alkenyl; 5 alkynyl; aralkyl; and heterocyclylalkyl; and one or more Rx radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -N02; alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; acyloxy; -OR13. 10 NR 1 3
R
14 ; -SR 13 ; -S(O)R 1 3 ; -S(O)2R 1 3 ; -S03R 1 3 ; _+R13Rl4A-; N 1 3 0R 1 4 1N 3 14R1 R 1 3 -O14 NR13OR ; -N NR R ; -CO2R1; -OM; -SO2OM; -S02NR 1 3
R
1 4 NR 4 C(O)R1 3 ; -C(O)NR 13
R
1 4 ; -C(O)OM; -COR 13 ; -OR 18 ; S(O)nNR1R4 -N13R18 180R ; -N+R 13 Rl 4
R
1 5 A~; -PR13Rl4 -P(O)R1 3
R
1 4 ; -P+R 13 Rl 4
R
15 A~; amino acid residue; peptide residue; 15 polypeptide residue; and carbohydrate residue; wherein the RX alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; acyloxy radicals optionally may be further substituted with one or more radicals selected from the group consisting of halogen; -CN; oxo; -OR 16 . 20 NR 9
R
1 0 ; -N+R 9 RlORwA-; -SR 16 ; -S(O)R9; -S02R 9 ; -SO3R16. C02R 1 6 ; -CONR 9
R
1 0 ; -S02NR 9 Rl 0 ; -PO(OR 6
)OR
7 ; -P 9
R
10 . P+R 9
R
1
R
12 A; -S+R 9 R 0 A~; and carbohydrate residue; and wherein the RX quaternary heterocyclyl radical optionally may be substituted with one or more radicals selected from the group consisting of 25 halogen; -CN; -N02; oxo; alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR 13 ; -NR 13
R
4 ; -SR 13 ; -S(O)R13 SO2R13; -S3R13; -NR 13 0R 14 - -M13N14R15; -C02R 1 3 ; OM; SO2OM; -S02NR 1 3 R 4 ; -C(O)NR 1 3 R 4 ; -C(O)OM; -COR 13 . _ WO 00/47568 PCT/USOO/02503 15
P(O)R
1 3
R
1 4 ; -P1 3
R
14 --P +R13R14R15A; -P(OR 1 3
)OR
14 ; -S+R 13
R
14 A
-N+R
1 3
R
14
R
15 A~; and carbohydrate residue; and wherein the Rx radicals comprising carbon optionally may have one or more carbons replaced by -0-; -NR 13 -; -N+R 13
R
1 4 A--; -S-; -SO-; -S02-; 5 -S+R 13 A-; -PR 13-; -P(O)R 13 -; -PR 1 3
R
14 ; -P+R 13
R
1 4 A--; phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; polyether; or polyalkyl; wherein said phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; and polyalkyl optionally may have one or more carbons replaced by -O-; -NR9- 10 -N+R 9
R
10 A~-; -S-; -SO-; -S02-; -S+R9A--; -PR9-- -P+R9R A--; or P(O)R 9 -; and wherein R 1 8 is selected from the group consisting of alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and 15 heterocyclylalkoxycarbonyl; and wherein the R 8 alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl radicals optionally may be substituted with one or more radicals selected from the group 20 consisting of halogen; -CN ; NO 2 ; oxo; -OR 9 ; -NR 9
R
1 0 ; -N+R 9 RI IR 12 A~;
-SR
9 ; -S(O)R 9 ; -S02R 9 ; -S03R 9 ; -C02R 9 ; -CONR 9
R
10 ; -SO2OM; S02NR 9
R
10 ; -PR 9
R
10 ; -P(OR1 3
)OR
1 4 ; -PO(OR 16
)OR
1 7 ; and -C(O)OM; and wherein R 9 , R1 0 , R 1 , R , R , R", R , R 6 , R", Rw, A, and M are as 25 defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In the various embodiments of the invention, R' and R 6 preferably are independently selected from the group consisting of H; aryl; WO 00/47568 PCT/USOO/02503 16 heterocyclyl; and quaternary heterocyclyl; wherein the R 5 and R 6 aryl; heterocyclyl; and quaternary heterocyclyl; radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -CN; 5 -NO2; oxo; alkyl; polyalkyl; haloalkyl; hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR"; -NR 13 RI4; -SR 13 ; -S(O)R1 3 . S02R 1 3 ; -S03R 13 ; -NR 1 3 0R 14 ; -NR 13
NR
14
R
1 5 ; -Co2R 1 3 ; -OM; SO2OM; -S02NR 1 3
R
14 ; -C(O)NR 1 3
R
14 ; -C(O)OM; -COR 13 . 10 NR' 3 C(O)RM; -NRC(O)NR R 5 ; -NRC0 2 R"; -OC(O)R; OC(O)NR1 3 R1 4 ; -NR'SOR1 4 ; -NR1 3 S0 2 R1 4 ; -NR1 3
SONRI
4 R1 5 ; NRBSO 2
NR'
4 R"; -PR 13
R
14 ; -P(O)R 13
R
1 4 ; -PR 13
R
1 4 ; -P+R 13 R14R15A~
-P(OR
13
)OR
14 ; -S+R 13
R
1 4 A; and -N+R 13
R
1 4
R
15 A_; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, 15 alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the R 5 and RI radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary 20 heterocyclyl; -OR 7 ; -N 7
R
8 ; -SR ; -S(O)R ; -SO2R ; -SO3R ;- C02R 7 - CONR7R8; -N+R 7
R
8
R
9 A-; -P(O)R 7
R
8 ; -PR 7
R
8 . _p+R7R8R9A~; and P(O)(OR 7
)OR
8 ; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, 25 heterocyclylalkyl, and polyether substituents of the RI and R 6 radicals optionally may have one or more carbons replaced by -0-; -NR -; N+R 7
R
8 A--; -S-; -SO-; -SO2-; -S+R 7 A--; -PR 7 -; -P(O)R -; -P+R 7
R
8 A--; or phenylene; and wherein R 7 and R 8 are independently selected from the group WO 00/47568 PCT/USOO/02503 17 consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R 1 3 , R 4 , and R 15 are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; 5 heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or wherein R" and R1 4 together with the nitrogen atom to which they 10 are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R 4 and R 15 together with the nitrogen atom to which they are attached form a cyclic ring; and 15 wherein the R 13 , R 4 , and R 15 alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether 20 radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl; hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl; -OR16- -NR9R 0; -NR 9 RlORwA-; -SR 1 6 ; -S(O)R9; -SO2R9 25 -S03R 16 ; -C02R 16 ; -CONR 9
R
1 0 ; -S02NR 9 R 1 0 ; -PO(OR 16 )OR 1 7 ; PR 9
R
10 . -P+R 9 R A-; -S+R9R10A-; and carbohydrate residue; and
R
13 , 14 an 15 wherein the R1, R , and R alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; WO 00/47568 PCT/USOO/02503 18 alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -0-; -NR 9 -- N+R 9
R
10 k-; -S-; -SO-; -SO 2 -; -S+R 9 A--; -PR 9 -; -P+R 9
R
10 A~-; -P(O)R 9 -; 5 phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R16 and R 7 are independently selected from the group consisting of R 9 and M; and wherein M is a pharmaceutically acceptable cation; and 10 wherein R9, R1 0 , R", R1 2 , R", and A~ are as previously set forth above for the compounds of Formula I. More preferably, R' or R 6 has the formula -Ar-(Ry)t wherein: t is an integer from 0 to 5; 15 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; isothiazolyl; indolyl; benzoimidazolyl; benzoxazolyl; benzothiazolyl; and benzoisothiazolyl; and 20 one or more Ry are independently selected from the group consisting of halogen; -CN; -N02; oxo; alkyl; polyalkyl; haloalkyl; hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR13; -NR 13
R
1 4; -SR 13 . S(O)R 1 3 ; -S02R 13 ; -S03R 1 3 ; -NR 13 0R 1 4 ; -NR 13
NR
1 4
R
1 5 ; -C02R 13
.
25 OM; -SO2OM; -S02NR 1 3
RI
4 ; -C(O)NR 13
R
1 4 ; -C(O)OM; -COR 13 _ NR"C(O)R1 4 ; -NR"C(O)NR1 4
R'
5 ; -NRI'CO 2
R
4 ; -OC(O)R; OC(O)NR1 3 R1 4 ; -NRUSOR 14 ; -NR 13
SO
2
R
4 ; -NR1 3 SONR1 4
R'
5 NR 13
SO
2 NR1 4
R
15 ; -P(O)R 13
R
1 4; -PR 13 R 4; -P+R 13 R 14
R
15 A; - WO 00/47568 PCT/USOO/02503 19
P(OR
13
)OR
1 4; -S+R 13
R
1 4 A; and -N+R 13 R 4
R
15 A~; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the Ry radicals optionally 5 may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR 7 ; - N7R 8 ; -SR 7 ; -S(O)R 7 ; -S02R 7 ; -S03R 7 ;- C02R 7 - CONR 7
R
8 ; -N+R 7
R
8
R
9 A-; -P(O)R 7
R
8 ; -PR 7
R
8 ; _p+R 7
R
8
R
9 A~; and 10 P(O)(OR 7
)OR
8 ; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the Ry radicals optionally may have one or more carbons replaced by -0-; -NR -; -N+R 7
R
8 A--; -S-; 15 SO-; -S02-; -S+R 7 A--; -PR 7 -; -P(O)R -; -P+R 7
R
8 A--; or phenylene; and wherein R 7 and R 8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R 13 , R 4 , and R 15 are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; 20 alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or 25 wherein R1 3 and RM together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R 4 and R15 together with the nitrogen atom to which they WO 00/47568 PCT/USOO/02503 20 are attached form a cyclic ring; and wherein the R 13 , R 14 , and R 1 5 alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; 5 alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl; hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary 10 heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl; -OR 16 ; -NR9R10; -N+R 9 R1ORwA ; -SR 1 6; -S(O)R9; -SO2R9 -S03R 16 ; -C02R 1 6 ; -CONR 9
R
10 ; -S02NR 9
R
1 0 ; -PO(OR 16
)OR
1 7 ; PR 9
R
10 ; -P+RRIORI A-; -S+R 9
R
10 A-; and carbohydrate residue; and wherein the R 1 3 , R 14 , and R 1 5 alkyl; haloalkyl; cycloalkyl; 15 polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -0-; -NR 9 -. 20 N+R 9
R
1 0 A--; -S-; -SO-; -SO 2 -; -S+R 9 A--; -P+R9R10A--; -P(O)R'phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R 16 and R 1 7 are independently selected from the group consisting of R 9 and M; and 25 wherein M is a pharmaceutically acceptable cation; and wherein R 9 , R1 0 , R' 1 , R 2 , Rw, and A~ are as previously set forth above for the compounds of Formula I. Still more preferably, at least one of R' or R 6 has the formula (II) WO 00/47568 PCTUSOO/02503 21 (Ri) t (II) wherein Ry and t are defined as above. 5 In the various embodiments of the invention, the compounds of Formula I preferably satisfy at least one or more of the following additional conditions: (1) R' and R2 are independently selected from the group consisting of hydrogen, alkyl and (C 3
.
10 )cycloalkyl. Preferably, R' and R2 are 10 independently selected from the group consisting of hydrogen and (C 1 . 10 )alkyl. More preferably, R' and R2 are independently selected from the group consisting of (C 1
I
10 )alkyl. Still more preferably, R' and R 2 are independently selected from the group consisting of (C 1 7 )alkyl. Still more preferably, R' and R 2 are independently selected from the group consisting 15 of (C 2
.
4 )alkyl. Still more preferably, RI and R 2 are the same (C 2
-
4 )alkyl. Still more preferably, R' and R 2 are each n-butyl; and/or (2) R 3 and R 4 are independently selected from the group consisting of hydrogen and -OR 9 wherein R 9 is defined as previously set forth above for the compounds of Formula I. Preferably, R 3 is hydrogen and R 4 is -OR 9 . 20 Still more preferably, R 3 is hydrogen and R 4 is hydroxy. Still more preferably, the hydroxy group is in a syn relationship to the structure of Formula II; and/or (3) R 5 is phenyl substituted with a radical selected from the group WO 00/47568 PCTIUSOO/02503 22 consisting of -OR, -NR' 3 R1 4 , -NR1 3
C(O)R
4 , -NR ' 3
C(O)NR
4
R
5 , NR1 3 C0 2
R
4 , -OC(O)R1 3 , -OC(O)NRR1 4 , -NR1 3
SOR
4 , -NR1 3 S0 2 R, NR"SONRW R 5 , and -NR1 3
SO
2 NR1 4 R wherein R1 3 , R1 4 and R are as previously set forth above for the compounds of Formula I. Still more 5 preferably, R' is phenyl substituted with -OR 3 or -NR1 3 C(O)R1 4 . Still more preferably, R' is phenyl substituted at the para or meta position with -OR 3 wherein R 3 comprises a quaternary heterocyclyl, quaternary heterocyclylalkyl or alkylammoniumalkyl, or R' is phenyl substituted at the para or meta position with -NR' 3 C(O)R1 4 wherein R1 3 is hydrogen and R1 4 10 comprises a quaternary heterocyclyl, quaternary heterocyclylalkyl or alkylammoniumalkyl; and/or (4) R 6 is hydrogen; and/or (5) RN is selected from the group consisting of hydrogen, alkyl and aralkyl. Preferably, RN is selected from the group consisting of hydrogen, 15 (CO)alkyl and aryl(C,1 0 )alkyl. More preferably, RN is selected from the group consisting of hydrogen, methyl, ethyl and benzyl. Still more preferably, RN is hydrogen; and/or (6) RX is independently selected from the group consisting of -OR 3 , NR 3 R1 4 , -N*R] 3 R1 4 R'A-, and polyether. More preferably, RX is selected 20 from the group consisting of -OR and -NR R . Still more preferably, RX is selected from the group consisting of alkoxy, amino, alkylamino and dialkylamino. Still more preferably, RX is selected from the group consisting of methoxy and dimethylamino; and/or (7) One or more Rx are present at the 7-, 8- or 9-position of the benzo 25 ring of the structure of Formula I. Preferably, said Rx are present at the 7 and 9-positions of the benzo ring of the structure of Formula I. More preferably, Rx is present at the 7-position of the benzo ring of the structure of Formula I; and/or (8) q is 1, 2 or 3. Preferably, q is 1 or 2, and more preferably q is 1; WO 00/47568 PCT/USOO/02503 23 and/or (9) t is 1 or 2. In still another embodiment of the invention, the compounds of Formula I satisfy at least one or more of the above-described conditions and 5 R' comprises a carbohydrate residue. A more preferred class of compounds comprises those compounds of Formula I wherein: q is an integer from 1 to 4; R and R2 are independently selected from the group consisting of 10 hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; arylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; alkylaryl; and (polyalkyl)aryl; or R and R2 taken together with the carbon to which they are attached form C 3
-C
1 0 cycloalkyl or C 3
-C
1 0 cycloalkenyl; and wherein the R 1 and R 2 alkyl; cycloalkyl; alkenyl; alkynyl; arylalkyl; 15 alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may be substituted with one or more radicals selected from the group consisting of -CN; halogen; oxo; -OR 9 ; -NR 9
R
10 - N+R 9 RloRw A~; -SR 9 ; -S*R 9
R'
0 A-; -PR 9
R
1 0 ; _P+R 9 R1ORwA~; -S(O)R 9 ' S02R 9 ; -S03R 9 ; -C02R 9 ; and -CONR 9 R 1 0 ; and 20 wherein the R and R2 alkyl; cycloalkyl; alkenyl; alkynyl; arylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may have one or more carbons replaced by -0-; -NR 9 -- N+R 9
R
10 A~; -S-; -SO-; -S02-; -S+R 9 A--; -PR 9 -; -P(O)R 9 -; -P+R9R10A--; or phenylene; and 25 wherein R , R 10 , and Rw are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; alkylammoniumalkyl; arylalkyl; heterocyclylalkyl; WO 00/47568 PCT/USOO/02503 24 carboxyalkyl; carboalkoxyalkyl; carboxyheterocyclyl; carboxyalkylamino; and acyl; and wherein A is a pharmaceutically acceptable anion; and R3 and R 4 are independently selected from the group consisting of 5 hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; -OR 9 ; -N 9
R
1 0. SR9; -S(O)R9; -SO2R9; and -SO3R 9; or R3 and R 4 together form =0; =NOR 9 ; =S; =NNR 9
R
1 0 ; =NR 9 ; or =CR R12. wherein R 1 and R 12 are independently selected from the group 10 consisting of hydrogen; -CN; halogen; oxo; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; carboxyalkyl; carboalkoxyalkyl; cycloalkyl; cyanoalkyl; -OR 9 ; -NR 9 R10; -SR 9 ; -S(O)R 9 ; -S02R 9 ; -S03R 9 ; -C02R 9 and -CONR 9
R
10 ; or R and R 12 together with the carbon atom to which they are 15 attached form a cyclic ring; and wherein R 9 and R" are as defined above; and R5 and R 6 are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; -OR 9 ; -SR 9 ; -S(O)R 9 ; -SO2R 9 ; and -S03R 9 ; 20 wherein the R 5 and R 6 alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; and quaternary heterocyclyl radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -CN; -N02; oxo; alkyl; polyalkyl; haloalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; 25 arylalkyl; heterocyclylalkyl; polyether; -OR 13; -NR 13
R
14 ; -SR 13 . S(O)R 1 3 ; -S02R 13 ; -S03R 1 3 ; -NR 1 3 OR; -NR 13 NR 4
R
15 ; -C02R 13 . OM; -SO2OM; -S02NR 1 3
R
14 ; -C(O)NR 1 3 R 1 4 ; -C(O)OM; -COR-13 NR1 3 C(O)R"; -NR1 3
C(O)NR"R'
5 ; -NR 13
CO
2 R"; -OC(O)R; OC(O)NR1 3 R1 4 ; -NRSOR 14 ; -NRS0 2 R1 4 ; -NR 3
SONR
4 R; - WO 00/47568 PCT/US0O/02503 25
NR
3
SO
2 NR1 4
R
15 ; -PR 13 R 1 4 ; -P(O)R 13
R
14 ; -P+R 13 R 4
R
1 5 A~ P(OR 13
)OR
1 4 ; -S+R 13 R 14 A; and -N+R 13 R 14
R
15 A~; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, 5 heterocyclylalkyl, and polyether substituents of the R' and R 6 radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR 7 ; -NR7R8; -SR; -S(O)R 7 ; -S2R 7; -S03R 7 ;- CO2R 10 CONR 7
R
8 ; -N+R 7
R
8
R
9 A-; -P(O)R 7
R
8 ; -PR 7
R
8 ; -P+R 7
R
8
R
9 A~; and P(O)(OR 7
)OR
8 ; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the R' and R' radicals 15 optionally may have one or more carbons replaced by -0-; -NR 7 -; N+R 7
R
8 A~-; -S-; -SO-; -SO2-; -S+R 7 A--; -PR7-; -P(O)R7-. -P+R7R8A--; or phenylene; and wherein R 7 and R 8 are independently selected from the group consisting of hydrogen and alkyl; and 20 wherein R 13 , R 1 4 , and R 15 are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; 25 carboxyalkylaminocarbonylalkyl; and polyether; or wherein R 13 and RM together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or WO 00/47568 PCT/USOO/02503 26 wherein R 1 4 and R 15 together with the nitrogen atom to which they are attached form a cyclic ring; and
R
1 3
R
14 and wherein the R1, R , and R alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; 5 arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; sulfoalkyl; 10 heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl; -OR 16 ; -NR 9
R
1 0 ; -N+R 9 RlORwA-; SR 16 ; -S(O)R 9 ; -S02R 9 ; -S03R 16 ; -C02R 1 6 ; -CONR 9
R
1 0 ; S02NR 9
R
10 ; -PO(OR 16
)OR
17 ; -PR9R10 _P+R 9
R
1 0
R
1 1 A-; -S+R9R10A and carbohydrate residue; and 15 wherein the R 13 , R , and R 15 alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether 20 radicals optionally may have one or more carbons replaced by -0-; -NR 9 -; N+R9R10 A--; -S-; -SO-; -S02-; -S+R 9 A--; -PR 9 -; -P+R 9
R
1 0 A--; -P(O)R 9 -; phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R16 and Rl are independently selected from the group 25 consisting of R 9 and M; and wherein M is a pharmaceutically acceptable cation; and wherein R 9 , R 10 , R", R", R", and A are as defined above; and RN is selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; and aralkyl; and WO 00/47568 PCT/USO0/02503 27 one or more R radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -N02; alkyl; cycloalkyl; polyalkyl; haloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; pojyether; acyloxy; -OR 13 ; -NR 13 R 14 ; -SR 13 ; -S(O)R13 5 S(O)2R 13 ; -SO3R 1 3 ; -SR 1 3 R 4 A-; -NR 1 3 OR 4
-NR
1 3 1R1 5 C02R 13 ; -OM; -S02OM; -S02NR 13 R 1 4 ; -NR" 4 C(O)R"; -C(O)NR 1 3 R 1 4 -C(O)OM; -COR 13 ; -OR 18 ; -S(O)nNR 13 R 1 4 ; -NR 13
R
18 ; -NR 1 8 0R 1 4 N+R 13 R 4 R15A~; -PR 13 R 14; -P(O)R 13 R 4 ; -P+R 1 3 R 14
R
1 5 A~; amino acid residue; peptide acid residue; polypeptide acid residue; and 10 carbohydrate acid residue; wherein the Rx alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; acyloxy radicals optionally may be further substituted with one or more radicals selected from the group consisting of halogen; -CN; oxo; -OR 16 . 15 NR 9
R
10 ; -N+R 9 Rl0RwA~; -SR 16 ; -S(O)R 9 ; -S02R 9 ; -S03R 16 ; C02R 16 ; -CONR9R10; -SO2NR 9
R
10 ; -PO(OR 6 )OR1 7 ; -PR 9
R
10 ; P+R 9
R
1 R 12 A~; -S+R 9
R
1 0 A; and carbohydrate acid residue; and wherein the Rx quaternary heterocyclyl radical optionally may be substituted with one or more radicals selected from the group consisting of 20 halogen; -CN; -N02; oxo; alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR 13 ; -NR 1 3
R
1 4; -SR 13 ; -S(O)R 13 . S02R 13 ; -S03R 13 ; -NR 13 OR 1 4 ; -NR 13 NR 1 4 R15; -C02R 1 3 ; OM; S020M; -S02NR 1 3 R 1 4 ; -C(O)NR 13 R 1 4 ; -C(O)OM; -COR 13 . _ 25 P(O)R 13 R 4 ; - -P+R 13 R 14
R
15 A; -P(OR 13 )OR 1 4 S+R 13 R 14 A; -N+R 13 R 14
R
15 A; and carbohydrate acid residue; and wherein the RX radicals comprising carbon optionally may have one or more carbons replaced by -0-; -NR 13 -; -N+R 13
R
1 4 A--; -S-; -SO-; -SO2-;
-S+R
13 A~-; -PR 13 -; -P(O)R 13 -; -PR 1 3 _; -P+R 13 R 14 A--; phenylene; amino WO 00/47568 PCT/USOO/02503 28 acid; peptide; polypeptide; carbohydrate; polyether; or polyalkyl; wherein said phenylene; amino acid; peptide; polypeptide; carbohydrate; and polyalkyl optionally may have one or more carbons replaced by -0-; -NR
-N+R
9
RA
1 ~ -; -S-; -SO-; -S2-; -S+R 9 A--; -PR 9 -; -P+R 9
R
10 A--; or 5 P(O)R 9 -; and wherein R18 is selected from the group consisting of alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl; and 10 wherein the R" 8 alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN ; oxo; -OR.
9 ; -NR 9
R
10 ; -N+R 9
R
1 1
R
12 A~; -SR 9 15 -S(O)R 9 ; -S02R 9 ; -S03R 9 ; -C02R 9 ; -CONR 9
R
1 0 ; -SO2OM; SO2NR 9
R
1 0 ; -PR 9
R
1 0; -P(OR 13
)OR
14 ; -PO(OR 16
)OR
1 7; and -C(O)OM; and wherein R 9 , R 10 , R", R', R', R", R , R 16 , R", Rw, A, and M are as defined above; or 20 a pharmaceutically acceptable salt, solvate, or prodrug thereof A class of compounds of interest comprises those compounds of Formula I wherein: q is an integer from 1 to 4; R and R2 are independently selected from the group consisting of 25 hydrogen; (CI-CIo)alkyl; (C 3
-C
1 o)cycloalkyl; (C 2 -Cio)alkenyl; (C 2 CIO)alkynyl; aryl(CI-CIO)alkyl; (CI-CIO)alkoxy(CI-CIO)alkyl; (C 1 Ci)alkoxy(C 2 -Cj)alkenyl; (C-Cj)alkoxy(C 2 -Ci)alkynyl; (Cl-CIO)alkylaryl; and (polyalkyl)aryl; or WO 00/47568 PCT/USO0/02503 29 RI and R 2 taken together with the carbon to which they are attached form (C 3
-C
1 o)cycloalkyl; and wherein the Ri and R 2 (Cr-Ci)alkyl; (C 3 -CiO)cycloalkyl; (C 2 CIO)alkenyl; (C 2 -Cio)alkynyl; aryl(C-Cio)alkyl; (C-Ci 0 )alkoxy(C-Cj 0 )alkyl; 5 (C-Cj)alkoxy(C 2 Ci)alkenyl; (C-Cj)alkoxy(C 2 Cj)alkynyl; (C
C
10 )alkylaryl; and (polyalkyl)aryl radicals optionally may be substituted with one or more radicals selected from the group consisting of -CN; halogen; oxo; -OR 9 ; -NR 9
R
1 0 ; -N+R 9 R1ORwA~; -SR 9 ; -S*R 9
R'
0 A-; -PR9R10. P+R 9 RORwA~; -S(O)R9; -S02R 9 ; R9; and -CONR 9
R
10 10 and wherein the RI and R 2 (C-CIO)alkyl; (C 3 -Clo)cycloalkyl; (C 2 CIO)alkenyl; (C 2 -Cio)alkynyl; aryl(C-CIO)alkyl; (CI-CIO)alkoxy(C-Cio)alkyl; (C-Cj)alkoxy(C 2 Ci)alkenyl; (C-C 10 )alkoxy(C 2 C )alkynyl; (C CIO)alkylaryl; and (polyalkyl)aryl radicals optionally may have one or more 15 carbons replaced by -0-; -NR 9 -; -N+R 9
R
1 0 A--; -S-; -SO-; -S02-; -S+R 9
A-
-PR
9 ; -P(O)R 9 -; -P+R 9
R
10 A--; or phenylene; and wherein R 9 , R 10 , and Rw are independently selected from the group consisting of hydrogen; (C-Clo)alkyl; (C 3
-C
1 o)cycloalkyl; (C 2 -Cio)alkenyl;
(C
2 -CIO)alkynyl; aryl; heterocyclyl; ammonium(C-CIO)alkyl;
(C
20 C O)alkylammonium(C-CIO)alkyl; aryl(C-Cio)alkyl; heterocyclyl(C CIO)alkyl; carboxy(C-CIO)alkyl; carbo(C-CIO)alkoxy(C-Cio)alkyl; carboxyheterocyclyl; carboxy(C-CIO)alkylamino; and acyl; and wherein A is a pharmaceutically acceptable anion; and R3 and R 4 are independently selected from the group consisting of 25 hydrogen; (C-CIO)alkyl; (C 2 -Clo)alkenyl; (C 2 -Clo)alkynyl; aryl; heterocyclyl;
-OR
9 ; -NR 9
R
1 0 ; -SR 9 ; -S(O)R 9 ; -S02R 9 ; and -S03R 9 ; or R3 and R 4 together form =0; =NOR 9 ; =S; =NNR 9
R
10 ; -NR 9 ; or =CRI 1
R
1 2 ; wherein RI I and R 12 are independently selected from the group WO 00/47568 PCT/USOO/02503 30 consisting of hydrogen; -CN; halogen; oxo; (C 1 -CIO)alkyl; (C 2 -CIO)alkenyl;
(C
2 -CIO)alkynyl; aryl; heterocyclyl; aryl(CI-C O)alkyl; carboxy(CI-CIO)alkyl; carbo(Cl-CIO)alkoxy(Ci-Cio)alkyl; (C 3 -CIO)cycloalkyl; cyano(C 1 -Cio)alkyl; OR9- -NR9R10; -SR 9 ; -S(O)R 9 ; -S02R 9 ; -S03R 9 ; -C02R 9 ; and 5 CONR 9
R
1 ; or Ri and R12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R 9 and R1 0 are as defined above; and R5 and R6 are independently selected from the group consisting of 10 hydrogen; (Ci-CIO)alkyl; (C 3 -Cio)cycloalkyl; (C 2 -Co)alkenyl; (C 2 Cio)alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; -OR 9 ; -SR 9 S(O)R 9 ; -S02R 9 ; and -S03R 9 ; wherein the R 5 and R6 (CI-CIO)alkyl; (C 3 -CIo)cycloalkyl; (C 2 CIO)alkenyl; (C 2
-C
1 O)alkynyl; aryl; heterocyclyl; and quaternary heterocyclyl 15 radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -CN; -N02; oxo; (CI-CIo)alkyl; polyalkyl; halo(CI-CiO)alkyl; (C 3 -CIO)cycloalkyl; (C 2 CIO)alkenyl; (C 2 -CIO)alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; aryl(Cl-Cio)alkyl; heterocyclyl(CI-CIO)alkyl; polyether; -OR 13 ; -NR 1 3
R
1 4 20 -SR13; -S(O)R13; -S02R 1 3 ; -S03R 1 3
NR
13 0R 1 4 ; -NR 1 3
NR
14
R
1 5 C02R 13 ; -OM; -SO2OM; -S02NR 1 3
RI
4 ; -C(O)NR 13
R
1 4 ; -C(O)OM; COR 13 ; -NR'C(O)R; -NR C(O)NR'R' 5 ; -NR"C0 2 R"; -OC(O)R; OC(O)NR1 3
R
4 ; -NR1 3
SOR
4 ; -NR1 3 S0 2 R1 4 ; -NR1 3
SONR
4 R15; NR"SO 2
NR'
4 R"; -P(O)R 13
R
1 4 ; - 3 -P+R 13
R
14
R
1 5 A~; 25 P(OR 1 3
)OR
14 ; -S+R 13
R
14 A; and -N+R 1 3
R
14
R
15 A; and wherein the (CI-C 1 o)alkyl, polyalkyl, halo(C 1 -CIO)alkyl, hydroxy(C, CIo)alkyl, (C 3 -CIO)cycloalkyl, (C 2 -CIO)alkenyl, (C 2 -CIO)alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, aryl(Cl-CIO)alkyl, heterocyclyl(C, Cro)alkyl, and polyether substituents of the R' and R 6 radicals optionally WO 00/47568 PCT/USOO/02503 31 may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; (CI-CIO)alkyl; (C 3
-C
1 o)cycloalkyl;
(C
2 -Cio)alkenyl; (C 2 -Cio)alkynyl; aryl; heterocyclyl; aryl(CI-CIO)alkyl; heterocyclyl(C 1 -CIO)alkyl; quaternary heterocyclyl; -OR 7 ; -NR 7
R
8 ; -SR 7 ; 5 S(O)R7; -SO2R7; -SO3R7;- C02R 7 ; -CONR 7
R
8 ; -N+R 7
R
8
R
9 A-; P(O)R 7
R
8 ; -PR 7
R
8 ; _p+R 7
R
8
R
9 A~; and -P(O)(OR 7
)OR
8 ; and wherein the (CI-CIo)alkyl, polyalkyl, halo(CI-C 1 o)alkyl, hydroxy(Cl CIO)alkyl, (C 3
-C
1 o)cycloalkyl, (C 2 -Cio)alkenyl, (C 2 -C o)alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, aryl(CI-CIO)alkyl, heterocyclyl(C 10 C 10 )alkyl, and polyether substituents of the R' and R 6 radicals optionally may have one or more carbons replaced by -0-; -NR 7 -; -N+R 7
R
8 A--; -S-; SO-; -S02-; -S+R 7 A--; -PR 7 -; -P(O)R 7 -; -P+R 7
R
8 A--; or phenylene; and wherein R 7 and R 8 are independently selected from the group consisting of hydrogen and (C 1
-C
1 o)alkyl; and 15 wherein R 1 3 , R 4 , and R 1 5 are independently selected from the group consisting of hydrogen; (CI-CIO)alkyl; halo(C 1 -CIO)alkyl; (C 3 CIO)cycloalkyl; polyalkyl; (C 2
-C
1 o)alkenyl; (C 2 -C o)alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; aryl(CI-CIO)alkyl; heterocyclyl(C CIO)alkyl; quaternary heterocyclyl(C 1 -CIO)alkyl; (C 1 -CIO)alkylaryl(Cl 20 CIO)alkyl; (CI-CIo)alkylheterocyclyl(C 1 -CIO)alkyl; (Ci CIO)alkylammonium(CI-CIO)alkyl; carboxy(C 1 -CIO)alkylaminocarbony(C 1 CIO)alkyl; and polyether; or wherein R1 3 and R1 4 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally 25 substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R 1 4 and R 15 together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R 13 , R 1 4 , and R 15 (CI-CIO)alkyl; halo(Ci-C 1 O)alkyl; (C 3
-
WO 00/47568 PCT/USOO/02503 32 CIO)cycloalkyl; polyalkyl; (C 2 -Clo)alkenyl; (C 2 -C o)alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; aryl(Ci-CIO)alkyl; heterocyclyl(C 1 C 10 )alkyl; quaternary heterocyclyl(C 1 -CIO)alkyl; (Cl-CIO)alkylaryl (C CIo)alkyl; (C 1
-C
10 )alkylheterocyclyl(C 1 -CIO)alkyl; (C 1 5 CIO)alkylammonium(CI-CIO)alkyl; aminocarbonyl(CI-CIO)alkyl; (C 1 CIO)alkylaminocarbonyl(C 1 -Cio)alkyl; carboxy(C 1 -Cio)alkylaminocarbonyl
(C
1 -CIO)alkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; (Ci-CIo)alkyl; sulfo(CI-CIO)alkyl; heterocyclyl; quaternary heterocyclyl; 10 quaternary heterocyclyl(C 1 -C O)alkyl; carboxy; carboxy(C 1
-C
10 )alkyl; guanidinyl; -OR 1 6; -NR 9
R
1 0 ; -NR 9 RlORwA ; -SR 1 6 ; -S(O)R9; -SO2R9; -S03R 16 ; -CO2R 1 6 ; -CONR 9
R
1 0 ; - -S02NR 9
R
1 0 ; -PO(OR 1 6
)OR
1 7 ; PR 9
R-
10
-P+R
9
R
10 R1 1
A-;-S+R
9
R
1 0 A-; and carbohydrate residue; and wherein the R 13 , R 14 , and R 15 (CI-CIO)alkyl; halo(C 1 -CIo)alkyl; (C 3 15 CIO)cycloalkyl; polyalkyl; (C 2 -Cio)alkenyl; (C 2 -Clo)alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; aryl(C 1 -CIO)alkyl; heterocyclyl(C 1 CIO)alkyl; quaternary heterocyclyl(CI-CIO)alkyl; (C 1
-C
10 )alkylaryl(C 1 CIO)alkyl; (CI-CIo)alkylheterocyclyl(CI-CIO)alkyl; (C 1 CIO)alkylammonium(C 1 -Cio)alkyl; aminocarbonyl(C 1 -Cio)alkyl; (C 1 20 CIO)alkylaminocarbonyl(C 1 -CIO)alkyl; carboxy(C 1 CIO)alkylaminocarbonyl(C 1 -CIO)alkyl; and polyether radicals optionally may have one or more carbons replaced by -0-; -NR 9 -; -N+R9RioA--; -S-; -SO-;
-SO
2 -; -S+R 9 A--; -PR 9 -; -P+R 9
R
1 0 A--; -P(O)R 9 -; phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and 25 wherein R 16 and R 17 are independently selected from the group consisting of R 9 and M; and wherein M is a pharmaceutically acceptable cation; and wherein R 9 , R'O, R", R 12 , R", and A~ are as defined above; and RN is selected from the group consisting of hydrogen; (CI-Cio)alkyl; WO 00/47568 PCT/USO0/02503 33
(C
2 -Cio)alkenyl; (C 2 -Clo)alkynyl; and aryl(CI-CIO)alkyl; and one or more Rx radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -N02; (CI-CIO)alkyl; (C 3 CIO)cycloalkyl; polyalkyl; halo(C-CIO)alkyl; (C 2 -Cio)alkenyl; (C 2 5 CIo)alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; aryl(C 1 -CIo)alkyl; polyether; acyloxy; -OR13; -NRR; -SR13; -S(O)R 13 ; -S(O)2R13 _ SO3R 13
;-S+R
13
R
1 4 A-; -NR 13
OR
14
-NR
13
NR
1 4
R
15 ; -C02R 13 ; -OM; SO2OM; -S02NR 13
R
1 4 ; -NR1 4 C(O)R1 3 ; -C(O)NR 13
R
14 ; -C(O)OM; COR 13 ; -OR 18 ; -S(O)nNR 1 3
R
1 4 ; -NR 1 3
R
18 ; -NR 1 8 OR14- 10 N+R 13
R
1 4
R
1 5 A~; -PR1 3
R
14 ; -P(O)R 13
R
1 4 ; -P+R 13 R1 4
R
15 A~; amino acid residue; peptide acid residue; polypeptide acid residue; and carbohydrate acid residue; wherein the RX (CI-CIO)alkyl; (C 3 -Clo)cycloalkyl; polyalkyl; halo(C Cio)alkyl; hydroxy(Ci-Cio)alkyl; (C 2 -Cj)alkenyl; (C 2 -C o)alkynyl; aryl; 15 heterocyclyl; aryl(C 1 -C o)alkyl; heterocyclyl(CI-Cio)alkyl; polyether; acyloxy radicals optionally may be further substituted with halogen; -CN; oxo; -OR 16 ; -NR 9
R
10 ; -N+R 9 R1 1
R
12 A~; -SR 16 ; -S(O)R 9 ; -S02R 9 - So3R 16 ; -CO2R 16 ; -CONR 9
R
1 0 ; -S02NR 9
R
10 ; -PO(OR1 6
)OR
7 PR 9
R
10 . -P+R 9
R
1 1
R
12 A~; or -S+R 9
R
1 0 A~; and 20 wherein the RX quaternary heterocyclyl radical optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; -NO2; oxo; (CI-CIO)alkyl; (C 3 -Clo)cycloalkyl; polyalkyl; halo(CI-CIO)alkyl; hydroxy(CI-Cro)alkyl; (C 2 -Clo)alkenyl; (C 2 -Ci)alkynyl; aryl; heterocyclyl; aryl(CI-CIO)alkyl; heterocyclyl(Cl-Cio)alkyl; polyether; 25 OR 1 3
-NR
1 3
R
14 ; -SR 1 3 ; -S(O)R13; -S2R 13; -SO3R,13. _- 13 OR ; NR 13
NR
14
R
15 ; -C02R 13 ; -OM; -SO2OM; -S02NR 13
R
14 ; C(O)NR 13
R
14 ; -C(O)OM; -COR 1 3 ; -P(O)R 13
R
14 ; -PR-13R P+R 13
R
14
R
15 A~; -P(OR 13
)OR
14 ; -S+R 1 3
R
14 A~; and -N+R 13
R
14
R
15 A~; and WO 00/47568 PCT/USOO/02503 34 wherein the RX radicals comprising carbon optionally may have one or more carbons replaced by -0-; -NR13-; -N+R 13
R
1 4 A--; -S-; -SO-; -S02-;
-S+R
13 A-; -PR 13-; -P(O)R 13 -; -PR 13 ; -P+R 13
R
14 A--; phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; 5 polyether; or polyalkyl; wherein said phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; and polyalkyl optionally may have one or more carbons replaced by -0-; -NR 9 -; -N+R 9
R
10 A~-; -S-; SO-; -S02-; -S+R 9 A--; -PR 9 -; -P+R 9
R
10 A--; or -P(O)R 9 -; and wherein R 18 is selected from the group consisting of (C-CIO)alkyl; 10 heterocyclyl; quaternary heterocyclyl; aryl(C-CIO)alkyl; acyl; and aryl(C CIO)alkoxycarbonyl; and wherein the R" 8 (C-CIO)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(C-Cio)alkyl; acyl; and aryl(C-Cio)alkoxycarbonyl radicals optionally may be substituted with one or more radicals selected from the group 15 consisting of halogen; -CN ; oxo; -OR 9 ; -NR 9
R
10 ; -N+R 9 R 1
R
12 A~; -SR 9
-S(O)R
9 ; -S02R 9 ; -S03R 9 ; -CO2R9; -CONR 9
R
10 ; -SO M; SO2NR 9
R
1 0 ; -PR 9
R
1 0; -P(OR 1 3 )OR 1 4; -PO(OR 16 )OR 1 7; and -C(O)OM; and wherein R 9 , R' 0 , R", R , R , R , R", R' 6 , R", R", A , and M are as 20 defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and provided that aryl is selected from the group consisting of optionally substituted phenyl, biphenyl and naphthyl; and provided that heterocyclyl is selected from the group consisting of 25 optionally substituted heterocyclyl comprising a 5 to 10 membered ring and comprising one or more ring atoms that are heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus. A class of compounds of particular interest comprises those WO 00/47568 PCT/USOO/02503 35 compounds of Formula I wherein: q is an integer from 1 to 4; R and R2 are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 5 tert-butyl, pentyl, hexyl, phenoxymethylene, phenoxyethylene, phenoxypropylene, pyridinyloxymethylene, pyridinyloxyethylene; methylpyridinyloxymethylene, methylpyridinyloxyethylene, pyrimidinyloxymethylene, and pyrimidinyloxyethylene; or RI and R2 taken together with the carbon to which they are attached 10 form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; and
R
3 and R 4 are independently selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, phenyl, pyridinyl, amino, methylamino, dimethylamino, ethylamino and diethylamino; and R5 and R 6 are independently selected from the group consisting of 15 hydrogen, phenyl, chlorophenyl, fluorophenyl, bromophenyl, iodophenyl, hydroxyphenyl, methoxyphenyl, ethoxyphenyl, methoxy(chlorophenyl), methoxy(fluorophenyl), methoxy(bromophenyl), methoxy(iodophenyl), ethoxy(chlorophenyl), ethoxy(fluorophenyl), ethoxy(bromophenyl), ethoxy(iodophenyl), nitrophenyl, aminophenyl, methylaminophenyl, 20 dimethylaminophenyl, ethylaminophenyl, diethylaminophenyl, trimethylammoniumphenyl, triethylammoniumphenyl, trimethylammoniummethylcarbonylaminophenyl, triethylammoniummethylcarbonylaminophenyl, trimethylammoniumethylcarbonylaminophenyl, 25 triethylammoniumethylcarbonylaminophenyl, trimethylammoniumpropylcarbonylaminophenyl, triethylammoniumpropylcarbonylaminophenyl, trimethylammoniumbutylcarbonylaminophenyl, triethylammoniumbutylcarbonylaminophenyl, methylcarbonylaminophenyl, WO 00/47568 PCT/USOO/02503 36 chloromethylcarbonylaminophenyl, fluoromethylcarbonylaminophenyl, bromomethylcarbonylaminophenyl, iodomethylcarbonylaminophenyl, ethylcarbonylaminophenyl, chloroethylcarbonylaminophenyl, fluoroethylcarbonylaminophenyl, bromoethylcarbonylaminophenyl, 5 iodoethylcarbonylaminophenyl, propylcarbonylaminophenyl, chloropropylcarbonylaminophenyl, fluoropropylcarbonylaminophenyl, bromopropylcarbonylaminophenyl, iodopropylcarbonylaminophenyl, butylcarbonylaminophenyl, chlorobutylcarbonylaminophenyl, fluorobutylcarbonylaminophenyl, bromobutylcarbonylaminophenyl, 10 iodobutylcarbonylaminophenyl, 3,4-dioxymethylenephenyl, pyridinyl, methylpyridinyl, pyridinium, methylpyridinium, thienyl, chlorothienyl, fluorothienyl, bromothienyl, iodothienyl; methoxycarbonylphenyl, ethoxycarbonylphenyl, trimethylammoniumethoxyethoxyethoxyphenyl, triethylammoniumethoxyethoxyethoxyphenyl, 15 chloroethoxyethoxyethoxyphenyl, fluoroethoxyethoxyethoxyphenyl, bromoethoxyethoxyethoxyphenyl, iodoethoxyethoxyethoxyphenyl, pyridiniumethoxyethoxyethoxyphenyl, piperazinyloxymethoxyethoxyethoxyphenyl, methylpiperazinyloxymethoxyethoxyethoxyphenyl, 20 dimethylpiperazinyloxymethoxyethoxyethoxyphenyl, piperidinyloxymethoxyethoxyethoxyphenyl, methylpiperidinyloxymethoxyethoxyethoxyphenyl, and dimethylpiperidinyloxymethoxyethoxyethoxyphenyl; and RN is selected from the group consisting of hydrogen, methyl, ethyl, 25 n-propyl, n-butyl, n-pentyl, n-hexyl and benzyl; and one or more Rx radicals are independently selected from the group consisting of hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, methylthio, methylsulfinyl, methylsulfonyl, ethylthio, ethylsulfinyl, ethylsulfonyl, WO 00/47568 PCT/USOO/02503 37 amino, hydroxyamino, methylamino, dimethylamino, ethylamino, diethylamino, trimethylammonium, triethylammonium, N-methyl-N carboxymethyl-amino, N,N-dimethyl-N-carboxymethyl-ammonium, methylcarbonylamino, chloromethylcarbonylamino, 5 fluoromethylcarbonylamino, bromomethylcarbonylamino, iodomethylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, n butylcarbonylamino, n-pentylcarbonylamino, n-hexylcarbonylamino, benzyloxycarbonylamino, aminoimidocarbonylamino, morpholinyl, N methyl-morpholinium, azetidinyl, N-methyl-azetidinium, pyrrolidine, N 10 methyl-pyrrolidinium, piperazinyl, N-methylpiperazinyl, N,N'-dimethyl piperazinium, piperidinyl, methylpiperidinyl, N-methyl-piperidinium, and thienyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. A class of compounds of specific interest comprises those 15 compounds of Formula I wherein: q is an integer from 1 to 4; R and R2 are independently selected from the group consisting of hydrogen and (CI-Cio)alkyl; or R and R2 taken together with the carbon to which they are attached 20 form (C 3 -Clo)cycloalkyl; and R3 and R 4 are independently selected from the group consisting of hydrogen and hydroxy; and
R
5 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from the group consisting of 25 halogen; hydroxy; -N02; (CI-CIO)alkyl; halo(Ci-C O)alkyl; aryl(CI-CIO)alkyl; heterocyclyl(CI-CIO)alkyl; polyether; -OR 13 ; -NR 13
R
1 4; and -NR 3
C(O)R
14 ; and wherein R 13 , R 4 , and R 1 5 are independently selected from the WO 00/47568 PCT/USOO/02503 38 group consisting of hydrogen; (CI-Cio)alkyl; halo(C 1 -CIO)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(C 1 -CIO)alkyl; heterocyclyl(CI-Co)alkyl; quaternary heterocyclyl(C-CIO)alkyl; (Cl-C o)alkylheterocyclyl(Cl CIO)alkyl; (C 1 -CIo)alkylammonium(C 1 -Clo)alkyl; and polyether; or 5 wherein the R 13 , R14, and R 15 (CI-CIo)alkyl; halo(CI-CIo)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(Ci-CIO)alkyl; heterocycly(C 1 CIO)alkyl; quaternary heterocyclyl(CI-CIo)alkyl; (C1 Cio)alkylheterocyclyl(CI-CIO)alkyl; (CI-CIO)alkylammonium(C 1 -CIO)alkyl; and polyether radicals optionally may be substituted with one or more 10 radicals selected from the group consisting of halogen; (C 1
-C
10 )alkyl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclyl(C 1 -CIO)alkyl; carboxy; carboxy(C 1 -Cio)alkyl; -OR 16 ; -NR 9
R
1 0 ; -N+R 9 R1ORwA; and CONR 9
R
10 ; and wherein R 9 and R10 are independently selected from the group 15 consisting of hydrogen; (CI-CIO)alkyl; heterocyclyl; ammonium(C 1 Cio)alkyl; (CI-CIO)alkylammonium(CI-CIO)alkyl; aryl(C 1 -CIO)alkyl; heterocyclyl(C 1 -CIO)alkyl; carboxy(C 1 -C O)alkyl; carbo(C 1 -CIO)alkoxy(C 1 CO)alkyl; carboxyheterocyclyl; carboxy(C 1 -CIO)alkylamino; and acyl; or wherein A~ is a pharmaceutically acceptable anion; and 20 wherein RI and R 12 are independently selected from the group consisting of hydrogen; (C-Cio)alkyl; heterocyclyl; aryl(CI-CIO)alkyl; carboxy(CI-Cio)alkyl; and carbo(CI-CIO)alkoxy(C 1 -CIO)alkyl; or R and R 12 together with the carbon atom to which they are attached form a cyclic ring; and 25 wherein R' and R 1 6 are as previously set forth above for the compounds of Formula I; and
R
6 is hydrogen; and RN is selected from the group consisting of hydrogen; (C 1 -CIO)alkyl; and aryl(C 1
-C
1 O)alkyl; and WO 00/47568 PCT/USOO/02503 39 one or more Rx radicals are independently selected from the group consisting of hydrogen; -N02; (Ci-CIO)alkyl; halo(CI-CIO)alkyl; -OR 13 NR13R14. wherein R" and R1 4 are as defined above; or 5 a pharmaceutically acceptable salt, solvate, or prodrug thereof; and provided that aryl is selected from the group consisting of optionally substituted phenyl, biphenyl and naphthyl; and provided that heterocyclyl is selected from the group consisting of optionally substituted heterocyclyl comprising a 5 to 10 membered ring and 10 comprising one or more ring atoms that are heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus. A class of compounds of high interest comprises those compounds of Formula I wherein: q is an integer from 1 to 4; 15 R 1 and R 2 are independently selected from the group consisting of ethyl and n-butyl; or R and R 2 taken together with the carbon to which they are attached form cyclopentyl; and one of R 3 and R 4 is hydrogen and the other of R 3 and R 4 is 20 hydroxy; and R5 is selected from the group consisting of phenyl, hydroxyphenyl, methoxyphenyl, ethoxyphenyl, nitrophenyl, aminophenyl, methylaminophenyl, dimethylaminophenyl, ethylaminophenyl, diethylaminophenyl, trimethylammoniumphenyl, triethylammoniumphenyl, 25 trimethylammoniummethylcarbonylaminophenyl, triethylammoniummethylcarbonylaminophenyl, trimethylammoniumethylcarbonylaminophenyl, triethylammoniumethylcarbonylaminophenyl, WO 00/47568 PCT/USOO/02503 40 trimethylammoniumpropylcarbonylaminophenyl, triethylammoniumpropylcarbonylaminophenyl, trimethylammoniumbutylcarbonylaminophenyl, triethylammoniumbutylcarbonylaminophenyl, methylcarbonylaminophenyl, 5 chloromethylcarbonylaminophenyl, fluoromethylcarbonylaminophenyl, bromomethylcarbonylaminophenyl, iodomethylcarbonylaminophenyl, ethylcarbonylaminophenyl, chloroethylcarbonylaminophenyl, fluoroethylcarbonylaminophenyl, bromoethylcarbonylaminophenyl, iodoethylcarbonylaminophenyl, propylcarbonylaminophenyl, 10 chloropropylcarbonylaminophenyl, fluoropropylcarbonylaminophenyl, bromopropylcarbonylaminophenyl, iodopropylcarbonylaminophenyl, butylcarbonylaminophenyl, chlorobutylcarbonylaminophenyl, fluorobutylcarbonylaminophenyl, bromobutylcarbonylaminophenyl, iodobutylcarbonylaminophenyl, 15 trimethylammoniumethoxyethoxyethoxyphenyl, triethylammoniumethoxyethoxyethoxyphenyl, chloroethoxyethoxyethoxyphenyl, fluoroethoxyethoxyethoxyphenyl, bromoethoxyethoxyethoxyphenyl, iodoethoxyethoxyethoxyphenyl, and pyridiniumethoxyethoxyethoxyphenyl; and 20 R 6 is hydrogen; RN is selected from the group consisting of hydrogen, methyl, ethyl, and benzyl; and one or more RX radicals are independently selected from the group consisting of hydroxy, methyl, ethyl, methoxy, ethoxy, amino, 25 hydroxyamino, methylamino, dimethylamino, ethylamino, diethylamino, trimethylammonium, triethylammonium, N-methyl-N-carboxymethyl amino, N,N-dimethyl-N-carboxymethyl-ammonium, methylcarbonylamino, chloromethylcarbonylamino, fluoromethylcarbonylamino, bromomethylcarbonylamino, iodomethylcarbonylamino, WO 00/47568 PCT/USOO/02503 41 ethylcarbonylamino, benzyloxycarbonylamino, and aminoimidocarbonylamino; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. A subclass of compounds of high interest comprises those 5 compounds of Formula I wherein: wherein: q is 1 or 2; RI and R2 are each independently alkyl; R3 is hydroxy; 10 R4 and R6 are hydrogen;
R
5 has the formula (II): (R ) wherein t is an integer from 0 to 5; one or more R are independently selected from the group consisting of hydrogen; halogen; -CN; -N02; oxo; alkyl; polyalkyl; haloalkyl; 15 hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR 13 . -NR 1 3
R
1 . SR13; -S(O)R 1 3 ; -S02R 13 ; -S03R 13 ; -NR 13 0R 14 - -NR 13
NR
14
R
1 5 _ C02R 1 3 ; -OM; -SO2OM; -S02NR 13
RI
4 ; -C(O)NR 13
RI
4 ; -C(O)OM; COR 13 ; -NR 1 3 C(O)RM; -NR1 3
C(O)NR
4
R
5 ; -NRC0 2 R"; -OC(O)R 13 20 OC(O)NRR"; -NR' 3 SOR1 4 ; -NR1 3 S0 2 R1 4 ; -NR 3
SONR
4
R.
5 ; NR"S0 2
NR
4
R
15 ; -P(O)R 13
R
14 ; -PR 1 3
R
14
-P+R
1 3
R
1
R
1 5 A~; P(OR 13
)OR
1 4 ; -S+R 13
R
1 4 A; and -N+R 1 3 Rl 4
R
1 5A~; and WO 00/47568 PCT/US00/02503 42 wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the Ry radicals optionally may be further substituted with one or more radicals selected from the group 5 consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR'; -NR 7
R
8 ; -SR; -S(O)R 7 ; -SO2 R7; ;- C02R 7 ; CONR 7
R
8 ; -N+R 7
R
8
R
9 A-; -P(O)R 7
R
8 ; -PR 7
R
8 ; -P+R 7
R
8
R
9 A~; and P(O)(OR 7
)OR
8 ; and 10 wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the Ry radicals optionally may have one or more carbons replaced by -0-; -NR 7 -; -N+R 7
R
8 A--; -S-; SO-; -S02-; -S+R 7 A--; -PR7-; -P(O)R-; -P+R7R 8A--; or phenylene; and 15 wherein R 7 and R 8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R 1 3 , R 4 , and R 15 are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; 20 heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or wherein R" and R" together with the nitrogen atom to which they 25 are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R 14 and R 1 5 together with the nitrogen atom to which they are attached form a cyclic ring; and WO 00/47568 PCT/USOO/02503 43
R
13
R
14 an 15 wherein the R1, R , and R alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; 5 alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl; hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; 10 guanidinyl;
-OR
16 ; -NR 9
R
1 0 ; -N+R 9 R1ORwA;
-SR
16 ; -S(O)R9; -S02R 9 ' -SO3R16; -C02R 1 6 ; -CONR 9
R
10 ; -SO2NR 9
R
1 0 ; -PO(OR 16 )OR 1 7 ; PR 9
R
10 . -P+R 9 R OR' A-; -S+R 9
R'
0 A-; and carbohydrate residue; and wherein the R 1 3 , R 4 , and R 1 5 alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; 15 arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -0-; -NR-; N+R9R 10A--; -S-; -SO-; -S02-; -S+R 9 A--; -PR 9 -; -P+R 9 R 10 A-; -P(O)R 9 -; 20 phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R 1 6 and R 7 are independently selected from the group consisting of R 9 and M; and wherein M is a pharmaceutically acceptable cation; and 25 wherein R 9 , R' 0 , R", R 12 , Rw, and A~ are as previously set forth above for the compounds of Formula I; and RN is selected from the group consisting of hydrogen; alkyl; and aralkyl; and one or more Rx radicals are independently selected from the group WO 00/47568 PCT/USO0/02503 44 consisting of alkoxy, alkylamino and dialkylamino; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. A family of specific compounds of particular interest within Formula I consists of the following compounds: 5 (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-2-methyl-5-(3 nitrophenyl)-1,2-benzothiazepin-4-ol 1,1-dioxide; (4R,5R)-5-(3-aminophenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro 2-methyl-1,2-benzothiazepin-4-ol 1,1-dioxide; 10 5-chloro-N-[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4 hydroxy-2-methyl-1,1-dioxido-1,2-benzothiazepin-5-yl]phenyl]pentanamide; 5-[[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2 methyl-1,1-dioxido-1,2-benzothiazepin-5-yl]phenyl]amino]-N,N,N-triethyl-5 oxo-pentanaminium trifluoroacetate; 15 2-chloro-N-[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4 hydroxy-2-methyl-1,1-dioxido-1,2-benzothiazepin-5-yl]phenyl]acetamide; 2-[[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino]-2,3,4,5-tetrahydro-4-hydroxy-2 methyl-1, 1 -dioxido- 1,2-benzothiazepin-5-yl]phenyl] amino]-NN,N-triethyl-2 oxoethanaminium chloride; 20 (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4 methoxyphenyl)-2-methyl-1,2-benzothiazepin-4-ol 1,1-dioxide; WO 00/47568 PCT/USOO/02503 45 (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4 hydroxyphenyl)-2-methyl-1,2-benzothiazepin-4-ol 1,1-dioxide; (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-(((2 iodoethyoxy)ethoxy)ethoxy)phenyl)-2-methyl-1,2-benzothiazepin-4-o 1,1 5 dioxide; 1-[2-[2-[2-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4 hydroxy-2-methyl-1,1-dioxido-1,2-benzothiazepin-5 yl]phenoxy]ethoxy]ethoxy]ethyl]pyridinium; 10 2-[2-[2-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4 hydroxy-2-methyl-1,1-dioxido-1,2-benzothiazepin-5 yl]phenoxy]ethoxy]ethoxy]-N,N,N-triethylethanaminium iodide; (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3 methoxyphenyl)-2-methyl-1,2-benzothiazepin-4-ol 1,1-dioxide; 15 (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl) 1,2-benzothiazepin-4-ol 1,1-dioxide and (4S,5R)-3,3-dibutyl-7 (dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-1,2-benzothiazepin-4-ol 1,1-dioxide; 20 (4R,5R)-5-(3-aminophenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro 1,2-benzothiazepin-4-ol 1,1-dioxide; 5-bromo-N-[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4 hydroxy-1,1-dioxido-1,2-benzothiazepin-5-yl)phenyl]pentanamide; WO 00/47568 PCT/USOO/02503 46 5-[[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2, 3 ,4,5-tetrahydro-4-hydroxy 1,1 -dioxido- 1,2-benzothiazepin-5-yl]phenyl]amino]-N,N,N-triethyl-5-oxo- 1 pentanaminium trifluoroacetate; (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-phenyl-1,2 5 benzothiazepin-4-ol 1,1-dioxide; (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4 methoxyphenyl)-1,2-benzothiazepin-4-ol 1,1-dioxide; (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4 hydroxyphenyl)-1,2-benzothiazepin-4-ol 1,1-dioxide; 10 2-[2-[2-[4-[(4R,5R)-3,3-dibutyl-7- (dimethylamino)-2,3,4,5-tetrahydro-4 hydroxy-1,1-dioxido-1,2-benzothiazepin-5-yl]phenoxy]ethoxy]ethoxy]-N,N,N triethylethanaminium iodide; (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-2 15 (phenylmethyl)-1,2-benzothiazepin-4-ol 1,1-dioxide; (4R,5R)-3,3-dibutyl-7-(dimethylamino)-5-[3-(ethylamino)phenyl]- 2
,
3
,
4
,
5 tetrahydro-2-(phenylmethyl)-1,2-benzothiazepin-4-ol 1,1-dioxide; (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4 methoxyphenyl)-2-(phenylmethyl)-1,2-benzothiazepin-4-ol 1,1-dioxide; and 20 (4R,5R)-7-dimethylamino)-2-ethyl-4,5-dihydro-5-(4-methoxyphenyl) spiro[1,2-benzothiazepine-3(2H),1'-cyclopentan]-4-ol 1,1-dioxide; and WO 00/47568 PCT/USOO/02503 47 the pharmaceutically-acceptably salts thereof. The invention further comprises a compound selected from among: R20 R 1- R21 (Formula DI)
R
22 20 19 __ 21 (Formula DII), R R R a nd R2 R R -R21 (Formula DII) R 2 5 wherein R" 9 is selected from the group consisting of alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate residue, amino acid residue, peptide residue, and polypeptide residue; and wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy 10 diyl, polyether diyl, polyalkoxy diyl, carbohydrate residue, amino acid residue, peptide residue, and polypeptide residue optionally may have one or more carbon atoms replaced by -0-, -NR 7 -, -N+R 7
R
8 A--, -S-, -SO-, -S02-, -S*R 7 A-, PR 7 -, -PR 7
R
8 A--, phenylene, heterocyclyl, quaternary heterocyclyl, or aryl; wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy 15 diyl, polyether diyl, polyalkoxy diyl, carbohydrate residue, amino acid residue, peptide residue, and polypeptide residue optimally can be substituted with one WO 00/47568 PCTIUSOO/02503 48 or more radicals independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocyclyl, arylalkyl, halogen, oxo, -OR 13 ; -NR 13
RI
4 ; -SR 1 3 ; -S(O)R 1 3 ; -S02R 1 3 . _ S03R 1 3 ; -NR 13 0R 14 ; -NR 13
NR
14
R
1 5 ; -N02; -C02R 1 3 ; -CN; -OM; 5 SO20M; -S02NR 13
RI
4 ; -C(O)NR 13
RI
4 ; -C(O)OM; -COR 13 ; P(O)R 13
R
14 ; -PR 13
R
1 4 ; -P+R 1 3
R
1 4 R'A-; -P(ORD)OR" 14 ; -S*R 13 R"A-; and N+R 1 3 Rl 4
R
15 A~; wherein R1 3 , R' 4 , R", M and A- are as previously set forth above for the compounds of Formula I; and 10 wherein R 1 9 can further comprise functional linkages by which R 1 9 is bonded to R 20 and/or R 2 in the compounds of Formula DI; to R 2 0 , R 2 1 and/or
R
22 in the compounds of Formula DII; and to R 2 0 , R 2 1 , R 22 and/or R 2 3 in the compounds of Formula DIII; and wherein each of R 2 0 , R 2 1 , or R 22 and R 23 comprises a benzothiazepine 15 moiety as described above that is therapeutically effective in inhibiting ileal bile acid transport. Exemplary R1 9 substituents include, but are not limited to, the following: R 26e R 2 5 R 2 R~ 30 R 3 1 0 0 WO 00/47568 PCTIUSOO/02503 49 R 0 Ra32 0 0 Ra33
R
3 5
R
3 k R 5 wherein:
R
2 1 is selected from the group consisting of carbon and nitrogen; and
R
26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 3 2 , R 33 , R 34 , R 35 , R 3 6 , and R 37 are independently selected from the group consisting of: WO 00/47568 PCT/USOO/02503 50 R 38
-CH
2
-
-N---. --- R 3 9 s
-N
oN H-NH-;
-
-- N~~~NH ;
NH
2 -S 0
-NHSO
2
-
and -S - O
R
4 0 o Rt 4 1 wherein R" , R 3 9 , R 40 and R 4 ' are independently selected from the group consisting of alkyl, alkenyl, alkylaryl, aryl, arylalkyl, cycloalkyl, heterocyclyl, 5 and heterocyclylalkyl; A- is a pharmaceutically acceptable anion; and h, i, j and k are independently selected from the group consisting of integers from 1 to 10 inclusive.
WO 00/47568 PCT/USOO/02503 51 The invention is also directed to a compound selected from among Formula DI, Formula DII and Formula DIII in which each of R 20 , R 2 1 , R 22 and
R
23 comprises a benzothiazepine moiety corresponding to the Formula DIV or Formula DIVA: 5 N 1 R R2 (Formula DIV) R 5 R wR R R R or: (R) q RN S-N RI R 2 (Formula DIVA) R3 R 55 wherein R', R2, R3, R4, R1, RW, RN, RW, q, and n are as previously defined above for the compounds of Formula I, and R 5 is either a covalent bond or arylene.
WO 00/47568 PCTIUSOO/02503 52 In compounds of Formula DIV, it is particularly preferred that each of
R
20 , R 21 , R 22 , and R 23 in Formulae DI, DII and DIII be bonded at its 7- or 8 position to R 9 . In compounds of Formula DIVA, it is particularly preferred that R" comprise a phenylene moiety bonded at a m- orp-carbon thereof to 5 R1 9 . Examples of Formula DI include: RN 1 2 R 1ARNA \ R R 2 R3Aa 0 N RR R R4A N 0 yA x (RY )t (R ),(R ) (Rx)q and (RY) (R y) (R()
R
4 A R4 R (v SR IV) R R 1 R 2A R N-Ss (-N R N //O (Rx)q (R' )r 0// NA R o R and WO 00/47568 PCT/USOO/02503 53 (RYA ) x/ N R 4 R A 01 I 2 A (V) \ N R 4 R R RS R Ss-N R (R' ) N o RNA (R )t (RX)q wherein RA, R 2 A, R 3 A, R 4 ^, RNA, RyA, R'^, r and u have the same definitions as stated above for R', R2, R 3 , R 4 , RNA, RY, RX, q and t, respectively. 5 In any of the compounds of the present invention, R' and R2 can be, among other combinations, ethyl/butyl or butyl/butyl. Illustrative dimeric compounds include the following: WO 00/47568 PCT/USOO/02503 54 N N H P E 0 0 0 0 0 OOH N \ N H S-N -- 1 H H N 0 0 s 0 0N0 O N. OH 11OH WO 00/47568 PCT/USOO/02503 55 In another embodiment, a core moiety backbone, R", as discussed herein in Formulae DI, DII and DIII can be multiply substituted with more than four pendant active benzothiazepine units, i.e., R 20 , R 2 1 , R 22 , and R 2 3 as discussed above, through multiple functional groups within the core moiety 5 backbone. The core moiety backbone unit, R" 9 , can comprise a single core moiety unit, multimers thereof, and multimeric mixtures of the different core moiety units discussed herein, i.e., alone or in combination. The number of individual core moiety backbone units can range from about one to about 100, preferably about one to about 80, more preferably about one to about 50, and 10 even more preferably about one to about 25. The number of points of attachment of similar or different pendant active benzothiazepine units within a single core moiety backbone unit can be in the range from about one to about 100, preferably about one to about 80, more preferably about one to about 50, and even more preferably about one to about 25. Such points of attachment 15 can include bonds to C, S, 0, N, or P within any of the groups encompassed by the definition of R1 9 . The more preferred benzothiazepine moieties comprising R 20 , R 21 , R 22 and/or R 2 3 conform to the preferred structures as outlined above for Formula I. The 3-position carbon on each benzothiazepine moiety can be achiral, and the 20 substituents R1, R 2 , R 3 , R4, R' and Rx can be selected from the preferred groups and combinations of substituents as discussed above. The core structures can comprise, for example, poly(oxyalkylene) or oligo(oxyalkylene), especially poly- or oligo(oxyethylene) or poly- or oligo(oxypropylene). Methods of Treatment 25 In another aspect, the present invention provides a pharmaceutical composition for the prophylaxis and/or treatment of a disease, condition and/or disorder for which a bile acid transport inhibitor is indicated, such as a hyperlipidemic condition, for example, atherosclerosis. Such compositions WO 00/47568 PCT/USOO/02503 56 comprise any of the compounds disclosed above, alone or in combination, in an amount effective to reduce bile acid levels in the blood, or to reduce transport thereof across digestive system membranes, alone or in a composition comprising, for example, one or more pharmaceutically acceptable carriers, 5 excipients, and/or diluents. In any of the dimeric or multimeric structures discussed immediately above, for example, the benzothiazepine compounds of the present invention can be used alone or in various combinations. In a further aspect, the present invention also provides a method of treating a disease, condition and/or disorder in mammals, including humans, 10 for which a bile acid transport inhibitor is indicated, comprising administering to a patient in need thereof a compound of the present invention in an effective amount in unit dosage form or in divided doses. In yet a further aspect, the present invention comprises the use of the compounds of Formula I and/or the dimeric or multimeric compounds of 15 Formulae DI, DII and/or DIII in the preparation of a medicament useful for the prophylaxis and/or treatment of a disease, condition and/or disorder for which a bile acid transport inhibitor is indicated. The compounds of Formula I are also useful for the prophylaxis and/or treatment of gallstones. 20 In yet a further aspect, the present invention also provides processes for the preparation of compounds of the present invention. Further scope of the applicability of the present invention will become apparent from the detailed description provided below. However, it should be understood that the following detailed description and examples, while 25 indicating preferred embodiments of the invention, are given by way of illustration only since various changes and modifications within the spirit and scope of the invention will beomce apparent to those skilled in the art from this detailed description. 30 Definitions and Abbreviations WO 00/47568 PCT/US00/02503 57 In order to aid the reader in understanding the following detailed description, the following definitions are provided: The term "hydrocarbyl" refers to radicals consisting exclusively of the elements carbon and hydrogen. These radicals include, for example, alkyl, 5 cycloalkyl, alkenyl, cycloalkenyl, alkynyl, and aryl moieties. These radicals also include alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Preferably, these moieties comprise 1 to 20 carbon atoms. 10 The term "substituted hydrocarbyl" refers to a hydrocarbyl radical that is substituted with a group comprising at least one atom other than carbon, such as but not limited to, halogen, oxygen, nitrogen, sulfur and phosphorus. Examples of such substituted hydrocarbyl include hydrocarbyl radicals substituted with groups such as, but not limited to, lower alkoxy such as 15 methoxy, ethoxy, and butoxy; halogen such as chloro and fluoro; ethers; acetals; ketals; esters; heterocyclyl such as furyl and thienyl; alkanoxy; hydroxy; protected hydroxy; acyl; acyloxy; nitro; cyano; amino; and amido. Substituted hydrocarbyl also includes hydrocarbyl radicals in which a carbon chain atom is replaced with a heteroatom such as nitrogen, oxygen, sulfur, or a 20 halogen. Where the term "alkyl" is used, either alone or within other terms such as "haloalkyl", and "hydroxyalkyl", it embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are "lower alkyl" radicals having 25 one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso amyl, hexyl and the like. Even more preferred are lower alkyl radicals having one to three carbon atoms. Where the term "alkenyl" is used, either alone or within other terms 30 such as "arylalkenyl", it embraces linear or branched radicals having at least WO 00/47568 PCT/USOO/02503 58 one carbon-carbon double bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkenyl radicals are "lower alkenyl" radicals having two to about six carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4 5 methylbutenyl. The terms "alkenyl" and "lower alkenyl", embrace radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. The term "alkynyl" denotes linear or branched radicals having two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. 10 More preferred alkynyl radicals are "lower alkynyl" radicals having two to about ten carbon atoms. Most preferred are lower alkynyl radicals having two to about six carbon atoms. Examples of such radicals include propargyl, butynyl, and the like. The term "cycloalkyl" embraces saturated carbocyclic radicals having 15 three to about twelve carbon atoms. More preferred cycloalkyl radicals are "lower cycloalkyl" radicals having three to about ten carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "cycloalkyl" additionally encompasses spiro systems wherein the cycloalkyl ring has a carbon ring atom in common with the seven-membered 20 heterocyclic ring of the benzothiazepine. The term "cycloalkenyl" embraces partially unsaturated carbocyclic radicals having three to twelve carbon atoms. Cycloalkenyl radicals that are partially unsaturated carbocyclic radicals that contain two double bonds (that may or may not be conjugated) can be called "cycloalkyldienyl". More 25 preferred cycloalkenyl radicals are "lower cycloalkenyl" radicals having four to about ten carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl. The term "halo" and "halogen" means halogens such as fluorine, chlorine, bromine or iodine atoms. The term "haloalkyl" embraces radicals 30 wherein any one or more of the alkyl carbon atoms is substituted with halo as WO 00/47568 PCT/US0O/02503 59 defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a 5 combination of different halo radicals. "Lower haloalkyl" embraces radicals having one to six carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and 10 dichloropropyl. "Perfluoroalkyl" means alkyl radicals having all hydrogen atoms replaced with fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl. The term "hydroxyalkyl" embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted 15 with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are "lower hydroxyalkyl" radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. Even more preferred are lower hydroxyalkyl radicals having one to three carbon atoms. 20 The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one or more rings wherein such rings may be attached together in a pendent manner or may be fused. The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl, and anthracenyl. More preferred aryl is phenyl. Said "aryl" group 25 may have one to three substituents such as lower alkyl, hydroxy, halo, haloalkyl, nitro, cyano, alkoxy and lower alkylamino. The term "heterocyclyl" embraces saturated, partially saturated and unsaturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Preferred heterocyclyl are 30 3-10 membered ring heterocyclyl, particularly 5-8 membered ring heterocyclyl.
WO 00/47568 PCTIUS0O/02503 60 Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl]; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen 5 atoms [e.g. morpholinyl]; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Examples of unsaturated heterocyclic radicals, also termed "heteroaryl" radicals, include unsaturated 5 10 to 6 membered heteromonocyclyl groups containing 1 to 4 nitrogen atoms, for example, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3 triazolyl, 2H-1,2,3-triazolyl]; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, 15 benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [1,5-b]pyridazinyl); unsaturated 3 to 6 membered heteromonocyclic groups containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic groups containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; 20 unsaturated 5- to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl]; unsaturated 5 to 6 25 membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl]; unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl] and the like. The term also embraces 30 radicals where heterocyclic radicals are fused with aryl radicals. Examples of WO 00/47568 PCT/USOO/02503 61 such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Said "heterocyclyl" group may have 1 to 3 substituents such as lower alkyl, hydroxy, oxo, amino and lower alkylamino. Heterocyclic radicals can include fused or unfused radicals, particularly 5 3-10 membered fused or unfused radicals. Preferred examples of heteroaryl radicals include benzofuryl, 2,3-dihydrobenzofuryl, benzothienyl, indolyl, dihydroindolyl, chromanyl, benzopyran, thiochromanyl, benzothiopyran, benzodioxolyl, benzodioxanyl, pyridyl, thienyl, thiazolyl, furyl, and pyrazinyl. More preferred heteroaryl radicals are 5- or 6-membered heteroaryl, containing 10 one or two heteroatoms selected from sulfur nitrogen and oxygen, selected from thienyl, furanyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, piperidinyl and pyrazinyl. The term "heteroaryl" means a fully unsaturated heterocyclyl. In either "heterocyclyl" or "heteroaryl," the point of attachment to the 15 molecule of interest can be at the heteroatom or elsewhere within the ring. The term "triazolyl" includes all positional isomers. In all other heterocyclyl and heteroaryl which contain more than one ring heteroatom and for which isomers are possible, such isomers are included in the definition of said heterocyclyl and heteroaryl. 20 The term "quaternary heterocyclyl" means a heterocyclyl in which one or more of the heteroatoms, for example, nitrogen, sulfur, phosphorus or oxygen, has such a number of bonds that it is positively charged (and therefore the term is intended to encompass both ternary and quaternary positively charged structures). The point of attachment of the quaternary heterocyclyl to 25 the molecule of interest can be at a heteroatom or elsewhere. The term "quaternary heteroaryl" means a heteroaryl in which one or more of the heteroatoms, for example, nitrogen, sulfur, phosphorus or oxygen, has such a number of bonds that it is positively charged (and therefore the term is intended to encompass both ternary and quaternary positively charged 30 structures). The point of attachment of the quaternary heteroaryl to the WO 00/47568 PCTIUSOO/02503 62 molecule of interest can be at a heteroatom or elsewhere. The term "diyl" means a diradical moiety wherein said moiety has two points of attachment to molecules of interest. The term "oxo" means a doubly bonded oxygen. 5 The term "polyalkyl" means a branched or straight hydrocarbon chain having a molecular weight up to about 20,000, more preferably up to about 10,000, and most preferably up to about 5,000. The term "polyether" means a polyalkyl wherein one or more carbons are replaced by oxygen, wherein the polyether has a molecular- weight up to 10 about 20,000, more preferably up to about 10,000, and most preferably up to about 5,000. The term "polyalkoxy" means a polymer of alkylene oxides, wherein the polyalkoxy has a molecular weight up to about 20,000, more preferably up to about 10,000, and most preferably up to about 5,000. 15 The term "carbohydrate residue" encompasses residues derived from carbohydrates such as, but is not limited to, mono-, di-, tri-, tetra- and polysaccharides wherein the polysaccharides can have a molecular weight of up to about 20,000, for example, hydroxypropyl-methylcellulose or chitosan residue; compounds derived from aldoses and ketoses with 3 to 7 carbon atoms 20 and which belong to the D- or L-series; aminosugars; sugar alcohols; and saccharic acids. Nonlimiting specific examples of such carbohydrates include glucose, mannose, fructose, galactose, ribose, erythrose, glycerinaldehyde, sedoheptulose, glucosamine, galactosamine, glucoronic acid, galacturonic acid, gluconic acid, galactonic acid, mannoic acid, glucamine, 3-amino- 1,2 25 propanediol, glucaric acid and galactaric acid. The term "peptide residue" means polyamino acid residue containing up to about 100 amino acid units. The term "polypeptide residue" means a polyamino acid residue containing from about 100 amino acid units to about 1000 amino acid units, 30 more preferably from about 100 amino acid units to about 750 amino acid WO 00/47568 PCT/US0O/02503 63 untis, and most preferably from about 100 amino acid units to about 500 amino acid units. The term "alkylammoniumalkyl" means an an -NH 2 group or a mono-, di- or tri-substituted amino group, any of which is bonded to an alkyl wherein 5 said alkyl is bonded to the molecule of interest. The term "sulfo" means a sulfo group, -SO 3 H, and its salts. The term "sulfoalkyl" means an alkyl group to which a sulfonate group is bonded, wherein said alkyl is bonded to the molecule of interest. The term "aralkyl" embraces aryl-substituted alkyl radicals. Preferable 10 aralkyl radicals are "lower aralkyl" radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Even more preferred are lower aralkyl radicals having phenyl attached to alkyl portions having one to three carbon atoms. Examples of such radicals include benzyl, diphenylmethyl and phenylethyl. The aryl in said aralkyl may be additionally substituted with halo, 15 alkyl, alkoxy, halkoalkyl and haloalkoxy. The term "arylalkenyl" embraces aryl-substituted alkenyl radicals. Preferable arylalkenyl radicals are "lower arylalkenyl" radicals having aryl radicals attached to alkenyl radicals having The term "heterocyclylalkyl" means an alkyl radical that is substituted with one or more heterocyclyl groups. Preferable heterocyclylalkyl radicals are 20 "lower heterocyclylalkyl" radicals having one or more heterocyclyl groups attached to an alkyl radical having one to ten carbon atoms. The term "heteroarylalkyl" means an alkyl radical that is substituted with one or more heteroaryl groups. Preferable heteroarylalkyl radicals are "lower heteroarylalkyl" radicals having one or more heteroaryl groups attached 25 to an alkyl radical having one to ten carbon atoms. The term "quaternary heterocyclylalkyl" means an alkyl radical that is substituted with one or more quaternary heterocyclyl groups. Preferable quaternary heterocyclylalkyl radicals are "lower quaternary heterocyclylalkyl" radicals having one or more quaternary heterocyclyl groups attached to an alkyl 30 radical having one to ten carbon atoms.
WO 00/47568 PCT/USOO/02503 64 The term "quaternary heteroarylalkyl" means an alkyl radical that is substituted with one or more quaternary heteroaryl groups. Preferable quaternary heteroarylalkyl radicals are "lower quaternary heteroarylalkyl" radicals having one or more quaternary heteroaryl groups attached to an alkyl 5 radical having one to ten carbon atoms. The term "alkylheteroarylalkyl" means a heteroarylalkyl radical that is substituted with one or more alkyl groups. Preferable alkylheteroarylalkyl radicals are "lower alkylheteroarylalkyl" radicals with alkyl portions having one to ten carbon atoms. 10 The term "alkoxy" means an alkyl radical which is attached to the molecule of interest by oxygen, such as a methoxy radical. More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, iso-propoxy, butoxy and tert-butoxy. 15 The term "carboxy" means the carboxy group, -CO 2 H, or its salts. The term "carboxyalkyl" means an alkyl radical that is substituted with one or more carboxy groups. Preferable carboxyalkyl radicals are "lower carboxyalkyl" radicals having one or more carboxy groups attached to an alkyl radical having one to six carbon atoms. 20 The term "carboxyheterocyclyl" means a heterocyclyl radical that is substituted with one or more carboxy groups. The term "carboxyheteroaryl" means a heteroaryl radical that is substituted with one or more carboxy groups. The term "carboalkoxyalkyl" means an alkyl radical that is substituted 25 with one or more alkoxycarbonyl groups. Preferable carboalkoxyalkyl radicals are "lower carboalkoxyalkyl" radicals having one or more alkoxycarbonyl groups attached to an alkyl radical having one to six carbon atoms. The term "carboxyalkylamino" means an amino radical that is mono- or di-substituted When used in combination, for example "alkylaryl" or 30 "arylalkyl," the individual terms listed above have the meaning indicated WO 00/47568 PCT/US0O/02503 65 above. The term "acyl" means an organic acid group in which the hydroxy of the carboxy group has been removed. Examples of acyl groups include, but are not limited to, acetyl and benzoyl. 5 The term "active compound" means a compound of the present invention that inhibits transport of bile acids. The term "a bile acid transport inhibitor" means a compound capable of inhibiting absorption of bile acids from the intestine into the circulatory system of a mammal, such as a human. This includes increasing the fecal excretion of 10 bile acids, as well as reducing the blood plasma or serum concentrations of cholesterol and cholesterol ester, and more specifically, reducing LDL and VLDL cholesterol. Conditions and/or diseases that benefit from the prophylaxis and/or treatment by bile acid transport inhibition include, for example, a hyperlipidemic condition such as atherosclerosis. 15 The abbreviations used in this application have the following meanings: The term "THF" means tetrahydrofuran; The term "PTC" means phase transfer catalyst; The term "Aliquart 336" means methyltricaprylylammonium chloride; The term "MCPBA" means m-chloroperbenzoic acid; 20 The term "Celite" refers to a brand of diatomaceous earth filtering aid; The term "DMF" means dimethylformamide; The term "DME" means ethylene glycol dimethyl ether; The term "BOC" means t-butoxycarbonyl; The term "Me" means methyl; 25 The term "Et" means ethyl; The term "Bu" means butyl; The term "EtOAc" means ethyl acetate; The term "Et 2 0" means diethyl ether; The term "LAH" means lithium aluminum hydride; WO 00/47568 PCT/US0O/02503 66 The term "DMSO" means dimethylsulfoxide; The term "KOSiMe 3 " means potassium trimethylsilanolate; The term "PEG" means polyethylene glycol; The term "MS" means mass spectrometry; 5 The term "HRMS" means high resolution mass spectrometry; The term "ES" means electrospray; The term "NMR" means nuclear magnetic resonance spectroscopy; The term "GC" means gas chromatography; The term "MPLC" means medium pressure liquid chromatography; 10 The term "HPLC" means high pressure liquid chromatography; The term "RPHPLC" means reverse phase high pressure liquid chromatography The term "RT" means room temperature; The terms "h" or "hr" means hour(s); and 15 The term "min" means minute(s); Alternate Forms of Compounds The compounds of the present invention can have at least two asymmetrical carbon atoms, and therefore include racemates and stereoisomers, such as diastereomers and enantiomers, in both pure form and in admixture. 20 Such stereoisomers can be prepared and separated using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present invention. Isomers may include geometric isomers, for example cis isomers or trans isomers across a double bond. All such isomers are contemplated among the compounds of the present 25 invention. The compounds of the present invention also include tautomers, salts, solvates and prodrugs of such compounds.
WO 00/47568 PCT/USOO/02503 67 Compound Syntheses The starting materials for use in the preparation of the compounds of the invention are commercially available or can be prepared by conventional methods known to a skilled person or in an analogous manner to processes 5 described in the art. Generally, the compounds of the present invention can be prepared by the procedures described below.
WO 00/47568 PCT/USOO/02503 68 Schffm 1 Et(:CC H PhCHO _,N Ph RI bs t N, ,Ph -,F EtO 2 C h FX ae 2 EfCX~ 0 Ha HO,,NqA.CI
SS
2 CI H -~N-I Et 3 N
SO
2 NH H - (F~t) R< OH 7 R R 2 THF q:Y 2 3 TBDMSa inidazole ~DW (FW~)q NSO 2 N<T (W~ R TBDMS bae Cr R FeT~ DM 4 5I)nr-BuUITHF (Onit ifRH) 2) B(0Ovb) 3 3) R 5 CI-1 2 )qPd(PPh 3
)
4 1 MNa 2
CO
3 toluenelEtOH ON RSON
-~S
2 n-Bu 4 NF SN (FW)q± R>OTBMS (RW)q ~ OHR THE
R
5 '6 7R 5 (aGo) 2 ~SN i-Pr 2 NEt (W)qH R 1 R 9.R FeOH KOt-BuS ,CH N ~~(W~)q± ~ H (Fe)q± R 1 Fe 8 WO 00/47568 PCT/USOO/02503 69 Scheme 1 illustrates the preparation of racemic benzothiazepines 9a and 9b. Reaction of benzenesulfonyl chloride 1 with aminoalcohol 2 in the presence of a base, such as triethylamine, in a solvent, such as tetrahydrofuran, yields benzenesulfonamide 3 which can be converted to protected 5 benzenesulfonamide 4. Protected benzenesulfonamide 4 optionally can be treated with an alkyl halide, such as methyl iodide, in the presence of a base such as sodium hydride, in a solvent, such as dimethylformamide, to yield N substituted benzenesulfonamide 5. Protected benzenesulfonamide 4 or N substituted benzenesulfonamide 5 is then successively reacted with (i) a strong 10 base (such as n-butyllithium in hexanes) in a solvent (such as tetrahydrofuran), (ii) an electrophile (such as trimethyl borate), and (iii) a base (such as sodium carbonate), a benzyl halide (such as p-methoxybenzyl chloride), and a catalyst (such as tetrakis(triphenylphosphine)palladium(O)) to yield sulfonamide 6. Treatment of sulfonamide 6 with a fluoride source, such as 15 tetrabutylammonium fluoride, in a solvent, such as tetrahydrofuran, provides the deprotected sulfonamide alcohol 7. Sulfonamide alcohol 7 is successively oxidized using a method such as Swem Oxidation to yield sulfonamide aldehyde 8. Upon treatment with a base such as potassium tert-butoxide, aldehyde 8 is converted to racemic benzothiazepines 9a and 9b. R 1 , R 2 , R, RN, 20 Rx and q are as previously defined above for compounds of Formula I.
WO 00/47568 PCT/USOO/02503 70 SCHEME 2 Alternative Synthesis of sulfonamide alcohol SO2Cl HO RN-H 2 Et 3 N L SO 2 NH L,- R
R
2 1 R>2OH 10 11 12 Where L F, Cl, Br, NO 2 , TsO, TfO (RX)gM
SO
2 NH 0 %H (RX)q Ja R R 3 Scheme 2 illustrates an alternative synthetic scheme for the preparation of sulfonamide alcohol 3 used in Scheme 1. Reaction of benzenesulfonyl chloride 10 with aminoalcohol 11 in the presence of a base, such as 5 triethylamine, in a solvent, such as tetrahydrofuran, yields sulfonamide 12. Substituent L of benzenesulfonyl chloride 10 is a suitable leaving group such as fluoro, chloro, bromo, nitro, tosyloxy or trifluoromethylsulfonyloxy. Reaction of sulfonamide 12 with a suitable nucleophile in the presence of a base, such as triethylamine, in a solvent, such as tetrahydrofuran, yields 10 benzenesulfonamide 3 which can be further reacted in accordance with Scheme 1. R', R 2 , R* and q are as previously defined above for compounds of Formula I. Substituent M is a metal, preferably an alkali metal, or a hydrogen.
WO 00/47568 PCT/USOOI 02503 71 SCHEME 3 ~SON 0] sor~S0 2 N R Re 9~ 1F 13 019 La~essods HN\R 1 0 ' UiAJH 4 Iej/en NB(O~c)H III SO N Q N ~S 0 2 N 14 LA F4 2120 w I-nF ~ ~ SO 2 N ~SH S02N 15 16 (FIt)q R 18
~SCN
2 IFP Ka
KCN
2 SK l O0H F 5 Ms F5 9 122M 21FO R (F)q 23 2 WO 00/47568 PCT/US0O/02503 72 Scheme 3 illustrates the preparation of benzothiazepines having 4 position substituents other than hydroxy. In the preparation of 4-thioxo-, thio-, sulfinyl- or sulfonyl benzothiazepines, benzothiazepine 9a or 9b is first oxidized to 5 benzothiazepine-4-one 13. Conventional oxidizing agents, such as PCC, or Swern conditions can be used. Benzothiazepine-4-one 13 is then reacted with Lawesson's Reagent to produce 4-thioxo-benzothiazepine 14. 4-Thioxo benzothiazepine 14 can be reacted with a suitable reducing agent, such as lithium aluminum hydride, in a suitable solvent, such as tetrahydrofuran, to 10 yield 4-mercapto-benzothiazepine 15. 4-Mercapto-benzothiazepine 15 can be reacted with a suitable alkylating agent, such as an alkyl halide, in the presence of a base, such as sodium hydride, in a suitable solvent, such as dimethylformamide, to yield 4-alkylthio-benzothiazepine 16. 4-Alkylthio benzothiazepine 16 can be reacted with a suitable oxidizing agent, such as t 15 butyl hydroperoxide or m-chloroperbenzoic acid, to yield, successively, 4 alkylsulfinyl-benzothiepine 17 and 4-alkylsulfonyl-benzothiazepine 18. Alternatively, 4-amino- or imino-benzothiazepines can be prepared by reacting benzothiazepine-4-one 13 with ammonia or a primary amine in a suitable solvent, such as tetrahydrofuran, to produce 4-imino-benzothiazepine 20 19. 4-Imino-benzothiazepine 19 can be reacted with a suitable reducing agent, such as lithium aluminum hydride, in a suitable solvent, such as tetrahydrofuran, to yield 4-amino-benzothiazepine 20. Benzothiazepine-4-one 13 also can undergo reductive alkylation by reaction with ammonia, a primary amine or a secondary amine in the presence of an reducing agent, such as 25 sodium triacetoxyborohydride, in a suitable solvent, such as tetrahydrofuran, to produce 4-amino-benzothiazepine 21. Scheme 3 also illustrates the preparation of 4-alkyl-benzothiazepine 23 and 4-alkoxycarbonyl-benzothiazepine 25. The 4-position hydroxy of benzothiazepine 9a or 9b is first converted to a suitable leaving group such as 30 mesyloxy to form protected benzothiazepine 22. Protected benzothiazepine 22 WO 00/47568 PCT/USOO/02503 73 is then reacted with a suitable nucleophile, such as butyl lithium, in a suitable solvent, such as tetrahydrofuran, to yield 4-alkyl-benzothiazepine 23. Alternatively, protected benzothiazepine 22 can be reacted with a suitable cyanidating agent, such as an potassium cyanide, in a suitable solvent, such as 5 dimethylformamide, to yield 4-cyano-benzothiazepine 24. 4-Cyano benzothiazepine 24 is converted to 4-alkoxycarbonyl-benzothiazepine 25 by reaction with a suitable alcohol in the presence of a base, such as potassium hydroxide.
WO 0 0/47568 PCT/USOO/02503 74 I 0 0 0 0 Ir)0 z2 - zbc )U )V ~= I-~ -2 x i 0 0 C: 16 LL. a) 0 y 0 ,It = 0- -0 0 0 ) )U) t CO T Z of -- X l cn z W 0~ 04 C 0 U) 0 - 0i cc 0 U) Cl) LO 0 Cl U) / \ 0
F~
WO 00/47568 PCT/USOO/02503 75 Scheme 4 illustrates the preparation of benzothiazepine-4-ene 36 and benzothiazepine-4-one 33. Reaction of phenol 26 with a thiocarbamyl chloride, such as dimethylthiocarbamyl chloride, in a solvent, such as methanol:tetrahydrofuran yields 0-thiocarbamate 27. Heating of 0 5 thiocarbamate 27 in a solvent, such as tetradecane, yields S-thiocarbamate 28. Hydrolysis of S-thiocarbamate 28 in the presence of a base, such as sodium hydroxide, in a solvent, such as methanol:tetrahydrofuran, yields thiophenol 29. Thiophenol 29 can be treated with a sulfonylating agent, such as sulfonyl chloride, in the presence of a oxidant such as potassium nitrate, -in a solvent, 10 such as tetrahydrofuran, to yield sulfonyl chloride 30. Sulfonyl chloride 30 is then reacted with an aminoalcohol in a solvent, such as tetrahydrofuran, to yield benzenesulfonamide 31. Benzenesulfonamide 31 optionally can be hydroxyl protected with a silylating group agent, such as tert butyldimethylsilyl chloride, in the presence of a base, such as imidazole, in a 15 solvent, such as tetrahydrofuran, to yield protected benzenesulfonamide 32. Protected benzenesulfonamide 32 can be treated with an alkyl halide, such as methyl iodide, in the presence of a base such as sodium hydride, in a solvent, such as dimethylformamide, to yield N-substituted benzenesulfonamide 33. Deprotection of the protected N-substituted benzene sulfonamide 33 with a 20 fluoride source, such as tetrabutylammonium fluoride, in a solvent, such as tetrahydrofuran, yields N-substitued benzenesulfonamide 34. Benzenesulfonamide 31 or N-substituted benzenesulfonamide 34 is then oxidized with a suitable oxidizing agent or under Swern conditions to form aldehyde 35. Upon treatment with zinc and titanium trichloride aldehyde 35 is 25 converted to a mixture of benzothiazepine-4-ene 36 and benzothiazepine-4-one 37. The recovery, isolation and purification of the intermediates and the reaction products of this invention, and in particular the intermediates and the reaction products illustrated in Schemes 1, 2, 3 and 4, can be accomplished by 30 conventional methods well known to those skilled in the art, such as WO 00/47568 PCT/USOO/02503 76 precipitation, filtration, extraction, or chromatography. Except where otherwise indicated, conditions, solvents, and reagents are either conventional, not narrowly critical, or both. Additional Embodiments and Examples 5 Another class of compounds of specific interest comprises those compounds of Formula I wherein R' and R 2 are selected from among substituted and unsubstituted C 110 alkyl wherein substituted C- 10 alkyl comprises one or more radicals independently selected from among, for example, alkylcarbonyl, alkoxy, hydroxy, and nitrogen-containing heterocyclyl 10 joined to the C- 1 0 alkyl through an ether linkage. These R' and R 2 substituents include ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, -CH 2
C(=O)C
2
H
5 ,
-CH
2 0C 2
H
5 , and -CH 2 0-(4-picoline). Ethyl, n-propyl, n-butyl, and isobutyl are preferred. In certain particularly preferred compounds of the present invention, substituents R' and R 2 are identical, for example n-butyl/n-butyl, so 15 that the compound is achiral at the 3-position carbon. Eliminating optical isomerism at the 3-position carbon simplifies the selection, synthesis, separation, and quality control of the compound used as an ileal bile acid transport inhibitor. In the compounds of the present invention having a chiral 3-position 20 carbon as well as those having an achiral 3-position carbon, substituents RX on the benzo ring can include, for example, hydrogen, aryl, alkyl, hydroxy, halo, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkyl, haloalkoxy, (N) hydroxy-carbonylalkylamino, haloalkylthio, haloalkylsulfinyl, haloalkylsufonyl, amino, N-alkylamino, N,N-dialkylamino, (N) 25 alkoxycarbamoyl, (N)-aryloxycarbamoyl, (N)-aralkyloxycarbamoyl, trialkylammonium (especially with a halide counterion), (N)-amido, (N) alkylamido, N,N-dialkylamido, (N)-haloalkylamido, (N)-sulfonamido, (N) alkylsulfonamido, (N)-haloalkylsulfonamido, carboxyalkylamino, trialkylammonium salt, (N)-carbamic acid, alkyl or benzyl ester, N-acylamino, WO 00/47568 PCT/USOO/02503 77 hydroxylamino, haloacylamino, carbohydrate residue, thiophene, a trialkyl ammonium salt having a carboxylic acid or hydroxy substituent on one or more of the alkyl substituents, an alkylene bridge having a quaternary ammonium salt substituted thereon, -[O(CH2)d ],-X where e is 2 to 12, d is 2 or 3 and X is 5 a halo or a quaternary ammonium salt, and (N)-nitrogen containing heterocyclyl wherein the nitrogen of said heterocyclyl is optionally quaternized. Among the preferred species which may constitute RX are methyl, ethyl, isopropyl, t-butyl, hydroxy, methoxy, ethoxy, isopropoxy, methylthio, iodo, 10 bromo, fluoro, methylsulfinyl, methylsulfonyl, ethylthio, amino, hydroxylamino, N-methylamino, N,N-dimethylamino, N,N-diethylamino, (N) benzyloxycarbamoyl, trimethylammonium A-, -NHC(0)CH 3 , NHC(=0)C 5 H, , -NHC(=0)CH 13 , carboxyethylamino, (N)-morpholinyl, (N) azetidinyl, (N)-N-methylazetidinium A-, (N)-pyrrolidinyl, pyrrolyl, (N)-N 15 methylpyridinium A-, (N)-N-methylmorpholinium A-, and N-N' methylpiperazinyl, (N)-bromomethylamido, (N)-N-hexylamino, thiophene, N+(CH 3
)
2
CO
2 H I-, -NCH 3
CH
2
CO
2 H, -(N)-N'-dimethylpiperazinium I, (N) t-butyloxycarbamoyl, (N)-methylsulfonamido, (N)N'-methylpyrrolidinium, and
-(OCH
2
CH
2
)
3 1, where A- is a pharmaceutically acceptable anion. 20 The benzo ring can be mono-substituted at the 6, 7 or 8 position, or disubstituted at the 7- and -8 positions. Also included are the 6,7,8-trialkoxy compounds, for example the 6,7,8-trimethoxy compounds. A variety of other substituents can be advantageously present on the 6, 7, 8, and/or 9- positions of the benzo ring including, for example, guanidinyl, cycloalkyl, carbohydrate 25 residue (e.g., a 5 or 6 carbon monosaccharide residue), peptide residue, and quaternary ammonium salts linked to the ring via poly(oxyalkylene) linkages, e.g., -(OCH 2 CH 2)x -N+R 1 3 R1 4 R1 5 A-, where x is 2 to 10. In further compounds of the present invention, R and R 6 are independently selected from among hydrogen and ring-carbon substituted or 30 unsubstituted aryl, thiopene, pyridine, pyrrole, thiazole, imidazole, pyrazole, WO 00/47568 PCT/US0O/02503 78 pyrimidine, morpholine, N-alkylpyridinium, N-alkylpiperazinium, N alkylmorpholinium, or furan in which the substituent(s) are selected from among, for example, halo, hydroxyl, trihaloalkyl, alkoxy, amino, N alkylamino, N,N-dialkylamino, quaternary ammonium salts, a C, to C 4 5 alkylene bridge having a quaternary ammonium salt substituted thereon, alkoxycarbonyl, aryloxycarbonyl, alkylcarbonyloxy and arylcarbonyloxy, (0,0)-dioxyalkylene, -[O(CH 2 )d]eX where e is 2 to 12, d is 2 or 3 and x comprises halo or a quaternary ammonium salt, thiophene, pyridine, pyrrole, thiazole, imidazole, pyrazole, or furan. The aryl group of RI or R 6 is preferably 10 phenyl, phenylene, or benzene triyl, i.e., may be unsubstituted, mono substituted, or di-substituted. Among the species that may constitute the substituents on the aryl ring of RI or RI are fluoro, chloro, bromo, methoxy, ethoxy, isopropoxy, trimethylammonium (preferably with an iodide or chloride counterion), 15 methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, propanoyl, (N) hexyldimethylammonium, hexylenetrimethylammonium, tri(oxyethylene)iodide, and tetra(oxyethylene)trimethyl-ammonium iodide, each substituted at the p-position, the m-position, or both of the aryl ring. Other substituents that can be present on a phenylene, benzene triyl or other 20 aromatic ring includes 3, 4-dioxymethylene (5-membered ring) and 3, 4 dioxyethylene (6-membered ring). One group of compounds of interest are those in which RI or R 6 is selected from phenyl, p-fluorophenyl, m fluorophenyl, p-hydroxyphenyl, m-hydroxyphenyl, p-methoxyphenyl, m methoxyphenyl, p-N,N-dimethylaminophenyl, m-N, N-dimethylaminophenyl, 25 1- p-(CH 3
)
3 -N+-phenyl, I- m-(CH 3
)
3 -N+-phenyl, I- m-(CH 3
)
3
-N-CH
2
CH
2 (OCH 2
CH
2
)
2 -0-phenyl, I p-(CH 3
)
3
-N*-CH
2
CH
2
-(OCH
2
CH
2
)
2 -0-phenyl, I m (N,N-dimethylpiperazinium)-(N')-CH 2
-(OCH
2
CH
2
)
2 -0-phenyl, 3-methoxy-4 fluorophenyl, thienyl-2-yl, 5-cholorothienyl-2-yl, 3, 4-difluorophenyl, I- p (N,N-dimethylpiperazinium)-(N')-CH 2
-OCH
2
CH
2
)
2 -0-phenyl, 3-fluoro-4 30 methoxyphenyl, 4-pyridinyl, 2-pyridinyl, 3-pyridinyl, N-methyl-4-pyridinium, WO 00/47568 PCT/USO0/02503 79 I- N-methyl-3-pyridinium, 3, 4-dioxymethylenephenyl, 3, 4 dioxyethylenephenyl, and p-methoxycarbonylphenyl. Preferred compounds include 3-ethyl-3-butyl and 3-butyl-3-butyl compounds having each of the above preferred RI substituents in combination 5 with the RX substituents shown in Tables 1, 2 and 3 below. It is particularly preferred that one, but not both, of R' and R 6 is hydrogen. It is especially preferred that R 4 and R 6 be hydrogen, that R 3 and RI not be hydrogen, and that RI and R 5 be oriented in the same direction relative to the plane of the molecule, i.e., both in a- or both in P-configuration. It is further 10 preferred that, where R2 is butyl and R1 is ethyl, then R' has the same orientation relative to the plane of the molecule as R3 and R1. A class of compounds of particular interest comprises those 1,2 benzothiazepines wherein the R', R 2 , R 3 , R4 and R' radicals are as set forth in Table 1 below; the R 6 radical is hydrogen; the RN radical is selected from the 15 group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n hexyl and benzyl; and the Rx radical or radicals are independently selected from the group of RX radicals disclosed in Table 1 below. The first part of Table 1 identifies the R', R2, R1, R and RI radicals for each compound and the second part of Table 1 identifies the Rx radical or radicals for those compounds.
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I'.)
WO 00/47568 PCT/USOO/02503 V0 0 0 0 0 0 000 0I 2 m WO 00/47568 PCTUSOO/02503 0 o o 0 0 0 0 4 0 0 0W ~ ~ o C- 4 CN CNcNI N N N N C' Nq rqr qc qC Ac N C.4 N N N, C I H . .
WO 00/47568 PCT/USOO/02503 x X 0 0 t~ t ~~~0 0 0 (0 0~ C0 0 C0 0~ C0 0 0 0 0 0~ 0 C0 0 C0 C0 C C -0 0. 1 0 0 'E Cd - - - - Cl A 00 -1 N 0 -, 05 -> -> N 00 0\ 0 - C 0 00 0000) C? CClClC Cl~C Cl CC lC l00000000 0 0 0, 0 WO 00/47568 PCTUSOO/ 02503 5E I H -- -- -0- 5EE \Co r- 00 C C CU C> m U It CU \0 t-- w C U CD C4 mU Ln CU CU CU C C CU CU CU CU CU 0 CU CU CU C C. C) .) C. C) . C D C D) C D 0 C.) . C.) C.) C.) C) ) C C C . C)) C> C .) C.) C) C.) C ) . = C. C C) C.) C ) I I I I I I I I I II I g I I I WO 00/47568 PCTUSOO/02503 - - - -i- -, 5 rlrlr 5 - o E EO E EEOEO E E E EOE E EO EOOE F! C- - ~ ) U a0 0) 0 >C ) 0 C) C) <D CU 0 0 U 0 U U 0 0 r- r - - i I g I I C I I L I I I I I I I I WO 00/47568 PCT/USOO/02503 o000 00 00 00 00 00 00 00 0 0 00 0 00 00 0 000 S S SSS S S-S S S E E Ei2 2 5 E5r2lE S .5 .5 2 z A5 .55 55 I I I I I I I I I I I I I I I * . I I I I I I I I WO 00/47568 PCTUSOO/02503 0 0 w 0 0 0 0o~o ~~ 0 Co E c d Nz 0swmCsm a r- m - -- N m-tW- --- wc- ) N m 1 n -0 , m' --- m m-- m m m m ' tItI 'TqT ntn - n n WO 00/47568 PCT/USOO/02503 00 0 0 0o 0 0 0 0 0 o .0 g0 0 cz E E E Ej E -F 0 7s 0 7s! S S2 S 2 NE Eo r O?&- 4 r E5 E E N I N w-N0 -C4m" n Dr 0C\0 C M ,- k '- WON0 - m n\.
W)kn V W C C"o\0\o - - - - r-I-- - I-- - -0-0w000 0o WO 00/47568 PCT/USOO/02503 0 0 o0 0 o 00 0 o0o o 0 Cd- u) v Q) u ) 4 N 5 tZ I t- a I p I N ~ N N N N NN NNNN Co4 N0~ WO 00/47568 PCT/USOO/ 02503 0 0 0 0 00 0 00 0 0 0 0 0000 000 0 0 wo E 0w c 0 ct cz m l Q o 00 I I I I I II I a -6 6 -5 -a -a -6 -6 -s - ; ' WO 00/47568 PCT/USOO/02503 0 .0 -S S S S S z e -SE e SSS -S S5555 -S -S S CO C O O C O OvC C O 0 C v- vC O O C C uC C O C C O C C.)~~~ ~ N. a.) C.) 4 C.) C.)l C4 C.) N) N. N. N. N. N C.) 4C CC.) N C) N. N N ) C 14 N.~ WO 00/47568 PCT[USOO/02503 0 0 00 00 00 0 0 0 0 0 0 0 0 0 o 0 0 cl 02 *0 . o2 o R0 o x ~0 51 5-1 - V 4 ) r- r-~ rti r '.0~~~~ ~~ - -C -~ - 00 - - -~ - -~ -0 - - - - - WO 00/47568 PCTUSOOIO25O3 Cf) 0 0 0 Xc E 0 0 EE 00 CO-0 M :TonI'o--W cq .
WO 00/47568 PCT/USOO/ 02503 0 0 00 A E 0 .- , .8 E~ .= . -S -E- - - - -. s-S. 0a0 NO 0N -n\ tnVI W 0 .O WO 00/47568 PCT[USOO/02503 EE SE E SEE SESESEE ES E ES ES E E E E E c, e ' c c C,3a ct 0 m~ m~ m m ~ m ~ m ~ m ~ m ~ w ~ m m m E 2 mt - r-2 N- 00 M- M0 M- m- m- m 0N0 0 - e~ I)'0N0 ~0 - m- m-) m f WO 00/47568 PCTIUSOO/02503 0 0 00 0 00 0 0 0 r, E - E E S -S E S S E E -S E S E . E .S E .5 . . E ES E S SE E E E E E S S 5 5 E E C E E E E E E E E E E E E E E E E E 5 E S\ O 5 OZ O . e e - - - - - - e - -S !s N5 5 09 N s N5N S 0 0 0 a) v v N 00 Q) 0 0' 0 0 u 00 uN 0- u u. N ) 0 E E .E- EA E - E E- E - ------ --- E-------------------------. ------------------------------------------------------------------------ ----- ------------------------------------------------------------- -4- WO 00/47568 PCT/USOO/ 02503 E iE EE E E55 E E E E S e S SES -1 0 o ~ M 0- c If - WCN C 0 - W'4 1.0 Ir l- 00 O 0 - WO 00/47568 PCT/US0O/02503 208 Another class of compounds of particular interest comprises those 1,2 benzothiazepines wherein the R', R 2 , R3, R 4 , R', R , RN and Rx radicals are selected from among the radicals disclosed in Table 2 below. Preferably, R 6 is hydrogen and R' is other than hydrogen; and/or R 3 is hydroxy and R4 is 5 hydrogen; and/or R' and R2 are alkyl. More preferably, R 1 and R2 are the same. Table 2 S N 8 9 \R1 7 R2 RN
R
6 -R5 R 4 WO 00/47568 PCT/US00/02503 209 R1/R2 R 3 /R R 5
/R
6 (Rx)q RN 4 ethyl HO- H 7-methyl H n-propyl H- Ph- 7-ethyl methyl n-butyl p-F-Ph- 7-iso-propyl ethyl n-pentyl m-F-Ph- 7-tert-butyl n-propyl n-hexyl p-CH30-Ph- 7-OH n-butyl iso-propyl p-HO-Ph- 7-OCH3 n-pentyl iso-butyl m-CH30-Ph- 7-O(iso-propyl) n-hexyl iso-pentyl m-HO-Ph- 7-SCH3 benzyl CH20C2H5 p-(CH3)2N-Ph- 7-SOCH3 CH20-(4- m-(CH3)2N-Ph- 7-SO2CH3 picoline) p-H2N-Ph- 7-SCH2CH 3
CH
2
CH
2
CH
2 m-H2N-Ph- 7-NH2
CF
3 I-, p-(CH3)3-N+-Ph- 7-NHOH I-, m-(CH3)3-N+-Ph- 7-NHCH3 I-, p-(CH3)3-N+- 7-N(CH3)2 CH2CH2- 7-N+(CH 3
)
3 , I (OCH2CH2)2-0- 7-NHC(O)CH 3 Ph- 7-N(CH 2
CH
3
)
2 I~, m-(CH3)3-N+- 7-NMeCH2CO2H CH2CH2- 7-N+(Me)2CH2CO 2 H, (OCH2CH2)2-O- I Ph- 7-(N)-morpholine I-, p-(N,N-dimethyl- 7-(N)-azetidine piperazine)-(N')- 7-(N)-N CH2- methylazetidinium, 1- 7 (OCH2CH 2
)
2 -0- (N)-pyrrolidine Ph- 7-(N)-N-methyl I-, m-(N,N-dimethyl- pyrrolidinium, I- 7-(N) piperazine)-(N')- N-methyl CH2- morpholinium, I (OCH2CH2) 2 -O- 7-(N)-N' Ph- methylpiperazine m-F, p-CH30-Ph- 7-(N)-N' 3,4,dioxymethylene-Ph dimethylpiperazinium, I m-CH30-, p-F-Ph- 7-NH-CBZ 4-pyridine 7-NHC(O)C 5
H
1 1 N-methyl-4-pyridinium, 7-NHC(O)CH2Br I~ 7-NH-C(NH)NH 2 3-pyridine 7-(2)-thiophene N-methyl-3-pyridinium, 8-methyl I~ 8-ethyl 2-pyridine 8-iso-propyl p-CH302C-Ph- 8-tert-butyl thienyl-2-yl 8-OH 5-Cl-thienyl-2-yl 8-OCH3 WO 00/47568 PCT/USOO/02503 210 R/2 R 3 /R R 5
/R
6 (RX)q R N 4 8-O(iso-propyl) 8-SCH3 8-SOCH3 8-SO2CH3 8-SCH2CH3 8-NH2 8-NHOH 8-NHCH3 8-N(CH3)2 8-N+(CH3)3, I 8-NHC(O)CH 3 8-N(CH2CH3)2 8-NMeCH2CO2H 8-N+(Me)2CH2CO 2 H,
I
8-(N)-morpholine 8-(N)-azetidine methylazetidinium, I 8-(N)-pyrrolidine 8-(N)-N-methyl pyrrolidinium, I- 8-(N) N-methyl morpholinium, I methy-lieazn dmethylpiperazinium
I
8-NH-CBZ 8-NHC(O)C 5
H
1 1 8-NHC(O)CH2Br 8-NH-C(NH)NH2 8-(2)-thiophene 9-methyl 9-ethyl 9-iso-propyl 9-tert-butyl 9-OH 9-OCH3 9-O(iso-propyl) 9-SCH 3 9-SOCH3 9-SO2CH3 9-N+(Me)2CH2CO2H,
I-
WO 00/47568 PCT/USOO/02503 211
RI/R
2
R
3 /R R 5
/R
6 (RX)q 4 RN 9-SCH2CH3 9-NH2 9-NHOH 9-NHCH3 9-N(CH3)2 9-N+(CH3)3, I~ 9-NHC(O)CH 3 9-N(CH2CH3)2 9-NMeCH2CO2H 9-(N)-morpholine 9-(N)-azetidine 9-(N)-N methylazetidinium,
I
9-(N)-pyrrolidine 9-(N)-N-methyl pyrrolidinium, I- 9-(N)
N
methyl morpholinium, I 9-(N)-N' methylpiperazine 9-(N)-N'-dimethyl piperazinium, I 9-NH-CBZ 9-NHC(O)C5H1 1 9-NHC(O)CH2Br 9-NH-C(NH)NH2 9-(2)-thiophene 7-OCH3, 8-OCH3 7-SCH3, 8-OCH3 7-SCH3, 8-SCH3 6-OCH3, 7-OCH3, 8 OCH3 Another class of compounds of particular interest comprises those 1,2 benzothiazepines wherein the R', R 2 , R3, R 4 and RI radicals are as set forth in Table 3 below; R 6 is hydrogen; the RN radical is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and 5 benzyl; and the Rx radical or radicals are independently selected from the group of R^ radicals disclosed in Table 2 above. In one embodiment of the compounds of Table 3, for example, q is 1 and RX is 7-dimethylamino.
WO 00/47568 PCTIUSOO/02503 00 WO 00/47568 PCTIUSOO/02503 0 o 0 0 o 0 0 0 0 0 4 0 0 0 z0 o u WO 00/47568 PCT/USOO/02503 00 0 OT z OT z OT z 0 0 0 o 0 0 W) W WO 00/47568 PCTIUSOO/02503 0 00 +& 0 + 0 0 0 000 WO 00/47568 PCT/USOO/02503 z z Z 0 0 0 0( o o 0 WO 00/47568 PCT/USOO/02503 0000 O 0 = zi z z 0)0 WO 00/47568 PCTUSOO/02503 0~ W= 0 0--c 0 0-- C/)-- 0 z z z o o 0 00 ON WO 00/47568 PCTIUSOO/02503 00 0 z z I z 0 +& o~ 0 0 0 C> C14 WO 00/47568 PCTUSOO/02503 00 0i 00zj -o-
-KD
.5'Ell .~It WO 00/47568 PCT/USOO/02503 Iz z I z 2) 4Q 0 0 0 0 0 0 N 00 N N N WO 00/47568 PCT/USOO/02503 0 0 o 0 0 WO 00/47568 PCTIUSOO/02503 0= c= 0 0 0 00 00 00 WO 00/47568 PCTUSOO/02503 a) 0) / z /Cz z 2 0 0 0 00 0 00 00 00 WO 00/47568 PCT/USOO/02503 O O N 0 0 0 0 00 0 0 WO 00/47568 PCTUSOO/02503 zz z 00 0 00 00 WO 00/47568 PCT/USOO/02503 0 0 0 0 00 0' O WO 00/47568 PCT/USOO/02503 w w wj z z z z zz z z 0.)) 0. .kn :1 WO 00/47568 PCT/USOO/02503 z z 0 0 0 0 00 CN C) WO 00/47568 PCT/USOO/02503 1-0 0 f) z + 0 + cuz Z+ - fn WO 00/47568 PCT/USOO/02503 ______________ ;~3j ~ z U Z * U z - z 'I ~ / a \ / a 0/ z z z / N Iz -' z NU NU z 0 \/ 0 0 0 0 0 -~ -~ 4.) '0 o 0 0 tr~ WO 00/47568 PCT/USOO/ 02503 00 z z0 =Z Z =Z z z0 .0 N 00 C. C0 WO 00/47568 PCT/USOO/02503 Zp33 ______ N 0 0 zI 0 0 0 \/ 0 0 00 -D ..D WO 00/47568 PCT/USOO/02503 z z I I0 0 WO 00/47568 PCT/USOO/02503 0 00 0 0 N 0N WO 00/47568 PCT/USOO/02503 z + + I+ [; 00 WO 00/47568 PCT/USOO/02503 zz0 0 [z z z 0a 0& +0 +& o 00 0 WO 00/47568 PCTIUSOO/02503 0 o 00 0~ 0~ 0 0 0 0. 0 z 0 z z 0 0 WO 00/47568 PCT[USOO/02503 0=z 0_ _ _ _ _ 0=____0_0_____
C)
+ + + zz z +C)0 0 +00 o o o0 WO 00/47568 PCTUSOO/02503 C.) (N) Z 0 0o 0 0 0 0 0 00 Mc M WO 00/47568 PCTUSOO/02503 0 0 z. 0 0 z S0 0 0 0 0 0n 0 0 WO 00/47568 PCT/USOO/02503 _ 2 I~C_ 00 0 00 oD 00 0 0 0 WO 00/47568 PCTIUSOO/02503 z z z + + + 00Z Z Z 0 0 0 0 0 0= 0= 0= o0& 0= 0 0 ONz on -n W) In In ~ tn k WO 00/47568 PCT/USOO/02503 z z Z= 0 0 Nn 00 WO 00/47568 PCT/USOO/02503 z z z z i + 1+D z z Z, 0 00 00 0 0 1 '.0 '.ell WO 00/47568 PCT/USOO/02503 z z zz z+ z+ 0 z+ z+ 00 0 0 0 =( -- = Z =0 < - WO 00/47568 PCT/USOO/02503 z z + V+ 0 0 Z- 0 = 0 N 000 WO 00/47568 PCT/USOO/02503 0 0 z z z m 0o o=< 0= 0= Z-= Z-= Z- M Z-= Z- M 0 0 0 0 -~~~ - ~~ kn W) In.k WO 00/47568 PCT/USOO/02503 z +z 0 0 00 O00 kn In n WO 00/47568 PCT/USOO/02503 z z z z V z z z 0 0 0 00 00 00 00 WO 00/47568 PCTIUSOO/02503 0 0 0 0 00 00 00 00 00 WO 00/47568 PCT/USOO/02503 0 00 0 0 0 0 U 00 < 0 < 0o z--z z z 0 0 0 0 000 00 00 WO 00/47568 PCT/USOO/02503 z z z 0 0 OA O 0l; 0 0 0 00 N tn~ WO 00/47568 PCT/USOO/02503 o 0 00
C\.
WO 00/47568 PCT/USOO/02503 0 00 0 - - : 0-M 1 00I WO 00/47568 PCT/USOO/02503 0 00 U) )U 0l~ Z-= Z-I 0X 0-(/) 0/ 0P \
Z-=Z-=.-
WO 00/47568 PCT/USOO/02503 0 o C/ C) oa-U / 0 ~ / 0000 WO 00/47568 PCTUSOOO25O3 0 0 ca cc(a ( o 0 0 0 0 0 0 CYC "0 0 oo 0 0 0 z-M Z-M - -K en0'.
WO 00/47568 PCT/USOO/02503 02 0 0. G Z, 0 0 00 Cc 00 WO 00/47568 PCTUSOO/02503 0 0 0 0 0 0 0 0 00 0 0 o 0 0 0 0 0 :3 C: ~ c0 -5-5:. :3 .0 -9 1E - WO 00/47568 PCTUSOO/02503 0 0 00 00 0 0 0 WO 00/47568 PCT/USOO/ 02503 0 0 o 0 0 0 0 0 0x 0 WO 00/47568 PCT/USOO/02503 0 0 0 0 0 00 0 0 0 0 0 00 WO 00/47568 PCTUSOO/02503 0 0 0 0 0 0 0 0 0 -0 0 0 0 -0 00 0 0 0 .0 Z=Z WO 00/47568 PCT/US0O/02503 2(,& 0 0 0 0 0 0 0 0 0 0 o QoO O0O C 0 0 ~0 ~0 .f4l WO 00/47568 PCT/USOO/02503 0 0 0 00 0 0 0 0 0 0 00 o 0 .0 .0 00 rn rn O WO 00/47568 PCT/USOO/02503 0 0 0 0 0 0 00 zx 0 0z WO 00/47568 PCT/USOO/02503 000 0 0 z 0 Z= 0 Z= 0 Z= z *0 WO 00/47568 PCTUSOO/02503 00 00 0 0 0 0 z0 0 0 x 0 0 0 0 0 0 00 WO 00/47568 PCTIUSOO/02503 0 0 0 0 0 0 0 o 0 0z -- 0Z tI-x Ij tn kn WO 00/47568 PCT/USOO/02503 0 0 0 '7 kn WO 00/47568 PCT/USOO/02503 272 Another group of compounds of interest consists of those compounds of Formula I wherein R' and R 2 are alkyl, preferably n-butyl; R 3 is hydroxy;
R
4 and R 6 are hydrogen; RN is hydrogen; Rx radicals are selected from the group consisting of amino, dimethylamino and methoxy; and R' is phenyl 5 substituted at the para or meta position with one of the following groups: cI O N+ CO2 H O N CO 2 H CO 2 H N _,CO 2 H H N NH 10OO -0-S-Me 11 0 WO 00/47568 PCTIUSOO/02503 273
N
C0 2 H 0 0 , +Nt 3 1 -0-S-Me 11 0 0 R R=1000OMW PEG 20 0 11 -01 -0/Me WO 00/47568 PCTUSOO/02503 274 r0 C02 H N> C 2 H >00 ~N+ 0-O CF 3 ' 0 I~OH >0 ~OH H N,, ,C0 2 H 0 S N I- N -C0 2
H
WO 00/47568 PCT/USO0/02503 275 0 N CO 2 H C0 2 H 0 N+ -0-S-Me 11 0 OH H N 0 - NMe >0 > Cl 5 0 N N CO 2 H. CO2
H
WO 00/47568 PCT/USOO/02503 276 N H ; and O NH NH O N NH-M-NH H ; NH NH wherein M is selected from the group consisting of Co", Co", Mn", M 1nr, Fe", Fe"', Nil, Nil', CrIr, Cul, Zn", Cd", Ga"', Ini"', VIv, Ru", PtIv, Rhm" 5 and Ir"i. Dosages, Formulations, and Routes of Administration The ileal bile acid transport inhibitor compounds of the present invention can be administered for the prophylaxis and/or treatment of hyperlipidemic diseases, conditions and/or disorders by any means, preferably 10 oral, that contacts these compounds with their site of action in the body, for example in the ileum of a mammal such as a human. For the prophylaxis and/or treatment of the diseases, conditions and/or disorders referred to above, the compounds of the present invention can be used as the compound per se. Pharmaceutically acceptable salts are 15 particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compound. Such salts comprise a pharmaceutically acceptable anion or cation. Suitable pharmaceutically WO 00/47568 PCT/USOO/02503 277 acceptable acid addition salts of the compounds of the present invention where appropriate include those salts derived from inorganic acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, 5 citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids. The chloride salt is particularly preferred for medical purposes. Suitable pharmaceutically acceptable base salts where appropriate include ammonium salts, alkali metal salts such as sodium and 10 potassium salts, and alkaline earth salts such as magnesium and calcium salts. The anions of the definition of A- in the present invention are pharmaceutically acceptable anions such as those anions selected, for example, from the above list. The compounds of the present invention also can be administered in 15 the form of a pharmaceutical composition comprising additional ingredients such as acceptable carriers, diluents, excipients, adjuvants and the like (collectively referred to herein as "carrier materials"). Acceptable carrier materials are compatible with the other ingredients of the composition and are not deleterious to the recipient. A carrier material can be a solid or a liquid, 20 or both, and is preferably formulated with the compound as a unit-dose composition, for example, a tablet or capsule, which can contain from 0.05% to 95% by weight of the active compound. Other pharmacologically active substances can also be present, including other compounds of the present invention. The pharmaceutical compositions of the invention can be prepared 25 by any of the well known techniques of pharmacy, consisting essentially of admixing the components. These compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as an individual therapeutic compound in a monotherapeutic regimen or as a combination of WO 00/47568 PCT/USOO/02503 278 therapeutic compounds in a combination therapy regimen. The amount of compound that is required to achieve the desired biological effect will depend on a number of factors such as the specific compound chosen, the use for which it is intended, the mode of 5 administration, and the clinical condition of the recipient. In general, a daily dose can be in the range of from about 0.3 to about 100 mg/kg bodyweight/day, preferably from about 1 mg to about 50 mg/kg bodyweight/day, and more preferably from about 3 to about 10 mg/kg bodyweight/day. This total daily dose can be administered to the patient in a 10 single dose, or in proportionate multiple subdoses. Subdoses can be administered 2 to 6 times per day. Doses can be in sustained release form effective to obtain desired results. Orally administrable unit dose formulations, such as tablets or capsules, can contain, for example, from about 0.1 to about 100 mg of 15 benzothiazepine compound, preferably about 1 to about 75 mg of compound, more preferably from about 10 to about 50 mg of compound. In the case of pharmaceutically acceptable salts, the weights indicated above refer to the weight of the benzothiazepine ion derived from the salt. Oral delivery of an ileal bile acid transport inhibitor of the present 20 invention can include formulations, as are well known in the art, to provide prolonged or sustained delivery of the drug to the gastrointestinal tract by any number of mechanisms. These include, but are not limited to, pH sensitive release from the dosage form based on the changing pH of the small intestine, slow erosion of a tablet or capsule, retention in the stomach based on the 25 physical properties of the formulation, bioadhesion of the dosage form to the mucosal lining of the intestinal tract, or enzymatic release of the active drug from the dosage form. The intended effect is to extend the time period over which the active drug molecule is delivered to the site of action (the ileum) by manipulation of the dosage form. Thus, enteric-coated and enteric-coated WO 00/47568 PCT/USOO/02503 279 controlled release formulations are within the scope of the present invention. Suitable enteric coatings include cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methacrylic acid methyl ester. 5 When administered intravenously, the dose can, for example, be in the range of from about 0.1 mg/kg body weight to about 1.0 mg/kg body weight, preferably from about 0.25 mg/kg body weight to about 0.75 mg/kg body weight, and more preferably from about 0.4 mg/kg body weight to about 0.6 mg/kg body weight. This dose can be conveniently administered as an 10 infusion of from about 10 ng/kg body weight to about 100 ng/kg body weight per minute. Infusion fluids suitable for this purpose can contain, for example, from about 0.1 ng to about 10 mg, and preferably from about 1 ng to about 10 mg per milliliter. Unit doses can contain, for example, from about 1 mg to about 10 g of the compound of the present invention. Thus, ampoules for 15 injection can contain, for example, from about 1 mg to about 100 mg. Pharmaceutical compositions according to the present invention include those suitable for oral, rectal, topical, buccal (e.g., sublingual), and parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) administration, although the most suitable route in any given case will depend 20 on the nature and severity of the condition being treated and on the nature of the particular compound which is being used. In most cases, the preferred route of administration is oral. Pharmaceutical compositions suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each 25 containing a predetermined amount of at least one compound of the present invention; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As indicated, such compositions can be prepared by any suitable method of pharmacy which includes the step of bringing into association the active WO 00/47568 PCT/USOO/02503 280 compound(s) and the carrier material (which can constitute one or more accessory ingredients). In general, the compositions are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier material, or both, and then, if necessary, shaping the 5 product. For example, a tablet can be prepared by compressing or molding a powder or granules of the compound, optionally with one or more assessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface 10 active/dispersing agent(s). Molded tablets can be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid diluent. Pharmaceutical compositions suitable for buccal (sub-lingual) administration include lozenges comprising a compound of the present 15 invention in a flavored base, usually sucrose, and acacia or tragacanth, and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia. Pharmaceutical compositions suitable for parenteral administration conveniently comprise sterile aqueous preparations of a compound of the 20 present invention. These preparations are preferably administered intravenously, although administration can also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations can conveniently be prepared by admixing the compound with water and rendering the resulting solution sterile and isotonic with the blood. Injectable 25 compositions according to the invention will generally contain from 0.1 to 5% w/w of a compound disclosed herein. Pharmaceutical compositions suitable for rectal administration are preferably presented as unit-dose suppositories. These can be prepared by admixing a compound of the present invention with one or more conventional WO 00/47568 PCTIUSOO/02503 281 solid carrier materials, for example, cocoa butter, and then shaping the resulting mixture. Pharmaceutical compositions suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, 5 aerosol, or oil. Carrier materials that can be used include vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound is generally present at a concentration of from 0.1 to 15% w/w of the composition, for example, from 0.5 to 2%. Transdermal administration is also possible. Pharmaceutical 10 compositions suitable for transdermal administration can be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain a compound of the present invention in an optionally buffered, aqueous solution, dissolved and/or dispersed in an adhesive, or dispersed in a polymer. 15 A suitable concentration of the active compound is about 1% to 35%, preferably about 3% to 15%. As one particular possibility, the compound can be delivered from the patch by electrotransport or iontophoresis, for example, as described in Pharmaceutical Research, 3(6), 318 (1986). In any case, the amount of active ingredient that can be combined with 20 the carrier materials to produce a single dosage form to be administered will vary depending upon the host treated and the particular mode of administration. The solid dosage forms for oral administration including capsules, tablets, pills, powders, and granules noted above comprise one or more 25 compounds of the present invention admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and WO 00/47568 PCT/USOO/02503 282 pills can additionally be prepared with enteric coatings. Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such 5 compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using 10 suitable dispersing or setting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride 15 solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Pharmaceutically acceptable carrier materials encompass all the 20 foregoing and the like. Treatment Regimen The dosage regimen to prevent, give relief from, or ameliorate a disease, condition and/or disorder relating to hyperlipemia, e.g., atherosclerosis, or to protect against or treat further high cholesterol plasma or 25 blood levels with the compounds and/or compositions of the present invention is selected in accordance with a variety of factors. These include the type, age, weight, sex, diet, and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as WO 00/47568 PCT/USOO/02503 283 the activity, efficacy, pharmacokinetics and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized, and whether the compound is administered as part of a drug combination. Thus, the dosage regimen actually employed may vary widely and therefore 5 deviate from the preferred dosage regimen set forth above. Initial treatment of a patient suffering from a hyperlipidemic condition can begin with the dosages indicated above. Treatment should generally be continued as necessary over a period of several weeks to several months or years until the hyperlipidemic disease condition has been controlled or 10 eliminated. Patients undergoing treatment with the compounds or compositions disclosed herein can be routinely monitored by, for example, measuring serum cholesterol levels by any of the methods well known in the art, to determine the effectiveness of therapy. Continuous analysis of such data permits modification of the treatment regimen during therapy so that optimal 15 effective amounts of compounds of the present invention are administered at any point in time, and so that the duration of treatment can be determined as well. In this way, the treatment regimen/dosing schedule can be rationally modified over the course of therapy so that the lowest amount of ileal bile acid transport inhibitor of the present invention which exhibits satisfactory 20 effectiveness is administered, and so that administration is continued only so long as is necessary to successfully treat the hyperlipidemic condition. The following non-limiting examples serve to illustrate various aspects of the present invention. Examples of Synthetic Procedures 25 The starting materials used in the preparation of the compounds of the following examples, as well as other compounds of the present invention, are commercially available or can be prepared by conventional methods known to one of ordinary skill in the art or in an analogous manner to conventional WO 00/47568 PCT/USOO/02503 284 methods described in the art. The starting materials of the following examples were obtained from commercial sources unless otherwise noted. The ethyl 2 amino-2-butylhexanoate hydrochloride used below was prepared in an analogous manner to the literature method of Stork (J. Org. Chem. 41, 3491 5 (1976)). Example 1 (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-2-methyl-5 (3-nitrophenyl)-1,2-benzothiazepin-4-ol 1,1-dioxide 0 0 N OH N O N~O 0 Step 1. 2-Amino-2-butylhexanol 10 HO
NH
2 Bu Bu To a solution of 29.75 g (0.12 mol) of ethyl 2-amino-2-butylhexanoate hydrochloride in 100 mL of tetrahydrofuran cooled to -20 *C was added 148.8 mL of a 1.0 M solution of lithium aluminum hydride in tetrahydrofuran while WO 00/47568 PCT/USOO/02503 285 maintaining a temperature below -15 'C. The reaction mixture was stirred for one hour at -20 *C, warmed to room temperature and stirred for 16 hours. The reaction mixture was then cooled to -20 C and 6 mL of water was added, followed by 5.6 mL of 3.75 M aqueous sodium hydroxide and 16 mL of water. 5 The reaction mixture was stirred for one hour and warmed to room temperature. The resulting slurry was filtered and washed with 100 mL ethyl acetate. The ethyl acetate solution was washed with water (2x200 mL) and then brine (300 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated. The resulting yellow oil was dissolved in 300 mL of 10 tetrahydrofuran and concentrated to give 20.61 g of 2-amino-2-butylhexanol as an oil. Step 2. N-[1-Butyl-1-(hydroxymethyl)pentyl]-4-fluorobenzenesulfonamide Bu Bu SO2NH OH F To a solution of 16.95 g (0.09 mol) of 4-fluorobenzene sulfonyl chloride in 150 mL of tetrahydrofuran was added 36.4 mL of triethylamine. 15 The reaction mixture was cooled to 0 *C and a solution of 19.61 g of 2-amino 2-butylhexanol (prepared in step 1 above) in 70 mL of tetrahydrofuran was added. The reaction mixture was stirred 30 minutes at 0 0 C and then 16 hours at room temperature. The reaction mixture was concentrated and then the residue was dissolved in 250 mL of ethyl acetate. This ethyl acetate solution 20 was washed with water (2 x 200 mL) and brine (300 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated to give 29.47 g of N [1-butyl-1-(hydroxymethyl)pentyl]-4-fluorobenzenesulfonamide as an oil.
WO 00/47568 PCTIUSOO/02503 286 Step 3. N-(1-Butyl-1-(hydroxymethyl)pentyl]-4-(dimethylamino) benzenesulfonamide Bu Bu NON -N s 2 NH OH A solution containing 28.89 g (0.09 mol) of the oil prepared in Step 2 above, 872 mL of 2.0 M dimethylamine in tetrahydrofuran and 100 mL of neat 5 dimethylamine was prepared and placed in a bomb. The reaction mixture was heated to 110 'C for 16 hours, cooled, and then concentrated to give 25.46 g of N-[1-butyl-1-(hydroxymethyl)pentyl]-4-(dimethylamino)benzenesulfonamide as an solid. Step 4. N-[I1-Butyl-1-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl] 10 4-(dimethylamino)benzenesulfonamide Bu Bu SO2NH s 2 NOTBDMS To a solution of 15.51 g (0.10 mol) of t-butyldimethylsilyl chloride in 158 mL of dimethylformamide was added 24.46 g (0.07 mol) of the solid prepared in Step 3 and then 14.01 g of imidazole. The reaction mixture was stirred 3 days and then diluted with 1 L of ethyl acetate and 500 mL of water. 15 The ethyl acetate solution was washed with 5% hydrochloric acid solution (2 x WO 00/47568 PCTIUSOO/02503 287 200 mL), water (200 mL) and then brine (200 mL). The ethyl acetate layer was dried with magnesium sulfate and concentrated to an oil. The oil was stirred with hexane and the resulting solid was filtered to give 25.31 g of N-[1 butyl-1-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4 5 (dimethylamino)benzenesulfonamide as a white solid. Step 5. N-[1-Butyl-1-[[[(1,1dimethylethyl)dimethylsilyl]oxy]methyl]pentyl] 4-(dimethylamino)-N-methylbenzenesulfonamide Bu Bu S O N O 2 T OTBDMS To a solution of 0.476 g (11.90 mmol) of 60% sodium hydride dispersion in mineral oil in 43 mL of tetrahydrofuran was added 4.0 g (8.50 10 mmol) of the solid prepared in Step 4 above and then 1.6 mL of dimethyl sulfate dropwise. The reaction mixture was heated at reflux for one hour, cooled to 0 *C, and then water was added. The reaction mixture was concentrated and 250 mL ethyl acetate and 250 mL water added. The layers were separated and the ethyl acetate solution was washed with 1 M 15 hydrochloric acid (2 x 200 mL), saturated sodium bicarbonate (2 x 200 mL), water (200 mL) and then brine (200 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated to give 4.63 g of a residue. The residue was purified by flash chromatography with 15% ethyl acetate/hexane as eluent to give 3.35 g of N-[1-butyl-1-[[[(l,ldimethylethyl) dimethylsilyl] 20 oxy]methyl]pentyl]-4-(dimethylamino)-N-methylbenzenesulfonamide as an oil.
WO 00/47568 PCT/USOO/02503 288 Step 6. B u Bu SON 2 OTBDMS N B ( OH ) 2 To a solution of 3.35 g (6.90 mmol) of the oil prepared in Step 5 above in 35 mL of tetrahydrofuran cooled to 0 'C was added dropwise 9.66 mL of 1.6 M n-butyllithium in hexanes. The reaction mixture was stirred 30 minutes 5 at 0 'C, warmed to room temperature, and stirred one hour. To the reaction mixture was added 6.5 mL of 5% hydrochloric acid and then the Tetrahydrofuran was evaporated. To the residue was added 200 mL dichloromethane and 200 mL water and the layers separated. The dichloromethane layer was washed with brine (200 mL), dried over 10 magnesium sulfate and concentrated to give 3.12 g of a yellow solid. Step 7. N-[1-Butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4 (dimethylamino)-2-[(3-nitrophenyl)methyl]-N-methylbenzenesulfonamide BU Bu SO N N 2 OTBDMS N
NO
2 To a solution of 130 mg (0.11 mmol) of tetrakis(triphenylphosphine) palladium(0) in 10 mL of toluene was added 825 mg of 3-nitrobenzyl WO 00/47568 PCT/USOO/02503 289 bromide. After the toluene solution was stirred 10 minutes, a degassed solution of 2.02 g (3.82 mmol) of the solid prepared in Step 6 above in 8 mL ethanol was added followed by 10 mL of 1 M sodium carbonate. The reaction mixture was heated at reflux 45 minutes and then cooled and concentrated. To 5 the residue was added 250 mL of ethyl acetate. The ethyl acetate mixture was washed with brine (2 x 200 mL), dried over magnesium sulfate and concentrated to give 2.76 g of a residue. To the residue was added 200 mL of 30% ethyl acetate in hexane, and the mixture was stirred 1.5 hours and then filtered through silica. The ethyl acetate solution was concentrated to give 10 2.30 g of N-[ 1 -butyl- 1 -[[[(1 -dimethylethyl)dimethylsilyl]oxy]methyl]pentyl] 4-(dimethylamino)- 2 -[(3-nitrophenyl)methyl]-N-methylbenzenesulfonamide as a yellow solid. Step 8. N-[1-Butyl-1-(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(3 nitrophenyl)methyl]-N-methylbenzenesulfonamide Bu Bu SO N > 2 OH N
NO
2 15 To a solution of 2.16 g (3.48 mmol) of the solid prepared in Step 7 above in 10 mL of tetrahydrofuran cooled to 0 'C was added 4.4 mL of 1 M tetrabutylammonium fluoride in tetrahydrofuran. The reaction mixture was stirred 15 minutes at 0 *C and then 12 hours at room temperature. To the reaction mixture was added 250 mL of ethyl acetate. The ethyl acetate 20 solution was washed with water (200 mL) and brine (200 mL). The ethyl WO 00/47568 PCT/USOO/02503 290 acetate layer was dried over magnesium sulfate and concentrated to give 1.88 g of a brown oil residue. The residue was purified by flash chromatography with 30% ethyl acetate in hexane as eluent to give 1.49 g of N-[1-butyl-1 (hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N 5 methylbenzenesulfonamide as a yellow oil. Step 9. N-[1-Butyl-1-formylpentyl]-4-(dimethylamino)-2-[(3-nitrophenyl) methyl]-N-methylbenzenesulfonamide. Bu Bu SO N 2 CHO NO 2 To a solution of 1.49 g (2.95 mmol) of the oil prepared in Step 8 above in 10 mL of dimethylsulfoxide was added 1.23 mL of triethylamine and then 10 1.41 g of sulfur trioxide pyridine complex. The reaction mixture was stirred one hour and then diluted with 200 mL water. The aqueous mixture was washed with ethyl acetate (3 x 100 mL). The combined organic layers were washed with 5% hydrochloric acid (100 mL) and brine (100 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated. The residue 15 was purified by flash chromatography with 25% ethyl acetate in hexane as eluent to give 1.31 g of N-[1 -butyl-1 -formylpentyl]-4-(dimethylamino)-2-[(3 nitrophenyl)methyl]-N-methylbenzenesulfonamide as a yellow oil. Step 10. (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-2-methyl 5-(3-nitrophenyl)-1,2-benzothiazepin-4-ol 1,1-dioxide WO 00/47568 PCT/USOO/02503 291 To a solution of 504 mg (2.60 mmol) of the oil prepared in Step 9 above in 50 mL of tetrahydrofuran cooled to 0 *C was added 2.80 mL of 1 M potassium t-butoxide in tetrahydrofuran. The reaction mixture was stirred for 15 minutes, water was added, and then the mixture was concentrated to yield a 5 residue. The residue was dissolved in 100 mL ethyl acetate. The ethyl acetate solution was washed with water (100 mL) and brine (100 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated to give 1.25 g of a semi-solid. The residue was purified by crystallization with ethyl acetate and hexane to give 737.5 mg of (4R,5R)-3,3-dibutyl-7 10 (dimethylamino)-2,3,4,5-tetrahydro-2-methyl-5-(3-nitrophenyl)-1,2 benzothiazepin-4-ol 1,1-dioxide as a yellow crystalline solid. 'H NMR (CDCl 3 ) 5 0.90-1.00 (in, 6H), 1.05-1.80 (in, 12H), 2.50-2.60 (in, 1H), 2.79 (s, 6H), 2.85 (s, 3H), 4.09 (d, J= 9.0 Hz, 1H), 5.76 (d, J= 2.0 Hz, 1H), 5.88 (s, 1H), 6.53 (dd, J= 2.4, 8.9 Hz, 1H), 7.59 (t, J= 7.9 Hz, 1H), 7.84-7.88 (in, 15 2H), 8.22 (dd, J= 1.0, 8.1 Hz, 1H), 8.47 (s, 1H). MS (M+H+) 504. Example 2 (4R,5R)-5-(3-aminophenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5 tetrahydro-2-methyl-1,2-benzothiazepin-4-ol 1,1-dioxide 0 0 // S-N N O H Q N H2 WO 00/47568 PCT/USOO/02503 292 A solution of 737 mg (1.46 mmol) of the solid prepared in Step 10 of Example 1 was dissolved in 110 mL of ethanol in a 3 oz. Fisher/Porter vessel, and about 150 mg of 10% Pd/C catalyst was added. This mixture was hydrogenated at 40 psi H 2 for 20 hours and then filtered. The filtrate was 5 concentrated to give 0.82 g of a semi-solid material. The semi-solid material was crystallized from ethyl acetate and hexane to give 0.51 g of (4R,5R)-5-(3 aminophenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-2-methyl-1,2 benzothiazepin-4-ol 1,1-dioxide as colorless crystals. 'H NMR (CDCl 3 ) 6 0.89 (t, J= 6.6 Hz, 3H), 0.92 (t, J= 7.2 Hz, 3H), 1.10-1.45 (in, 8H), 1.60-1.75 (in, 10 3H), 1.98-2.10 (in, 1H), 2.48-2.58 (in, 1H), 2.79 (s, 6H), 2.81 (s, 3H), 3.69 (s, 2H), 4.12 (d, J= 7.8 Hz, 1H), 5.62 (s, 1H), 6.07 (d, J= 2.1 Hz, 1H), 6.46 (dd, J= 2.4, 8.7 Hz, 1H), 6.61 (br d, J= 7.8 Hz, 1H), 6.80 (br s, 1H), 6.89 (br d, J = 2.1 Hz, 1H), 7.15 (t, J= 7.8 Hz, 1H), 7.79 (d, J= 8.7 Hz, 1H). MS (M+H+) 474. 15 Example 3 5-bromo-N-[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4 hydroxy-2-methyl-1,1-dioxido-1,2-benzothiazepin-5-yl]phenyl]pentanamide S~N N \O H 0 N B r H To a solution of 0.25 g (0.53 mmol) of the solid prepared in Example 2 WO 00/47568 PCT/US0/02503 293 above in 3 mL of tetrahydrofuran was added 153 pL of triethylamine followed by 86 pL of 5-bromovaleryl chloride. The reaction mixture was stirred one hour and then concentrated to form a residue. Water (50 mL) was added to the residue. The aqueous solution was extracted with ethyl acetate (2 x 50 mL). 5 The combined ethyl acetate layers were washed with 5% hydrochloric acid (2 x 25 mL), saturated sodium bicarbonate solution (2 x 25 mL) and brine (25 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated to give 0.29 g of a solid. The solid was purified by crystallization with ethyl acetate and hexane to give 202.3 mg of 5-bromo-N 10 [3-[(4R,5R)-3, 3 -dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2 methyl-1, 1 -dioxido- 1, 2 -benzothiazepin-5-yl]phenyl]pentanamide as a tan solid. 'H NMR (CDC 3 ) 8 0.88 (t, J= 7.2 Hz, 3H), 0.92 (t, J= 6.9 Hz, 3H), 1.20-1.42 (in, 8H), 1.57-2.10 (in, 8H), 2.37 (t, J= 6.9 Hz, 2H), 2.46-2.57 (m, 1H), 2.78 (s, 6H), 2.81 (in, 3H), 3.41 (t, J= 6.3 Hz, 2H), 4.10 (d, J= 8.5 Hz, 15 1H), 5.69 (s, 1H), 5.97 (s, 1H), 6.47 (dd, J= 2.4, 8.9 Hz, 1H), 7.24-7.40 (m, 4H), 7.76 (br s, 1H), 7.80 (d, J= 8.7 Hz, 1H). MS (M+H+) 636, 638. Example 4 5-[[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2 methyl-1, 1 -dioxido- 1,2-benzothiazepin-5 -yl]phenyl] amino]-N,N,N-triethyl-5 20 oxo-pentanaminium trifluoroacetate WO 00/47568 PCT/USOO/02503 294 oO -N N OH 0 + N N H
CF
3
CO
2 To a solution of 100 mg (0.16 mmol) of the solid prepared in Example 3 above in 1 mL of acetonitrile was added 87 ptL of triethylamine. The reaction mixture was heated at 55 *C for 28 hours and then at 75 *C for 16 hours. The 5 reaction mixture was concentrated to form a residue. The residue was purified by reverse phase high pressure liquid chromatography to give 16.2 mg of 5 [[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2 methyl-1, 1 -dioxido- 1,2-benzothiazepin-5-yl]phenyl] amino]-N,N,N-triethyl-5 oxo-pentanaminium trifluoroacetate as a white solid. 'H NMR was consistent 10 with the product. MS (M*) 657. Example 5 2-chloro-N-[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4 hydroxy-2-methyl- 1,1 -dioxido- 1,2-benzothiazepin-5-yl]phenyl]acetamide WO 00/47568 PCT/USOO/02503 295 0 S-N N 0 H To a solution of 100 mg (0.21 mmol) of the solid prepared in Example 4 above in 2 mL of tetrahydrofuran was added 29 mg of bromoacetic acid, 29 iL of triethylamine, and then 40 mg of 5 ethyldimethylaminopropylcarbodiimide hydrochloride. The reaction mixture was stirred 16 hours and then 50 mL ethyl acetate was added. The ethyl acetate solution was washed with water, 5% hydrochloric acid (2 x 25 mL), saturated sodium bicarbonate solution (2 x 25 mL), and then brine (25 mL). The ethyl acetate layer was dried over magnesium sulfate and then 10 concentrated to give 88 mg of an oil. The oil was purified by flash chromatography with 50% ethyl acetate in hexane as eluent to give 72.0 mg of cis-3,3-dibutyl-2,3,4,5-tetrahydro-4-hydroxy-2-methyl-7-dimethylamino-5-(3 (2-chloroaceamido)phenyl)-1,2-benzothiazepine with a trace of 2-chloro-N-[3 [(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2 15 methyl-1,1-dioxido-1,2-benzothiazepin-5-yl]phenyl]acetamide present. IH NMR was consistent with the product. MS (M+H*) 550.
WO 00/47568 PCT/USOO/02503 296 Example 6 2-[[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino]-2,3,4,5-tetrahydro-4-hydroxy-2 methyl-1, 1 -dioxido- 1,2-benzothiazepin-5 -yl]phenyl]amino]-NN,N-triethyl-2 oxoethanaminium chloride S N N O H 0~ CI N N H 5 To a mixture of 63 mg (0.12 mmol) of the material prepared in Example 5 above in 1 mL of tetrahydrofuran was added 64 gL of triethylamine. The reaction mixture was heated to reflux for three days and then concentrated. The residue was triturated with ether to give 66.5 mg of 2 [[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino]-2,3,4,5-tetrahydro-4-hydroxy-2 10 methyl- 1,1 -dioxido- 1,2-benzothiazepin-5-yl]phenyl]amino]-N,N,N-triethyl-2 ~ oxoethanaminium chloride as a tan solid. 'H NMR was consistent with the product. MS (M*) 615. Example 7 (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4 15 methoxyphenyl)-2-methyl-1,2-benzothiazepin-4-ol 1,1-dioxide WO 00/47568 PCT/USO0/02503 297 O //0 S-N N O OH 0 Step 1. N-[1-Butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4 5 (dimethylamino)-2-[(4-methoxyphenyl)methyl]-N-methylbenzenesulfonamide 2- 1 OTBDMS N 0 To a solution of 1.00 g (2.06 mmol) of the material from Step 5 of Example 1 above in 10 mL of tetrahydrofuran cooled to 0 *C was added 2 mL of 1.6 M n-butyllithium in hexanes. The reaction mixture was stirred one hour at 0 'C. To the reaction mixture was added 480 pL of trimethyl borate and the 10 mixture stirred 15 minutes at 0 'C and then one hour at room temperature. The reaction mixture was concentrated to form a residue. The residue was dissolved in 20 mL of toluene and 2.1 mL of 2 M aqueous sodium carbonate.
WO 00/47568 PCT/USOO/02503 298 To the mixture was added 300 ptL ofp-methoxybenzyl chloride and then 71 mg of tetrakis(triphenylphosphine)palladium(0). The reaction mixture was heated at 100 *C for 16 hours, cooled, and then 50 mL of toluene added. The reaction mixture was washed with water (50 mL) and brine (50 mL), filtered 5 through silica, and concentrated to form a residue. The residue was purified by flash chromatography to give 0.82 g of N-[1-butyl-1-[[[(1 dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(4 methoxyphenyl)methyl]-N-methylbenzenesulfonamide as an oil. Step 2. N-[1-Butyl-1-(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(4 10 methoxyphenyl)methyl]-N-methylbenzenesulfonamide Bu Bu SO2N OH 0 The procedure of Step 8 of Example 1 above was followed except that N-[1-butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4 (dimethylamino)-2-[(4-methoxyphenyl)methyl]-N-methylbenzenesulfonamide was used in place of N-[ 1 -butyl- 1 -[[[(1 -dimethylethyl)dimethylsilyl]oxy] 15 methyl]pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N methylbenzenesulfonamide.
WO 00/47568 PCT/USOO/02503 299 Step 3. N-[1-Butyl-1-formylpentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl) methyl]-N-methylbenzenesulfonamide Bu Bu S O N ~ 2 CHO N 0 The procedure of Step 9 of Example 1 above was followed except that N-[1-butyl-1-(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(4 5 methoxyphenyl)methyl]-N-methylbenzenesulfonamide was used in place of N [1 -butyl-1-(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(3 nitrophenyl)methyl]-N-methylbenzenesulfonamide. Step 4. (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4 methoxyphenyl)-2-methyl-1,2-benzothiazepin-4-ol 1,1-dioxide 10 The procedure of Step 10 of Example 1 above was followed except that N-[ 1 -butyl- 1 -formylpentyl]-4-(dimethylamino)-2-[(4 methoxyphenyl)methyl]-N-methylbenzenesulfonamide was used in place of N [1 -butyl- 1 -formylpentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl)-N methylbenzenesulfonamide. 15 'H NMR (CDCl 3 ) 5 0.83-0.96 (m, 6H), 1.15-1.38 (m, 6H), 1.69-1.83 (m, 4H), 2.00-2.08 (m, 1H), 2.55-2.59 (m, 1H), 2.81 (s, 6H), 2.83 (s, 3H), 3.84 (s, 3H), 4.10-41.6 (m, 1H), 5.70 (s, 1H), 5.99 (s, 1H), 6.52 (s, 1H), 6.93 (d, J= 8.6 Hz, WO 00/47568 PCT/US0O/02503 300 2H), 7.43 (d, J= 8.4 Hz, 2H), 7.83 (d, J= 8.6 Hz). Example 8 (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4 hydroxyphenyl)-2-methyl-1,2-benzothiazepin-4-ol 1,1-dioxide 5 0 S-N N SOH O H To a solution of 0.52 g (1.06 mmol) of the solid prepared in Step 4 of Example 7 above in 10 mL of dichloromethane cooled to -78 *C was added 300 pL of boron tribromide. The reaction mixture was stirred for one hour at 10 78 'C and then 100 mL of water and 100 mL of dichloromethane were added. The dichloromethane solution was washed with 10% aqueous sodium carbonate(100 mL), 10% hydrochloric acid (100 mL) and brine (100 mL). The dichloromethane layer was dried over magnesium sulfate and concentrated to give 0.46 g of (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5 15 tetrahydro-5-(4-hydroxyphenyl)-2-methyl-1,2-benzothiazepin-4-ol 1,1-dioxide as a solid. 'H NMR (CDC1 3 ) 60.82-0.97 (m, 6H), 1.15-1.40 (m, 6H), 1.67 1.76 (m, 4H), 2.00-2.10 (m, 1H), 2.51-2.59 (m, 1H), 2.83 (s, 6H), 2.84 (s, 9H), 4.12 (d, J= 8.0 Hz, 1H), 4.88 (br s, 1H), 5.69 (s, 1H), 6.07 (d, J= 2.2 Hz, 1H), 6.60 (dd, J= 2.2, 8.6 Hz, 1H), 6.88 (d, J= 8.6 Hz, 2H), 7.38 (d, J= 8.3 Hz, 20 2H), 7.85 (d, J= 8.6 Hz). HRMS (ES) Calc'd for C 2 6
H
39
N
2 0 4 S: 475.2631.
WO 00/47568 PCT/US0O/02503 301 Found: 475.2649. Example 9 (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-(((2 iodoethyoxy)ethoxy)ethoxy)phenyl)-2-methyl-1,2-benzothiazepin-4-o1 1,1 5 dioxide O S-N N \ 3 OH 0 H 00 To a solution of 0.38 g (0.80 mmol) of the solid prepared in Example 8 in 8 mL dimethylformamide was added 44 mg of 95% sodium hydride and then 730 tL of 1,2-bis(2-iodoethoxy)ethane. The reaction mixture was stirred one hour. To the reaction mixture was added 100 mL of water and 100 mL of 10 ethyl acetate and the reaction mixture extracted with ethyl acetate. The ethyl acetate layer was washed with brine (100 mL), dried over magnesium sulfate and concentrated to form a residue. The residue was purified by flash chromatography with 10-25% ethyl acetate in hexane as eluent to give 0.37 g of (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-(((2 15 iodoethyoxy)ethoxy)ethoxy)phenyl)-2-methyl-1,2-benzothiazepin-4-ol 1,1 dioxide as a solid. HRMS (ES) Calc'd for C 32
H
50
N
2 0SI: 717.2434. Found: 717.2419. 'H NMR is consistent with the structure of the product.
WO 00/47568 PCT/USOO/02503 302 Example 10 1-[2-[2-[2-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4 hydroxy-2-methyl-1,1-dioxido-1,2-benzothiazepin-5 yl]phenoxy]ethoxy]ethoxy]ethyl]pyridinium 0 S-N N SOH O O O 0 N 5 A solution of 75 mg of the solid prepared in Example 9 above in 5 mL of pyridine was heated at 70 'C for 16 hours. The reaction mixture was concentrated to form a residue. The residue was triturated with ether to give 56.8 mg of 1-[2-[2-[2-[4-[(4R,5R)-3,3-dibutyl-7- (dimethylamino)-2,3,4,5 tetrahydro-4-hydroxy-2-methyl-1,1-dioxido-1,2-benzothiazepin-5 10 yl]phenoxy]ethoxy]ethoxy]ethyl]pyridinium as a solid. 'H NMR (CDCl 3 ) 5 0.89-0.97 (m, 6H), 1.19-1.40 (m, 6H), 1.70-1.74 (m, 4H), 2.00-2.10 (m, 1H), 2.60-2.69 (m, 1H), 2.80 (s, 6H), 2.83 (s, 3H), 3.69-3.72 (m, 4H), 3.83-3.87 (m, 2H), 4.09-4.15 (m, 511), 5.23-5.27 (m, 2H), 5.70 (s, 1H), 5.97 (d, J= 2.4 Hz, 1H), 6.50 (dd, J= 2.4, 8.8 Hz, 1H), 6.93 (d, J= 8.8 Hz, 2H), 7.46 (d, J= 8.7 15 Hz, 2H), 7.83 (d, J= 8.7 Hz, 1H), 7.96-8.01 (m, 2H), 8.63-8.67 (m, 2H), 9.52 (d, J= 6.0 Hz, 1H). HRMS (ES) Calc'd for C 37
H
54
N
3 0 6 S: 668.3733. Found: 668.3762.
WO 00/47568 PCT/USOO/02503 303 Example 11 2-[2-[2-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4 hydroxy-2-methyl-1,1-dioxido-1,2-benzothiazepin-5 yl]phenoxy]ethoxy]ethoxy]-N,N,N-triethylethanaminium iodide 0 S-N N SOH 0 O O N + 5 The procedure of Example 10 was followed except that triethylamine was used in place of pyridine and heating was at 90 'C for 6 hours. 'H NMR is consistent with the desired product. 'H NMR (CDCl 3 ) 6 0.90-0.97 (m, 6H), 1.12-1.45 (m, 15H), 1.60-1.73 (m, 4H), 2.09-2.11 (m, 1H), 2.52-2.55 (m, 1H), 2.82 (s, 6H), 2.83 (s, 3H), 3.06-3.15 (m, 2H), 3.53 (q, J= 7.2 Hz, 6H), 3.74 10 3.75 (m, 4H), 3.86-3.89 (m, 2H), 4.04-4.16 (m, 5H), 5.70 (s, 1H), 5.98 (m, 1H), 6.50 (d, J= 3.0 Hz, 1H), 6.93 (d, J= 8.7 Hz, 2H), 7.45 (d, J= 8.7 Hz, 2H), 7.83 (d, J= 8.7 Hz, 1H). HRMS (ES) Calc'd for C 38
H
64
N
3 0 6 S: 690.4516. Found: 690.4548. Example 12 15 (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3 methoxyphenyl)-2-methyl-1,2-benzothiazepin-4-ol 1,1-dioxide WO 00/47568 PCT/USOO/02503 304 0 0~>~ S-N N O H 0 The procedures set forth in Example 1 above were followed except that 3-methoxybenzyl chloride was substituted for 3-nitrobenzyl chloride. 'H NMR was consistent with the product. 'H NMR (CDCl 3 )6 0.90-0.97 (m, 6H), 1.17 1.38 (m, 8H),1.69-1.73 (m, 2H), 2.04-2.08 (m, 1H), 2.55-2.62 (m, 1H), 2.81 5 (s, 6H), 2.84 (s, 3H), 3.82 (s, 3H), 4.15 (d, J= 7.8 Hz, 1H), 5.72 (s, 1H), 6.01 (d, J= 2.4 Hz, 1H), 6.50 (dd, J= 2.4, 8.4 Hz, 1H), 6.86-6.89 (m, 1H), 7.05 (br s, 1H), 7.13-7.16 (m, 1H), 7.32 (t, J= 8.1 Hz, 1H), 7.83 (d, J= 8.7 Hz, 1H). MS (M+H+) 489. 0 O // N OH N O 0 WO 00/47568 PCT/US0O/02503 305 Example 13 (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl) 1,2-benzothiazepin-4-ol 1,1-dioxide and (4S,5R)-3,3-dibutyl-7 (dimethylamino)-2, 3 ,4,5-tetrahydro-5-(3-nitrophenyl)-1,2-benzothiazepin-4-ol 5 1,1-dioxide 0_ // SNH N SOH N + 0~ 0 Step 1. N-[i-Butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methylpentyl]- 4 (dimethylamino)-2-[(3-nitrophenyl)methyl]benzenesulfonamide Bu Bu SO NH SO2 OTBDMS NO 2 To a solution of 2.0 g (4.25 mmol) of the material prepared in Step 4 of Example 1 above in 10 mL of tetrahydrofuran cooled to 0 *C was added 8.0 10 mL of 1.6 M n-butyllithium in hexane. The reaction mixture was stirred at 0 IC for 30 minutes. To the reaction mixture was added 1.9 mL of trimethyl WO 00/47568 PCT/USOO/02503 306 borate and the mixture stirred 10 minutes at 0 'C and then one hour at room temperature. To the reaction mixture was added 100 mL of water and 5% hydrochloric acid to bring the solution to a pH of 6-7 and then the volatiles were evaporated. To the aqueous solution was added 100 mL of ethyl acetate 5 and the solution extracted. The ethyl acetate layer was washed with water (100 mL) and brine (100 mL), dried over magnesium sulfate and concentrated to form a residue. The residue was dissolved in 7 mL of ethanol and degassed with nitrogen. In a separate flask was placed 150 mg of tetrakis(triphenylphosphine)palladium(0), 10 mL of toluene and 918 mg of 3 10 nitrobenzaldehyde. The ethanol solution was added to the toluene solution followed by 10 mL of 1 M aqueous sodium carbonate. The reaction mixture was heated to reflux for one hour, cooled to room temperature, and then stirred for 16 hours. The reaction mixture was concentrated and dissolved in 100 mL of ethyl acetate. The ethyl acetate solution was washed with water (100 mL) 15 and brine (100 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated to form a residue. The residue was purified by flash chromatography to give 1.72 g of N-[1-butyl-1-[[[(1 dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(3 nitrophenyl)methyl]benzenesulfonamide. 20 Step 2. N-[l-Butyl-1-(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(3 nitrophenyl)methyl]benzenesulfonamide BU Bu CHO N NO 2 WO 00/47568 PCTIUSO0/02503 307 The procedure of Step 8 of Example 1 was followed except that N-[1 butyl- 1-[[[(1 -dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4 (dimethylamino)-2-[(3-nitrophenyl)methyl]benzenesulfonamide was used in place of N-[1-butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4 5 (dimethylamino)-2-[(3-nitrophenyl)methyl]-N-methylbenzenesulfonamide. Step 3. N-[l1-Butyl-1-formylpentyl]-4-(dimethylamino)-2-[(3-nitrophenyl) methyl]benzenesulfonamide Bu Bu SO 2NH OH NO 2 To a solution of 79 pL of oxalyl chloride in 2 mL of dichloromethane cooled to -78 *C was added 107 pL of dimethylsulfoxide and the mixture 10 stirred 20 minutes. To the cooled reaction mixture was added a solution of 370 mg (0.75 mmol) of the alcohol from Step 2 above in 2 mL of dichloromethane and the mixture was stirred one hour at -78 'C. To the cooled reaction mixture was added 660 pL of diisopropylethylamine. The reaction mixture was warmed to room temperature and stirred for 30 minutes. 15 To the reaction mixture was added 100 mL of water and mixture was extracted with dichloromethane (2 x 50 mL). The combined dichloromethane layers were washed with brine (50 mL), dried over magnesium sulfate and concentrated to give 0.47 g of a yellow oil. The residue was dissolved in 25 mL of 25% ethyl acetate in hexane and filtered through silica and 20 concentrated. The residue was crystallized with ethyl acetate and hexane to WO 00/47568 PCT/USOO/02503 308 give 301.6 mg of N-[ 1 -butyl- 1 -formylpentyl]-4-(dimethylamino)-2-[(3 nitrophenyl)methyl]benzenesulfonamide as a yellow solid. Step 4. (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3 nitrophenyl)-1,2-benzothiazepin-4-o1 1,1-dioxide and (4S,5R)-3,3-dibutyl-7 5 (dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-1,2-benzothiazepin-4-ol 1,1-dioxide To a solution of 150 mg (0.31 mmol) of the material prepared in Step 3 above in 6 mL of tetrahydrofuran cooled to -15 'C was added 0.90 mL 1 M of potassium t-butoxide in tetrahydrofuran. The reaction mixture was stirred for 10 15 minutes at -15 'C and then water was added. The organics were evaporated and 100 mL of ethyl acetate was added and then extracted. The ethyl acetate layer was washed with brine (100 mL), dried over magnesium sulfate and concentrated to form a residue. The residue was purified by flash chromatography with 30% ethyl acetate in hexane as eluent to give 61.8 mg of 15 (4S,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl) 1,2-benzothiazepin-4-ol 1,1-dioxide, and 65.7 mg of (4R,5R)-3,3-dibutyl-7 (dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-1,2-benzothiazepin-4-ol 1,1-dioxide. 1H NMR and mass spectra were consistent with the product. Example 14 20 (4R,5R)-5-(3-aminophenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro 1,2-benzothiazepin-4-ol 1,1-dioxide WO 00/47568 PCT/USOO/02503 309 00 0K // S -N H N 0 H
NH
2 The procedure of Example 2 above was followed except that (4R,5R) 3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-1,2 benzothiazepin-4-ol 1,1 -dioxide was used in place of (4R,5R)-3,3-dibutyl-7 (dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-2-methyl-1,2 5 benzothiazepin-4-ol 1,1-dioxide. 'H NMR was consistent with the product. MS (M*) 460. Example 15 5-bromo-N-[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4 hydroxy-1,1-dioxido-1,2-benzothiazepin-5-yl)phenyl]pentanamide 10 0 0 N OH 0 N B r
H
WO 00/47568 PCT/USOO/02503 310 The procedure of Example 3 above was followed except that (4R,5R) 5-(3-aminophenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-1,2 benzothiazepin-4-ol 1,1-dioxide was used in place of (4R,5R)-5-(3 aminophenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-2-methyl-1,2 5 benzothiazepin-4-ol 1,1-dioxide. 'H NMR was consistent with the product. MS (M+H+) 623. Example 16 5-[[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy 1,1 -dioxido- 1, 2 -benzothiazepin-5-yl]phenyl]amino]-N,N,N-triethyl-5-oxo- 1 10 pentanaminium trifluoroacetate S-NH N O H 0I N N + CF aC0O H To a solution of 54.1 mg (0.09 mmol) of the bromide prepared in Example 15 above in 1 mL of tetrahydrofuran was added 48 ptL of triethylamine. The reaction mixture was heated at reflux for three days. The solvent was evaporated and the residue triturated with ether. The solid was 15 purified by reverse phase high pressure liquid chromatography to give 17.9 mg of 5-[[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4 hydroxy- 1,1 -dioxido- 1, 2 -benzothiazepin-5-yl]phenyl]amino] -NN,N-triethyl- WO 00/47568 PCT/USOO/02503 311 5-oxo-1-pentanaminium trifluoroacetate as a white solid. 'H NMR was consistent with the product. MS (M*) 643. Example 17 (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-phenyl-1,2 5 benzothiazepin-4-ol 1,1-dioxide 0 //0 S-NH N OH Step 1-2. N-[1-Butyl-1-(hydroxymethyl)pentyl]-4-(dimethylamino)-2 (phenylmethyl)benzenesulfonamide Bu Bu SO NH S2 -\ OH N The procedure of Steps 1-2 of Example 7 was followed except that N [1 -butyl- 1-[[[(1,1 dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4 10 (dimethylamino)benzenesulfonamide and benzyl chloride were used in place of N-[1 -butyl-1-[[[(1,1 dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4 (dimethylamino)-N-methylbenzenesulfonamide and p-methoxybenzyl WO 00/47568 PCT/USOO/02503 312 chloride. Step 3. N-[l-Butyl-1-formylpentyl]-4-(dimethylamino)-2-(phenylmethyl) benzenesulfonamide Bu Bu SO NH 2 CHO -N The procedure of Step 3 of Example 13 was followed except that N-[1 5 butyl-1-(hydroxymethyl)pentyl]-4-(dimethylamino)-2-(phenylmethyl) benzenesulfonamide was used in place of N-[1-butyl-1-(hydroxymethyl) pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]benzenesulfonamide. Step 4. (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-phenyl 1,2-benzothiazepin-4-ol 1,1-dioxide 10 The procedure Step 4 of Example 7 was followed except that N-[1 Butyl-1-formylpentyl]-4-(dimethylamino)-2-(phenylmethyl) benzenesulfonamide was used in place of N-[1-butyl-1-formylpentyl]-4 (dimethylamino)-2-[(4-methoxyphenyl)methyl]-N-methylbenzene sulfonamide. 'H NMR (CDCl 3 ) 8 0.9 (m, 6H), 1-1.7 (m, 13H), 2.3 (m, 1H), 15 2.8 (s, 6H), 4.0 (s, 2H), 5.5 (s, 1H), 5.9 (s, 1H), 6.5 (m, 1H), 7.4 (m, 3H), 7.5 (m, 2H), 7.8 (m, 1H). MS (M+H+) 445.0.
WO 00/47568 PCT/USOO/02503 313 Example 18 (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4 methoxyphenyl)-1,2-benzothiazepin-4-ol 1,1-dioxide O K S -NH N OH 0 Step 1. N-[1-Butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4 5 (dimethylamino)-2-[( 4 -methoxyphenyl)methyl]benzenesulfonamide Bu Bu S02NH O 2 N OTBDMS N 0 The procedure of Step 1 of Example 7 was followed except that N-[1 butyl-1-[[[(1,1dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4 (dimethylamino)benzenesulfonamide was used in place of N-[1-butyl-1 [[[(1,1 dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-N 10 methylbenzenesulfonamide.
WO 00/47568 PCT/USOO/02503 314 Step 2. N-[1-Butyl-1-(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(4 methoxyphenyl)methyl]benzenesulfonamide Bu Bu SO NH O -N 0 The procedure of Step 8 of Example 1 was followed except that N-[1 butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4 5 (dimethylamino)-2-[(4-methoxyphenyl)methyl]benzenesulfonamide was used in place of N-[1-butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl] pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N-methylbenzene sulfonamide. Step 3. N-[l-Butyl-1-formylpentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl) 10 methyl]benzenesulfonamide Bu Bu SO NH7CHO N2 CHO -N 0 WO 00/47568 PCTIUSOO/02503 315 The procedure of Step 3 of Example 13 was followed except that N-[l butyl- 1 -(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl) methyl]benzenesulfonamide was used in place of N-[1-butyl-1-[[[(1 dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(3 5 nitrophenyl)methyl]-N-methylbenzenesulfonamide. Step 4. (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4 methoxyphenyl)-1,2-benzothiazepin-4-ol 1,1-dioxide The procedure of Step 10 of Example 1 was followed except that N-[1 butyl-1-formylpentyl]-4-(dimethylamino)-2-[(4-methoxyphenyl)methyl] 10 benzenesulfonamide was used in place of N-[1-butyl-1-formylpentyl]-4 (dimethylamino)-2-[(3-nitrophenyl)methyl]-N-methylbenzenesulfonamide. 'H NMR (CDC1 3 ) 80.89-1.00 (m, 6H), 1.06-1.73 (m, 11H), 2.36 (t, J= 9.5 Hz, 1H), 2.80 (s, 6H), 2.98 (s, 1H), 3.85 (s, 3H), 3.97 (s, 1H), 4.03 (d, J= 9.0 Hz, 1H), 5.47 (s, 1H), 6.00 (d, J= 2.4 Hz, 1H), 6.50 (dd, J= 2.6, 8.9 Hz, 1H), 6.95 15 (d, J= 8.8 Hz, 2H), 7.44 (d, J= 8.5 Hz, 2H), 7.81 (d, J= 8.7 Hz, 1H). Example 19 (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4 hydroxyphenyl)-1,2-benzothiazepin-4-ol 1,1-dioxide S -NH N OH O H WO 00/47568 PCT/USOO/02503 316 The procedure set forth in Example 8 above was followed except that (4R,5R) 3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-methoxyphenyl)-1,2 benzothiazepin-4-ol 1,1-dioxide was used in place of (4R,5R)-3,3-dibutyl-7 (dimethylamino)-2,3,4,5-tetrahydro-5-(4-hydroxyphenyl)-2-methyl-1,2 5 benzothiazepin-4-ol 1,1-dioxide and a reaction temperature of 0 *C was employed. 'H NMR (CDCl 3 ) 5 0.86-0.97 (m, 6H), 1.15-1.75 (m, 1 1H), 2.35 (t, J= 9.9 Hz, 1H), 2.80 (s, 6H), 3.98 (s, 1H), 4.02 (d, J= 8.6 Hz, 1H), 5.12 (s, 1H), 5.45 (s, 1H), 5.98 (d, J= 2.4 Hz, 1H), 6.48 (dd, J= 2.6, 8.6 Hz, 1H), 6.88 (d, J= 8.8 Hz, 2H), 7.38 (d, J= 8.1 Hz, 2H), 7.80 (d, J= 8.7 Hz, 1H). 10 Example 20 2-[2-[2-[4-[(4R,5R)-3,3-dibutyl-7- (dimethylamino)-2,3,4,5-tetrahydro-4 hydroxy-1,1-dioxido-1,2-benzothiazepin-5-yl]phenoxy]ethoxy]ethoxy]-N,N,N triethylethanaminium iodide S -NH N OH 0 00 WO 00/47568 PCT/USOO/02503 317 Step 1 0 // S-NH N \O H 0 H . 0 0 0 N + The procedure set forth in Example 9 above was followed except that (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4 5 hydroxyphenyl)-1,2-benzothiazepin- 4 -ol 1,1-dioxide was used in place of (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-(((2 iodoethyoxy)ethoxy)ethoxy)phenyl)-2-methyl-1,2-benzothiazepin-4-ol 1,1 dioxide and 3.3 equivalents of 95% sodium hydride was used instead of 2.2 equivalents. IH NMR was consistent with the product. 10 Step 2. 2-[2-[2-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro 4-hydroxy-1,1-dioxido-1,2-benzothiazepin-5-yl]phenoxy]ethoxy]ethoxy] N,N,N-triethylethanaminium iodide The procedure set forth in Example 10 above was followed except that the benzothiazepine prepared in Step 1 above was used. 'H NMR (CDCl 3 ) 6 15 0.88-0.05 (m, 6H), 1.14-1.60 (in, 20H), 2.31-2.39 (m, 1H), 2.82 (s, 6H), 3.06- WO 00/47568 PCT/USOO/02503 318 3.15 (m, 2H), 3.54 (q, J= 7.3 Hz, 6H), 3.75-3.81 (m, 4H), 3.88-4.17 (m, 7H), 5.47 (s, 1H), 5.98-6.02 (m, 1H), 6.47-6.54 (m, 1H), 6.93-6.98 (m, 2H), 7.42 7.47 (m, 2H), 7.81-7.84 (m, 1H). Example 21 5 (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl) 2-(phenylmethyl)-1,2-benzothiazepin-4-o 1,1-dioxide 0 " 0 S-N N SOH N O 0 Step 1. N-[1-Butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4 (dimethylamino)-2-[(3-nitrophenyl)methyl]-N-(phenylmethyl) benzenesulfonamide Bu Bu SO N SO2N OH
NO
2 WO 00/47568 PCT/USOO/02503 319 To a solution of 4.24 g (7.0 mmol) of the sulfonamide prepared in Step 1 of Example 13 in 30 mL of acetone was added 2.90 g of potassium carbonate, 0.517 g of tetra-n-butylammonium iodide then 2.394 g of benzyl bromide. The reaction mixture was heated at reflux for five days. To the 5 reaction mixture was added 2.394 g of benzyl bromide, 0.517 g of tetra-n butylammonium iodide, and then 2.90 g of powdered potassium carbonate. The reaction mixture was heated at reflux for one day. To the reaction mixture 250 mL of ethyl acetate was added. The ethyl acetate solution was washed with water (3 x 100 mL) and brine (200 mL). The ethyl acetate layer was 10 dried over magnesium sulfate and concentrated to a residue. The residue was purified by flash chromatography to give 1.82 g of N-[1-butyl-1-[[[(1 dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(3 nitrophenyl)methyl]-N-(phenylmethyl)benzenesulfonamide. Step 2. N-[l-Butyl-1-(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(3 15 nitrophenyl)methyl]-N-(phenylmethyl)benzenesulfonamide Bu Bu so2N CHO 7 I
NO
2 The procedure of Step 8 of Example 1 was followed except that N-[1 butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4 (dimethylamino)-2-[(3-nitrophenyl)methyl]-N-(phenylmethyl) benzenesulfonamide was used in place of N-[1-butyl-1-[[[(1- WO 00/47568 PCT/USOO/02503 320 dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(3 nitrophenyl)methyl]-N-methylbenzenesulfonamide. Step 3. N-[1-Butyl-1-formylpentyl]-4-(dimethylamino)-2-[(3 nitrophenyl)methyl]-N-(phenylmethyl)benzenesulfonamide SO N OTBDMS N NO 2 5 The procedure of Step 3 of Example 13 was followed except that N-[1 Butyl-1-(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(3-nitrophenyl) methyl]-N-(phenylmethyl)benzenesulfonamide was used in place of N-[1 butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4 (dimethylamino)-2-[(3-nitrophenyl)methyl]benzenesulfonamide. 10 Step 4. (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3 nitrophenyl)-2-(phenylmethyl)-1,2-benzothiazepin-4-ol 1,1-dioxide The procedure of Step 10 of Example 1 was followed except that N-[1 butyl-1-fonnylpentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N (phenylmethyl)benzenesulfonamide was used in place of N-[1-butyl-1 15 formylpentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N methylbenzenesulfonamide. 'H NMR was consistent with the product. MS (M+H*) 580.
WO 00/47568 PCT/USOO/02503 321 Example 22 (4R,5R)-3,3-dibutyl-7-(dimethylamino)-5-[3-(ethylamino)phenyl]-2,3,4,5 tetrahydro-2-(phenylmethyl)-1,2-benzothiazepin-4-ol 1,1-dioxide /0 OSIO S-N N OH N H To a solution of 50 mg (0.09 mmol) of the compound prepared in Step 5 4 of Example 21 in 50 mL ethanol was added about 10 mg of Pearlman's Catalyst. This mixture was hydrogenated at 60 psi H 2 for 20 hours. To the reaction mixture was added about 10 mg of Pearlman's Catalyst and the mixture was hydrogenated at 60 psi at 60 *C for 20 hours. The reaction mixture was filtered and washed with 50 mL of ethyl acetate. The filtrate was 10 washed with water (2 x 50 mL) and brine (50 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated to give 39.8 mg of a residue. The residue was purified by flash chromatography to give 12.6 mg of (4R,5R)-3,3-dibutyl-7-(dimethylamino)-5-[3-(ethylamino)phenyl]-2,3,4,5 tetrahydro-2-(phenylmethyl)-1,2-benzothiazepin-4-ol 1,1-dioxide. 'H NMR 15 (CDCl 3 ) 6 0.72 (t, J= 6.6, 3H), 0.90 (t, J= 7.4 Hz), 1.00-1.98 (in, 15H), 2.81 (s, 6H), 3.17 (q, J= 7.2 Hz, 2H), 4.15 (d, J= 7.8 Hz, 1H), 4.39 (s, 2H), 5.69 (s, 1H), 6.12 (s, 1H), 6.47 (dd, J= 2.7, 9.0 Hz, 1H), 6.61-6.65 (in, 1H), 6.78 6.83 (in, 1H), 6.95-7.00 (in, 1H), 7.16-7.31 (in, 5H), 7.40 (d, J= 7.2 Hz, 1H), 7.81 (d, J= 8.7 Hz, 1H). MS (M+H+) 578.
WO 00/47568 PCT/USOO/02503 322 Example 23 (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4 methoxyphenyl)-2-(phenylmethyl)-1,2-benzothiazepin-4-ol 1,1-dioxide 0 //
S
N O H 0 Step 1. N-[1-Butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4 5 (dimethylamino)-2-[(4-methoxyphenyl)methyl]-N (phenylmethyl)benzenesulfonamide Bu Bu SO N -N
O
WO 00/47568 PCT/USOO/02503 323 To a solution of 2.15 g (4.05 mmol) of the sulfonamide prepared in Step 1 of Example 7 above in 30 mL of dimethylformamide was added 123 mg of 95% sodium hydride and then 964 tL of benzyl bromide. The reaction mixture was stirred 18 hours. To the reaction mixture was added 250 mL of 5 ethyl acetate and the mixture was washed with saturated sodium bicarbonate solution (100 mL) and brine (150 mL). The ethyl acetate layer was dried over magnesium sulfate and concentrated to give 2.88 g of N-[1-butyl-1-[[[(1 dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(4 methoxyphenyl)methyl]-N-(phenylmethyl)benzenesulfonamide. 10 Step 2. N-[1-Butyl-1-(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(4 methoxyphenyl)methyl]-N-(phenylmethyl)benzenesulfonamide Bu Bu SO2N OTBDMS N 0 The procedure of Step 8 of Example 1 was followed except that N-[1 butyl- 1 -[[[(1 -dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4 15 (dimethylamino)-2-[(4-methoxyphenyl)methyl]-N (phenylmethyl)benzenesulfonamide was used in place of N-[ 1 -butyl- 1 -[[[(1 dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-2-[(3 nitrophenyl)methyl]-N-methylbenzenesulfonamide. Step 3. N-[1-Butyl-1-formylpentyl]-4-(dimethylamino)-2-[(3- WO 00/47568 PCT/USOO/02503 324 nitrophenyl)methyl]-N-(phenylmethyl)benzenesulfonamide Bu Bu SO 2N CHO N 0 The procedure of Step 3 of Example 13 was followed except that N-[1 butyl- 1 -(hydroxymethyl)pentyl]-4-(dimethylamino)-2-[(4 methoxyphenyl)methyl]-N-(phenylmethyl)benzenesulfonamide was used in 5 place of N-[1-butyl-1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4 (dimethylamino)-2-[(3-nitrophenyl)methyl]-N-methylbenzenesulfonamide. Step 4. (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4 methoxyphenyl)-2-(phenylmethyl)-1,2-benzothiazepin-4-ol 1,1-dioxide 10 The procedure of Step 10 of Example 1 was followed except that N-[1 butyl-1-formylpentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N (phenylmethyl)benzenesulfonamide was used in place of N-[1-butyl-1 formylpentyl]-4-(dimethylamino)-2-[(3-nitrophenyl)methyl]-N methylbenzenesulfonamide. 'H NMR (CDCl 3 ) 6 0.7 (m, 3H), 0.9 (m, 3H), 1 15 1.7 (m, 10H), 1.9 (m, 1H), 2.1 (m, 1H), 2.8 (s, 6H), 3.8 (s, 3H), 4.1 (s, 1H), 4.4 (s, 2H), 5.8 (s, 1H), 6.0 (s, 1H), 6.5 (m, 1H), 7.0 (d, J= 8 Hz, 1H), 7.1-7.5 (m, 7H), 7.8 (m, 1H).
WO 00/47568 PCT/US00/02503 325 Example 24 (4R,5R)-7-dimethylamino)-2-ethyl-4,5-dihydro-5-(4-methoxyphenyl) spiro[1,2-benzothiazepine-3(2H),1'-cyclopentan]-4-ol 1,1-dioxide
SO
2 N Me 2 N OH MeO Step 1. N-[1 -(hydroxymethyl)cyclopentyl]-4-fluorobenzenesulfonamide Hs OH SO N F0 2 F 5 The procedure of Step 2 of Example 1 was followed except that cycloleucinol was substituted for 2-amino-2-butylhexanol. Step 2-3. N-[1-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]cyclopentyl]-4 (dimethylamino)benzenesulfonamide HS OTBDMS N 2 N s N The procedure of Steps 3 and 4 of Example 1 was followed except that WO 00/47568 PCT/USOO/02503 326 N-[1 -(hydroxymethyl)cyclopentyl]-4-fluorobenzenesulfonamide was used in place of N-[ 1 -butyl- 1 -(hydroxymethyl)pentyl]-4-fluorobenzenesulfonamide. Step 4. N-[1-[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]cyclopentyl]-4 (dimethylamino)-2-[(4-methoxyphenyl)methyl]-N-methylbenzenesulfonamide H OTBDMS SO N > 2 N 5 0 The procedure of Step 1 of Example 7 was followed except that N-[1 [[[(1,1 -dimethylethyl)dimethylsilyl]oxy]methyl]cyclopentyl]-4 (dimethylamino)benzenesulfonamide was used in place of N-[1-butyl-1 [[[(1,1 dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4-(dimethylamino)-N 10 methylbenzenesulfonamide. Step 5. N-[1-(hydroxymethyl)cyclopentyl]-4-(dimethylamino)-2-[(4 methoxyphenyl)methyl]-N-ethylbenzenesulfonamide SOTBDMS S O 2N So2N N 0 WO 00/47568 PCT/USOO/02503 327 To a solution of 0.25 g (0.49 mmol) of the sulfonamide prepared in Step 4 above in 5 mL of tetrahydrofuran was added 25 mg of 95% sodium hydride. After 15 minutes, 125 pL of ethyl iodide was added to the reaction mixture. The reaction mixture was stirred 16 hours. To the reaction mixture 5 was added 5 mL of dimethylformamide and the mixture stirred four hours. To the reaction mixture 100 mL of water was added and the mixture extracted with 100 mL of ethyl acetate. The ethyl acetate layer was washed with brine (100 mL), dried over magnesium sulfate and concentrated to give 0.27g of an oil. 10 Step 6-8. (4R,5R)-7-dimethylamino)-2-ethyl-4,5-dihydro-5-(4 methoxyphenyl)-spiro[1,2-benzothiazepine-3(2H),1'-cyclopentan]-4-ol 1,1 dioxide The procedure of Steps 8-10 of Example 1 was followed except that N [1 -(hydroxymethyl)cyclopentyl]-4-(dimethylamino)-2-[(4 15 methoxyphenyl)methyl]-N-ethylbenzenesulfonamide was used in place of N [1-butyl-1 -[[[(1-dimethylethyl)dimethylsilyl]oxy]methyl]pentyl]-4 (dimethylamino)-2-[(3-nitrophenyl)methyl]-N-methylbenzenesulfonamide. IH NMR was consistent with product. MS (M+H*) 445. Biological Assays 20 The utility of the compounds of the present invention is shown by the following assays. These assays are performed in vitro and in animal models essentially using a procedure recognized to show the utility of the present invention. In Vitro Assay Of Compounds That Inhibit IBAT-Mediated Uptake Of ["Cl 25 Taurocholate (TC) in H14 Cells Baby hamster kidney cells (BHK) transfected with the cDNA of WO 00/47568 PCT/USOO/02503 328 human IBAT (H14 cells) are seeded at 60,000 cells/well in 96 well Top-Count tissue culture plates for assays run within 24 hours of seeding; 30,000 cells/well for assays run within 48 hours; and 10,000 cells/well for assays run within 72 hours. 5 On the day of assay, the cell monolayer is gently washed once with 100 mL assay buffer (Dulbecco's Modified Eagle's medium with 4.5 g/L glucose + 0.2% (w/v) fatty acid free bovine serum albumin ((FAF)BSA). To each well 50 mL of a two-fold concentrate of test compound in assay buffer is added along with 50 mL of 6 mM ["C]-taurocholate in assay buffer (final 10 concentration of 3 mM ["C]-taurocholate). The cell culture plates are incubated two hours at 370 C prior to gently washing each well twice with 100 mL of 4* C Dulbecco's phosphate-buffered saline (PBS) containing 0.2% (w/v) (FAF)BSA. The wells are then gently washed once with 100 mL of 40 C PBS without (FAF)BSA. To each 200 mL of liquid scintillation counting fluid is 15 added, the plates are heat sealed and shaken for 30 minutes at room temperature prior to measuring the amount of radioactivity in each well on a Packard Top-Count instrument. In Vitro Assay Of Compounds That Inhibit Uptake Of r'Cl-Alanine The alanine uptake assay is performed in an identical fashion to the 20 taurocholate assay, with the exception that labeled alanine is substituted for the labeled taurocholate. Data from each of the noted compounds in this assay is as set forth in Table 4 below: WO 00/47568 PCT/USOO/02503 329 Table 4 COMPOUND HUMAN TC IC 50 ALANINE UPTAKE (EXAMPLE (pM) IC 50 NUMBER) 5 1 1.2 2 0.32 3 0.69 4 0.083 >100 5 0.97 10 6 0.32 7 0.57 8 0.58 10 0.31 11 0.20 15 12 1.2 13 (cis) 0.044 13 (trans) 0.21 14 0.006 15 0.022 20 16 0.0016 17 0.035 18 0.026 19 0.003 >100 20 0.008 25 21 >1.0 22 2.5 24 13.9 WO 00/47568 PCT/USOO/02503 330 In Vivo Assay Of Compounds That Inhibit Rat Ileal Uptake Of ["'Cl Taurocholate into Bile (See "Metabolism of 3a,7 dihydroxy-7p-methyl-5 -cholanoic acid and 3a,7 -dihydroxy-7a-methyl-5 -cholanoic acid in hamsters" in Biochimica et 5 Biophysica Acta 833 (1985) 196-202 by Une et al.) Male wistar rats (200-300 g) are anesthetized with inactin @100 mg/kg. Bile ducts are cannulated with a 10 " length of PE10 tubing. The small intestine is exposed and laid out on a gauze pad. A canulae (1/8" luer lock, tapered female adapter) is inserted at 12 cm from the junction of the small intestine 10 and the cecum. A slit is cut at 4 cm from this same junction (utilizing a 8 cm length of ileum). 20 mL of warm Dulbecco's phosphate buffered saline, pH 6.5 (PBS) is used to flush out the intestine segment. The distal opening is cannulated with a 20 cm length of silicone tubing (0.02" I.D. x 0.037" O.D.). The proximal cannulae is hooked up to a peristaltic pump and the intestine is 15 washed for 20 minutes with warm PBS at 0.25 mL/minute. Temperature of the gut segment is monitored continuously. At the start of the experiment, 2.0 mL of control sample ([' 4 C]-taurocholate @ 0.05 mi/mL with 5 mM cold taurocholate) is loaded into the gut segment with a 3 mL syringe and bile sample collection is begun. Control sample is infused at a rate of 0.25 20 mL/minute for 21 minutes. Bile samples fractions are collected every three minutes for the first 27 minutes of the procedure. After the 21 minutes of sample infusion, the ileal loop is washed out with 20 mL of warm PBS (using a 30 mL syringe), and then the loop is washed out for 21 minutes with warm PBS at 0.25 mL/minute. A second perfusion is initiated as described above 25 but with the test compound being administered as well (21 minutes administration followed by 21 minutes of wash out) and bile sampled every three minutes for the first 27 minutes. If necessary, a third perfusion is performed as above that typically contains the control sample.
WO 00/47568 PCT/US0O/02503 331 Measurement Of Hepatic Cholesterol Concentration (HEPATIC CHOL) Liver tissue is weighed and homogenized in chloroform:methanol (2:1). After homogenization and centrifugation the supernatant is separated and dried under nitrogen. The residue is dissolved in isopropanol and the cholesterol 5 content is measured enzymatically, using a combination of cholesterol oxidase and peroxidase, as described by Allain, C. A., et al. (1974) Clin. Chem. 20, 470. Measurement Of Hepatic HMG CoA-Reductase Activity (HMG COA) Hepatic microsomes are prepared by homogenizing liver samples in a 10 phosphate/sucrose buffer, followed by centrifugal separation. The final pelleted material is resuspended in buffer and an aliquot is assayed for HMG CoA reductase activity by incubating for 60 minutes at 370 C in the presence of 14 C-HMG-CoA (Dupont-NEN). The reaction is stopped by adding 6N HCl followed by centrifugation. An aliquot of the supernatant is separated, by thin 15 layer chromatography, and the spot corresponding to the enzyme product is scraped off the plate, extracted and radioactivity is determined by scintillation counting. (Reference: Akerlund, J. and Bjorkhem, I. (1990) J. Lipid Res. 31, 2159). Determination Of Serum Cholesterol (SER.CHOL, HDL-CHOL, TGI and 20 VLDL + LDL) Total serum cholesterol (SER.CHOL) is measured enzymatically using a commercial kit from Wako Fine Chemicals (Richmond, VA); Cholesterol C11, Catalog No. 276-64909. HDL cholesterol (HDL-CHOL) is assayed using this same kit after precipitation of VLDL and LDL with Sigma 25 Chemical Co. HDL Cholesterol reagent, Catalog No. 352-3 (dextran sulfate method). Total serum triglycerides (blanked) (TGI) are assayed enzymatically with Sigma Chemical Co. GPO-Trinder, Catalog No. 337-B. VLDL and LDL WO 00/47568 PCT/USOO/02503 332 (VLDL + LDL) cholesterol concentrations are calculated as the difference between total and HDL cholesterol. Measurement Of Hepatic Cholesterol 7-a Hydroxylase Activity (7a-OHase) Hepatic microsomes are prepared by homogenizing liver samples in a 5 phosphate/sucrose buffer, followed by centrifugal separation. The final pelleted material is resuspended in buffer and an aliquot is assayed for cholesterol 7-a-hydroxylase activity by incubating for 5 minutes at 370 C in the presence of NADPH. Following extraction into petroleum ether, the organic solvent is evaporated and the residue is dissolved in acetonitrile/ 10 methanol. The enzymatic product is separated by injecting an aliquot of the extract onto a C 18 reversed phase HPLC column and quantitating the eluted material using UV detection at 240nm. (Reference: Horton, J. D., et al. (1994) J. Clin. Invest. 93, 2084). Rat Gavage Assay 15 Male Wister rats (275-300g) are administered IBAT inhibitors using an oral gavage procedure. Drug or vehicle (0.2% Tween 80 in water) is administered once a day (9:00-10:00 a.m.) for four days at varying dosages in a final volume of 2 mL per kilogram of body weight. Total fecal samples are collected during the final 48 hours of the treatment period and analyzed for 20 bile acid content using an enzymatic assay as described below. Compound efficacy is determined by comparison of the increase in fecal bile acid (FBA) concentration in treated rats to the mean FBA concentration of rats in the vehicle group. Table 5 describes the results of this assay when the compound of Example 4 was tested.
WO 00/47568 PCT/USOO/02503 333 Table 5 COMPOUND DOSE (mg/kg/day) % INCREASE IN (EXAMPLE FECAL BILE ACID 5 NUMBER) CONCENTRATION 4 5 217.2 4 0.4 157.8 4 0.04 244.0 Measurement Of Fecal Bile Acid Concentration (FBA) 10 Total fecal output from individually housed hamsters is collected for 24 or 48 hours, dried under a stream of nitrogen, pulverized and weighed. Approximately 0.1 gram is weighed out and extracted into an organic solvent (butanol/water). Following separation and drying, the residue is dissolved in methanol and the amount of bile acid present is measured enzymatically using 15 the 3a-hydroxysteroid steroid dehydrogenase reaction with bile acids to reduce NAD. (Reference: Mashige, F., et al. (1981) Clin. Chem. 27, 1352).
[
3 H1taurocholate Uptake in Rabbit Brush Border Membrane Vesicles (BBMV) Rabbit Ileal brush border membranes are prepared from frozen ileal mucosa by the calcium precipitation method described by Malathi et al. 20 (Reference: (1979) Biochimica Biophysica Acta, 554, 259). The method for measuring taurocholate is essentially as described by Kramer et al. (Reference: (1992) Biochimica Biophysica Acta, 1111, 93) except the assay volume is 200 pL instead of 100 tL. Briefly, at room temperature a 190 pL solution containing 2pM [ 3 H]-taurocholate(0.75 ptCi), 20 mM tris, 100 mM NaCl, 100 25 mM mannitol pH 7.4 is incubated for 5 seconds with 10 tL of brush border membrane vesicles (60-120 jig protein). The incubation is initiated by the addition of the BBMV while vortexing and the reaction is stopped by the WO 00/47568 PCT/USOO/02503 334 addition of 5 mL of ice cold buffer (20 mM Hepes-tris, 150 mM KCl) followed immediately by filtration through a nylon filter (0.2 pim pore) and an additional 5 mL wash with stop buffer. Acyl-CoA: cholesterol Acyl Transferase (ACAT) 5 Hamster liver and rat intestinal microsomes are prepared from tissue as described previously (Reference: (1980) J. Bio. Chem. 255, 9098) and used as a source of ACAT enzyme. The assay consists of a 2.0 mL incubation containing 24 pM Oleoyl-CoA (0.05 pCi) in a 50 mM sodium phosphate, 2 mM DTT ph 7.4 buffer containing 0.25 % BSA and 200 pg of microsomal 10 protein. The assay is initiated by the addition of oleoyl-CoA. The reaction proceeds for five minutes at 370 C and is terminated by the addition of 8.0 mL of chloroform/methanol (2:1). To the extraction is added 125 jig of cholesterol oleate in chloroform methanol to act as a carrier and the organic and aqueous phases of the extraction are separated by centrifugation after 15 thorough vortexing. The chloroform phase is taken to dryness and then spotted on a silica gel 60 TLC plate and developed in hexane/ethyl ether (9:1). The amount of cholesterol ester formed is determined by measuring the amount of radioactivity incorporated into the cholesterol oleate spot on the TLC plate with a Packard instaimager. The examples herein can be repeated 20 with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples. The invention being thus described, it is apparent that the same can be varied in many ways. Such variations are not to be regarded as a departure 25 from the spirit and scope of the present invention, and all such modifications and equivalents as would be obvious to one skilled in the art are intended to be included within the scope of the following claims.

Claims (166)

1. A compound of formula (I): 0 S - N S 1 2 R 55 (RR) Re 10 R' wherein: q is an integer from 1 to 4; 15 R and R2 are independently selected from the group consisting of hydrogen and hydrocarbyl, wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group 20 consisting of oxygen, nitrogen, sulfur and phosphorus; R3 and R 4 are independently selected from the group consisting of hydrogen; hydrocarbyl; -OR 9 ; -NR 9 R 1 0 ; -SR 9 ; -S(O)R 9 ; -S02R 9 ; and S03R 9 ; or R3 and R 4 together form =0; =NOR 9 ; =S; =NNR 9 R 10 ; =NR 9 ; or 25 =CR1R12. wherein R9 and R10 are independently selected from the group consisting of hydrogen; hydrocarbyl; amino; and hydrocarbylamino; wherein said hydrocarbyl moeities may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl 30 moieties optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; and WO 00/47568 PCT/USOO/02503 336 wherein R 1 and R12 are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; hydrocarbyl; -OR 9 ; -NR 9 R 10 . 35 SR 9 ; -S(O)R 9 ; -S02R 9 ; and -S03R 9 ; wherein said hydrocarbyl moeities may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl moieties optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; 40 or R 1 1 and R 12 together with the carbon atom to which they are attached form a cyclic ring; and R5 and R 6 are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary 45 heterocyclyl; -OR 9 ; -SR 9 ; -S(O)R 9 ; -S02R 9 ; and -S03R 9 . wherein the R5 and R 6 radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -N02; -CN; oxo; hydrocarbyl; -OR 13 -NR 13 Rl 4 ; -SR 1 3; -S(O)R 1 3 ; S02R 13 ; -S03R 1 3 1 4 -M13NR14RR15; -C02R 1 3 ; -OM; 50 S020M; -S02NR 13 R 1 4 ; -C(O)NR 1 3 R 1 4 ; -C(O)OM; -COR 1 3 . NRI 3 C(O)R"; -NR 3 C(O)NRM R- 5 ; -NR' 3 C0 2 R 14 ; -OC(O)R 13 ; -OC(O)NR1 3 R1 4 ; -NR1 3 SOR1 4 ; -NR 1 'SO 2 R1 4 ; -NR 3 SONR1 4 R"; -NR' 3 SO 2 NR1 4 R1 5 ; -PR 13 RI4- P(O)R 13 R- 1 4 -P+R 13 R 14 R 15 A~; -P(OR 13 )OR 14 ; -S+R 13 R 14 A; and N+R13R 14R 15A~; wherein said hydrocarbyl may be optionally substituted 55 with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; wherein R", R", and R' 5 are independently selected from the group 60 consisting of hydrogen or hydrocarbyl, wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; or 65 wherein R 3 and R 14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally WO 00/47568 PCT/USOO/02503 337 substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein RI4 and R15 together with the nitrogen atom to which they 70 are attached form a cyclic ring; and wherein A~ is a pharmaceutically acceptable anion, and M is a pharmaceutically acceptable cation; and wherein R 9 is as defined above; or R 4 and R 6 together represent a bond; and 75 RN is selected from the group consisting of hydrogen and hydrocarbyl, wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, 80 nitrogen, sulfur and phosphorus; one or more RX radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -N02; hydrocarbyl; -OR 13 NR 1 3 R 1 4 ; -SR 13 ; -S(O)R 1 3 ; -S(O)2R 1 3 ; -S03R 1 3 ; _+R13R 4A-; NR 13 0R 1 4 ; -NR 13 NR 14 R 1 5 ; -C02R 1 3 ; -OM; -SO2OM; -S02NR 1 3 RI 4 - 85 NR"C(O)R"; -C(O)NR 13 RI 4 ; -C(O)OM; -COR 13 ; -S(O)nNR 13 R14; N+R 1 3 Rl 4 R 15 A~; -PR 13 R14; -P(O)R 1 3 RI4; -P+R 13 Rl 4 R 15 A~; amino acid residue; peptide residue; polypeptide residue; and carbohydrate residue, wherein said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein said hydrocarbyl 90 optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus; and wherein n is 0, 1 or 2; and wherein R", R1 4 , R', A~, and M are as defined above; or 95 a pharmaceutically acceptable salt, solvate, or prodrug thereof; and provided that at least one of R 1 , R2, R 3 , R 4 , R 5 , and R 6 is a radical other than hydrogen or alkyl; and provided that when R 5 or R 6 is aryl, the other of R 5 and R 6 is a radical other than heterocycylalkyl. 100 WO 00/47568 PCT/USOO/02503 338
2. A compound of claim 1 wherein: q is an integer from 1 to 4; RI and R2 are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; heterocyclyl; 5 arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl; or Ri and R2 taken together with the carbon to which they are attached 10 form C 3 -Cio cycloalkyl or C 3 -C 10 cycloalkenyl; wherein the Ri and R2 alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; 15 alkylaryl; and (polyalkyl)aryl radicals optionally may be substituted with one or more radicals selected from the group consisting of -CN; halogen; oxo; OR 9 ; -NR 9 R 10 ; -N+R 9 RlORwA~; -SR 9 ; -S*R 9 R' 0 A-; -PR 9 R 10 P+R 9 RlORwA~; -S(O)R 9 ; -S02R 9 ; -S03R 9 ; -C02R 9 ; and -CONR 9 R 1 0 ; and wherein the Ri and R2 alkyl; cycloalkyl; alkenyl; cycloalkenyl; 20 alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may have one or more carbons replaced by -0-; -NR 9 -; -N+R 9 R 1 0 A-; -S-; -SO-; -SO2-; -S+R 9 A 25 PR 9 -; -P(O)R 9 -; -P+R 9 R 1 0 A--; or phenylene; and wherein R 9 , R 1 0 , and Rw are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; alkylammoniumalkyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl; carboalkoxyalkyl; carboxyaryl; carboxyheterocyclyl; amino; alkylamino; 30 carboxyalkylamino; alkoxyalkylamino; and acyl; and wherein A~ is a pharmaceutically acceptable anion; and R 3 and R 4 are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; -OR 9 ; -NR 9 R 10 ; -SR 9 ' S(O)R9; -SO2R 9; and -SO3R 9; or WO 00/47568 PCT/US0O/02503 339 35 R3 and R 4 together form =0; =NOR 9 ; =S; =NNR 9 R 1 o- =NR 9 ; or =CRI IR 12 ; wherein RI I and R12 are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl; 40 carboalkoxyalkyl; cycloalkyl; cycloalkenyl; haloalkyl; hydroxyalkyl; cyanoalkyl; -OR 9 ; -NR 9 R 1 0 ; -SR 9 ; -S(O)R 9 ; -S02R 9 ; -S03R 9 ; -C02R 9 and -CONR 9 R 10 ; or Ri and R 12 together with the carbon atom to which they are attached form a cyclic ring; and 45 wherein R 9 and R 0 are as defined above; and R 5 and R6 are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; -OR 9 ; -SR 9 ; -S(O)R9; -SO2R9; and -SO3R9' wherein the R 5 and R 6 alkyl; cycloalkyl; alkenyl; alkynyl; aryl; 50 heterocyclyl; and quaternary heterocyclyl radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -CN; -N02; oxo; alkyl; polyalkyl; haloalkyl; hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR 13 . -NR 1 3 Rl4- 55 SR13; -S(O)R 1 3 ; -S02R 1 3 313 _NR 13 0R 1 4 - -NR13N14R15. C02R 1 3 ; -OM; -SO2OM; -S02NR 13 Rl 4 ; -C(O)NR 13 RI 4 ; -C(O)OM; COR 13 ; -NR' 3 C(O)R"; -NRC(O)NR' 4 R 15 ; -NR"C0 2 R1 4 ; -OC(O)R; OC(O)NR 3 R1 4 ; -NR 3 SOR 4 ; -NR' 3 S0 2 R 4 ; -NR 3 SONR 4 R1 5 ; NR1 3 SO 2 NR1 4 R"; -PR 13 RI 4 ; -P(O)R 13 R 14 ; -P+R 1 3 R 14 R 15 A~; 60 P(OR 1 3 )OR 1 4 ; -S+R 13 R 14 A~; and -N+R 13 R 4 R 1 5 A~; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the R' and R 6 radicals optionally may be further substituted with one or more radicals selected from 65 the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR 7 ; -NR 7 R 8 ; -SR7; -S -S2R 7 ; -SO3R7;- C02R 7 ; CONR 7 R 8 ; -N+R 7 R 8 R 9 A-; -P(O)R7R8; -PR -R8 _P+R 7 R 8 R 9 A~; and P(O)(OR 7 )OR 8 ; and WO 00/47568 PCT/USOO/02503 340 70 wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the R' and R 6 radicals optionally may have one or more carbons replaced by -0-; -NR -; -N+R 7 R8A -; -S-; -SO-; -SO2-; -S+RA--; -PR 7 -; -P(O)R 7 - -P+R 7 R 8 A-; or phenylene; 75 and wherein R 7 and R 8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R 1 3 , R 1 4 , and R 15 are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; 80 alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminoalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or 85 wherein R" and R1 4 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R 1 and R15 together with the nitrogen atom to which they 90 are attached form a cyclic ring; and wherein the R 1 3 , R , and R 1 5 alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminoalkyl; 95 aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl; hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary 100 heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl; -OR 16 ; -NR 9 R 1 0 . _ N+R 9 R 1 ORwA~; -SR 1 6 ; -S(O)R 9 ; -S02R 9 ; -S03R 16 ; -C02R 1 6 CONR 9 R 1 0 ; -S02NR 9 R 10 ; -PO(OR 16 )OR' 7 - P 9 R ' -P+R 10 P+ R 1 0 R 1 1 A- S+R 9 R 1 A-; and carbohydrate residue; and WO 00/47568 PCT/USOO/02503 341 wherein the R 1 3 , R 1 4 , and R alkyl; haloalkyl; cycloalkyl; polyalkyl; 105 alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminoalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have 110 one or more carbons replaced by -0-; -NR 9 -; -N+R 9 R 1 0 A--; -S-; -SO-; -S02-; -S+R 9 A--; -PR 9 -; -P+R 9 R10A--; -P(O)R 9 -; phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R 16 and R 1 7 are independently selected from the group consisting of R 9 and M; and 115 wherein M is a pharmaceutically acceptable cation; and wherein R 9 , R1 0 , R", R1 2 , Rw, and A~ are as defined above; and RN is selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aralkyl; and heterocyclylalkyl; and one or more Rx radicals are independently selected from the group 120 consisting of hydrogen; halogen; -CN; -N02; alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; acyloxy; -OR 13. NR 13 R 14 ; -SR13; -S(O)R 13 ; -S(O)2R 1 3 ; -S03R 13 ;_+R13R14A-; NR13OR ; -NR1 R15; -CO2R1; -OM; -S02OM; -SO2NR 13 R 14 - 125 NR 4 C(O)R1 3 ; -C(O)NR 1 3 R 14 ; -C(O)OM; -COR 1 3 ; -OR 18 _ S(O)nNR13R14 -NR 13 R 1 8 -NR 18 0R 1 4 ; 15A~; -PR13R14 P(O)R 1 3 R 14 ; -P+R 13 R 1 4 R 1 5 A~; amino acid residue; peptide residue; polypeptide residue; and carbohydrate residue; wherein the Rx alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; 130 alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; acyloxy radicals optionally may be further substituted with one or more radicals selected from the group consisting of halogen; -CN; oxo; -OR 16 _ NR 9 R 1 0 ; -N+R 9 RI0RwA~; -SR 1 6 ; -S(O)R9; -SO2R9; -SO3R16; -CO2R 16 CONR 9 R 1 0 ; -S02NR 9 R 1 0 ; -PO(OR1 6 )OR 17 ; -P 9 R 10 ; -P+R 9 R 1 1 R 12 A~; 135 S+R 9 R 10 A; and carbohydrate residue; and wherein the RX quaternary heterocyclyl radical optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; -N02; oxo; alkyl; cycloalkyl; polyalkyl; haloalkyl; WO 00/47568 PCT/USOO/02503 342 hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; 140 heterocyclylalkyl; polyether; -OR 13 -NR 13 R 1 4 ; -SR 13 ; -S(O)R 1 3 ; -S02R 1 3 . -SO3R13- -NR 13 0R 1 4 - -NR13N14R5 ; -CO2R 1 3 ; OM; -SO2OM; S02NR 13 RI 4 ; -C(O)NR 13 R 1 4 ; -C(O)OM; -COR 13 ; -P(O)R 13 R 1 4 - p13R 14; -P+R13R14R15A~; -P(OR1 3 )OR 1 4 ; -S+R 13 R 14 A; N+R 1 3 RI 4 R 1 5 A; and carbohydrate residue; and 145 wherein the RX radicals comprising carbon optionally may have one or more carbons replaced by -0-; -NR 13 -; -N+R 1 3 R 14 A--; -S-; -SO-; -SO2-; S+R 13 A-; -PR 13 -; -P(O)R 13 -; -PR 1 3 R 14 ; -P+R 13 R1 4 A--; phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; polyether; or polyalkyl; wherein said phenylene; amino acid residue; peptide 150 residue; polypeptide residue; carbohydrate residue; and polyalkyl optionally may have one or more carbons replaced by -0-; -NR 9 -; -N+R 9 R 10 A~-; -S-; SO-; -S02-; -S+R 9 A--; -PR 9 -; -P+R9R'OA--; or -P(O)R 9 -; and wherein R 1 8 is selected from the group consisting of alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; 155 heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl; and wherein the R" alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl radicals optionally may 160 be substituted with one or more radicals selected from the group consisting of halogen; -CN ; NO 2 ; oxo; -OR 9 ; -NR 9 R 10 ; -N+R 9 R I R 12 A~; -SR 9 ' S(O)R 9 ; -S02R 9 ; -S03R 9 ; -C02R 9 ; -CONR 9 R 1 0 ; -S02OM; -S02NR 9 R 10 . -PR 9 R 10 ; -P(OR 13 )OR 14 ; -PO(OR 16 )OR 1 7 ; and -C(O)OM; and wherein R 9 , R1 0 , R", R, R, R, R' 5 , R, R, R", A, and M are as 165 defined above;or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
3. A compound of claim 1 wherein: q is an integer from 1 to 4; Ri and R 2 are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; arylalkyl; alkoxyalkyl; 5 alkoxyalkenyl; alkoxyalkynyl; alkylaryl; and (polyalkyl)aryl; or WO 00/47568 PCT/USOO/02503 343 R and R2 taken together with the carbon to which they are attached form C 3 -Cio cycloalkyl or C 3 -Cio cycloalkenyl; wherein the Ri and R 2 alkyl; cycloalkyl; alkenyl; alkynyl; arylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; alkylaryl; and (polyalkyl)aryl 10 radicals optionally may be substituted with one or more radicals selected from the group consisting of -CN; halogen; oxo; -OR 9 ' -NR 9 R 1 0 ; -N+R 9 RlORwA~ ; -SR9; -S*R 9 R 0 A~; -PR 9 R 10 . -P+R 9 R10RA~; -S(O)R9; -S02R 9 ; -S03R 9 - C02R 9 ; and -CONR 9 R 10 ; and wherein the RI and R2 alkyl; cycloalkyl; alkenyl; alkynyl; arylalkyl; 15 alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may have one or more carbons replaced by -0-; -NR 9 -; N+R9R'OA--, -S-; -SO-; -S02-; -S+R 9 A--, -PR 9 -; -P(O)R 9 -; -P+R 9 R 10 A--, or phenylene; and wherein R , R 1 0 , and Rw are independently selected from the group 20 consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; alkylammoniumalkyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; carboalkoxyalkyl; carboxyheterocyclyl; carboxyalkylamino; and acyl; and wherein A~ is a pharmaceutically acceptable anion; and R3 and R 4 are independently selected from the group consisting of 25 hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; -OR 9 ; -NR 9 R 1 0 ; -SR 9 S(O)R 9 ; -S02R 9 ; and -S03R 9 ; or R3 and R 4 together form =0; =NOR 9 ; =S; =NNR 9 R 10 ; =NR 9 ; or =CRI IR 12 ; wherein RI I and R 12 are independently selected from the group 30 consisting of hydrogen; -CN; halogen; oxo; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; carboxyalkyl; carboalkoxyalkyl; cycloalkyl; cyanoalkyl; -OR 9 ; -NR 9 R1 0 ; -SR 9 ; -S(O)R 9 ; -S02R 9 ; -S03R 9 ; -C02R 9 . and -CONR 9 R 1 0 ; or R I I and R 12 together with the carbon atom to which they are attached 35 form a cyclic ring; and wherein R 9 and R' 0 are as defined above; and R5 and R 6 are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; -OR 9 ; -SR 9 ; -S(O)R 9 ; -S02R 9 ; and -S03R 9 ; WO 00/47568 PCT/USOO/02503 344 40 wherein the R 5 and R 6 alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; and quaternary heterocyclyl radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -CN; -N02; oxo; alkyl; polyalkyl; haloalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; 45 arylalkyl; heterocyclylalkyl; polyether; -OR 13 -NR 1 3 RI 4 ; -SR 13 ; -S(O)R 1 3 . -S02R 1 3 ; -S03R 1 3 ; -NR 1 3 0R 14 ; -N 13 NR 14 R 1 5 ; -C02R 1 3 ; -OM; SO2OM; -S02NR 1 3 R 1 4 ; -C(O)NR 1 3 R 14 ; -C(O)OM; -COR 13 . NR1 3 C(O)R"; -NR' 3 C(O)NR 4 R 5 ; -NR1 3 C0 2 R1 4 ; -OC(O)R 3 ; -OC(O)NR1 3 R 4 ; -NR1 3 SOR1 4 ; -NR' 3 S0 2 R 14 ; -NR1 3 SONR 4 R"; -NR 3 SO 2 NR'R 5 ; -PR 13 R. 14 50 P(O)R 13 R 14 -P+R 1 3 R 1 4 R 15 A~; -P(OR 13 )OR 1 4 ; -S+R 13 R 14 A; and N+R 1 3 R 14 R 1 5A~; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the R' and R 6 radicals 55 optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR, -7R8; -SR7; -S(O)R 7 ; -SO2R7; -S03R 7 ;- C02R 7 ; CONR 7 R 8 ; -N+R 7 R 8 R 9 A-; -P(O)R 7 R 8 ; -PR 7 R 8 ; -P+R 7 R 8 R 9 A~; and 60 P(O)(OR 7 )OR 8 ; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the R' and R 6 radicals optionally may have one or more carbons replaced by -0-; -NR -; -N+R 7 R 8 A 65 -; -S-; -SO-; -S02-; -S+R 7 A--; -PR 7 -; -P(O)R 7 -; -P+R 7 R 8 A--; or phenylene; and wherein R 7 and R 8 are independently selected from the group consisting of hydrogen and alkyl; and wherein R 13 , R 14 , and R 15 are independently selected from the group 70 consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or WO 00/47568 PCT/USOO/02503 345 75 wherein R" and R1 4 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R 1 and R15 together with the nitrogen atom to which they 80 are attached form a cyclic ring; and R 13 , 14 and wherein the R1, R , and R alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; 85 alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; sulfoalkyl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl; -OR 16 ; -NR 9 R 1 0 ; -N+R 9 RlORwA~; -SR 16 . _ 90 S(O)R 9 ; -S02R 9 ; -SO3R16; -C02R 1 6 ; -CONR 9 R 10 ; -S02NR 9 R 1 0 . PO(OR 1 6 )OR 1 ; -PR 9 R 10 . -P+R 9 RIO R 1 A-; -S+R 9 R 1 0 A-; and carbohydrate residue; and wherein the R1, R , and R alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; 95 heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -0-; -NR 9 -; N+RAIOA--; -S-; -SO-; -SO 2 -; -S+R9A- -; -P+R 9 R 1 OA--; -P(O)R- 100 phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R 16 and R 17 are independently selected from the group consisting of R 9 and M; and wherein M is a pharmaceutically acceptable cation; and 105 wherein R 9 , R', R", R1 2 , R', and A~ are as defined above; and RN is selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; and aralkyl; and one or more Rx radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -N02; alkyl; cycloalkyl; polyalkyl; WO 00/47568 PCT/USOO/02503 346 110 haloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; polyether; acyloxy; -OR 13 ; -NR 13 R 1 4 ; -SR 13 ; -S(O)R13 _ S(O)2R 13 ; -S03R 1 3 ; -S+R 13 R 14 A-; -NR 13 0R 1 4 ; -NR 13 NR 1 4 R 1 5 CO2R 1 3 ; -OM; -S02OM; -S02NR 13 R 4 ; -NR"C(O)R; -C(O)NR 1 3 R 1 4 - C(O)OM; -COR 13 ; -OR 1 8 ; -S(O)nNR 13 R 1 4 ; -NR 1 3 R 1 8 -NR 1 8 0RI 4 115 N+R 13 Rl 4 R 15 A~; -PR 13 RI 4 ; -P(O)R 1 3 Rl 4 ; -P+R 13 Rl 4 R 1 5 A~; amino acid residue; peptide acid residue; polypeptide acid residue; and carbohydrate acid residue; wherein the R* alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; 120 and acyloxy radicals optionally may be further substituted with one or more radicals selected from the group consisting of halogen; -CN; oxo; -OR 16 . NR9R 1 0 ; -N+R 9 RlORwA-; -SR 1 6 ; -S(O)R 9 ; -S02R 9 ; -SO3R16; -CO2R 16 . _ CONR9RIO; -S02NR 9 R 1 0 ; -PO(OR 6 )OR"; -PR 9 R 1 0; -P+R 9 R 1 R 12 A; S +RA10A~; and carbohydrate residue; and 125 wherein the R* quaternary heterocyclyl radical optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; -N02; oxo; alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR 13 . _N13R 4; -SR13; -S(O)R 13 ; -S02R 1 3 . 130 -SO3R13; _N130R14- -M13N14R15; -CO2R 1 3 ; OM; -S02OM; S02NR 1 3 R 1 4 ; -C(O)NR 13 Rl 4 ; -C(O)OM; -COR 13 ; -P(O)R 1 3 R 1 4 ; PR 13 R 1 4 -P+R 1 3 R 14 R 1 5 A; -P(OR 13 )OR 1 4 ; -S+R 13 R 1 4 A; and N+R 1 3 R 1 4 R 1 5 A~; and carbohydrate residue; and wherein the RX radicals comprising carbon optionally may have one or 135 more carbons replaced by -0-; -NR 13 -; -N+R 13 R 14 A-; -S-; -SO-; -S02-; S+R 1 3 A~-; -PR 13 -; -P(O)R 13 -; -PR 13 -P+R 13 R 14 A--; phenylene; amino acid; peptide; polypeptide; carbohydrate; polyether; or polyalkyl; wherein said phenylene; amino acid; peptide; polypeptide; carbohydrate; and polyalkyl optionally may have one or more carbons replaced by -0-; -NR-; 140 N+R 9 R 1 0 A-; -S-; -SO-; -S02-; -S+R 9 A--; -PR 9 -; -P+R 9 R 1 0 A--; or -P(O)R 9 -; and wherein R18 is selected from the group consisting of alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; WO 00/47568 PCT/USOO/02503 347 heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and 145 heterocyclylalkoxycarbonyl; and wherein the R" alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl radicals optionally may be substituted with one or more radicals selected from the group consisting of 150 halogen; -CN ; oxo; -OR 9 ; -NR9R0; -N+R9R, 1R12A~; -SR 9 ; -S(O)R 9 - S02R 9 ; -S03R 9 ; -C02R 9 ; -CONR 9 R 10 ; -SO20M; -SO2NR 9 R 1 0 . PR9R10; -P(OR13)ORI4; -PO(OR 16)OR' ; and -C(O)OM; and wherein R 9 , R1 0 , R", R 2 , R', R", R1 5 ,R 6 , R R',A,andMareas defined above; or 155 a pharmaceutically acceptable salt, solvate, or prodrug thereof.
4. A compound of claim 1 wherein: q is an integer from 1 to 4; RI and R 2 are independently selected from the group consisting of hydrogen; (CI-CIO)alkyl; (C 3 -Clo)cycloalkyl; (C 2 -Clo)alkenyl; (C 2 -C o)alkynyl; 5 aryl(Cl-CIO)alkyl; (C-C 10 )alkoxy(C 1 -C 0 )alkyl; (C -Ci)alkoxy(C 2 -Cj 0 )alkenyl; (C -Ci)alkoxy(C 2 -Ci 0 )alkynyl; (CI-CIO)alkylaryl; and (polyalkyl)aryl; or R and R 2 taken together with the carbon to which they are attached form (C 3 -C 1 o)cycloalkyl; wherein the RI and R 2 (CI-CIO)alkyl; (C 3 -Cio)cycloalkyl; (C 2 10 CIO)alkenyl; (C 2 -C 1 o)alkynyl; aryl(CI-CIO)alkyl; (C 1 -Cj 0 )alkoxy(Ci-Ci 0 )alkyl; (Ci-Cj)alkoxy(C 2 -CI 0 )alkenyl; (C-C )alkoxy(C 2 -Cj)alkynyl; (Cl CIO)alkylaryl; and (polyalkyl)aryl radicals optionally may be substituted with one or more radicals selected from the group consisting of -CN; halogen; oxo; -OR 9 ; -NR 9 R 1 0 ; -N+R 9 R1oRwA~; -SR 9 ; -S*R 9 R'OA-; -PR 9 R 10 ; 15 P+R 9 R1 ORwA~; -S(O)R 9 ; -S02R 9 ; -SO3R 9 ; -C02R 9 ; and -CONR 9 R 1 0 ; and wherein the RI and R 2 (CI-CIO)alkyl; (C 3 -C 1 o)cycloalkyl; (C 2 CIO)alkenyl; (C 2 -C 1 o)alkynyl; aryl(CI-CIO)alkyl; (Ci-Cj 0 )alkoxy(C 1 -Cj 0 )alkyl; (C-C )alkoxy(C 2 -Cj)alkenyl; (C-Cj)alkoxy(C 2 -C )alkynyl; (C 1 C 1 o)alkylaryl; and (polyalkyl)aryl radicals optionally may have one or more 20 carbons replaced by -0-; -NR 9 -; -N+R 9 R 1 0 A--; -S-; -SO-; -S02-; -S+R 9 A- PR 9 ; -P(O)R9- -P+R 9 R 10 A--; or phenylene; and WO 00/47568 PCT/USOO/02503 348 wherein R 9 , R 10, and Rw are independently selected from the group consisting of hydrogen; (CI-CIO)alkyl; (C 3 -C 1 o)cycloalkyl; (C 2 -Cio)alkenyl; (C 2 -Cio)alkynyl; aryl; heterocyclyl; ammonium(CI-CIO)alkyl; (C 25 CIO)alkylammonium(CI-CIO)alkyl; aryl(CI-CIO)alkyl; heterocyclyl(C, CIO)alkyl; carboxy(CI-CIO)alkyl; carbo(CI-CIO)alkoxy(Ci-CIO)alkyl; carboxyheterocyclyl; carboxy(CI-CIO)alkylamino; and acyl; and wherein A~ is a pharmaceutically acceptable anion; and R 3 and R 4 are independently selected from the group consisting of 30 hydrogen; (Ci-CIO)alkyl; (C 2 -Clo)alkenyl; (C 2 -C 1 o)alkynyl; aryl; heterocyclyl; OR; -NR 9 R 10 ; -SR 9 ; -S(O)R9; -SO2R 9; and -S03R 9 ; or R3 and R4 together form =0; =NOR 9 ; =S; =NNR 9 R 10 . _ 9; or =CRI IR 12 ; wherein Ri and R12 are independently selected from the group 35 consisting of hydrogen; -CN; halogen; oxo; (CI-CIO)alkyl; (C 2 -Clo)alkenyl; (C 2 -Ci)alkynyl; aryl; heterocyclyl; aryl(CI-CIO)alkyl; carboxy(CI-CIo)alkyl; carbo(CI-CIO)alkoxy(CI-C o)alkyl; (C 3 -Clo)cycloalkyl; cyano(CI-CIO)alkyl; OR 9 ; -NR 9 R 10 ; -SR 9 ; -S(O)R 9 ; -S02R9; -S03R 9 ; -C02R 9 ; and CONR 9 R 1 0 ; or 40 Rl 1 and R12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R 9 and R' 0 are as defined above; and R 5 and R 6 are independently selected from the group consisting of hydrogen; (CI-CIO)alkyl; (C 3 -Cio)cycloalkyl; (C 2 -C o)alkenyl; (C 2 -Clo)alkynyl; 45 aryl; heterocyclyl; quaternary heterocyclyl; -OR 9 ; -SR 9 ; -S(O)R 9 ; -S02R 9 ; and -S03R 9 ; wherein the R 5 and R 6 (CI-CIO)alkyl; (C 3 -C 1 o)cycloalkyl; (C 2 C o)alkenyl; (C 2 -C O)alkynyl; aryl; heterocyclyl; and quaternary heterocyclyl radicals optionally may be substituted with one or more radicals independently 50 selected from the group consisting of halogen; -CN; -N02; oxo; (C 1 CIo)alkyl; polyalkyl; halo(C 1 -Cio)alkyl; (C 3 -Clo)cycloalkyl; (C 2 -C o)alkenyl; (C 2 -Clo)alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; aryl(Ci-CIO)alkyl; heterocyclyl(C-Clo)alkyl; polyether; -OR 1 3 -NR 1 3 R 1 ; -SR 1 3 ; -S(O)R 1 3 . S02R 1 3 ; -S03R 13 ; -NR 13 0R 14 ; -M 13 N 14 R 1 5 ; -C02R 1 3; -OM; 55 SO2OM; -S02NR 13 R 1 4 ; -C(O)NR 13 RI 4 ; -C(O)OM; -COR 13 . NR 3 C(O)R"; -NR1 3 C(O)NR' 4 R1 5 ; -NR"CO 2 R1 4 ; -OC(O)R"; -OC(O)NR 3 R 4 ; WO 00/47568 PCT/USOO/02503 349 -NRD SOR1 4 ; -NIRD 3 SO 2 R 4 ; -NR"SONR 4 R 5 ; -NR 3 SO 2 NR 4 R1 5 ; P(O)R 13 R 1 4 ; -PR1 3 R 14 -P+R 1 3 R 1 4 R 15 A~; -P(OR 1 3 )OR 1 4 ; -S+Rl 3 R 1 A ; and -N+R 1 3 R 14 R 1 5A~; and 60 wherein the (CI-CIO)alkyl, polyalkyl, halo(CI-Clo)alkyl, hydroxy(C CIO)alkyl, (C 3 -Clo)cycloalkyl, (C 2 -C 1 o)alkenyl, (C 2 -C 1 )alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, aryl(CI-CIO)alkyl, heterocyclyl(Cl CIO)alkyl, and polyether substituents of the R' and R 6 radicals optionally may be further substituted with one or more radicals selected from the group 65 consisting of -CN; halogen; hydroxy; oxo; (Ci-CIO)alkyl; (C 3 -CIO)cycloalkyl; (C 2 -Clo)alkenyl; (C 2 -Clo)alkynyl; aryl; heterocyclyl; aryl(CI-CIO)alkyl; heterocyclyl(C-CIO)alkyl; quaternary heterocyclyl; -OR 7 ; -NR 7 R 8 ; -SR 7 S(O)R 7 ; -S02R 7 ; -S03R 7 ;- C02R 7 ; -CONR 7 R 8 ; -N+R 7 R 8 R 9 A-; P(O)R 7 R 8 ; -PR 7 R 8 . -P+R7R8R9A~; and -P(O)(OR7)OR8; and 70 wherein the (CI-CIO)alkyl, polyalkyl, halo(CI-Cio)alkyl, hydroxy(C 1 CIO)alkyl, (C 3 -C 1 o)cycloalkyl, (C 2 -Clo)alkenyl, (C 2 -CIO)alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, aryl(C 1 -Cio)alkyl, heterocyclyl(Cl CIO)alkyl, and polyether substituents of the R' and R 6 radicals optionally may have one or more carbons replaced by -0-; -NR 7 -; -N+R 7 R 8 A--; -S-; -SO-; 75 SO2-; -S+R 7 A--; -PR -; -P(O)R -; -P+R 7 R 8 A--; or phenylene; and wherein R 7 and R 8 are independently selected from the group consisting of hydrogen and (C 1 -CIO)alkyl; and wherein R 13 , R , and R 1 5 are independently selected from the group consisting of hydrogen; (CI-CIO)alkyl; halo(C 1 -CIO)alkyl; (C 3 -C o)cycloalkyl; 80 polyalkyl; (C 2 -C 1 o)alkenyl; (C 2 -Cio)alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; aryl(CI-CIo)alkyl; heterocyclyl(C 1 -Cio)alkyl; quaternary heterocyclyl(C 1 -C 1 o)alkyl; (C-C 0 )alkylaryl(Cj-Cj)alkyl; (C CIO)alkylheterocyclyl(CI-C 1 o)alkyl; (CI-CIO)alkylammonium(Ci-CIO)alkyl; carboxy(CI-CIO)alkylaminocarbonyl(CI-C o)alkyl; and polyether; or 85 wherein R" and R1 4 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R14 and R15 together with the nitrogen atom to which they 90 are attached form a cyclic ring; and WO 00/47568 PCT/USO0/02503 350 wherein the R 1 3 , R 14 , and R 1 5 (C-CIO)alkyl; halo(C-CIO)alkyl; (C 3 CIO)cycloalkyl; polyalkyl; (C 2 -CIO)alkenyl; (C 2 -Cio)alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; aryl(C-CIO)alkyl; heterocyclyl(C-CIO)alkyl; quaternary heterocycly(C-CIO)alkyl; (C-Cio)alkylaryl (C-Cio)alkyl; (C 95 CIO)alkylheterocyclyl(C-CIO)alkyl; (C-CIO)alkylammonium(C-CIO)alkyl; aminocarbonyl(C-CIO)alkyl; (C-CIO)alkylaminocarbonyl(C-Cio)alkyl; carboxy(C-CIO)alkylaminocarbonyl (C-Cio)alkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; (C-CIO)alkyl; sulfo(C 100 CIO)alkyl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclyl(C CIO)alkyl; carboxy; carboxy(C-Cio)alkyl; guanidinyl; -OR 1 6 ; NR 9 RIO; N+R 9 RlORwA-; -SR 16 ; -S(O)R 9 ; -S02R 9 ; -SO3R 16 ; -CO2R 1 6 ; CONR 9 R 1 0 ; - -S02NR 9 R 1 0 ; -PO(OR 16 )OR 1 7 ; -PR9R10; -P+R9R1 A ; -S+R 9 R1OA-; and carbohydrate residue; and 105 wherein the R 13 , R 14 , and R 15 (C-CIO)alkyl; halo(C-Cio)alkyl; (C 3 CIO)cycloalkyl; polyalkyl; (C 2 -C 1 o)alkenyl; (C 2 -Cj 0 )alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; aryl(C-CIO)alkyl; heterocyclyl(C-Cio)alkyl; quaternary heterocyclyl(C-CIO)alkyl; (C-CIO)alkylaryl(C-CIO)alkyl; (C CIO)alkylheterocyclyl(C-Cio)alkyl; (C-CIO)alkylammonium(C-CIO)alkyl; 110 aminocarbonyl(C-CIO)alkyl; (C-CIO)alkylaminocarbonyl(C-CIO)alkyl; carboxy(C-CIO)alkylaminocarbonyl(C-CIO)alkyl; and polyether radicals optionally may have one or more carbons replaced by -0-; -NR'-; N+R 9 R 10 A--; -S-; -SO-; -S02-; -S+R9A--; -PR9; -P+R 9 R 1 0 A--; -P(O)R98 phenylene; carbohydrate residue; amino acid residue; peptide residue; or 115 polypeptide residue; and wherein R 1 6 and RI 7 are independently selected from the group consisting of R 9 and M; and wherein M is a pharmaceutically acceptable cation; and wherein R 9 , R1 0 , R", R1 2 , Rw, and A~ are as defined above; and 120 RN is selected from the group consisting of hydrogen; (C-CIO)alkyl; (C 2 -Clo)alkenyl; (C 2 -Clo)alkynyl; and aryl(C-CIO)alkyl; and one or more Rx radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -N02; (C-CIO)alkyl; (C 3 CIO)cycloalkyl; polyalkyl; halo(C-CIO)alkyl; (C 2 -Clo)alkenyl; (C 2 -C 1 o)alkynyl; 125 aryl; heterocyclyl; quaternary heterocyclyl; aryl(C-CIO)alkyl; polyether; WO 00/47568 PCT/USOO/02503 351 acyloxy; -OR 13 ; -NR 13 RI 4 ; -SR 13 ; -S(O)R 1 3 ; -S(O)2R 1 3 ; -SO3R1 3 . _ S+R 13 R 14 A; -NR13OR14- -N13NR 1 4 R 1 5 ; -C02R 1 3 ; -OM; -S02GM; S02NR 13 RI 4 ; -NR 4 C(O)R' 3 ; -C(O)NR 13 R 1 4 ; -C(O)OM; -COR 1 3; -OR18 -S(O)nNR 13 R 1 4 ; -NR 13 R 1 8 ; NR 1 8 0R 14 ; -N+R 1 3 Rl 4 R 1 5 A~; -PR 1 3 Rl 4 . 130 P(O)R 13 Rl 4 ; -P+R 13 R 14 R 15 A~; amino acid residue; peptide acid residue; polypeptide acid residue; and carbohydrate acid residue; wherein the Rx (CI-Cio)alkyl; (C 3 -Clo)cycloalkyl; polyalkyl; halo(Ci C 10 )alkyl; hydroxy(CI-CIO)alkyl; (C 2 -C o)alkenyl; (C 2 -Ci)alkynyl; aryl; heterocyclyl; aryl(CI-CIO)alkyl; heterocyclyl(CI-CIO)alkyl; polyether; and 135 acyloxy radicals optionally may be further substituted with halogen; -CN; oxo; -OR 16 ; -NR 9 R 1 0 ; -N+R 9 Rl 1 R 12 A~; -SR 1 6 ; -S(O)R 9 ; -S02R 9 ; -S03R 16 ; C02R 16 ; -CONR 9 R 1 0 ; -S02NR 9 R 10 ; -PO(OR 16 )OR"; -PR 9 R 1 0 . P+R 9 R 1 R 12 A~; or -S+R 9 R 0 A~; and wherein the Rx quaternary heterocyclyl radical optionally may be 140 substituted with one or more radicals selected from the group consisting of halogen; -CN; -N02; oxo; (CI-CIo)alkyl; (C 3 -Clo)cycloalkyl; polyalkyl; halo(Cl-CIO)alkyl; hydroxy(C 1 -CIo)alkyl; (C 2 -Cio)alkenyl; (C 2 -C 1 )alkynyl; aryl; heterocyclyl; aryl(CI-CIO)alkyl; heterocyclyl(CI-CIO)alkyl; polyether; OR 13 ; -NR 13 RI 4 ; -SR 13 ; -S(O)R 1 3 ; -S02R 13 ; -S03R 13 ; -NR 13 0R 14 ; 145 NR 1 3 NR 14 R 1 5 ; -C02R 1 3 ; -OM; -SO20M; -S02NR 13 RI4; -C(O)NR 13 R 1 4 -C(O)OM; -COR 13 ; -P(O)R13R14; -PR13R14; - P + R 1 1R 4 ;15A~; P(OR 1 3 )OR 1 4; -S+R1 R 14 A; and -N+R 1 3 Rl 4 R 15 A~; and wherein the RX radicals comprising carbon optionally may have one or more carbons replaced by -0-; -NR13-; -N+R13R 1A~-; -S-; -SO-; -S02-; 150 S+R 1 3 A~-; -PR13-; -P(O)R13-; -PR13_ -p+R13RA--; phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; polyether; or polyalkyl; wherein said phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; and polyalkyl optionally may have one or more carbons replaced by -0-; -NR 9 -; -N+R 9 RIOA~-; -S-; 155 SO-; -S02-; -S+R 9 A-; -PR9, -P+R9R'OA--; or -P(O)R 9 -; and wherein R 1 8 is selected from the group consisting of (CI-Cio)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(CI-C 1 O)alkyl; acyl; and aryl(Cl CIo)alkoxycarbonyl; and wherein the R" (CI-CIO)alkyl; heterocyclyl; quaternary heterocyclyl; 160 aryl(CI-C 1 O)alkyl; acyl; and aryl(CI-CIO)alkoxycarbonyl radicals optionally WO 00/47568 PCT/USOO/02503 352 may be substituted with one or more radicals selected from the group consisting of halogen; -CN; oxo; -OR 9 ; -NR 9 R 1 0 ; -N+R 9 RR 1 2 A~; -SR 9 S(O)R 9 ; -S02R 9 ; -S03R 9 ; -C02R 9 ; -CONR 9 R 1 0 ; -SO2OM; -S02NR 9 R 1 0 -PR9R10; -P(OR 1 3 )OR 1 4 ; -PO(OR 16 )OR 1 7 ; and -C(O)OM; and 165 wherein R 9 , R' 0 , R", R", R", R", R , R' 6 , R 7 , Rw, A, and M are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and provided that aryl is selected from the group consisting of optionally substituted phenyl, biphenyl and naphthyl; and 170 provided that heterocyclyl is selected from the group consisting of optionally substituted heterocyclyl comprising a 5 to 10 membered ring and comprising one or more ring atoms that are heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus.
5. A compound of claim 1 wherein: q is an integer from 1 to 4; Ri and R 2 are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert 5 butyl, pentyl, hexyl, phenoxymethylene, phenoxyethylene, phenoxypropylene, pyridinyloxymethylene, pyridinyloxyethylene; methylpyridinyloxymethylene, methylpyridinyloxyethylene, pyrimidinyloxymethylene, and pyrimidinyloxyethylene; or RI and R 2 taken together with the carbon to which they are attached 10 form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; and R 3 and R 4 are independently selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, phenyl, pyridinyl, amino, methylamino, dimethylamino, ethylamino and diethylamino; and R 5 and R 6 are independently selected from the group consisting of 15 hydrogen, phenyl, chlorophenyl, fluorophenyl, bromophenyl, iodophenyl, hydroxyphenyl, methoxyphenyl, ethoxyphenyl, methoxy(chlorophenyl), methoxy(fluorophenyl), methoxy(bromophenyl), methoxy(iodophenyl), ethoxy(chlorophenyl), ethoxy(fluorophenyl), ethoxy(bromophenyl), ethoxy(iodophenyl), nitrophenyl, aminophenyl, methylaminophenyl, 20 dimethylaminophenyl, ethylaminophenyl, diethylaminophenyl, trimethylammoniumphenyl, triethylammoniumphenyl, WO 00/47568 PCT/US0O/02503 353 trimethylammoniummethylcarbonylaminophenyl, triethylammoniummethylcarbonylaminophenyl, trimethylammoniumethylcarbonylaminophenyl, 25 triethylammoniumethylcarbonylaminophenyl, trimethylammoniumpropylcarbonylaminophenyl, triethylammoniumpropylcarbonylaminophenyl, trimethylammoniumbutylcarbonylaminophenyl, triethylammoniumbutylcarbonylaminophenyl, methylcarbonylaminophenyl, 30 chloromethylcarbonylaminophenyl, fluoromethylcarbonylaminophenyl, bromomethylcarbonylaminophenyl, iodomethylcarbonylaminophenyl, ethylcarbonylaminophenyl, chloroethylcarbonylaminophenyl, fluoroethylcarbonylaminophenyl, bromoethylcarbonylaminophenyl, iodoethylcarbonylaminophenyl, propylcarbonylaminophenyl, 35 chloropropylcarbonylaminophenyl, fluoropropylcarbonylaminophenyl, bromopropylcarbonylaminophenyl, iodopropylcarbonylaminophenyl, butylcarbonylaminophenyl, chlorobutylcarbonylaminophenyl, fluorobutylcarbonylaminophenyl, bromobutylcarbonylaminophenyl, iodobutylcarbonylaminophenyl, 3,4-dioxymethylenephenyl, pyridinyl, 40 methylpyridinyl, pyridinium, methylpyridinium, thienyl, chlorothienyl, fluorothienyl, bromothienyl, iodothienyl; methoxycarbonylphenyl, ethoxycarbonylphenyl, trimethylammoniumethoxyethoxyethoxyphenyl, triethylammoniumethoxyethoxyethoxyphenyl, chloroethoxyethoxyethoxyphenyl, fluoroethoxyethoxyethoxyphenyl, 45 bromoethoxyethoxyethoxyphenyl, iodoethoxyethoxyethoxyphenyl, pyridiniumethoxyethoxyethoxyphenyl, piperazinyloxymethoxyethoxyethoxyphenyl, methylpiperazinyloxymethoxyethoxyethoxyphenyl, dimethylpiperazinyloxymethoxyethoxyethoxyphenyl, 50 piperidinyloxymethoxyethoxyethoxyphenyl, methylpiperidinyloxymethoxyethoxyethoxyphenyl, and dimethylpiperidinyloxymethoxyethoxyethoxyphenyl; and RN is selected from the group consisting of hydrogen, methyl, ethyl, n propyl, n-butyl, n-pentyl, n-hexyl and benzyl; and 55 one or more Rx radicals are independently selected from the group consisting of hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, WO 00/47568 PCT/USO0/02503 354 tert-butyl, sec-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, methylthio, methylsulfinyl, methylsulfonyl, ethylthio, ethylsulfinyl, ethylsulfonyl, amino, hydroxyamino, methylamino, dimethylamino, ethylamino, diethylamino, 60 trimethylammonium, triethylammonium, N-methyl-N-carboxymethyl-amino, N,N-dimethyl-N-carboxymethyl-ammonium, methylcarbonylamino, chloromethylcarbonylamino, fluoromethylcarbonylamino, bromomethylcarbonylamino, iodomethylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, n-butylcarbonylamino, n-pentylcarbonylamino, n 65 hexylcarbonylamino, benzyloxycarbonylamino, aminoimidocarbonylamino, morpholinyl, N-methyl-morpholinium, azetidinyl, N-methyl-azetidinium, pyrrolidine, N-methyl-pyrrolidinium, piperazinyl, N-methylpiperazinyl, N,N' dimethyl-piperazinium, piperidinyl, methylpiperidinyl, N-methyl piperidinium, and thienyl; or 70 a pharmaceutically acceptable salt, solvate, or prodrug thereof.
6. A compound of claim 1 wherein: q is an integer from 1 to 4; RI and R 2 are independently selected from the group consisting of hydrogen and (C-Cio)alkyl; or 5 Ri and R 2 taken together with the carbon to which they are attached form (C 3 -Cio)cycloalkyl; and R3 and R 4 are independently selected from the group consisting of hydrogen and hydroxy; and R 5 is phenyl, wherein said phenyl is optionally substituted with one or 10 more radicals independently selected from the group consisting of halogen; hydroxy; -N02; (C-CIO)alkyl; halo(C-CIO)alkyl; aryl(C-CIO)alkyl; heterocyclyl(C-CIO)alkyl; polyether; -OR 13 ; -NR 13 RI 4 ; and -NR 13 C(O)R"; and wherein R 1 3 , R , and R are independently selected from the group 15 consisting of hydrogen; (C-CIO)alkyl; halo(C-CIO)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(C-CIO)alkyl; heterocyclyl(C-CIo)alkyl; quaternary heterocyclyl(C-CIO)alkyl; (C-Cio)alkylheterocyclyl(C-CIO)alkyl; (C-Cio)alkylammonium(C-Cio)alkyl; and polyether; or wherein the R13, R14, and R15 (C-Cio)alkyl; halo(C-Cio)alkyl; 20 heterocyclyl; quaternary heterocyclyl; aryl(C-C o)alkyl; heterocyclyl(C- WO 00/47568 PCT/USOO/02503 355 CIO)alkyl; quaternary heterocyclyl(Ci-CIO)alkyl; (Ci-C o)alkylheterocyclyl(Ci CIo)alkyl; (CI-CIO)alkylammonium(C 1 -C O)alkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; (Ci-Cio)alkyl; heterocyclyl; quaternary 25 heterocyclyl; quaternary heterocyclyl(Ci-CIO)alkyl; carboxy; carboxy(C CIO)alkyl; -OR 16 ; -NR 9 R 1 0 ; -N+R 9 RORwA~; and -CONR 9 R 10 ; and wherein R9 and Rio are independently selected from the group consisting of hydrogen; (CI-C o)alkyl; heterocyclyl; ammonium(CI-C 1 o)alkyl; (CI-CIO)alkylammonium(C 1 -Cio)alkyl; aryl(CI-CIO)alkyl; heterocyclyl(Cl 30 CIO)alkyl; carboxy(CI-CIO)alkyl; carbo(C-CIO)alkoxy(CI-Cio)alkyl; carboxyheterocyclyl; carboxy(C 1 -C 1 o)alkylamino; and acyl; and wherein A~ is a pharmaceutically acceptable anion; and wherein Ri 1 and R 12 are independently selected from the group consisting of hydrogen; (CI-CIO)alkyl; heterocyclyl; aryl(CI-CIO)alkyl; 35 carboxy(CI-CIO)alkyl; and carbo(CI-CIo)alkoxy(Ci-Cio)alkyl; or RI and R 12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R' and R 6 are as defined in claim 2; and R 6 is hydrogen; and 40 RN is selected from the group consisting of hydrogen; (CI-Cio)alkyl; and aryl(Cl-CIO)alkyl; and one or more Rx radicals are independently selected from the group consisting of hydrogen; -N02; (CI-CIO)alkyl; halo(CI-CIo)alkyl; -OR 1 3 ; _ NR 1 3 R14; 45 wherein R" and R1 4 are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and provided that aryl is selected from the group consisting of optionally substituted phenyl, biphenyl and naphthyl; and provided that heterocyclyl is selected from the group consisting of 50 optionally substituted heterocyclyl comprising a 5 to 10 membered ring and comprising one or more ring atoms that are heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus.
7. A compound of claim 1 wherein: 55 q is an integer from 1 to 4; WO 00/47568 PCTIUSOO/02503 356 Rl and R2 are independently selected from the group consisting of ethyl and n-butyl; or Ri and R2 taken together with the carbon to which they are attached form cyclopentyl; and 60 one of R3 and R4 is hydrogen and the other of R3 and R4 is hydroxy; and R5 is selected from the group consisting of phenyl, hydroxyphenyl, methoxyphenyl, ethoxyphenyl, nitrophenyl, aminophenyl, methylaminophenyl, dimethylaminophenyl, ethylaminophenyl, 65 diethylaminophenyl, trimethylammoniumphenyl, triethylammoniumphenyl, trimethylammoniummethylcarbonylaminophenyl, triethylammoniummethylcarbonylaminophenyl, trimethylanmmoniumethylcarbonylaminophenyl, triethylammoniumethylcarbonylaminophenyl, 70 trimethylammoniumpropylcarbonylaminophenyl, triethylammoniumpropylcarbonylaminophenyl, trimethylammoniumbutylcarbonylaminophenyl, triethylammoniumbutylcarbonylaminophenyl, methylcarbonylaminophenyl, chloromethylcarbonylaminophenyl, fluoromethylcarbonylaminophenyl, 75 bromomethylcarbonylaminophenyl, iodomethylcarbonylaminophenyl, ethylcarbonylaminophenyl, chloroethylcarbonylaminophenyl, fluoroethylcarbonylaminophenyl, bromoethylcarbonylaminophenyl, iodoethylcarbonylaminophenyl, propylcarbonylaminophenyl, chloropropylcarbonylaminophenyl, fluoropropylcarbonylaminophenyl, 80 bromopropylcarbonylaminophenyl, iodopropylcarbonylaminophenyl, butylcarbonylaminophenyl, chlorobutylcarbonylaminophenyl, fluorobutylcarbonylaminophenyl, bromobutylcarbonylaminophenyl, iodobutylcarbonylaminophenyl, trimethylammoniumethoxyethoxyethoxyphenyl, 85 triethylammoniumethoxyethoxyethoxyphenyl, chloroethoxyethoxyethoxyphenyl, fluoroethoxyethoxyethoxyphenyl, bromoethoxyethoxyethoxyphenyl, iodoethoxyethoxyethoxyphenyl, and pyridiniumethoxyethoxyethoxyphenyl; and R 6 is hydrogen; WO 00/47568 PCT/USOO/02503 357 90 RN is selected from the group consisting of hydrogen, methyl, ethyl, and benzyl; and one or more RX radicals are independently selected from the group consisting of hydroxy, methyl, ethyl, methoxy, ethoxy, amino, hydroxyamino, methylamino, dimethylamino, ethylamino, diethylamino, 95 trimethylammonium, triethylammonium, N-methyl-N-carboxymethyl-amino, N,N-dimethyl-N-carboxymethyl-ammonium, methylcarbonylamino, chloromethylcarbonylamino, fluoromethylcarbonylamino, bromomethylcarbonylamino, iodomethylcarbonylamino, ethylcarbonylamino, benzyloxycarbonylamino, and aminoimidocarbonylamino; or. 100 a pharmaceutically acceptable salt, solvate, or prodrug thereof
8. A compound of claim 1 selected from the compounds of the group consisting of: (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-2-methyl-5-(3 5 nitrophenyl)-1,2-benzothiazepin-4-o 1,1-dioxide; (4R,5R)-5-(3-aminophenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro 2-methyl-1,2-benzothiazepin-4-ol 1,1-dioxide; 10 5-chloro-N-[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4 hydroxy-2-methyl-1,1-dioxido-1,2-benzothiazepin-5-yl]phenyl]pentanamide; 5-[[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-2 methyl-1, 1 -dioxido- 1,2-benzothiazepin-5 -yl]phenyl] amino]-N,N,N-triethyl-5 oxo-pentanaminium trifluoroacetate; 2-chloro-N-[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4 hydroxy-2-methyl-1,1-dioxido-1,2-benzothiazepin-5-yl]phenyl]acetamide; 2-[[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino]-2,3,4,5-tetrahydro-4-hydroxy-2 methyl-1, 1 -dioxido- 1,2-benzothiazepin-5-yl]phenyl] amino] -N,N,N-triethyl-2 oxoethanaminium chloride; WO 00/47568 PCT/USOO/02503 358 (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4 methoxyphenyl)-2-methyl-1,2-benzothiazepin-4-ol 1,1-dioxide; (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4 hydroxyphenyl)-2-methyl-1,2-benzothiazepin-4-ol 1,1-dioxide; (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4-(((2 iodoethyoxy)ethoxy)ethoxy)phenyl)-2-methyl-1,2-benzothiazepin-4-ol 1,1 dioxide; 1-[2-[2-[2-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4 hydroxy-2-methyl-1,1-dioxido-1,2-benzothiazepin-5 yl]phenoxy]ethoxy]ethoxy]ethyl]pyridinium; 2-[2-[2-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4 hydroxy-2-methyl-1,1-dioxido-1,2-benzothiazepin-5 yl]phenoxy]ethoxy]ethoxy]-N,N,N-triethylethanaminium iodide; (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3 methoxyphenyl)-2-methyl-1,2-benzothiazepin-4-ol 1,1-dioxide; (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl) 1,2-benzothiazepin-4-ol 1,1-dioxide and (4S,5R)-3,3-dibutyl-7 (dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-1,2-benzothiazepin-4-ol 1,1-dioxide; (4R,5R)-5-(3-aminophenyl)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro 1,2-benzothiazepin-4-ol 1,1-dioxide; 5-bromo-N-[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4 hydroxy-1,1-dioxido-1,2-benzothiazepin-5-yl)phenyl]pentanamide; 5-[[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy 1,1 -dioxido- 1,2-benzothiazepin-5 -yl]phenyl]amino]-N,N,N-triethyl-5-oxo- 1 pentanaminium trifluoroacetate; WO 00/47568 PCT/US0O/02503 359 (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-phenyl- 1,2 benzothiazepin-4-ol 1,1-dioxide; (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4 methoxyphenyl)-1,2-benzothiazepin-4-ol 1,1-dioxide; (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4 hydroxyphenyl)-1,2-benzothiazepin-4-ol 1,1-dioxide; 2-[2-[2-[4-[(4R,5R)-3,3-dibutyl-7- (dimethylamino)-2,3,4,5-tetrahydro-4 hydroxy-1,1-dioxido-1,2-benzothiazepin-5-yl]phenoxy]ethoxy]ethoxy]-N,N,N triethylethanaminium iodide; (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-2 (phenylmethyl)-1,2-benzothiazepin-4-ol 1,1-dioxide; (4R,5R)-3,3-dibutyl-7-(dimethylamino)-5-[3-(ethylamino)phenyl]-2,3,4,5 tetrahydro-2- (phenylmethyl)-1,2-benzothiazepin-4-ol 1,1-dioxide; (4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-(4 methoxyphenyl)-2-(phenylmethyl)-1,2-benzothiazepin-4-ol 1,1-dioxide; and (4R,5R)-7-dimethylamino)-2-ethyl-4,5-dihydro-5-(4-methoxyphenyl) spiro[1,2-benzothiazepine-3(2H),1'-cyclopentan]-4-ol 1,1-dioxide; and their pharmaceutically acceptable salts.
9. A compound of claim 2 wherein R5 and R6 are independently selected from the group consisting of H; aryl; heterocyclyl; and quaternary heterocyclyl; wherein the R5 and R 6 aryl; heterocyclyl; and quaternary heterocyclyl 5 radicals optionally may be substituted with one or more radicals independently selected from the group consisting of halogen; -CN; -N02; oxo; alkyl; polyalkyl; haloalkyl; hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; - WO 00/47568 PCT/USOO/02503 360 OR 13 ; -NR13Rl4; -SR13; -S(O)R 1 3 ; -S02R 1 3 ; -S03R 13 ; _ 13 OR 1 4 - 10 NR 13 NR 1 4 R 1 5 ; -C02R 1 3 ; -OM; -SO2OM; -S02NR 1 3 R 1 4 ; -C(O)NR 13 R 1 4 . -C(O)OM; -COR 1 3 ; -NR 3 C(O)R"; -NR"C(O)NRR 5 ; -NR"C0 2 R; OC(O)R 13 ; -OC(O)NR"R 14 ; -NR1 3 SOR1 4 ; -NR 13 S0 2 R 14 ; -NR 13 SONRI 4 R"; NR 13 SO 2 NR' 4 R"; -PR 13 R 14 ; -P(O)R1 3 R 14 ; -PR 13 R 14 ; -P+R 1 3 R 1 4 R 1 5 A-; P(OR 13 )OR1 4 ; -S+R 1 3 R 14 A; and -N+R 13 R 14 R 15 A~; and 15 wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the R 5 and R 6 radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl; 20 alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR 7 ; -NR 7 R 8 ; -SR 7 ; -S(O)R 7 ; -S02R 7 ; -S03R 7 ;- C02R 7 . CONR 7R 8 ; -N+R 7 R 8 R 9 A-; -P(O)R 7 R 8 ; -PR 7 R 8 ; -P+R 7 R 8 R 9 A~; and P(O)(OR 7 )OR 8 ; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, 25 alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the R' and R 6 radicals optionally may have one or more carbons replaced by -0-; -NR 7 -; -N+R 7 R 8 A -; -S-; -SO-; -S02-; -S+R 7 A--; -PR 7 -; -P(O)R 7 - -P+R 7 R 8 A--; or phenylene; and 30 wherein R 7 and R 8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R 1 3 , R 14 , and R 1 5 are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; 35 heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or wherein R 13 and R1 4 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted 40 with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R 14 and R15 together with the nitrogen atom to which they are attached form a cyclic ring; and WO 00/47568 PCT/USOO/02503 361 wherein the R 1 3 , R 14 , and R 15 alkyl; haloalkyl; cycloalkyl; polyalkyl; 45 alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from 50 the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl; hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl; -OR 16 ; -NR 9 R 1 0 ; -N+R 9 RIORwA~; -SR 16 ; -S(O)R 9 ; -S02R 9 ; -S03R 16 . C02R 1 6; -CONR 9 R 1 0; -SO2NR 9 R 1 0; -PO(OR 16 )OR 1 7 ; -PR 9 R 1 0; 55 P+R 9 R 1 OR" A-; -S+R 9 R 1 0 A-; and carbohydrate residue; and wherein the R 1 3 , R , and R 1 5 alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; 60 alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -0-; -NR 9 -- N+R9RIOA--; -S-; -SO-; -SO 2 -; -S+R 9 A--; -PR 9 -; -P+R 9 R 10 A--; -P(O)R 9 -; phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and 65 wherein R 16 and Rl are independently selected from the group consisting of R 9 and M; and wherein M is a pharmaceutically acceptable cation; and wherein R 9 , R 10 , R", R1 2 , Rw, and A are as defined in claim 2.
10. A compound of claim 2 wherein R 5 or R 6 has the formula -Ar-(Ry), 5 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; WO 00/47568 PCTIUSOO/02503 362 10 pyrimidinyl; thiazolyl; triazolyl; isothiazolyl; indolyl; benzoimidazolyl; benzoxazolyl; benzothiazolyl; and benzoisothiazolyl; and one or more R are independently selected from the group consisting of halogen; -CN; -N02; oxo; alkyl; polyalkyl; haloalkyl; hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; 15 arylalkyl; heterocyclylalkyl; polyether; -OR 13 ; -NR13RI4; -SR13; -S(0)R13 -SO2R13; -SO3R13- -NR 13 0R 1 4 - -NR 1 3 NR 1 4 R 1 5 ; -C02R 1 3; -OM; -132R4 3 13S01R 13. SO2OM; -S02NR 1 3 R 1 4 ; -C(O)NR 13 R 14 ; -C(O)OM; -COR 1 3 . _ NR1 3 C(O)R1 4 ; -NR 13 C(O)NR" 4 R 5 ; -NR 3 C0 2 R"; -OC(O)R1 3 ; -OC(O)NR 3 R" 14 ; -NR 13 SOR 14 ; -NR 13 SO 2 R"; -NR 13 SONR 14 R"; -NR 3 S0 2 NR 14 R 5 ; 20 P(O)R 13 R 1 4 ; -PR 13 R 1 4 ; -P+R 13 R 14 R 15 A~; -P(OR 1 3 )OR 1 4 ; -S+R 13 R1 4 A~; and -N+R 13 Rl 4 R 15 A~; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the Ry radicals optionally may 25 be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl; alkynyl; 7. aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR ; -NR 7 R 8 ; -SR 7 ; -S(O)R 7 ; -S02R 7 ; -S03R 7 ;- C02R 7 ; -CONR 7 R 8 ; N+R 7R8RA-; -P(O)R 7 R 8 ; -PR 7 R 8 . -P+R 7 R 8 R9A~; and -P(O)(OR 7 )OR 8 . 30 and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the Ry radicals optionally may have one or more carbons replaced by -0-; -NR 7 -; -N+R 7 R 8 A--; -S-; -SO-; 35 S02-; -S+R 7 A--; -PR 7 -; -P(O)R 7 -; -P+R 7 R 8 A--; or phenylene; and wherein R 7 and R 8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R 1 3 , R 14 , and R 15 are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; 40 alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or WO 00/47568 PCT/USOO/02503 363 wherein R" and R" together with the nitrogen atom to which they are 45 attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R 1 and R15 together with the nitrogen atom to which they are attached form a cyclic ring; and 50 heei te 13 R 14 and 50 wherein the R13, R , and R1 alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether 55 radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl; hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl; -OR 16 ; -NR 9 R 1 0 ; -N+R 9 R1oRwA-; -SR 16 ; -S(O)R 9 ; -S02R 9 ; -S03R 1 6 . _ 60 C02R 16 ; -CONR 9 R 10 ; -SO2NR 9 R 1 0; -PO(OR 16 )OR 1 7; -PR 9 R 1 0. P+R 9 R 10 R 1 A-; -S+R 9 R 1 0 A-; and carbohydrate residue; and wherein the R1, R , and R alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; 65 alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -0-; -NR 9 -; N+R9R10A--; -S-; -SO-; -S02-; -S+R 9 A--; -PR 9 -; -P+R 9 R 1 0 A--; -P(O)R 9 -; phenylene; carbohydrate residue; amino acid residue; peptide residue; or 70 polypeptide residue; and wherein R 16 and R 17 are independently selected from the group consisting of R 9 and M; and wherein M is a pharmaceutically acceptable cation; and wherein R 9 , R' 0 , R 11 , R 2 , Rw, and A~ are as defined in claim 2.
11. A compound of claim 2 wherein at least one of R 5 and R 6 has the formula WO 00/47568 PCT/USOO/02503 364 5 (R") t (II) 10 wherein RY and t are defined as in claim 10.
12. A compound of claim 11 wherein RN is selected from the group consisting of hydrogen, alkyl and aralkyl.
13. A compound of claim 11 wherein RN is selected from the group consisting of hydrogen, (Cl-Cio)alkyl and aryl(CI-CIO)alkyl.
14. A compound of claim 11 wherein RN is selected from the group consisting of hydrogen, methyl, ethyl and benzyl.
15. A compound of claim 11 wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, alkyl, and (C 3 -CIO)cycloalkyl.
16. A compound of claim 11 wherein RI and R2 are independently selected from the group consisting of hydrogen and (CI-Cio)alkyl.
17. A compound of claim 11 wherein RI and R 2 are independently selected from the group consisting of (CI-CIO)alkyl.
18. A compound of claim 11 wherein RI and R2 are independently selected from the group consisting of(Ci-C 7 )alkyl.
19. A compound of claim 11 wherein R 1 and R 2 are independently selected from the group consisting of(C 2 -C 4 )alkyl. WO 00/47568 PCT/USOO/02503 365
20. A compound of claim 11 wherein Rl and R 2 are the same (Ci CIO)alkyl.
21. A compound of claim 11 wherein R 1 and R2 are independently selected from the group consisting ethyl; n-propyl; n-butyl; and isobutyl.
22. A compound of claim 11 wherein R 1 and R 2 are each n-butyl.
23. A compound of claim 11 wherein one of Ri and R2 is ethyl and the other of R and R 2 is n-butyl.
24. A compound of claim 11 wherein q is 1, 2, or 3.
25. A compound of claim 11 wherein q is 1 or 2.
26. A compound of claim 11 wherein q is 1.
27. A compound of claim 11 wherein R 3 and R 4 are independently selected from the group consisting of hydrogen and -OR 9 .
28. A compound of claim 27 wherein R 9 is hydrogen.
29. A compound of claim 28 wherein said hydroxy group is in a syn relationship to said structure of formula (II).
30. A compound of claim 11 wherein RX radicals are present at the 7-, 8- and 9-positions of the benzo ring of the structure of formula (I).
31. A compound of claim 11 wherein an Rx radical is present at one or more of the 7-, 8-, or 9-positions of the benzo ring of the structure of formula (I).
32. A compound of claim 11 wherein RX radicals are present at the 7- and 9-positions of the benzo ring of the structure of formula (I). WO 00/47568 PCT/USOO/02503 366
33. A compound of claim 11 wherein an RX radical is present at the 7-position of the benzo ring of the structure of formula (I).
34. A compound of claim 32 wherein said one or more RX are independently selected from the group consisting of alkyl; aryl; cycloalkyl; heterocyclyl; polyalkyl; acyloxy; polyether; halogen; -OR 13 ; -NR1 3 R 1 4 ; NR 13 NR 14 R 1 5 ; -N+R 9 R 1 R 12 A~; -SR 13 -S+R 13 R1 4 A-; -C02R 13 ; and 5 NR 14 C(O)R 1 3 ; wherein alkyl; aryl; cycloalkyl; heterocyclyl; polyalkyl; acyloxy; and polyether; can be further substituted with -OR 1 6. -NR 9 R 10 ; -N+R 9 RlORwA~; -SR 16 ; -S(O)R 9 ; -S02R 9 ; -S03R 1 6 ; oxo; -C02R 1 6 ; -CN; halogen; CONR9Rl0; -SO 2 NR 9 R 10 ; -PO(OR 1 6 )OR 17 ; -PR 9 R 10 ; -P+R 9 R 1 1 R 1 2A~; or 10 -S+R 9 R 10 A~; and wherein in Rx, one or more carbons are optionally replaced by -0-; NR_ 1 3 ; -N+R 1 3 RA-; -S-; -SO-; -SO2-; -S R 1 3 A--; -PR 1 3 -; -P(O)R 13 _ P+R 13R14A~-; phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; polyether; or polyalkyl; and 15 wherein in said polyalkyl; phenylene; amino acid residue; peptide residue; polypeptide residue; and carbohydrate residue; one or more carbons are optionally replaced by -0-; -NR 9 -; -N+R 9 R 10 A--; -S-; -SO-; -S02-; S+R 9 A--; -PR 9 -- -P+R 9 R 1 0 A--; or -P(O)R9
35. A compound of claim 33 wherein said one or more RX are independently selected from the group consisting of alkyl; aryl; cycloalkyl; heterocyclyl; polyalkyl; acyloxy; polyether; halogen; -OR 1 3 ; -NR1 3 RI 4 ; NPR13NR1R15; -N+R 9 R 1 1 R 12 A~; -SR 1 3 -S+R 13 R1 4 A-; -C02R 13 ; and 5 NR 14 C(O)R 1 3 ; wherein alkyl; aryl; cycloalkyl; heterocyclyl; polyalkyl; acyloxy; and polyether; can be further substituted with -OR 16 -NR 9 R 1 0 ; -N+R 9 RlORwA~; -SR 1 6 ; -S(O)R 9 ; -S02R 9 ; -S03R 16 ; oxo; -C02R 1 6 ; -CN; halogen; CONR 9 R' 0 ; -S0 2 NR 9 R 10 ; -PO(OR 1 6)OR 17 ; -PR9RIO; -P+R 9 R 1 KI2A~; or 10 -S+R9R'OA~; and wherein in Rx, one or more carbons are optionally replaced by -0-; NR13-; -N+R1 3 R 1 4 A-; -S-; -SO-; -S02-; -S+R 13 A-; -PR 13 -; -P(O)R 1 3 _; - WO 00/47568 PCT/USOO/02503 367 P+R13R14A~-; phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; polyether; or polyalkyl; and 15 wherein in said polyalkyl; phenylene; amino acid residue; peptide residue; polypeptide residue; and carbohydrate residue; one or more carbons are optionally replaced by -0-; -NR 9 -; -N+R 9 R 1 0 A--; -S-; -SO-; -SO2-; S+R 9 A--; -PR 9 -; -P+R 9 R 10 A-; or -P(O)R 9
36. A compound of claim 34 wherein said one or more RK are independently selected from the group consisting of polyether; -OR 13 ; NR13RI4; and -N+R 9 R 1 1 R 12 A.
37. A compound of the claim 35 wherein said Rx is selected from the group consisting of polyether; -OR 13 ; -NR13RI4; and -N+R 9 R 1 IR 12 A~.
38. A compound of claim 36 wherein said one or more RX are independently selected from the group consisting of -OR1 3 and -NR 13 R 1 4 .
39. A compound of claim 37 wherein said Rx is independently selected from the group consisting of -OR 1 3 and -NR 1 3 R 1 4 .
40. A compound of claim 38 wherein R 13 and R 14 are each methyl.
41. A compound of the claim 39 wherein R 1 3 and RI 4 are each methyl.
42. A compound of claim 11 wherein an Ry substituent is attached at the 3- or the 4-position of the phenyl ring of the structure of formula (II).
43. A compound of claim 11 wherein t is 1 or 2.
44. A compound of claim 42 wherein t is 1 or 2.
45. A compound of claim 11 wherein said one or more Ry are independently selected from the group consisting of hydrogen; halogen; hydroxy; -N02; (CI-C O)alkyl; halo(Ci-C O)alkyl; aryl(CI-CIO)alkyl; WO 00/47568 PCT/USOO/02503 368 heterocyclyl(Ci-CIO)alkyl; polyether; -OR 13 ; -NR 13 RI4; and -NR1 3 C(O)R 14 ; 5 and wherein R 1 3 , R , and R are independently selected from the group consisting of hydrogen; (CI-C o)alkyl; halo(C 1 -CIO)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(C 1 -CIO)alkyl; heterocyclyl(CI-Cio)alkyl; quaternary heterocyclyl(CI-CIO)alkyl; (Ci-C o)alkylheterocyclyl(CI-CIO)alkyl; 10 (Ci-Cio)alkylammonium(Ci-CIO)alkyl; and polyether; or wherein the R 1 3 , R 14 , and R 15 (CI-CIo)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(CI-CIO)alkyl; halo(CI-CIO)alkyl; heterocyclyl(Ci-Cio)alkyl; quaternary heterocyclyl(CI-Cio)alkyl; (CI-C o)alkylheterocyclyl(CI-CIO)alkyl; (CI-Clo)alkylammonium(CI-Co)alkyl; and polyether radicals optionally may be 15 substituted with one or more radicals selected from the group consisting of halogen; (Ci-Cio)alkyl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclyl(Ci-CIO)alkyl; carboxy; carboxy(CI-CIO)alkyl; -OR 1 6; -NR 9 R 1 0; _ N+R 9 RlORwA~; and -CONR 9 R 10 ; and wherein R 9 , R 1 0 , and Rw are independently selected from the group 20 consisting of hydrogen; (CI-C o)alkyl; heterocyclyl; ammonium(CI-CIO)alkyl; (CI-Cro)alkylammonium(C 1 -CIO)alkyl; aryl(CI-CiO)alkyl; heterocyclyl(Cl CIO)alkyl; carboxy(CI-CIO)alkyl; carbo(C 1 -Cio)alkoxy(CI-Cio)alkyl; carboxyheterocyclyl; carboxy(CI-CIO)alkylamino; and acyl; and wherein A~ is a pharmaceutically acceptable anion; and 25 wherein Ri 1 and R12 are independently selected from the group consisting of hydrogen; (Ci-Cio)alkyl; heterocyclyl; aryl(Ci-C o)alkyl; carboxy(CI-CIO)alkyl; and carbo(CI-C 1 o)alkoxy(CI-CIO)alkyl; or Ri 1 and R1 2 together with the carbon atom to which they are attached form a cyclic ring; and 30 wherein R 1 6 and R 1 7 are independently selected from the group consisting of R 9 and M; and wherein M is a pharmaceutically acceptable cation.
46. A compound of claim 11 wherein said Ry is independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, hydroxy, methoxy, ethoxy, nitro, amino, methylamino, dimethylamino, ethylamino, diethylamino, trimethylammonium, triethylammonium, 5 trimethylammoniummethylcarbonylamino, WO 00/47568 PCT/USOO/02503 369 triethylammoniummethylcarbonylamino, trimethylammoniumethylcarbonylamino, triethylammoniumethylcarbonylamino, trimethylammoniumpropylcarbonylamino, 10 triethylammoniumpropylcarbonylamino, trimethylammoniumbutylcarbonylamino, triethylammoniumbutylcarbonylamino, methylcarbonylamino, chloromethylcarbonylamino, fluoromethylcarbonylamino, bromomethylcarbonylamino, iodomethylcarbonylamino, ethylcarbonylamino, 15 chloroethylcarbonylamino, fluoroethylcarbonylamino, bromoethylcarbonylamino, iodoethylcarbonylamino, propylcarbonylamino, chloropropylcarbonylamino, fluoropropylcarbonylamino, bromopropylcarbonylamino, iodopropylcarbonylamino, butylcarbonylamino, chlorobutylcarbonylamino, fluorobutylcarbonylamino, 20 bromobutylcarbonylamino, iodobutylcarbonylamino, methoxycarbonyl, ethoxycarbonyl, trimethylammoniumethoxyethoxyethoxy, triethylammoniumethoxyethoxyethoxy, chloroethoxyethoxyethoxy, fluoroethoxyethoxyethoxy, bromoethoxyethoxyethoxy, iodoethoxyethoxyethoxy, pyridiniumethoxyethoxyethoxy, 25 piperazinyloxymethoxyethoxyethoxy, methylpiperazinyloxymethoxyethoxyethoxy, dimethylpiperazinyloxymethoxyethoxyethoxy, piperidinyloxymethoxyethoxyethoxy, methylpiperidinyloxymethoxyethoxyethoxy, and 30 dimethylpiperidinyloxymethoxyethoxyethoxyphenyl.
47. A compound of claim 11 wherein said one or more R are independently selected from the group consisting of hydroxy, methoxy, ethoxy, nitro, amino, methylamino, dimethylamino, ethylamino, diethylamino, trimethylammonium, triethylammonium, 5 trimethylammoniummethylcarbonylamino, triethylammoniummethylcarbonylamino, trimethylammoniumethylcarbonylamino, triethylammoniumethylcarbonylamino, trimethylammoniumpropylcarbonylamino, WO 00/47568 PCT/USOO/02503 370 10 triethylammoniumpropylcarbonylamino, trimethylammoniumbutylcarbonylamino, triethylammoniumbutylcarbonylamino, methylcarbonylamino, chloromethylcarbonylamino, fluoromethylcarbonylamino, bromomethylcarbonylamino, iodomethylcarbonylamino, ethylcarbonylamino, 15 chloroethylcarbonylamino, fluoroethylcarbonylamino, bromoethylcarbonylamino, iodoethylcarbonylamino, propylcarbonylamino, chloropropylcarbonylamino, fluoropropylcarbonylamino, bromopropylcarbonylamino, iodopropylcarbonylamino, butylcarbonylamino, chlorobutylcarbonylamino, fluorobutylcarbonylamino, 20 bromobutylcarbonylamino, iodobutylcarbonylamino, trimethylammoniumethoxyethoxyethoxy, triethylammoniumethoxyethoxyethoxy, chloroethoxyethoxyethoxy, fluoroethoxyethoxyethoxy, bromoethoxyethoxyethoxy, iodoethoxyethoxyethoxy, and pyridiniumethoxyethoxyethoxy.
48. A compound of claim 11 wherein said one or more R are independently selected from the group consisting of trimethylammonium, triethylammonium, trimethylammoniummethylcarbonylamino, triethylammoniummethylcarbonylamino, 5 trimethylammoniumethylcarbonylamino, triethylammoniumethylcarbonylamino, trimethylammoniumpropylcarbonylamino, triethylammoniumpropylcarbonylamino, trimethylammoniumbutylcarbonylamino, 10 triethylammoniumbutylcarbonylamino, trimethylammoniumethoxyethoxyethoxy, and triethylammoniumethoxyethoxyethoxy.
49. A compound of claim 11 wherein: RN is selected from the group consisting of hydrogen, alkyl and aralkyl; and RI and R 2 are independently selected from the group consisting of 5 hydrogen, alkyl, and (C 3 -C 1 )cycloalkyl. WO 00/47568 PCT/US00/02503 371
50. A compound of claim 11 wherein: RN is selected from the group consisting of hydrogen, alkyl and aralkyl; and R 3 and R4 are independently selected from the group consisting of 5 hydrogen and hydroxy.
51. A compound of claim 50 wherein said hydroxy group is in a syn relationship to said structure of formula (II).
52. A compound of claim 11 wherein: RN is selected from the group consisting of hydrogen, alkyl and aralkyl; and Rx is selected from the group consisting of polyether; -OR13. 5 NR 1 3 R 1 4; and -N+R 9 R R 1 2A~; wherein Ri, R 1 , R1 2 , R1 3 and R 14 are as defined in claim 2.
53. A compound of claim 11 wherein: RI and R2 are independently selected from the group consisting of hydrogen, alkyl, and (C 3 -Cio)cycloalkyl; and R 3 and R 4 are independently selected from the group consisting of hydrogen and 5 hydroxy.
54. A compound of claim 11 wherein: Ri and R2 are independently selected from the group consisting of hydrogen, alkyl, and (C 3 -CIO)cycloalkyl; and RX is selected from the group consisting of polyether; -OR 13 ; -NR 1 3 RI 4 ; and 5 N+R 9 R 1 1 R 12 A~; wherein R?, R", R 2 , R 13 and R1 4 are as defined in claim 2.
55. A compound of claim 11 wherein: RW and R 4 are independently selected from the group consisting of hydrogen and hydroxy; and Rx is selected from the group consisting of polyether; -OR 13 . 5 NR1 3R1 ; and -N+R 9 RI 1 2A; WO 00/47568 PCT/US0O/02503 372 wherein R 9 , R 1 , R 12 , R 13 and R 4 are as defined in claim 2.
56. A compound of claim 11 wherein: RN is selected from the group consisting of hydrogen, alkyl and aralkyl; R and R 2 are independently selected from the group consisting of hydrogen, alkyl, and (C 3 -C 1 o)cycloalkyl; and R 3 5 and R 4 are independently selected from the group consisting of hydrogen and hydroxy.
57. A compound of claim 11 wherein: RN is selected from the group consisting of hydrogen, alkyl and aralkyl; R and R 2 are independently selected from the group consisting of hydrogen, alkyl, and (C 3 -Cio)cycloalkyl; and Rx 5 is selected from the group consisting of polyether; -OR 13 ; -NR 13 RI 4 ; and N+R 9 R 1 R 12 A~; wherein R 9 , R 11 , R 12 , R1 3 and R 4 are as defined in claim 2.
58. A compound of claim 11 wherein: RN is selected from the group consisting of hydrogen, alkyl and aralkyl; RW and R 4 are independently selected from the group consisting of hydrogen and hydroxy; and 5 Rx is selected from the group consisting of polyether; -OR 1 3 ; _ NR13RI 4 ; and -N+R 9 R 1R1 2A~; wherein R 9 , R", R', R . and R" are as defined in claim 2.
59. A compound of claim 11 wherein: R and R 2 are independently selected from the group consisting of hydrogen, alkyl, and (C 3 -CIO)cycloalkyl; R 3 and R 4 are independently selected from the group consisting of 5 hydrogen and hydroxy; and RX is selected from the group consisting of polyether; -OR 13 NR13RI 4 ; and -N+R 9 R 1R1 2A~; wherein R?, R 11 , R1 2 , R1 3 and R 14 are as defined in claim 2.
60. A compound of claim 11 wherein: WO 00/47568 PCT/US00/02503 373 RN is selected from the group consisting of hydrogen, alkyl and aralkyl; RI and R 2 are independently selected from the group consisting of hydrogen, alkyl, and (C 3 -C 1 o)cycloalkyl; R 3 and R 4 5 are independently selected from the group consisting of hydrogen and hydroxy; and 13. Rx is selected from the group consisting of polyether; -OR13. NR13RI 4 ; and -N+R 9 RI lR1 2 A~; wherein R 9 , R", R 1 2 , R" and R1 4 are as defined in claim 2.
61. A compound of claim 60 wherein RN is selected from the group consisting of hydrogen, (Ci-CIO)alkyl and aryl(CI-CIO)alkyl.
62. A compound of claim 60 wherein RN is selected from the group consisting of hydrogen, methyl, ethyl and benzyl.
63. A compound of claim 60 wherein RI and R 2 are independently selected from the group consisting of hydrogen and (Ci-CIO)alkyl.
64. A compound of claim 60 wherein R 1 and R 2 are independently selected from the group consisting of (CI-CIO)alkyl.
65. A compound of claim 60 wherein RI and R2 are independently selected from the group consisting of (C 2 -C 4 )alkyl.
66. A compound of claim 60 wherein RI and R2 are independently selected from the group consisting ethyl; n-propyl; n-butyl; and isobutyl.
67. A compound of claim 60 wherein R' and R 2 are each n-butyl.
68. A compound of claim 60 wherein one of RI and R 2 is ethyl and the other of RI and R 2 is n-butyl.
69. A compound of claim 60 wherein q is 1, 2, or 3.
70. A compound of claim 60 wherein q is 1 or 2. WO 00/47568 PCT/USOO/02503 374
71. A compound of claim 60 wherein q is 1.
72. A compound of claim 60 wherein RX radicals are present at the 7-, 8- and 9-positions of the benzo ring of the structure of formula (I).
73. A compound of claim 60 wherein an Rx radical is present at one or more of the 7-, 8-, or 9-positions of the benzo ring of the structure of formula (I).
74. A compound of claim 60 wherein Rx radicals are present at the 7- and 9-positions of the benzo ring of the structure of formula (I).
75. A compound of claim 60 wherein an RX radical is present at the 7-position of the benzo ring of the structure of formula (I).
76. A compound of claim 60 wherein said one or more RX are independently selected from the group consisting of -OR 13 and -NR1R wherein R" and RM are as defined in claim 2..
77. A compound of claim 76 wherein R 13 and R 14 are each methyl.
78. A compound of claim 60 wherein an Ry substituent is independently attached at the 3- or the 4-position of the phenyl ring of formula (II).
79. A compound of claim 60 wherein t is 1 or 2.
80. A compound of claim 60 wherein t is 1.
81. A compound of claim 60 wherein said one or more Ry are independently selected from the group consisting of hydrogen; halogen; hydroxy; -N02; (CI-C 1 o)alkyl; halo(Ci-CIo)alkyl; aryl(C 1 -Cio)alkyl; heterocyclyl(CI-CO)alkyl; polyether; -OR 1 3 ; -NR 13 R 1 4 ; and -NR 13 C(O)R"; 5 and WO 00/47568 PCT/USOO/02503 375 wherein R 1 3 , R 14 , and R are independently selected from the group consisting of hydrogen; (C-Cio)alkyl; halo(C-Cio)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(C-CIO)alkyl; heterocyclyl(C-Cio)alkyl; quaternary heterocyclyl(C-CIO)alkyl; (C-CIO)alkylheterocyclyl(C-CIO)alkyl; 10 (C-CIO)alkylammonium(C-CIO)alkyl; and polyether; or wherein the R13, R14, andR15 (C-CIO)alkyl; halo(C-CIO)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(C -C 10 )alkyl; heterocyclyl(C CIO)alkyl; quaternary heterocyclyl(C-CIO)alkyl; (C-CIO)alkylheterocyclyl(C CIO)alkyl; (C-CIO)alkylammonium(C-CIO)alkyl; and polyether radicals 15 optionally may be substituted with one or more radicals selected from the group consisting of halogen; (C-CIO)alkyl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclyl(C-CIO)alkyl; carboxy; carboxy(C CIO)alkyl; -OR 16 ; -NR 9 R 10 ; -NR 9 R1ORwA~; and -CONR 9 R 10 ; and wherein R9, R 10 , and Rw are independently selected from the group 20 consisting of hydrogen; (C-CIO)alkyl; heterocyclyl; ammonium(C-Cio)alkyl; (C-CIO)alkylammonium(C-CIO)alkyl; aryl(C-Cio)alkyl; heterocyclyl(C CIO)alkyl; carboxy(C-Cio)alkyl; carbo(C-CIO)alkoxy(C-CIO)alkyl; carboxyheterocyclyl; carboxy(C-CIO)alkylamino; and acyl; and wherein A~ is a pharmaceutically acceptable anion; and 25 wherein RI and R 12 are independently selected from the group consisting of hydrogen; (C-CIO)alkyl; heterocyclyl; aryl(C-CIO)alkyl; carboxy(C-CIO)alkyl; and carbo(C-CIO)alkoxy(C-CIO)alkyl; or RI and R 1 2 together with the carbon atom to which they are attached form a cyclic ring; and 30 wherein R 16 and R 17 are independently selected from the group consisting of R 9 and M; and wherein M is a pharmaceutically acceptable cation.
82. A compound of claim 60 wherein said Ry is independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, hydroxy, methoxy, ethoxy, nitro, amino, methylamino, dimethylamino, ethylamino, diethylamino, trimethylammonium, triethylammonium, 5 trimethylammoniummethylcarbonylamino, triethylammoniummethylcarbonylamino, trimethylammoniumethylcarbonylamino, WO 00/47568 PCT/USOO/02503 376 triethylammoniumethylcarbonylamino, trimethylammoniumpropylcarbonylamino, 10 triethylammoniumpropylcarbonylamino, trimethylammoniumbutylcarbonylamino, triethylammoniumbutylcarbonylamino, methylcarbonylamino, chloromethylcarbonylamino, fluoromethylcarbonylamino, bromomethylcarbonylamino, iodomethylcarbonylamino, ethylcarbonylamino, 15 chloroethylcarbonylamino, fluoroethylcarbonylamino, bromoethylcarbonylamino, iodoethylcarbonylamino, propylcarbonylamino, chloropropylcarbonylamino, fluoropropylcarbonylamino, bromopropylcarbonylamino, iodopropylcarbonylamino, butylcarbonylamino, chlorobutylcarbonylamino, fluorobutylcarbonylamino, 20 bromobutylcarbonylamino, iodobutylcarbonylamino, methoxycarbonyl, ethoxycarbonyl, trimethylammoniumethoxyethoxyethoxy, triethylammoniumethoxyethoxyethoxy, chloroethoxyethoxyethoxy, fluoroethoxyethoxyethoxy, bromoethoxyethoxyethoxy, iodoethoxyethoxyethoxy, pyridiniumethoxyethoxyethoxy, 25 piperazinyloxymethoxyethoxyethoxy, methylpiperazinyloxymethoxyethoxyethoxy, dimethylpiperazinyloxymethoxyethoxyethoxy, piperidinyloxymethoxyethoxyethoxy, methylpiperidinyloxymethoxyethoxyethoxy, and 30 dimethylpiperidinyloxymethoxyethoxyethoxyphenyl.
83. A compound of claim 60 wherein said one or more R are independently selected from the group consisting of hydroxy, methoxy, ethoxy, nitro, amino, methylamino, dimethylamino, ethylamino, diethylamino, trimethylammonium, triethylammonium, 5 trimethylammoniummethylcarbonylamino, triethylammoniummethylcarbonylamino, trimethylammoniumethylcarbonylamino, triethylammoniumethylcarbonylamino, trimethylammoniumpropylcarbonylamino, 10 triethylammoniumpropylcarbonylamino, trimethylammoniumbutylcarbonylamino, WO 00/47568 PCT/USOO/02503 377 triethylammoniumbutylcarbonylamino, methylcarbonylamino, chloromethylcarbonylamino, fluoromethylcarbonylamino, bromomethylcarbonylamino, iodomethylcarbonylamino, ethylcarbonylamino, 15 chloroethylcarbonylamino, fluoroethylcarbonylamino, bromoethylcarbonylamino, iodoethylcarbonylamino, propylcarbonylamino, chloropropylcarbonylamino, fluoropropylcarbonylamino, bromopropylcarbonylamino, iodopropylcarbonylamino, butylcarbonylamino, chlorobutylcarbonylamino, fluorobutylcarbonylamino, 20 bromobutylcarbonylamino, iodobutylcarbonylamino, trimethylammoniumethoxyethoxyethoxy, triethylammoniumethoxyethoxyethoxy, chloroethoxyethoxyethoxy, fluoroethoxyethoxyethoxy, bromoethoxyethoxyethoxy, iodoethoxyethoxyethoxy, and pyridiniumethoxyethoxyethoxy.
84. A compound of claim 60 wherein said one or more R are independently selected from the group consisting of trimethylammonium, triethylammonium, trimethylammoniummethylcarbonylamino, triethylammoniummethylcarbonylamino, 5 trimethylammoniumethylcarbonylamino, triethylammoniumethylcarbonylamino, trimethylammoniumpropylcarbonylamino, triethylammoniumpropylcarbonylamino, trimethylammoniumbutylcarbonylamino, 10 triethylammoniumbutylcarbonylamino, trimethylammoniumethoxyethoxyethoxy, and triethylammoniumethoxyethoxyethoxy.
85. A compound of claim 60 wherein said hydroxy group is in a syn relationship to said structure of formula (II).
86. A compound of formula (I): 5 WO 00/47568 PCT/USOO/02503 378 0 R R N qis 1 os2; 1 2 R 10 < R3>3 6 4 R 2 P R 6s R 3 (R R Rx 15 wherein: q is 1 or 2; Ri and R2 are each independently alkyl; R3 is hydroxy; 20 R4 and R6 are hydrogen; R 5 has the formula (II): 25 wherein t is an integer from 0 to 5; 30 one or more Ry are independently selected from the group consisting of hydrogen; halogen; -CN; -NO2; oxo; alkyl; polyalkyl; haloalkyl; hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR13' -NR13Rl4' SR 13 ; -S(O)R 1 3 ; -S02R 13 ; -S03R 13 ; -NR 13 0R 14 - -NR 13 NR 14 R 1 5. 35 C02R 1 3 ; -OM; -SO20M; -SO2NR1 3 RI 4 ; -C(O)NR 1 3 R 1 4 ; -C(O)OM; COR 13 ; -NR' 3 C(O)R"; -NR"C(O)NR1 4 R 5 ; -NR"C0 2 R 4 ; -OC(O)R"; OC(O)NR"R 14 ; -NR1 3 SOR1 4 ; -NR"S0 2 R1 4 ; -NR 13 SONR 1 4 R"; NR1 3 S0 2 NR 4 R 5 ; -P(O)R 13 R 14 ; -PR 13 R 1 4 ; -P+R 13 RR 14 R 5 A; P(OR 13 )OR 14 ; -S+R 13 R 14 A ; and -N+R 13 Rl 4 R 15 A~; and WO 00/47568 PCT/USOO/02503 379 40 wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the Ry radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl; alkynyl; 45 aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR7 -NR 7 R 8 ; -SR 7 ; -S(O)R 7 ; -S02R 7 ; -S03R 7 ;- C02R 7 ; -CONR 7 R 8 ; N+R 7 R 8 R 9 A-; -P(O)R 7 R 8 ; -PR 7 R 8 ; -P+R 7 R 8 R 9 A~; and -P(O)(OR 7 )OR 8 . and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, 50 alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the Ry radicals optionally may have one or more carbons replaced by -0-; -NR -; -N+R 7 R 8 A--; -S-; -SO-; S02-; -S+R 7 A--; -PR 7 -; -P(O)R 7 -; -P+R 7 R 8 A--; or phenylene; and wherein R 7 and R 8 are independently selected from the group 55 consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R 3 , R , and R 15 are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; 60 alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or wherein R1 3 and R" together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, 65 and quaternary salts; or wherein RI4 and R15 together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R 13 , R , and R 15 alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; 70 heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl; WO 00/47568 PCTIUSOO/02503 380 75 hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl; -OR 16 ; -NR9R 10 ; -N+R 9 R1oRwA~; -SR1 6 ; -S(O)R 9 ; -S02R 9 ; -S03R 16 ; _ C02R 1 6 ; -CONR 9 R 10 ; -S02NR 9 R 1 0; -PO(OR 16 )OR 17 ; -PR 9 R 1 0 P+R 9 R 1 OR1 1 A-; -S+R 9 R 10 A-; and carbohydrate residue; and 80 '1 3 , R 14 an 1 5 80 wherein the R3, R , and R alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether 85 radicals optionally may have one or more carbons replaced by -0-; -NR-; N+R9R10 A--; -S-; -SO-; -SO 2 -; -S+R 9 A--; -PR 9 -; -P+R 9 R 10 A--; -P(O)R 9 -; phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R 1 6 and RI 7 are independently selected from the group 90 consisting of R 9 and M; and wherein M is a pharmaceutically acceptable cation; and wherein R 9 , R 10 , R", R", Rw, and A~ are as defined in claim 2; and RN is selected from the group consisting of hydrogen; alkyl; and aralkyl; and 95 one or more RX radicals are independently selected from the group consisting of alkoxy, alkylamino and dialkylamino; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
87. A compound of claim 86 wherein R 1 and R 2 are each the same (C CIo)alkyl.
88. A compound of claim 86 wherein RI and R 2 are each n-butyl.
89. A compound of claim 86 wherein one or more R' are independently selected from the group consisting of methoxy and dimethylamino.
90. A compound of claim 86 wherein q is 1. WO 00/47568 PCT/USOO/02503 381
91. A compound of claim 86 wherein q is 1, and Rx is selected from the group consisting of methoxy and dimethylamino.
92. A compound of claim 86 wherein RN is selected from thegroup consisting of hydrogen; methyl, ethyl and benzyl.
93. A compound of claim 86 wherein said hydroxy group is in a syn relationship to said structure of formula (II).
94. A compound of claim 86 wherein t is 1.
95. A compound of claim 86 wherein t is 1 and RY is in the para position.
96. A compound of claim 86 wherein t is 1 and RY is in the meta position.
97. A compound of claim 86 wherein one or more RY are independently selected from selected from the group consisting of halogen; hydroxy; -N02; (CI-Cio)alkyl; halo(CI-C o)alkyl; aryl(Ci-CIO)alkyl; heterocyclyl(C 1 -CIO)alkyl; polyether; -OR 1 3- -NR13R 4; and -NR' 3 C(O)R"; and 5 wherein R 1 3 , R 4 , and R 15 are independently selected from the group consisting of hydrogen; (CI-CIo)alkyl; halo(CI-C O)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(CI-CIO)alkyl; heterocyclyl(Cl-CIO)alkyl; quaternary heterocyclyl(Cl-C o)alkyl; (CI-CIO)alkylheterocyclyl(C 1 -CIO)alkyl; (CI-CIO)alkylammonium(CI-C 1 o)alkyl; and polyether; or 10 wherein the R 13 , R 14 , and R 15 (C 1 -CIO)alkyl; halo(CI-CIO)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(CI-Cio)alkyl; heterocyclyl(Cl CIo)alkyl; quaternary heterocyclyl(CI-CIO)alkyl; (CI-CIO)alkylheterocyclyl(Cl C o)alkyl; (CI-CIO)alkylammonium(C 1 -Cio)alkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the 15 group consisting of halogen; (CI-CIO)alkyl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclyl(CI-CIo)alkyl; carboxy; carboxy(Cl CIO)alkyl; -OR 16 ; -NR 9 R 1 0 ; -N+R 9 R1ORwA~; and -CONR 9 R 1 0 ; and WO 00/47568 PCT/USO0/02503 382 wherein R 9 , R 10 , and Rw are independently selected from the group consisting of hydrogen; (CI-CIO)alkyl; heterocyclyl; ammonium(CI-CIO)alkyl; 20 (C-CIO)alkylammonium(CI-CIO)alkyl; aryl(CI-CIO)alkyl; heterocyclyl(C CIO)alkyl; carboxy(CI-CIO)alkyl; carbo(CI-Clo)alkoxy(Ci-CIO)alkyl; carboxyheterocyclyl; carboxy(CI-CIO)alkylamino; and acyl; and wherein A~ is a pharmaceutically acceptable anion; and wherein RI I and R12 are independently selected from the group 25 consisting of hydrogen; (CI-CIO)alkyl; heterocyclyl; aryl(CI-CIO)alkyl; carboxy(Ci-CIO)alkyl; and carbo(CI-CIO)alkoxy(C 1 -CIo)alkyl; or R 1 and R 12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R16 and R 1 7 are independently selected from the group 30 consisting of R 9 and M; and wherein M is a pharmaceutically acceptable cation.
98. A compound of claim 97 wherein: R 1 and R 2 are each the same (CI-CIO)alkyl; one or more RX are independently selected from the group consisting of methoxy and dimethylamino; 5 said hydroxy group is in a syn relationship to said structure of formula (II); t is 1; and RY is in the meta or para position.
99. A compound of claim 97 wherein RI and R 2 are each n-butyl.
100. A compound of claim 97 wherein q is 1.
101. A compound of claim 97 wherein RN is selected from the group consisting of hydrogen; methyl, ethyl and benzyl.
102. A compound of claim 97 wherein RY is in the para position.
103. A compound of claim 97 wherein RY is in the meta position. WO 00/47568 PCT/USOO/02503 383
104. A compound of the formula (III): IRR2A RN R2 R1R NA R R2 0 N RaR4 R19 R4A N y y xA ( R) (R ) (R ) (Rx) 5 wherein: q and r are independently integers from 0 to 4; t and u are independently integers from 0 to 4; R 1 , R 2 , RiA, and R 2 A are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; 10 heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl; or R and R2 taken together with the carbon to which they are attached 15 form C 3 -Co cycloalkyl or C 3 -C 1 0 cycloalkenyl; or RiA and R 2 A taken together with the carbon to which they are attached form C 3 -C 10 cycloalkyl or C 3 -C 0 cycloalkenyl; wherein the R, R 2 , R A, and R 2 A alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; 20 alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may be substituted with one or more radicals selected from the group consisting of CN; halogen; oxo; -OR 9 ; -NR 9 R 1 0 ; -N+R 9 RlORwA~; -SR 9 ; -S*R 9 R' 0 A; - WO 00/47568 PCT/USOO/02503 384 25 PR9R10. _P+R9R10RwA~; -S(O)R9; -SO2R 9 ; -SO3R 9 ; -C02R 9 ; and CONR 9 R 10 ; and wherein the R 1 , R 2 , RiA, and R 2 A alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; 30 aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may have one or more carbons replaced by -0-; -NR9-; -N+R9R10A--; -S-; -SO-; S02-; -S+R 9 A--; -PR 9 -; -P(O)R 9 -; -P+R 9 R 1 0 A--; or phenylene; and wherein R 9 , R 1 0 , and Rw are independently selected from the group 35 consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; alkylammoniumalkyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl; carboalkoxyalkyl; carboxyaryl; carboxyheterocyclyl; amino; alkylamino; carboxyalkylamino; alkoxyalkylamino; and acyl; and wherein A~ is a pharmaceutically acceptable anion; and 40 R 3 , R 4 , R 3 A and R 4 A are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; -OR 9 ; NR 9 R1 0 ; -SR 9 ; -S(O)R 9 ; -S02R 9 ; and -S03R 9 ; or R3 and R4 together form =0; =NOR 9 ; =S; =NNR 9 R 1 0 ; =NR9; or =CR R12; or 45 R 3 A and R 4 A together form =O; =NOR 9 ; =S; =NNR 9 R 10 ; =NR9; or =CR 1 1 R 12 ; wherein RI and R 12 are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl; 50 carboalkoxyalkyl; cycloalkyl; cycloalkenyl; haloalkyl; hydroxyalkyl; cyanoalkyl; -OR 9 ; -NR9R10; -SR9; -S(O)R 9 ; -S02R 9 ; -S03R 9 ; -C02R 9 ; and -CONR 9 R 1 0 ; or R and R 12 together with the carbon atom to which they are attached form a cyclic ring; and 55 wherein R 9 and R 0 are as defined above; and one or more Ry and RyA are independently selected from the group consisting of halogen; -CN; -N02; oxo; alkyl; polyalkyl; haloalkyl; hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR 1 3 ; -NR 13 RI 4 - WO 00/47568 PCT/USOO/02503 385 60 SR13; -S(O)R 1 3 ; -S02R 13 ; -S03R 13 ; -NR 1 3 0R 14 -NR 13 NR 1 4 R 1 5 _ C02R 1 3 ; -OM; -SO20M; -S02NR 13 RI 4 ; -C(O)NR 13 RI 4 ; -C(O)OM; COR 13 ; -NR 1 C(O)R1 4 ; -NRUC(O)NR 4 R' 5 ; -NR"C0 2 R 14 ; -OC(O)R; OC(O)NR1 3 R1 4 ; -NR"SOR1 4 ; -NR1 3 S0 2 R1 4 ; -NR1 3 SONR1 4 R 5 ; NR"SO 2 NR1 4 R1 5 ; -P(O)R 1 3 R 14 ; -PR 13 R 1 R15A~; 65 P(OR 13 )OR 14 ; -S+R 13 R 1 4 A; and -N+R 1 3 Rl 4 R 15 A~; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the Ry and RYA radicals optionally may be further substituted with one or more radicals selected from 70 the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR, -NR7R8; -SR; -S(O)R 7 ; -S02R 7 ; -S03R 7 ;- C02R 7 CONR 7 R 8 ; -N+R 7 R 8 R 9 A-; -P(O)R 7 R 8 ; -PR 7 R 8 ; -P+R 7 R 8 R 9 A~; and P(O)(OR 7 )OR 8 ; and 75 wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the Ry and RyA radicals optionally may have one or more carbons replaced by -0-; -NR 7 -; -N+R 7 R 8 A -; -S-; -SO-; -S02-; -S+R 7 A--; -PR 7 -; -P(O)R 7; -P+R 7 R 8 A--; or phenylene; 80 and wherein R 7 and R 8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R 13 , R 1 4 , and R 1 5 are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; 85 alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or wherein R" and R" together with the nitrogen atom to which they are 90 attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R 14 and R 15 together with the nitrogen atom to which they are attached form a cyclic ring; and WO 00/47568 PCT/USOO/02503 386 95 heei te 13 R 14 and 95 wherein the R13, R, and R1 alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether 100 radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl; hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl; -OR 1 6 - -NR 9 R 1 0 ; -N+R 9 R1oRwA-; -SR 1 6 ; -S(O)R9; -SO2R9; -SO3R16. 105 C02R 16 ; -CONR 9 R 10 ; -S02NR 9 R 10 ; -PO(OR 16 )OR 1 7 ; -PR 9 R 0 P+R 9 R 1 O RI IA-; -S+R 9 R 1 0 A-; and carbohydrate residue; and R 13 R 14 an 15 wherein the R1, R , and R alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; 110 alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -0-; -NR 9 -; N+R9R10A--; -S-; -SO-; -S02-; -S+R 9 A--; -PR 9 -; -P+R 9 R 1 0 A--; -P(O)R 9 -; phenylene; carbohydrate residue; amino acid residue; peptide residue; or 115 polypeptide residue; and wherein R16 and R 1 7 are independently selected from the group consisting of R 9 and M; and wherein n is 0, 1 or 2; and wherein M is a pharmaceutically acceptable cation; and 120 wherein R 9 , R1 0 , R", R 2 , Rw, and A~ are as defined above; and RN and RNA are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aralkyl; and heterocyclylalkyl; and one or more Rx and RXA radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -N02; alkyl; cycloalkyl; 125 polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; uaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; acyloxy; OR 13 -NR 1 3 RI 4 ; -SR 13 ; -S(O)R 1 3 ; -S(O)2R 1 3 ; -S03R 1 3 ; -S+R R 14 A-; N 13 0R 14 13' 1R 4 R 1501R 13 1 4 . NR13OR ;' -NR1NR R1; -C02R 13 ; -OM; -SO2OM; -SO2NR1R , NR"C(O)R"; -C(O)NR 1 3 R 4 ; -C(O)OM; -COR 13 ; -OR 1 8; -SOnNR 13 R 18 - WO 00/47568 PCT/USOO/02503 387 130 NR 18 0R 14 ; -N+R 13 R 14 R 15 A; -PR 13 R 14 ; -P(O)R 13 R 14 P+R 13 R 14 R 15 A; amino acid residue; peptide residue; polypeptide residue; and carbohydrate residue; wherein the Rx and RXA alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; 135 polyether; acyloxy radicals optionally may be further substituted with one or more radicals selected from the group consisting of halogen; -CN; oxo; -OR 16 ; -NR 9 R 0; -N+R 9 RloRwA~; -SR16; -S(O)R 9 ; -SO2R 9; -S03R 16 ; -C02R 16 . _ CONR 9 R10; -S02NR 9 R 1 0 ; -PO(OR 6 )OR1 7 ; -PR 9 R 1 0 ; -P+R 9 R 1 1 R 12 A~; S+R 9 R 1 0 A; and carbohydrate residue; and 140 wherein the RX and RX^ quaternary heterocyclyl radical optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; -N02; oxo; alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR 1 3 -NR 13 R; 14 -SR 13 ; -S(O)R 1 3 ; -SO2R 13 ; -S03R 13 ; 145 NR 13 OR 4 -NR 13 N 14 R 15 ; -C02R 13 ; OM; -S020M; -S02NR 13 R 1 4 - C(O)NR 1 3 R 14 ; -C(O)OM; -COR 13 ; -P(O)R 13 R 1 4 ; -PR 13 R 1 4 P+R 13 R 1 4 R 15 A~; -P(OR 13 )OR 1 4 ; -S+R 13 R 14 A; -N+R 13 R 14 R 15 A; and carbohydrate residue; and wherein the Rx and RXA radicals comprising carbon optionally may 150 have one or more carbons replaced by -0-; -NR13-; -N+R 13 R 1 4 A-; -S-; -SO-; -S02-; -S+R 13 A~-; -PR 1 3 -; -P(O)R 13 _; -P+R 13 R 14 A-; phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; polyether; or polyalkyl; wherein said phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; and polyalkyl optionally may have 155 one or more carbons replaced by -0-; -NR 9 -; -N+R 9 R 10 A-; -S-; -SO-; -SO 2 -; -S+R 9 A--; -PR 9 -; -P+R 9 R 10 A--; or -P(O)R 9 -; and wherein R 18 is selected from the group consisting of alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and 160 heterocyclylalkoxycarbonyl; and heterocyclylalkoxycarbonyl; and wherein the R" alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl radicals optionally may be substituted with one or more radicals selected from the group consisting of WO 00/47568 PCT/USOO/02503 388 165 halogen; -CN ; NO 2 ; oxo; -OR 9 ; -NR 9 R 10 ; -N+R 9 R 1 lR 12 A~; -SR 9 ; -S(O)R 9 -S02R 9 ; -S03R 9 ; -C02R 9 ; -CONR 9 R 10 ; -SO2OM; -S02NR 9 R 10 ; -PR 9 R 1 0 -P(OR 16 )OR 1 7 ; -PO(OR 16 )OR 1 7 ; and -C(O)OM; and wherein R 9 , R 0 , R 1 , R , R , R 1 , R", R" 6 , R , Rw, A, and M are as defined above; and 170 R 19 is selected from the group consisting of alkane diyl; alkene diyl; alkyne diyl; polyalkane diyl; alkoxy diyl; polyether diyl; polyalkoxy diyl; carbohydrate; amino acid; and peptide; polypeptide; wherein alkane diyl; alkene diyl; alkyne diyl; polyalkane diyl; alkoxy diyl; polyether diyl; polyalkoxy diyl; carbohydrate residue; amino acid residue; peptide residue; and 175 polypeptide residue; can optionally have one or more carbons replaced by -0-; -NR-; -N +R7R8A--; -S-; -SO-; -S02; -S+R 7 A~-; -PR 7 -; -P+R7R8A--; phenylene; heterocyclyl; quaternary heterocyclyl; or aryl; wherein alkane diyl; alkene diyl; alkyne diyl; polyalkane diyl; alkoxy diyl; polyether diyl; polyalkoxy diyl; carbohydrate residue; amino acid residue; 180 peptide residue; and polypeptide residue can be substituted with one or more substituent groups independently selected from the group consisting of alkyl; alkenyl; alkynyl; polyalkyl; polyether; aryl; haloalkyl; cycloalkyl; heterocyclyl; arylalkyl; halogen; oxo; -OR 13 -NR 1 3 R 1 4 ; -SR13; -S(O)R 1 3 ; -S02R 1 3 . _ S03R 13 ; -NR 13 OR . 4 ; -NR 13 NR 14 R 1 5 ; -N02; -C02R 13 ; -CN; -OM; 185 SO20M; -S02NR 13 Rl 4 ; -C(O)NR 1 3 R 1 4 ; -C(O)OM; -COR 13 ; P(O)R 1 3 R 1 4 ; -PR 13 RI 4 ; -P+R13R 1R1A-; -P(OR)OR 4 ; -S*R"R'A~; and N+R 1 3 Rl 4 R 1 5 A ; wherein R 7 , R', R", R , R , RM R , and A are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
105. A compound of claim 104 wherein RI, R1A, R 2 , and R 2 Are independently selected from the group consisting of hydrogen and alkyl.
106. A compound of claim 104 wherein R 1 , R1A, R 2 , and R 2 A are independently selected from the group consisting of hydrogen and C 1 -Cl 0 alkyl.
107. A compound of claim 104 wherein R', RIA, R 2 , and R 2 A are independently selected from the group consisting of C 2 -C 7 alkyl. WO 00/47568 PCT/USOO/02503 389
108. A compound of claim 104 wherein R', R^, R 2 , and R 2 A are independently selected from the group consisting of C 2 -C 4 alkyl.
109. A compound of claim 104 wherein R', RI^, R 2 , and R 2 Are independently selected from the group consisting of ethyl; n-propyl; n-butyl; and isobutyl.
110. A compound of claim 104 wherein R 3 , R 3 A, R 4 , and R 4 A are independently selected from the group consisting of hydrogen and -OR 9 , wherein R 9 is as defined in claim 104.
111. A compound of claim 110 wherein R 9 is hydrogen.
112. A compound of claim 104 wherein RN and RNA are independently selected from the group consisting of hydrogen, alkyl and aralkyl.
113. A compound of claim 104 wherein RN and RNA are independently selected from the group consisting of hydrogen, (C 1 -C 10 )alkyl and aryl(C 1 -Cro)alkyl.
114. A compound of claim 104 wherein RN and RNA are independently selected from the group consisting of hydrogen, methyl, ethyl and benzyl.
115. A compound of claim 104 wherein one or more RX and RxA are independently selected from the group consisting of methoxy and dimethylamino.
116. A compound of claim 104 wherein q and r are each 1.
117. A compound of claim 104 wherein one or more RY are independently selected from selected from the group consisting of halogen; hydroxy; -N02; (CI-CIO)alkyl; halo(C 1 -CIO)alkyl; aryl(C 1 -CIO)alkyl; WO 00/47568 PCT/US00/02503 390 heterocyclyl(CI-CO)alkyl; polyether; -OR 13 ; -NR 13 Rl4; and -NR 13 C(O)R 14 ; 5 and wherein R 1 3 , R 1 4 , and R 15 are independently selected from the group consisting of hydrogen; (CI-CIO)alkyl; halo(C 1 -CIO)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(CI-CIO)alkyl; heterocyclyl(C 1 -Cio)alkyl; quaternary heterocyclyl(CI-C 1 O)alkyl; (C 1 -CIO)alkylheterocyclyl(C 1 -CIO)alkyl; 10 (CI-CIO)alkylammonium(CI-C O)alkyl; and polyether; or wherein the R 13 , R 14 , and R 15 (C 1 -Cio)alkyl; halo(C 1 -CIO)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(Cl-Cio)alkyl; heterocyclyl(C CIO)alkyl; quaternary heterocyclyl(C 1 -CIO)alkyl; (CI-Cio)alkylheterocyclyl(C Cio)alkyl; (CI-Cio)alkylammonium(CI-CIO)alkyl; and polyether radicals 15 optionally may be substituted with one or more radicals selected from the group consisting of halogen; (CI-Clo)alkyl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclyl(C 1 -CIO)alkyl; carboxy; carboxy(C1 Cio)alkyl; -OR16' -NR9RO; -N+R9R OkwA~; and -CONR 9 R 10 ; and wherein R , R 1 0, and Rw are independently selected from the group 20 consisting of hydrogen; (CI-CIO)alkyl; heterocyclyl; ammonium(C 1 -CIO)alkyl; (C 1 -Cio)alkylammonium(C 1 -CIO)alkyl; aryl(CI-CIO)alkyl; heterocyclyl(C 1 CIo)alkyl; carboxy(CI-Cio)alkyl; carbo(C 1 -C 10 )alkoxy(C 1 -CIO)alkyl; carboxyheterocyclyl; carboxy(C-CIO)alkylamino; and acyl; and wherein A~ is a pharmaceutically acceptable anion; and 25 wherein RI 1 and R 12 are independently selected from the group consisting of hydrogen; (C 1 -Cio)alkyl; heterocyclyl; aryl(C 1 -Cio)alkyl; carboxy(C 1 -C 10 )alkyl; and carbo(CI-Cio)alkoxy(CI-CIO)alkyl; or R I and R 12 together with the carbon atom to which they are attached form a cyclic ring 30 wherein R 16 and R 17 are independently selected from the group consisting of R 9 and M; and wherein M is a pharmaceutically acceptable cation.
118. A compound of claim 104 wherein R 19 is selected from the group consisting of alkane diyl; polyalkane diyl; alkoxy diyl; and polyalkoxy diyl; wherein alkane diyl and polyalkane diyl can optionally have one or more carbons replaced by -0-; -NR7-; -N+R7R8A--; -S-; -SO-; -SO2-; -S+RA--; - WO 00/47568 PCT/USOO/02503 391 5 PR 7 -; -P(O)R 7 -; -P+R 7 R 8 A--; or phenylene, wherein R 7 and R 8 are defined as in claim 104.
119. A compound of claim 104 wherein R 9 is selected from the group consisting of alkoxy diyl and polyalkoxydiyl wherein one or more carbons are optionally replaced by -0-; -NR 7 -; -N+R R 8 A--; -S-; -SO-; -S02-; -S+R 7 A--; -PR 7 -; -P(O)R 7 -; -P+R 7 R 8 A--; phenylene; amino acid residue; 5 peptide residue; polypeptide residue; carbohydrate residue; or polyalkyl, wherein R 9 and R 0 are defined as in claim 104.
120. A compound of claim 104 having the formula: N N H H 0 00 00 00 00 00 N \O HO . AN /S-N _N
121. A compound of the formula (IV): WO 00/47568 PCT/US00/02503 392 -- (Y) tRYA) (R) t 4 A R 3 A IV) ( R R 19 R 2A R R 2 A 10 N-S N R N // q ( R" ) r \ NA R 0 o R wherein 15 q and r are independently integers from 0 to 3; t and u are independently integers from 0 to 5; R 1 , R 2 , RIA, and R 2 A are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; 20 alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl; or R and R 2 taken together with the carbon to which they are attached form C 3 -CIe cycloalkyl or C 3 -C 1 0 cycloalkenyl; or 25 RI A and R 2 A taken together with the carbon to which they are attached form C 3 -C 1 0 cycloalkyl or C 3 -C 10 cycloalkenyl; wherein the R 1 , R 2 , RiA, and R 2 A alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; 30 aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may be substituted with one or more radicals selected from the group consisting of CN; halogen; oxo; -OR 9 ; -NR 9 R 1 0 ; -N+R 9 RlORwA~; -SR 9 ; -S+R 9 R' 0 A-; PR 9 R 1 0 ; -P+R 9 R 1ORwA~; -S(O)R 9 ; -S02R 9 ; -S03R 9 ; -C02R 9 ; and 35 CONR 9 R 10 ; and WO 00/47568 PCT/USOO/02503 393 R 1 R 2 R A an 2 A wherein the R', R2, R ,and R alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl; 40 heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may have one or more carbons replaced by -0-; -NR9-; -N+RA 0A--; -S-; -SO-; SO2-; -S+R 9 A--; -PR 9 -; -P(O)R 9 -; -P+R 9 R 10 A--; or phenylene; and wherein R 9 , R 10 , and Rw are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; 45 alkylammoniumalkyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl; carboalkoxyalkyl; carboxyaryl; carboxyheterocyclyl; amino; alkylamino; carboxyalkylamino; alkoxyalkylamino; and acyl; and wherein A~ is a pharmaceutically acceptable anion; and R 3 , R 4 , R 3 A, and R 4 A are independently selected from the group 50 consisting of hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; -OR 9 ; NR 9 R 10 ; -SR 9 ; -S(O)R 9 ; -S02R 9 ; and -S03R 9 ; or R3 and R4 together form=0; =NOR9; =S;=NNR9Rlo- =NR9; or =CR 1 IR 12 ; R 3 A and R 4 A together form =0; =NOR 9 ; =S; =NNR 9 R 1 0 ; NR 9 ; or 55 =CR 1 1 R 12 ; wherein Ri 1 and R 12 are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl; carboalkoxyalkyl; cycloalkyl; cycloalkenyl; haloalkyl; hydroxyalkyl; 60 cyanoalkyl; -OR 9 ; -NR 9 R 0 ; -SR 9 ; -S(O)R 9 ; -SO2R9; -SO3R9; -C02R 9 ; and -CONR 9 R 10 ; or R 1 and R12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R 9 and R 0 are as defined above; and 65 one or more Ry and RyA are independently selected from the group consisting of hydrogen; halogen; -CN; -N02; oxo; alkyl; polyalkyl; haloalkyl; hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR 13 ; - 13 Rl 4 SR1 3 ; -S(O)R13; -SO2R13; -SO3R13; -NR 13 0R 1 4 - -M13NR14R15 _ 70 C02R 13 ; -OM; -SO2OM; -S02NR 13 RI 4 ; -C(O)NR 13 R 1 4 ; -C(O)OM; - WO 00/47568 PCT/USOO/02503 394 COR 13 ; -NR 'C(O)R 4 ; -NR1 3 C(O)NR' 4 R1 5 ; -NR"C0 2 R 14 ; -OC(O)R; OC(O)NR1 3 R1 4 ; -NR 3 SOR 4 ; -NR S0 2 R1 4 ; -NR 13 SONR 14 R 5 ; NR S0 2 NR 1 4 R"; -P(O)R 13 R 14 ; -PR 13 R 14 ; -P+R 13 R 1 4 R 1 5 A~; P(OR 13 )OR 1 4 ; -S+R1 3 R14A~; and -N+R 13 R 1 4 R 1 5 A~; and 75 wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the Ry and RyA radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl; 80 alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclyl; -OR 7 ; -NR 7 R 8 ; -SR ; -S(O)R ; -SO2R ; -SO3R ;- C02R 7 ; CONR 7 R 8 ; -N+R 7 R 8 R 9 A-; -P(O)R 7 R 8 ; -PR 7 R 8 ; -P+R 7 R 8 R 9 A~; and P(O)(OR 7 )OR 8 ; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, 85 alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the Ry and RyA radicals optionally may have one or more carbons replaced by -0-; -NR 7 -; -N+R 7 R 8 A -; -S-; -SO-; -S02-; -S+R 7 A--; -PR 7 -; -P(O)R 7 _; -P+R 7 R 8 A--; or phenylene; and 90 wherein R 7 and R 8 are independently selected from the group consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R 1 3 , R 14 , and R 15 are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; 95 heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or wherein R 13 and R" together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted 100 with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or wherein R14 and R15 together with the nitrogen atom to which they are attached form a cyclic ring; and wherein the R1, R , and R alkyl; haloalkyl; cycloalkyl; polyalkyl; 105 alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; WO 00/47568 PCT/USOO/02503 395 heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from 110 the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl; hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl; -O- SR 16; -S(O)R9; -S02R 9 ; -SO3R 16 CO2R16; -CONR9RI ; -SO2NR 9 R 1 0 ; -PO(OR 16 )OR 17 ; -PR 9 Rio 115 P+R 9 R 10 R 1 A-; -S+R 9 R 1 0 A-; and carbohydrate residue; and wherein the R 13 , R 14 , and R alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; 120 alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may have one or more carbons replaced by -0-; -NR 9 -- N+R 9 R 1 0 A--; -S-; -SO-; -S02-; -S+R 9 A--; -PR 9 -; -P+R 9 R 10 A--; -P(O)R 9 -; phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and 125 wherein R 16 and R 1 7 are independently selected from the group consisting of R 9 and M; and wherein M is a pharmaceutically acceptable cation; and wherein n is 0, 1 or 2; and wherein R 9 , R' 0 , R' 1 , R1 2 , Rw, and A~ are as defined above; and 130 RN and RNA are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aralkyl; and heterocyclylalkyl; and one or more RX and Rx^ radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -N02; alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; 135 quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; acyloxy; OR 1 3 -NR 13 RI 4 ; -SR 13 ; -S(O)R 1 3 ; -S(O)2R 1 3 ; -S03R 13 ; -S+R 13 R 14 A- ~ 13 OR 14 1314 15 -C2 13 -3OM4 NR13OR ;- -NR1NR R5; -CO2R1; -OM; -SO2OM; -S02NR 1 3 R 1 4 NR" 4 C(O)R' 3 ; -C(O)NR 13 R 4 ; -C(O)OM; -COR 13 ; -OR 1 8; -SOnNR 1 3 R 14 ; NR 1 8 0R 1 4 ; -N+R 13 R 4 R 15 A ; -PR 13 Rl 4 ; -P(O)R 13 RI 4 ; - WO 00/47568 PCT/USO0/02503 396 140 P+R 13 RI 4 R 1 5 A; amino acid residue; peptide residue; polypeptide residue; and carbohydrate residue; wherein the RX and RXA alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; acyloxy radicals optionally may be further substituted with one or 145 more radicals selected from the group consisting of halogen; -CN; oxo; -OR 16 ; -NR 9 R 1 0 ; -N+R 9 RlORwA-; -SR 1 6 ; -S(O)R9; -SO2R9; -S03R 16 ; -C02R 1 6 . _ CONR 9 R 1 0 ; -S02NR 9 R 10 ; -PO(OR1 6 )OR"; -PR 9 R 1 0 -P+R 9 Rl 1 R 12 A; S+R 9 R 1 0A; and carbohydrate residue; and wherein the RX and RXA quaternary heterocyclyl radical optionally may 150 be substituted with one or more radicals selected from the group consisting of halogen; -CN; -N02; oxo; alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR 13 ; -NR 13 Rl 4 ; -SR 13 ; -S(O)R 1 3 ; -S02R 13 ; -S03R 13 ; NR 1 3 OR 4 ; -NR 1 3 NR 14 R 15 ; -C02R 1 3 ; OM; -S020M; -S02NR 1 3 R 1 4 ; 155 C(O)NR 13 RI4; -C(O)OM; -COR 13 ; -P(O)R 13 R 1 4 ; -PR 13 R1 4 P+R 1 3 R 1 4 R 15 A~; -P(OR 1 3 )OR 1 4 ; -S+R 13 R 1 4 A; -N+R 13 Rl 4 R 15 A~; and carbohydrate residue; and wherein the RX and RXA radicals comprising carbon optionally may have one or more carbons replaced by -0-; -NR 1 3 -; -N+R1 3 R 14 A--; -S-; -SO-; 160 -S02-; -S+R 13 A~-; -PR 13 -; -P(O)R 1 3 _; -P+R 1 3 R 14 A--; phenylene; amino acid; peptide; polypeptide; carbohydrate; polyether; or polyalkyl; wherein said phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; and polyalkyl optionally may have one or more carbons replaced by -0-; -NR9-; -N+R9R10A~-; -S-; -SO-; -SO 2 -; -S+R 9 A--; -PR 9 -; 165 P+R 9 R 1 0 A--; or -P(O)R 9 -; and wherein R 1 8 is selected from the group consisting of alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl; and heterocyclylalkoxycarbonyl; and 170 wherein the R1 8 alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN ; NO 2 ; oxo; -OR 9 ; -NR 9 R 1 0 ; -N+R 9 R 1 I R 12 A~; -SR 9 ; -S(O)R 9 - WO 00/47568 PCT/USOO/02503 397 175 -S02R 9 ; -S03R 9 ; -C02R 9 ; -CONR 9 R 10 ; -SO20M; -SO2NR9R10; -PR9R10 -P(OR 16 )OR 1 7 ; -PO(OR 1 6 )OR 1 7 ; and -C(O)OM; and wherein R 9 , R 1 0 , R", R , R , R , R', R' 6 , R", R", A , and M are as defined above; and R1 9 is selected from the group consisting of alkane diyl; alkene diyl; 180 alkyne diyl; polyalkane diyl; alkoxy diyl; polyether diyl; polyalkoxy diyl; carbohydrate; amino acid; and peptide; polypeptide; wherein alkane diyl; alkene diyl; alkyne diyl; polyalkane diyl; alkoxy diyl; polyether diyl; polyalkoxy diyl; carbohydrate residue; amino acid residue; peptide residue; and polypeptide residue; can optionally have one or more carbons replaced by -0-; 185 -NR,-; -N+R7R8A--; -S-; -SO-; -S02-; -S+R 7 A--; -PR 7 -; -P(O)R7_ P+R 7 R 8 A--; phenylene; heterocyclyl; quaternary heterocyclyl; or aryl; wherein alkane diyl; alkene diyl; alkyne diyl; polyalkane diyl; alkoxy diyl; polyether diyl; polyalkoxy diyl; carbohydrate residue; amino acid residue; peptide residue; and polypeptide residue can be substituted with one or more 190 substituent groups independently selected from the group consisting of alkyl; alkenyl; alkynyl; polyalkyl; polyether; aryl; haloalkyl; cycloalkyl; heterocyclyl; arylalkyl; halogen; oxo; -OR,13 -NR13R14; -SR 1 3 ; -S(O)R 13 ; -SO2R13 S03R 13 ; -NR 13 OR 14 ; -NR 13 NR 14R 15 ; -N02; -C02R 13 ; -CN; -OM; SO2OM; -S02NR 1 3 R 1 4 ; -C(O)N 13 R 1 4 ; -C(O)OM; -COR 13 195 P(O)R 1 3 R 14 ; -PR 13 R 1 4 ; -P+R 1 3 R 1 4 AR'; -P(OR")OR1 4 ; -SR 13 R1 4 A-; and N+R 9 R 1 R 12 A~; wherein R 7 , R', R", R , R, R' R , and A are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
122. A compound of claim 121 wherein R1, RA, R 2 , and R 2 A are independently selected from the group consisting of hydrogen and alkyl.
123. A compound of claim 121 wherein RI, R^, R 2 , and R 2 Are independently selected from the group consisting of hydrogen and CI-C 0 alkyl.
124. A compound of claim 121 wherein RI, RA, R2, and R 2 A are independently selected from the group consisting of C 2 -C 7 alkyl. WO 00/47568 PCT/USOO/02503 398
125. A compound of claim 121 wherein R', RI^, R 2 , and R 2 A are independently selected from the group consisting of C 2 -C 4 alkyl.
126. A compound of claim 121 wherein RI, RIA, R 2 , andR are independently selected from the group consisting of ethyl; n-propyl; n-butyl; and isobutyl.
127. A compound of claim 121 wherein R3, R 3 A, R 4 , and R 4 are independently selected from the group consisting of hydrogen and -OR 9 , wherein R' is as defined in claim 121.
128. A compound of claim 126 wherein R 9 is hydrogen.
129. A compound of claim 121 wherein RN and RNA are independently selected from the group consisting of hydrogen, alkyl and aralkyl.
130. A compound of claim 121 wherein RN and RNA are independently selected from the group consisting of hydrogen, (C 1 -Clo)alkyl and aryl(Cl-CIO)alkyl.
131. A compound of claim 121 wherein RN and RNAre independently selected from the group consisting of hydrogen, methyl, ethyl and benzyl.
132. A compound of claim 121 wherein one or more RX and Rx are independently selected from the group consisting of methoxy and dimethylamino.
133. A compound of claim 121 wherein q and r are each 1.
134. A compound of claim 121 wherein one or more RY are independently selected from selected from the group consisting of halogen; hydroxy; -N02; (CI-CIo)alkyl; halo(CI-CIO)alkyl; aryl(CI-CIo)alkyl; WO 00/47568 PCTIUSOO/02503 399 heterocyclyl(CI-Cio)alkyl; polyether; -OR 13 ; -NR 13 R 1 4; and -NR 3 C(O)R 4 ; 5 and wherein R 13 , R 14 , and R 15 are independently selected from the group consisting of hydrogen; (CI-C 10 )alkyl; haloC,-Cio)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(CI-CIO)alkyl; heterocyclyl(C 1 -CIO)alkyl; quaternary heterocyclyl(CI-CIO)alkyl; (CI-C 1 o)alkylheterocyclyl(Ci-Cio)alkyl; 10 (CI-CIO)alkylammonium(Ci-CIo)alkyl; and polyether; or wherein the R 1 3 , R 14 , and R 1 5 (CI-CIO)alkyl; halo(CI-CIO)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(CI-CIO)alkyl; heterocyclyl(C C o)alkyl; quaternary heterocyclyl(CI-CIO)alkyl; (CI-CIO)alkylheterocyclyl(Ci CIO)alkyl; (C 1 -Clo)alkylammonium(C 1 -Cio)alkyl; and polyether radicals 15 optionally may be substituted with one or more radicals selected from the group consisting of halogen; (C 1 -CIO)alkyl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclyl(CI-CIO)alkyl; carboxy; carboxy(C 1 CIO)alkyl; -OR 1 6 ; -NR 9 R 1 0; -N+R 9 R1oRwA-; and -CONR 9 R 10 ; and wherein R , R 1 0 and Rw are independently selected from the group 20 consisting of hydrogen; (CI-CIO)alkyl; heterocyclyl; ammonium(C 1 -CIO)alkyl; (CI-C 1 o)alkylammonium(CI-C O)alkyl; aryl(CI-CIO)alkyl; heterocyclyl(C CIO)alkyl; carboxy(C 1 -CIO)alkyl; carbo(CI-CIO)alkoxy(Ci-Cio)alkyl; carboxyheterocyclyl; carboxy(CI-CIo)alkylamino; and acyl; and wherein A~ is a pharmaceutically acceptable anion; and 25 wherein RI I and R 12 are independently selected from the group consisting of hydrogen; (CI-C o)alkyl; heterocyclyl; aryl(CI-CIO)alkyl; carboxy(CI-CIO)alkyl; and carbo(C 1 -CIO)alkoxy(CI-CIo)alkyl; or RI 1 and R12 together with the carbon atom to which they are attached form a cyclic ring; 30 wherein R16 and R 17 are independently selected from the group consisting of R9 and M; and wherein M is a pharmaceutically acceptable cation.
135. A compound of claim 121 wherein R 9 is selected from the group consisting of alkane diyl; polyalkane diyl; alkoxy diyl; and polyalkoxy diyl; wherein alkane diyl and polyalkane diyl can optionally have one or more carbons replaced by -0-; -NR 7 -; -N+R 7 R 8 A--; -S-; -SO-; -S02-; -S+R 7 A-; - WO 00/47568 PCT/US0O/02503 400 5 PR 7 -; -P(O)R 7 -; -P+R 7 R 8 A--; or phenylene, wherein R 7 and R 8 are defined as in claim 121.
136. A compound of claim 121 wherein R 19 is selected from the group consisting of alkoxy diyl and polyalkoxydiyl wherein one or more carbons are optionally replaced by -0-; -NR 7 -; -N+R 7 R 8 A--; -S-; -SO-; -S02-; -S+R 7 A--; -PR 7 -; -P(O)R 7 -; -P+R 7 R 8 A--; phenylene; amino acid residue; 5 peptide residue; polypeptide residue; carbohydrate residue; or polyalkyl, wherein R 9 and R'" are defined as in claim 121.
137. A compound of claim 121 having the structural formula: PEG N N H P 0 5 0 0 0 10 0 N-N 0 N N 15 OH OH
138. A compound of formula (V): WO 00/47568 PCT/USOO/02503 401 (RYA). 5 N R 4 A SR R 4 R R 100 Z SN R4 10 ~~(R x )r 0 R, \\NA 100 R (Rx)q 15 wherein: q is an integer from 0 to 4; r is an integer from 0 to 3; t is an integer from 0 to 4; 20 u is an integer from 0 to 5; R', R 2 , R1A, and R 2 A are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl; 25 heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl; or R and R2 taken together with the carbon to which they are attached form C 3 -Ci 0 cycloalkyl or C 3 -C 10 cycloalkenyl; or R1A and R 2 A taken together with the carbon to which they are attached 30 form C 3 -CI 0 cycloalkyl or C 3 -C 10 cycloalkenyl; wherein the R , R 2 , R1A, and R 2 A alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl; 35 heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may be substituted with one or more radicals selected from the group consisting of CN; halogen; oxo; -OR 9 ; -NR 9 R 1 0; -N+R 9 R 1 ORwA~; -SR 9 ; -S*R 9 R' 0 A-; - WO 00/47568 PCT/USOO/02503 402 P+R 9 R10RwA ; -S(O)R9; -S02R 9 ; -SO3R9; -CO2R 9 ; and CONR 9 R 10 ; and 40 wherein the R , R2, RA, and R 2 A alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; aryloxyalkyl; aryloxyalkenyl; aryloxyalkynyl; heterocylcyloxyalkyl; heterocycloxyalkenyl; heterocyclyloxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may 45 have one or more carbons replaced by -0-; -NR 9 -; -N+R 9 R 1 0 A--; -S-; -SO-; S02-; -S+R 9 A--; -PR 9 -; -P(O)R 9 -; -P+R 9 R 10 A--; or phenylene; and wherein R 9 , R 1 0, and Rw are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; alkylammoniumalkyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl; 50 carboalkoxyalkyl; carboxyaryl; carboxyheterocyclyl; amino; alkylamino; carboxyalkylamino; alkoxyalkylamino; and acyl; and wherein A~ is a pharmaceutically acceptable anion; and R 3 , R 4 , R 3 A, and R 4 A are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; -OR 9 ; 55 NR 9 R 10 ; -SR 9 ; -S(O)R9; -SO2R9; and -SO3R9; or R3 and R 4 together form =0; =NOR 9 ; =S; =NNR 9 R 10 ; NR 9; or =CR 1R12. R 3 A and R 4 A together form =0; =NOR 9 ; =S; =NNR9RO. -NR9; or =CR 1R12. 60 wherein R 11 and R 12 are independently selected from the group consisting of hydrogen; -CN; halogen; oxo; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl; carboalkoxyalkyl; cycloalkyl; cycloalkenyl; haloalkyl; hydroxyalkyl; cyanoalkyl; -OR9' -NR9R10; -SR9; -S(O)R 9 ; -S02R 9 ; -SO3R9; -C02R 9 ; and 65 -CONR 9 R 10 ; or R 1 1 and R 12 together with the carbon atom to which they are attached form a cyclic ring; and wherein R 9 and R 0 are as defined above; and one or more Ry and RyA are independently selected from the group 70 consisting of halogen; -CN; -N02; oxo; alkyl; polyalkyl; haloalkyl; hydroxyalkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR 13 ; -NR 13 R 14 ; - WO 00/47568 PCT/USOO/02503 403 SR 1 3 ; -S(O)R 1 3 ; -S02R 1 3 ; -S03R 13 ; -NR 1 3 OR 14 ; -NR 13 N 14 R 15 . _ C02R 13 ; -OM; -SO2OM; -S02NR 13 R 14 ; -C(O)NR 13 R 14 ; -C(O)OM; 75 COR 13 ; -NR 13 C(O)R1 4 ; -NR1 3 C(O)NR 4 R"; -NR'C0 2 R1 4 ; -OC(O)R; OC(O)NR1 3 R1 4 ; -NR'SOR 4 ; -NRU'S0 2 R1 4 ; -NR1 3 SONR1 4 R"; NR 3 SO 2 NR1 4 R"; -P(O)R 13 R 14 ; -PR 13 R 14 ; -P+R 13 R 14 R 15 A~; P(OR 13 )OR 14 ; -S+R13R 14A; and -N+R 13 R 1 4 R 15 A~; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, 80 alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, heterocyclylalkyl, and polyether substituents of the Ry and RyA radicals optionally may be further substituted with one or more radicals selected from the group consisting of -CN; halogen; hydroxy; oxo; alkyl; cycloalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary 85 heterocyclyl; -OR 7 ; -NR 7 R 8 ; -SR 7 ; -S(O)R 7 ; -S02R 7 ; -S03R 7 ;- C02R 7 - CONR 7 R 8 ; -N+R 7 R 8 R 9 A-; -P(O)R 7 R 8 ; - _p+R 7 R 8 R 9 A~; and P(O)(OR 7 )OR 8 ; and wherein the alkyl, polyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, quaternary heterocyclyl, arylalkyl, 90 heterocyclylalkyl, and polyether substituents of the Ry and RyA radicals optionally may have one or more carbons replaced by -0-; -NR -; -N+R 7 R 8 A -; -S-; -SO-; -S02-; -S+R 7 A--; -PR 7 -; -P(O)R 7 -; -P+R 7 R 8 A-; or phenylene; and wherein R 7 and R 8 are independently selected from the group 95 consisting of hydrogen; alkyl, alkenyl; alkynyl; aryl; and heterocyclyl; and wherein R 13 , R , and R 1 5 are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; 100 alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether; or wherein R1 3 and R1 4 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, 105 and quaternary salts; or wherein R 1 4 and R 15 together with the nitrogen atom to which they are attached form a cyclic ring; and WO 00/47568 PCT/USOO/02503 404 R 1 3 , 14 an 1 5 wherein the R1, R , and R alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; 110 heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether radicals optionally may be substituted with one or more radicals selected from the group consisting of halogen; -CN; sulfo; oxo; alkyl; haloalkyl; 115 hydroxyalkyl; sulfoalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclylalkyl; carboxy; carboxyalkyl; guanidinyl; 16 10 + 111 R 16 S~' 9 S0 9 )R 16 -OR 16 ; -N 9 R 10 ; -N+R 9 R R 12 A~; -SR ; -S(O)R ; -SO2R ; -SO3R C02R 1 6 ; -CONR 9 R 1 O; -S02NR 9 R 1 0 ; -PO(OR 16 )OR 1 7 ; -PN9R ; P+R 9 R OR' I A-; -S+R 9 R 10 A-; and carbohydrate residue; and 120 wherein the R 13 , R 1 , and R 15 alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocarbonylalkyl; and polyether 125 radicals optionally may have one or more carbons replaced by -0-; -NR 9 -- N+RA10A--; -S-; -SO-; -S02-; -S+R 9 A-; -PR 9 -; -P+R 9 R 10 A--; -P(O)R 9 -; phenylene; carbohydrate residue; amino acid residue; peptide residue; or polypeptide residue; and wherein R 16 and R 17 are independently selected from the group 130 consisting of R 9 and M; and wherein M is a pharmaceutically acceptable cation; and wherein n is 0, 1 or 2; and wherein R 9 , R' 0 , R", R", Rw and A~ are as defined above; and RN and RNA are independently selected from the group consisting of 135 hydrogen; alkyl; alkenyl; alkynyl; aralkyl; and heterocyclylalkyl; and one or more Rx and R'^ radicals are independently selected from the group consisting of hydrogen; halogen; -CN; -N02; alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; acyloxy; 140 OR13- -NR 13 RI 4 ; -SR 13 ; -S(O)R 1 3 ; -S(O)2R 1 3 ; -S03R 1 3 ; -S+R 13 R 14 A-; NR1 3 0R 14 ; -NR 13 NR 14 R 1 5 ; -C02R 1 3 ; -OM; -SO2OM; -S02NR 1 3 RI4- NR"C(O)R; -C(O)NR 13 R 1 4 ; -C(O)OM; -COR 13 ; -OR18; -S(O)nNR 13 RI4- WO 00/47568 PCTIUSOO/02503 405 -NR 13 R 1 8 -NR 1 8 0R 14 ; -N+R 13 Rl 4 R 15 A~; -PR13RI; -P(O)R13RI4 P+R 13 Rl 4 R 1 5 A~; amino acid residue; peptide residue; polypeptide residue; 145 and carbohydrate residue; wherein the RX and RXA alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; acyloxy radicals optionally may be further substituted with one or more radicals selected from the group consisting of halogen; -CN; oxo; -OR16. 150 -NR,9RI; -N+R 9 RlORwA~; -SR 16 ; -S(O)R9; -SO2R 9 ; -SO3R 16 ; -CO2R 1 6 _ CONR 9 R 10 ; -S02NR 9 R 1 0; -PO(OR 6 )ORD; -PR 9 R 1 0; -P+R 9 RI 1 R 1 2A~; S+R 9 R 1 0 A~; and carbohydrate residue; and wherein the RX and RXA quaternary heterocyclyl radical optionally may be substituted with one or more radicals selected from the group consisting of 155 halogen; -CN; -N02; oxo; alkyl; cycloalkyl; polyalkyl; haloalkyl; hydroxyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; polyether; -OR 13 -NR 13 RI 4 ; -SR 1 3; -S(O)R 1 3 ; -S02R 13 ; -S03R 13 ; 13 1 13 NR 14 R 15 13C1014 -N 1 3 R 14 R ; -C2R 1 3 ; OM; -S02OM; -S02NR 1 3 R 1 4 C(O)NR 13 R 14 ; -C(O)OM; -COR 1 3 ; -P(O)R 1 3 R 4 ; -PR 13 R 1 4 - 160 P+R 13 R 14 R 15 A~; -P(OR 1 3 )OR 1 4 ; -S+R13R 1A~; -N+R13R4R15A ; and carbohydrate residue; and wherein the RX and R radicals comprising carbon optionally may have one or more carbons replaced by -0-; -NR 13 -; -N+R 13 RI 4 A--; -S-; -SO-; -S02-; -S+R 13 A~-; -PR 13 -; -P(O)R 13 _; -P+R 13 R 14 A--; phenylene; amino acid 165 residue; peptide residue; polypeptide residue; carbohydrate residue; polyether; or polyalkyl; wherein said phenylene; amino acid residue; peptide residue; polypeptide residue; carbohydrate residue; and polyalkyl optionally may have one or more carbons replaced by -0-; -NR 9 -; -N+R 9 R 1 OA-; -S-; -SO-; -S02-; -S+R 9 A--; -PR 9 -; -P+R 9 R 1 0 A--; or -P(O)R 9 -; and 170 wherein R 1 8 is selected from the group consisting of alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl; and wherein the R 8 alkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary 175 heterocyclyl; arylalkyl; heterocyclylalkyl; acyl; alkoxycarbonyl; arylalkoxycarbonyl; and heterocyclylalkoxycarbonyl radicals optionally may be substituted with one or more radicals selected from the group consisting of WO 00/47568 PCT/USOO/02503 406 halogen; -CN ; NO 2 ; oxo; -0 9 ; -NR 9 R 1 0 ; -N+R 9 R 1 1 R 12 A; -SR 9 ; -S(O)R 9 -S02R 9 ; -S03R 9 ; -C02R 9 ; -CONR 9 R 10 ; -SO2OM; -S02NR 9 R 10 ; -PR 9 R 10 . 180 -P(OR 1 6 )OR 1 7 ; -PO(OR 16 )OR 1 7 ; and -C(O)OM; and wherein R 9 , R' 0 , R", R", R, R , R , R' 6 , R'?, R', A~, and M are as defined above; and R 9 is selected from the group consisting of alkane diyl; alkene diyl; alkyne diyl; polyalkane diyl; alkoxy diyl; polyether diyl; polyalkoxy diyl; 185 carbohydrate residue; amino acid residue; peptide residue; and polypeptide residue; wherein alkane diyl; alkene diyl; alkyne diyl; polyalkane diyl; alkoxy diyl; polyether diyl; polyalkoxy diyl; carbohydrate residue; amino acid residue; peptide residue; and polypeptide residue; can optionally have one or more carbons replaced by -0-; -NR -; -N+R 7 R 8 A--; -S-; -SO-; -S02-; -S+R7A--; 190 PR 7 -; -P(O)R 7 -; -P+R 7 R 8 A--; phenylene; heterocyclyl; quaternary heterocyclyl; or aryl; wherein alkane diyl; alkene diyl; alkyne diyl; polyalkane diyl; alkoxy diyl; polyether diyl; polyalkoxy diyl; carbohydrate residue; amino acid residue; peptide; and polypeptide residue can be substituted with one or more 195 substituent groups independently selected from the group consisting of alkyl; alkenyl; alkynyl; polyalkyl; polyether; aryl; haloalkyl; cycloalkyl; heterocyclyl; arylalkyl; halogen; oxo; -OR 13 ; -NR 3 R 1 4 ; -SR13; -S(O)R13; -SO2R13 S03R 13 ; -NR 13 OR 14 ; -NR13 14R15; -NO2; -C02R 13 ; -CN; -OM; SO2OM; -S02NR 13 R 1 4 ; -C(O)NR 13 R 1 4 ; -C(O)OM; -COR 13 ; 200 P(O)R 13 R 14 ; -PR1 3 R 4 ; -P+R1 3 R 4 RA-; -P(OR 3 )OR1 4 ; -SR1 3 R1 4 A-; and N+R 13 R 1 4 R 1 5 A; wherein R?, RI, R", R1 2 , R1 3 , R 14 R", and A~ are as defined above; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
139. A compound of claim 138 wherein RI, RIA, R 2 , and R 2 A are independently selected from the group consisting of hydrogen and alkyl.
140. A compound of claim 138 wherein R', RIA, R2, and R 2 Are independently selected from the group consisting of hydrogen and CI-Clo alkyl.
141. A compound of claim 138 wherein R', RIA, R 2 , and R 2 A are independently selected from the group consisting of C 2 -C 7 alkyl. WO 00/47568 PCT/USOO/02503 407
142. A compound of claim 138 wherein R', R^, R 2 , and R 2 A are independently selected from the group consisting of C 2 -C 4 alkyl.
143. A compound of claim 138 wherein R', RI^, R 2 , and R 2 Are independently selected from the group consisting of ethyl; n-propyl; n-butyl; and isobutyl.
144. A compound of claim 138 wherein R 3 , R 3 ^, R 4 , and R 4 ^ are independently selected from the group consisting of hydrogen and -OR 9 , wherein R 9 is as defined in claim 138.
145. A compound of claim 144 wherein R 9 is hydrogen.
146. A compound of claim 138 wherein RN and RNA are independently selected from the group consisting of hydrogen, alkyl and aralkyl.
147 A compound of claim 138 wherein RN and RNA are independently selected from the group consisting of hydrogen, (C-CIO)alkyl and aryl(C-CIO)alkyl.
148. A compound of claim 138 wherein RN and RNA are independently selected from the group consisting of hydrogen, methyl, ethyl and benzyl.
149. A compound of claim 138 wherein one or more RX and RxA are independently selected from the group consisting of methoxy and dimethylamino.
150. A compound of claim 138 wherein q and r are each 1.
151. A compound of claim 138 wherein one or more Ry are independently selected from selected from the group consisting of halogen; hydroxy; -N02; (C-CIO)alkyl; halo(C-CIO)alkyl; aryl(Ci-co)alkyl; WO 00/47568 PCT/USOO/02503 408 heterocyclyl(C-CIO)alkyl; polyether; -OR 13 ; -NR 13 RI 4 ; and -NR' 3 C(O)R"; 5 and wherein R 13 , R , and R 15 are independently selected from the group consisting of hydrogen; (CI-CIO)alkyl; halo(CI-Cio)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(C 1 -CIO)alkyl; heterocyclyl(CI-CIO)alkyl; quaternary heterocyclyl(CI-C O)alkyl; (CI-CIO)alkylheterocyclyl(C 1 -CIO)alkyl; 10 (C 1 -CIO)alkylammonium(CI-CIO)alkyl; and polyether; or wherein the R 13 , R 14 , and R 15 (CI-CIO)alkyl;halo(C 1 -Cio)alkyl; heterocyclyl; quaternary heterocyclyl; aryl(CI-CIO)alkyl; heterocyclyl(Ci CIO)alkyl; quaternary heterocyclyl(Ci-CIO)alkyl; (CI-CIO)alkylheterocyclyl(C 1 CIO)alkyl; (C 1 -CIO)alkylammonium(C 1 -CIO)alkyl; and polyether radicals 15 optionally may be substituted with one or more radicals selected from the group consisting of halogen; (Ci-Cio)alkyl; heterocyclyl; quaternary heterocyclyl; quaternary heterocyclyl(C-CIO)alkyl; carboxy; carboxy(Ci CIO)alkyl; -OR 16 ; -NR9R10; -N+ RRIORwA~; and -CONR 9 R 10 ; and wherein RAnd Rio are independently selected from the group 20 consisting of hydrogen; (CI-CIO)alkyl; heterocyclyl; ammonium(Ci-CIO)alkyl; (CI-Cio)alkylammonium(CI-CIO)alkyl; aryl(C 1 -CIO)alkyl; heterocyclyl(Cl CIO)alkyl; carboxy(CI-Cio)alkyl; carbo(CI-CIO)alkoxy(CI-C O)alkyl; carboxyheterocyclyl; carboxy(CI-CIO)alkylamino; and acyl; and wherein A~ is a pharmaceutically acceptable anion; and 25 wherein RI I and R 12 are independently selected from the group consisting of hydrogen; (C 1 -CIo)alkyl; heterocyclyl; aryl(CI-CIO)alkyl; carboxy(CI-CIO)alkyl; and carbo(CI-C O)alkoxy(CI-CIO)alkyl; or RI I and R 1 2 together with the carbon atom to which they are attached form a cyclic ring; 30 wherein R16 and R 1 7 are independently selected from the group consisting of R 9 and M; and wherein M is a pharmaceutically acceptable cation.
152. A compound of claim 138 wherein R 9 is selected from the group consisting of alkane diyl; polyalkane diyl; alkoxy diyl; and polyalkoxy diyl; wherein alkane diyl and polyalkane diyl can optionally have one or more carbons replaced by -O-; -NR-; -N+R R8A--; -S-; -SO-; -S02-; -S+R 7 A- - WO 00/47568 PCT/USOO/02503 409 5 PR 7 -; -P(O)R 7 -; -P+R 7 R 8 A--; or phenylene, wherein R 7 and R 8 are defined as in claim 138.
153. A compound of claim 138 wherein R 1 9 is selected from the group consisting of alkoxy diyl and polyalkoxydiyl wherein one or more carbons are optionally replaced by -0-; -NR 7 -; -N+R 7 R 8 A--; -S-; -SO-; -S02-; -S+R 7 A--; -PR 7 -; -P(O)R7_ -P+R 7 R8A--; phenylene; amino acid; peptide; 5 polypeptide; carbohydrate; or polyalkyl, wherein R 9 and R 0 are defined as in claim 138.
154. A compound of claim 138 having the formula: N N H H 0 0 0 NN o 0 N - \OH > S -- N N O H S-N 0 0
155. A pharmaceutical composition comprising an anti hyperlipidemic effective amount of a compound of formula (I) of claim 1; and a pharmaceutically acceptable carrier. WO 00/47568 PCT/USOO/02503 410
156. A pharmaceutical composition comprising an anti atherosclerotic effective amount of a compound of formula (I) of claim 1; and a pharmaceutically acceptable carrier.
157. A pharmaceutical composition comprising an anti hypercholesterolemia effective amount of a compound of formula (I) of claim 1; and a pharmaceutically acceptable carrier.
158. A pharmaceutical composition comprising an anti hyperlipidemic effective amount of a compound of formula (I) of claim 2; and a pharmaceutically acceptable carrier.
159. A pharmaceutical composition comprising an anti atherosclerotic effective amount of a compound of formula (I) of claim 2; and a pharmaceutically acceptable carrier.
160. A pharmaceutical composition comprising an anti hypercholesterolemia effective amount of a compound of formula (I) of claim 2; and a pharmaceutically acceptable carrier.
161. A method for the prophylaxis or treatment of a hyperlipidemic condition comprising administering to a patient in need thereof a composition of claim 155 in unit dosage form.
162 A method for the prophylaxis or treatment of an atherosclerotic condition comprising administering to a patient in need thereof a composition of claim 156 in unit dosage form.
163. A method for the prophylaxis or treatment of hypercholesterolemia comprising administering to a patient in need thereof a composition of claim 157 in unit dosage form. WO 00/47568 PCT/USO0/02503 411
164. A method for the prophylaxis or treatment of a hyperlipidemic condition comprising administering to a patient in need thereof a composition of claim 158 in unit dosage form.
165. A method for the prophylaxis or treatment of an atherosclerotic condition comprising administering to a patient in need thereof a composition of claim 159 in unit dosage form.
166. A method for the prophylaxis or treatment of hypercholesterolemia comprising administering to a patient in need thereof a composition of claim 160 in unit dosage form.
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