AU730024B2 - Combination therapy employing ileal bile acid transport inhibiting benzothiepines and HMG Co-A reductase inhibitors - Google Patents

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

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AU730024B2
AU730024B2 AU64408/98A AU6440898A AU730024B2 AU 730024 B2 AU730024 B2 AU 730024B2 AU 64408/98 A AU64408/98 A AU 64408/98A AU 6440898 A AU6440898 A AU 6440898A AU 730024 B2 AU730024 B2 AU 730024B2
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heterocycle
heteroaryl
quaternary
alkyl
aryl
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AU730024C (en
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Kevin C. Glenn
Bradley T. Keller
Robert E Manning
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GD Searle LLC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Description

COMBINATION THERAPY EMPLOYING ILEAL BILE ACID TRANSPORT INHIBITING BENZOTHIEPINES AND HMG Co-A REDUCTASE
INHIBITORS
BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to novel benzothiepines, derivatives and analogs thereof, in combination with hMG Co-A reductase inhibitors, pharmaceutical compositions containing them, and use of these compositions in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions such as is associated with atherosclerosis or hypercholesterolemia, in mammals.
Description of Related Art It is well-settled that hyperlipidemic conditions associated with elevated concentrations of total cholesterol and low-density lipoprotein cholesterol are major risk factors for coronary heart disease and particularly atherosclerosis. Interfering with the 2 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 e .ooooi WO 98/40375 PCT/US98/03792 atherosclerosis. Stedronsky, in "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 surrounding bile acids and cholesterol.
Pathophysiologic alterations are shown to be consistent with interruption of the enterohepatic circulation of bile acids in humans by Heubi, et al. See "Primary Bile Acid Malabsorption: Defective in -Vitro Ileal Active Bile Acid Transport", Gastroenteroloy, 1982:83:804-11.
In fact, cholestyramine binds the bile acids in the intestinal tract, thereby interfering with their normal enterohepatic circulation (Reihner, E. et al, in "Regulation of hepatic cholesterol metabolism in humans: stimulatory effects of cholestyramine on HMG- CoA reductase activity and low density lipoprotein receptor expression in gallstone patients", Journal of Lipid Research, Volume 31, 1990, 2219-2226 and Suckling el al, "Cholesterol Lowering and bile acid excretion in the hamster with cholestyramine treatment", Atherosclerosis, 89(1991) 183-190). This results in an increase in liver bile acid synthesis by the liver using cholesterol as well as an upregulation of the liver LDL receptors which enhances clearance of cholesterol and decreases serum LDL cholesterol levels.
In another approach to the reduction of recirculation of bile acids, the ileal bile acid transport system is a putative pharmaceutical target for the treatment of hypercholesterolemia based on an interruption of the enterohepatic circulation with specific transport inhibitors (Kramer, et al, "Intestinal Bile Acid Absorption" The Journal of Biological Chemistry, Vol. 268, No. 24, Issue of August pp. 18035-18046, 1993).
WO 98/40375 PCT/US98/03792 In a series of patent applications, eg Canadian Patent Application Nos. 2,025,294; 2,078,588; 2,085,782; and 2,085,830; and EP Application Nos. 0 379 161; 0 549 967; 0 559 064; and 0 563 731, Hoechst Aktiengesellschaft discloses polymers of various naturally occurring constituents of the enterohepatic circulation system and their derivatives, including bile acid, which inhibit the physiological bile acid transport with the goal of reducing the LDL cholesterol level sufficiently to be effective as pharmaceuticals and, in particular for use as hypocholesterolemic agents.
In vitro bile acid transportinhibition is disclosed to show hypolipidemic activity in The Wellcome Foundation Limited disclosure of the world patent application number WO 93/16055 for "Hypolipidemic Benzothiazepine Compounds" Selected benzothiepines are disclosed in world patent application number W093/321146 for numerous uses including fatty acid metabolism and coronary vascular diseases.
Other selected benzothiepines are known for use as hypolipaemic and hypocholesterolaemic agents, especially for the treatment or prevention of atherosclerosis as disclosed by application Nos. EP 508425, FR 2661676, and WO 92/18462, each of which is limited by an amide bonded to the carbon adjacent the phenyl ring of the fused bicyclo benzothiepine ring.
The above references show continuing efforts to find safe, effective agents for the prophylaxis and treatment of hyperlipidemic diseases and their usefulness as hypocholesterolemic agents.
Additionally selected benzothiepines are disclosed for use in various disease states not within the present invention utility. These are EP 568 898A as abstracted by Derwent Abstract No. 93-351589;
WO
89/1477/A as abstracted in Derwent Abstract No. 89- 370688; U.S. 3,520,891 abstracted in Derwent 50701R-B; US 3,287,370, US 3,389,144; US 3,694,446 abstracted in Derwent Abstr. No. 65860T-B and WO 92/18462.
HMG Co-A reductase inhibitors have been used as cholesterol-lowering agents. This class of compounds inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG Co- A) reductase. This enzyme catalyzes the conversion of HMG Co-A to mevalonate, which is an early and ratelimiting step in the biosynthesis of cholesterol.
Benzothiazepine anti-hyperlipidemic agents are disclosed in WO 94/18183, WO 94/18184, WO 96/05188, WO 96/16051, AU-A-30209/92, AU-A-61946/94, AU-A-61948/94, and AU-A- 61949/94.
The present invention furthers such efforts by providing novel pharmaceutical compositions and methods for the treatment of hyperlipidemic conditions.
With reference to the use of the word(s) "comprise" or "comprises" or "comprising" throughout the present specification, unless the context requires otherwise, those words are used on the basis and clear understanding that they are to be interpreted inclusively, rather than exclusively, and each of those words to be so interpreted in construing the description and/or the following claims.
SUMMARY OF THE INVENTION In a first aspect, the present invention provides a composition, comprising an ileal bile acid transport inhibitor and an HMG Co-A reductase inhibitor.
a In a second aspect, the present invention provides a S pharmaceutical composition, comprising: a first amount of an ileal bile acid transport inhibitor, and a second amount of an HMG Co-A reductase inhibitor, wherein said first and second amounts of said inhibitors together comprise an anti-hyperlipidemic condition effective amount of said inhibitors, and a pharmaceutically acceptable carrier.
In a third aspect, the present invention provides the use of a composition for the manufacture of a medicament for treatment of an anti-hyperlipidemic condition in a mammal.
In a fourth aspect, the present invention provides a combination therapy method for the prophylaxis or treatment of a hyperlipidemic condition in a mammal, comprising: administering to said patient a first amount of an ileal bile acid transport inhibitor, and administering to said patient a second amount of an HMG Co-A reductase inhibitor, wherein said first and second amounts of said inhibitors together comprise an anti-hyperlipidemic condition effective amount of said inhibitors.
In preferred embodiments of the first, second, third and fourth aspects of the invention: the HMG Co-A reductase inhibitor is selected from the group consisting of lovastatin, simvastatin, pravastatin and fluvastatin; or the HMG Co-A reductase inhibitor is atorvastatin; or the ileal bile acid transport inhibitor is a compound of formula 6 4 2 S PR 4 R' 1 R2 S 5 P4
R
4
(I)
wherein: q is an integer from 1 to 4; 20 n is an integer from 0 to 2; R' and R 2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituents selected from the group consisting of OR 9
NR
9 R'o, N.R'RlORwA, SR 9
S'R
9
R'OA
SP'R
9 R'oR"A, S(O)R 9
SO
2
R
9 S0 3
R
9 C0 2
R
9 CN, halogen, oxo, and CONR 9
RO,
wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or more carbons replaced by O, NR 9
N*R
9 R'OA, S, SO, SO S*R 9
P'R
9 or phenylene, wherein R 9
R'
0 and R" are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, heteroaryl, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; or R' and R 2 taken together with the carbon to which they are attached form C 3 -CIo cycloalkylidene; R' and R 4 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, heteroaryl, OR 9
NR
9 R'o, SR 9
S(O)R
9
SO
2
R
9 and S0 3
R
9 wherein R 9 and R'O are as defined above; or
R
3 and R 4 together form =NdR 11 S, =NNR"RL, =NR 9 or =CR' 12t wherein R" and R' are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, heteroaryl, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR 9
NR
9 R'O, SR 9 S R 9
SOR
9 S0 3
R
9 C0 2
R
9
CN,
halogen, oxo, and CONR 9 R'o, wherein R 9 and R' are as defined above, provided that both R 3 and R 4 cannot be OH,
NH
2 or SH, or R" and R' 2 together with the nitrogen or carbon atom to which they are attached form a cyclic ring;
R
5 and R 6 are independently selected from the group ~L\AN consisting of H, alkyl, alkenyl, alkynyl, aryl, S, 3 ycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteraryl, SR', S(O)R 9 S0 2
R
9 and S0 3
R
9 wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR NR SR', S (0)R,
SO
2 R SO 3
R
3 NR OR 4 NR13NR' 4 Rs, NO 2
CO
2 CN, OM, SO OM,
SO
2 NR1 3
R
4 C NR 3
R'
4 C OM, COR13, P R 3
R
4 P'R1 3
R
4
P(OR'
3 OR14, S'
R
R
4 and N'R 9 R"Rl 2
A-,
Wherein: A- is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can be further substituted with one or more substituent groups selected from the group consisting of OR 7 NR7R8,
SR
7 S(0) R 7 S0 2
R
7 S0 3
R
7 C0 2
R
7 CN, oxo, CONR 7
R
8
N'R
7
R
8
R
9
A-,
alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R 7
R
8 pR 7
RR
9 A, and P(O) (OR 7
OR
8 and ;2 wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can optionally have one or more carbons *replaced by O, NR', N'R R S, SO, SO 2 SR PR', P(O)R',
PR
7 RaA, or phenylene, and R1 3 and are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, heteroaryl and polyalkyl optionally have one or more carbons replaced by O, NR 9
N*R
9 R'OA, S, SO, SO
S.+R
9 A PR 9
P+R
9 RIOA, P R 9 phenylene, carbohydrate, amino acid, peptide, or polypeptide, and
R"
3
R
14 and R" 5 are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR 9
NR
9
R'
0
N*R
9
R'
1 2
A
SR
9 S(0)R 9 S0 2
R
9 S0 3
R
9 oxo, C0 2
R
9 CN, -halogen, CCNR 9 R1 0
SO
2 CM, SO 2
NR
9
R'
0
PO(OR'
6 )CR 1 7
P'R
9
R'
0 R"A, S*R 9
R'
0 A, and C CM, wherein R' 6 and R' are independently selected from the substituents constituting R 9 and M; or
R'
4 and R1' 5 together with the nitrogen atom to which they are attached, form a cyclic ring; R 7 and R' are independently selected from the group consisting of hydrogen and alkyl; and one or more R' are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR' 3
NR'
3
SR"
3 S S (0) 2
R'
3 S0 3
R
3
S'R'R
4 A NR' 3 0R'
NNR'
4 R1 5 N0 2
CO
2 CN, CM, SO 2 OMI SO 2
NR
3
R'
4
NR'
4
R'
3 C NR 3 R 1 4
NR'
4 C (0)R R' 3 C CM, COR1 3 OR', S rINR' 8
NR'R
8
NR
18 0R' 4
N'R
9
E)R
9 R"R'A, amino acid, peptide, polypeptide, and carbohydrate, wherein'alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, heteroaryl, acyloxy, arylalkyl, h aloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR 9
NR
9
R'
0
N'R
9 R1R 1 2 A, SR 9
S(O)R
9 SOR, S0 3
R
9 oxo, C0R 9
CN,
halogen, CONR 9
R'
0
SO
2 OM; SO 2
NR
9
R'
0 20 (OR' 6 )OR 1 7
P*R
9 RIR 1 2
A-,
9+R 9 R'OA, or C(0)OM, and wherein R1 8 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroar-yl, alkyl, quaternary heterocycle and quaternary heteroar-yl, wherein acyl, arylalkoxycarbonyl, arylalkyl, v\N ~>eterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group consisting of OR 9
NR
9
R
1
N'R
9
R"R
2
SR
9
S(O)R
9
SO
2
R
9 S0 3
R
9 oxo, C0 2
R
9 CN, halogen, CONR 9
R'
0
SO
3
R
9
SO
z
OM,
SO
2
NR
9
R
10 PO (OR 16
)OR
17 and C(O)OM, wherein in Rx, one or more carbons are optionally replaced by O, NR", N'R"R 1 4 S, SO, SO 2
S*R
3
PR",
P(0)R 13
P'R'
4 RA-, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by O, NR 9
N'R
9 R'A S, SO,
SO
2
PR
9
P'R
9 Ri'A", or P(O)R 9 wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, halogen, oxo, OR' 1
NR
3 SR", S(0) SO 2
SO
3
R
13
NROR
4
NR'
3
NR
4 R1 5
NO
2
CO
2
R
13 CN, OM, SO 2 OM, SO 2
NR
3 R14, C(O)NR "R 4 C(0)OM, COR 1 3
R
3 R1 4
P'R
3
R
4 RiSA P(OR 3
OR
14
S-R
1 3 R4A-, and N'R 9
R"R
2
A-,
provided that both R s and R 6 cannot be hydrogen, OH or SH, and when R 5 is OH, RL, R 2 R3, R4 R 7 and R' cannot be all hydrogen; provided that when RS or R 6 is phenyl, only one of R 1 or R 2 is H; provided that when q 1 and Rx is styryl, anilido, or anilinocarbonyl, only one of R' or R 6 is alkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
6 Mre preferably, R and R are independently selected from the group consisting of H, aryl, heterocycle, heteroaryl, quaternary heterocycle, and quaternary heteroaryl, wherein said aryl, heterocycle, heteroaryl, A quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups I ndependently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, halogen, oxo,, OR' 3 bNR1 3 R 1 4
SR'
3 1 S R1 3 SO R* 3 so3R 1 3 NR1 3 0OR 4 NR 1 3 NR1 4
R
15
NO
2
CO
2 R 1 3 CN, OM, SO 2 0M,
SO
2 NR13R1 4 C NR1 3 R 1 4 C CMI COR' 3 P R 3 R 1 4 ,*1R14R5 P (OR 1 3 OR 1 4
S+R
3 R'1 4 A, and N'R 9 R"R 1 2
A,
wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can optionally have one or more carbons replaced by 0, NR', N*R R 8 A, S, SO, SO 2 S*R A PR P R
P'R
7
R
8 A, or phenylene, wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can be further substituted with one or more substituent groups selected from the group consisting of OR 7
NR
7
R
8 SR 7 S(O)R 7 S0 2
R
7 S0 3 R 7 C0 2 R 7 CN, oxo,
CONR
7
N-R
7
R
8
R
9 alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R 7
R",
P*R
7
R
8
R
9 A, 'and 2(0) (0R 7 )0R 8
S.
25 5 6 Still--more preferably, Ror R has the formula: -Ar- (RY)t *6
S
S
S. S S
S
wherein: t is an integer from 0 to Ar is selected from the group consisting of phenyl, thiophenyl, pyridyl, piperazinyl, piperonyl, pyrrolyl, :3b naphthyl, furanyl, anthracenyl, quinolinyl, isoquinolinyl, quinoxalinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrimindinyl, thiazolyl, triazolyl, isothiazolyl, indolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, and benzoisothiazolyl; and 35 one or more Ry are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, -cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR 9
SR
9 S(o)R 9 S0 2
R
9 and S0 3
R
9 wherein said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, and heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, halogen, oxo, OR' 3
NR'
3
R'
4
SR'
3 S R' 3 So 2 R13,
SO
3
RI
3
NR'
3 OR'1, NR' 3
NRI
4 R1 5
NO
2
CO
2
R'
3 CN, OM, SOOM,
SO
2
NR
3 R1' 4 C NR' 3 R1 4 C OM, COR' 3 P(O)R R'R, P- 13R1 4
R'
5
A-,
P (OR' 3
OR'
4
S+R'
3 R'A and N*R 9
R"R'
2
A,
wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can be further substituted with one or more substituent groups selected from the group consisting of
OR
7
NR
7
R
8
SR
7 S R, S0 2
R
7 S0R 7 C0 2
R
7 CN, oxo,
CONR
7
N*R
7 R8R 9 alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R 7
R
8
P-R
7
R
8
R
9 and P(O) (OR 7 )ORa; and wherein said alkyl, alkenyl, alkynyl, polyalkyl,
S..
polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can optionally have one or more carbons replaced by 0, NR 7
N'R
7
R
8 S, SO, SO,, S-R 7
PR
7
P(O)R
7
P+R
7
R
8 or -phenylene.
5 6 Still more preferablyi R or R has the formula (II) a
RY
9*Y) Accordingly, among its various apects, the present invention provides compounds of formula (1)
R
3 wherein: q i san integer from 1 to 4; n -is an integer from 0 to 2;-
R
1 a 2 R andR are independently selected from* the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyJ-, 00 58 *0 a
POSOV!
00 WO 98/40375 WO 9840375PCT/US98/03792 dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalky., dialkylamino, alkylthjo, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituents selected from the group consisting of OR 9 NR R 10
N*RR
10 Rw,
SR
9
S+R
9
R
0 A, R S02R 9 S03R ,C02R 9 CN, halogen, oxo, and CONR R 10 wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cyc2.oalkyl optionally have one or more carbons replaced by 0, NR 9 N +R 9R.1 S, SO, S02, S+R P +R 9R 10A-, or phenylene, 9 1 wherein R R 10 and Rw are independently selected from the group consisting of H, al~kyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, heteroaryl, ammoniumalkyl, alkylammoniunalkyl, and arylalkyl; or Rl nd 2taken together with the carbon to which they are attached form cycloalkylidene; R 3and R 4are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heteroc~~R eRR 0 SRAd(OR S02R and S03R wherein R" and RIO are as defined above; or Rand
R
4 together form
=NOR
11
=NNR
1 1
R
1 =NR or C R wherein R and R are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle aor~iokyalkyl, carboalkoxyalkyl,' cycloalkyl, cyanoalkyl,
OR
9 NR R 10 SR
S(O)R
9 S02R S03R C02R 9 CN, halogen, oxo, and CONR 9
R
1
S-
WO 98/40375 PCT/US98/03792 9 10 wherein R and R 0 are as defined above, provided that both R and R 4 cannot be OH, NH and SH, or 11 12 R and R 12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring;
R
5 and R 6 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, heteroaryl; cycloalkyl, heter 6 cyCle,aquaternary heterocycle, quaternary 9 9 9 9 heteroaryl, SR ,S(O)R SO 2 R and SO 3 R9 wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroary1 heterocycle,Aquaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,heteroaryl arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR 1 3
N
13
R
14
SR
13 S(0)R 13 S02R 1 3 1 3 1 3
R
1 4 13 14 15 C02R 13
CN,
S02R13, S03R13, NR1OR 1 4, NR1NR1R 1 5, NO2, C02R 1 3
CN,
OM, S, S0M, S02NR 13
R
14
C(O)NR
13
R
4 C(O)OM, COR 13 P(O)R13R 1 4
P+R
1 3R 4 R5A-, P(OR")OR", and N RR 1 1
R
1 2
A-,
wherein: A is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can be further substituted with one or more substituent groups selected from the group consisting of OR 7
NR
7
R
8 SR7, S(O)R7, S02R 7 SO3R ,.C02R CN, oko, CONR R, N RR 8 R alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary WO 98/40375 PCT/US98/03792 7 8 heterocycle, quaternary heteroaryl, P(O)R R 8 p+R 7
R
8 RA and P(O) (OR 7
)OR
8 and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl,heterocycle and heteroaryl can optionally have one or more carbons replaced by 0, 7 +78 +7 7 7
NR
7 NR R S, SO, S02, S R PR 7
P(O)R
7 +7 8 13 14 15 P R R or phenylene, and R 1 3
R
14 and R 1 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heteroaryl, heterocycle,A and polyalkyl optionally have one or more carbons replaced by O, NR', N+R R 1 0 S, SO, S02, 9 9 9 S R A PR P+R R phenylene, carbohydrate, amino acid, peptide, or polypeptide, and
R
1
R
1 and R 1 are optionally substituted with one or more groups selected from the group consisting heteroccle, heteroaryl, le, quaternary of sulfoaJy,quaternary terocycle, quaternary heteroaryl, OR 9
NR
9
R
1 0
NR
9
R
1
R
2 A SR 9
S(O)R
9 S02R S03R oxo, C02R 9 CN, halogen, CONR 9
R
10 SO2NR 9 R0, PO(OR 1 6
)OR
1 7 p+R9R 1 R S+R9ROA-, and C(O)OM, wherein R 16 and R 17 are independently selected from the substituents constituting R 9 and M; or 14 15 R and R 15 together with the nitrogen atom to which they are attached, form a cyclic ring; 7 8 R and R are independently selected from the group consisting of hydrogen and alkyl; and one or more R x are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, WO 98/40375 PCT/US98/03792 haloalkyl, cycloalkyl, heterocycle, heteroaryl) polyether, quaternary heterocycle, quaternary heteroaryl,
OR
13
NR
13
R
14
SR
1 3
S(O)R
13 S(O)2R 13 13 13
R
14 13 0R 14
NR
13
NR
14
R
1 5 NO2, C 12R 3 S03R S R R NRO R RR N0,C2 CN, OM, S020M, S02NRR 14 NR C(O)R1, C(O)NR R 14 13 13 18 18 13 1 NR C(O)R C(O)OM, COR OR S(O)nNR NR R 18
R
14
N+R
9 R1R2A p+R 9
R
11
R
12 NR OR N .R R A, amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, 10 h teroary, polyalkyl, heterocycl e iacyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR9, NR 9
R
10 +9 11 12 9 s~)9 S29 9 N R R R A S R S S OxO, C02R 9 10 9 10~ OO1)O' CN, halogen, CONR R S02aM, S02NR R PO(OR")R',
P+R
9
R
1 1
R
1 2
S-R'R
10 or C(O)OM, and wherein
R
1 8 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaxyl, alkyl, quaternary heterocycle, and quaternary heteroaryl wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl)quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substiti.BI selected from the group 9 9 10 9 11 12 9 9(OR consisting of OR 9 NR R N R.R R A SR S(a)R 9 9 9 9 10 9 S02R S03R oxo,.CO2R CN, halogen, CONR R SO3R 1 9 10 16 17 SOOM, SO2NR R PO(OR )OR and C(O)OM, wherein in Rx, one or more carbons are optionally 13 b+ 13 14 13 replaced by NR N R S, SO, SO, S R A-, 13 13 13 14 PR P(O)R PRRA-, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, WO 98/40375 WO 9840375PCT/US98/03792 wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by 0, NR N R R A-, 9 9 910 S, SO, S02, S R PR P R R A- or P(O)R'; wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocy~ePl]ylalkyl, halogen, oxo-, OR 1 3
N
1 R R SR 13
S(O)R
13 S02R 13 S03R 13 NR 13
O
14 NR 13 NR 14
R
15 NO2, CO2R 13 CN, OM, S02CM, S02NR' 3
R
1 C(O )NR 13
R
1 C(O)OM, COR 13
P(O)R
13
R
1 P +R 1 3 R 14R 15A-,, P(OR 1 S'R"R KA, and N R 9 R 11
R
12
A-,
provided that both R 5 and R 6 cannot be hydrogen, 51 2 3 4 78 OH, or SH.,and when R 5 is OH, R, R R R R 7 and R cannot be all hydrogen; provided that when R 5 or R' is phenyl, only one of RIor R 2 is H; provided that when q 1 and R' is styryl, anilido, or anilinocarbonyl, only one of R' or R 6 is alkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Preferably, R 5 and R 6 can independently be selected from the group consisting of H, aryl, heterocyceAguternary heterocycle, and quaternary heteroaryl, wher ein said aryl, heterocycle, heteroaryl, quaternary heterocycle, and quaternary heteroaryl can be.
substituted with one or more subs tituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, halalkl, yclalylhetrhe~pTinavi halolky, cclolkyl heer~c.LA rylalkyl, halogen, 13 13 14 13 13 13 13 oxo, OR NR R SR, S(O)R, S02R S03R WO 98/40375 WO 9840375PCT/US98/03792 NR OR 1 4
NR
13
NR
14
R
1 N02, C02R 13 CN, OM, S020M, S02NR' 3
R
1
C(O)NR
13
R
1 C(O)OM, C0R 13
P(O)R
13
R
1 P +R 1 3 R 1 4 .R 1 5A-, P OR" 4 S+R"RA, and N+R 9 R 11
R
12
A-
wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and ItrcaLyJ can optionally have one or more carbons replaced by 0, 7 78 7 77 NR N R R S, SO, S02, S R PR P(O)R 7 P+R 7R8A-, or phenylene, -wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and hatmyl can be further substituted with one or more substituent 7 groups selected from the group consisting of OR NR R SR 7 S(OR S02R S03R C02R CN, oxo, CONR 7
R
8 N +R 7 R 8 R 9 alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle,~arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R 7R 8, P R R R9A-, and P )OR".
More pref erably, R" or RG has the f ormula: -Ar- wherein: t is an integer from 0 to 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, benzo 'imidazolyl, benzoxazolyl, benzothiazolyl, and benzoisothiazolyl; and one or more RY are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, WO 98/40375 PCT/US98/03792 cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, 9 9 9 9 9 quaternary heteroaryl OR SR S(O)R SO 2 R, and S 3
R,
wherein alkyl, alkenyl, alkynyl, aryl, cycloalkvl.
heterocycle, and heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, hlentrryl, arylalkyl, halogen, oxo, OR 13
NR
1 3 14
S
13 S(0)R 13 SO2R 1 3 SO3R 13
NR
13
OR
14
NR
13
NR
14 R, N02, C02R 13
CN,
1013 14 13 14 13 OM, SO2OM, SO2NR 13
R
14
C(O)NR
13
R
14 C(O)OM, COR 13 13 14 1314 15 14 2 1 P(O)R1 R 1 P R R R P(OR")OR, SR"R"'A, and NfRRll12 N+R 9
R
11 R A., wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl,jEtmrydle, a--red iy1 can be further substituted with one or more substituent groups selected from the group consisting of OR 7 ~78 7 7 77 NR7R SR S(O)R S02R SO3R CO2R CN, oxo, 7 8 78 9 CONR7R N R7R R alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, hetayl, arylalkyl, qatbany heterocycle, quaternary heteroaryl, P(O)R 7
R
8
P+R
7
R
8
A-,
and P(O) and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, and heteroayl can optionally have one or more carbons replaced by O,
N
7 8 7 77 R25 NR R S, SO, SO2, S R PR P(O)R, P R or phenylene.
Most preferably, R5 or R6 has the formula Most preferably, R or R has the formula (II): WO 98/40375 WO 9840375PCTIUS98/03792
(II)
(RY)t The invention is further sele-cted from among: R 20 R 1 9 R 2 1 directed to a compound (Formula DI) R 20 1 R 2 1 (Formula DII), and R 20 1 R 2 1 (Formula DIII) R 23 wherein R" is selected from the group consisting of alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy-diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide, wherein alkane diyl,-alkene diyl, alkyne' diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can optionally have one or more carbon atoms replaced by 0, NR 7, N R 7R 8, S, so, S0 2 S R R WO 98/40375 PCT/US98/03792 7 +7 8 PR P p R phenylene, heterocycle, heteroaryl, quaterncry heterocycle, quaternary heteroaryl, or aryl, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can be substituted with one or more eubstituent groups independently selected from the group Consisting of alkyl, alkenyl, alkynyl, polyalkyl.
polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, halogen, oxo, OR3, NR 13
R
14
SR
13
S(O)R
1 3 S02R 13 S03R 13
NR
13
R
1 4 NR13NRl 4 RS N02, C02R 13
CN.
0, S020, S02NR 13
R
14 C(0)NR13R14, C(O)OM, CR 13 13 14 314. 15 P(O)R R P R 13 R R P(OR")OR',
S*R
1 R"A, and
N'R
9
RR
1 2
A-;
wherein
R
1 further comprises functional linkages by which R is bonded to R, R, or R in the compounds of Formulae DII and DIII, and R0 in the compounds of Formula DIII. Each of R!8, R3 1 or en and R' comprises a benzothiepine moiety as described above that is therapeutically effective in inhibiting ileal bile acid transport.
The invention is also directed to a compound selected from among Formula DI, Formula DII and Formula Dill in which each of R 3 R and R" comprises a benzothiepine moiety corresponding to the Formula: 4r (Formula
DIV)
or: WO 98/40375 PCT/US98/03792 N (Formula
DIVA)
wherein R, R2, R, R R, R R q, and n are as defined in Formula I as described above, and R" is either a covalent bond or arylene.
In compounds of Formula DIV, it is particularly preferred that each of R 2 and R" in Formulae
DII
and DIII, and R" in Formula DIII, be bonded at its 7or 8 -position to R. In compounds of Formula DIVA, it is particularly preferred that R" comprise a phenylene moiety bonded at a m- or p-carbon thereof to R".
Examples of Formula DI include: R R R 2 RA RA R R3 RA R8A R R 4 R I0 +sdS R
R
19
R
4 A S+Ole) j
III)
WO 98/40375 WO 9840375PCT/US98/03792 ,(RI)t R1 RW" (IV) R'RS"X 1 RA I
R
7 (R Il R 7
A
and R4 R
M
+d RA IR)
R
7
A
(RYnt e (RXnq In any of the dimeric or multimeric structures discussed immediately above, benzothiepine cqmpounds of the present invention can be used'alone or in' various combinations.
in any of the compounds of the present invention, Rand R2 can be ethyl/butyl or butyl/butyl.
WO 98/40375 PCT/US98/03792 Other compounds useful in the present invention as ileal bile acid transport inhibitors are shown in Appendix A.
In another aspect, the present invention provides a pharmaceutical composition for the prophylaxis or treatment of a disease or condition for which a bile acid transport inhibitor is indicated, such as a hyperlipidemic condition, for example, atherosclerosis.
Such compositions comprise any of the compounds disclosed above, alone or in combination, in an amount effective to reduce bile acid levels in the blood, or to reduce transport thereof across digestive system membranes, and a pharmaceutically acceptable carrier, excipient, or diluent.
In a further aspect, the present invention also provides a method of treating a disease or condition in mammals, including humans, for which a bile acid transport inhibitor is indicated, comprising administering to a patient in need thereof a compound of the present invention in an effective amount in unit dosage form or in divided doses.
In yet a further aspect, the present invention also provides processes for the preparation of compounds of the present invention.
In yet another aspect, the present invention provides a combination therapy comprising the use of a first amount of an ileal bile acid transport.inhibitor and a second amount of a HMG Co-A reductase inhibitor useful to treat hyperlipidemic disorders, wherein said first and second amounts together comprise an antihyperlipidemic condition effective amount of said compounds.
HMG Co-A reductase inhibitor-compounds useful in the present invention are shown in Appendix B.- Further scope of the applicability of the present invention will become apparent from the detailed description provided below. However, it should be WO 98/40375 PCT/US98/03792 understood that the following detailed dscription and examples, while indicating preferred embodiments of the invention, are given by way of illustration only since various changes and modifications within the spirit and scope of the invention will beomce apparent to those skilled in the art from this detailed description.
DETAILED DESCRIPTION OF THE INVENTION The following detailed description is provided to aid those skilled in the art in practicing the present invention. Even so, this detailed description should not be construed to unduly limit the present invention as modifications and variations in the emobodiments discussed herein can be made by those of ordinary skill in the art without departing from the spirit or scope of the present inventive discovery.
The contents of each of the references cited herein, including the contents of the references cited within these primary references, are herein incorporated by reference in their entirety.
Definitions In order to aid the reader in understanding the following detailed description, the following definitions are provided: "Alkyl", "alkenyl," and "alkynyl" unless otherwise noted are each straight chain or branched chain hydrocarbons of from one to twenty carbons for alkyl or two to twenty carbons for alkenyl and alkynyl in the present invention and therefore mean, for example, methyl, ethyl, propyl, butyl, pentyl or hexyl and ethenyl, propenyl, butenyl, pentenyl, or hexenyl and ethynyl, propynyl, butynyl, pentynyl, or hexynyl respectively and isomers thereof.
"Aryl" means a fully unsaturated mono- or multiring carbocyle, including, but not limited to, WO 98/40375 PCT/US98/03792 substituted or unsubstituted phenyl, naphthyl, or anthracenyl.
"Heterocycle" means a saturated or unsaturated mono- or multi-ring carbocycle wherein one or more carbon atoms can be replaced by N, S, P, or O. This includes, for example, the following structures:
Z
z or wherein Z, Z" or is C, S, P, 0, or N, with the proviso that one of Z, Z" or is other than carbon, but is not O or S when attached to another Z atom by a double bond or when attached to another 0 or S atom. Furthermore, the optional substituents are understood to be attached to Z, Z" or only when each is C.
The term "heteroaryl" means a fully unsaturated heterocycle.
In either "heterocycle" or "heteroaryl," the point of attachment to the molecule of interest can be at the heteroatom or elsewhere within the ring.
The term "quaternary heterocycle" means a heterocycle in which one or more of the heteroatoms, for example, 0, N, S, or P, has such a number of bonds that it is positively charged. The point of attachment of the quaternary heterocycle to the molecule of interest can be at a heteroatom or elsewhere.
The term "quaternary heteroaryl" means a.
heteroaryl in which one or more of the heteroatoms, for example, 0, N, S, or P, has such a number of bonds that it is positively charged. The point of attachment of the quaternary heteryaryl to the molecule of interest can be at a heteroatom or elsewhere.
WO 98/40375 PCT/US98/03792 The term "halogen" means a fluoro, chloro, bromo or iodo group.
The term "haloalkyl" means alkyl substituted with one or more halogens.
The term "cycloalkyl" means a mono- or multiringed carbocycle wherein each ring contains three to ten carbon atoms, and wherein any ring can contain one or more double or triple bonds.
The term "diyl" means a diradical moiety wherein said moiety has two points of attachment to molecules of -interest.
The term "oxo" means a doubly bonded oxygen.
The term "polyalkyl" means a branched or straight hydrocarbon chain having a molecular weight up to about 20,000, more preferably up to about 10,000, most preferably up to about 5,000.
The term "polyether" means a polyalkyl wherein one or more carbons are replaced by oxygen, wherein the polyether has a molecular weight up to about 20,000, more preferably up to about 10,000, most preferably up to about 5,000.
The term "polyalkoxy" means a polymer of alkylene oxides, wherein the polyalkoxy has a molecular weight up to about 20,000, more preferably up to about 10,000, most preferably up to about 5,000.
The term "cycloaklylidene" means a mono- or multiringed carbocycle wherein a carbon within the ring structure is doubly bonded to an atom which is not within the ring structures.
The term "carbohydrate" means a mono-, di-, tri-, or polysaccharide wherein the polysaccharide can have a molecular weight of up to about 20,000, for example, hydroxypropyl-methylcellulose or chitosan.
The term "peptide" means polyamino acid'containing up to about 100 amino acid units.
The term "polypeptide" means polyamino acid containing from about 100 amino acid units to about WO 98/40375 PCT/US98/03792 1000 amino acid units, more preferably from about 100 amino acid units to about 750 amino acid untis, most preferably from about 100 amino acid units to about 500 amino acid units.
The term "alkylammoniumalkyl" means a NH, group or a mono-, di- or tri-substituted amino group, any of which is bonded to an alkyl wherein said alkyl is bonded to the molecule of interest.
The term "triazolyl" includes all positional isomers. In all other heterocycles and heteroaryls which contain more than one ring heteroatom and for which isomers are possible, such isomers are included in the definition of said heterocycles and heteroaryls.
The term "sulfoalkyl" means an alkyl group to which a sulfonate group is bonded, wherein said alkyl is bonded to the molecule of interest.
The term "active compound" means a compound of the present invention which inhibits transport of bile acids.
When used in combination, for example "alkylaryl" or "arylalkyl," the individual terms listed above have the meaning indicated above.
The term "a bile acid transport inhibitor" means a compound capable of inhibiting absorption of bile acids from the intestine into the circulatory system of a mammal, such as a human. This includes increasing the fecal excretion of bile acids, as well as reducing the blood plasma or serum concentrations of cholesterol and cholesterol ester, and more specifically, reducing LDL and VLDL cholesterol. Conditions or diseases which benefit from the prophylaxis or treatment by bile acid transport inhibition include, for example, a hyperlipidemic condition such as atherosclerosis.
The phrase "combination therapy" refers to the administration of an ileal bile acid transport inhibitor and a HMG Co-A reductase inhibitor to treat a hyperlipidemic condition, for example atherosclerosis WO 98/40375 PCT/US98/03792 and hypercholesterolemia. Such administration encompasses co-administration of these inhibitors in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each inhibitor agent. In addition, such administration also encompasses use of each type of inhibitor in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the hyperlipidemic condition.
The phrase "theraputically effective" is intended to qualify the combined amount of inhibitors in the combination therapy. This combined amount will achieve the goal of reducing or eliminating the hyperlipidemic condition.
Compounds The compounds of the present invention can have at least two asymmetrical carbon atoms, and therefore include racemates and stereoisomers, such as diastereomers and enantiomers, in both pure form and in admixture. Such stereoisomers can be prepared using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present invention.
Isomers may include geometric isomers, for example cis isomers or trans isomers across a double bond. All such isomers are contemplated among the compounds of the present invention.
The compounds of the present invention also include tautomers.
The compounds of the present invention as discussed below include their salts, solvates and prodrugs.
Compound Syntheses WO 98/40375 PCT/US98/03792 The starting materials for use in the preparation of the compounds of the invention are known or can be prepared by conventional methods known to a skilled person or in an analogous manner to processes described in the art.
Generally, the compounds of the present invention can be prepared by the procedures described below.
For example, as shown in Scheme I, reaction of aldehyde II with formaldehyde and sodium hydroxide yields the hydroxyaldehyde III which is converted to mesylate IV with methanesulfonyl chloride and triethylamine similar to the procedure described in Chem. Ber. 98, 728-734 (1965). Reaction of mesylate IV with thiophenol V, prepared by the procedure described in WO 93/16055, in the presence of triethylamine yields keto-aldehyde VI which can be cyclized with the reagent, prepared from zinc and titanium trichloride in refluxing ethylene glycol dimethyl ether (DME), to give a mixture of 2 3 -dihydrobenzothiepine VII and two racemic steroisomers of benzothiepin-(5H)-4-one
VIII
when R' and R 2 are nonequivalent. Oxidation of VII with 3 equivalents of m-chloro-perbenzoic acid (MCPBA) gives isomeric sulfone-epoxides IX which upon hydrogenation with palladium on carbon as the catalyst yield a mixture of four racemic stereoisomers of 4-hydroxy- 2,3,4,5-tetrahydrobenzothiepine-l,1-dioxides X and two racemic stereoisomers of 2 ,3,4,5-tetrahydrobenzothiepine-l,l-dioxides XI when R' and R' are nonequivalent.
Optically active compounds of the present invention can be prepared by.using optically active starting material III or by resolution of compounds X with optical resolution agents well known in the art as described in J.
Org. Chem., 39, 3904 (1974), ibid., 42, 2781 (1977), and ibid., 44, 4891 (1979).
WO 98/40375 WO 9840375PCT/US98/03792 Alternatively, keto-aldehyde vi where Fe is H can be prepared by reaction of thiopheno. V with a 2substituted acrolein.
WO 98/40375 PCT/US98/03792 Benzothiepin-(5H)-4-one VIII can be oxidized with MCPBA to give the benzothiepin-(5H)-4-one-l,l-dioxide
XII
which can be reduced with sodium borohydride to give four racemic stereoisomers of X. The two stereoisomers of X, Xa and Xb, having the OH group and R' on the opposite sides of the benzothiepine ring can be converted to the other two isomers of X, Xc and Xd, having the OH group and R' on the same side of the benzothiepine ring by reaction in methylene chloride with 40-50% sodium hydroxide in the presence of a phase transfer catalyst (PTC). The transformation can also be carried out with potassium t-butoxide in THF.
WO 98/40375 PCT/US98/03792 The compounds of the present invention where R' is OR, NRR' or S(O).R and R' is hydroxy can be prepared by reaction of epoxide IX where R 3 is H with thiol, alcohol, or amine in the presence of a base.
WO 98/40375 PCT/US98/03792
R
T R4 R1 S R 2
(R
3 0 HOR, or HNRR' or HS(O).R base
II
RR OH (RR 2
R
s OR, NRR 1
S(O).R
Another route to Xc and Xd of the present invention is shown in Scheme 2. Compound VI is oxidized to compound XIII with two equivalent of m-chloroperbenzoic acid.
Hydrogenolysis of compound XIII with palladium on carbon yields compound XIV which can be cyclized with either potassium t-butoxide or sodium hydroxide under phase transfer conditions to a mixture of Xc and Xd.
Separation of Xc and Xd can be accomplished by either HPLC or fractional crystallization.
WO 98/40375 PCT/US98/03792 The thiophenols XVIII and V used in the present invention can also be prepared according to the Scheme 3. Alkylation of phenol XV with an arylmethyl chloride in a nonpolar solvent according to the procedure in J.
Chem. Soc., 2431-2432 (1958) gives the ortho substituted phenol XVI. The phenol XVI can be converted to the thiophenol XVIII via the thiocarbamate XVII by the procedure described in J. Org. Chem., 31, 3980 (1966). The phenol XVI is first reacted with dimethyl thiocarbamoyl chloride and triethylamine to give thiocarbamate XVII which is thermally rearranged at 200-300 OC, and the rearranged product is hydrolyzed with sodium hydroxide to yield the thiophenol
XVIII.
Similarly, Thiophenol V can also be prepared from 2acylphenol XIX via the intermediate thiocarbamate
XX.
WO 98/40375 PCT/US98/03792 Scheme 4 shows another route to benzothiepine-1,1dioxides Xc and Xd starting from the thiophenol XVIII.
Compound XVIII can be reacted with mesylate IV to give the sulfide-aldehyde XXI. Oxidation of XXI with two equivalents of MCPBA yields the sulfone-aldehyde
XIV
which can be cyclized with potassium t-butoxide to a mixture of Xc and Xd. Cyclyzation of sulfide-aldehyde with potassium t-butoxide also gives a mixture of benzothiepine XXIIc and XXIId.
WO 98/40375 PCT/US98/03792 Examples of amine- and hydroxylamine-containing compounds of the present invention can be prepared as shown in Scheme 5 and Scheme 6. nitrobenzophenone is reduced with triethylsilane and trifluoromethane sulfonic acid to nitrodiphenylmethane 32. Reaction of 32 with lithium sulfide followed by reacting the resulting sulfide with mesylate IV gives sulfide-aldehyde XXIII. Oxidation of XXIII with 2 equivalents of MCPBA yields sulfonealdehyde XXIV which can be reduced by hydrogenation to the hydroxylamine XXV. Protecting the hydroxylamine
XXV
with di-t-butyldicarbonate gives the N,O-di-(t- WO 98/40375 PCTIUS98/03792 butoxycarbonyl) hydroxylamino derivative
XXVI.
Cyclization of XXVI with potassiumi t-butoxide and removal of the t-butoxycarbonyl protecting group gives a mixture of hydroxylamino derivatives xxviic and XXVIId. The primary amine XXXIIIc and XXXIIId derivatives can also be prepared by further hydrogenation of XXIV or XXVI1c and XXVIId.
WO 98/40375 PCT/US98/03792 Scm 5 WL~ bU~b I urS
IV
NO
NO
2 n hiadfl~~±Hrre~
NO
2
N(BOC)O(BC)
cxvi
R
2 2 MCPBA RZ ;-Pd/C XoaH (Boc)0o I poi-m t-butid& 2 acid wetim
NHOH
HOHN
R2 Ph
OH
pH/ XXel PdIC--1o pd. 50 ec 0"0 Ph R2 2 N
OH
Ph ,ocVgA t PdC.R 2 .10 ps. 5O -C e' O
R,
Ph
OH
xXmdd In Scheme 6, reduction of the sulfone-aldehyde
XXV
with hydrogen followed by reductive alkylation of the resulting amino derivative with hydrogen and an aldehyde catalyzed by palladium on carbon in the same reaction vessel yields the substituted amine derivative WO 98/40375 PCT/US98/03792 &h 6me 0O Ht Re QCO 0 o C rC_ xVI KOu
IMF
0 t N. O M XXVIII. Cyclization of XXVIII with potassium t-butoxide yields a mixture of substituted amino derivatives of this invention XXIXc and XXIXd.
Scheme 7 describes one of the methods of introducing a substituent to the aryl ring at the position of benzothiepine. Iodination of derivative XXX with iodine catalyzed by mercuric triflate gives the iodo derivative XXXI, which upon palladium-catalyzed carbonylation in an alcohol yields the carboxylate XXXII. Hydrolysis of the carboxylate WO 98/40375 PCT/US98/03792 and derivatization of the resulting acid to acid derivatives are well known in the art.
Abbreviations used in the foregoing description have the following meanings: THF-- -tetrahydrofuran WO 98/40375 PCT/US98/03792 PTC---phase transfer catalyst Aliquart 33 6---methyltricaprylylammonium chloride MCPBA---m-chloroperbenzoic acid Celite--- a brand of diatomaceous earth filtering aid DMF---dimethylformamide DME----ethylene glycol dimethyl ether BOC---t-butoxycarbonyl group R and R 2 can be selected from among substituted and unsubstituted C, to alkyl wherein the substituent(s) can be selected from among alkylcarbonyl, alkoxy, hydroxy, and nitrogen-containing heterocycles joined to the C to alkyl through an ether linkage. Substituents at the 3-carbon can include ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl,
-CH
2
C(=O)C
2 H, -CH,0C,H,, and -CH,0-(4picoline). 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 that the compound is achiral at the 3-carbon. Eliminating optical isomerism at the 3 -carbon simplifies the selection, synthesis, separation, and quality control of the compound used as an ileal bile acid transport inhibitor. In both compounds having a chiral 3-carbon and those having an achiral 3 -carbon, substituents
(R)
on the benzo- ring can include hydrogen, aryl, alkyl, hydroxy, halo, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkyl, haloalkoxy, (N)-hydroxycarbonylalkyl amine, haloalkylthip, haloalkylsulfinyl, haloalkylsufonyl, amino, N-alkylamino,
N,N-
dialkylamino, (N)-alkoxycarbamoyl, aryloxycarbamoyl, (N)-aralkyloxycarbamoyl, trialkylammonium (especially with a halide counterion), amido, (N)-alkylamido, -N-alkylamido,
-N,N-
31 WO 98/40375 PCT/US98/03792 dialkylamido, (N)-haloalkylamido, (N)-sulfonamido, alkylsulfonamido, (N)-haloalkylsulfonamido, carboxyalkylamino, trialkyl-ammonium salt, (N)-carbamic acid, alkyl or benzyl ester, N-acylamine, hydroxylamine, haloacylamine, carbohydrate, thiophene a trialkyl ammonium salt having a carboxylic acid or hydroxy substituent on one or more of the alkyl substituents, an alkylene bridge having a quaternary ammonium salt substituted thereon, where x is 2 to 12, w is 2 or 3 and X is a halo or a quaternary ammonium salt, and (N)-nitrogen containing heterocycle wherein the nitrogen of said heterocycle is optionally quaternized. Among the preferred species which may constitute Rx are methyl, ethyl, isopropyl, t-butyl, hydroxy, methoxy, ethoxy, isopropoxy, methylthio, iodo, bromo, fluoro, methylsulfinyl, methylsulfonyl, ethylthio, amino, hydroxylamine, N-methylamino, N,Ndimethylamino, N,N-diethylamino, (N)-benzyloxycarbamoyl, trimethylammonium,
A-,
-NHC(=0)CH, -NHC(=0) CsH 11 -NHC
CH,
carboxyethylamino, (N)-morpholinyl, (N)-azetidinyl, -N-methylazetidinium -pyrrolidinyl, pyrrolyl, -N-methylpyridinium -N-methylmorpholinium
A-,
and N-N'-methylpiperazinyl, (N)-bromomethylamido, N-hexylamino, thiophene, (CH,),COH I, -NCH,CH COH, -dimethylpiperazinium I, butyloxycarbamoyl, (N)-methylsulfonamido, methylpyrrolidinium, and -(OCHCH,),I, where A' is a pharmaceutically acceptable anion. The benzo ring can be mono-substituted at the 6, 7 or 8 position, or disubstituted at the 7- and -8 positions. Also included are the 6 ,7,8-trialkoxy compounds, for example the 6,7,8-trimethoxy compounds. A variety of other substituents can be advantageously present on the 6, 7, 8, and/or 9- positions of the benzo ring, including, for example, guanidinyl, cycloalkyl, carbohydrate a 5 or 6 carbon monosaccharide), peptide, and WO 98/40375 PCT/US98/03792 quaternary amnmonium salts linked to the ring via poly (oxyalkylene) linkages,
(OCH
2
CH.).-NR
3
R
1 4 R 1 A, where x is 2 to 10. Exemplary compounds are those set forth below in Table 1.
WO 98/40375 PCT/US98/03792 TABLE 1 Alternative comaunds 13 (!a=.mly FlOl.xx.yyy) S 3 z ~OH
R,
PIefiz M- F. Cpd) vvv)
R
1
=R
2 F101.00. 01 n-Prpy! n-propyl n-propy2 n-popyl n-propyl.
n-propyi n-Propy! n-propyl n-propyl Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 7-atbhy.
7-e hyl 7--o-buOyI.
7-tez=-hujtyl 7-O!, 7-CcH3 7-0 Cizo-p:opy!) 7-SC% 3 7-SC:C 3 7-S02CH3 General Notes In the description of the substituents indicates that a nitrogen bearing substituent is bonded to the ring structure via the nitrogen'atom.
Similarly, 2-thiophene indicates a bond in the 2 position of the thiophene ring. A similar convention is used for other heterocyclic sibstituents.
Abbreviations and Definitions NH-CBZ is defined as -mHC(=0)0CH 2 Ph WO 98/40375 WO 9840375PCTIUS98/03792 n-propyl n-p ropyl n-p ropyl r-propyl n-propyl n-propyJ.
n-propyl n-propyl n-propyl n-propy2.
n-p ropyl n-propy2.
n-propy2.
nt-p ropyl n-propyl n-propy2.
n-propyJ.
n-propyl n-propyl n-p ropyl n-propyl n-propyl n-propyl Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 7-SCH2CH3 7-NH2 7-KHOH 7-NHCH3 7-N1(CR3) 2 7-N+ (CH3) 3, 1- 7-NRC CH3 7-N(CCR2CR3) 2 7-NXeCH2CO2R 7-N+ (Me) 2CH2CO2H, I 7- -morpholino 7- -azetidine 7- -1-ethylazetidinium, I- 7- -pyrrolidine 7- -N-methyl-morpholiniun, I- 7- (N1) -N'-methylpiperazine 7-NH-CBZ 7-NF-C C5H11 7-NFC 7-NFH-C (NH) NH2 7- -thophene 34 n-prepyl n-propyl 36 n-propyJ.
37 n-propy2.
38 n-propyJ.
39 n-propyl n-propyl 41 n-propyl 42 n-propyl 43 n-prepyl 44 n-propyl n-p ropyl 46 n-propyJ.
47 n-propyl 48 n-propyl 49 n-propyl so n-propyl 51 n-propyl 52 n-propyl 8-rmethyl 8-ethyl 8-iso-propyl 8-tert-butyl 8-OH 8-OCH3 8-0 iso-propyl) B-SCH3 8-SOCH3 8-SO2CH3 8 -SCH2CH3 8-11H2 8 -NHOH 8 -NHCH3 8-N1(CR3) 2 8-N+(CH3)3, I- 9-NHC CR3 8-N (CH 2 CH3) 2 9 -NMeCH2C02H WO 98/40375 WO 9840375PCT1US98/03792 53 54 56 57 58 59 61 62 63 64 66 67 68 69 71 72 73 74 76 77 78 79 81 82 83 84 86 87 88 89 91 92 93 93 n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyJ.
n-propyl n-propyl fl-propyl n-propy].
n-propyl fl-propyl n-propyl n-propyl fl-propyl fl-propyl n-propyl n-propy].
n-propyl n-propyl n-propyl n-propyl fl-propyl n-propyl fl-propyl n-p ropy3.
fl-propyl n-propyl n-propyj.
n-propyl n-propyl n-propyl n-propyl n-propy2.
n-propyl n-propyl n-propyl F-propyl Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph-.
8-N* (Me) 2 CH2C 2
HPMUT
8- -morpholine 8- -azetidine 8- -N-methyazetidin±=,
I-
8- -pyrrolidine 8- -N-methyl-pyrrolidinium,
I-
8- -N-methyl-morpholinium,
I-
8 -methylpiperazine 8- (N)-N'-dimethylpjperazini=r,
I
8 -NH -CB Z 8-NHC (0)CS 8-NHC (0)CH2Br 8 -NH -C (NH) NH2 8- -thiophene 9-methyl 9-ethyl 9- 9-teprt-buty].
9-OC-43 9-0 (iso-propyl) 9-SCH 3 9-SOCH3 9-S02_CMq 9-SCH2CH 3 9 -NM2 9-NHoH 9-N (CH 3 9-NEC CH3 9-N (CH2CH 3 2 9-N~eCH2C0 2
H
9-N*(Me) 2 CH2CO 2 H, I- 9-M()-me rpholine 9- -a zetidine 9- -N-methylazetidinium,
I-
9- -pyrrolidine 9 -(N)-N-methyl-pyrrolidinium,
I-
9- -N-methyl-morpholinium,
I-
9- -N'I-methylpipera zine 9- -dime thylp ipe ra zinium, I- 9-NH-CBZ WO 98/40375 WO 9840375PCTIUS98/03792 n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-croovl Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 9-NHC CSHI.2 9-NHC CH2Br 9-NH-c (NH) NH2 9- -thiephene 100 101 102 103 7-OCH3, S-OCH3 7-SCH3, S-0CH3 7-SCH3, 8-SCH3 6-OCH3, 7-OCl3, 8-OCH3 Prefix Cpduw R 1 =R2 RS (R) (FFT vYV) F101.002 01.
02 03 04 06 07 08 09 11.
12 13 14 16 17 18 19 21.
22 23 24 26 27 29 31 n-butyl n-butyl n-butyl n-buty2.
n-butyl n-butyl n-buty.
r-butyl n-butyl n-butyl n-buty2.
n-butyl n-butyl n-butyl n-butyl n-buty.
n-butyl n-buty.
n-butyl n-butyl n-butyl n-buty3.
n-butyl n-butyl n-buty2.
n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 7-methyl 7-ethy2.
7-iso-oropy1 7-te rt-!utyl 7-OR.
7- L(iso-p ropyl) 7-SOCI- 3 7-SC 2CH3 7-SCH%2C*H3 7-NH2 7-NHOH 7-NHC!H3 7-N 2 3, 1- 7-NHC C-O) CH3 7-N (CH12CH3) 2 7-NheCH2C02H 7-N' (Me) 2CH2CO2H, I- 7-M()-morpholine 7- -azetidine 7- -N-methylazetidinium, I- 7- -pyrrolidine 7- -&V-methyl-pyrrolidili=f, I- 7- -N-methyl-=orphoini=, I- 7- -methylpiperazine 7- -dime thylpipe razili=, I- 7-NH-CBZ 7-NHC CSHl 7-NHC (0)CH2Br WO 98/40375 WO 9840375PCTIUS98/03792 34 36 37 38 39 41 42 43 44 46 47 48 49 so 51 52 53 54 56 57 58 59 61 62 63 64 66 67 68 69 71 72 73 n-but'kl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl n-butyl m-butyl n-butyl n-biutyl n-butyl n-butyl n-bu.tyl ri-butyl n-butyl ri-butyl ri-butyl n-butyl n-butyl n-butyl n-butyl ri-butyl n-buty2.
n-butyl a-uy n-butyJ.
n-butyl n-buty2.
n-butyl Ph- 7-NH-C (NH) NH2 Ph- 7- -thiophene Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 8-methyl 8 -ethyl 8-iso-propyl 8-tert-butyl 8 -OH 8-OCH3 8 -0 (iso -propyl) 8 -SCH3 S -SOCM 3 8 -S02CH3 8 -SCH2CH 3 8 -NH2 8 -NFOH 8 -NHCF'.3 8 -N (CH3) 2 8-N 4
(CH
3
I-
8-NYC) C1 3 8-N(CH2CF3) 2 8 -NlmeCH4 2
CO
2
F
8-Ni-(Me) 2C%:2CO2H,
I-
8-M()-merpholine 8 -a zetidine 8- (N)-N-ethlazetidni=,
I-
8- -pyr-rolidine 8- -N-methyl-pyrro lidiir,
I-
8- -N-m.ethyl-me rpholinium,
I-
8- -trethylpiperazine 8- -N'-dimethylpliperazinium, 8 -NH-CE I 8 -NHC C5 H 1 1 8 -NHC CH2 Br 8 -NH-C (NH) NH2 8- -thiophene 9-methyl 9-ethyl 9 -isO-propyl 9 -tert-butyl 9-oH 9-0CM 3 9-0 (is0-propyl) Ph- Ph- Ph- Ph- Ph- Ph- Ph- 41 WO 98/40375 WO 9840375PCTIUS98/03792 74 76 77 78 79 so 81 82 83 84 86 87 88 89 91 92 93 93 96 97 98 99 100 101 102 103 ri-buty2.
n-butyl n-butyl n-butyl n-butyl rn-buty1 n-butyl n-butyl n-butyl n-buty2.
n-butyl n-butyl n-butyl, n-butyl, n-butyl n-butyl.
n-butyl n-butyl n-buty.
n-butyl' n-butyl n-butyl n-butyl n-butyl.
n-butyl n-butyl, n-butyl n-butyJ.
n-butyJ.
Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 9-SCH3 9-SOCH3 9-SO2CH3 9-SCH.2CH3 9-NH2 9-NHOH 9-NHCH3 9-N (CH 3 2 9-N"'(CH 3 3 1- 9-NHC CH3 9-N CCH2CH 3 2 9-NMeCH2CO 2
H
9-U* (Me) 2CH%2CQZR, I- 9- -mo -pho line 9- -azetidine 9-CU)-N-rethylazetidinium,
I-
9- WN) -pyrrolidlne -N-=ethyl-mpol;jdnu, 3I- 9- -methylpiperazine 9-CM) -dim:.ethyipe~azinium,
I-
9-NH-CBZ 9-NFHC CH2B: 9-NHF-c 04H) NF2 9-C 2) -thicophene 7-OCH3, 8-CC-T3 7-SCH 3 8-OCH3 7-SCH 3 8-SCH3 pef~x Cpd#
R.R
2
R
5
(R)
w) F101.003 01 n-pentyl Ph- 7-methyl 02 03 04 06 07 08 09 n-pentyl fl-pentyl.
fl-pentyl n-pentyl fl-pentyl ri-pentyl n-pentyl fl-pentyl Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 7-ethyl 7 1 7-te rt-butyl 7-Oil 7-OCH3 7-0 (13o-p ropyl) 7-SCH 3 7-SOCH3 42.
WO 98/40375 WO 9840375PCT/US98/03792 11 12 13 14 16 17 18 19 21 22 23 24 26 27 28 29 31 32 33 34 36 37 38 39 41 42 43 44 46 47 48 49 51 n-pentyl n-penty2.
n-pen tyl n-pentyl n-pentyl n-pentyi n-pezityl n-pentyl fl-pezntyl n-pentyl n-penty2.
fi-pentyl n-pentyl n-pentyl n-penty3.
fl-pentyl n-pentyl n-pentyl n-pentyl n-penty2.
n-penty2.
n-pentyl n-pentyl n-pentyl n-pentyl n-pentyJ.
n-perity2.
n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-penty].
n-pentyl n-pezityl n-pentyl n-pentyl Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 7-SO2CH3 7-SCH2CM3 7-NH2 7-NHOPH 7 -NHCH3 7-N CCH3) 2 7-N+(CH 3 3
I-
7-NHlC CH3 7-N (CH 2
CH
3 2 7-NMeCH2C02H 7-N+ (MIe) 2CH2CO2H, I- 7- -morpholine -azetidine -pyrrolidine 7- -rmethylpiperazi-ne 7-NE-C 7- -thiophene S-ethyl S-iso-propvl 8-tert-butyl 8-oH 8-OCH 3 8-O0 -propyl) 8-SCH 3
S-SOCH
3 S-So 2
CH
3 8 -SCH2CH 3 8-NH 2 8-NHOK S-NHCH3 8-N (CH3) 2 8-N(CcH 3 3
I-
8 -NHC CH 3 8-N CCH2CH 3 2 4-3 WO 98/40375 WO 9840375PCT/US98/03792 52 53 54 56 57 58 59 61 62 63 64 66 67 68 69 71 72 73 74 7S 76 77 78 79 so 81 82 83 84 86 87 88 89 91 92 93 93 n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-perityl ri-pentyl n-pentyl n-peityl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyi.
n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyJ.
n-pentyl n-perxtyl n-pentyl n-pentyl n-pentyl n-rpentyl n-pentyl n-pentyl n-pentyl n-pentyl n-pentyl Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 9 -NMeCH2CO2 H 8-N*(Me) 2 CH2CO2H, I- 8-CN) -morpholine 8- -azetidine 8- -N-methylazetidiiu, I- 8- -pyrrelidine 8 -N-methyl-pyrro lidinium, I- 8- -N-zrethyl-morphcliniun, I- 8- -methylpiperazine 8- -dimethylpiperazinium, I- 8-NH-CSZ 8-NH'C CSHL1 8-NHC (0)CH2Br 8-NH-C (NH) NH2 8- -thiophene 9-rmethyl 9-ethyl 9-iso-propyl 9-ti=16-butyl 9-OH 9-OCH3 9-0 (iso-propyl) 9-SC'H3 9-SOCH3 9-SO2CH3 9-SCH2CH3 9-NH2 9-NHOH 9-NHCH3 9 -N (CH 3) 2 3, 1- 9-NHC CH3 9-N (CH2CH3) 2 9-NMeCH2CO2H 9-N 4 (Me) 2 CH2CO2H, I- 9- -=crpho line 9-(N)-azetidine 9- -N-methylazetidilium, I- 9- -pyrrelidiie 9- -N-methyl-pyrrolidilium, I- 9- -N-methyl-morpholifliu, I- 9- -methylpiperazile 9- -dime thylp ipe ra z iiu, I- 44 WO 98/40375 WO 9840375PCT/US98/03792 96 97 98 99 100 101 102 103 n-pentyl n-pentyl n-penty2.
n-pentyl n-perxtyl n-pentyl n-pentyl n-pentyl Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 9-NH-CBZ 9-NHC C5H 1 1 9-NHC (0)CH2Br 9-NH-c (NH) NH2 9- -thipherie 7-OCH3, S-0CH3 7-SCH3, 8-OCH3 7-SCH3, 8-SCH 3 n-ventvlPh- 6-Ocx 3 7-OCH3, 8-OCH3 P~eixCpd#
R
1
.R
2 R5 (A) 110.00.U4 -L Illexy.L Ph- 02 03 04 06 07 08 09 11 12 13 14 16 17 18 19 21 22 23 24 26 27 28 29 n-hexyl n-hexyl n-hexyl n-hexy2.
n-hexyl n-hexyl n-hexyl n-he xyl n-he xylI n-hexyl n-he xy 21 n-hexyl n-h exyl n-he xyl n-hexyl n-hexy3.
n-he xyl n-hexyl n-hexyl n-hexyl n-hexyl n-h exyl2 n-hexyl n-hexyl n-h exyl n-hexy2.
n-hexyl n-hexyl n-hexyl Ph- Ph- Ph- Ph- Ph- Ph- Ph Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 7-methyl 7-ethyl 7 -iso-propyl 7-OH 7-OCW.3 7-SCla-po 3 l 7-SoCm 3 7-SO~CH 3 7-SCH 2
CH
3 7-NH 2
F
7-NHICH3 7-.Nr(CH 3 2 7-NHC (-0)CH 3 7-N (CH2CH 3 2 7-NMeCH2CO 2
H
7-N (Me) 2CH2CO 2 H, I- 7- -morpho line 7- -azetidine 7- -N-methylazetidinium,
I-
7- -PYrrolidine 7- -N-methyl-pyrrlidinium,
I-
7- -N-methyl-morpholnium,
I-
7- -methylpiperazine 7- -dime thylp ipe raz inium, 7-NH-CBZ 7-NHC C5H 1 WO 98/40375 WO 9840375PCTIUS98/03792 31 n-hexyl Ph- 7-NR.C CH2Br 32 n-hexyl Ph- 7-NH-C (NH) NH2 33 n-hexyl Ph- 7 C2) -thiphene 34 n-hexyl Ph- 8-methyl n-hexyl Ph- 8-ethyl 36 n-hexy. Ph- 8 -iso-propyl 37 n-hexyl Ph- 8-tert-butyl 38 n-hexyl Ph- 8-OH 39 n-hexyJ. Ph- 8-OCH3 n-hexyl Ph- 8-O(iso-propyl) 41 n-hexyl Ph- 8-SCH 3 42 n-hexyl Ph- 8-SOCH 3 43 n-hexyl Ph- S-SO2CH3 44 n-hexyl Ph- 8-SCH42CH3 n-hexyl Ph- 8-NH 2 46 n-hexyl Ph- 8 47 n-hexyl Ph- 8-NFHC:-1 48 n -hexyl Ph- 8-N (CH 3 2 49 n-hexyl Ph- 8,-W (CH 3 3 ,1 n-hexyl Ph- 8 -11HC CH 3 51 n-hexyl Ph- 8-&V (CH2CH 3 2 52 n-hexyl Ph- 8-NMeCH2C0ZH 53 n-hexyl Ph- 8-(e 2 CH2CO 2 H, I- 54 n-hexyl Ph- 8 -rno rpholIine n-hexyl Ph- 8-(N)-azetidine 56 n-hexyl Ph-. 8-(N-N-methylazetidinium,
I-
57 n-hexyl Ph- 8-(N)-pyrrolidine 58 n-hexyl Ph- 8- -N-methyl-pyrrolidiniurni,
I-
59 n-hexyl Ph- 8 -N-methy-morphoini=,
I-
n-hexyl Ph- 8 -(N-N'-methylpiperazine 61 n-hexyl Ph- 8 -NI -dimethylpiperazin-um,
I-
62 n-hexyl Ph- 8-NH-CBZ 63 n-hexy]. Ph- 8-NHC(0) C 5
H
1 64 n-hexyl Ph- 8-NHC (0)CH2Br n-hexy2. Ph- NHC()N2 66 n-hexyl Ph- 8 2 )-thiphene 67 n-hexyl Ph- 9-methyl 68 n-hexyl Ph- 9-ethyl 69 n-hexyl Ph- 9-iso-propyl n-hexyl Ph- 9-tert-butyl 71 n-heacyl Ph- 9-OH 72 n-hexyl Ph- 9-OCH3 4(.
WO 98/40375 WO 9840375PCTIUS98/03792 73 74 76 77 78 79 so 82.
82 83 84 86 87 88 89 91 92 93 93 96 97 98 99 100 101 102 103 n-hexyl n-hexyl ri-hexyl n-hexyl ri-hexyl n-he xyl ri-h exy2.
ri-hexyl n-hexy2.
ri-hexyl ri-hexyl n-hexyl n-hexy2.
n-hexyl ri-hexyl n-hexyl n-hexyl ri-hexyJ.
ri-he xy).
ri-he xyl2 n-he xy2.
ri-hexyl n-he xyl ri-hexyl ri-he xyl1 n-hexy2.
n-h exyl n-hexyl n-h e.xvl n-he xy2.
Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Fh- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 9-0 (iso-p ropyl) 9-SCH3 9-SOCH3 9-SO2CH 3 9-SCH2CH3 9-NH2 9-NHOH 9-NHCH 3 9-N (CH3) 2 9-N+(CH3) 3
I-
9-NHC CH3 9-N (CH2CH3) 2 9-N,'1IeCH2CO2H 9-N* (Me) 2CH2CO 2 H, I- 9- N) no rpholine 9-M()-azetidine 9- -N-m-ehyazetidniu,
I-
9- -py::olidine 9- C71-'r.-ethy-rnorphoini=,
I-
9- -W'-methylpiperazine 9- -&m-ethylpime-zazi-n±-L,
I-
9-NhC Cr! 2 Br 9-N' C WHO) NH2 9- -thiophene 7-0CH3, S-OCH3 7-SC.,i 3 8-OCH3 7-SCH 3 8-SCH3 6-OCH3, 7-CCH3, S-OCH3 n-hexvlPh- Prefix Cpdt CFT.Zz. Yy) F101.005 01 02 03 04 06 07 08 (2R 1 ise-propyl iso-propyl iso-propyl iso-propy2.
iso-propyl iso-propyl iso-p ropyl iso-propyl Ph- 7 -methyl Ph- 7 -ethyl Ph- 7 -iso-propyl Ph- 7 -tert-butyl Ph- 7-oH Ph- 7-OCH3 Ph- -7-0 (iso-propyl) Ph- 7-SCH3 47 WO 98/40375 WO 9840375PCT/US98/03792 iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl ise-propyl iso-propyl iso-propyl iso-propy.
iso-propyl iso-propyl is 0-p ropyl izo-prepyl iso-propyl iso-propy].
iso-p ropyl iso-propyl iso-propyl iso-propyl iso-p ropyJ.
iso-propyl iso-p ropyl iso-propyl iso-propy].
iso-propy2.
iso-p ropyl iso-propyl iso-propy).
iso-propyl iso-propy3.
iso-p ropyl iso-propyl iso-propyl iso-p ropyl iso-propyl iso-propyl iso-propyl iso-p ropyl iso-p ropyl ise-propyl 13O-propyl.
iso-propyl Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph1*- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 7-SOCH3 7-SO2CH3 7-SCH2CH3 7-NH2 7-NHOH 7-NHCH3 7-N (CH3) 2 7-N 4 (CH3)3, I- 7-NR-C CH3 7-N (CH2CH3) 2 7-&VieC-2C02H 7-N*(Me) 2 CH2C02H, I" 7- -morpholine 7-(N)-azetidine 7- -N-wethylazetidiniu-n, I- 7- -pyrrolidine 7- -NI-methyl-pyrrolidinium, I- 7- -N-=ethyl-morpholiniu=, I- 7- -VI -zrethypiperazine -dimethylpiperazi-ni, I- 7-NH-CBZ 7-nHFC CSHII 7-NR.C CHi2Br 7--nF-C (NH) NH2 7- -thi;ophene 8-mnethyl 8-ethyl 8-iso-propyl 8-tert-butyl 8-OH 8-OCH3 8-0 (is o-propyl) S-SCH3 8-SOCH3 8-SO2CH3 8 -SCH2CH3 8 -NH2
S-NHOH
8-NHCH3 8-N (CR3) 2 B-N"'(CH3)3, I- S-NHC CR3 WO 98/40375 WO 9840375PCTIUS98/03792 iso-propyl iso-propyl 13o-propyl i~o-propy1 13O-propyl iso-propy.
iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl is c-p ropyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propy.
iso-propyl iso-propyl izo-propyl iso-p ropyl iso-propyl iso-prepy.
i3o-p rOpyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propy.
iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propyl iso-propy.
iso-propyl iso-p ropy.
iso-propy.
iso-propyl Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- -Ph- 4-9 8-N (CH2CH3) 2 8-NMeCH2CO2H ?CH2CO2H, I- 8- -mc rpho line 8-M()-azetidine 8- -N-methylazetidiiium, I- 8- -pyrrolidine 8- -N-rethyl-pyrralidinium,
I-
8- -N-methyl-morpholinium, i- 8- -methylpiperazine 8- -dimethylpiperazini=r, i- 8-NH-CBZ 8-NHC C5H 1 1 S-NHC CH2Br 8-NH-C (NH) NH 2 8- -thiophene 9-metkxyl 9-ethyl 9-tert-butyl 9-OH 9-OCH3 9-0 (isZo-pzopyl) 9-SCH3 9-SOCH3 9-S02CH3 9-SCHZCH3 9-NH2 9-NHOH 9-NHCH3 9-N (CH3) 2 9-N*c C31 9-N (CH2CH3) 2 9-NMeCH2CO2H 9-N (Me) zCH2CO2H, I- 9- -mc rpholine 9- -azetidine -N-methylazetidinium,
I-
9- -pyrrolidine 9- -N-methyl-pyrrolidinium,
I-
-u-methyl-morpholinium, I- 9- -methylpiperazine WO 98/40375 WO 9840375PCTIUS98/03792 93 i3o-propy1 Ph- 9- -N'diehlU num I- ±30-propyl Ph- 9-NiCcZ 96 iso-propyl Ph- 9-NHC (0)C 5 Hll 97 iso-propyl Ph- 9-NHC (0)CH 2 3r 98 iso-propyl Ph- 9 -NH -C (NH) NH2 99 ±so-propyl Ph- 9- -thiophene 100 iso-propy2. Ph- 7-OCp{ 3 8-OCH3 101 iso-propyl Ph- 7-SCM 31 -0H 102 iso-propyl Ph- 7-SCH3, S-SCH3 103 so-oooviPh- 6-OCH3, 7-OCH3, 8OH preflz pd
RI=R
2 5 azq (rFT vYY) R R)c FlO01.00o6 01 iso-butyl Ph- 7-methyl 02 iso-butyl Ph- 7-ethyl 03 iso-butyl Ph- 7 _iso-pro%)yj 04 iso-butyl P- 7 t~-uy iso-butyl Ph- 7-tetbuy 06 iso-butyl Ph- 7-04U3 07 iso-butyl Ph 0S iso-butyl Ph- 7SH 09 iso-butyl Ph- 7-SOCH 3 iso-butyl ch- 7 S2H 11 iso-butyl P- 7 -SC2CH 3 12 iso-butyl Ph- 7-SH 2
CH
iso-utylPh- 7
-NHOM
14 iso-butyl Ph- 7
-NHCH
3 iso-butyl Ph- -H3 iso-butyl Ph- 7-N (CH 3 17 iso-butyl Ph- 7-NHC (C0) C3, 18 iSo-butyl Ph- 7 -N(CH2CH 3 2 19 13o-butyl Ph- 7 -NMeCH 2
CO
2
H
13o-butyl Ph- 7-N* (Mie) 2CH2CO 2 H, I- 21 13o-butyl Ph- 7- -morpholine 22 iso-butyl Ph- 7- -azetidine 23 13o-butyl Ph- 7- -N-methyazetidini=,I 24 iso '-butyl Ph- 7-M()-pyrzolidine 13o-butyl Ph- 7- -N-methy-pyrrolidini±,
I-
26 iso-butyl Ph- 7- -N-=ethy-morpholinium
I
27 iso-butyl Ph- 7- -N'-frethypiprazine 28 13o-butyl Ph- 7- -dimethypiperazinium
I
29 iso-butyl Ph- 7-NH-Caz WO 98/40375 WO 9840375PCT/US98/03792 ise-butyl iso-butyl is 0-butyl is 0-butyl Ph- Ph- Ph- Phiso-butyl iso-buty].
iso-butyl iso-butyl 4 30-buty! iso-butyl iso-buty2.
is o-butyl iso-buty2.
iso-butyl iso-butyl iso-butyl is o-butyl iso-butyl iso-butyl iso-butyl is o-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyJ.
iso-butyl iso-butyl iso-butyl iso-butyl is o-butyl iso-butyl iso-butyl 13o-butyl is o-butyl iso-butyl iso-butyl is o-butyl iso-butyl iso-butyl iso-buty2.
iso-buty3.
P'h- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 7-NHC (O)CSH].l 7-NEC 0(25 7-NH-C (NH) NH2 7- -thiophene 8-methyl 8-ethyl 8-iso-propyl 8-tert-butyl 8-00(3 8-0 (iso-propyl) 8-SCE3 8 -SOCH3 S-SO2CH3 S-SCH2CH3 8-NH2 8-NhOH S -NE-CH3 8--N(CH3) 2 8 -NE-C CsEi 8-N (CH2CH13) 2 8 -NlIeCH2C0 2
H
8-N'(Me) 2 CH2CO2H, I- 8- -=~rpho line 8- -azetidirie 8- (N-N-methylazetidinum, I- 8- -pyrrolidine 8- -N-methyl-pyrrolidinium, i- 8-M()-N-methyl-morpholinium, I- 8- -NI -methylpiperazine 8- (N)-N'-dimethylpiperaziniumc,
I-
B-NH-CBZ
8-NHC (0)CS~ll 8-NEC CH2B= 8-NH-C (NH) NH2 8-M()-thiophene 9-methyl 9-ethyl 9-iso-propy.
9-tert-buty.
9--OH WO 98/40375 WO 9840375PCT/US98103792 72 73 74 76 77 78 79 82 83 84 86 87 88 89 91.
92 93 93 96 97 98 99 100 101 102 103 iao-butyl iao-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butyl 13o-butyl iso-butyl ise-butyl iso-butyl iso-butyl iso-butyl is o-butyl iso-butyl iso-butyl iso-butyl iso-buty.
iso-butyl iso-bu~tyl iso-buty.
iso-butyl iso-butyl 13o-butyl iso-buty.
iso-butyl izo-butyl iso-butyl iso-butyl iso-butyl iso-butyl iso-butvl Ph- Fh- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 9-OCH3 9-0 (is o-propyl) 9-SCM 3 9-S0CH 3 9-SO2CH3 9-SCH2CH 3 9-NH2 9-NHOH 9-NHCH3 9-N (CM 3 2 9-N 4 (CH3) 3
I-
9-NH.C CH3 9-N (CH2CH3) 2 9-N1'eCH2CO 2
H
9-N* (Me) 2CH2CO2H, I- 9- -mropholine 9- -azetidine 9- -N-.methylazetidinu..,
I-
-pyrrolidine 9- -NmthyI-mo rpho liniu, I- 9- -N'-methylpiperazine 9- -di..ethylp;peraz-nium,
I-
9-NH-CBZ 9-NFC CSM 1 9-vHC CH28z 9-NH-C (NH) H2 9- -thio~chene 7-OCH3, 8-CCH3 7-SCH3, 8-OCM3 7-SCH3, 8-SCH3 6-OCH3, 7-OCH3, S-OCH3 Ph- Prefix Cpdl Rl 1
R
2
RS
5
(RI)
(PIT. x. YYY F101.007 01 iz-en- 02 03 04 06 07 iso-pezityl iso-penty.
iso-pentyl iso-pentyl iso-penty.
Ph- Ph- Ph- Ph- Ph- Phi-1eLlY4.L 7-ethyl 7 -iso-propyl 7-tert -butyl 7-OH 7-OCH 3 7-0 (iso-propyl) WO 98/40375 WO 9840375PCT/US9/03792 08 13o-pentyl Ph- 7-SCH3 09 iso-perityl Ph- 7-SOCH3 iso-pentyl Ph- 7-S02CH3 11 ise-perityl Ph- 7-SCH2CH3 12 iso-perityl Ph- 7-NH2 13 iso-pentyl Ph- 7-NHOH 14 iso-pelty. Ph- 7-NFRCH3 iso-perityl Ph- '7-N (CH 3 2 16 13o-pen~tyl Ph- _tCjyT 17 iso-pentyl Ph- 7-NHC CH3 18 13o-pen~tyl Ph- 7-N (CH2CH3) 2 19 iso-penty. Ph- 7-W~eCH2CO2H iso-perntyl Ph- 7-N* (Me) 2CF2CO2H,
I-
21 iso-pentyl Ph- 7 -CN-morpholine 22 iso-peityl Ph- 7-(N1-azetid-4ne 23 13o-pentyl Ph- 7 -N-methylazetidinium,
I
24 iso-pentyl Ph- 7 -MN-pyrrolidine iso-pentyl 7 -'J-me hy -pyrr 1,dinium,
I-
26 i30-pentyl Ph- )?-ehymohoiiI 27 iso-pentyl Ph- 7 -nethypiperazine 28 iso-pentyl Ph- 7 -(4.4'I-dnehvlpiperazinum,
I-
29 iso-pentyl Ph- 7-%4H-CBZ iso-pentyl Ph- 7-NHC 31 iso-pentyl Ph- 7 -NH-C(0) CH 2
B
32 iso-pentyl Ph- 7-NVH-C (NH) NH2 33 iso-pentyl Ph- 7- -thiophene 34 iso-pentyl Ph- 8-.e t hylI iso-pentyl Ph- 8-ethyl 36 iso-pentyl Ph- 8-iso-propyl 37 iso-pentyl Ph- 8-tert-butvj.
38 iso-pentyl Ph- S-oH 39 iso-pentyl Ph- 8-OCH3 1so-pentyl Ph- 8-0 (iso-propyl) 41 iso-pentyl Ph- S-SCH3 42 iso-pentyl Ph- 8-SOCH3 43 iso '-penty. Ph- 8-S0 2
CF~
3 44 iso-pentyl Ph- 8-SCH2CH 3 iso-pentyl Ph- 8-NH2 46 iso-pentyl Ph- 8-NHOH 47 13o-pentyl Ph- S-NHCH 3 48 iso-pentyl Ph- 8-N(CH 3 )z 49 iso-pentyl Ph- S-N+ (CH 3 3, 1- WO 98/40375 WO 9840375PCTIUS98/03792 so 51 52 53 54 56 57 58 5-9-- 61 62 63 64 66 67 68 69 71 72 73 74 76 77 78 79 81.
82 83 84 86 87 88 89 91 92 iso-pentyl iso-penty2.
is 0-pentyl iso-pentyl iso-pentyl is 0-pentyl iso-pentyl 13o-pentyl.
iao-pentyl '3 0-pentyl iso-p entyl iso-pentyl iso-penty2.
ise-perityl iso-pentyl iso-pentyl iSo-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pe ntyl iso-pentyl iso-pentyl is0-perti2 ±so-pentyl iso-pentyl iso-pentyl is5o-pentyl iso -perity 1 i~o-pentyj.
is 0-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl 13o-pentyl iso-pentyl iso-pentyl iso-pentyl iso-pentyl iSo-pentyl Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 8-NHC (-0)C(3 8 -N (CH2CH3) 2 8 -N~1eCH2CO 2
H
8-WN (Me) 2CH2CO2H,
I-
8- -znorpholine 8 -a zetidine 8- -N-methyazetidni= 8- -pyrrolidiie Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph1- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 8- -N-methyl-morphojini
I
8- -methylpiperazine 8- -dimethylpiperazini,
I-
8 -NH-CBZ 8-N.C 8-NC CH2Br 8-NH-C (NH) NH2 8- -thiophene 9-methyl 9-e.hyl 9-OH 9 -0CH 3 9-0 (iso-propyl) 9-SCM 3 9-SOCH 3 9-S02CH~3 9-SCH2CH 3 9-VH 2 9-N (CH3) 2 9-N+ (CH 3 3 1- 9-NHC CH3 9-N (CH2CH 3 2 9 -N,4eCII 2
CO
2
H
9-N' (Me) 2CH2CO2H,
I-'
9- -morpholine 9- -azetid±ne 9- -N-methylazetidinim,.
I-
9 -(N)-Pyrrolidine 9- (N)-N-methy-pyrro jdinji,
I-
9- -N-methy-=rholini=,
I-
5i7 WO 98/40375 WO 9840375PCT/US98/03792 93 93 96 97 98 99 i3o-pentyl i3o-pentyl iso-penty2.
iso-peity2.
iso-peity.
iso-penty.
iao-pentyl is o-pentyl iso-pentyl iso-pentyl Ph- Ph- Ph.- Ph- Ph- Ph- Ph- 9- -NI -mehypioDE~te 9- -dimethylpiperazjn±,
I-
9-NH-CBz 9-RC 9-NHC C) CM2Br 9-NH-C (NH) NH2 9- -thiophene Ph- 7-n6gM A-eu 101.
102 103 7-SCH3, 8-CCR 3 7-SCH3, 8-SCM 3 6-0CH 3 7-0CH 3 8-0CH 3 4 Prefix Cpd# w~rv
R
1
=R
2 Its (Rx) q F101. 008 CH 2 C C 2
H
5
CH
2 C C 2
HS
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CM
2 C (-0)C 2
H
5
CH
2 C C 2 14 5
CH
2 C C 2
H
5
CM
2 C (-0)C 2
F'
5 CH1 2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2 Hi
CH
2 C (-0)C 2
H
5
CH
2 C C 2
H
5
CH
2 C
C
2
HS
CH
2 C (uO) C 2
H
5
CH
2 C C 2
H
5
CM
2 C C 2
H
5
CH
2 C C 2
H
5
CM
2 C C 2
H
5
CH
2 C (-0)C 2
H
5
CH
2 C C 2
H
5
S
CM
2 C C 2
H
5
CH
2 C C 2
HS
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5 Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 7-methyl 7-ethyl 7-is c-p opyl 7-CM3 7-0 (is o-propyl) 7- SCH3 7-SOCH3 7-SO2CF.
3 7-SCHZCH3 7-NHZ 7-NhjoF 7-NFCH3 7-N (CH3) 2 7-N+ (CH 3 3 7 -Nlic CH3 7-N (CH2CM 3 2 7-N2~eCFH2CO2H 7-N 4 (Me) 2CH2CO2H,
I-
7- -morpholine 7- -a zetidine 7- -N-methylazetidinium,
I-
7- -pyrrolidine 7- -N-methyl-pyrrolidini=,
I-
7- -N-methyl-morpholinium,
I-
7- -methylpiperazine 7- -dimethylpiperazinim,
I-
WO 98/40375 WO 9840375PCTIUS98/03792 29 31 32 33 34 36 37 38 39 41 42 43 44 46 47 48 49 51 52 53 54 56 57 58 59 61 62 63 64 66 67 68 69
CH
2 C C 2
H,
5
CH
2 C C 2
H(
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
H
5 Ph- Ph- Ph- Ph- Ph- 7
-NH-CBZ
7-NHC 7-NW.C CH2Br 7-NH-C (NH) NH2 -thiophene 8-methyl 8 -ethyl
CH
2 C C 2
H.
5
CH
2 C C 2
HS
CH
2 C
C
2
H
5
C-&
2 C C 2
HS
CH'
2 C C 2
H
5
CH
2 C C 2
H
5
C-'
2 C (-0)C 2 Hj CH4 2
C
2
H
5 CHq 2
C
2
H
5
CH
2 C C 2
H
5 CFi 2 C C 2
H
5
CH
2 C (iO) C 2 Hi
CH
2 C C 2
H
5
CH
2 C C 2 1: 5 C*1 2 C C 2
HS
CI%
2
C
2 Hi C-t 2 C C 2
HS
CHq 2
C
2
HS
CHt 2 C C 2
HS
C.H
2 C C 2
H
5 C*1 2
C
2
HS
C-H
2 C C 2
H
5
CF
2 C C 2
H
5 C-t 2 C C 2
H
5 CH1 2
C
2
H
5
CH
2 C C 2
H
5
CH
2 C C 2 H5
CH
2 C C 2
H
5
CH
2 C C 2
H
5
CH
2 C C 2
HS
CH
2 C C 2
HS
CH
2 C C 2
H
5
CH
2 C
C
2
H
5
CH
2 C C 2
HS
CH
2 C C 2 Hi
CH
2 C C 2
H
5 Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 8-tezt-butyl 8 -OH 8-OCH 3 8-0 (izo-propyl) 8-SCH 3 8 -SOC-43 S-S02CH 3 8 -SCiiZCH 3 8-NH 2 8-NHOH.
8-N*(CH3)3 8 C CH 3 8-N (CH2CH 3 2 8--NeCR 2
CO
2
H
8-N'(HAe) 2C-2C0 2 H, I- 8 -no rpho line -azetidine 8- -pyrrolidine 8- (N)-,-ehlproii m I- 8- -N-trethyl-morphoini=,I 8- -N'-methylpiperazine dimethypperazini=,1 8 -NH-CBZ 8-NHC 8 -NFIc CH2 Br 8-NH-C (NH) NH2 8-(2)-thiopherie 9-methyl 9-ethyl 9 -is0-propyl WO 98/40375 WO 9840375PCT/US98/03792 CH2C (-0)C 2 HS Ph- 71
CH
2 C C 2
H
5 Ph- 72 CH2C C2H 5 Ph- 73 CH2C
C
2 H5 Ph- 74 CH2C
C
2
H
5 Ph- CH2C
C
2
H
5 Ph- 76
CH
2 C C 2
H
5 Ph- 77 CH2C
C
2 HS Ph- 78
CH
2 C C 2
H
5 Ph- 7 8o CH2C
C
2
H
5 Ph- 81 CH2C
C
2
H
5 Ph- *82 CH2C(-0)C2H 5 Ph- 83 CH2C(-0)C 2 RS Ph- 84
CH
2 C C 2
H
5 Ph- CH2C(=0)C2H 5 Ph 86 CH2C
C
2 H= Ph- 87 CH2C(-0)C 2 P Ph 88 CHZ2C(-0)C2H 5 Ph- 89 CH2C(-O)C 2 F.Ph
CH
2 C C 2 HS Ph- 91
CH
2
C(-O)C
2
F~
5 Ph 92
CH
2 C C 2 Hi h 93 CH2C(=O)C 2 5 Ph- 93
CH
2 'C C 2 P. I2 Ph-
CH
2 C(-0)C 2 Ph- 96
CH
2 C(=0)C 2 .S Ph- 97 CHZC(-0)C 2
H
5 Ph- 98 CH2C
C
2 HS Ph- 99 CH2C
C
2 5 Ph- 9-tert-butyl 9-OH 9-0CH 3 9-0 (13o-propyl) 9-SCH 3 9-S0CH 3 9-S 02CH3 9-SCH2CH 3 9-NH2 -S9NHOv-- 9-NHCH 3 9-K (CR3) 2 9EC(=0) CH3 9-N (CH2CH 3 2 9-N (Me) 2CAH2CO 2 H, I- 9- -rnormholine 9- M) -azetidine 9- (SY-N-r.-ethylazetdnju, i- 9- -pyrzolidine 9- N-.Tethyl-pyrzolidni=,
I-
9- -N-methyl-mo rpho linium,
I-
9- -N'-methylpiperazine 9- WN) -dimethvlpiperazini=,
I-
9-NH-CBZ 9 -NF.C C5H 11 9-'L&HC CM2Br 9-NH-C (UH) NH2 9-M()-thiophene 100 CH2C(-0)C2HS Ph- 7-OCYH3, S-OCH3 101
CH
2 C C 2 HS Ph- 7-SCM 3 8-OCH3 102 CH2C
C
2 HS Ph- 7-SCH 3 S-SCH3 103 CH2C (iO) C2H5 Ph- 6-OCH3, 7-OCH3, 80OCH3 Pefix CPd#
RI=R
2 R.5 (R)q (rFF -zx. vv) F101.009 01
CH
2 0C 2
H
5 Ph- 7 -methyl 02
CH
2
OC
2
H
5 Ph- 7 -ethyl 03
CH
2 0C 2
R
5 Ph- 7 -iso-propyl 04
CH
2 0C 2
H
5 Ph- 7-tert-butyl WO 98/40375 WO 9840375PCT/US98/03792 CH20OC 2
.H
5 Ph- 7-OK 06
CH
2 0C 2 Hj Ph- 7-0C13 07 CH{ 2 0C 2 Hi Ph- 7 -O(izo-propyl) 08
CH
2 0C 2
H
5 Ph- 7-SCH3 09
CH
2 0C 2
H
5 Ph- 7-SOCiH 3
CH
2 0C 2 HS Ph- 7-SO2CH3 11
CH
2
OC
2 HS Ph- 7-SCH2CH 3 12
CH
2
OC
2
H
5 Ph- 7-NH2 13
CH
2 0OC 2 H Ph- 7-NHOH 14
CH
2 0C 2
H
5 Ph- 7-NHCH3
CH
2
OC
2 Hj Ph- 7-N(CH 3 2 16
CH
2 0C 2 Hj Ph- 7-.N+(CH 3 3
I
17
CH
2
OC
2 HS Ph- 7-NC CH3 18
CH
2 0C 2
H
5 Ph- 7-NCCH2C{ 3 2 19
CH
2 0C 2
H
5 Ph- 7 -N,4eCl12CO 2
H
CH
2 0C 2 HS Ph- 7 -W(Me) 2 C!{2C0 2 H, I- 21
CH
2 oc 2
H
5 Ph- 7-CN)-morpholine 22 Cm 2
OC
2
H
5 Ph- 7- -azet-idine 23 CH 2 0C 2 HS Ph- 7- !N-rnehyazeti-diniuna,
I-
24
CH
2
OC
2
H
5 Ph- 7 CiYpr~o 1-d-ne CH20C 2
H
5 Ph- -N-rehl-pyro1idniu-,
I-
-26
CH
2
OC
2
H
5 Ph- 7 -(N)-N-methy1-morphelini=r,
I-
27 CH 2
OCC
2
H
5 Ph- 7 -NI -methylpiperazine 28
CH
2
OC
2
H
5 Ph- 7 -CM) -dime thylp ipe ra zlnium, 29
CH
2
OC
2
H
5 Ph- 7-NVH-cBz
CF
2 0C 2
H
5 Ph- 7-NHC (0)C 5 1.
1 1 31
CH
2 0C 2
H
5 Ph- 7 -NHC CH2Br 32 CH20C 2
H
5 Ph- 7-NH-C (NH) NH 2 33
CH
2
OC
2
H
5 Ph- 7 2 )-thiophene 34
CH
2
OC
2
H
5 Ph- 8-methyl CH20C 2
H
5 Ph- 8-ethyl 36
CH
2 0C 2
H
5 Ph- 8 -iso-propyl 37
CH
2 0C 2
H
5 Ph- 8-te:t-butyl 38 CH 2
OC
2
H
5 Ph- 8-OH 39
CH
2
OC
2 HS Ph- 8-OCH3
CH
2
OC
2
H
5 Ph- 8 -0(iso-propyl) 41 C9 2
OC
2
H
5 Ph- SSH 42
CH
2
OC
2
H
5 Ph-
SOCH
3 43
CH
2 0C 2
H
5 Ph- S-So 2 Cjj 3 44 CH20C 2
H
5 Ph- 8-SCH 2
CH
3
CH
2
OC
2
H
5 Ph- 8-N1I2 46
CH
2 0C 2
H
5 Ph- S-NHOH WO 98/40375 WO 9840375PCT/US98/03792 47 48 49 51 52 53 54 56 57 58 59 61 62 63 64 66 67 68 69 71 72 73 74 76 77 78 79 81.
82 83 84 86 87
CH
2
OC
2
H
5 Ph- 8-NHCH3
CH
2
OC
2 H.S Ph- 8 -N (CH 3 2
CH
2
OC
2 HS Ph- 8-N+(CH3) 3
I-
CH
2
OC
2
H
5 Ph- 8-NHC(-o)CH 3
CH
2
OC
2 HS Ph- 8-N(CH 2
CH
3 2
CH
2
OC
2
H
5 Ph- 8-NMeCH2CO2H
CH
2 0C 2 H.S Ph- 8-N. (Me) 2 CH2CO2H, I-
CH
2
OC
2
H
5 Ph- 8 -mo rholine
CH
2
OC
2
H
5 Ph- 8- -azetidine
CH
2
OC
2
H
5 Ph- 8-M()-N-mthylazetidinium,
I-
CH
2 0C 2
H
5 Ph- 8-M()-pyrzolidine
CH
2
OCZH
5 Ph- 8-M()-N-mnethy-pyrro'idinium,
I-
CH
2
OC
2
H
5 Ph- 8-M()-N-methyl-mo rpholinium, I-
CH
2 0C 2
H
5 Ph- 8- CN) -NI -=ethylpiperazine
CH
2 0C2H.S Ph- 8 -dime thylp ipe ra ziniura, r
CH
2
OC
2
H
5 Ph- 8 -NH-CB Z
CH
2 CZH5 Ph- 8-.c()cH
CH
2 oC 2
H
5 Ph- 8 -NFC (0)CH 2 Br
CH
2
OC
2
H
5 Ph- 8 NH 2 CH2OC2H5 Ph- 8- (2rY-thlochene,
CH
2 0C 2
F-S
CH
2 0C 2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
CHl 2 0C 2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
HS
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2 0C 2
HS
CH
2
OC
2
H
5
CH
2
OC
2
HS
CH
2
OC
2
HS
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2 0C 2
H
CH
2
OC
2
H
5
CH
2
OC
2
HS
9-.T.eth v I 9-ethyl 9 -iso-propy! 9-OH 9-OC-1 3 9-0 (iso-propyl) 9-SCH 3 9-SOCH3 9-So 2
CH
3 9-SCH2CH 3 9-NHZ 9-NHOH 9-NHCH 3 9-N (CH3) 2 9-N+ (CH3) 3
I-
9-NHC (uO) CH3 9-N (CH2CH3) 2 9-N* (Me) 2CH2CO2H, I- 9- holine S i WO 98/40375 WO 9840375PCT/US98/03792 se 09 91.
92 93 93 C 95 97 98 99
CH
2
OC
2
H
5
CH
2
OC
2
H
5 CHj 2
OC
2
HS
CH
2
OC
2
HS
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2 0C 2
H
5 CH1 2
CC
2
H
5 CH2OC2H5
CH
2
OC
2
H
5
CH
2
OC
2
H
5
CX
2
OC
2
H
5
CH
2
OC
2
H
5
CH
2 0C 2
H
5
C-'
2
OC
2
HS
CH,)OC7, Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 9-CN) -azetidine 9-M()-N-nmethyazetidinium, I- 9- -pyrzolidine 9- -N-rmethyl-pyro lidiniu, i- -N-methyl-morpholinim, I- 9- -methylpiperazine 9- -dimethylpiperazinium, I 9-NH-CBZ 9-NHC-(O)-C 5 ll- 9-NHC CH2Br 9-NH(-C (14H) NH2 9- -thiaphene PhI*- Ph- Ph- Ph- 7-OCHi 3 S-OCH3 7-SC-13, 8-OCH3 7-SCH 3 S-SCH3 6-OC*H 3 7-OCH43, 8-OCH3 ire:! i Cpd#t Rl=a 2 R R (IY vvv) F101.0O10
CH
2 CH- (OH) C 2
H
5
CH
2 CH' (OH) C 2
HS
CH
2 CH (OH) C 2
H
5 C-4 2 CH (OH) CzHS
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
HS
CH
2 CH (OH) C 2
HS
CH
2 CH (OH) C 2
HS
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
HS
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
HS
CH
2 CH (OH) C 2 Hs C-4 2 CH (OH) C 2
H
5
CH'
2 CH (OH) C 2
H
5
CH
2 CH (OH) C2HS
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
HS
CH1 2 CH (OH) CAS 5 Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 7-methv2.
7-ethvl.
7-iso-propyl 7-OH 7-OCF-3 7-0 (i3o-propyl) 7-SCH3 7-SOCH3 7-S02CH3 7-SCH2CH3 7-UH2 7-KHOH 7-NHCH3 7-N (CH3) 2 7-N+(CH3) 3
I-
7-NHC CH3 7-N (CH2CH3) 2 7-NMeCH9C0 2
H
7-N 4 (Me) 2CH2CO2H, I- 7 -mo rpho line 7- -azetidine (go WO 98/40375 WO 9840375PCT/US98/03792 23 24 26 27 28 29 31 .33 34 39 37 38 39 41 42 43 44 46 47 48 49 so 51 52 53 54 56 57 58 59 61 62 63 64
CH
2 CH (OH) C 2
HS
CH
2 CH (OH) C 2
HS
CH
2 CH (OH) C 2
HS
CH
2 CH (OH) C 2
HS
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
HS
CH
2 CH (OH) C 2
HS
CH
2 CH (OH) C 2
H
5
_CH
2 CHCOH)CjH_
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) CAS 5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH" (OH) C 2
F
5
CH
2 CH (OH) C 2
H
5
CH
2 C*H (OH) C 2
P.
5
CH
2 CH- (OH) C 2
HS
CHZC-H (OH) C 2
H
5 Cli 2 CH (OH) C 2 Ha
CH
2 CH (OH) C 2
HS
C%
2 CH*- (OH) CZH 5
CR
2 CH (OH) C 2
H
5
CR
2 CF (OH) CAS 5
CH-
2 C'H (OH) C 2
H
5
CH
2 CH (OH) C 2 H5
CH!
2 CFH (OH) C 2
HS
CH!
2 CH (OR) C 2
H
5
CH
2 CH (OH) C 2
HS
CR
2 CH (OH) C 2
H
5
CH-
2 CR (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C2H 5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CR (OH) C 2
H
5
CH
2 CX (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
HS
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
H
5
CH
2 CH (OH) C 2
HS
Ph- 7- -N-=ethylazeA~~jw.m, I- Ph- -pyrrolidine Ph- 7- -N-methyl-pyrrolidin±un, I- Ph- 7- (M)-N-methyl-morpholiniun, I- Ph- 7- (N -methylpiperazine Ph- -dimethylpiperaziniu-a, i- Ph- 7-NH-CBZ Ph- 7-NiC C5H11 Ph- 7-NHC(O)CH2Br H-(H)N7 Ph- -thiophene Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- P h- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 8-methyl 8-ethyl 8-iso-prapyl 8-OH S-OCH3 8-Q( Uso-p ropyl) 8 SCH 3 8 -SOCH3 8-SO2CH3 8-SCH2CH3
S-NH
2 8-NHOH 8 -NHCH3 8-N(CH-3)2 8-NHC(-CH3 I 8-N (CH2CH3) 2 8 -NMeCH2CO2H 8-N' (Me) 2CH2CO2H, I- 8-M()-morpholine 8-M()-azetidine 8- -N-methylazetidinium, I- 8- -pyrrolidine 8- -N-methyl-pyrrolid~inium, I- 8- -N-methyl-=orpholinim, I- 8- -inethylpiperazine 8- -dimethylpiperazinium, t- 8 -N1-CBZ 8-NHC CSH11 8-NHC CH2Br WO 98/40375 WO 9840375PCT/US98/03792
CH
2 CH (OH) C 2
H
5 Ph- 8-NH-C (NH) NH2 66
CH
2 CH (OH) C 2
H
5 Ph- 8- -thiephene 67
CH
2 CH (OH) C 2 HS Ph- 9-mnethyl 68
CH
2 CH (OH)CAHS Ph- 9-ethyl 69 C-1 2 CH (OH) C 2
H.
5 Ph- 9 -i3o-propyl
CH
2 CH (OH) C 2
H
5 Ph- 9-tert-butyl 71
CH
2 CH (OH) C 2
H
5 Ph- 9-OH 72 C4 2 Pt (PH KCZHS PL- 9htm-OCH 3 73
CH
2 CH (OH) C 2 HS Ph- 9 -o(i~o-procyl) 74
CH
2 CH (OH) C 2
H
5 Ph- 9-SCH 3 CH2CH (OH) C 2 Hs Ph- 9-SOCH 3 76
CH
2 C-t (OH) C 2
H
5 Ph- 9-SO2CH3 77
CH
2 CH (OH) C 2
H
5 Ph- 9-SCHZCH 3 78 CH2C.H(OH)
C
2 HS Ph- 9-NH2 79
CH
2 CHi (OH) C 2
H
5 Ph- 9-NHOH CH2CH1(OH)
C
2 p.
5 Ph- 9-NHCH 3 81
CH
2 CH (OH) CZiJ. Ph- 9-N(CH 3 2 82 C 2 CH (OH) C 2
H
5 Ph- 9-L 3 3 1- 83 CH?1CHi(OF-)C 2
H
5 Ph- 9-NFC-)C 84 CH2C.-i(OH)
C
2 5 Ph- 9--n(CH 2 C4 3 2 (OF) C2 5 Ph- 9-;W.eC:.
2
CO
2
H
86
CA!
2 C*H Oki) C 2 Ph- 9.Vl(me) 2C.!2CO 2 H, I- 87 CH2CHI (OH) C 2
H
5 Phl- 9- -:or--ho line 88 CH 2 CH (OH) C 2 F5 Ph- 9 -(M)-azetidi-ne 89
CH
2 CHCOH) C 2 h5 Ph- 9 -(N)-&V-methylazetidiim
T-
CHn 2 CH (OH) C 2
FH
5 Ph- 9-M()-pyrzolidine 91 CM2CH COH) C 2 n 5 Ph- 9 -N-r.ehyl.pyrolidinium
I-
92
C-H
2 CF (OH) C 2
F
5 Ph- 9 (N)-N-methyl-morphoini=,I 93
CH
2 CH (OH) CZHS Ph- 9- -methylpiperazine 93 CHZCH (OH) C 2
P.
5 Ph- 9- -dimethylpiperazini,
I-
CH
2 CH C 2
H
5 Ph- 9-KH-c~z 96
CH
2 CH COH) C 2 H Ph- 9-NHC
CH
1 1 97 CH2CH (OH) CZH 5 Ph- 9 -NHC(O)CHi 2 Br 98
CH
2 CH (OH) C 2 HS Ph- -HCN)2 99
CH
2 CH (OH) C 2 HS Ph- 9 2 thiophene 100 CH2PH (OH) C 2 H5 Ph- 7-OCH 3 8-0CH 3 101
CH
2 CH (OH) C 2
H
5 'Ph- 7.-SCH 3 8-OCH3 102 CHzCH (OH) C 2 HS Ph- 7-SCH 3 8-SCH3 103
CH
2 CH (OH) C 2
H
5 Ph- 6-OCH 3 7-OCH3, 8-0CH 3 (a WO 98/40375 WO 9840375PCTIUS98103792 prefiz Cpdf pl.R 2 02 03 04 06 08 09 11 12 13 14 16 17 18 19 21 22 23 24 26 27 28 29 31 32 33
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- 4 -picoline) CHZO- (4-picoline)
CH
2 0- 4 -picoline) -CHj-a---4 -p0 doIrln)
CH
2 O- (4-pica line)
CH
2 O- (4-picoline)
CH
2 O- (4-pica line)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-picoline)
CHJ
2 O- (4-p icoline)
CH
2 O- (4-picoline)
CH
2 O- 4 -picoline)
CH
2 O- (4-picoline) CH20- (4-picoline) CF20- (4-picoline)
CH
2 O- (4-picoline)
CH
2 O- 4 -picoline)
CH
2 O- 4 -picoline)
CH
2 O- (4-pica line)
CH
2 O- (4-picoline)
CH
2 O- 4 -picoline)
CH
2 O- (4-picoline)
CH
2 0- 4 -picoline)
CH
2 O- C 4 -picoline)
CH
2 O- (4-picoline)
CH
2 O- (4-pica line)
CH
2 0- (4-pica line)
CH
2 0- 4 -picoline)
CH
2 0- (4-picoline)
CH
2 O- C 4 picoline)
CH
2 O- 4 -picoline)
CH
2 O- 4 -picoline)
CH
2 O- C( 4 -picoline)
CH
2 O- (4-pica line) Ph- 7-methyl Ph- Ph- Ph- Ph- Ph- Ph Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Phl*- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Phph- Ph- Ph- Ph- Ph- 7-ethyl 7 -izo-propyl 7-tert-butyl 7-OH 7-OCH 3 7-0 (is o-propyl) 7-SCH 3 7-SOCH3 7-SO2CH3 7-SCH2CH3 7-NH2 7-N.OH 7-NHCH3 7-M (CH3) 2 7-N(CH2CX 3 2 7-"N>!eCH 2
CO
2
H
7-N'4 2CH2CO2H, I- 7- -ma :pholine 7- MN -azeti- d;ne -N-mTethylazetidinium, I- 7-M()-pyrroiidine 7- -N-me thyl-pyrroiid-intim., I- 7- (N -N-me thyl-mo rpho liniumn, I- 7- -N'-methylpiperazine 7- -dim-ethylpiperazinium,
I-
7-NH-CBZ 7-NH.C (0)CS 7-NHC (0)CH2Br 7-NH-C (NH) NH2 7- -thiophene 8-methyl 8 -ethyl S-iso-pzrapyl 8-tert-butyl s-OH S-CCH3 WO 98/40375 WO 9840375PCT/US98/03792
CH
2 O- (4-picoline) 41. CH 2 O- 4 -picoline) 42 CH 2 O- 4 -picoline) 43 CH 2 O- 4 -pieoline) 44 CH 2 O- (4-picoline)
CH
2 0- 4 -Picoline) 46 CH 2 0- 4 -picoline) 47 CH 2 0- 4 -picoline) Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 48 49 51 52 53 54 56 57 58 59 61 62 63 64 66 67 68 69 71 72 73 74 76 77 78 79 81
CH
2 0- 4 -piceline)
CH
2 0- 4 -Picoline)
CH
2 O- 4 -Picoline)
CH
2 O- 4 -picoline)
CH
2 0- 4 -picoline)
CH
2 O- 4 -picoline)
CH
2 O- 4 -picoline)
CH
2 O- 4 -picoline)
CH
2 O- 4 -Picaliie)
CH
2 O- 4 -picoline)
CH
2 O- C 4 -picaline)
CH
2 0- 4 -picoline) CHq 2 O- (4-picoli;ne)
CH
2 O- 4 -picoline)
C.
2 O- 4 -Picoline)
CH
2 0- 4 -picoline)
CH
2 O- (4-picaline)
CH
2 O- 4 -picoline) CFHzO- 4 -picoline)
CH
2 0- 4 -picoline)
CH
2 O- 4 -picoline)
CH
2 O- 4 -picoline)
CH
2 O- (4-picoline)
CH
2 O- 4 -picoline)
CH
2 O- 4 -pieoline)
CM
2 0- (4-piceline) CH2O-(4picoline)
CH
2 O- 4 -piCOline) CHZO- 4 -picoline) CH20- (4-pico line)
CH
2 O- (4-picoline)
CH
2 O- (4-pica line)
CH
2 0- 4 -picoline) Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- 8-0 (iU3o-propyl) 8 -SCH3 8 -SOCH3 8 -SO2CH3 8-SCH2CH 3 8-NHOH 8 -NFICH3 8-N (CH3) 2 8-N+ (CH3) 3, 1- 8 -NHC CH3 8-N(CH2C.H 3 )2 8-NY~eCH 2 C0 2
H
8-N' (Me) 2CH%2CO2H, I- 8 -m a ho line 8- -azetidine 8- -pyzrolidine 8 -N-=ethy! -pyrrelidini=,
I-
8(N) -N-=,.ethyl-mcrpholinium,
I-
-NI' -ethylpiperazine 8- -dimet~hylpiperazinium, 8-NH%-cBz 8 -UHc C 5.
1 1 8 -NFC CH-2 Br 8-NH-C NH2 8- -thiophene 9-methyl 9-ethyl 9 -iao-propyl 9-OH 9-OCH3 9-0 (iso-propyl) 9-SCH3 9-SOCH 3 9-S02CH 3 9-SCH2CH 3 9-NH-2 9-NHOH 9-NHCH 3 9-N (CH 3 2 Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- Ph- WO 98/40375 WO 9840375PCT/US98/03792 82 83 84 8s 86 87 88 89 90.- 91 92 93 93 96 97 98 99 100 101 102 103
CH
2 O- (4-picoliie) Ph- CH20- (4-picoline) Ph-
CH
2 O- (4-picoline) Ph- Cl2O-(4-picoline) Ph-
CH
2 0- (4-picoline) Ph- Cl{ 2 0- (4-pica line) Ph-
CH
2 0- (4-pica line) Ph-
CH
2 0- (4 -piLco Iine) Ph-
CH
2 0- (A4-pica-ni-e) -Ph--
CH
2 O- 4 -picaline) Ph-
CH
2 O- (4-picoline) Ph-
CH
2 0- 4 -picaline) Ph-
CH
2 O- C 4 -picoline) Ph-
CH
2 O- 4 -piceline) Ph- CH-(4-picoline) Ph-
CH
2 O- 4 -picoline) Ph- CF2-(4picoline) Ph-
CH
2 0- 4 -picoline) Ph- 9-N' *(CH 3 3, 1- 9-NHC CH3 9-N CCH2CH3) 2 9-NXCCH2CO2H 9-N*(Me) 2 CH2CO2H, I- 9-M()-morpholine 9- -azetidine 9- -N-trethylazetidinium, i- 9 -(N--pyrrlidine 9- -N-rethyl-pyrrolidinium,
I-
9- -N-me thyl-me rpholinim, I- 9- -methylpiperazine 9- -dirnethylpiperazinium,
I-
9-NH-CaZ 9-&NHC CSH.
1 9-NHC (0)CR28: 9-NH-C (NH) NH2 9- -thiaphene 7-0CH.3, S-OCH3 7-SCH 3 S-OCH3 7-SCH3, S-SCH3 6-OCH3, 7-QCH3, S-OCH3
CH
2 O- 4 -picaline)
CH
2 O- 4 -picoline)
C.!
2 0- (4-pi-Colirie)
CH
2 O- (4-picoline) Ph- Ph- Ph- Ph- Additional Structures of the Present Invention Compound
J(
101 ethyl n-butyl OH H phenlyl H 0 102 ethyl n-but I OH I f phliyl H at tile 7-position )03 n-butyl ethyl OH H p~e~lH 74triineth lammonim n dide 104 ethyl n-butyl O-H- *TH Ihnt 7-dimletlhylimino 105 thyl n-buyphOenyIl)fI H 1 7 -mothaaiesulloiiamido 106 edlyl n-btutyl 0 1 -'lwity II 1 7-( 2 rontoicetamido) 107 -n-butyl ethyl OH H 4-(deCYloxY)pltelyl H -aIun-inL 108 eth~yl i-btityl OH- TF phellyl H 7-(hexylaanido) 109 ethyl n-butyl OH H- 4-(decyloxy)Phelyl
H-
110 etlyl n-butyl- ORT H phenlyt 7-ctan 111n-bt I~FF TF4-liydroxyplhenyl H 7 -amino 11') I I I iIlysI Itf-butyi I H [0 0\ne 11 yl~.,y s-etlxpiiy 4-hdrlbellyl 4oehpllyl plienlyl plienyl phellyl plienyl_ I I I I ethlv n-bulvi 1 2butA ethlty ni-blitv OH I H- iti -c L.
"-EjutI I Ll eillv I l- ethyl n-buivi 117 jEV ethyl 1-blityl OH I Iethyl n-butl OH 1-1 120 n-butyL_ ethyl OH_ TF 121 eth~yl itn-buityl -oaF TFR 122 n-butyl ethyl OH HF 123 ethyl n-butyl OH Tff- 124 n-butyI eth Il OH HF 125 n- ty F 126 n-butyl- ethyl OH HF 127 n1-bulyl ethyl OH TF_
H
H_
H
H
H
H
H
H
H
H_
H
7-amnm 7 -aanino l-(-benzylcarbamato) 7 -P(Oe-but .ycarsamt) eii nzylc r rnaito) -(O-enzbuylcarbmao) I -(-bezaraio T 7-hexylaminlo -T 7 -(hexylamino) at the Sip sition 7 -(O-bejizvlcarbamnato1 I 7-amino 7 benzylcarbamato) 'It lite 7 -pt'sitilrn -4-fitiorop 4-thion hleityl elily' fl-butyl 29 1 is I I I- !t N w w C ly n,-uiv r .L.1 'lityl 4 -iltioroplienyl 4-Iluioropphenyl emp fl-butyl OHi I H 132 1 ethyl I ~tl OHIHI- aulocsvl 133 1 ethyli 1 n-bII 1 niltI u 1I 1C t i.i I no r; vr y sJmy! phenyl
H
135 I ethvlI n-butvI 1 0H 1W i I pJ i nIIs 13- ethyl n-butyl OHF HF phllyl r 137 n-butyl ethyl OH H phelyI
H-
13 n-butyl I ethyl 7WF iT -a II4 at lite 8-posit ioal S-(hexyloxy) at the S-Position -iat lte B-position N0 at the 7-position 8-ncetoxV i t lte 7 -position 7rn-mehyimercaplo 7-ethoxy 139 1 nbii I t i I nsI~i ftI aI pinenyi I L 142 ethlyl I nbuty I-I 1- ,l
H
1-1 IAI 61 1 1. I i e 11 te
IAA
es Iy' n-Dutly' 3-lflethoxy 1 )lnyl 4 -fitiorulhllyl ethyl n-lu sOul 263 1 I -I 1 I W Ar i -InllIiox yphllyI I I I, I 3-moo xy- I 264e- -bu H ley 264etyl n-uyl UF 3-triflunornctlay pheny I H 7-methoy- 265 ethyl n-butyl H dH H 3 -trifluro 7 -omeliuoxy 1 methyl.
266 illl n ulyl H Etnyl 26 ehy nbuyHO 3-hydroxyphenyl H 7-hydr-oxy 267 ethyl n-butyl OH H 3-hydroxyphenyl H 1-metho Y- 268 ethyl nbll OH -H 4-fluoriiplienyl H 1 7-metlloxy 269 eth. yl n-butyl H T 74- N. oir. 7-inetlioxy 270 ethyl n-butyl OH H4-flturophiiyl ph1nyldox 271 ethyI n-butyl OH -H 3-ntetltaxyphenyl H 17-byromo 272 ethyl n1-butyl H .i 3-mtlxy. -ron phenyl 273 ethyl n-butyl H ~~TII4-I1tioro- 7?4tuor phienyl 274 ethl v n-butyl OH TF4-fitioroplienyl H -7-fluioro 275 eltyl n-bu tyl HF 0~ H 3 -mettuxy- l -fitior-o phenyl 276 ethyl n-butyl OH H Ximethuoxyphlyl H 7 Iur 27ethyl n buyl OUH HT 3-1Ilunniplicityl H 2-onetboxy 278 elhyjE n-by H OH 2 -ftcmowphacoiyl 7-niethoxy 279- n-b utl H 3-fludiroeiv-yl H 280 ethyl it-buflyl OH- 11 2 -fitionsapctaLayl 11 -T7-meehcuxy 281 ety n-butyl OH H 4-Ilitoroplienyl T- ?7-methlylmercapto 282 edy 1T 1Tyl -OR 4-fluoroplit-nyl FF -7-methyl 283 ethyl n-butyl H OHT H -lur -ety 4-fenylo 284 eth~yl n-butyl OH HF p-lucpinthnyl-upheiao 285 ~~~~MISSING 286 ethlyl ethyl 01-1 T pliel-yl -rbnycabainato) 287 eltyl eth~yl O Phienyl H 7-asnino 2H8 methyl methyl OH -H lienylH7-sic 289 n-but I n-cay OH HF placicyt 290 n-buty n-butyl 01- HTF 1amino 291 n-butyl n-butyl O H iectH L 7 -(O-bnaban 292 n-buiyl n-butyl OH- H H 7-asnialello M 293 -n-butyl. n-butyl OH H-lifyl1 n-butyL- nbtl ohen H 7-benzlamnisu, 295 ethyl n-butyl pliey -H I 7-dlimethylamn H -~7-antino 0
N
4
.N(C-
3 3 0 0 00 1000 ethyl n-bulyl OH H y H 7-dimethylamino 3
H
1001 ethyl n-buF OHF HF H 7-dimethylamino
N(CH
2
CH
3 3 1002 ethyl n-butyl OH d H 7-dimethylamino 1003 Ht~l -Tj~ T 7-dij hlylainino 1004 ethyl w~buotyl OH H H -iehlmn cr.jcoo. 0 0
(CH
3
CH
2 13N 1005- n-butyl n-but-yl -OT T I 7 -ditnedylasnino cr.,coo. 0
I
,N(CH
2
CH
3 3
I
1024 n-btityl IIinty OH H 7-dimethylamino 0 610 3
-N
102 n-buiyl Rbtyl OHT HF qF H 7dstylamino 'N N(CH 2 CH6 3 4 6--uy Ibuy H Hu 7-dimethylaniato I. +1 *Ig~r -nbu-tyT n-btF Tf- -If- HI I- ~N 1028 n-ull nTbut1yrl OHF H 0 H7.dlmethiynu 00 00
00 L01 1041 i1.butyl i-Wil TF OH Hn- H -iieh~m 0 N 6101 3I~ 1042 n-butyl n-ibI** OHF HF H 7-dimetitylamino I 1043 n-butyl n-butyl OH H H 7-dimeltylamino 0 1044 n-butyl n-butyl owF TFr F HPCO 7-dimetihylamino 0,, 4 o,,N(CH 2
CH
3 3 1045 n-buiyl .n-butyl OH H .F -pco 7-dimetIhylamino 1046 n-but I n-but I OH T+ N(CH 2
CH
3 3 H dmtlafi) 04 blyl nbl O H 3-arninopIhenyl -iehImn 1047 -br I~~j ItFFty OH H ditelhy ainto 00 6 to--
N(HCH.
I w 10411 II.butul aI-LnalyI 11i H H 7-dinilyat I. 1049 n-bulyl n-bulyl OHF HF F NoF 7-dimethylarnino 1050 n-butyl n-butyl OHF H 0F7dmtblmn oll, N 00105F n~butyl n-butyl OHF H FP F -co 7-dimethylamino ~i T n-bulyl n-butyl OHf H"I H 7-dimethylaiw N J 0 -Ioo00 .1053 a-butyl -butyl OH 11 F H 7daclyalt lop, CI? CO2
N\
NC
1055 n-butyl n-butyl OHF HF 7-dimethylamino N N N N 1056 n-butyl n-butyl 6fF IF H 7-dimethylamino 0 0 N'
-N
0 0
%C
00
WO 98/40375 PCT/US98/03792
0 '0 00 -a tim 0 ri~ ~0 00 0 -4 '0 N(CH3) 3 1122 n-butyl n-butyl OH4 H Hot H7-dienethylamino 0 1123 n-butyl n1-butyl OHF H-f 4-lurplienyl H. 9-dimethylameno 1131 etyl n-b t O H TF -nieioxypheiiyl H 7-dimetitylamino U 1132* n-bulyl n-butyl HF TF 3-dlor-4-netuxyIaeyI F 1126 n-butyl n-butyl OH H 4-ynonT mlpi 7-dimethylaino 1127 ethylj n-butyl OH1F HF 7 -dime lyla siRn
I--
-113S- u11-butyl n-bauWI 014i H I3,4-dimetlsisacypliessyl H1 I 7-dimetitylainin;o 1136~ n-butyl n-bulyl Uff HF H 7 -dimethiylantino 00 1137 n-b[y n-uyl OH H 4-fluecruphenyl Tr 9-(2',2'-dimeetlltydrazino) 1138 -61Fty TFbty OH 7-dimeethylamino NIN 1139 n-:utyl n-tiy OH1 H 3,4-diflutaropleeyl HF 7-diineth lamino 1141 n-bulyl nI-butyl off 3-nmetlmotyph~enyI 7-(2-,T-dimetliylhsydrazinco) 1141 ae-butyl n-bulyl OHT ii 4-Iliimi'tenyI Hf I 7-ctlylmelylamino 1 1 4 2at -b ty l11 -b ly l0 t ,F H7 -d i n e tle y la m in o 1143 -n-btyl n-bulyl HT OH! H 3-fuorco-- 7-dimethIytninino metIloxy.
1144 n-uy n1-Lo I I I OH 5-pE!=IYl H- 7-dimel iylamino II4 E n-b-y aeb9y F I -dimethylamino 116 n-uy i-utl OH--f 7-dienethla~mi 0 N(CH,), 1147 n-btityl n-uy OH H- 3-metit~euypuhellyI -ill an 1148 butyli it-uty IOR -R 4-hluimieuInyl 7 unc t ylninu ioee 1141) ro-bilyl i1-butyl Oil1 -Tf 4-I11aeur'p1iL1JeyIii 1 7-cilcla saate 1150 n-butyl nt-butyl OH H 3-melutyphiteeyl H 1 7 -etltylineathylamni list n-butyl edy OH HT 3-.ituurt-4-titlmoxypluclyI 1- I 7-durnetltylimino 1152 et-butyl IFbtty OR -1 pikellyl TF*-F i(etltoxyanctlyl) nitthylainino)k, 1153 n butyl n-butyl Oil1 i 4-Iluomplieiyl HI 7-netleylimino 1154 n-butyl n-bugyl OHA 1F 3-atllmotypheityl H 9-Inettilx 1155 n-bioly IIbly OH:1 H 4-Ilsmeirplietiyl H7mt j16 n-butyl I n-butyl OH I H 1 I I *'~*'~~Si'Pli~liVl I l.J Il-butyl a1-biyl OuH 1-1- 4 luoraplalyI H I fl-btyii I nbutvl OH I 1- Ii-uu'v' eulviy
OH'
fl-DOt Vi )IV l OH 1 n-L'utvl n-bulvl plienly 4-pyridintyl 3 -fitioro-4-inelhoxypEl uy 1162-btl but 1163 n-btitYl I 11-buty OH -14 1164 n-butyl n-buty OqH H
H
H
H
H
H
-metllylinercapto
I
7 -fluoro, I 9 -dimet lamino 1. 7 -me~lhoxV 7 dimelthyl-nanio 7-diellethylam i -oU S 7-dimethylmin 7-meltuxy T;.tnimethylmmonum iodide -t.rimethylammonium iodide fi.Uutyl WWOLIV 1166 I n-bmaeul I n-h.*d fu u y l -h droy y me wl 1167 w-b- t I I l I 6 y -buy-I ci
H
1168 r n-bill I n-buiv I OH_ r4 i n-b elyi fi-btivi 1170 it-~bill I n1Fily't -ffi r 1171 I-ulvi it- uWN 117) -b t l 1173 11bmy oilball 1174l u [tbuilyl 0 f17 I_ 014- L 1175 ethIf OH buiy 1176 n-buay I atyl 4 -(trifiLatr~inietlykiv atyi~lv~ xy)plieiyI pyritadI 3-llilhoiiI)YpieIVSYI 3-mtrsliol[ely 3 -mtetlnoxyPliyl nIbUlIIV 1111 I .11IN n-butyl It-bulI
H
H
H
H
H
H
H
H
Ht
H
H
H
lt7n I n-b ul 1 n.Lbu'vl Ilan 1 ni..m.u plicuivi I .1 11111 *iLMhiyi El-ut IV 1182 n-butyl -oy FJF .dmf~yanaopir 1183 nbtlIn-butyl fI~fF UH HIexy~ety I -inet liyTamin o -?trehlammoniam iodide 8-d ignethylasnino 7 -Illy~pralpylamiinu I 7 -dineli ulIollfli I 7-butY lineilty lanjo I /-dimnelisylamino T S-metlhuxy '-trimet ly Imnitl iodide *7btlnelthylamjauo 7-eth -Iluor; I 9 -Iluloro 74Iim1 1-~m~,tm ioid I 7-bruro 7 ydroxy 7-hsyd mxy 7-dinitylanino Il-bDol n-butyl 4 -I1tttiphenyI Uss b l 1 n- uty n-butyl 1 OH 1 H n-butyl n-butyl 4-flinrtip~setyI piienlyl 1187 t n-butyl ll-btatyl 01-1 4 -fitiomopheLnylI- 1188 n-butyl fn-bulyl OH 4-rnetloxyPellyl f H 1189 J n-butyl fn-butyl OH- -1 )p dilwaroly1 11950 n-biotyl n-butyl 011 f H- ,.ik~r I 4~-brlalanipteyl_______ 1191 n-but I n-butyl OH 4 i letlyl no hell-ny I 1192 1 n-butul n-biul lN. l OH l 3-(ditli i I iit))I) ieii yl I-I ll y y UH 4 2 2 l l k I -iiic iy l)rol)yl))plteiiyI 1194 n-butyl in-butyl OH H-H 7-diinetlsylainino F HO sAo 1195 n-butyl n-bulyl OR- HF 4-muelixyphenyl 7 -(f-methylpiprazin-1.y1) 1196i n-butyl n-butyl OFF- TFf- 7-methoxy K- N(CH3) 3 11rl97 it-butyl ethyl R3 3 TI""Y 7-(N-metIhyIforstmonido) R4~ M= OXO ISM4) 1199 n-butyl nibuity OHF HF -~yiitr oi 7-dimethylamino 1200 n-b~ylpbutyl H OH HJ.pey 7-dimetlit lamino 1 IF ii-iuyF ii-iiijl OHF H H -H 7-methyl 1202 n-butyl II-butyl OH !H
II
7 at~~c
N(CH
3 3 1203 n-biyl Cl- H- 5S-perazinyl H 7 -(4'-tert-buIYlpluenyl) 1204 n-bulyl n-bu 1F R- 4 *Iluuoroplienyl H 7-methuxV 1205 -n-butyl ORbuyI F ff- 1206 n-butyl n-butyl 0" H- 7dmehlmn K
N(CH
2
CH
3 3 1207 n-butyl ±-but! OH HT 3 doIrophnyl 7-ditnethylamino 1208 n-butyl- i-buiy, FT T 4 -muetlioxypitenyl I 7 -di-metinylamino 1209 n-butyl- n-buty acetoxy HF plienyl 1210 n-butyI n-butyl OH Hr 2-(d imeII~YIa mino)pIhenyl 1211 ethyl n-butyl OH -H7clmFylmn 1212 n-buty n-butyl OH W4-ieIi-piny 123 -utl tyl H3-Iluow-4- 7 -dimetliylamino mellwxy- 1214 n-buy th-yl -OFF phenlyl T1 lfrinamido) 121 H!e ±l O 4-onetho4xypllenyl H I 9 -inethylmercapto- 1216 nebly 1bity l OH4 H- iy H 7-bruntu 1217 n-baatyl Is-bulyl 0H -14-carbaoxvipbeoyl H 7-dieneth ylamino 1218 n-buyl -butl OF- 4-ethoyphityl- 9-methylsulfonyl 1219J m-butyl aI-butyl TT FF IF-Tf 7 -dinimetiylamino 1220 n-btatyl n-bulyl OH~I H H 7 -isopropylaanino 1221 n-butyl *%-butyl OH xyIey H ?-dimetitylamnino 1222 n-b i[ n-butyl OHF H 3 -nietbaoxyphaeityI H 1 ?.thiylamino 1223 nii4iijF ORbtl F T pilalyl 1r 8-bromo; T 7-meili!aino 1224 it-buiyI n-btityl OHi [Ii 3-stilropaisiyI H 7-lo 1225 n-bulyl eltyl OH H 3 -meIthylliny H 7-dirnietiylainino 1226 ethlyl n-butyl OHI F TF 5-piperootyl 7-bromo 1227 n-butyl n-butyl OH IF 4-Iitioropheityl H 7 rat-butylamino- 1228 n-butyl n-butyl OH H 2 -pyrrt.IyI H 8-bromo; 7-dimethtylamino 1229 n-butyl 11-butyl OHF T 3-cltloru--4-Iaydroxypwaayl H 7 -dimetlaylainino 1230 i-bitjF n-buty-l Fr T-F phellyl R ~9-dimetitylamino; I 7-I luoro 12371 -n tyl n-butyl OH H H 7-dimethltyImino 1232 11-buty I nbyE H OH H 4 )-iopliettyml Han 1233 n-busyl n 1-butyl OH HF H-Iip y -i 7-dinmethylainitto \fNr 12341 st-butyl It-bsityl O1il 1III7dmiti~min GoC 1235 n-bulyI n-butiyl- OH HF7dmth mn 1236 n- ulyl n-butyl OHFF HF 4-bromuinetIhy)phenyI H. 7-dimeithylamiaio 1237 n-butyl n-bulyl OH H H. 7-dimeltylamino 1238 n-butyl n-bulyTl DR HF F HTFiehyann E nyl7-dimethylainao 1232 n-bulyl n-butyl 1fl- TH F -dimethylarnino XIl 1242 n-bulyl n-butyl OH HFH 7 dml~imn 1243~ W-uy ~uyl T i 1 7-dimellhylamino N
"12!55 n-butyl nTI&I OHl HTH 7.dimethy anino
I--
N(CH
3 3 125 n-butyl n-buy! O3FF H 3-n1iiruplhnYl H 7-dimethyain 1257.. n-buty nWibii~U -OVF T-Ff phenyl H _________7-dimethylamino 1258 n-butyl n-butyl ONIF 4-I1uuropisenyI H 9-(Iert-butylamino) 125 ethyl n-uV H o H phey 7-dirnetlainino ethyl___ n-uV -Ufl ~H 3.liydruxypltenyl H7-dimetttylamino 1261 n-uyTT n utyl ff- 1T- H 7-dimethylamino 1262 n-butyI OH H1 2-thiophenyI HF~ 7-diineilylamino 1263 n-butyl Wbulyl OTHF F 5-piperonyl -7-bromo 1264 n-buty n-butyl OHI HF 4-iluoropienyl H soproIyl mino 1265 n-but vi n-bul I UHI H 4-Ilunorophenyl H 9-isopropytamino -1266- n--utyr- nr utF +n FR 7-dinet kytamino N(CH3) 2 ~OCH, 1267 n-uy ety OHF HF -piperunyl H1~ 7-carboxy -Ity ester' 1268 n-butyl n-butyl 0"1 H1 F 7-dirnetIhylarino -7f 1270 aI-butyl n-bwlyl 0OH TpH ~7diet~~m~n 1271 n-butyl n-butyl 0F 7-dirnelitylamino 3 1272 n-buy n-btyl OH H
C
2 H 7 dmI~lm 1273 n-bulyl n-butyl OH HF I-dimetitylamino 1274 n-butyl n-butyl OHF H IF CI
_F
~C!
'N 2
J n-uu7I n -butyl I CHl p SO S(C"2CH3)2
H-
7-diiuieltylamino -1ur I I efox T=mlyamino -n 00 1 ~-kI I tL I1- 1301 n1 -biw I tu I nu--i- 1 -L phenyl I I__ 132 n-bulI n-buty IF OH H 3-tydmoxypheityl H z1
J.
N(CH3)3 1201 t 1 T n-butyl~~~~~R -~tI O XPlnl1 7 -feri-butylamino 13M nbuty n 0 1, 07-dimethylamlno -o CF 2 137 n-buiyl n-butyl OHF HF H- 9--medWooxy. tn eTylr jF -MIF HF 9 F h I 7-dimethylamgno 0 1309-- -buyl n-utl H- 1- 4-nwtlhixyphlwayI 9-Ilu-oro -910elw.- n-uy onr P1L.Imyl 7-amino nbtstlO plieilyl 7-hd xylarnliw 132nbuy tyl OH H ~,tmy I8-I1exyiaxy 1313 n-bIyl el O -dH I- phewnyl 1-1 H/ll )x 1316 n-butyl ethyl OH H pheniyl H l-lhydnixy 1317 n-butyl ethyl OH 'H piwnlyl
H
the 8-position 1318 ethyl n-butyl O H phienyl H -mtylmo 1320 ii~ -uyi IF F 3-metlhoxyphenyl T 7-fluoro 130ethyl n-uy F F TF phtenyl ______7-amino 1321 n-butyl ethyl OH H phenyl H t the 8-position 1322 n-butyl n-butyl OH H H 7-dlimethylamino 12 n-butyl n-buty OH HF 0 -H 7-dimethylaniino
N
H
1324 n-buyl 1-bull OH H H7-climetlhylamino
IN
1325 n-butyl IF TFuy__lO 4-((dieitylantinto)ntetliyl)plienlyl_ 7-dimethy amln
-W
00
0
'C
-4 ~4~
'C
00
C
w -4
'C
mi-L btlyl a%~LtI 0- 7 -dfimethylamilno 00
(CH
3
CH
2
CH
3
CH
23
N
1353 n-butyl n-bulyl OF* H F FF -dimetliylameigio 2
CH),
1354 n-butyl n-butyl OH H 3 ?dieIyamn 0 N- 13S5 n-buiyl OHbty HF W 7-dimethylamino
I-
NO:
136 -butyl n-butyl -Or HF7-dlimethylamno r 0 1 3 5 7n b u y l b u l l F F lF 7 i m t lyfi rn 04..,o,%00
WO 98/40375 PTU9/39 PCT/US98/03792 110
WO 98/40375 PCTIUS98/03792
1392 n1-butyl it-beosyl 011 H H 7-ditneltiyiarntilu
I
N 0r 1393 n-butyl n-butyl OH H H7-dirniettylamino 111111 N. ~N(CH2CH3)3 1394 n-butyl n-butyl OH H H1 7-diinetylamino 139S n-busyl n-butyl OH H H 7-dimethylamieto 0C0
-+-N(CH
2
CH
3 1) 3 IWOii 7dimetyiaminao 0 00
+C
-dimethylamino
~~NQ
H 7 .dim clylantino
F/
N-
'0 IH 7-dirnetitylamino
F
F 0 00 -4
S-OH
0I
1407 11-bulyl It-billyI OH- HH -icttailn (0
(CH
3
CH
2 3
N
1408 n-butyl n-i-b-utyl Oth H dmehamn nbll nbll FF F H7dimethylim-ino
F
000 14109 nbutyl n-butyl- OH H F OHH 7 -dimetlamino
F
00 rw
I.
N 2
CH
3 3
1431 n-buy -butyl o014 H 7-dimethy-lamtllino N 0 '0
N(CH-
2 CH3)3 1433 n-butyl n-butyl -OHF H 7-dimethylamino
F
N
NN~
HO"-S~
1434 n-bulyl n-bulyl OH H 1-iehyann 1435 n-butyl n-butyl OH H N(HC,3H-7-dimetityl-amino
F
N' N 00 N OH 0' 1406 n-bulyl nt-blyl OH H H7-dimetilylamiuio 1437 n-butyl n-butyl OH H H7diehlmn Or
P(C
6 HJ 1438 n-butyl n-butyl OIF H H 7-d imedlylfamino K ~N(CH 2
CH-
3 3 1439 n-butyl n-bmtyI OH HTF-iielyl 144 n-uiy n-uty OH -H
H
7 -dimnetIhylamino 1440 n-buyl n-bulyl OH H 7-di etIy2a iOH 144 nbuyl n~ull H IFF H 7-dianethylamono-
N(CH
2 CH 3 3 w 00
CO
2 H 1443 n-butyt n-butyl ORF H H I 7-dimethylamino N
N
u iW -'dEjF -bty -Hl- 144Sn-buyl -butl H7-dimetIhylamino 1445 n-butyl n-butyl OH H r H7nittoy 147nbtl n-uy H HH 17-dimethylamino I SQNa SS.3 1448 n-bulyl n-Ltutyl OH H F Na 7-dinithiylamelo 0 00 1449 11-butyl n1-butyl OH H H 7-dimethylamino 1450 n-butyl n-btityl OH H phenyl H 7-d imethylamnino 1451 n-butyl n-butyl OH HH 7-dimethylaMlino WO 98/40375 PCT/US98/03792 PEG 3400 molecular weight polyethylene glycol polymer chain H H N- or PEG 3400 molecular weight polyethylene glycol polymer chain A-7 WO 98/40375 WO 9840375PCT/US98/03792 PEG 3400 molecular weight polyethylene glycol polymer chain WO 98/40375 PCT/US98/03792 C22 KM N 03S 387.343 fl-eu molamI0 C22 W23 N 03 37.543 i- WO 98/40375 WO 9840375PCT/US98/03792 F C22 M28 OS 340.33 n-Bu ~2I~gET 240.OH n-Bu IE T WO 98/40375 WO 9840375PCT/1JS98/03792 C22 Ku2 03 s. 32s a0 0s 743.08! '3' WO 98/40375 PCTIUS98/03792 C28 H41 M 03 S ql.n04 Ph' C24 k3O03 S 40.36! WO 98/40375 WO 9840375PCT/US98/03792 C22 W3! N 04 S 4=3.343 0-.
133 WO 98/40375 WO 9840375PCT1US98/03792 C24 M30 03 S a-+ 123+ WO 98/40375 WO 9840375PCT/US98/03792 135 WO 98/40375 WO 9840375PCT/US98/03792 123( WO 98/40375 WO 9840375PCT/US98/03792 C22 M29 0-4 S C22 M26 03 3 I~ 2cm MS2 I 104. 353 fl Bu (3'1 WO 98/40375 PCT/US98/03792 CZZ IQ 2 03 S 924.22 2I 424 03 26.496 13's WO 98/40375 WO 9840375PCT/US98/03792 C23 1420 04 S a\//0 C23 1430 04 S 42.5W5 n-Stu t 39 WO 98/40375 WO 9840375PCTIUS98/03792 Cl. W20 03 S 319..21 0 0 WO 98/40375 WO 9840375PCT/US98/03792 =22 W28 03 s 272.5sn a n-Bu WO 98/40375 PCT/US98/03792 In further compounds of the present invention, R' and R' are independently selected from among hydrogen and ring-carbon substituted or unsubstituted aryl, thiophene, pyridine, pyrrole, thiazole, imidazole, pyrazole, pyrimidine, morpholine, N-alkylpyridinium,
N-
alkyl-piperazinium, N-alkylmorpholinium, or furan in which the substituent(s) are selected from among halo, hydroxyl, trihaloalkyl, alkoxy, amino, N-alkylamino, N,N-dialkylamino, quaternary ammonium salts, a C to C 4 alkylene bridge having a quaternary ammonium salt substituted thereon, alkoxycarbonyl, aryloxycarbonyl, alkylcarbonyloxy and arylcarbonyloxy, dioxyalkylene, where x is 2 to 12, w is 2 or 3 and X comprises halo or a quaternary ammonium salt, thiophene, pyridine, pyrrole, thiazole, imidazole, pyrazole, or furan. The aryl group of R' or
R
6 is preferably phenyl, phenylene, or benzene triyl, may be unsubstituted, mono-substituted, or disubstituted. Among the species which may constitute the substituents on the aryl ring of R' or R6 are fluoro, chloro, bromo, methoxy, ethoxy, isopropoxy, trimethylammonium (preferably with an iodide or chloride counterion), methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, propanoyl, (N)-hexyldimethylammonium, hexylenetrimethylammonium, tri(oxyethylene)iodide, and tetra(oxyethylene)trimethylammonium iodide, each substituted at the p-position, the m-position, or both of the aryl ring. Other substituents that can be present on a phenylene, benzene triyl or other aromatic ring include 3 4 -dioxymethylene (5-membered ring) and 3,4-dioxyethylene membered ring). Among compounds which have been or can be demonstrated to have desirable ileal bile acid transport inhibiting properties are those in which R' or R' is selected from phenyl, p-fluorophenyl, m-fluorophenyl, phydroxyphenyl, m-hydroxyphenyl, p-methoxyphenyl, mmethoxyphenyl, p-N,N-dimethylaminophenyl, m-N,N- NL2 WO 98/40375 WO 9840375PCT/US98/03792 dime thylaininophenyl, V p- (Cm 3 -W-phenyl, V in- CC,y-Nphenyl. -I m- (CH),-(-CXCH1- COc{cH,) 2 -o-phenyl, I' p- 2 -N-CCi- (OCII C) ),-O-phanyl, I- n- N-dimethy3,piperaziniun) I -CH 2 (OCH4C)-O-phenyl, 3-methoxy-4fluorophenyl, thienyl-2-yl, 5-cholorothienyl-2-yl, 3I 4-difluorophenyl, X* p- N-dimethylpiperazinium) (N I -CM1- OC,1iC),-O-phenyl, 3-f luoro-4-inethoxyphenyl, 4-pyridinyl. 2-pyridinyl,- 3-pyridinyl, N-methyl-4pyridinium, V. N-methyl-3-pyridinium, 3,4diioxymethylenephenyl. '3,4 -dioxyethylenephenyl, and pmethoxycarbonylphenyl. Preferred compounds include 3ethyl-3-butyl and 3-butyl-3-butyl compounds having each of the above preferred R' substituents in combination with the R' substituents shown in Table 1. it; is 1s particularly preferred that one but not both of and is hydrogen.
it is especially preferred that R4. and R' be hydrogen, that R' and R' not be hydrogen, and that P.' and R' be oriented in the samne direction relative to the plane of the molecule, both in at- or both in 9-configuration. It is further preferred that, where R' is butyl and R I is ethyl, then has the same orientation relative to the plane of the molecule as R.' and R'.
Set forth in Table IA are lists of species of IR' and r-.
143 WO 98/40375 WO 9840375PCTIUS98/03792 P A c E (44 44--ii
LEPT
I'-e1 WO 98/40375 WO 9840375PCTIUS98/03792 Table lA Alternative R groups 0 (Rx)q, R 2 R4 ethyl R-p:@pyl U-buty.
A-pentyi.
anhexyi.
Lac-propfil Lac-butyl Lso-pentyl c3 2 c C2E1 C3 2
CC
2 33
CN
2 C! COB) 2 3 5 C3jO- I4-picoLIi~e) 3 A
S
I-
So-
P-CS
3 0-FPhu-CR 3 O-php- (Cx 3 2 a- ZN-ph- M- 3 31%* C=c 2 2 -0
(CC
2
CJ
2 2 -0 Ph- 2 CCc d-ioxyme:z.yl rn-C230-, P-r-Ph 4-pyridlne N-rnechyl-4-cyri 3-py: l4lie 2-pyridine thi~enyl-2-y! UchlenyL-2- 3. 4-difluco rn-F. P-CH 0-P 3 (Ra) cr 7-zechyl 7-Lso-propyl 7-te::-butyL.
7-CC3 7-0 dsc-propyl) 7-SC!3 Ph- 7-SOCt-* Ph- 7-SC 2 cl.3 7-NH2 7-N?.OP.
7-4 (CA 3 2 7-N~'eC3 2
CO
2
R
sraz±.) 7-N CIme) 2C!EZ02Fl. I c Z -0 7 (N a z e p± d l i e 7-CN)-M-=etylazec_diniu.wIen-. 7- errl-pdilninem Z 7-Cl)-4-sechyl-ma.-phoLLiu. Id~tur 7- -macylpperazine 7- -diLnehylpiperariniu, t- 7-4HC( .O)CI~t 2 ar yl 7 2) -th opherie h h cantiaued next page. WO 98/40375 PCTIIJS98/03792 S-2chyl 8-ise-pccpyt 8-teert-bucyI
$-OR
I-C (iso-propyl) a-SCS 3 3 S1-50 2
CH
3
I-NUI
B-HEC!3 I-SECC-O) C 3 U-N (C3 2
CZ
3 2 *-MMOC9 2 C0 2
R
G-H' (MO) 2CP.
3 C0 2 R. I- 8- -marpho Line 8- -py::oidne 8- ethylpl~craz±i a-NH-C3Z 8-.4%C Cg!3,i 8-NEFC (M C! 3 8-Sa- (2)-cico.) N continued next page...
(4' WO 98/40375 WO 9840375PCT/US98/03792 9-cetftyl 9-echyl 9-iso-prepyl 9-tort-butyl 9-OK 9-vCHR cise-propyI) 9-sc2 3 9-SOCH 3 9-Nil 2 9-Rio 9-NECC! 3 9-H(CH 3 2 1 9-NHC C23 9-N 2 "i 3 1 9-NMOeC 2
CO
2
H
9-N 2
CHICO
2 H, I- 9-IN) -morplin±ze 9-IN)-azecidine 9-IN) -N-=e:hylazetidiiu. I- 9-IN) -py::oCiine 9- -N-rn4e-hyl -pyr:o lid -Iiu, I- -N-,.ezftyl-=arphcliniu.m, r 9- -41 mehypierazLnm, 9-NH-C3Z 9-*qkc Cs! 9-4:!c CH- 2 3: 9-NH-C R) NFZ 9-12)-chilphene 7-ccA 3 a-CC!! 3 7-scH 3 S-CC.2 3 7-3c.%j, a-5CH 3
G-CC*!
3 7-CV!3. 89-OC! 3 'I -I WO 98/40375 PCT/US98/03792 Further preferred compounds of the present invention comprise a core structure having two or more pharmaceutically active benzothiepine structures as described above, covalently bonded to the core moiety via functional linkages. Such active benzothiepine structures preferably comprise: R X T y j cKWX7~; (Formula DIV) or: (Formula DIVA) where R 3 X, q and n are as defined above, and R" is either a covalent bond or.
arylene.
WO 98/40375 WO 9840375PCT/US98/03792 The core moiety can comprise alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, and peptide, polypeptide, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, and peptide polypeptide, can optionally have one or-more carb *o n replaced byo,
N.R
7 7 S, SO, SO 2 a 7 +7 8
SR
7 R PR P R R phenylene, heterocycle, quatarnary heterocycle, quaternary heteroaryl, or aryl, -wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR 13
NR
13
R
1
SR
13
S(O)R
1 3 S02R 1 S03R 1
NR
1 3
OR
1 4
NR
13
NR
14
R
1 N02, C02R 13
CN,
OM, S02aM, S02NR' 3
C(O)NR
13
R
1 C(O)OM, COR 1 3 P) R3 14 13 1 4 P(lR Rl4 R.-l .R P S*R'R"A and N +R 9 R 11
R
12
A-;
wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group cons'isting of OR 7 7 8 7 7 7 7 7 NR R SR ,S(O)R S02R S03R C02R CN, oxo,
CONR
7 R 8 N +R 7 R 8 R 9 alkyl, alkenyl, alkynyl .aryl, cycloalkyl, heterocycle, arylalkyl, quaternary WO 98/40375 WO 9840375PCT1US98/03792 heterocycle,*quaternary heteroaryl, P(O)R R P R R A and P(O) (0R 7 OR%, and wherein said alkyl., alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by 0, 7 78 7 77 NR N R R S, SO, S02, S R PR P(0)R, P ±R 7RA-m, or phenylene. Exemplary core moieties include: 26 R 2 27
R
R
2 8 27 'so WO 98/40375 WO 9840375PCT/US98/03792
R
2 .r 2 wherein: is selected from the group consisting of C and N, an:d R2' and R 2 are independently selected from the group consisting of: 30
R
(0)X -CH2- 0 S 0 S
'I
C-
R3 1
_N+
R 3 1 -Si
J
3 2 NH -I -NHS0 2 and \H2 wherein R! 9 R30and R31 are independently selected from alkcyl, alkenyl, alkylaryl, aryl., arylalkyl. cycloalkyl_, heteroacycleri-and ete'oyccloal-ky-l,- A is a Pharmaceutically acceptable anion, and k= 2. to WO 98/40375 PCT/US98/03792 In compounds of Formula DIV, R" in Formulae DII and DIII, and R 2 in Formula DIII can be bonded at any of their or 9- positions to In compounds of Formula DIVA, it is preferred that R" comprises a phenylene moiety bonded at a m- or pposition thereof to R".
In another embodiment, a core moiety backbone, R", as discussed herein in Formulas DII and DIII can be multiply substituted with more than four pendant active benzothiepine units,
R
20 R" and R" as discussed above, through multiple functional groups within the core moiety backbone. The core moiety backbone unit, can comprise a single core moiety unit, multimers thereof, and multimeric mixtures of the different core moiety units discussed herein, i.e., alone or in combination. The number of individual core moiety backbone units can range from about one to about 100, preferably about one to about 80, more preferably about one to about 50, and even more preferably about one to about 25. The number of points of attachment of similar or different pendant active benzothiepine units within a single core moiety backbone unit can be in the range from about one to about 100, preferably about one to about 80, more preferably about one to about 50, and even more preferably about one to about 25. Such points of attachment can include bonds to C, S, O, N, or P within any of the groups encompassed by the definition of R".
The more preferred benzothiepine moieties comprising R" and/or R" conform to the preferred structures as outlined above for Formula I.
The 3-carbon on each benzothiepine moiety can be achiral, and the substituents
R
2 R' and R" 152 WO 98/40375 PCT/US98/03792 can be selected from the preferred groups and combinations of substituents as discussed above. The core structures can comprise, for example, polY(oxyalkylene) or oligo(oxyalkylene), especially poly- or oligo(oxyethylene) or poly- or oligo(oxypropylene).
Dosages, Formulations, and Routes of Administration The ileal bile acid transport inhibitor compounds of the present invention can be administered for the prophylaxis and treatment of hyperlipidemic diseases or conditions by any means, preferably oral, that produce contact of these compounds with their site of action in the body, for example in the ileum of a mammal, a human.
For the prophylaxis or treatment of the conditions referred to above, the compounds of the present invention can be used as the compound per se.
Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compound. Such salts must clearly have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids. The chloride salt is 153 WO 98/40375 PCT/US98/03792 particularly preferred for medical'purposes. Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, and alkaline earth salts such as magnesium and calcium salts.
The anions of the definition of A- in the present invention are, of course, also required to be pharmaceutically acceptable and are also selected from the above list.
The compounds of the present invention can be presented with an acceptable carrier in the form of a pharmaceutical composition. The carrier must, of course, be acceptable in the sense of being compatible with the other ingredients of the composition and must not be deleterious to the recipient. The carrier can be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from 0.05% to 95% by weight of the active compound.
Other pharmacologically active substances can also be present, including other compounds of the present invention. The pharmaceutical compositions of the invention can be prepared by any of the well known techniques of pharmacy, consisting essentially of admixing the components.
These compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic compounds or as a combination of therapeutic compounds.
The amount of compound which is required to achieve the desired biological effect will, of course, depend on a number of factors such as the specific compound chosen, the use for which it is intended, the WO 98/40375 PCT/US98/03792 mode of administration, and the clinical condition of the recipient.
In general, a daily dose can be in the range of from about 0.3 to about 100 mg/kg bodyweight/day, preferably from about 1 mg to about 50 mg/kg bodyweight/day, more preferably from about 3 to about mg/kg bodyweight/day. This total daily dose can be administered to the patient in a single dose, or in proportionate multiple subdoses. Subdoses can be administered 2 to 6 times per day. Doses can be in sustained release form effective to obtain desired results.
Orally administrable unit dose formulations, such as tablets or capsules, can contain, for example, from about 0.1 to about 100 mg of benzothiepine compound, preferably about 1 to about 75 mg of compound, more preferably from about 10 to about 50 mg of compound.
In the case of pharmaceutically acceptable salts, the weights indicated above refer to the weight of the benzothiepine ion derived from the salt.
Oral delivery of an ileal bile acid transport inhibitor of the present invention can include formulations, as are well known in the art, to provide prolonged or sustained delivery of the drug to the gastrointestinal tract by any number of mechanisms.
These include, but are not limited to, pH sensitive release from the dosage form based on the changing pH of the small intestine, slow erosion of a tablet or capsule, retention in the stomach based on the physical properties of the formulation, bioadhesion of the dosage form to the mucosal lining of the intestinal tract, or enzymatic release of the active drug from the dosage form. The intended effect is to extend the time WO 98/40375 PCT/US98/03792 period over which the active drug molecule is delivered to the site of action (the ileum) by manipulation of the dosage form. Thus, enteric-coated and entericcoated controlled release formulations are within the scope of the present invention. Suitable enteric coatings include cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methacrylic acid methyl ester.
When administered intravenously, the dose can, for example, be in the range of from about 0.1 mg/kg body weight to about 1.0 mg/kg body weight, preferably from about 0.25 mg/kg body weight to about 0.75 mg/kg body weight, more preferably from about 0.4 mg/kg body weight to about 0.6 mg/kg body weight. This dose can be conveniently administered as an infusion of from about 10 ng/kg body weight to about 100 ng/kg body weight per minute. Infusion fluids suitable for this purpose can contain, for example, from about 0.1 ng to about 10 mg, preferably from about 1 ng to about 10 mg per milliliter. Unit doses can contain, for example, from about 1 mg to about 10 g of the compound of the present invention. Thus, ampoules for injection can contain, for example, from about 1 mg to about 100 mg.
Pharmaceutical compositions according to the present invention include those suitable for oral, rectal, topical, buccal sublingual), and parenteral subcutaneous, intramuscular intradermal, or intravenous) administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on'the nature of the particular compound WO 98/40375 PCT/US98/03792 which is being used. In most cases, the preferred route of administration is oral.
Pharmaceutical compositions suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or waterin-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 compound(s) and the carrier (which can constitute one or more accessory ingredients). In general, the compositions are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet can be prepared by compressing or molding a powder or granules of the compound, optionally with one or more assessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). Molded tablets can be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid diluent.
Pharmaceutical compositions suitable for buccal (sub-lingual) administration include lozenges comprising a compound of the present invention in a flavored base, usually sucrose, and acacia or tragacanth, and pastilles comprising the compound in an WO 98/40375 PCTIUS98/03792 inert base such as gelatin and glycerin or sucrose and acacia.
Pharmaceutical compositions suitable for parenteral administration conveniently comprise sterile aqueous preparations of a compound of the present invention. These preparations are preferably administered intravenously, although administration can also be effected by means of subcutaneous, ,intramuscular, or intradermal injection. Such preparations can conveniently be prepared by admixing the compound with water and rendering the resulting solution sterile and isotonic with the blood.
Injectable compositions according to the invention will generally contain from 0.1 to 5% w/w of a compound disclosed herein.
Pharmaceutical compositions suitable for rectal administration are preferably presented as unit-dose suppositories. These can be prepared by admixing a compound of the present invention with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
Pharmaceutical compositions suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which can be used include vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound is generally present at a concentration of from 0.1 to 15% w/w of the composition, for example, from 0.5 to 2%.
Transdermal administration is also possible.
Pharmaceutical compositions suitable for transdermal administration can be presented as discrete patches WO 98/40375 PCT/US98/03792 adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain a compound of the present invention in an optionally buffered, aqueous solution, dissolved and/or dispersed in an adhesive, or dispersed in a polymer. A suitable concentration of the active compound is about 1% to 35%, preferably about 3% to 15%. As one particular possibility, the compound can be delivered from the patch by electrotransport or iontophoresis, for example, as described in Pharmaceutical Research, 318 (1986).
In any case, the amount of active ingredient that can be combined with carrier materials to produce a single dosage form to be administered will vary depending upon the host treated and the particular mode of administration.
The solid dosage forms for oral administration including capsules, tablets, pills, powders, and granules noted above comprise one or more compounds of the present invention admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
Such compositions may also comprise adjuvants, such as WO 98/40375 PCT/US98/03792 wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or setting agents and suspending agents.
The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Pharmaceutically acceptable carriers encompass all the foregoing and the like.
In combination therapy, administration of the ileal bile acid transport inhibitor and HMG Co-A reductase inhibitor may take place sequentially in separate formulations, or may be accomplished by simultaneous administration in a single formulation or separate formulations. Administration may be accomplished by oral route, or by intravenous, intramuscular, or subcutaneous injections. The formulation may be in the form of a bolus, or in the form of aaqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more pharmaceutically-acceptable WO 98/40375 PCT/US98/03792 carriers or diluents, or a binder such as gelatin or hydroxypropylmethyl cellulose, together with one or more of a lubricant, preservative, surface active or dispersing agent.
For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension, or liquid. Capsules, tablets, etc., can be prepared by conventional methods well known in the art. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient or ingredients. Examples of dosage units are tablets or capsules. These may with advantage contain one or more ileal bile acid transport inhibitors in an amount described above. In the case of HMG Co-A reductase inhibitors, the dose range may be from about 0.01 mg to about 500 mg or any other dose, dependent upon the specific inhibitor, as is known in the art.
The active ingredients may also be administered by injection as a composition wherein, for example, saline, dextrose, or water may be used as a suitable carrier. A suitable daily dose of each active inhibitor is one that achieves the same blood serum level as produced by oral administration.as described above.
The active inhibitors may further be administered by any dual combination of oral/oral, oral/parenteral, or parenteral/parenteral route.
Pharmaceutical compositions for use in the treatment methods of the present invention may be administered in oral form or by intravenous administration. Oral administration of the combination therapy is preferred. Dosing for oral administration WO 98/40375 PCT/US98/03792 may be with a regimen calling for single daily dose, or for a single dose every other day, or for multiple, spaced doses throughout the day. The inhibitors which make up the combination therapy may be administered simultaneously, either in a combined dosage form or in separate dosage forms intended for substantially simultaneous oral administration. The inhibitors which make up the combination therapy may also be administered sequentially, with either inhibitor being administered by a regimen calling for two-step ingestion. Thus, a regimen may call for sequential administration of the inhibitors with spaced-apart ingestion of the separate, active agents. The time period between the multiple ingestion steps may range from a few minutes to several hours, depending upon the properties of each inhibitor such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the inhibitor, as well as depending upon the age and condition of the patient. The inhibitors of the combined therapy whether administered simultaneously, substantially simultaneously, or sequentially, may involve a regimen calling for administration of one inhibitor by oral route and the other inhibitor by intravenous route. Whether the inhibitors of the combined therapy are administered by oral or intravenous route, separately or together, each such inhibitor will be contained in a suitable pharmaceutical formulation of pharmaceuticallyacceptable excipients, diluents or other formulations components. Examples of suitable pharmaceuticallyacceptable formulations containing the inhibitors for oral administration are given above.
10o2- WO 98/40375 PCT/US98/03792 The dosage regimen to prevent, give relief from, or ameliorate a disease condition having hyperlipemia as an element of the disease, atherosclerosis, or to protect against or treat further high cholesterol plasma or blood levels with the compounds and/or compositions of the present invention is selected in accordance with a variety of factors. These include the type, age, weight, sex, diet, and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetics and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized, and whether the compound is administered as part of a drug combination. Thus, the dosage regimen actually employed may vary widely and therefore deviate from the preferred dosage regimen set forth above.
Initial treatment of a patient suffering from a hyperlipidemic condition can begin with the dosages indicated above. Treatment should generally be continued as necessary over a period of several weeks to several months or years until the hyperlipidemic disease condition has been controlled or eliminated.
Patients undergoing treatment with the compounds or compositions disclosed herein can be routinely monitored by, for example, measuring serum LDL and total cholesterol levels by any of the methods well known in the art, to determine the effectiveness of the combination therapy. Continuous analysis of such data permits modification of the treatment regimen during l(3 WO 98/40375 PCT/US98/03792 therapy so that optimal effective amounts of each type of inhibitor are administered at any point in time, and so that the duration of treatment can be determined as well. In this way, the treatment regimen/dosing schedule can be rationally modified over the course of therapy so that the lowest amount of ileal bile acid transport inhibitor and HMG Co-A reductase inhibitor which together exhibit satisfactory effectiveness is administered, and so that administration is continued only so long as is necessary to successfully treat the hyperlipidemic condition.
A potential advantage of the combination therapy disclosed herein may be reduction of the amount of ileal bile acid transport inhibitor, HMG Co-A reductase inhibitor, or both, effective in treating hyperlipidemic conditions such as atherosclerosis and hypercholesterolemia.
The following non-limiting examples serve to illustrate various aspects of the present invention.
WO 98/40375 PCT/US98/03792 EXAMPLES OF SYNTHETIC PROCEDURES Preparation 1 aC- 2-Ethyl-2-(mesyloxymethyl)hexanal (1) To a cold (10 oC) solution of 12.6 g (0.11 mole) of methanesulfonyl chloride and 10.3 g (0.13 mole) of triethylamine was added dropwise 15.8 g of 2-ethyl-2- (hydroxymethyl)hexanal, prepared according to the procedure described in Chem. Ber. 98, 728-734 (1965), while maintaining the reaction temperature below 30 oC.
The reaction mixture was stirred at room temperature for 18 h, quenched with dilute HC1 and extracted with methlyene chloride. The methylene chloride extract was dried over MgSO, and concentrated in vacuo to give 24.4 g of brown oil.
Preparation 2 2-((2-Benzoylphenylthio)methyl)-2-ethylhexanal (2) A mixture of 31 g (0.144 mol) of 2-
M
mercaptobenzophenone, prepared according to the procedure described in WO 93/16055, 24.4 g (0.1 mole) of 2-ethyl-2-(mesyloxymethyl)-hexanal 14.8 g (0.146 mole) of triethylamine, and 80 mL of 2methoxyethyl ether was held at reflux for 24 h. The reaction mixture was poured into 3N HC1 and extracted WO 98/40375 PCT/US98/03792 with 300 mL of methylene chloride. The methylene chloride layer was washed with 300 mL of 10% NaOH, dried over MgSO, and concentrated in vacuo to remove 2methoxyethyl ether. The residue was purified by HPLC (10% EtOAc-hexane) to give 20.5 g of 2 as an oil.
Example 1 3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepine cis-3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepin- (5H)4-one (4a) and trans-3-Butyl-3-ethyl-5-phenyl-2,3dihydro-benzothiepin-(5H)4-one (4b) A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047 mole) of TiC1, and 80 mL of anhydrous ethylene glycol dimethyl ether (DME) was held at reflux for 2 h.
The reaction mixture was cooled to 5 OC. To the reaction mixture was added dropwise a solution of 3.54 g (0.01 mole) of 2 in 30 mL of DME in 40 min. The reaction mixture was stirred at room temperature for 16 h and then was held at reflux for 2 h and cooled before being poured into brine. The organic was extract into methylene chloride. The methylene chloride extract was dried over MgSO, and concentrated in vacuo. The residue was purified by HPLC (hexane) to give 1.7 g of 3 as an oil in the first fraction. The second fraction was discarded and the third fraction was further purified by HPLC (hexane) to give 0.07 g of 4a in the earlier fraction and 0.1 g of 4b in the later fraction.
ExamDle 2 cis-3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepin- (5H)4-one-l,l-dioxide (5a) and trans-3-Butyl-3-ethyl-5phenyl-2,3-dihydro-benzothiepin-(5H)4-one-, 1-dioxide (5b) So, To a solution of 1.2 g (3.5 mmTe) of 50-60% MCPBA in mL of methylene chloride was added 0.59 g (1.75 WO 98/40375 PCT/US98/03792 mmole) of a mixture of 4a and 4b in 10 mL of methylene chloride. The reaction mixture was stirred for 20 h. An additional 1.2 g (1.75 mmole) of 50-60% MAPBA was added and the reaction mixture was stirred for an additional 3 h then was triturated with 50 mL of 10% NaOH. The insoluble solid was filtered. The methylene chloride layer of the filtrate was washed with brine, dried over MgSO,, and concentrated in vacuo. The residual syrup was purified by HPLC EtOAc-hexane) to give 0.2 g 5a as an oil in the first fraction and 0.17 g of 5b as an oil in the second fraction.
Example 3 :C (3a,4a,5b) 3-Buty-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5tetrahydrobenzothiepine-l1,-dioxide (3a,4b,5a) 3- Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydro- 0Y' benzothiepine-l1,-dioxide (3a,4a,5a) 3-Butyl-3- ethyl-4-hydroxy-5-phenyl-2,3,4,5- ou tetrahydrobenzothiepine-l,l-dioxide and (L (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5tetrahydrobenzothiepine-1,1-dioxide (6d) A. Reduction of 5a and 5b with Sodium Borohydride To a solution of 0.22 g (0.59 mmole) of 5b in 10 mL of ethanol was added 0.24 g (6.4 mmole) of sodium borohydride. The reaction mixture was stirred at room temperature for 18 h and concentrated in vacuo to remove ethanol. The residue was triturated with water and extracted with methylene chloride. The methylene chloride extract was dried over MgSO, and concentrated in vacuo to give 0.2 g of syrup. In a separate experiment, 0.45 g of 5a was treated with 0.44 g of sodium borohydride in 10 mL of ethanol and was worked up as described above to give 0.5 g of syrup which was identical to the 0.2 g of syrup obtained above. These two materials were combined and purified by HPLC using EtOAc-hexane as eluant. The first fraction was 0.18 g of 6a as a syrup. The second fraction was 0.2 g \lP WO 98/40375 PCT/US98/03792 of 6b also as a syrup. The column was then eluted with 20% EtOAc-hexane to give 0.077 g of 6c in the third fraction as a solid. Recrystallization from hexane gave a solid, mp 179-181 oC. Finally, the column was eluted with 30% EtOAc-hexane to give 0.08 g (12%) of 6d in the fourth fraction as a solid.
Recrystallization from hexane gave a solid, mp 160-161 oC.
B. Conversion of 6a to 6c and 6d with NaOH and PTC To a solution of 0.29 g (0.78 mmole) of 6a in 10 mL CHC1L was added 9 g of 40% NaOH. The reaction mixture was stirred for 0.5 h at room temperature and was added one drop of Aliquat-336 (methyltricaprylylammonium chloride) phase transfer catalyst (PTC). The mixture was stirred for 0.5 h at room temperature before being treated with 25 mL of ice-crystals then was extracted with CH 2 C1L (3x10 ml), dried over MgSO, and concentrated in vacuo to recover 0.17 g of a colorless film. The components of this mixture were separated using an HPLC and eluted with EtOAc-hexane to give 12.8 mg of 2- (2-benzylphenylsulfonylmethyl)-2-ethylhexenal in the first fraction, 30.9 mg of 6c in the second fraction and 90.0 mg of 6d in the third fraction.
Oxidation of 6a to To a solution of 0.20 g (0.52 mmole) of 6a in 5 mL of CHC1, was added 0.23 g (1.0 mmole) of pyridinium chlorochromate. The reaction mixture was stirred for 2 h then was treated with additional 0.23 g of pyridinium chlorochromate and stirred overnight. The dark reaction mixture was poured into a ceramic filterfrit containing silica gel and was eluted with CHC1 2 The filtrate was concentrated in vacuo to recover 167 mg of 5b as a colorless oil.
I(oS WO 98/40375 PCT/US98/03792 Example 4 3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepine-1,1dioxide S To a solution of 5.13 g (15.9 mmole) of 3 in 50 mL of CHCl,was added 10 g (31.9 mmole)of 50-60% MCPBA (mchloroperoxybenzoic acid) portionwise causing a mild reflux and formation of a white solid. The reaction mixture was allowed to stir overnight under N, and was triturated with 25 mL of water followed by 50 mL of NaOH solution. The organic was extracted into CHC1, (4x20 mL). The CHC1, extract was dried over MgSO, and evaporated to dryness to recover 4.9 g of an opaque viscous oil.
Example (laa,2b,8ba 2-Butyl-2-ethyl-8b-phenyl-la,2,3,8btetrahydro-benzothiepino[4,5-b]oxirene-4,4-dioxide (8a) (laa,2a,8ba) 2-Butyl-2-ethyl-8b-phenyl-la,2,3,8btetrahydro-benzothiepino [4,5-b]oxirene-4,4-dioxide 8 b) OL To 1.3 g44.03 mole) of in 25 mL of CHC1, was added portionwise 5 g (14.1 mmole) of 50-60 MCPBA causing a mild exotherm. The reaction mixture was stirred under N, overnight and was then held at reflux for 3 h. The insoluble white slurry was filtered. The filtrate was extracted with 10% potassium carbonate (3x50 mL), once with brine, dried over MgSO and concentrated in vacuo to give 1.37 g of a light yellow oil. Purification by HPLC gave 0.65 g of crystalline product. This product is a mixture of two isomers. Trituration of this crystalline product in hexane recovered 141.7 mg of a white crystalline product. This isomer was characterized by NMR and mass spectra to be the (laa,2b,8ba) isomer 8a. The hexane filtrate was concentrated in vacuo to give 206 mg of white film which is a mixture of 30% 8a and 70% 8b by 'H NMR.
WO 98/40375 PCT/US98/03792 Example 6 0^ 8fY cis-3-Butyl-3-ethyl-B-phenyl-2,3, 5-tetrahydro- (7 benzothiepine-1,1-dioxide trans-3-Butyl-3-ethyl- 5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide and 3 -Butyl-3-ethyl-4-hydroxy-5-cyclohexylidine- 2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide A mixture of 0.15 g (0.4 mmole) of a 3:7 mixture of 8a and 8b was dissolved in 15 ml MeOH in a 3 oz.
-Fisher/Porter vessel, then was added 0.1 g of 10% Pd/C catalyst. This mixture was hydrogenated at 70 psi H 2 for 5 h and filtered. The filtrate was evaporated to dryness in vacuo to recover 0.117 g of a colorless oil.
This material was purified by HPLC eluting with EtOAchexane. The first fraction was 4.2 mg of 9b. The second fraction, 5.0 mg was a 50/50 mixture of 9a and 9b. The third fraction was 8.8 mg of 6a The fourth fraction was 25.5 mg of 6b. The fifth fraction was 9.6 mg of a mixture of 6b and a product believed to be 3-butyl-3-ethyl-4,5-dihydroxy-5phenyl-2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide based on mass spectrum. The sixth fraction was 7.5 mg of a mixture of 6d and one of the isomers of Example 7 In another experiment, a product (3.7 g) from epoxidation of 3 with excess MCPBA in refluxing CHC1, under air was hydrogenated in 100 mL of methanol using 1 g of 10% Pd/C catalyst and 70 psi hydrogen. The product was purified by HPLC to give 0.9 g of 9b, 0.45 g of 9a, 0.27 g of 6a, 0.51 g of 6b, 0.02 g of 6c, 0.06 g of one isomer of 10a and 0.03 g of another isomer of 10, WO 98/40375 PCT/US98/03792 S Example 8 2-((2-Benzoylphenylthio)methyl)butyraldehyde (11) To an ice bath cooled solution of 9.76 g (0.116 mole of 2-ethylacrolein in 40 mL. of dry THF was added 24.6 g (0.116 mole) of 2-mercaptobenzophenone in 40 mL of THF followed by 13 g (0.128 mole) of triethylamine. The reaction mixture was stirred at room temperature for 3 days diluted with ether, and was washed successively with dilute HC1, brine, and 1 M potassium carbonate.
The ether layer was dried over MgSO 4 and concentrated in vacuo. The residue was purified by HPLC (10% EtOAchexane) to give 22 g of 11 in the second fraction. An attempt to further purifiy this material by kugelrohr distillation at 0.5 torr (160-190 OC) gave a fraction (12.2 g) which contained starting material indicating a reversed reaction during distillation.
This material was dissolved in ether (100 mL) and was washed with 50 mL of 1 M potassium carbonate three times to give 6.0 g of a syrup which was purified by HPLC (10% EtOAc-hexane) to give 5.6 g of pure 11.
Example 9
S
3-Ethyl-5-phenyl-2,3-dihydrobenzothiepine (12) To a mixture of 2.61 g (0.04 mole) of zinc dust and mL of DME was added 7.5 g (0.048 mole) of TiC1,. The reaction mixture was held at reflux for 2 h. A solution of 2.98 g (0.01 mole) of 11 was added dropwise in 1 h.
The reaction mixture was held at reflux for 18 h, cooled and poured into water. The organic was extracted into ether. The ether layer was washed with brine and filtered through Celite. The filtrate was dried over MgSO, and concentrated. The residual oil (2.5 g) was purified by HPLC to give 2.06 g of 12 as an oil in the second fraction.
I'l WO 98/40375 PCT/US98/03792 s0o Example 10 0< (IS) (laa,2a,8ba) 2-Ethyl-8b-phenyl-la,2,3,8b-tetrahydrobenzothiepino-[4,5-b]oxirene-4,4-dioxide (13) To a solution of 1.5 g (5.64 mmole) of 12 in 25 ml of CHC1, was added 6.8 g (19.4 mmole) of 50-60% MCPB portionwise causing an exothem and formation of a white solid. The mixture was stirred at room temperature overnight diluted with 100 ml methylene chloride and washed successively with 10% KCO, (4x50 ml), water (twice with 25 ml) and brine. The organic layer was then dried over MgSO, and evaporated to dryness to recover 1.47 g of an off white solid. 'H NMR indicated that only one isomer is present. This solid was slurried in 200 ml of warm Et 2 O and filtered to give 0.82 g of 13 as a white solid, mp 185-186.5 oC.
Example 11 (3a,4b,5a)- 3 -Ethyl-4-hydroxy-5-phenyl-2,3,4,5tetrahydro-benzothiepine-l,1-dioxide (14a), (3a,4b,5b) 3-Ethyl-4-hydroxy-5-phenyl-2,3,4,5tetrahydrobenzothiepine-l,l-dioxide (14b), and cis-3- Ethyl-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1, dioxide (15) A mixture of 0.5 g (1.6 mole) of 13, 50 ml of aceic acid and 0.5 g of 10% Pd/C catalyst was hydrogenated with 70 psi hydrogen for 4 h. The crude reaction slurry was filtered and the filtrate was stirred with 150 ml of a saturated NaHCO, solution followed by 89 g of NaHCO, powder portionwise to neutralize the rest of acetic acid. The mixture was extracted with methylene chloride (4x25 ml), then the organic layer was dried over MgSO, and concentrated in vacuo to give 0.44 g of a voluminous white solid which was purified by HPLC (EtOAc-Hexane) to give 26.8 mg of 15 in the first fraction, 272 mg of 14a as a solid, mp 142- (1- WO 98/40375 PCT/US98/03792 143.5 OC, in the second fraction, and 35 mg of impure 14b in the third fraction.
Example 12 2-Ethyl-2-((2-Hydroxymethylphenyl)thiomethyl)hexenal (16 ClSC A mixture of 5.0 g (0.036 mole) of 2-mercaptobenzyl alcohol, 6.4 g (0.032 mole) of 1, 3.6 g (0.036 mole) of triethylamine and 25 mL of 2-methoxyethyl ether was held at reflux for 7 h. Additional 1.1 g of mercaptobenzyl alcohol and 0.72 g of triethylamine was added to the reaction mixture and the mixture was held at reflux for additional 16 h. The reaction mixture was cooled and poured into 6N HC1 and extracted with methylene chloride. The methylene chloride extract was washed twice with 10% NaOH, dried over MgSO, and concentrated in vacuo to give 9.6 g of residue.
Purification by HPLC (20% EtOAc-hexane) gave 3.7 g (41%)of 16 as an oil.
Example 13 2-Ethyl-2-((2-formylphenyl)thiomethyl)hexenal (17) A mixture of 3.7 g of 16, 5.6 g (0.026 mole) of pyridinium chlorochromate, 2 g of Celite and 30 mL of methylene chloride was stirred for 18 h and filtered through a bed of silica gel. The silica gel was eluted with methylene chloride. The combined methylene chloride eluant was purified by HPLC (20% ETOAc-hexane) to give 2.4 g of an oil.
Example 14 3-Butyl-3-ethyl-2,3-dihydrobenzothiepine (18) A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047 mole) of TiC1,, and 50 mL of DME was held at 1n3 WO 98/40375 PCT/US98/03792 reflux for 2 h and cooled to room temperature. To this mixture was added 2.4 g (8.6 mmole) of 17 in 20 mL of DME in 10 min. The reaction mixture was stirred at room temperature for 2 h and held at reflux for 1 h then was let standing at room temperature over weekend. The reaction mixture was poured into dilute HC1 and was stirred with methylene chloride. The methylene chloride-water mixture was filtered through Celite. The methylene chloride layer was washed with brine, dried over MgSO,, and concentrated in vacuo to give 3.0 g of a residue. Purification by HPLC gave 0.41 g of 18 as an oil in the early fraction.
Example (laa,2a,8ba 2-Butyl-2-ethyl-la,2,3,8b-tetrahydrobenzothiepino[4,5-b]oxirene-4,4-dioxide (19a) and (laa,2b,8ba) 2-Butyl-2-ethyl-8b-phenyl-la,2,3,8btetrahydro-benzothiepino[4,5-b]oxirene-4,4-dioxide (19b) I IDSO To a solution of 0.4 g of 0.4 g (1.6 mmole) of 18 in mL of methylene chloride was added 2.2 g (3.2 mmole) of 50-60% MCPBA. The reaction mixture was stirred for 2 h and concentrated in vacuo. The residue was dissolved in 30 mL of CHC1, and was held at reflux for 18 h under N,.
The reaction mixture was stirred with 100 mL of NaOH and 5 g of sodium sulfite. The methylene chloride layer was washed with brine, dried over MgSO, and concentrated in vacuo. The residue was purified by HPLC (20% EtOAc-hexane) to give a third fraction which was further purified by HPLC (10% EtOAc-hexane) to give 0.12 g of syrup in the first fraction.
Recrystallization from hexane gave 0.08 g of 19a, mp 89.5-105.5 oC. The mother liquor from the first fraction was combined with the second fraction'and was further purified by HPLC to give additional 19a in the first fraction and 60 mg of 19b in the second fraction.
i_-7+ WO 98/40375 PCT/US98/03792 Crystallization from hexane gave 56 mg of a white solid.
Example 16 3-Butyl-3-ethyl-4,5-dihydroxy-5-phenyl-2,3, 4 5 tetrahydro-benzothiepine-1,1-dioxide (20) sol This product was isolated along with 6b from oy hydrogenation of a mixture of Sa and 8b. Example 17 3-Butyl-3-ethyl-4-hydroxy-5-phenylthio-2,3,4,5tetrahydro-benzothiepine-1,1-dioxide (21) iSu l A mixture of 25 mg (0.085 mmole) of 19b, 0.27 g (2.7 (i\ mmole) of thiophenol, 0.37 g (2.7 mmole) of potassium carbonate, and 4 mL of DMF was stirred at room temperature under N, for 19 h. The reaction mixture was poured into water and extracted with methylene chloride. The methylene chloride layer was washed successively with 10% NaOH and brine, dried over MgSO,, and concentrated in vacuo to give 0.19 g of semisolid which contain substantial amounts of diphenyl disulfide. This material was purified by HPLC EtOAc-hexane) to remove diphenyl disulfide in the first fraction. The column was then eluted with 20% EtOAchexane to give 17 mg of a first fraction, 4 mg of a second fraction and 11 mg of a third fraction which.
were three different isomers of 21, i.e. 21a, 21b, and 21c, respectively, by 'H NMR and mass spectra.
Example 18 Alternative Synthesis of 6c and 6d A. Preparation from 2-((2-Benzoylphenylthio)methyl)-2ethylhexanal (2) Step 1. 2-((2-Benzoylphenylsulfonyl)methyl)-2ethylhexanal (44) SO 2 6 ~1Gt WO 98/40375 PCT/US98/03792 To a solution of 9.0 g (0.025 mole) of compound 2 in 100 ml of methylene chloride was added 14.6 g (0.025 mol) of 50-60% MCPBA portionwise. The reaction mixture was stirred at room temperature for 64 h then was stirred with 200 ml of 1 M potassium carbonate and filtered through Celite. The methylene chloride layer was washed twice with 300 ml of 1 M potassium carbonate, once with 10% sodium hydroxide and once with brine. The insoluble solid formed during washing was removed by filtration through Celite. The methylene .chloride solution was dried and concentrated in vacuo to give 9.2 g (95%)of semisolid. A portion (2.6 g) of this solid was purified by HPLC(10% ethyl acetatehexane) to give 1.9 g of crystals, mp 135-136 °C Step 2. 2-((2-Benzylphenylsulfonyl)methyl)-2- g ethylhexanal (45)
L
1+ 4-h A solution of 50 g (0.13 mole) of crude 44 in 250 ml of methylene chloride was divided in two portions and charged to two Fisher-Porter bottles. To each bottle was charged 125 ml of methanol and 5 g of 10% Pd/C. The bottles were pressurized with 70 psi of hydrogen and the reaction mixture was stirred at room temperature for 7 h before being charged with an additional 5 g of Pd/C. The reaction mixture was again hydrogenated with 70 psi of hydrogen for 7 h. This procedure was repeated one more time but only 1 g of Pd/C was charged to the reaction mixture. The combined reaction mixture was filtered and concentrated in vacuo to give 46.8 g of 45 as brown oil.
Step 3. (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl- 2,3,4,5-tetrahydrobenzothiepine-l,l-dioxide and (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5tetrahydrobenzothiepine-1,1-dioxide (6d) I'l( WO 98/40375 PCT/US98/03792 To a solution of 27.3 g (73.4 mmole) of 45 in 300 ml of anhydrous THF cooled to 2 OC with an ice bath was added 9.7 g (73.4 mmole) of 95% potassium t-butoxide. The reaction mixture was stirred for 20 min, quenched with 300 ml of 10% HC1 and extracted with methylene chloride. The methylene chloride layer was dried over magnesium sulfate and concentrated in vacuo to give 24.7 g of yellow oil. Purification by HPLC (ethyl acetate-hexane) yielded 9.4 g of recovered 45 in the first fraction, 5.5 g of 6c in the second fraction and 6.5 g of 6d in the third fraction.
B. Preparation from 2-hydroxydiphenylmethane S Step 1. 2-mercaptodiphenylmethane (46) To a 500 ml flask was charged 16 g (0.33 mol) of sodium hydride oil dispersion. The sodium hydride was washed twice with 50 ml of hexane. To the reaction flask was charged 100 ml of DMF. To this mixture was added a solution of 55.2 g (0.3 mol) of 2hydroxydiphenylmethane in 200 ml of DMF in 1 h while temperature was maintained below 30 OC by an ice-water bath. After complete addition of the reagent, the mixture was stirred at room temperature for 30 min then cooled with an ice bath. To the reaction mixture was added 49.4 g (0.4 mole) of dimethyl thiocarbamoyl chloride at once. The ice bath was removed and the reaction mixture was stirred at room temperature for 18 h before being poured into 300 ml of water. The organic was extracted into 500 ml of toluene. The toluene layer was washed successively with 10% sodium hydroxide and brine and was concentrated in vacuo to give 78.6 g of a yellow oil which was 95% pure dimethyl O-2-benzylphenyl thiocarbamate. This oil was heated at 280-300 OC in a kugelrohhr pot under house vacuum for 30 min. The residue was kugelrohr distilled at 1 torr (180-280 OC).
The distillate (56.3 g) was crystallized from methanol to give 37.3 g of the rearranged product dimethyl Iml WO 98/40375 PCT/US98/03792 S-2-benzylphenyl thiocarbamate as a yellow solid. A mixture of 57 g (0.21 mole) of this yellow solid, 30 g of potassium hydroxide and 150 ml of methanol was stirred overnight then was concentrated in vacuo. The residue was diluted with 200 ml of water and extracted with ether. The aqueous layer was made acidic with concentrate HC1, The oily suspension was extracted into ether. The ether extract was dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from hexane to give 37.1 g of 2mercaptodiphenylmethane as a yellow solid.
Step 2. 2-((2-Benzylphenylthio)methyl)-2-ethylhexanal (47) 9161% A mixture of 60 g (03 mole) of yellow solid from step 1, 70 g (0.3 mole) of compound 1 from preparation 1, 32.4 g (0.32 mole) of triethylamine, 120 ml of 2methoxyethyl ether was held at reflux for 6 hr and concentrated in vacuo. The residue was triturated with .500 ml of water and 30 ml of concentrate HC1. The organic was extracted into 400 ml of ether. The ether layer was washed successively with brine, 10% sodium hydroxide and brine and was dried over magnesium sulfate and concentrated in vacuo. The residue (98.3 g) was purified by HPLC with 2-5% ethyl acetate-hexane as eluent to give 2-((2-benzylphenylthio)methyl)-2ethylhexanal 47 as a yellow syrup.
Step 3. 2-((2-Benzylphenylsulfonyl)methyl)-2ethylhexanal To a solution of 72.8 g (0.21 mole) of yellow syrup from step 2 in 1 liter of methylene chloride cooled to 10 °C was added 132 g of 50-60% MCPBA in 40 min. The reaction mixture was stirred for 2 h. An additional 13 g of 50-60% MCPBA was added to the reaction mixture.
The reaction mixture was stirred for 2 h and filtered ('1 WO 98/40375 PCT/US98/03792 through Celite. The methylene chloride solution was washed twice with 1 liter of 1 M potassium carbonate then with 1 liter of brine. The methylene chloride layer was dried over magnesium sulfate and concentrated to 76 g of 2-((2-benzylphenylsulfonyl)methyl)-2ethylhexanal 45 as a syrup.
Step 4. (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl- 2,3,4,5-tetrahydrobenzothiepine-l,l-dioxide and (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5tetrahydrobenzothiepine-l,l-dioxide (6d) Reaction of 45 with potassium t-butoxide according to the procedure in step 3 of procedure A gave pure 6c and 6d after HPLC. 5J s Examle 19 o (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5phenyl-2,3,4,5-tetrahydrobenzothiepine-1,l-dioxide and (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (26) Step 1. Preparation of 2-((2-benzoyl-4-methoxy phenylthio)methyl)-2-ethylhexanal (22) 2-Hydroxy-4-methoxybenzophenone was converted to the dimethyl O-2-benzoyphenyl thiocarbamate by methods previously described in example 18. The product can be isolated by recrystallization from ethanol. Using this improved isolation procedure no chromatography was needed. The thermal rearrangement was performed by reacting the thiocarbamate( 5 g) in diphenyl ether at 260 OC as previously described. The improved isolation procedure which avoided a chromatography step was described below.
The crude pyrolysis product was then heated at 65 OC in 100 ml of methanol and 100 ml of THF in the presence of g of KOH for 4 h. After removing THF and methanol WO 98/40375 PCT/US98/03792 by rotary evaporation the solution was extracted with NaOH and ether. The base layer was acidified and extracted with ether to obtain a 2.9 g of crude thiophenol product. The product was further purified by titrating the desired mercaptan into base with limited KOH. After acidification and extraction with ether pure 2 -mercapto-4-methoxybenzophenone (2.3 g) was isolated.
2 -mercapto-4-methoxybenzophenone can readily be converted to the 2-((2-benzoyl-4methoxyphenylthio)methyl)-2-ethyihexanal (22) by reaction with 2-ethyl-2-(mesyloxymethyl)hexanal as previously described.
Step 2. 2- 2-ethylhexanal (23) s(126 Substrate 22 was readily oxidized to 2-((2-benzoyl-5methoxyphenyl-sulfonyl)methyl)-2-ethyhexanal (23) as described in example 18. 7 S0 cN-> SK (2+)7 O 2I) Step 3. 2-((2-benzyl-5-methoxyphenylsulfonyl)methyl)-2ethylhexanal (24) Sulfone 23 was then reduced to 2-((2-benzyl-5methoxyphenyl-sulfonyl)methyl)-2-ethylhexana1 (24) as described in example 18. CD SO
CU
Step 4. (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-8-methoxy- 5-phenyl-2,3,4, 5-tetrahydrobenzothiepine-1,1-dioxide and (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-8methoxy-5-phenyl-2,3,4,5-tetrahydr6benzothiepine-1,1dioxide (26) Ufa O A 3-neck flask equipped with a powder addition 'u funnel,thermocouple and nitrogen bubbler was charged with 19.8 g (0.05 mole) of sulfone 24 in 100 ml dry THF. The reaction was cooled to -1.6 oC internal WO 98/40375 PCT/US98/03792 temperature by means of ice/salt bath. Slowly add 5.61 g (0.05 mole) of potassium t-butoxide by means of the powder addition funnel. The resulting light yellow solution was maintained at -1.6 oC. After 30 min reaction 400 ml of cold ether was added and this solution was extracted with cold 10 HC1. The acid layer was extracted with 300 ml of methylene chloride.
The organic layers were combined and dried over magnesium sulfate and after filtration stripped to dryness to obtain 19.9 g of product. 'H nmr and glpc indicated a 96% conversion to a 50/50 mixture of 25 and 26. The only other observable compound was 4% starting sulfone 24.
The product was then dissolved in 250 ml of 90/10 hexane/ethyl acetate by warming to 50 The solution was allowed to cool to room temperature and in this way pure 26 can be isolated. The crystallization can be enhanced by addition of a seed crystal of 26. After 2 crystallizations the mother liquor which was now 85.4% and has a dry weight of 8.7 g. This material was dissolved in 100 ml of 90/10 hexane/ethyl acetate and ml of pure ethyl acetate at 40 C. Pure 25 can be isolated by seeding this solution with a seed crystal of 25 after storing it overnight at 0 C.
Examnle 20 7) (3a,4a,5a) 3-Butyl-3-ethyl-4,8-dihydroxy-5-phenyl- 2,3,4,5-tetrahydrobenzothiepine-l,l-dioxide (27) In a 25 ml round bottomed flask, 1 g of 26( 2.5 mmoles) and 10 ml methylene chloride were cooled to 78 °C with stirring. Next 0.7 ml of boron mmole) was added via syringe. The reaction was allowed to slowly warm to room temperature and stirred for 6 h.
The reaction was then diluted with 50 ml methylene chloride and washed with saturated NaC1 and then water.The organic layer was dried over magnesium sl WO 98/40375 PCT/US98/03792 sulfate. The product (0.88g) 27 was characterized by NMR and mass spectra.
Examle 21 General Alkylation of phenol 27 A 25 ml flask was charged with 0.15 g of 27(0.38 mmole), 5 ml anhydrous DMF, 54 mg of potassium carbonate(0.38 mmole) and 140 mg ethyl iodide (0.9 mmole). The reaction was stirred at room temperature ,overnight.The reaction was diluted with 50 ml ethyl ether and washed with water (25 ml) then 5% NaOH ml) and then sat. NaC1. After stripping off the solvent the ethoxylated product 28 was obtained in high yield.
The product was characterized by NMR and mass spectra.
This same procedure was used to prepare products listed in table 1 from the corresponding iodides or bromides.
For higher boiling alkyl iodides and bromides only one equivalent of the alkyl halide was used.
o o RO 5 WO 98/40375 PCT/US98/03792 Table 1 Compound No. R 27 H 26 Me 28 Et 29 hexyl Ac 31 (CH2)6-N-pthalimide Example 22 (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-7-hydroxyamino-5phenyl-2,3,4,5-tetrahydrobenzothiepine-l,l-dioxide (37) and (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-7hydroxyamino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine- 1,1-dioxide (38) Step 1. Preparation of (32) Procedure adapted from reference :Synthesis -Stuttgart 9 770-772 (1986) Olah G. Et al Under nitrogen, a 3 neck flask was charged with 45 g (0.172 mole of 2-chloro-5-nitrobenzophenone in 345 ml methylene chloride and the solution was cooled to ice/water temperature. By means of an additional funnel, 150 g( 0.172 mole) of trifluoromethane sulfonic acid in 345 ml methylene chloride was added slowly.
Next 30 g of triethylsilane (0.172 mole) in 345 ml methylene chloride was added dropwise to the chilled solution. Both addition steps( trifluoromethane sulfonic acid and triethylsilane)were repeated. After the additions were completed the reaction was allowed to slowly warm up to room temperature and stirred for 12 h under nitrogen. The reaction.mixture was then poured into a chilled stirred solution of 1600 ml of saturated sodium bicarbonate. Gas evolution occurred.
Poured into a 4 liter separatory funnel and separated layers. The methylene chloride layer was isolated and (3 WO 98/40375 PCT/US98/03792 combined with two 500 ml methylene chloride extractions of the aqueous layer. The methylene chloride solution was dried over magnesium sulfate and concentrated in vacuo. The residue was recrystallized from hexane to give 39 g product. Structure 32 was confirmed by mass spectra and proton and carbon NMR. 5 G Step 2. Preparation of 2-((2-benzyl-4--- 4 nitrophenylthio)methyl)-2-ethylhexanal (33) (1 The 2-chloro-5-nitrodiphenylmethane product 32 (40 g, 0.156 mole) from above was placed in a 2 liter 2 neck flask with water condenser. Next 150 ml DMSO and 7.18 g (0.156 mole) of lithium sulfide was added and the solution was stirred at 75 oC for 12 h. The reaction was cooled to room temperature and then 51.7 g of mesylate IV was added in 90 ml DMSO. The reaction mixture was heated to 80 oC under nitrogen. After 12 h monitored by TLC and added more mysylate if necessary.
Continued the reaction until the reaction was completed. Next the reaction mixture was slowly poured into a 1900 ml of 5% acetic aqueous solution with stirring, extracted with 4 X 700 ml of ether, and dried over MgS04. After removal of ether, 82.7 g of product was isolated. The material can be further purified by silica gel chromatography using 95% hexane and 5 ethyl acetate. If pure mysylate was used in this step there was no need for further purification. The product 33 was characterized by mass spectra and NMR.
Step 3. Oxidation of the nitro product 33 to the sulfone 2-((2-benzyl-4-nitrophenylsulfonyl)methyl)-2ethylhexanal (34) The procedure used to oxidize the sulfide 33 to the sulfone 34 has been previously described.
\14 WO 98/40375 PCT/US98/03792 Step 4. Reduction of 34 to 2-((2-benzyl-4hydroxyaminophenylsulfonyl) methyl) -2 -ethylhexanal A 15 g sample of 34 was dissolved in 230 ml of ethanol and placed in a 500 ml rb flask under nitrogen. Next g of 10 wt.% Pd/C was added and hydrogen gas was bubbled through the solution at room temperature until the nitro substrate 34 was consumed. The reaction could be readily monitored by silica gel TLC using 80/20 hexane/EtOAc. Product 35 was isolated by filtering off the Pd/C and then stripping off the EtOH solvent. The product was characterized by NMR and mass spectra.
Step 5. Preparation of the 2-((2-benzyl-4-N,O-di-(tbutoxy-carbonyl)hydroxyaminophenylsulfonyl) methyl)-2ethylhexanal et A 13.35 g sample of 35 (0.0344 mole) in 40 ml of dryo 1-4 THF was stirred in a 250 ml round bottomed flask. Next added 7.52 g (0.0344 mole) of di-t-butyl dicarbonate in 7 ml THF. Heated at 60 OC overnight. Striped off THF and redissolved in methylene chloride. Extracted with 1 HC1; and then 5% sodium bicarbonate.
The product was further purified by column chromatography using 90/10 hexane/ethyl acetate and then 70/30 hexane/ethyl acetate. The product 36 was obtained (4.12 g) which appeared to be mainly the di- (t-butoxycarbonyl) derivatives by proton NMR. Step 6. (3a,4a,Sa) 3-Butyl-3-ethyl-4-hydroxy-7- c 4 hydroxyamino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine- (3 1,1-dioxide (37) and (3a,4b,5b) 3-Butyl-3-ethyl-4hydroxy-7-hydroxyamino-5-phenyl-2,3,4,5- i tetrahydrobenzothiepine-1, 1-dioxide (38) c(f o 0 A 250ml 3-neck round bottomed flask was charged with 4 g of 36 (6.8 mmoles), and 100 ml of anhydrous THF and cooled to -78 oC under a nitrogen atmosphere. Slowly add 2.29 g potassium tert-butoxide(20.4 mmoles) with WO 98/40375 PCT/US98/03792 stirring and maintaining a -78 oC reaction temperature.
After 1 h at -78 oC the addition of base was completed and the temperature was brought to -10 OC by means of a ice/salt bath. After 3 h at -10 OC, only trace 36 remained by TLC. Next add 35 ml of deionized water to the reaction mixture at -10 OC and stirred for 5 min.
Striped off most of the THF and added to separatory funnel and extracted with ether until all of the organic was removed from the water phase. The combined ether phases were washed with saturated NaCl and then dried over sodium sulfate. The only products by TLC and NMR were the two BOC protected isomers of 37 and 38.
The isomers were separated by silica gel chromatography using 85% hexane and 15 ethyl acetate; BOC-37 (0.71 g) and BOC- 38 (0.78 g).
Next the BOC protecting group was removed by reacting 0.87 g of BOC-38 (1.78 mmoles) with 8.7 ml of 4 M HC1 (34.8 mmoles)in dioxane for 30 min. Next added 4.74 g of sodium acetate (34.8 mmoles) to the reaction mixture and 16.5 ml ether and stirred until clear. After transferring to a separatory funnel extracted with ether and water and then dried the ether layer with sodium sulfate. After removing the ether, 0.665 g of 38 was isolated. Isomer 37 could be obtained in a similar procedure. s -3& 1 4 0 Aj 4 Example 23 (3a,4a,5a) 3-Butyl-3-ethyl-7-(n-hexylamino)-4-hydroxy- 5-phenyl-2,3,4, 5-tetrahydrobenzothiepine-1, 1-dioxide and (3a,4b,5b) 3-Butyl-3-ethyl-7-(n-hexylamino)-4hydroxy- 5 -phenyl-2, 3,4, 5-tetrahydrobenzothiepine- 1, 1dioxide (41) Step 1. 2-((2-Benzyl-4-(nhexylamino)phenylsulfonyl)methyl)-2-ethylhexanal (39) In a Fischer porter bottle weighed out 0.5 g of 34 (1.2 mmoles) and dissolved in 3.8 ml of ethanol under
(M
WO 98/40375 PCT/US98/03792 nitrogen. Next added 0.1 g of Pd/C and 3.8 ml of hexanal. Seal and pressure to 50 psi of hydrogen gas.
Stirred for 48 h. After filtering off the catalyst and removing the solvent by rotary evaporation 39 was isolated by column chromatography (0.16 g) using 90/10 hexane ethyl acetate and gradually increasing the mobile phase to 70/30 hexane/ethyl acetate. The product was characterized by NMR and mass spectra.
Step 2. (3a,4a,5a) 3-Butyl-3-ethyl-7-(n-hexylamino)-4hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1, 1dioxide (40) and (3a,4b,5b) 3-Butyl-3-ethyl-7-(nhexylamino)-4-hydroxy-5-phenyl-2,3,4,5- 0 SO tetrahydrobenzothiepine-1,1-dioxide (41) A 2-neck, 25 ml round bottomed flask with stir bar was charged with 0.158 g 39 (0.335 mmole) and 5 ml anhydrous THF under nitrogen. Cool to -10 OC by means of a salt/water bath. Slowly add 0.113 g of potassium tert butoxide (0.335 mmole). After 15 min at -10 OC all of the starting material was consumed by TLC and only the two isomers 40 and 41 were observed. Next added ml of chilled 10% HC1 and stirred at -10 OC for 5 min.
Transferred to a separatory funnel and extract with ether. Dried over sodium sulfate. Proton NMR of the dried product (0.143 g) indicated only the presence of the two isomers 40 and 41. The two isomers were separated by silica gel chromatography using 90/10 hexane ethyl acetate and gradually increasing the mobile phase to 70/30 hexane/ethyl acetate. 40 53.2 mg); 41(58.9 mg). so Example 24 C O
H
Quaternization of amine substrates 40 and 41 Amine products such as 40 and 41 can be readily alkylated to quaternary salts by reaction with alkyl halides. For example 40 in DMF with 5 equivalents of l%1 WO 98/40375 PCT/US98/03792 methyl iodide in the presence of 2,6 dimethyl lutidine produces the dimethylhexylamino quaternary salt.
(42) Example (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-5-(4-iodophenyl)- 2,3,4,5-tetrahydrobenzothiepine-l,l-dioxide (42) In a 25 ml round bottomed flask 0.5 g (1.3 mmole) of 6d 0.67 g of mercuric triflate were dissolved in 20 ml of dry methylene chloride with stirring. Next 0.34 g of Iodine was added and the solution was stirred at room temperature for 30 h. The reaction was then diluted with 50 ml methylene chloride and washed with 10 ml of 1 M sodium thiosulfate; 10 ml of saturated KI and dried over sodium sulfate. See Tetrahedron, No. 17, pp 5139-5146 (1994) Bachki, F. Et al.Mass spectrum indicated a mixture of 6d mono iodide 42 and a diiodide adduct. The mixture was separated by column chromatography and 42 was characterized bt NMR and mass spectra. s Example 26 o (3a,4b,5b) 3-Butyl-5-(4-carbomethoxyphenyl)-3-ethyl-4hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (43) A 0.1 g sample of 42 0.212 mmole), 2.5 ml dry methanol, 38 ul triethylamine (0.275 mmole) 0.3 ml toluene and 37 mg of palladium chloride (0.21 mmole) was charged to a glass lined mini reactor at 300 psi carbon monoxide. The reaction was heated at 100 °C overnight. The catalyst was filtered and a high yield of product was isolated.
The product was characterized by NMR and mass spectra.
Note the ester functionalized product 43 can be converted to the free acid by hydrolysis.
WO 98/40375 PCT/US98/03792 Example 27 (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide and (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-7methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1dioxide (49) s o Step 1. 2 -Mercapto-5-methoxybenzophenone OCIA, (S__j Reaction of 66.2 g of 4-methoxythiophenol with 360 ml of 2.5 N n-butyllithium, 105 g of tetramethylethylenediamine and 66.7 g of benzonitrile in 600 ml cyclohexane according to the procedure in WO 93/16055 gave 73.2 g of brown oil which was kugelrohr distilled to remove 4-methoxythiophenol and gave 43.86 g of crude 50 in the pot residue.
Step 2. 2 -Benzoyl-4-methoxyphenylthio)methyl)-2ethyihexanal (51) 8 (51) Reaction of 10 g (0.04 mole) of crude 50 with 4.8 g (0.02 mole)of mesylate 1 and 3.2 ml (0.23 mole) of triethylamine in 50 ml of diglyme according to the procedure for the preparation of 2 gave 10.5 g of crude product which was purified by HPLC ethyl acetatehexane) to give 1.7 g of 51.
Step 3. 2-((2-Benzoyl-4-methoxyphenylsulfonyl)methyl)- 2-ethyl-hexanal (52) o M652.
A solution of 1.2 g (3.1 mmoles) of 51 in 25 ml of methylene chloride was reacted with 2.0 g (6.2 mmoles) of 50-60% MCPBA according to the procedure of step 2 of procedure A in example 18 gave 1.16 g of 52 as a yellow oil.
Step 4. 2-((2-Benzyl-4-methoxyphenylsulfonyl)methyl)- 2-ethyihexanal (53) s CO, at
I.'
(89 (6~ WO 98/40375 PCT/US98/03792 Hydrogenation of 1.1 g of 52 according to the procedure of step 3 of procedure A of example 18 gave 53 as a yellow oil (1.1 g).
Step 5. (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy- 5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide and (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-7methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-, 1dioxide (49) a -L A solution of 1.1 g of 53, .36 g o potassium tbutoxide and 25 ml of anhydrous THF was held at reflux for 2 h and worked up as in step 4 of procedure A of example 18 to give 1.07 g of a crude product which was purified by HPLC to give 40 mg of 48 as crystals, mp 153-154 oC and 90 mg of 49 as solid, mp 136-140 OC.
SUO
Examole 28 (55 "a 5-Phenyl-2, 3-dihydrospirobenzothiepine-3,1 -cyclohexane (57) Step 1. 1-(Hydroxymethyl)-cyclohexanecarboxaldehyde (54) To a cold (O'C'mixture of 100 g (0.891 mole) of cyclohexanecarboxaldehyde, 76.5 g of 37% of formaldehyde in 225 ml of methanol was added dropwise ml of 1 N Sodium hydroxide in 1 h. The reaction mixture was stirred at room temperature over 48 then was evaporated to remove methanol. The reaction mixture was diluted with water and extracted withmethylene chloride. The organic layer was washed with water, brine, and dried over sodium sulfate and concentrated under vacuum to give 75 g of thick oil. Proton NMR and mass spectra were consistent with the product.
Step 2. 1-(mesyloxymethyl)cyclohexanecarboxaldehyde a 141<-
-O
0 IQ4b0t z LI ,iI I IV WO 98/40375 PCT/US98/03792 To a cold (0*C'mixture of alcohol 54 (75 g, 0.54 mole) and 65.29 g (0.57 mole) of methanesulfonyl chloride in ml of methylene chloride was added a solution of pyridine (47.96 g, 0.57 mole) in 40 ml of methylene chloride. The reaction mixture was stirred at room temperature for 18 h then quenched with water, acidified with cone. HC1 and extracted with methylene chloride. The organic layer was washed with water, brine, and dried over sodium sulfate and concentrated under vacuum to give 91.63 g of thick oil.
Proton NMR and mass spectra were consistent with the product.
Step 3. (So Benzoylphenylthio)methyl)cyclohexanecarboxaldehyde (56) A mixture of 69 g (0.303 mole) of 2mercaptobenzophenone, 82 g (0.303 mole) of mesylate 32 g of triethylamine, and 150 ml of diglyme was stirred and held at reflux for 24 h. The mixture was cooled, poured into dil. HC1 and extracted with methylene chloride. The organic layer was washed with NaOH, water, brine, and dried over sodium sulfate and concentrated under vacuum to remove excess diglyme.
This was purified by silica gel flush column EtOAc: Hexane) and gave 18.6 g of yellow oil. Proton NMR and mass spectra were consistent with the product.
Step 4. 5-Phenyl-2,3-dihydrospirobenzothiepine-3,1'cyclohexane (57) To a mixture of 6.19 g of zinc dust and 100 ml of dry DME was added TiC1,(16.8 g, 0.108 mole) The reaction mixture was heated to reflux for 2 h. A solution of compound 56 (8.3 g, 0.023 mole) in 50 ml of DME was added dropwise to the reaction mixture in 1 h and the mixture was held at reflux for 18 h. The mixture was 11 WO 98/40375 PCT/US98/03792 cooled, poured into water and extracted with ether. The organic layer was washed with water, brine, and dried over sodium sulfate, filtered through celite and concentrated under vacuum. The residue was purified by HPLC (10% EtOAc: Hexane) to give 4.6 g of white solid, mp 90-91 Proton and carbon NMR and mass spectra were consistent with the product.
Example 29 8b-Phenyl-la,2,3,8b-tetrahydrospiro(benzothiepino[4,5bloxirene-2,1'-cyclohexane)-4,4-dioxide (58) To a solution of 57 (4.6 g, 15 mmole) in 50 ml chloroform under nitrogen was added 55% MCPBA (16.5 g, 52.6 mmole) portionwise with spatula. The reaction was held at reflux for 18 h and washed with 10% NaOH(3X), water, brine, and dried over sodium sulfate and concentrated under vacuum to give 5 g of crude product.
This was recrystallized from Hexane/EtOAc to give 4.31 g of yellow solid, mp 154-155 Proton and carbon NMR and mass spectra were consistent with the product.
QSOL
Example 30 c trans-4-Hydroxy-5-phenyl-2, 3,4,5-tetrahydro spiro(benzothiepine-3,1'-cyclohexane) -1,1-dioxide (59) A mixture of 0.5 g (1.4 mmoles) of 58 20 ml of ethanol,10 ml of methylene chloride and 0.4 g of Pd/C catalyst was hydrogenated with 70 psi hydrogen for 3 h at room temperature. The crude reaction slurry was filtered through Celite and evaporated to dryness. The residue was purified by HPLC (10% .EtOAc-Hexane, EtOAc-Hexane). The first fraction was 300 mg as a white solid, mp 99-100 Proton NMR showed this was a trans isomer. The second fraction gave 200 mg of solid which was impure cis isomer.
WO 98/40375 PCT/US98/03792 Examnle 31 04 cis-4-Hydroxy-5-phenyl-2,3,4,5-tetrahydro spiro(benzothiepine-3,1'-cyclohexane)-1,1-dioxide To a solution of 0.2 g (0.56 nmmole) of 59 in 20 ml of CHC1,, was added 8 g of 50% NaOH and one drop of Aliquat-336 (methyltricaprylylammonium chloride) phase transfer catalyst. The reaction mixture was stirred for 10 h at room temperature. Twenty g of ice was added to the mixture and the mixture was extracted with CH,C1, (3x10 ml) washed with water, brine and dried over MgSO, and concentrated in vacuo to recover 0.15 g of crude product. This was recrystallized from Hexane/EtOAc to give 125 mg of white crystal, mp 209-210 *C Proton and carbon NMR and mass spectra were consistent with the product. &S 5 B 24 Example 32 (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5tetrahydrobenzothiepine and (3a,4b,5b) 3-Butyl-3ethyl-4-hydroxy-5-phenyl-2,3,4,5tetrahydrobenzothiepine (62) To a solution of 0.5 g (1.47 nmmole) of compound 47 in ml of anhydrous THF was added 0.17 g (1.47 mmole) of potassium t-butoxide. The reaction mixture was stirred at room temperature for 18 h and quenched with ml of 10% HC1. The organic was extracted into methylene chloride. The methylene chloride extract was dried over magnesium sulfate and concentrated in vacuo.
The residue was purified by HPLC EtOAc-hexane) to give 47 mg of 61 in the second fraction and 38 mg of 62 in the third fraction. Proton NMR and mass spectra were consistent with the assigned structures.
SI S B
,OIL
,193 WO 98/40375 PCTIUS98/03792 (3a,4a,Sa) 3-Butyl-3ethyl-4-hydroxy-7-amino-5-phenyl- 2,3,4, 5-tetralydrobenzothiepine-1, 1-dioxide (63) and (3a,4b,Sb) 3-Butyl-3-ethyl-4-hydroxy-7-amino-5-phenyl- 2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(64) An autoclave was charged with 200 mg of 37 in 40 cc ethanol and .02 g 10 Pd/C. After purging with nitrogen the dave was charged with 100 psi hydrogen and heated to 55 C. The reaction was monitored by TLC and mass spec and allowed to proceed until all of 37 was consumed. After the reaction was complete the catalyst was filtered and the solvent was removed in vacuo and the only observable product was amine 63.
This same procedure was used to produce 64 from 38.
.4 L-t 00 IN, A cc6 Examle 34 c4cc e3 o~y 3 (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-(3'methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-l,1dioxide and (3a,4b,Sb) 3 -Butyl-3 -ethyl-4 -hydroxy- 7-methoxy-5-(3'-methoxyphenyl)-2,3,4,5tetrahydrobenzothiepine-l,1-dioxide (66) Alkylation of e-methoxyphenol with 3-methoxybenzyl chloride according to the procedure described in J.
Chem. Soc, 2431 (1958) gave 4-methoxy-2-(3'methoxybenzyl)phenol in 35% yield. This material was converted to compound 65, mp 138.5-141.5 OC, and compound 66, mp 115.5-117.5 OC, by the procedure similar to that in Example 18 method B.
Examnle (3a,4a,Sa) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-(3'- (trifluoromethyl)phenyl)-2,3,4,5tetrahydrobenzothiepine-1,1-dioxide and.
(3a,4b,'5b) 3-Butyl-3-ethy-4-hydroxy-7-methoxr'5-(3 (trifluoromethyl)phenyl)-2,3,4,5tetrahydrobenzothiepine-1,1-dioxide (68).
SOL SOE Lc 196L4 WO 98/40375 PCT/US98/03792 Alkylation of 4-methoxyphenol with 3- (trifluoromethyl)benzyl chloride according to the procedure described in J. Chem. Soc. 2431 (1958) gave 4-methoxy-2- (trifluoromethyl)benzyl)phenol. This material was converted to compound 67, mp 226.5-228 0
C,
and compound 68, mp 188-190 0 C, byu the procedure similar to that in Example 18 method B. 501: Il u Example Cj OWr~tUL 6 (3a,4a,5a) 3:-Buty -3 -ethyl-5-(4- .fluo rophenyl)-4hydroxy-7-methoxy-2, 3,4, 5-tetrahydrobenzothiepine-1, 1dioxide and (3a,4b,5b) 3-Butyl-3-ethyl-5-(4'fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5tetrahydrobenzothiepine-1,1-dioxide Alkylation of 4-methoxyphenol with 4-fluorobenzyl chloride according to the procedure described in J.
Chem. Soc, 2431 (1958) gave 4-methoxy-2-(4'fluorobenzyl)phenol. This material was converted to compound 69 and compound 70 by the procedure similar to that in Example 18 method B.
Exam(le 37 0 0A (3a,4a,5a) 3-Butyl-3-ethyl-5-(3'-fluorophenyl)-4hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1dioxide and (3a,4b,Sb) 3-Butyl-3-ethyl-5-(3'fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5tetrahydrobenzothiepine-1,1-dioxide (72).
Alkylation of 4-methoxyphenol with 3-fluorobenzyl chloride according to the procedure described in J.
Chem. Soc, 2431 (1958) gave 4-methoxy-2-(3'fluorobenzyl)phenol. This material was converted to compound 71 and compound 72 by the-procedure similar to that in Example 18 method B.
Example 44"'r~~d I t F '3 ,I, L 13) o 4 WO 98/40375 WO 9840375PCT/US98/03792 (3a,4a,5a) 3-Butyl-3-ethyl-5-(21-fluorophenyl)-4hydroxy-7-methoxy-2, 3,4, 5-tetrahydrobenzothiepine-1, 1dioxide and (3a,4b,5b) 3-Butyl-3-ethyl-S-(2'fluorophenyl) -4-hydroxy-7-rnethoxy-2, 3,4, tetrahydrobenzothiepine-1,l--dioxide (74).
Alkylation of 4-methoxyphenol with 2-f luorobenzyl chloride according to the procedure described in J.
Chem. Soc, 2431 (1958) gave 4-methoxy-2-(2'fluorobenzyl)phenol. This material was converted to compound 73 and compound 74 by the procedure similar to that in Example 18 method B. 0"SLA6kc Exarnnle 39 0 (3a,4a,5a) 3-Butyl-7-bromo-3-ethyl-4-iiydroxy-S-(3rnethoxyphenyl) 5-tetrahydrobenzothiepine-1, 1dioxide and (3a,4b,5b) 3-Butyl-7-bromo-3-ethyl-4- (3 S-methoxyphenyl) -2,3,4,5tetrahydrobenzothiepine-1,1-dioxide (76).
Alkylation of 4-bromophenol with 3-methoxybenzyl chloride according to the procedure described in J.
Chem. Soc, 2431 (1958) gave 4-bromo-2-(31methoxybenzyl)phenol. This material was converted to compound 75, mp 97-101.5 OC, and compound 76, mp 102- 106 OC, by the procedure similar to that in Example 18 method B. F Exarle 40 R Oj 1' (3a,4a,Sa) 3-Butyl-3-ethyl-7-fluoro-5-(41-~ fluorophenyl) -4-hydroxy-2, 3, 4, tetrahydrobenzothiepine- 1, 1 -dioxide _and* (3a,4b,5b)' 3-Butyl-3-ethyl-7-fluoro-5-(41fluorophenyl) -4-hydroxy-2 4, tetrahydrobenzothiepine-1,1-dioxide (78).
Alkylation of 4-f luoropheno. with 4-f luorobenzy.
chloride according to the procedure described in J.
104 WO 98/40375 PCT/US98/03792 Chem. Soc, 2431 (1958) gave 4-fluoro-2-(4'fluorobenzyl)phenol. This material was converted to compound 77, mp 228-230 oC, and compound 78, mp 134.5- 139 OC, by the procedure similar to that in Example 18 method B. 6d
PF
Examrle 41 7) o l o) d CI43 1 (3a,4a,5a) 3-Butyl-3-ethyl-7-fluoro-4-hydroxy-5-(3'methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1dioxide and (3a,4b,5b) 3-Butyl-3-ethyl-7-fluoro- 40hydroxy-5-(3'-methoxyphenyl)-2,3,4,5tetrahydrobenzothiepine-1,1-dioxide Alkylation of 4-fluorophenol with 3-methoxybenzyl chloride according to the procedure described in J.
Chem. Soc, 2431 (1958) gave 4-fluoro-2-(3'methoxybenzyl)phenol. This material was converted to compound 79, as a solid and compound 80, mp 153-155 OC, by the procedure similar to that in Example 18 method B. o Examile 42 04 (3a,4b,Sb) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4hydroxy-7-methylthio-2,3,4,5-tetrahydrobenzothiepine- 1,1-dioxide (81).
A mixture of 0.68 (1.66 mmol) of compound 77, 0.2 g mmol) of sodium methanethiolate and 15 ml of anhydrous DMF was stirred at room temperature for 16 days. The reaction mixture was dilute with ether and washed with water and brine and dried over MSO. The ether solution was concentrated in vacuo. The residue was purified by HPLC (20% ethyl acetate in hexanes). The first fraction was impure (3a,4a,5a) 3-butyl-3-ethyl-4hydroxy-7-methylthio-5-(4 '-fluorophenyl)-2,3,4,5tetrahydrobenzothiepine-l,1-dioxide. The second fraction was compound 81, mp 185-186.5 OC.
Ir,7 WO 98/40375 PCT/US98/03792 Exanile 43 (3a,4b,5b) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4hydroxy-7-(1-pyrrolidinyl)-2,3,4,5tetrahydrobenzothiepine-l,l-dioxide (82).
A mixture of 0.53 g (1.30 mmol) of compound 78 and 5 ml of pyrrolidine was held at reflux for 1 h. The reaction mixture was diluted with ether and washed with water and brine and dried over M.SO,. The ether solution was concentrated in vacuo. The residue was crystallized from ether-hexanes to give compound 82, mp 174.5-177 oC. s 8 Example 44 o 4 43 (3a,4b,5b) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4 S O hydroxy-7-(1-morpholinyl)-2,3,4,5- r3 tetrahydrobenzothiepine-l,1-dioxide 0 A mixture of 0.4 g (0.98 mmol) of compound 78 and 5.0 g (56 mmol) of morpholine was held at reflux for 2 h and concentrated in vacuo. The residue was diluted with ether (30 ml) and washed with water and brine and dried over M,SO,. The ether solution was concentrated in vacuo. The residue was recrystallized from etherhexanes to give compound 83, mp 176.5-187.5 OC.
Example (3a,4a,5a) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4hydroxy-7-methyl-2,3,4,5-tetrahydrobenzothiepine-1, 1dioxide and (3a,4b,5b) 3-Butyl-3-ethyl-5-(4'fluorophenyl)-4-hydroxy-7-methyl-2,3,4,5tetrahydrobenzothiepine-1,l-dioxide Alkylation of 4-methylphenol with 4-fluorobenzyl' chloride according to the procedure described in J.
Chem. Soc, 2431 (1958) gave 4-methyl-2-(4'fluorobenzyl)phenol). This material was converted to WO 98/40375 PCT/US98/03792 compound 84 and compound 85 by that in Example 18 method B. J rocedure similar to 'SW c rD ou 011 Example 46 (96) (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-5-(4'- o hydroxyphenyl)-7-methoxy-2,3,4,5tetrahydrobenzothiepine-1,1-dioxide and (3a,4b,5b) 3-Butyl-3-ethyl-4,7-dihydroxy-5-(4'hydroxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1dioxide (87).
"U
(81) To a solution of 0.52 (1.2 mmol) of compound 66 in ml of methylene chloride was added 1.7 g (6.78 mmol) of born tribromide. The reaction mixture was cooled to 78 oC and was stirred for 4 min. An additional 0.3 ml of boron tribromide was added to the reaction mixture and the reaction mixture was stirred at -78 OC for 1 h and quenced with 2 N HC1. The organic was extracted into ether. The ether layer was washed with brine, dried over MSO,, and concentrated in vacuo. The residue (0.48 g) was purified by HPLC (30% ethyl acetate in hexanes). The first fraction was 0.11 g of compound 86 as a white solid, mp 171.5-173 OC. The second fraction was crystallized from chloroform to give 0.04 g of compound 87 as a white solid, mp 264 °C (dec). o Example 47 o( 4
(C)
(3a,4b,5b) 3-Butyl-3-ethyl-4,7-dihydroxy-5-(4'fluorophenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1dioxide (88).
Reaction of compound 70 with excess boron tribromide at room temperature and worked up as in Example :46 gave compound 88 after an HPLC purification.
Example 48 sO,
F
WO 98/40375 PCT/US98/03792 (3a,4b,5b) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)- 4 hydroxy-7- (1-azetidinyl) -2,3,4,5tetrahydrobenzothiepine-l,1-dioxide (89).
A mixture of 0.20 g (0.49 mmol) of compound 78, and g (35 mmol) of aztidine was held at reflux for 3 h and concentrated in vacuo. The residue was diluted with ether (30 ml) and washed with water and brine and dried over MgSO4. The ether solution was concentrated on a steam bath. The separated crystals were filtered to give 0.136 g of 89 as prisms, mp 196.5-199.5 OC.
Examole 49 s (90 4 c ck (3a,4a,5a) 3-Butyl-3-etlyl-5-(3'-methoxyphenyl)-4hydroxy-7-methylthio-2,3,4,5-tetrahydrobenzothiepine- 1,1-dioxide (3a,4b,5b) 3-Butyl-3-ethyl-5-(3'methoxyphenyl)-4-hydroxy-7-methylthio-2,3,4,5tetrahydrobenzothiepine-1,1-dioxide (91).
A mixture of 0.4 g (0.95 mmol) of compound 79, 0.08 g (1.14 mmol) of sodium methanethiolate and 15 ml of anhydrous DMF was stirred at 60 OC for 2 h. An additional 1.4 mmol of sodium methanethiolate was added to the reaction mixture and the mixture was stirred at 60 OC for an additional 2 h. The reaction mixture was triturated with 100 ml of water and extracted methylene chloride. The methylene chloride water mixture was filtered through Celite and the methylene'chloride layer was dried over MSO, and concentrated in vacuo.
The first fraction (0.1 g) was compound 90, mp 117-121 oC. The second fraction (0.16 g) was compound 91, mp 68-76 °C.
-0 o0 WO 98/40375 WO 9840375PCT/US98/03792 Examole Preparation of polyethyleneglyco. functionalized benzothiepine A.
OCH 3 No. 141No No.
136 A 50 ml rb flash under a nitrogen atmosphere was charged with 0.54 g of M-Tres-5000 (Polyethy,.eneglycol WO 98/40375 PCT/US98/03792 Tresylate [methoxy-PEG-Tres,MW 5000] purchased from Shearwater Polymers Inc., 2130 Memorial Parkway, SW, Huntsville, Alabama 35801), 0.055 g Compound No. 136, 0.326 C,CO, and 2cc anhydrous acetonitrile. The reaction was stirred at 30 C for 5 days and then the solution was filtered to remove salts. Next, the acetonitrile was removed under vacuum and the product was dissolved in THF and then precipitated by addition of hexane. The polymer precipitate was isolate by filtration from the solvent mixture (THF/hexane). This precipitation procedure was continued until no Compound No. 136 was detected in the precipitated product (by TLC Si02). Next, the polymer precipitate was dissolved in water and filtered and the water soluble polymer was dialyzed for 48 hours through a cellulose dialysis tube (spectrum® 7 ,45 mm x 0.5 ft, cutoff 1,000 MW). The polymer solution was then removed from the dialysis tube and lyophilized until dried. The NMR was consistent with the desired product A and gel permeation chromatography indicated the presence of a 4500 MW polymer and also verified that no free Compound No. 136 was present. This material was active in the IBAT in vitro cell assay.
WO 98/40375 PCT/US98/03792 Example 51 Preparation of Compound 140 No. 140 No. 111 A 2-necked 50 ml round bottom Flask was charged with 0.42g of Tres-3400 (Polyethyleneglycol Tresylate [Tres- PEG-Tres,MW 3400] purchased from Shearwater Polymers Inc., 2130 Memorial Parkway, SW, Huntsville, Alabama 35801), 0.1 potassium carbonate, 0.100g of Compound No.
11i and 5 ml anhydrous DMF. Stir for 6 days at 27 OC.
TLC indicated the disappearance of the starting Compound No. 111. The solution was transferred to a separatory funnel and diluted with 50 cc methylene chloride and then extracted with water. The organic layer was evaporated to dryness by means of a rotary WO 98/40375 PCT/US98/03792 evaporator. Dry wgt. 0.4875 g. Next, the polymer was dissolved in water and then dialyzed for 48 hours at OC through a cellulose dialysis tube (spectrum® 7 x 0.5 ft, cutoff 1,000 MW). The polymer solution was then removed from the dialysis tube and lyophilized until dried 0.341 NMR was consistent with the desired product B.
Example 52 0 o
I
No. 134 A 10 cc vial was charged with 0.21 g of Compound No.
136 (0.5mmoles), 0.17g (1.3 mmoles)potassium carbonate, 0.6g (1.5 mmoles) of 1,2-bis-(2-iodoethoxy)-ethane and cc DMF. The reaction was stirred for 4 days at room temperature and then worked up by washing with ether/water. The ether layer was stripped to dryness and the desired product Compound No. 134 was isolated on a silica gel column using 80/20 hexane ethyl acetate.
lo0+ WO 98/40375 Examnle 53 PCT/US98/03792 No. 112 Exampl1e 54 H2 No. 113 WO 98/40375 PCT/US98/03792 A two necked 25 ml round bottom Flask was charged with (1.24mmoles) of 69462, 13 mis of anhydrous DMF, 0.055g of 60% NaH dispersion and 0.230g (0.62 mmoles) of 1,2-Bis [2-iodoethoxylethane] at 10 OC under nitogen. Next, the reaction was slowly heated to OC. After 14 hours all of the Compound No. 113 was consumed and the reaction was cooled to room temperature and extracted with ether/water. The ether layer was evaporated to dryness and then chromatographed on Silicage (80/20 ethyl acetate/hexane). Isolated Compound No. 112 (0.28 g) was characterized by NMR and mass spec.
ExamDle No. 135
H
IP-
OH
d No. 135 No. 136 WO 98/40375 PCT/US98/03792 In a 50 ml round bottom Flask, add 0.7g (1.8 mmoles) of Compound No. 136, 0.621g of potassium carbonate, 6 ml DMF, and 0.33g of 1,2-Bis [2-iodoethoxylethane]. Stir at 40 OC under nitrogen for 12 hours. The workup and isolation was the same procedure for Compound No. 112.
Examples 56 and 57 (Compound Nos. 131 and 137) The compositions of these compounds are shown in Table 3.
The same procedure as for Example 55 except appropriate benzothiepine was used.
Example 58 (Compound No. 139) The composition of this compound is shown in Table 3.
Same procedure as for Example 55 with appropriate benzothiepine 1,6 diiodohexane was used instead of 1,2- Bis [2-iodoethoxylethane].
Examnle 59 (ComDound No 101) Examnle 59 (Commound No. 1011 No.
101 This compound is prepared by condensing the 7-NH, benzothiepine with the 1,12-dodecane dicarboxylic acid or acid halide.
IoLa WO 98/40375 PCT/US98/03792 Example 60 (Compound No. 104) 0"'"OH No. 104 2-Chloro-4-nitrobenzophenone is reduced with triethylsilane and trifluoromethane sulfonic acid to 2chloro-4-nitrodiphenylmethane 32. Reaction of 32 with lithium sulfide followed by reacting the resulting sulfide with mesylate IV gives sulfide-aldehyde XXIII.
Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIV (see Scheme Reduction of the sulfone-aldehyde XXV formaldehyde and 100 psi hydrogen and 55 C for 12 hours catalyzed by palladium on carbon in the same reaction vessel yields the substituted dimethylamine derivative XXVIII. Cyclization of XXVII with potassium t-butoxide yields a mixture of substituted amino derivatives of this invention Compound No. 104.
WO 98/40375 WO 9840375PCT/US98/03792 Scheme 6 02 M3 *POI C-f R6COel 14\ R
I
XXI V ft.!- IKet Bu TN P 0 0 XXI Xe XXI Xd ExamDle 61 No. 102 A 1 oz. Fisher-porter bottle was charged with 0.14 g (0.34 mmoles) of 70112, 0.97 gins inmoles) of methyl iodide, and 7 ml of anhydrous acetonitrile. Heat to *C for 4 days. The quat. Salt Compound No. 192 was WO 98/40375 PCTIUS98/03792 isolated by concentrating to 1 cc acetonitrile and then precipitating with diethyl ether.
WO 98/40375 Example 62 PCT/US98/03792
N
i;1 No. 125 A 0.1 g (0.159 mmoles) sample of Compound No. 134 was dissolved in 15 ml of anhydrous acetonitrile in a Fischer-porter bottle and then trimethylamine was bubbled through the solution for 5 minutes at 0 OC and then capped and warmed to room temperature. The reaction was stirred overnight and the desired product was isolated by removing solvent by rotary evaporation.
Example 63 (Compound No. 295)
I.,,OH
,o Nh 2 No. 295 WO 98/40375 PCT/US98/03792 2 No. 113 Sodium Hydride 60% (11 mg, 0.27 mmoles) in 1 cc of acetonitrile at 0 0 C was reacted with 0.248 inmoles g) of Compound No. 54 in 2.5cc of acetonitrile at 0 *C.
Next, 0.(980g 2.48 rnmoles) of 1,2-Bis (2iodoethoxylethane). After warming to room temperature, stir for 14 hours. The product was isolated by column chromatography.
Examrole 64 (Comnound No. 286) 0 0 0 PhCH 2
AN
H No. 286 Following a procedure similar to the one described in Example 86, infra (see Compound No. 118),' the title compound was prepared and purified as a colorless solid; mp 180-181 'H NMR (CHC1 3 8 0.85 J 6 Hz, 0.92 J 6 Hz, 3Hi), 1.24-1.42 (in, 2H1), 1.46-1.56 (in, 1H), 1.64-1.80 (in, 1H), 2.24-2.38 (in, 1H), 3.15 (AB, JAB 15 Hz, Av 42 Hz, 2H), 4.20 J WO 98/40375 PCT/US98/03792 8 Hz, 1H), 5.13 2H), 5.53 1H), 6.46 111), 6.68 1H), 7.29-7.51 (in, 10H), 7.74 J 8 Hz, 1H), 8.06 -J 8 Hz, 1H). FABMS in/z 494 HRMS calcd for 494.2001, found 494.1993. Anal. Calcd.
f or C2. H3,NO 5 S: C, 68.13; H, 6.33; N, 2.84. Found: C, 68.19; H, 6.56; N, 2.74.
WO 98/40375 WO 9840375PCT/US98/03792 Example 65 (Compound No. 287) No. 287 Following a procedure similar to the one described in Example 89, infra, (see Compound No. 121), the title compound was prepared and purified as a colorless solid: mp 245-246 0 C, 'H NNR (CDC1,) 8 0.84 J 6 Hz, 3H), 0.92 J 6 Hz, 3H), 1.28, J 8 Hz, 1H), 1.32-1.42 Cm, 1H), 1.48-1.60 1H), 1.64-1.80 1H), 2.20-2.36 (in, 1H), 3.09 CAB, 15 Hz, Av= 42 Hz, 2H), 3.97 Cbs, 2H), 4.15 J 8 Hz, 1H), 5.49 1H), 5.95 1H), 6.54 J 7 Hz, 1H), 7.29- 7.53 5H), 7.88 J 8 Hz, 1H); ESMS 366 (M+Li).
Anal. Calcd. for C., 0 2 5 N0 3 S: C, 66.82; H, 7.01; N, 3.90.
Found: C, 66.54; H, 7.20; N, 3.69.
Example-66 (Compound No. 288) r~X No. 288 214 WO 98/40375 PCT/US98/03792 Following a procedure similar to the one described in Example 89, infra (see Compound No. 121), the title compound was prepared and purified by silica gel chromatography to give the desired product as a colorless solid: mp 185-186 0 C; 'H NMR (CDC1,) 61.12 (s, 3H), 1.49 3H), 3.00 J 15 Hz, 1H), 3.28 J 15 Hz, 1H), 4.00 1H), 5.30 1H), 5.51 1H), 5.97 1H), 6.56 (dd, J 2.1, 8.4 Hz, 1H), 7.31-7.52 5H), 7.89 J 8.4 Hz, 1H). MS (FAB+) m/z 332.
Example 67 (Compound No. 289) H2 No. 289 Following a procedure similar to the one described in Example 89 (see Compound No. 121), the title compound was prepared and purified by silica gel chromatography to give the desired product as a white solid: mp 205-206 OC; 'H NMR (CDC1,) 8 0.80-0.95 (m, 6H), 1.10-1.70 7H), 2.15 1H), 3.02 J 15.3 Hz, 2H), 3.15 J 15.1 Hz, 2H), 3.96 br, 2H), 4.14 7.8 Hz, 1H), 5.51 1H), 5.94 J 2.2, 1H), 6.54 (dd, J 8.5, 2.2 Hz, 1H), 7.28-7.50 (m, 6H), 7.87 J 8.5 Hz, 1H). MS (FAB): m/z 388 Example 68 (Compound No. 290) WO 98/40375 WO 9840375PCT/US98/03792 H 2N' "0H No. 290 Following a procedure similar to the one described in Example 89, infra (see Compound No. 121), the title compound was prepared and purified as a colorless solid: mp 96-98 I' NMR (CDC1 3 5 0.92 J 7 Hz, 6H), 1.03-1.70 (in, 11H), 2.21 J 8 Hz, 1H), 3.09 (AB, J 18 Hz, Av 38 Hz, 2H) 3.96 (bs, 2H) 4.14 J =7 Hz, 1H), 5.51 IH), 5.94 1H), 6.56 J =9 Hz, 1H), 7.41-7.53 (in, 6H), 7.87 J 8 Hz, 1H); FABMS m/z 416 Example 69 o0 0 PhCH 2 OKW~a~c::: H O No. 291 Following a procedure similar to the one described in Example 86, infra (see Compound-No. 118), the title compound was prepared and purified as a colorless solid: 'H NM'R (CDCl 3 8 0. 91 J 7 Hz, 6Hi), 1. 02- 1.52 (mn, 11Hi), 1.60-1.70 (mn, 1Hi), 2.23 J 8 Hz, WO 98/40375 PCTIUS98/03792 1H), 3.12 (AB, JAS 18 Hz, Av 36 Hz, 4.18 J 7 Hz, 1H) 5.13 2H) 5.53 1H) 6.43 1H) 6.65 1H), 7.29-7.52 (mn, 10H!), 7.74 J 9 Hz, iH), 8.03 3 8 Hz, 1H); ESMS mlz 556 (M+Li).
WO 98/40375 WO 9840375PCTIUS98/03792 Examp~le 70 (Compound No. 292) No. 292 Following a procedure similar t6 the one descried in Example 89, infra. (see Compound No. 121), the title compound was prepared and purified as a colorless solid: mp 111-112.5"C, 'H NMR (CD)C1,) 5 0.90 J 8 Hz, 6H), 1.03-1.50 (in, 10H), 1.55-1.70 (mn, 2H), 2.18 J 12 Hz, 2H), 3.07 (AB, JAS 15 Hz, Av 45 Hz, 2H), 4.09 (bs, 2H), 5.49 1H), 5.91 1H), 6.55 J 9 Hz, 1H), 7.10 J 7 Hz, 2H), 7.46 J 6 Hz, 2H), 7.87 J 9 Hz, 1H).
Exainyle 71 (Comp~ound No. 293) PhCH 2M ii No. 293 During the preparation of Compound No. 290 from Compound No. 291 using BBr,, the title compound was WO 98/40375 PCT/US98/03792 isolated: 'H NMR (CDC1,) 8 0.85 J 6 Hz, 6H), 0.98- 1.60 10H), 1.50-1.66 2H), 2.16 J 8 Hz, 1H), 3.04 (AB, J, 15 Hz, Av 41 Hz, 2H), 4.08 (s, 1H), 4.12 1H), 5.44 1H), 5.84 1H), 6.42 (d, J 9 Hz, 1H), 7.12 J 8 Hz, 2H), 7.16-7.26 (m, 7.83 J 8 Hz, 1H); ESMS m/z 512 (M+Li).
Example 72 (Compound No. 294) Following a procedure similar to the one described in Example 60 (Compound No. 104), the title compound was prepared and purified as a colorless solid: 'H NMR (CDC1,) 6 0.90 J 6 Hz, 6H), 1.05-1.54 9H), 1.60-1.70 1H), 2.24 J 8 Hz, 1H), 2.80 (s, 6H), 3.05 (AB, J 15 Hz, Av 42 Hz, 2H), 4.05-4.18 2H), 5.53 1H), 5.93 1H), 6.94 J 9 Hz, 1H), 7.27-7.42 4H), 7.45 J 8 Hz, 2H), 7.87 J 9 Hz, 1H); ESMS m/z 444 Structures of the compounds of Examples 33 to 72 are shown in Tables 3 and 3A.
Examples 73-79, 87, 88 and 91-102 Using in each instance a method generally described in those of Examples 1 to 72 appropriate to the substituents to be introduced, compounds were prepared having the structures set forth in Table 3.
The starting materials illustrated in the reaction schemes shown above were varied in accordance with principles of organic synthesis well known to the art to introduce the indicated substituents in the 4- and positions and in the indicated position on the benzo ring WO 98/40375 PCT/US98/03792 Structures of the the compounds produced in Examples 73-102 are set forth in Tables 3 and 3A.
Examples 80-84 Preparation of 115, 116, 111, 113 Preparation of 4-chloro-3-[4-methoxyphenylmethyl]-nitrobenzene.
In a 500 ml 2-necked rb flask weigh out 68.3 gms phosphorus pentachloride (0.328 mole 1.1 eq). Add mis chlorobenzene. Slowly add 60 gms nitrobenzoic acid (0.298 mole). Stir at room temp overnight under N2 then heat 1 hr at Remove chlorobenzene by high vacuum. Wash residue with hexane. Dry wt=55.5 gms.
In the same rb flask, dissolve acid chloride (55.5 g 0.25 mole) from above with 100 mis anisole (about 3.4 eq). Chill solution with ice bath while purging with N2. Slowly add 40.3g aluminum chloride (1.2 eq 0.3 mole). Stir under N, for 24 hrs.
After 24 hrs, the solution was poured into 300 mis 1N HC1 soln. (cold). Stir this for 15 min. Extract several times with diethyl ether. Extract organic layer once with 2% aqueous NaOH then twice with water.
Dry organic layer with MgS04, dry on vac line. Solid is washed well with ether and then ethanol before drying. Wt=34.57g (mixture of meta, ortho and para).
Elemental theory found C 57.65 57.45 H 3.46 5.51 N 4.8 4.8 C1 12.15 12.16 WO 98/40375 PCT/US98/03792 With the next step of the reduction of the ketone with trifluoromethane sulfonic aid and triethyl silane, crystallization with ethyl acetate/hexane affords pure 4-chloro-3-[4-methoxy-phenylmethyl]-nitrobenzene.
4-Chloro-3-[4-methoxy-phenylmethyl]-nitrobenzene was then reacted as specified in the synthesis of 117 and 118 from 2-chloro-4-nitrophenylmethane. From these procedures 115 and 116 can be synthesized. Compounds 111 and 113 can be synthesized from the procedure used to prepare compound 121.
Compound 114 can be prepared by reaction of 116 with ethyl mercaptan and aluminum trichloride.
Examples 85 and 86 Preparation of 117 and 118 2-Chloro-4-nitrobenzophenone is reduced with triethylsilane and trifluoromethane sulfonic acid to 2chloro-4-nitrodiphenylmethane 32. Reaction of 32 with lithium sulfide followed by reacting the resulting sulfide with mesylate IV gives sulfide-aldehyde XXIII.
Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIII. Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIV (see Scheme The sulfone-aldehyde (31.8 g) was dissolved in ethanol/toluene and placed in a parr reactor with 100 ml toluene and 100 ml of ethanol and 3.2 g of 10% Pd/C and heated to 55 C and 100 psi of hydrogen gas for 14 hours. The reaction was then filtered to remove the catalyst. The amine product (.076 moles, 29.5 g) from this reaction was then reacted with benzyl chloroformate (27.4g) in toluene in the presence of g of potassium carbonate and stirred at room 2l.X WO 98/40375 PCT/US98/03792 temperature overnight. After work up by extraction with water, the CBZ protected amine product was further purified by precipitation from toluene/hexane.
The CBZ protected amine product was then reacted with 3 equivalents of potassium t-butoxide in THF at 0 C to yield compounds 117 and 118 which were separated by silica gel column chromatography.
Examples 89 and Preparation of 121 or 122 Compound 118 (.013 moles, 6.79g) is dissolved in 135 ml of dry chloroform and cooled to -78 C, next 1.85 ml of boron tribromide (4.9 g) was added and the reaction is allowed to warm to room temperature.
Reaction is complete after 1.5 hours. The reaction is quenched by addition of 10% potassium carbonate at 0 C and extract with ether. Removal of ether yields compound 121. A similar procedure can be used to produce 122 from 117.
Examples 93-96 Compounds 126, 127, 128 and 129 as set forth in Table 3 were prepared substantially in the manner described above for compounds 115, 116, 111 and 113, respectively, except that fluorobenzene was used as a starting material in place of anisole.
WO 98/40375 WO 9840375PCT/US98/03792 TABLE 3 Specific cempounds (4102-111, 1-3,12 134, 136, 13i,142-144,262-296) 0.*
S
R
e -CP RI R2 R3 4 R3
R
tbc.
61 102 Et- n-Eu- HO- H- Ph- 73 103 n-Bu-, 104 E-t- 74 105 Et- Et- Ho- Phn-Bu- .n-Bu-
HO-
Ho- Ph-., Ph- Ph1- 106 Et- n-Bu- HO- H-
(CH
3 3
N'-
7- (CFH3) 3
N+-
7- 2
N-
7-
C*H
3
SO
2
NH:-
7-Br-CH-2-
CONH-
7-NH--- 7-
CSE~I.CONFH-
7-NI12- 7-CH 3
CONH-
7-NE2- 76 107 n-Eu- Et- HO- p-n-CIGF-21- -0-Ph- 77 108 Et- n-Bu- HO0- Ph- 109 Et- n-Eu- HO0p-n-CloH~zl- -0-Ph- H- Ph- H- p-EO-Ph- 110 ill Etn-Eun-Eu- Et-
HO-
so- 113 114 115 Et- Etn-Eun-Bun-Eu- Et-
HO-
HO0-
HO-
HO-
p-EO-Ph-
P-CH
3 O-Ph1-
P-CH
3 O-Ph1- 7 -NH-CB Z 7-NH-CBZ 84 116 Et- n-Eu- H- p-CE 3 O-Pha2t3 WO 98/40375 WO 9840375PCT/US98/03792 117 118 119 n-Bu- Et- Et- HOn-Eu- HOn-Eu- HO- Ph- Ph- Ph1- 88 120 n-Bu- Et- HO- 121 122 123 Etn-Eu- Ein-Eu- HO- Et- n-Eu- HO- H- ph- H- Ph- H- ph- H- Ph- 7-NH-CD Z 7-NH-CEZ 7-NHCO 2 -t Eu 7-NHCOZ-t- Eu 7-NH2- 7-NH 2 7-n-C 6
H
1 3
NH-
a-
(CH
3 3 N 4 C--zCH2O) 3 7-NHi-CBZ 7 2 7-NH-CBZ 7-NH2- 92 124 n-Bu- Et- Ho- H- Ph- 62 125 Et- n-Bu- F.O- 126 127 128 129 n-Bun-Eu- Et- Et- Et- Etn-Bun-Bu-
HO-
HO-
HO0- HO0p--h- 97 130 Et- n-Bu- HO0- Ph- 8-
(CH
3 3
N+
C 6
H
1 ilO- 98 132 Et- n-Eu- HO-
HO-
HO-
Ph- 99 133 52 134 S-phthal.imidyl- C 6 HI2O- S-n-CIOH21- 8- 1- (C2H 4 0) 3- Et-. n-Du- Et- n-Bu- Ph- Ph- 100 136 Et- n-Eu- HO- H- P-H-8HO Ph- H- 8 Ho- WO 98/40375 WO 9840375PCTIUS98/03792 138 n-Bu- Et- HO- H- Ph- 8- CH 3 CO2- Et- 91 Et- 89 Etn-Eu- Hn-Eu- Hon-Eu- HO- Ho-
H-
m-CH30-P hp-F-Phn-CH 3 O-Ph-
H-
H-
7-CH3S- 7-CH3Sazetidine 66 Et- n-Eu- HO- rn-C?' 3 -Ph- Et- n-Eu- H- HO0- F.- 68 F.t n-Eu- HO- M, -CF3-Ph- 67 Et- n-Eu- HO- F.- 87 n-Eu- HO- H- 86 Zt- n-Eu- HO- H- rn,-H.O-Ph- E-t- n-Eu- HO0- p -F-.Ph 69 Et- n-Eu- H- HO0- H- 88 Et- n-Eu- HO0- H- p- F-.Dh 76 Ft- n-Eu- HO0- r-CH 3 0-Ph- Et- n-Eu- H- HO- H- 77 Ft- n-Eu- H- H*O- H- 78 Et- n-Eu- HO- H- p--F-Ph- 79 Et- n-Eu- H- HO- H- Et- n-Eu- HO0- Hi- m-CH 3 -Ph- 72 Et- n-Eu- HO- H- rn-F-Ph- 73 Et- n-Eu- H- HO- H 71 Et- n-Eu- R- HO0-
H.-
rn-C*F.
3 0-Ph- F. n- CF3-Ph-
F.-
H.-
F.-
H-
m-CH 3 0-Php-F-Ph-
H-
m-CF.30-Pha-F-Phrn-F-Ph- 7-C'-'30- 7-CH 3
O-
7-CH.30- 7 -CH3O- 7-Er- 7-Er- 7-F- 7-F- 7-r- 7-F- 7-CH 3 0- 7-CH3O- 7-CH 3 0- WO 98/40375 38 42 44 43 64 66 67 68 69 71 72 63 74 81 85 84 83 Et- Et- Et- Et- Etn-Bun-Bun-Bun-Bu- -n-Eu-
HO-
HO-
HO-
H-
Ho-
H-
p-F-Php-F-Ph-
H-
p-F-Ph- 82 Et- n-Eu- HO- H- p-F-Ph- 286 287 288 289 290 291.
292 293 294 295 Et- -Et- Et- Et- CH3- CH3-
C
3 h'7- C 3 H7n-Bu- n-Bun-Eu- n-Bun-Eu- n-Bun-Eu- n-Eu- Et- n-Eu-
HO-
HO0-
HO-
HO0-
H-
HO0- HO0-
F.O-
HO-
HO0- Ph- Ph- Ph- Phh
H-
H.-
H.-
F.-
H-
H-
F.-
H-
PCT1US98/03792 7-CH3O- 7-CHt 3
S-
'7-CH3- '7-CH3morpholine pyrrolidine 7-NH.-CBZ 7 2 7-NH-2- 7-NH.-CE Z 7-PhCS 2 14- 7- (C- 3 2
N-
7-NHF- Ph- Php-F -Pb- Ph- Php-I- (C2H 4 O) 3- Php-
(CH
3 3 N'*(C2
H
4 O) 3-Ph- 102 296 Et- n-Eu- HO- 7-NF-2- WO 98/40375 WO 9840375PCTIUS98/03792 TABLE 3A Bridged Benz otb.iephenes (al0l, 112,121, 135,137,139-141) CPD V-101 (Ex. 59) CPD 40112 (Ex. 53) CPD#"131 (Mx. 56) WO 98/40375 WO 9840375PCTIUS98/03792 CPD VA135 (Ex. CPD W4137 (Ex. 57) CPD #139 (x 8 (EX. 58) WO 98/40375 WO 9840375PCTIUS98/03792
NH
2 '-polyethyleneglycoi-o/ NH 2 3400 MW polyethylene glycol bridge CPO #4140 (EX. 51) r'\bo
OCH
3 N CPD -1141. (EX. WO 98/40375 PCT/US98/03792 Examples 104-231 Using in each instance a method generally described in those of Examples 1 to 72 appropriate to the substituents to be introduced, including where necessary other common synthesis expedients well known to the art, compounds are prepared having the structures set forth in Table 4. The starting materials illustrated in the reaction schemes shown above are varied in accordance with principles of organic synthesis well known to the art in order to introduce the indicated substituents in the 4- and positions and in the indicated position on the benzo ring 130 WO 98/40375 WO 9840375PCT/US98/03792 TABLE 4 AltrntIve compounds al (,0302-312, 314-430) 0 0 J'/1 (Rx) q Et n.Bu
OH
Cpd# R (R2) q 302 303 304 305 306 307 308 309 310 311 312 314 315 316 317 318 319 p-F-Php-F-Ph- P-F-Php-F-Php-F-Php-F-Php-F-Php-F-Php-F-Php-F-Php-F-Phm-CH 3 0-Ph m-CH30-Phm-CH30-Ph-
M-CH
3 0-Ph-.
m-CH30-Phm-CH30-Ph- 7- (1-aziridine) 7-EtS- 7-Ca" 3 S(0) 7-CE3S 2 7-PhS-- 7-CH 3
S-
9-CH 3
S-
7-CHi 3 0- 9-CH 3 0- 7-ip:- 7-t-Bu- 7- (1-pyrazole) 7-(1-a zetidine) 7- (1-aziridine).
7-EtS- 7-CH 3 S(0) 7-CH 3 S 2 7-PhS- WO 98/40375 WO 9840375PCT/US98/03792 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 m-CH 3 0-Ph m-CH30-Ph -C H 3 0-P h m-CH 3 0-Ph m-CH 3 0-Ph p-F-Php-F-Php-F-Phy-F-Php-F-Php-F-Php-F-Php-F-Php-F-Php-F-Php-F-Phlp-F-Ph- 7-CH3S- 9-CH3S- 7-CH30-
S-CH
3 0- 7-Et- 7-iPr- 7-t-Bu- 6-CH 3 0- '7-CH 3 0- 8-CH 3 0- 7- (1-azetidine) 9-CH 3 Q9-CH 3 7-C:-3S 9-CH 3 7-CHE3S 2- 9-CE- 3 7-PhS- 9-CH 3 7-CH- 3
S-
9-CH 3 7-CH30- 9-CH-3- 7-CH 3 9-CH 3 7-CH30- 9-CH 3 0- 7- (1-pyrrole) 7- -methylpiperazine WO 98/40375 WO 9840375PC/US98/03792 337 338 339 340 341 342 343 p-F-Php-F-Php-F-Php-F-Phlp-F-Php-F-Php-F-Ph- Ph- 7-CH 3 C (=CH2)- 7-cycipropyl 7 -(CH 3 2NH 7- -azetidine 9-CH 3
S-
7- (N-pyrrolidifle) 9-CHR 3
S-
7- (CH 3 2
N-
9 CR1 3 S 344 345 346 347 348 349 350 351 352 353 m-CH 3 0-P h- M-CRH.O-Phrn-CH30-Phm-CH 3 O-Phm-C=3O-Phrn-CR 3 0-Ph rn-CH 3 0-Phrn-CH 3 0-Phm-CH30-Phrn-CH30-Ph- 7- (1-pyrazole) 7- (N)*-ntypieai Ph- 7-C'RH 3 C (=Ch2)- 7 -cyc lopropoy 7-(C'R* 3 2
NH-
7- -azetidine 9-CH3S- 7- (N-pyrrolidile) 9-CH3S- 7- (CR3) 2N- 9-CH 3
S-
6-CH 3
O-
7-CH3O- 8 -CH 3
O-
7- (1-azetidine) 9-CH3- 354 r-CH30-Ph- WO 98/40375 WO 9840375PCT/US98/03792 355 356 357 358 359 360 361.
362 363 364 365 366 367 368 369 370 371 372 373 374 rn-CH3O-Zhrn-CH30-Ph- M-CH3-Phrn-CH30-Phrn-CH3-Phm-CH3O-Phrn-C H 3 0-P hrn-CH3-Phthien-2-y2.
thien-2-yJ.
thien-2-yl thien-2-yl thien-2-yl thien-2-yJ.
thien-2-yJ.
thien-2-yJ.
thien-2-yl thien-2-yJ.
thieri-2-y2.
thien-2-yl 7-EtS- 9-CH3- 7-CH3S 9-CH3- 7-CH3S 2 9-CH 3 7-PhS- 9-CH3- 7-CH3S- 9-CH3- 7-CH-3O- 9-CH 3 7-CH 3 9-CH3- 7-CH 3
O-
9-CH30- 7- (1-aziridine) 7-EtS- 7-CH 3 S '7-CH 3 S(0) 2 7-P hS 7-CH 3
S-
9-CH3S- 7 -CH3O- 9-CH3O- 7-Et- 7-iPr- 7-t-Bu- 7- (2-pyrrole) 7 -CH3O- WO 98/40375 WO 9840375PCTIUS98/03792 375 376 377 378 379 380 381 382 383 384 385 386 387 38 8 389 390 391 392 393 394 395 thien-2-yl thien-2-yl thien-2-yl 5-Cl-thien-2-yl 5-Cl-thien-2-yl 5-C1-thien-2-yl 5-Cl-thien-2-yl 5-Cl-thien-2-yl 5-C1-thien-2-y3.
5-Cl-thien-2-yl 5-Cl-thi4en-2-yl 5-Cl-thien-2-yl 5-C1-thien-2-yl 5-C1-thien-2-y2.
5-Cl -thi en- 1i 5-C1-thien-2-y3.
5-Cl-thien-2-yl thien-2-yl thien-2-yl thi en- 2-yJ.
thien-2-yl 7-CH3S- 7- (1-azetidile) 7-Me- 7- (1-azetidile) 7- (1-aziridile) 7-EtS- 7-Cl1 3 S(0) 7-CH 3 S 2 7-PhS- 7-CH 3
S-
9-CH 3
S-
7-CH30- 9-CH 3
O-
7-rt- 7-ipr- 7-t-Bu- 7 -CH 3
O-
7-CH3S- 7-Me 7- (1-azetidine) 9-CH 3 7-EtS- 9-CH 3 7-Ck 3 S 9-CH3- 7-CH 3 S (0)2- 9-CH3- WO 98/40375 WO 9840375PCT/US98/03792 396 397 398 399 400 thien-2-yl thien-2-yl thi en-2-yl thien-2-yl thien-2-yl 7 -PhS 9-CH3- 7-CH 3
S-
9-CH3- 7-CH 3
O-
9-CH 3 7-CH3- 9-CH3- 7-CH3O- 9-CH 3
O-
401 402 403 404 405 406 407 408 409 411 41It 413 414 415 416 thien-2-yJ.
thien-2-yl thien-2-yJ.
thien-2-yl thien-2-vl thien-2-yl thien-2-yl thien-2-yl thien-2-yl 5-C-thien-2-yl 5-Cl-thien-2-y]7 5-C-thien-2-yl 5-Cl-thien-2-yl 5-Cl-thien-2-yl 7- (1-pyrazrole) (N-'-rethylpiperazine Ph- 7-C H 3 C (-CH 2 7-cycluropyJ.
7- (CH 3 2 N 7- -azetidine 9-CH 3
S-
7- (N-pyrrolidine) 9-CH 3
S-
7- (CR 3 2N 9-CH3S-.
7- (l-pyrazrole) 7- -methylpiperazine Ph- 7-CH 3 C (=CH2)- 7-cyclopropyl 7- (CR 3 2 NHi 22,4 WO 98/40375 WO 9840375PCTIUS98/03792 417 418 419 420 421 422 423 424 425 426 427 428 429 430 5-Cl-thien-2-yl 5-Cl-thien-2-yl 5-Cl-thien-2-yl 5-Cl-thien-2-yl 5-Cl-thien-2-yJ.
5-Cl-thien-2-yJ.
5-Cl-thien-2-y2.
5-Cl-thien72- yl 5-Cl-thien-2-yl 5-Cl-thien-2-y2.
5-Cl -thi en y) 5-Cl-thieri-2-yl thien-2-yl 5-Cl-thien-2-yl 7- -azetidine 9-CH 3
S-
7- (N-pyrrolidifle) 9-CH3S- 7- (CH3) 2
N-
9-CH 3
S-
7- (1-azetidine) 9-CH 3 7-EtS- 9-CH 3 '7-CR-3S 9-CH3- '7-CH3S 2 9-CH 3 7-PhS- 9-CH 3 7-CH 3
S-
9-CH3- 7-C-'3O- 9-CH3- 7-CH3- 9-CH3- 7 -CH 3
O-
9-CH 3
O-
6-CH30- 7 -8-CH 3 O-w 6-CH 3 0- 7-CH 3
O-
8 -CH 3
O-
all WO 98/40375 PCT/US98/03792 Examples 232-1394 Using in each instance a method generally described in those of Examples 1 to 72 appropriate to the substituents to be introduced, including where necessary other common synthesis expedients well known to the art, compounds are prepared having the structures set forth in Table 1. The starting materials illustrated in the reaction schemes shown above are varied in accordance with principles of organic synthesis well known to the art in order to introduce the indicated substituents in the 4- and positions and in the indicated position on the benzo ring Example 1395 Dibutyl 4-fluorobenzene dialdehyde Bu
OHC
Br Step 1: Preparation of dibutyl 4-fluoro benzene dialdehyde To a stirred solution of 17.5 g (123 mmol) of difluorobenzaldehyde (Aldrich) in 615 mL of DMSO at ambient temperature was added 6.2 g (135 mmol) of lithium sulfide (Aldrich). The dark red solution was stirred at 75 C for 1.5 hours, or until the starting material was completely consumed, and then 34 g (135 mmol) of dibutyl mesylate aldehyde was added at about 50 C. The reaction mixture was stirred at 75 C for three hours or until the reaction was completed. The cooled solution was poured into water and extracted with ethyl acetate. The combined extracts were washed with water several times, dried (MgSO,) and WO 98/40375 PCT/US98/03792 concentrated in vacuo. Silica gel chromatographic purification of the crude product gave 23.6 g of fluorobenzene dialdehyde as a yellow oil: 1 H NMR (CDC13) d 0.87 J 7.05 Hz, 6H), 1.0-1.4 8H), 1.5-1.78 4H), 3.09 2H), 7.2-7.35 1H), 7.6 2H), 9.43 1H), 10.50 J 2.62 Hz, 1H).
Step 2: Preparation of dibutyl 4-fluorobenzyl alcohol To a solution of 22.6 g (69.8 mmol) of the dialdehyde obtained from Step 1 in 650 mL of THF at -60 C was added 69.8 mL (69.8 mmol) of DIBAL (1M in THF) via a syringe. The reaction mixture was stirred at -40 C for hours. To the cooled solution at -40 C was added sufficient amount of ethyl acetae to quench the excess of DIBAL, followed by 3 N HC1. The mixture was extracted with ethyl acetate, washed with water, dried (MgSO,), and concentrated in vacuo. Silica gel chromatographic purification of the crude product gave 13.5 g of recovered starting material, and 8.1 g of the desired fluorobenzyl alcohol as a colorless oil: 1 H NMR (CDC13) d 0.88 J 7.05 Hz, 6H), 1.0-1.4 8H), 1.5-1.72 4H), 1.94 (br s, 1H), 3.03 2H), 4.79 2H), 6.96 (dt, J 8.46, 3.02 Hz, 1H), 7.20 (dd, J 9.47, 2.82 Hz, 1H), 7.42 (dd, J 8.67, 5.64, 1H), 9.40 1H).
Step 3: Preparation of dibutyl 4-fluorobenzyl bromide To a solution of 8.1 g (25 mmol) of benzyl alcohol obtained from Step 2 in 100 mL of DMF at -40 C was added 47 g (50 mmol) of bromotriphenyphosphonium bromide (Aldrich). The resulting solution was stirred cold for 30 min, then was allowed to warm to 0--C.Tothe mixture was added 10% solution of sodium sulfite and ethyl acetate. The extract was .washed a few times with water, dried (MgS04), and concentrated in vacuo.
The mixture was stirred in small amount of ethyl acetate/hexane mixture (1:4 ratio) and filtered through a pad of silica gel, eluting with same solvent mixture.
WO 98/40375 PCT/US98/03792 The combined filtrate was concentrated in vacuo to give g of the desired product as a colorless oil: 1 H NMR (CDC13) d 0.88 J .7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.55-1.78 4H), 3.11 2H), 4.67 2H), 7.02 (dt, J 8.46, 3.02 Hz, 1H), 7.15 (dd, J 9.47, 2.82 Hz, 1H), 7.46 (dd, J 8.67, 5.64, 1H), 9.45 (s, 1H).
Step 4: Preparation of sulfonyl 4-fluorobenzyl bromide To a solution of 8.5 g (25 mmol) of sulfide obtained from Step 3 in 200 mL of CHC1, at 0 OC was added 15.9 g mmol) of mCPBA (64% peracid). The resulting solution was stirred cold for 10 min, then was allowed to stirred ambient temperature for 5 hours. To the mixture was added 10% solution of sodium sulfite and ethyl acetate. The extract was washed several times with saturated NaCO,, dried (MgSO,), and concentrated in vacuo to give 10.2 g of the desired product as a colorless oil: 1 H NMR (CDC13) d 0.91 J 7.05 Hz, 6H), 1.03-1.4 8H), 1.65-1.82 2H), 1.90-2.05 (m, 2H), 3.54 2H), 5.01 2H), 7.04-7.23 1H), 7.30 (dd, J 8.87, 2.42 Hz, 1H), 8.03 (dd, J 8.86, 5.64, 1H), 9.49 1H).
.4 o WO 98/40375 Example 1396 PCT/US98/03792 0'9 OH WO 98/40375 WO 9840375PCT/US98/03792 Generic Scheme X
F
CHO
t1. BuLi, PME -40 0 C, THF 2. DMF
F
1. Li 2 S, DMSO, heat 2. rnesylate aldehyde, heat
TA
PMETA:
N-
Rx CHO CHO DIBAL, THF -40 OC Rx
~OHCR
Br BrPh 3 PBr, -40 TC
HO
DMF
mTCPBA
OHC
Br
R
5
B(OR)
2 heat Pd(Ph 3
P)
4 Na 2
CO
3 EtOH, toluene or DME or
R
5 SnR 3 heat Pd(Ph 3
P)
4 solvent R H, or short alkyl (C I-C6) Rx
OHC
base; e KOtBu
'OH
Generic Scheme X: The nuc2.eophilic substitution of an appropriately substituted 2-f luorobenzaldehyde with WO 98/40375 PCT/US98/03792 lithium sulfide or other nucleophilic sulfide anion in polar solvent (such as DMF, DMA, DMSO, etc), followed by the addition of dialkyl mesylate aldehyde provided a dialkyl benzene dialdehyde Y. DIBAL reduction of the dialdehyde at low temperature yielded benzyl alcohol monoaldehyde Z. Conversion of benzyl alcohol to benzyl bromide, followed by oxidation of sulfide to sulfone yielded the key intermediate W.
Preparation of N-propvlsulfonic acid To a solution of 51 mg (111 vm) Compound X in ethanol (400 pl) was added 1,3 propane sultone (19.5 4l, 222 uim). The reaction was stirred in a sealed vial at oC for 25 hr. Sample was concentrated under a nitrogen stream and purified by reversed phase chromatography using acetonitrile/water as eluent (30-45%) and afforded the desired material as an off-white solid (28.4 mg, 'H NMR (CDCL,) d 0.82-0.96 6H) 1.11-1.52 (m of m, 10H), 1.58-1.72 1H), 2.08-2.21 1H), 2.36-2.50 2H), 2.93 6H), 3.02-3.22 (m of m, 5H), 3.58-3.76 2H), 4.15 1H), 5.51 (s, 1H), 6.45-6.58 1H), 6.92-7.02 1H), 7.35-7.41 1H), 7.41-7.51 2H), 8.08 J 8.1 Hz, 1H), 8.12-8.25 1H); MS ES- M-H m/z 579.
Example 1397 The 7-fluoro, 9-fluoro and 7,9-difluoro analogs of benzothiepine compounds of this inventEion can be reacted with sulfur and nitrogen nucleophiles to give the corresponding sulfur and nitrogen substituted analogs. The following example demonstrates the synthesis of these analogs.
3,3-Dibutyl-5a-(4'-fluorophenyl)-4a-hydroxy-7methylthio-2,3,4,5-tetrahydrobenzothiepine-, 1-dioxide.
-43 WO 98/40375 PCT/US98/03792 o. ,Bu Bu MeS OH
OH
F
A mixture of 0.4 g Of 3,3-dibutyl-7-fluoro-5a-(4'fluorophenyl)-4a-hydroxy-2,3,4,5tetrahydrobenzothiepine-1,1-dioxide, prepared by previously described method, 0.12 g of sodium methanethiolate and 20 ml of DMF was stirred at 50 C for 3 days. An additional 0.1 g of sodium methanethiolate was added to the reaction mixture and the mixture was stirred for additional 20 h at 50 C then was concentrated in vacuo. The residue was triturated with water and extracte wiith ether. The ether extract was dried over MgSO 4 and concentrated in vacuo to 0.44 g of an oil. Purification by HPLC EtOAc in hexane) gave 0.26 g of needles, mp 164-165.5
%C.
3,3-Dibutyl-9-dimethylamino-7-fluoro-5a-(4'fluorophenyl)-4a-hydroxy-2,3,4,5tetrahydrobenzothiepine-l,1-dioxide and 7,9- Bis(dimethylamino)-3,3-dibutyl-5a-(4'-fluorophenyl)-4ahydroxy-2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide.
Me 2 N O Me 2 N 0 U S SBu Bu Me 2 NBu F
OH
OH
F
7 F WO 98/40375 PCT/US98/03792 A solution of 0.105 g of 3,3-dibutyl-7,9-difluoro- 5a-(4'-fluorophenyl)-4a-hydroxy-2,3,4,5tetrahydrobenzothiepine-1,1-dioxide, prepared by the method described previously, in 20 ml of 2 N dimethylamine in THF was heated at 160 C in a sealed Parr reactor overnight. The reaction mixture was cooled and concentrated in vacuo. The residue was triturated with 25 ml of water and extracted with ether. The ether extract was dried over MgSO 4 and concentrated in vacuo.
The resdue was purified by HPLC (10% EtOAc in hexane) to give 35 mg of an earlier fraction which was identified as 3,3-dibutyl-9-dimethylamino-7-fluoro-5a- (4'-fluorophenyl)-4a-hydroxy-2,3,4,5tetrahydrobenzothiepine-l,1-dioxide, MS (CI) m/e 480 (M and 29 mg of a later fraction which was identified as 7,9-bis(dimethylamino)-3,3-dibutyl-5a- (4'-fluorophenyl)-4a-hydroxy-2,3,4,5tetrahydrobenzothiepine-1,1-dioxide, MS (CI) m/e 505
(M
The compounds of this invention can also be synthesized using cyclic sulfate below) as the reagent as shown in the following scheme. The following example describes a procedure for using the cyclic sulfate as the reagent.
WO 98/40375 WO 9840375PCT/US98/03792 R2 OH OH
SOC'
2 RuCI3 NaIO 4 RI R2 s 0 0 0 I.NaH, diglyrne2 9.RX)q ,~HO PCC, 2. Rp 0 0 3. H 2 S0 4
MCPBA
(R x) q* (Rx)q" KOtBu Dibutyl. cyclic sulfite: WO 98/40375 PCT/US98/03792
Q.
A solution of 2,2-dibutyl-l,3-propandiol (103g, 0.548 mol) and triethylamine (221g, 2.19 mol) in anhydrous methylene chloride (500 ml) and was stirred at 0 degrees C under nitrogen. To the mixture, thionyl chloride (97.8 g, 0.82 mol) was added dropwise and within 5 min the solution turned yellow and then turned black when the addition was completed within half an hour. The reaction mixture was stirred for 3 hrs. GC showed that there was no starting material left. The mixture was washed with ice water twice then with brine twice. The organic phase was dried over magnesium sulfate and concentrated under vacuum to give the cyclic sulfite 128 g (100%) as a black oil. Mass spectrum (MS) was consistent with the product.
To a solution of the above compound (127.5g 0.54 mol) in 600 ml acetonitrile and 500 ml of water cooled in an ice bath under nitrogen was added ruthenium(III) chloride (1 g) and sodium periodate (233 g, 1.08 mol).
The reaction was stirred overnight and the color of the solution turned black. GC showed that there was no starting material left. The mixture was extracted with 300 ml of ether and the ether extract was washed three -times. with brine.....The rganic phase was dried over magnesium sulfate and passed through celite. The filtrate was concentrated under vacuum and gave the cyclic sulfate 133 g as an-oil. Proton, carbon NMR and MS were consistent with the product.
2-[(2-(4,-Fluorobenzyl)-4methylphenylthio)methyl]-2-butylhexanol: WO 98/40375 PCT/US98/03792 Sodium hydride (60% oil dispersion), 0.27 g (6.68 mmole), was washed with hexane and the hexane wash was decanted. To the washed sodium hydride was added 20 ml of 2-methoxyethyl ether (diglyme) and the mixture was cooled in an ice bath. A solution of 1.55 g (6.68 mmole) of 2-(4'-fluorobenzyl)-4-methylbenzenethiol in ml of 2-methoxyethyl ether was added dropwise to the reaction mixture in 15 min. A mixture of 2.17 g (8.68 mmole) of the dibutyl cyclic sulfate in 10 ml of 2methoxyethyl ether was added once and stirred for min at 0 C then at room temperature for 1 hr under nitrogen. GC showed that there was no thiol left. The solvent was evaporated and triturated wth water then was extracted with ether twice. The water layer was separated, treated with 20 ml of 10% NaOH then was boiled for 30 min and cooled, acidified with 6N HC1 and boiled for 10 min. The reaction mixture was cooled and extracted with ether. The organic layer was washed successively with water and brine, dried over magnesium -sulfate and concentrated under vacuum-to-give-2.4 7 g 92.5%) of an oil. Proton NMR 13 C NMR and MS were consistent with the product.
2-[(2-(4'-Fluorobenzyl)-4methylphenylthio)methyl]-2-butylhexanal: WO 98/40375 PCT/US98/03792 To a solution of the above product (2 g 4.9 mmol) in 40 ml methylene chloride cooled in an ice bath under nitrogen was added pyridinium chlorochromate (2.18 g, 9.9 mmol) at once. The reaction was stirred with 3 hrs and filtered through a bed of silica gel.
The filtrate was concentrated under vacuum to give 1.39 g of an oil. Proton, carbon NMR and MS were consistent with the product.
2-[(2-(4'-Fluorobenzyl)-4methylphenylsulfonyl)methyl]-2-butylhexanal oQ
I
H3C 0 H
F
To a solution of the above product (0.44 g ,1.1 mmole) in 20 ml methylene chloride solution cooled in an ice bath under nitrogen was added 70% mchloroperbenzoic acid (0.54 g, 2.2 mmol) at once. The reaction mixture was stirred for 18 hrs and filtered.
PAI
WO 98/40375 PCT/US98/03792 The filtrate was washed successively with 10% NaOH water and brine, dried over magnesium sulfate and concentrated under vacum to give 0.42 g of an oil. Proton, carbon NMR and MS were consistent with the product.
3,3-Dibutyl-7-methyl-5a-(4'-fluorophenyl)-4ahydroxy-2,3,4,5-tetrahydrobenzothiepine-l,1-dioxide:
H
3 C OH
I
F
A mixture of 0.37 g (0.85 mmol) of the above product in 30 ml of anhydrous THF was stirred at 0 %C.
Then potassium t-butoxide (102 mg, 0.85 mmol) was added. After 3 hrs, TLC showed that there was a product and some starting material left. The crude reaction mixture was acidified with 10% HC1 and extracted with ether. The ether extract was washed successively with water and brine, dried with MgSO 4 and concentrated under vacuum. The residue was purified by HPLC EtOAc-Hexane). The first fraction was 0.1 g of starting material as an oil and the second fraction was a white solid, 0.27 g Proton NMR and carbon NMR were consistent- with-the desired product. Mass spectrum (CI) also confirmed the product, m/e 433 (M 1).
aSo WO 98/40375 PCT/US98/03792 Step 1 CI 0 /CH3 NOz
C
1 ,HoC1NO fw=291.69 In an inert atmosphere, weigh out 68.3 gms phosphorus pentachloride (0.328mole Aldrich 15,777-5) into a 2-necked 500ml round bottom flask. Fit flask with a N, inlet adapter and suba seal. Remove from inert atmosphere and begin N, purge. Add anhydrous chlorobenzene (Aldrich 28,451-3) to the PC1, via syringe and begin stirring with magnetic stir bar.
Weigh out 60 gms 2 -chloro-5-nitrobenzoic acid (0.298 mole Aldrich 12,511-3). Slowly add to the chlorobenzene solution while under N, purge. Stir at room temperature overnight. After stirring at room temperature for -20hrs, .place in oil bath and heat at 50C for Ihr. Remove chlorobenzene by high vacuum. Wash residue with anhydrous hexane. Dry acid chloride wt=61.95gms. Store in inert and dry atmosphere.
In inert atmosphere, dissolve acid chloride with 105mls anhydrous anisole (0.97 mole Aldrich 29,629-5).
Place solution in-a .2-necked 500mlround bottom flask.- Weigh out 45.1gms aluminum chloride (0.34 moles Aldrich 29,471-3) and place in a solid addition funnel.
Fit reaction flask with addition 'funnel and a N, inlet adapter. Remove from inert atmosphere. Chill reaction solution with ice bath and begin N, purge. Slowly add A1C1, to chilled solution. After addition is complete, allow to warm to room temperature. Stir overnight WO 98/40375 PCT/US98/03792 Quench reaction by pouring into a solution of 300 mis IN HC1 and ice. Stir 15 min. Extract twice with ether. Combine organic layers and extract twice with 2% NaOH, then twice with deionized H,0. Dry with MgSO,, filter and rotovap to dryness. Remove anisole by high vacuum. Crystalize product from 90% ethanol 10% ethyl acetate. Dry on vacuum line. Wt=35.2gms. Yield 41%.
Obtain NMR and mass spec (m/z=292).
Step 2 Cl
NO
C,
14 HC1NO, fw=277.71 Dissolve 38.10gms (0.131 moles) of the benzophenone from step 1 in 250mls anhydrous methylene chloride. Place in a 3 liter flask fitted with N, inlet, addition funnel and stopper. Stir with magnetic stir bar. Chill solution with ice bath.
Prepare a solution of 39.32 gms trifluoromethane sulfonic acid (0.262 mole Aldrich 15,853-4) and 170 mls anhydrous methylene chloride. Place in addition funnel and add dropwise to chilled solution under N,.
Stir 5 minutes after addition is complete.
Prepare a solution of 22.85 gms triethyl silane (0.197mole Aldrich 23,019-7) and 170mls anhydrous methylene chloride Place in-addition f Iunnl-and add dropwise to chilled solution under Stir 5 minutes after addition is complete.
Prepare a second solution of 39.32 gms trifluoromethane sulfonic acid and 170mls anhydrous methylene chloride. Place in addition funnel and add dropwise to chilled solution under Stir 5 minutes after addition is complete.
WO 98/40375 PCT/US98/03792 Prepare a second solution of 22.85 gms triethyl silane and 170mls anhydrous methylene chloride. Place in addition funnel and add dropwise to chilled solution under After all additions are made allow to slowly warm to room temperature overnight. Stir under N, overnight.
Prepare 1300 mls saturated NaHCO, in a 4 liter beaker. Chill with ice bath. While stirring vigorously, slowly add reaction mixture. Stir at chilled temperature for 30 min. Pour into a separatory funnel and allow separation. Remove organic layer and extract aqueous layer 2 times with methylene chloride.
Dry organic layers with MgSO,. Crystallize from ethanol. Dry on vacuum line. Dry wt=28.8gms. Confirm by NMR and mass spec (m/z=278).
Step 3 o/cj
S
NO,
C
2 ,H,,NO.S fw=443.61 Dissolve 10.12 gms (0.036 moles) of product 2 with 200 mls anhydrous DMSO. Place in a 500 ml round bottom flask with magnetic stir bar. Fit flask with water condenser, N, inlet, and stopper. Add 1.84 gms Li,S (0.040 moles Aldrich 21,324-1). Place flask in oil bath and heat at 75 0 C under N, overnight then cool to room temperature.
Weigh out 10.59 gms dibutyl mesylate (0.040 moles). Dissolve with anhydrous DMSO and add to reaction solution. Purge well with heat overnight a53 WO 98/40375 PCT/US98/03792 at Cool to room temperature. Prepare 500 mis of acetic acid in a 2 liter beaker. While stirring, slowly add reaction mixture. Stir 30 min. Extract with ether 3 times. Combine organic layers and extract with water and sat'd NaCl. Dry organic layer with MgSO,, filter and rotovap to dryness. Dry oil on vacuum line. Obtain pure product by column chromatography using 95% hexane and 5% ethyl acetate as the mobile phase. Dry wt=7.8 gms. Obtain NMR and mass spec (m/z=44 4 Step 4 0 NO2 C,,H,,NO,S fw=475.61 Dissolve 9.33 gms (0.021 moles) of product 3 with 120 mis anhydrous methylene chloride. Place in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N, inlet and stopper. Chill solution with ice bath under N, purge. Slowly add 11.54 gms 3chloroperbenzoic acid (0.0435 moles, Fluka 25800, After addition is complete warm to room temperature and monitor reaction by TLC. Reaction goes quickly to the sulphoxide intermediate but takes 8 hrs to convert to the sulphone. Chill solution over night in freezer. Filter solid from reaction, extract filtrate with 10% KCO,. Extract aqueous layer twice with methylene choride. Combine organic layers and dry WO 98/40375 PCT/US98/03792 with MgSO,. Filter and rotovap to dryness. Obtain pure product by crystallizing from ethanol or isolating by column chromatography. Obtain NMR and mass spec (m/z=476).
Step MHC CHC o C H,,NO 4 S fw=473.68 Reaction is done in a 300 ml stainless steel Parr stirred mini reactor. Place 9.68 gms (0.0204 moles) of product 4 in reactor base. Add 160 mls ethanol. For safety reasons next two compounds are added in a N, atmosphere glove bag. In glove bag, add 15.3 mls formaldehyde (0.204 moles, Aldrich 25,254-9, about 37 wt% in water) and 1.45 gms 10% Pd/Carbon (Aldrich 20,569-9). Seal reactor before removing from glove bag. Purge reactor three times with H 2 Heat to under Run reaction at 200 psig 55°C, and a stir rate of 250 rpm. Run overnight under these conditions.
Cool reactor and vent Purge with Check progress of run by TLC. Reaction is a mixture of desired product and intermediate. Filter reaction mixture over a bed of celite washing well with ether.
Rotovap and redissolve with ether. Extract with water.
Dry organic layer with MgSO 4 filter and rotovap to dryness. Dry on vacuum line.
Charge reactor again with same amounts, seal reactor and run overnight under same conditions.
WO 98/40375 PCT/US98/03792 After second run all of the material has been converted to the desired product. Cool and vent H, pressure.
Purge with Filter over a bed of celite, washing well with ether. Rotovap to dryness. Dissolve with ether and extract with water. Dry organic layer with MgSO,, filter and rotovap to dryness. Dry on vacuum line. Obtain NMR and mass spec (m/z=47 4 Step 6 0
N
H
3 C/
CH
3 C,H,,NOS fw=473.68 Dissolve 8.97 gms (0.0189 mole) of product 5 with 135 mls anhydrous THF. Place in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N, inlet and stopper. Chill solution with ice/salt bath under N, purge. Slowly add 2.55 gms potassium t-butoxide (0.227 mole Aldrich 15,667-1). After addition is complete, continue to stir at -10°C monitoring by TLC.
Once reaction is complete, quench by adding 135 mis HC1 stirring 10 min. Extract three times with ether. Dry organic layer with MgSO,, filter and rotovap to dryness. Crystallize from ether. Obtain NMR and mass spec (m/z=474).
Step 7 WO 98/40375 PCT/US98/03792 C,2H,,NOS fw=459.65 Dissolve 4.67 gms (0.01 moles) of product 6 with 100 mis anhydrous chloroform. Place in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N, inlet adapter and suba seal. Chill solution with dry ice /acetone bath under a N, purge. Slowly add, via syringe, 2.84 mis boron tribromide (0.03 moles Aldrich 20,220-7). Stir at cold temperature for 15 min after addition then allow to warm to room temperature.
Monitor reaction progress by TLC. Reaction is usually complete in 3 hrs.
Chill solution with ice bath. Quench with 100 mis KCO, while stirring rapidly. Stir 10 min. then transfer to sep funnel and allow separation. Remove aqueous layer. Extract organic layer once with HC1, once H,0, and once with saturated NaCi solution.
Dry organic layer with MgSO,, filter and rotovap to dryness. Crystallize product from ether. Obtain
NMR
and mass spec (m/z=460).
Step 8 WO 98/40375 PCT/US98/03792 C,,H,,NO,SI fw=701.71 Weigh 0.38 gms NaH (9.57 mmoles Aldrich 19,923-0 60% disp. in mineral oil) in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N, inlet and stopper. Chill NaH with ice bath and begin N, purge.
Dissolve 4.0 gms (8.7 mmoles) of product 7 with mis anhydrous DMF. Add to the cold NaH. Stir at cold temperature for 30 min. Add 1.33 gms K,CO, (9.57 mmoles Fisher P-208).
Dissolve 16.1 gms 1,2-bis-(2-iodoethoxy)ethane (43.5 mmoles Aldrich 33,343-3) with 60 mls anhydrous DMF. Add to cold reaction mixture. Warm to room temperature then heat to 40'C overnight under N,.
Cleanup by diluting with ether and extracting sequentially with 5% NaOH, H,O, and saturated NaCl.
Dry organic layer with MgSO,, filter and dry. Obtain pure product by column chromatography using 75% hexane ethyl acetate as the mobile phase. Obtain NMR and mass spec (m/z=702).
Step 9 WO 98/40375 PCT/US98/03792 'V
C
3
,H,,N
2 0,SI fw=802.90 Dissolve 1.0 gms (1.43 mmoles) of product 8 with 10 mis anhydrous acetonitrile. Place in a 3 ounce Fischer-Porter pressure reaction vessel with magnetic stir bar. Add 2.9 gms triethyl amine (28.6 mmoles Aldrich 23,962-3) dissolved in 10 mis anhydrous acetonitrile. Purge well with N, then close system Heat at 45°C. Monitor reaction by TLC. Reaction is usually complete in 48 hrs.
Perform cleanup by removing acetonitrile under vacuum. Redissolve with anhydrous chloroform and precipitate quaternary ammonium salt with ether.
Repeat several times. Dry to obtain crystalline product. Obtain NMR and mass spec (m/z=6 7 5 WO 98/40375 PCT/US98/03792 xample 1399 Step 1. Preparation of 1 Z& OCH 3 To a solution of 144 g of KOH (2560 mmol) in 1.1 L of DMSO was added 120 g of 2-bromobenzyl alcohol (641 mmol) slowly via addition funnel. Then was added 182 g of methyliodide (80 mL, 1282 mmol) via addition funnel.
Stirred at ambient temperature for fifteen minutes.
Poured reaction contents into 1.0 L of water and extracted three times with ethyl acetate. The organic layer was dried over MgSO 4 and concentrated ijn vacuo.
Purified by silica-gel chromatography through a 200 mL plug using hexanes (100%) as elutant yielded 103.2 g of 1 as a clear colorless liquid. 'H NMR (CDCl,) d 3.39 3H), 4.42 2H), 7.18-7.27 2H), 7.12 (d, J 7.45, 1H), 7.50 1H).
Step 2. Preparation of 2
-O
0 2 L OCH 3 To a cooled (-78 solution of 95 g (472 mmol) of 1 in 1.5 L THF was added 240 mL of 2.5 M n-butyl lithium (576 mmol). The mixture was stirred for one hour, and then to it was added 180 g of zinc iodide (566 mmol) dissolved in 500 ml THF. The mixture was stirred thirty minutes, allowed to warm to 5 C, cooled to °C and to it was added 6 g of Pd(PPh,) 4 (5.2 mmol) and 125 g 2,5-difluorobenzoyl chloride (708 mmol). The mixture was stirred at ambient temperature for 18 hoursand then cooled to 10 quenched with water, partitioned between ethyl acetate and water, and washed WO 98/40375 PCT/US98/03792 organic layer with IN HCL and with IN NaOH. The organic layer was dried over MgSO, and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500) using 5% ethyl acetate/hexanes as elutant gave 53.6 g (43 of 2 as an orange oil. 'H NMR (CDC1,) d 3.40 3H), 4.51 2H), 7.12-7.26 (m, 3H), 7.47 J 7.50, 1H), 7.57 J 7.45, 1H), 7.73 J 7.45, 1H), 7.80 1H).
Step 3. Preparation of 3 S Bu 0 OH OCH 3 A solution of 53 g (202.3 mmol) of 2 and 11.2 g Li2S (242.8 mmol) in 250 mL DMF was heated to 100 °C for 18 hours. The reaction was cooled (0 and 60.7 g of X (the cyclic sulfate compound of example 1397) (242.8 mmol) in 50 mL DMF was added. Stirred at ambient temperature for 18 hours then condensed in vacuo.
Added 1 L water to organic residue and extracted twice with diethyl ether. Aqueous layer acidified (pH 1) and -refluxed 2 days. Cooled to ambient temperature and extracted with methylene chloride, dried organic layer over MgSO, and condensed in vacuo. Purification by silica gel chromatography (Waters Prep-500) using ethyl acetate hexanes as elutant gave 42.9 g (48 of 3 as a yellow oil. 'H NMR (CDC1,) d 0.86 J 7.25 Hz, 6H), 1.10 1.26 12H), 2.83 2H), 3.32 (s, 2H), 3.40 3H), 4.48 3H), 7.02 (dd, J 8.26 Hz and 2.82 Hz, 1H), 7.16 (dt, J 8.19 Hz and 2.82 Hz, 1H), 7.45 J 7.65 Hz, 1H), 7.56-7.61 2H), 7.69 J 7.85 Hz, 1H), 7.74 1H), Step 4. Preparation of 4 WO 98/40375 PCT/US98/03792 Bu I CH 2 0H
F
l OCH 3 To a cooled (-40 solution of 42.9 g (96.2 rmol) of 3 in 200 mL of methylene chloride was added 21.6 g trifluoromethane sulfonic acid (12.8 mL, 144 mmol) followed by the addition -of 22.4 g triethyl silane (30.7 mL, 192.4 mmol). Stirred at -20 °C for two hours, quenched with water and warmed to ambient temperature.
Partitioned between methylene chloride and water, dried the organic layer over MgSO, and condensed in vacuo. Purification by silica gel chromatography (Waters Prep-50 0 using 10% ethyl acetate/ hexanes as elutant gave 24.2 g (60%)of 4 as a oil. 'H NMR (CDCl,) d 0.89 J 7.05 Hz, 6H), 1.17 1.40 12H), 1.46 J 5.84 Hz, 1H). 2.81 2H), 3.38 3H), 3.43 J 5.23 Hz, 2H), 4.16 2H), 4.42 2H), 6.80 J 9.67 Hz, 1H), 6.90 J 8.46 Hz, 1H), 7.09 J 7.45 Hz, 1H), 7.15 7.21 2H), 7.25 7.32 2H), 7.42 1H).
Step 5. Preparation of S Bu A CHO N.-..IOCH 3 To a cooled (15-18 solution of 24.2 g (55.8 mmol) of 4 in 100 mL DMSO was added 31.2 g sulfur trioxide pyridine complex (195 mmol). Stirred at ambient temperature for thirty minutes. Poured into cold water and extracted three times with ethyl acetate. Washed organics with 5% HCl (300 mL) and then with brine (300 mL), dired organics over MgSO, and condensed nacU to give 23.1 g (96 of 5 as a light brown oil. *H NMR WO 98/40375 PCT/US98/03792 (CDC1,) d 0.87 J 7.05 Hz, 6H), 1.01 1.32 (m, 8H), 1.53 1.65 4H), 2.98 2H), 3.38 3H), 4.15 2H), 4.43 2H), 6.81 (dd, J 9.66 Hz and 2.82 Hz, 1H), 6.91 J 8.62 Hz, 1H), 7.07 J 7.46 Hz, 1H), 7.14 1H), 7.19 J 7.65 Hz, 1H), 7.26 7.32 1H), 7.42 (dd, J 8.66 Hz and 5.64 Hz, IH), 9.40 1H).
Step 6. Preparation of 6 C Bu S Bu
CHO
6 ,OCH 3 To a cooled (0 solution of 23.1 g (53.6 mmol) of in 200 mL methylene chloride was added 28.6 g meta cholorperoxy-benzoic acid (112.6 mmol). Stirred at ambient temperature for 24 hours. Quenched with 100 mL Na 2 SO,, partitioned between water and methylene chloride. Dried organic layer over MgSO, and condensed in vacuo to give 24.5 g of 6 as a light yellow oil. 1H NMR (CDC1,) d 0.86 1.29 14H), 1.58 1.63 2H), 1.82 1.91 2H), 3.13 2H), 3.39 (s, 3H), 4.44 2H), 4.50 2H), 6.93 J 9.07 Hz, 1H), 7.10 7.33 5H), 8.05 IH), 9.38 1H).
Step 7. Preparartion of 7 B u N kJ CHO Me 2 Nr
OCH
3 To a solution of 24.5 g (52.9 mmol) of 6 in 20 mL of THF contained in a stainless steel reaction vessel was added 100 mL of a 2.0 M solution of dimethyl amine and WO 98/40375 PCT/US98/03792 mL of neat dimethyl amine. The vessel was sealed and heated to 110 °C for 16 hours. The reaction vessel was cooled to ambient temperature and the contents concentrated n vacuo. Purification by silica gel chromatography (Waters Prep-500) using 15 ethyl acetate/hexanes gave 21.8 g (84 of 7 as a clear colorless oil. 'H NMR (CDC1,) d 0.85 J 7.25 Hz, 6H), 0.93 1.29 8H), 1.49 1.59 2H), 1.70 1.80 2H), 2.98 8H), 3.37 3H), 4.41 2H), 4.44 2H), 6.42 1H), 6.58 (dd, J 9.0 Hz and 2.61 Hz, 1H), 7.13 J 7.45 Hz, 1H), 7.21 1H), 7.28 J 7.85 Hz, 1H), 7.82 J 9.06 Hz, 1H), 9.36 1H).
Step 8. Preparation of 8 Bu Me 2 N O 0 1-OCH3 A solution of 21.8 g (44.8 mmol) of 7 in 600 mL of THF was cooled to 0 58.2 mL of a 1 M solution of potassium t-butoxide was added slowly, maintaining the temperature at <5 Stirred for 30 minutes, then quenched with 50 mL of saturated ammonium chloride.
The organic layer was partitioned between ethyl acetate and water, dried over MgSO4 and concentrated in vacuo.
Purification by recrystalization from -10% ethyl acetate/hexanes gave 15.1 g of 8 as a white solid. The mother liquor was purified by silica gel chromatography (Waters Prep-5 00 using 30% ethyl acetate/hexanes as the elutant to give 3.0 g of 8 as a white solid.
MS
(FABLi') m/e 494.6. HRMS calculated for M+H 487.2756. Found 487.2746.
WO 98/40375 PCT/US98/03792 Step 9. Preparation of 9 ofiP <Bu Me 2 N 0H t OH C~2,/Br A solution of 2.0 g (4.1 mmol) of 8 in 20 mL of methylene chloride was cooled to -60 4.1 mL of a 1M solution of boron tribromide was added. Stirred at ambient temperature for thirty minutes. Cooled reaction to -10 °C and quenched with 50 mL of water.
The organic layer was partitioned between methylene chloride and water, dried over MgSO, and concentrated in vacuo. Purification by recrystalization from ethyl acetate/methylene chloride gave 1.95 g of 9 as a white solid. MS (FABH') m/e 537. HRMS (FAB) calculated for M 536.1834. Found 536.1822.
Step 10. Preparation of Bu Me 2
N
B
OH
r Br' A solution of 1.09 g (2.0 mmol) of 9 and 4.9 g (62 mmol) of pyridine in 30 mL of acetonitrile was stirred at ambient temperature for 18 hours. The reaction was concentrated in vacuo. Purification by recrystallization from methanol/ diethyl ether gave 1.19 g of 10 as an off white solid. MS (FAB') m/e 535.5.
WO 98/40375 PCT/US98/03792 Step 1. Preparation of 2 OV ^Bu
CHO
SNO
2 To a solution of 6.0 g of dibutyl 4-fluorobenzene dialdehyde of Example 1395 (14.3 mmol) in 72 mL of toluene and 54 mL of ethanol was added 4.7 g 3nitrobenzeneboronic acid (28.6 mmol), 0.8 g of tetrakis (triphenylphosphine) palladium(0) (0.7 mmol) and 45 mL of a 2 M solution of sodium carbonate in water. This heterogeneous mixture was refluxed for three hours, then cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was dried over MgSO, and concentrated in vacu.
purification by silica gel chromatography (Waters Prep- 2000) using ethyl acetate/hexanes (25/75) gave 4.8 g of the title compound as a yellow solid. 1H NMR (CDC1,) d 0.88 J 7.45 Hz, 6H), 0.99-1.38 8H), 1.62-1.75 2H), 1.85-2.00 2H), 3.20 2H), 4.59 2H), 6.93 (dd, J 10.5 and 2.4 Hz, 1H), 7.15 (dt, J 8.4 and 2.85 Hz, 1H), 7.46-7.59 2H), 8.05- 8.16 3H), 9.40 1H).
WO 98/40375 PCT/US98/03792 Step 3. Preparation of 3 0 1 (f^Y Bu i 'OH
"^NO
2 A solution of 4.8 g (10.4 rnmol) of 2 in 500 mL THF was cooled to 0 °C in an ice bath. 20 mL of a 1 M solution of potassium t-butoxide was added slowly, maintaining the temperature at <5 Stirring was continued for minutes, then the reaction was quenched with 100 mL of saturated ammonium chloride. The mixture was partitioned between ethyl acetate and water; the organic layer was washed with brine, then dried (MgSO,) and concentrated in vacuo. Purification by silica gel chromatography through a 100 ml plug using CHCl,2 as eluent yielded 4.3 g of 3 as a pale yellow foam.
H NMR (CDCl,) d 0.93 J 7.25 Hz, 6H), 1.00-1.55 8H), 1.59-1.74 3H), 2.15-2.95 1H), 3.16 (qAB' JAB 15.0 Hz, AV 33.2 Hz, 2H), 4.17 J Hz, IH), 5.67 1H), 6.34 (dd, J=9.6 and 3.0 Hz, 1H). 7.08 (dt, J 8.5 and 2.9 Hz, 1H), 7.64 J 8.1 Hz, 1H), 7.81 J 8.7 Hz, 1H). 8.13 (dd, J 9.9 and 3.6 Hz, 1H), 8.23-8.30 1H), 8.44 1H).
MS(FABH
m/e (relative intensity) 464.5 (100), 446.6 HRMS calculated for M+H 464.1907. Found 464.1905 U1l WO 98/40375 PCT/US98/03792 Step 4. Preparation of 4 S /Bu Me 2
OH
NO
2 To a cooled (0 solution of 4.3 g (9.3 mmol) of 3 in 30 ml THF contained in a stainless steel reaction vessel was added 8.2 g dimethyl amine (182 mmol). The vessel was sealed and heated to 110 °C for 16 hours.
The reaction vessel was cooled to ambient temperature and the contents concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-2 000 using an ethyl acetate/hexanes gradient (10-40% ethyl acetate) gave 4.0 g of 4 as a yellow solid. 'H NMR (CDC1,) d 0.80-0.95 6H), 0.96-1.53 8H), 1.60-1.69 3H), 2.11-2.28 1H), 2.79 6H), 3.09 (qAB, JAB 15.0 Hz, DV= 45.6 Hz, 2H), 4.90
J
9.0 Hz, 1H), 5.65 1H), 5.75 J 2.1 Hz, 1H), 6.52 (dd, J 9.6 and 2.7 Hz, 1H), 7.59 J 8.4 Hz, 1H), 7.85 J 7.80 Hz, 1H), 7.89 J 9.0 Hz, 1H), 8.20 (dd, J 8.4 and 1.2 Hz, 1H), 8.43 1H).
MS(FABH
m/e (relative intensity) 489.6 (100), 471.5 HRMS calculated for M+H 489.2423. Found 489.2456.
WO 98/40375 PCT/US98/03792 Step 5. Preparation of o.,P
/S
Bu Me 2 N 'H (aNH 2 To a suspension of 1.0 g (2.1 mmol) of 4 in 100 ml ethanol in a stainless steel Parr reactor was added 1 g palladium on carbon. The reaction vessel was sealed, purged twice with then charged with H, (100 psi) and heated to 45 °C for six hours. The reaction vessel was cooled to ambient temperature and the contents filtered to remove the catalyst. The filtrate was concentrated in vacuo to give 0.9 g of 5. 'H NMR (CDC1,) d 0.80-0.98 6H), 1.00-1.52 1.52-1.69 1H), 2.15-2.29 1H), 2.83 6H), 3.07 (qAB, JAB 15.1 Hz, DV 44.2 Hz, 2H), 3.70 (s, 2H), 4.14 1H), 5.43 1H), 6.09 J 2.4 Hz, 1H), 6.52 (dd, J 12.2 and 2.6 Hz, 1H), 6.65 (dd, J 7.8 and 1.8 Hz, 1H), 6.83 1H), 6.93 J 7.50 Hz, 1H), 7.19 J 7.6 Hz, 1H), 7.89 J 8.9 Hz, 1H). MS(FABH m/e (relative intensity) 459.7 (100).
HRMS calculated for M+H 459.2681. Found 459.2670.
WO 98/40375 PCT/US98/03792 Step 6. Preparation of 6 To a solution of 914 mg (2.0 mmol) of 5 in 50 ml THF was added 800 mg (4.0 mmol) 5-bromovaleroyl chloride.
Next was added 4 g (39.6 mmol) TEA. The reaction was stirred 10 minutes, then partitioned between ethyl acetate and brine. The organic layer was dried (MgSO,) and concentrated in vacuo. Purification by silica gel chromatography through a 70 ml MPLC column using a gradient of ethyl acetate(20-50%) in hexane as eluent yielded 0.9 g of 6 as a pale yellow oil.
IH NMR (CDC1,) d 0.84-0.95 6H), 1.02-1.53 1.53-1.68 1H), 1.80-2.00 4H), 2.12-2.26 (m, 4H), 2.38 J 6.9 Hz, 2H), 2.80 6H), 3.07 (qAB, JAB 15.6 Hz, DV 40.4 Hz, 2H), 3.43 J 6.9 Hz, 2H), 4.10 1H), 5.51 1H), 5.95 J 2.4 Hz, 1H), 6.51 (dd, J 9.3 and 2.7 Hz, 1H), 7.28 1H), 7.32-7.41 2H), 7.78 J 8.1 Hz, 1H), 7.90
J
9.0 Hz, 1H).
Step 7. Preparation of 7 0 o <Bu Bu Me 2
N
'OH
To a solution of 0.9 g (1.45 mmol) of 6 in 25 ml acetonitrile add 18 g (178 mmol) TEA. Heat at 55 °C for 16 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo.
Purification by reverse-phase silica gel chromatography (Waters Delta Prep 3000) using an acetonitrile /water gradient containing 0.05% TFA (20-65% acetonitrile) WO 98/40375 PCT/US98/03792 gave 0.8 g of 7 as a white foam. 'H NMR (CDC1,) d 0.80-0.96 6H), 0.99-1.54 19H), 1.59-1.84 (m, 3H), 2.09-2.24 1H), 2.45-2.58 2H), 2.81 (s, 6H), 3.09 (qAB, JAB 15.6 Hz, DV 18.5 Hz, 2H), 3.13- 3.31 8H), 4.16 1H), 5.44 1H), 6.08 J 1.8 Hz, 1H), 6.57 (dd, J 9.3 and 2.7 Hz, 1H), 7.24 J 7.5 Hz, 1H), 7.34 J 8.4 Hz, 1H), 7.56 (d, J 8.4 Hz, 1H), 7.74 1H), 7.88 J 9.0 Hz, 1H), 9.22 1H). HRMS calcd 642.4304; observed 642.4343.
Example 1400 Step 1
ON
C
14
H
13 0 2 F fw=232.25 A 12-liter, 4-neck round-bottom flask was equipped with reflux condenser,
N
2 gas adaptor, mechanical stirrer, and an addition funnel. The system was purged with N 2 A slurry of sodium hydride (126.0g/4.988mol) in toluene (2.5 L) was added, and the mixture was cooled to 6 C. A solution of 4-fluorophenol (560.5g/5.000mol) in toluene (2.5 L) was added via addition funnel over a period of 2.5 h. The reaction mixture was heated to reflux (100 C) for Ih. A solution of 3-methoxybenzyl chloride (783.0g/5.000mol) in toluene (750 mL) was added via addition funnel while maintaining reflux.
After 15 h. refluxing, the mixture was cooled to room temperature and poured into H20 (2.5 After 20 min.
stirring, the layers were separated, and the organic layer was extracted with a solution of potassium hydroxide (720g) in MeOH (2.5 The MeOH layer was added to 20% aqueous potassium hydroxide, and the WO 98/40375 PCT/US98/03792 mixture was stirred for 30 min. The mixture was then washed 5 times with toluene. The toluene washes were extracted with 20% aq. KOH. All 20% aq. KOH solutions were combined and acidified with concentrated HC1. The acidic solution was extracted three times with ethyl ether, dried (MgSO 4 filtered and concentrated in vacuo. The crude product was purified by Kugelrohr distillation to give a clear, colorless oil (449.0g/39% yield). 120-130 C/50mtorrHg. 1 H NMR and MS [(M H) 233] confirmed desired structure.
Step 2 s
N-CH)
C .3 OMe
F
C
17
H
1 8 N0 2 FS fw=319.39 A 12-liter, 3-neck round-bottom flask was fitted with mechanical stirrer and N 2 gas adaptor. The system was purged with N 2 4-Fluoro-2-(3-methoxybenzyl)-phenol (455.5g/1.961mol) and dimethylformamide were added.
The solution was cooled to 6 C, and sodium hydride (55.5g/2.197mol) was added slowly. After warming to room temperature, dimethylthiocarbamoyl chloride (242.4g/1.961mol) was added. After 15 h, the reaction mixture was poured into H20 (4.0 and extracted two times with ethyl ether. The combined organic layers were washed with H20 and saturated aqueous NaC1, dried (MgSO 4 filtered, and concentrated in vacuo to give the product (605.3g, 97% yield). 1H NMR and MS 320] confirm desired structure.
WO 98/40375 PCT/US98/03792 Step 3
SH
OMe
F
C
14
H
13 0FS fw=248.32 A 12-liter, round-bottom flask was equipped with N 2 gas adaptor, mechanical stirrer, and reflux condenser. The system was purged with N 2 4-Fluoro-2-( 3 methoxybenzyl)-phenyldimethylthiocarbamate (605.3g/1.895mol) and phenyl ether (2.0kg) were added, and the solution was heated to reflux for 2 h. The mixture was stirred for 64 h. at room temparature and then heated to reflux for 2 h. After cooling to room temperature, MeOH (2.0 L) and THF (2.0 L) were added, and the solution was stirred for 15 h. Potassium hydroxide (425.9g/7.
590 mol) was added, and the mixture was heated to reflux for 4 h. After cooling to room temparature, the mixture was concentrated by rotavap, dissolved in ethyl ether (1.0 and extracted with
H
2 0. The aqueous extracts were combined, acidified with concentrated HC1, and extracted with ethyl ether- The ether extracts were dried (MgSO,), filtered, and concentrated in vacuo to give an amber oil (463.0g, 98% yield). 1 H NMR confirmed desired structure.
Step 4 WO 98/40375 PCT/US98/03792 OMe
F
C
25
H
35 0 2 FS fw=418.61 A 5-liter, 3-neck, round-bottom flask was equipped with
N
2 gas adaptor and mechanical stirrer. The system was purged with N 2 4-Fluoro-2-(3-methoxybenzyl)thiophenol (100.0g/403.2mmol) and 2-methoxyethyl ether L) were added and the solution was cooled to 0 C.
Sodium hydride (9.68g/383.2mmol) was added slowly, and the mixture was allowed to warm to room temparature, 2,2-Dibutylpropylene sulfate (110.89g/443.6mmol) was added, and the mixture was stirred for 64 h. The reaction mixture was concentrated by rotavap and dissolved in H 2 0. The aqueous solution was washed with ethyl ether, and concentrated
H
2
SO
4 was added. The aqueous solution was heated to reflux for 30 min, cooled to room temperature, and extracted with ethyl ether. The ether solution was dried (MgSO 4 filtered, and conc'd in vacuo to give an amber oil (143.94g/ 8 5 yield). 1 H NMR and MS H) 419] confirm the desired structure.
Step WO 98/40375 PCT/US98/03792 0 Bu Bu OMe
F
C
25
H
33 0 2 FS fw=416.59 A 2-liter, 4-neck, round-bottom flask was equipped with
N
2 gas adaptor, and mechanical stirrer. The system was purged with N 2 The corresponding alcohol (143.94g/343.8mmol) and CH 2 C1 2 (1.0 L) were added and cooled to 0 C. Pyridinium chlorochromate (140.53g/651.6mmol) was added. After 6 CH 2 C12 was added. After 20 min, the mixture was filtered through silica gel, washing with CH 2 C1 2 The filtrate was concentrated in vacuo to give a dark yellow-red oil (110.6g, 77% yield). 1H NMR and MS H) 417] confirm the desired structure.
Step 6 0 Bu OMe
F
C
25
H
33 0 4 FS fw=448.59 A 2-liter, 4-neck, round-bottom flask was equipped with
N
2 gas adaptor and mechanical stirrer. The system was purged with N 2 The corresponding sulfide WO 98/40375 WO 9840375PCT/US98/03792 (ll0.6g/265.5mmol) and CH 2 Cl 2 (1.0 L) were added. The solution was cooled to 0 C, and 3-chleroperbflzoic acid (15B.21g/531.7ruol) was added portionwise. After min, the reaction mixture was allowed to warm to room temperature Afcer 3.5 h, the reaction mixture was cooled to 0 C and filtered through a fine fristed funnel. The filtrate was washed with 10% aqueous
K
2 C0 3 An emulsion formed which was extracted with ethyl ether. The organic layers were combined, dried (MgSO 4 filtered, and concentrated in vacuo to give the product (93.2g, 78% yield). 1)H zMR confirmed the desired structure.
WO 98/40375 PCT/US98/03792 Step 7 Uu ia
C
25
H
33 0 4 s fw=448.59 A 2-liter, 4-neck, round-bottom flask was equipped with
N
2 gas adaptor, mechanical stirrer, and a powder addition funnel. The system was purged with N 2 The corresponding aldehyde (93.2g/208mmol) and THF (1.0 L) were added, and the mixture was cooled to 0 C.
Potassium cert-butoxide (23.35g/208.mmol) was added via addition funnel. After 1h, 10% aql/ EC1 (1.0 L) was added. After 1 h, the mixture was extracted three times with ethyl ether, dried (MgS0 4 filtered, and concentrated in vacuo. The crude product was purified by recryst. from 80/20 hexane/ethyl acetate to give a white solid (32.18 The mother liquor was concentrated in vacuo and recrystelized from 95/5 toluene/ethyl acetate to give a white solid (33.60g/ combined yield: 'IN NMR confirmed the aesireB product.
a-fl WO 98/40375 PCT/US98/03792 Step 8
OH
o ou, OMe
C
2 7H 39 0 4 NS fw=4 7 3.67 A Fisher porter bottle was fitted with N 2 line and magnetic stirrer. The system was purged with N 2 The corresponding fluoro-compound (28.lg/62.6mmol) was added, and the vessel was sealed and cooled to -78 C.
Dimethylamine (17.lg/379mmol) was condensed via a C0 2 /acetone bath and added to the reaction vessel. The mixture was allowed to warm to room temperature and was heated to 60 C. After 20 h, the reaction mixture was allowed to cool and was dissolved in ethyl ether. The ether solution was washed with H 2 0, saturated aqueous NaCi, dried (MgS0 4 filtered, and concentrated in vacuo to give a white solid (28.5g/96% yield). 1 H NMR confirmed the desired structure.
WO 98/40375 PCT/US98/03792 Step 9 on
C
26
H
37 0 4 NS fw=45 9 .64 A 250-mL, 3-neck, round-bottom flask was equipped with
N
2 gas adaptor and magnetic stirrer. The system was purged with N 2 The corresponding methoxy-compound (6.62g/14.0mmol) and CHC1 3 (150 mL) were added. The reaction mixture was cooled to -78 C, and boron tribromide (10.50g/41.9mmol) was added. The mixture was allowed to warm to room temperature After 4 h, the reaction mixture was cooled to 0 C and was quenched with 10% K 2 C0 3 (100 mL). After 10 min, the layers were separated, and the aqueous layer was extracted two times with ethyl ether. The CHC1 3 and ether extracts were combined, washed with saturated aqueous NaC1, dried (MgS0 4 filtered, and concentrated in vacuo to give the product (6.27g/98% yield). 1H NMR confirmed the desired structure.
-1I WO 98/40375 PCT/US98/03792 Step
B
Bu
S
Bu
SOH
In a 250 ml single neck round bottom Flask with stir bar place 2- diethylamineoethyl chloride hydochloride (fw 172.10g/mole) Aldrich D8, 720-1 (2.4 mmol,4.12g), 34 ml dry ether and 34 ml of IN KOH(aqueous). Stir minutes and then separate by ether extraction and dry over anhydrous potassium carbonate.
In a separate 2-necked 250 ml round bottom flask with stir bar add sodium hydride (60% dispersion in mineral oil, 100 mg 2.6 mmol) and 34 ml of DMF. Cool to ice temperature. Next add phenol product(previous step) 1.1 g (2.4 mmilomoles in 5 ml DMF and the ether solution prepared above. Heat to 40C for 3 days. The product which contained no starting material by TLC was diluted with ether and extracted with 1 portion of 5% NaOH, followed by water and then brine. The ether layer was dried over magnesium sulfate and isolated by removing ether by rotary evaporation (1.3 gms).The product may be further purified by chromatography (Si02 99% ethyl acetate/l% NH40H at 5ml/min.). Isolated yield: 0.78 g (mass spec and HI NMR) WO 98/40375 PCT/US98/03792 Step 11
S
Bu
SOH
The product from step 10 0.57gms, 1.02 millimole fw 558.83 g/mole) and 1.6 gms iodoethane (10.02 mmol) was placed in 5 ml acetonitrile in a fischer-porter bottle and heated to 45 C for 3 days. The solution was evaporated to dryness and redissolved in 5 mls of chloroform. Next ether was added to the chloroform solution and the resulting mixture was chilled. The desired product is isolated as a precipitate 0.7272 gms. Mass spec M-I 587.9 H NMR).
Example 1401 Step 1
OH
OMe
F
C
14
H
13 0 2 F fw=232.25 A 12-liter, 4-neck round-bottom flask was equipped with WO 98/40375 PCT/US98/03792 reflux condenser, N 2 gas adaptor, mechanical stirrer, and an addition funnel. The system was purged with N 2 A slurry of sodium hydride (126.0g/4.988mol) in toluene (2.5 L) was added, and the mixture was cooled to 6 C. A solution of 4-fluorophenol (560.5g/5.000mol) in toluene (2.5 L) was added via addition funnel over a period of 2.5 h. The reaction mixture was heated to reflux (100 C) for lh. A solution of 3-methoxybenzyl chloride (783.0g/5.000mol) in toluene (750 mL) was added via addition funnel while maintaining reflux.
After 15 h. refluxing, the mixture was cooled to room temperature and poured into H 2 0 (2.5 After 20 min.
stirring, the layers were separated, and the organic layer was extracted with a solution of potassium hydroxide (720g) in MeOH (2.5 The MeOH layer was added to 20% aqueous potassium hydroxide, and the mixture was stirred for 30 min. The mixture was then washed 5 times with toluene. The toluene washes were extracted with 20% aq. KOH. All 20% aqueous KOH solutions were combined and acidified with concentrated HC1. The acidic solution was extracted three times with ethyl ether, dried over MgSO 4 filtered and concentrated in vacuo. The crude product was purified by-Kugelrohr distillation to give a clear, colorless oil (449.0g/39% yield). 120-130 1 H NMR and MS H) 233] confirmed desired structure.
Step 2 WO 98/40375 PCT/US98/03792 CH3 CH3 OMe
F
C
17
H
18
NO
2 FS fw=319.39 A 12-liter, 3-neck round-bottom flask was fitted with mechanical stirrer and N 2 gas adaptor. The system was purged with N 2 4-Fluoro-2-(3-methoxybenzyl)phenol (455.5g/1.961mol) and dimethylformamide were added. The solution was cooled to 6 C, and sodium hydride (55.5g/2.197mol) was added slowly. After warming to room temperature, dimethylthiocarbamoyl chloride (242.4g/l.961mol) was added. After 15 h, the reaction mixture was poured into H 2 0 (4.0 and extracted two times with ethyl ether. The combined organic layers were washed with H 2 0 and saturated aqueous NaC1, dried over MgSO 4 filtered, and concentrated in vacuo to give the product (605.3g, 97% yield). 1H NMR and MS 320) confirm desired structure.
Step 3 WO 98/40375 PCT/US98/03792
C
14
H
13 0FS fw=248.3 2 A 12-liter, round-bottom flask was equipped with
N
2 gas adaptor, mechanical stirrer, and reflux condenser. The system was purged with N 2 4-Fluoro-2- (3-methoxybenzyl)-phenyldimethylthiocarbamate (605.3g/1.895mol) and phenyl ether (2.0kg) were added, and the solution was heated to reflux for 2 h. The mixture was stirred for 64 h. at room temperature and then heated to reflux for 2 h. After cooling to room temperature, MeOH (2.0 L) and THF (2.0 L) were added, and the solution was stirred for 15 h. Potassium hydroxide (425.9g/7.590mol) was added, and the mixture was heated-to reflux for 4 h. After cooling to room temperature, the mixture was concentrated by rotavap, dissolved in ethyl ether (1.0 and extracted with
H
2 0. The aqueous extracts were combined, acidified with cone. HC1, and extracted with ethyl ether. The ether extracts were dried (MgSO,), filtered, and concentrated in vacuo to give an amber oil (463.0g, 98% yield). 1H NMR confirmed desired structure.
Step 4
OH
Bu Bu OMe
F
C
25
H
35 0 2 FS fw=418.61 A 5-liter, 3-neck, round-bottom flask was equipped with N 2 gas adaptor and mechanical stirrer. The system WO 98/40375 PCT/US98/03792 was purged with N 2 4-Fluoro-2-(3-methoxybenzyl)thiophenol (100.0g/403.2mmol) and 2-methoxyethyl ether L) were added and the solution was cooled to 0 C.
Sodium hydride (9.68g/383.2mmol) was added slowly, and the mixture was allowed to warm to room temperature 2,2-Dibutylpropylene sulfate (110.89g/443.6mmol) was added, and the mixture was stirred for 64 h. The reaction mixture was concentrated by rotavap and dissolved in H 2 0. The aqueous solution was washed with ethyl ether, and cone. H 2 S0 4 was added. The aqueous solution was heated to reflux for 30 min, cooled to room temperature, and extracted with ethyl ether. The ether solution was dried (MgSO 4 filtered, and concentrated in vacuo to give an amber oil (143.94g/85% yield). 1 H NMR and MS H) 419] confirm the desired structure.
Step
O
Bu S BBu OMe
F
C
25
H
33 0 2 FS fw=416.59 A 2-liter, 4-neck, round-bottom flask was equipped with N 2 gas adaptor, and mechanical stirrer. .The system was purged with N 2 The corresponding .alcohol (143.94 g/343.
8 mmol) and CH 2 C12 (1.0 L) were added and cooled to 0 C. Pyridinium chlorochromate (140.53g/651.6mmol) was added. After 6 CH 2 C12 was WO 98/40375 PCT/US98/03792 added. After 20 min, the mixture was filtered through silica gel, washing with CH 2 C1 2 The filtrate was concentrated in vacuo to give a dark yellow-red oil (110.6g, 77% yield). 1 H NMR and MS H) 417] confirm the desired structure.
WO 98/40375 PCT/US98/03792 Step 6 0 Bu OMe
F
C
25
H
33 0 4 FS fw=448.59 A 2-liter, 4-neck, round-bottom flask was equipped with N 2 gas adaptor and mechanical stirrer. The system was purged with N 2 The corresponding sulfide (110.6g/265.5mmol) and CH 2 C12 (1.0 L) were added. The solution was cooled to 0 C, and 3-chloroperbenzoic acid (158.21g/531.7mmol) was added portionwise. After min, the reaction mixture was allowed to warm to room temperature After 3.5 h, the reaction mixture was cooled to 0 C and filtered through a fine fritted funnel. The filtrate was washed with 10% aqueous
K
2
CO
3 An emulsion formed which was extracted with ethyl ether. The organic layers were combined, dried (MgS0 4 filtered, and concentrated in vacuo to give the product (93.2g, 78% yield). 1H NMR confirmed the desired structure.
WO 98/40375 PCT/US98/03792 Step 7 Bu /Su OMe
C
25
H
33 0 4 FS fw=448.59 A 2-liter, 4-neck, round-bottom flask was equipped with N 2 gas adaptor, mechanical stirrer, and a powder addition funnel. The system was purged with N 2 The corresponding aldehyde (93.2g/208mmol) and THF (1.0 L) were added, and the mixture was cooled to 0 C.
Potassium tert-butoxide (23.35g/208.lmmol) was added via addition funnel. After lh, 10% aq/ HC1 (1.0 L) was added. After 1 h, the mixture was extracted three times with ethyl ether, dried (MgS0 4 filtered, and concentrated in vacuo. The crude product was purified by recrystallized from 80/20 hexane/ethyl acetate to give a white solid (32.18g). The mother liquor was concentrated in vacuo and recrystallized from 95/5 toluene/ethyl acetate to give a white solid (33.60g, combined yield: 1 H NMR confirmed the desired product.
WO 98/40375 PCT/US98/03792 Step 8 o S 'w oOM/
C
27
H
39 0 4 NS fw=473.67 A Fisher porter bottle was fitted with N 2 line and magnetic stirrer. The system was purged with N 2 The corresponding fluoro-compound (28.lg/62.6mmol) was added, and the vessel was sealed and cooled to -78 C.
Dimethylamine (17.lg/379mmol) was condensed via a C0 2 /acetone bath and added to the reaction vessel. The mixture was allowed to warm to room temperature and was heated to 60 C. After 20 h, the reaction mixture was allowed to cool and was dissolved in ethyl ether. The ether solution was washed with H 2 0, saturated aqueous NaC1, dried over MgSO 4 filtered, and concentrated in vacuo to give a white solid (28.5g/96% yield). 1 H NMR confirmed the desired structure.
WO 98/40375 PCT/US98/03792 Step 9 o S OH
OH
C
26
H
37 0 4 NS fw=459.64 A 250-mL, 3-neck, round-bottom flask was equipped with N 2 gas adaptor and magnetic stirrer. The system was purged with N 2 The corresponding methoxy-compound (6.62g/14.0mmol) and CHC13 (150 mL) were added. The reaction mixture was cooled to -78 C, and boron tribromide (10.50g/41.9mmol) was added. The mixture was allowed to warm to room temperature After 4 h, the reaction mixture was cooled to 0 C and was quenched with 10% K 2 C0 3 (100 mL). After 10 min, the layers were separated, and the aqueous layer was extracted two times with ethyl ether. The CHC13 and ether extracts were combined, washed with saturated aqueous NaC1, dried over MgSO 4 filtered, and concentrated in vacuo to give the product (6.27g/98% yield). 1 H NMR confirmed the desired structure.
WO 98/40375 PCT/US98/03792 Step
S
Bu Bu
SOH
In a 250 ml single neck round bottom flask with stir bar place 2- diethylamineoethyl chloride hydochloride (fw 172.10g/mole) Aldrich D8, 720-1 (2.4 millimoles, 4.12g), 34 ml dry ether and 34 ml of 1N KOH (aqueous). Stir 15 minutes and then separate by ether extraction and dry over anhydrous potassium carbonate.
In a separate 2-necked 250 ml round bottom flask with stir bar add sodium hydride (60% dispersion in mineral oil, 100 mg, (2.6 mmol) and 34 ml of DMF. Cool to ice temperature. Next add phenol product (previous step) 1.1 g (2.4 mmol in 5 ml DMF and the ether solution prepared above. Heat to 40C for 3 days. The product which contained no starting material by TLC was diluted with ether and extracted with 1 portion of NaOH, followed by water and then brine. The ether layer was dried over Magnesium sulfate and isolated by removing ether by rotary evaporation (1.3 gms). The product may be further purified by chromatography (silica 99% ethyl acetate/l% NH40H at Sml/min..).
Isolated yield: 0.78 g (mass spec and H1 NMR) Step 11 WO 98/40375 PCT/US98/03792 (1 Bu W^
SOH
The product from step 10 (0.57gms, 1.02 millimole fw 558.83 g/mole) and iodoethane (1.6 gms (10.02 mmol)was place in 5 ml acetonitrile in a Fischer-Porter bottle and heated to 45 C for 3 days. The solution was evaporated to dryness and redissolved in 5 mls of chloroform. Next ether was added to the chloroform solution and the resulting mixture was chilled. The desired product is isolated as a precipitate 0.7272 gms. Mass spec M-I 587.9, 'H NMR) BIOLOGICAL ASSAYS The utility of the compounds of the present invention is shown by the following assays. These assays are performed in vitro and in animal models essentially using a procedure recognized to show the utility of the present invention.
In Vitro Assay of compounds that inhibit IBAT-mediated uptake of r"C1-Taurocholate (TC) in H14 Cells.
Baby hamster kidney cells (BHK) transfected with the cDNA of human IBAT (H14 cells) are seeded at 60,000 cells/well in 96 well Top-Count tissue culture plates for assays run within in 24 hours of seeding, 30,000 WO 98/40375 PCT/US98/03792 cells/well for assays run within 48 hours, and 10,000 cells/well for assays run within 72 hours.
On the day of assay, the cell monolayer is gently washed once with 100 ml assay buffer (Dulbecco's Modified Eagle's medium with 4.5 g/L glucose 0.2% 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 concentration of 3 mM ["C]-taurocholate). The cell culture plates are incubated 2 hours at 37° C prior to gently washing each well twice with 100 ml 4° C Dulbecco's phosphate-buffered saline (PBS) containing 0.2% (FAF)BSA. The wells are then gently washed once with 100 ml 4° C PBS without (FAF)BSA. To each 200 ml of liquid scintillation counting fluid is added, the plates are heat sealed and shaken for 30 minutes at room temperature prior to measuring the amount of radioactivity in each well on a Packard Top-Count instrument.
-9 3 WO 98/40375 PCT/US98/03792 In Vitro Assay of compounds that inhibit uptake of (4CC1-Alanine The alanine uptake assay is performed in an identical fashion to the taurocholate assay, with the exception that labeled alanine is substituted for the labeled taurocholate.
In vivo Assay of compounds that inhibit Rat Ileal uptake of r"Cl-Taurocholate into Bile (See"Metabolism of 3a,7b-dihydroxy-7a-methyl-5bcholanoic acid and 3a,7b-dihydroxy-7a-methyl-5bcholanoic acid in hamsters" in Biochimica et Biophysica Acta 833 (1985) 196-202 by Une et al.) Male wistar rats (200-300 g) are anesthetized with inactin @100 mg/kg. Bile ducts are cannulated with a length of PE10 tubing. The small intestine is exposed and laid out on a gauze pad. A canulae (1/8" luer lock, tapered female adapter) is inserted at 12 cm from the junction of the small intestine and the cecum.
A slit is cut at 4 cm from this same junction (utilizing a 8 cm length of ileum). 20 ml of warm Dulbecco's phosphate buffered saline, pH 6.5 (PBS) is used to flush out the intestine segment. The distal opening is cannulated with a 20 cm length of silicone tubing (0.02" I.D. x 0.037" The proximal cannulae is hooked up to a peristaltic pump and the intestine is washed for 20 min with warm PBS at 0.25 ml/min. Temperature of the gut segment is monitored continuously. At the start of the experiment, 2.0 ml of control sample (["C]-taurocholate 0.05 mi/ml with mM cold taurocholate) is loaded into the gut segment with a 3 ml syringe and.bile sample collection is begun. Control sample is infused at a rate of 0.25 ml/min for 21 min. Bile samples fractions are collected every 3 minute for the first 27 minutes of the procedure. After the 21 min of sample infusion, the ileal loop is washed out with 20 ml of warm PBS (using a 30 ml syringe), and then the loop is washed out for 21 min with warm PBS at 0.25 ml/min. A second 'q49 WO 98/40375 PCT/US98/03792 perfusion is initiated as described above but this with test compound being administered as well (21 min administration followed by 21 min of wash out) and bile sampled every 3 min for the first 27 min. If necessary, a third perfusion is performed as above that typically contains the control sample.
Measurement of Hepatic Cholesterol Concentration (HEPATIC CHOL) Liver tissue was weighed and homogenized in chloroform:m'thanol After homogenization and centrifugation the supernatant was separated and dried under nitrogen. The residue was dissolved in isopropanol and the cholesterol content was measured enzymatically, using a combination of cholesterol oxidase and peroxidase, as described by Allain, C. A., et al. (1974) Clin. Chem. 20, 470.
Measurement of Hepatic HMG CoA-Reductase Activity (HMG
COA)
Hepatic microsomes were prepared by homogenizing liver samples in a phosphate/sucrose buffer, followed by centrifugal separation. The final pelleted material was resuspended in buffer and an aliquot was assayed for HMG CoA reductase activity by incubating for minutes at 37° C in the presence of "C-HMG-CoA (Dupont- NEN). The reaction was stopped by adding 6N HC1 followed by centrifugation. An aliquot of the supernatant was separated, by thin-layer chromatography, and the spot corresponding to the enzyme product was scraped off the plate, extracted and radioactivity was determined by scintillation counting.
(Reference: Akerlund, J. and Bjorkhem, I. (1990) J.
Lipid Res. 31, 2159).
Determination of Serum Cholesterol (SER.CHOL, HDL-CHOL, TGI and VLDL LDL Total serum cholesterol (SER.CHOL) was measured enzymatically using a commercial kit from Wako Fine WO 98/40375 PCT/US98/03792 Chemicals (Richmond, VA); Cholesterol C11, Catalog No.
276-64909. HDL cholesterol (HDL-CHOL) was assayed using this same kit after precipitation of VLDL and LDL with Sigma Chemical Co. HDL Cholesterol reagent, Catalog No. 352-3 (dextran sulfate method). Total serum triglycerides (blanked) (TGI) were assayed enzymatically with Sigma Chemical Co. GPO-Trinder, Catalog No. 337-B. VLDL and LDL (VLDL LDL) cholesterol concentrations were calculated as the difference between total and HDL cholesterol.
Measurement of Hepatic Cholesterol 7-a-Hydroxylase Activity (7a-OHase) Hepatic microsomes were prepared by homogenizing liver samples in a phosphate/sucrose buffer, followed by centrifugal separation. The final pelleted material was resuspended in buffer and an aliquot was assayed for cholesterol 7-a-hydroxylase activity by incubating for 5 minutes at 370 C in the presence of NADPH.
Following extraction into petroleum ether, the organic solvent was evaporated and the residue was dissolved in acetonitrile/ methanol. The enzymatic product was separated by injecting an aliquot of the extract onto a reversed phase HPLC column and quantitating the eluted material using UV detection at 240nm.
(Reference: Horton, J. et al. (1994) J. Clin.
Invest. 93, 2084).
Measurement of Fecal Bile Acid Concentration
(FBA)
Total fecal output from individually housed hamsters was collected for 24 or 48 hours, dried under a stream of nitrogen, pulverized and weighed.
Approximately 0.1 gram was weighed out and extracted into an organic solvent (butanol/water). Following separation and drying, the residue was dissolved in methanol and the amount of bile acid present was measured enzymatically using the 3a-hydroxysteroid steroid dehydrogenase reaction with bile acids to reduce NAD. (Reference: Mashige, et al. (1981) WO 98/40375 PCT/US98/03792 Clin. Chem. 27, 1352).
*'Hltaurocholate Uptake in Rabbit Brush Border Membrane Vesicles (BBMV) Rabbit Ileal brush border membranes were prepared from frozen ileal mucosa by the calcium precipitation method describe by Malathi et al. (Reference: (1979) Biochimica Biophysica Acta, 554, 259). The method for measuring taurocholate was essentially as described by Kramer et al. (Reference: (1992) Biochimica Biophysica Acta, 1111, 93) except the assay volume was 200 pl instead of 100 il. Briefly, at room temperature a 190 pl solution containing 2pM ('H]-taurocholate(0.75 pCi), 20 mM tris, 100 mM NaCl, 100 mM mannitol pH 7.4 was incubated for 5 sec with 10 pl of brush border membrane vesicles (60-120 pg protein). The incubation was initiated by the addition of the BBMV while vortexing and the reaction was stopped by the addition of 5 ml of ice cold buffer (20 mM Hepes-tris, 150 mM KC1) followed immediately by filtration through a nylon filter (0.2 pm pore) and an additional 5 ml wash with stop buffer.
Acyl-CoA;cholesterol Acyl Transferase (ACAT) Hamster liver and rat intestinal microsomes were prepared from tissue as described previously (Reference: (1980) J. Biol. Chem. 255, 9098) and used as a source of ACAT enzyme. The assay consisted of a ml incubation containing 24 pM Oleoyl-CoA (0.05 pCi) in a 50 mM sodium phosphate, 2 mM DTT ph 7.4 buffer containing 0.25 BSA and 200 pg of microsomal protein. The assay was initiated by the addition of oleoyl-CoA. The reaction went for 5 min at 370 C and was terminated by the addition of 8.0 ml of chloroform/ methanol To the extraction was added 125 pg of cholesterol oleate in chloroform methanol to'act as a carrier and the organic and aqueous phases of the extraction were separated by centrifugation after thorough vortexing. The chloroform phase was taken to WO 98/40375 PCT/US98/03792 dryness and then spotted on a silica gel 60 TLC plate and developed in hexane/ethyl ether The amount of cholesterol ester formed was determined by measuring the amount of radioactivity incorporated into the cholesterol oleate spot on the TLC plate with a Packard instaimager.
Data from each of the noted compounds in the assays described above is as set forth in TABLES 5, 6, 7, and 8 as follows: WO 98/40375 WO 9840375PCT/1JS98/03792 T LE COMPOUND IC50 In vitro Control ijM* Inhibition Inhibition Transport of TC in of TC of Alanine Rat Ileum @3 0.1mM Uptake @3 Uptake @3 100 uM 100 uM Benzothiaze 2 0 45.4 +-0.7 pine= 12 3 0 4a 3 34 40 0 72.9 t 5.4 @3 0.5 mM 4b 9 18 6 14b 18 14a 13 13 23 19a 0 19b 8a 41 mixture of 69 8a and 8b Mixture of 6 9a and 9b, 6a WO 98/40375 WO 9840375PCT/US98/03792 9a 5 0% 25 rnN 53.7 +-3.9 Mixture of 13 6a and Mixture of 0.8 14% 6d and 10a mM 21a 37 21c 52 21b 6c 2 58.5 68.8 1-5.7 at 0.4 mM 6d 0.6 77.7 16.1 nmM 30.2 0.9 0.15 mM 17 7 50 49.3 7 77.6 62.4 0.2 mM lob 15 68.6 0.1 4% 10 mM 26.0 +-3.3 26 2 31% 25 87.9 rm 27 5 7% @20 mM 28 8 31% 29 88 @50 mm 968@50 mM 3141 @50 mM 37 3 0% @5 mM 38 0.3 11% 8 5mM 20.6 +-5.7 49 @50 mM S040 WO 98/40375 WO 9840375PCTIUS98/03792 41. 2 0% 42 43 1.5 16% 48 2 22%
M
49 0.15 21% 200 21.2 +-2.7 inN 57 51 50 m 58 20@ 50 M 59 9 59 61 30 175 62 63 90O@6nM 64 100 @6mM *In vitro Taurocholate Cell Uptake Unless otherwise noted Comparative Example is Example No. 1 in WO 93/16055 301 WO 98/40375 WO 9840375PCT/US98/03792 Compound TC-uptake TC-uptake TC-uptake ACAT ACAT (H114 Ileal (BBNV) (liver) intestine cells) Loop EC(S0) IC(50) IC(50) COMP. 1 mM 74 mM 3 mM 20 mM 20 mM
EXAMPLE*
6d 0.6 mM 31 mM 1.5 mm 25 mM 20 mM 38 0.3 mM 12 mM 2 MM isMm N.D.
49 0.1 mM 12 mM N.D. 6 mM N.D.
0.1 mM 20 mM 0. 8nm 8mM 8 mM Comparative Example is Example No. 1 in WO 93/16055 TABLE 7 EFFICACY OF COMPOUND NO. 25 IN CHOLESTEROL-FED HAMSTERS 1PARAMETER CONTROL 4% CHOLES- 10.2% TYRAMINE CPD. NO. WEIGHT (en±SEM, *p<0.Q5, A-Student's t, B- Dunnett' s) day 1 117 114 117(5) day 14 127(3) 127(3) 132(4) LIVER WEIGHT 5.4(0.3) 4.9(0.4) 5.8(0.2) SER.CHOL(mg%) 43P7) l(2-4-)AA, 12.(2.A.
HDL-CHOL(mg%). 89(4) 76(3)*A,B 76(1)*A,B.
VLDL LDL 54(7) 42(3)*A 50(3) TGI(mg%) 203(32) 190(15) 175(11) HEPATIC CHOL(mg/g) 2.5(0.3) 1.9(0.1)*A,B 1.9(0.1)*A,B HM'G COA (pm/mg/mmn.) 15.8(7.6) 448.8 312.9(37.5)*A A, BB 7a-OHase (pm/mg/min.) 1235.3(25.1
T
WO 98/40375 PCTIUS98/03792 24 HR. FECAL Wt )357.2(28.3)* 291.O(6.O)*A FBA (nmM/24H/1O0g) 2.3(0.1) A, B 2.4(0.04) 6.2(0.8) 2. 7(0. 1) B 11.9(0.5)*A,B 12. 3(1. 5) *A,
B
WO 98/40375 WO 9840375PCT/US98/03792 TABLE 8 EFFICACY OF COMPOUND NO. 25 IN RLAT ALZET MINIPUMP
MODEL
PARAMETER CNRL2
P/A
WEIGHT (mean SEM, *p<0.
05 A-Student's t, B- Dunnett day 1 307 307 (3) day 8 330 310 (4)*A,B LIVER WEIGHT 15.5 (0.6)T 14.6 (0.4) SER.CHOL(nmg%) 85 84 (3) HEPATIC CHOL(mg/g) 21 (0.03) 2.0 (0.03) HM4G COA pm/mg/min 75.1 318.0 (40.7)*A,B 7a-OHase (pmlrngrfif) 281.9 (13.9) 535.2 (35.7)*A,B 24 HR. FECAL WT 5.8 5.7 (0.4) FBA (mM/24H/lO0g) 17.9 39.1 Additional taurocholate uptake tests were conducted in the following compounds listed in Table 9.
WO 98/40375 PCTIUS98/03792 TASLE 9 Biological Assay Data for Some Compounds of the Present Invention Compound Human TC Alanine Uptake Number IC 50 1Percent Inhibition I@
AIM
101 0 102 0.083 103 13 0.25 104 0.0056 105 106 0.8 107 14.0 0.063 108 0.3 109 2.0 0.063 110 0.09 111 112 3.0 113 0.1 114 0.19 115 8.0 116 0.3 117 12.0 0.625 118 0.4 119 1.3 120 121 0.068 122 1.07 123 1.67 124 14.0@6.25 125 18.0 126 1.25 127 0.55 128 0.7 129 0.035 131 1.28 132 5.4 0.063 133 16.0 134 0.3 135 22.0 136 -605 TO. 9001 i?000*0 900t __9t 96Z el 996Z: _9*0 t6Z tso~o06Z r* 68Z GZ*9 @0,01 ___610'0 18__ VO 6LZ 11'0 LLZ EV0 9LZ L0O ZLZ zl0o OLZ o'o 69Z 6Z00O 89Z L00O L9Z 99Z 0Z 50*0
U~T
O'sz<6Et OT SET
LET
Z6LEOI86Sfl/JJ LOJ/6 SLEOP186 OM WO 98/40375 PCT/US98/03792 1007 0.001 1008 0.001 1009 0.001 1010 0.001 1011 0.001 1012 0.0015 1013 0.002 1014 0.002 1015 0.002 1016 0.002 1017 0.002 1018 0.002 1019 0.002 1020 0.002 1021 0.002 1022 0.002 1023 0.002 1024 0.002 1025 0.002 1026 0.002 1027 0.002 1028 .0.002 1029 0.002 1030 0.002 1031 0.002 1032 0.002 1033 0.002 1034 0.002 1035 0.002 1036 0.002 1037 0.0022 1038 0.0025 1039 0.0026 1040 0.003 1041 0.003 1042- 0.003- 1043 0.003 1044 0.003 1045 0.003 1046 0.003 1047 0.003 -048 0.003 2>01 WO 98/40375 PCT/US98/03792 1049 0.003 1050 0.003 1051 0.003 1052 0.003 1053 0.003 1054 0.003 1055 0.003 1056 0.003 1057 0.003 1058 0.003 1059 0.003 1060 0.0036 1061 0.004 1062 0.004 1063 0.004 1064 0.004 1065 0.004 1066 0.004 1067 0.004 1068 1069 0.004 1070 0.004 1071 0.004 1072 0.004 1073 0.004 1074 0.004 1075 0.0043 1076 0.0045 1077 0.0045 1078 0.0045 1079 0.005 1080 0.005 1081 0.005 1082 0.005 1083 0.005 1084 1085 0.005 1086 0.005 1087 0.005 1088 0.0055 1089 0.0057 1090 1 0.006 3o B WO 98/40375 PCT/US98/03792 1091 0.006 1092 0.006 1093 0.006 1094 0.006 1095 0.006 1096 0.006 1097 0.006 1098 0.006 1099 0.0063 1100 0.0068 1101 1102 0.007 1103 0.007 1104 0.007 1105 0.007 1106 0.0073 1107 0.0075 1108 0.0075 1109 0.008 1110 0.008 1111 0.008 1112 0.008 1113 0.009 1114 0.009 1115 0.0098 1116 0.0093 1117 0.01 1118 0.01 1119 0.01 1120 0.01 1121 0.01 1122 0.011 1123 0.011 1124 0.011 1125 0.012 1126 0-013 1127 0.013 1128 0.017 1129 0.018 1130 0.018 1131 0.02 1132 0.02 WO 98/40375 PCT/US98/03792 1133 0.02 1134 1135 0.021 1136 0.021 1137 0.021 1138 0.022 1139 0.022 1140 0.023 1141 0.023 1142 0.024 1143 0.027 1144 0.028 1145 0.029 1146 0.029 1147 0.029 1148 0.03 1149 0.03 1150 0.03 1151 0.031 1152 0.036 1153 0.037 1154 0.037 1155 0.039 1156 0.039 1157 1158 0.06 1159 0.06 1160 0.062 1161 0.063 1162 0.063 1163 1164 1165 0.11 1166 0.11 _116 0.12 1168 1169 1170 0.13 1171 0.14 1172 0.14 1173 0.15 1174 0.15 -3 t0 WO 98/40375 WO 9840375PCTIUS98/03792 1175 0.17 1176 0.18 1177 1178 0.19 1179 0.19 1180__ 0.32_ 11 10.2_ 0.35 1183 0.35 0.55 0.65 1192 1.03_ 1193 1194 .65_ 1189 1196 .05_ 1197 2. 1198 2.56_ 1199 1200 6.1 1201 8.3 1202 40.0 1203 0 0.063 1204 0.05 1205 0.034 1206 0.035 1207 0.068 1208 0.042 1209 0 0.063 1210 01~ 1211 0.28 1212 0.39 1213 1.7 1214 0.75 1215 0.19 1216 0.39 WO 98/40375 PCTIUS98/03792 1217 1218 0.19 1219 1220 0.2 1221 0.041 1222 0.065 1223 1224 0.33 1225 0.12 1226 0.046 1227 1228 0.038 1229 0.049 1230 0.062 1231 0.075 1232 1233 1234 0.067 1235 0.045 1236 0.05 1237 0.07 1238 1239 0.035 1240 0.016 1241 0.047 1242 0.029 1243 0.63 1244 0.062 1245A 1246 0.018 1247 0.017 1248 0.33 1249 10.2 1250 0.013 1251 0.62 1252 29. 1253 0.3 1254 0.85 1255 0.69 1256 0.011 1257 0.1 1 1258 0.12 p WO 98/40375 PCTIUS98103792 1259 1260 0.012 1261 0.019 1262 1263 0.079 1264 0.21 1265 0.24 1266 0.2 1267 0.2 9 1268 0.035 1269 0.0_ 1270 0.02- 1271 0.011 1272 0.047 1273 0.029 1274 1275 1276 0.029 1277 0.018 1278 0.017 1279 0.028 1280 1281 0.055 1282 0.17 1283 0.17 1284 0.011 1285 0.027 1286 0.068 1287 0.071 1288 0.013 1289 0.026 1290 0.017 1291 0.013 1292 0.025 1293 0.019 1294 0:-1 1295 0.014 1296 0.063 1297 0.029 1298 0.018 1299 0.012 1300 1.0 WO 98/40375 WO 9840375PCTIUS98/03792 I1301 0.15 1302 1.4 1303 0.26 1304 0.25 1305 0.25 1306 1.2 1307 3.1 1308 0.04 1309 0.24 1310 1.16 1311 3.27 1312 1313 6.1 1314 0.26 1315 1.67 1316 3.9 1317 21.0 1319 11.0 Q 0.25 1321 11.10@5.0 1322 3.0 0.0063 1323 4.0 0.0063 1324 43.0 0.0008 1325 1.0 @0.0063 1326 36.0 0.0008 1327 3.0 0.0063 1328 68.0 0.0063 1329 2.0 0.0063 1330 9.0 0.0063 1331 57.0 0.0008 1332 43.0 0.0008 1333 0 0.0063 1334 50.0 0.0008 1335 38.00@ 0.0008 1336 45.0 0 0.0008 1337 0 0.0063 -1338- 0-0-0,25 1339 0.063 1340 9.0 0 0.063 1341 1.0 0.063 1342 1.0 0.063 1345 13.0 0.25 1347 0.0036 3t4 WO 98/40375 PCTIUS98/03792 1351 0.44 1352 0.10 1353 0.0015 1354 0.006 1355 0.0015 1356 0.22 1357 0.023 1358 0.008 1359 1360 0.003 1361 0.004 1362 0.019 1363 0.008 1364 0.006 1365 0.008 1366 0.015 1367 0.002 1368 0.005 1369 0.005 1370 0.002 1371 0.004 1372 1373 0.008 1374 0.007 1449 0.052 1450 0.039 E 1451 0.014 315 WO 98/40375 PCT/US98/03792 The examples herein can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
Novel compositions of the invention are further illustrated in attached Exhibits A and B.
The invention being thus described, it is apparent that the same can be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the present invention, and all such modifications and equivalents as would be obvious to one skilled in the art are intended to be included within the scope of the following claims.
WO 98/40375 PCT/US98/03792 Table C2: Alternative compounds #2 (Families F101-F123) (RI)q R 2 Family Cpd# R1=R2 R5 (R) Flol CHOSEN FROM TABLE D* F102 CHOSEN FROM TABLE D F103 CHOSEN FROM TABLE D F104 CHOSEN FROM TABLE D F105 CHOSEN
FROM
TABLE D F106 CHOSEN FROM TABLE D F107 CHOSEN FROM TABLE D F108 CHOSEN FROM TABLE D F109 CHOSEN FROM TABLE D Filo CHOSEN
FROM
TABLE D Fill CHOSEN FROM TABLE D F112 CHOSEN FROM TABLE D Ph- CHOSEN FROM TABLE D p-F-Ph- CHOSEN FROM TABLE D r-F-Ph- CHOSEN FROM TABLE D p-CH30-Ph- CHOSEN
FROM
TABLE D Mn-CH30-Ph- CHOSEN
FROM
TABLE D p-(CH 3 2 N-Ph- CHOSEN
FROM
TABLE D m-(CH3)2N-Ph CHOSEN FROM TABLE D p- (CH 3 -Ph- CHOSEN
FROM
TABLE D r-(CH3 3 CHOSEN
FROM
TABLE D P-(CH) 3 -N*-CH 2 CH2- CHOSEN
FROM
(OCH2CH2) 2 -O-Ph- TABLE
D
m-(CH3) 3-N+-CH2CH-i -CHOSEN-
FROM
(OCH
2
CH
2 2 -O-Ph- TABLE
D
CHOSEN FROM dimethylpiperazine)-(N')- -TABLE D CH2- (OCHZCH2) 2 -O-Ph- Exhibit A WO 98/40375 WO 9840375PCT/US98/03792 F113 F114 F115 F116 F118 F119 F120 F121 F123 CHOSEN FROM TABLE
D
CHOSEN
FROM
TABLE
D
CHOSEN
FROM
TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN
FROM
TABLE
D
CHOSEN
FROM
TABLE D CHOSEN
FROM
TABLE D CHOSEN
FROM
TABLE D CHOSEN FROM TABLE D CHOSEN
FROM
TABLE
D
m-(N,Ndimethylpiperazile) CH2- (OCH2CH2) 2 -O-Phr-F-Ph- P-CH3O- 3, 4,dioxy-flethylefle-Phr-F-Php- F- Phm-CH3Op-F-Ph- 4-pyridifle N-methyl- 4-pyridiliUm 3-py: idine N-rethyl-3-pyridinium 2-pyridifle p-CH.
3
O
2 C-Ph- CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE
D
CHOSEN FROM TABLE D CHOSEN FROM TABLE D CHOSEN FROM TABLE D as RI Et and Similar families can be generated where Rl<>R 2 such R- n-Bu, but (Rx)q is chosen from table Cl.
WO 98/40375 WO 9840375PCT/US98/03792 0 Et
'ON
NCCH
3 2 0
F
Buu 'O ON q NC CH 3 2 NC 3 3 0
ON/
N Et MeI F Bu
MCM
3 Exhibit B WO 98/40375 WO 9840375PCT/US98/03792 2) o WO 98/40375 PCT/US98/03792 O u H2N as Ba Me
R
t HO MeO OH O'0 H Or O
CHCH
O a z Et j 1z' 41 Ho 39 a Bu 'OH 8 u Me i I H 3,22 heileal b-i1'- acid tre-ns--or- ird-ibitors Lsed L- the tpresencz izivent-ion in-uc'e, !OTr e-Xant 1 L cm:u Alocendi-x A.
A-1 Thec compounds of the formula (1) R S.1
RR
-ncrein R 1 and R 2 are the sat-ne or d etand each is ootionaiJly v siue C', alkyL C3- 6 cycloa1-kyi, or R 1 ndR togetr 11ich -,he cabnatom to. Which are Zau.cted form ant oz,ona~lY suostir.;ted C 3 6 spiro-c-.cvz1*ak-, group: R' ;s a C 6 14 airyl. or a C3- 13 heteroau-vl zroup cach option~ally subsitutetd -I th o,-e, to egtS'.bszituenrs5 wiCh a1e tesint or c~eetazd each scie-e trwP ha:,ogen-, hydroxy, aI'tro, Ph-enYI-C 1-6 aikox-y, C 1 -6 alkoxy, optionally Subs:itute1d C 1 6 alkyl, S(O)nR 8 S 0 2
N-R
8 R0 9 CO-,Rg, c(c:-H cH 2 0) nR 3 0S02,O O(C:-T-7)pSO 3
R
8 O(CH,)pN-R 9 RIO anid O(CH)p'>JR 9 1 0
R
1 I whren 8 to R 11
I
arc the s=me or di~Ercnt and are independe-ntly selcced fr-om hvdro-.Cn or opciorully su-bstituted C 1 -6 alk-yl and wherein p is an Integer :romn I and n is 3rn integer tra-m 0-3; R~a, R~b, R Sc, and R5d each represent atorrs or groups which aie the sameC or diFferent and each is hydrogen. halogecn. cyano, 170-actrylide, OR 8 oprionally subszt-Lued Cj-, alkyl, COR 8
CH(OI{)R
8 S(O),10 8
SO
2
NP
8
R
9
P(OXORS)
2
OCOR
8 OCF, OCIN, SCLN, LNEIN, C.HiOR 8 C-70, (CH 2 ))pCN. CONRC-R 10
(C-
2
),,CO
2
R
8 (CH-jNpR 9
R
1 0 CO-7R 8 NHCOCF-,:, \TFTSO-R 8 OCH-00R 8
OCH--R
8 O(C 'a1CH- 2 O)nR 8
OSO-,R
8
O(CH))PSO
3
R
8 O(CH-))pNrR 9 -,lO and
O(CH
2 )pYN-R 9
R
1 0
R
1 I I wherein R 8 to RI 1, n, and p arc as hcreinbefore de6.ncd; or R~a and R~b, R~b and RSc, or RSc and R~d togethcer widi ihe ring to which they are a-tached formr a cyclic group -O(CR 9 R'%mO- wherein R 9 and RIO are as herei;nbe-Fore defined and mn is I or 2; AMENDED)
SHIEET
6 ad R' cr he an or 3:irv-- "r sbUu~ alkYl- C3- 6 c:;caikY1, or R 0 adR'tgterwt neca-on atom-' to whjch 2ar-lchedl form an ootionally subsiwt Id
C
6 3 ru: X is C=0, C=S, or C=N-fi% whercjn RS'Is as hereinbefore dc. ned: and I is an integer from 0-2; and salts, solvates or a phy~iologically 6iinctionaJ derivatives thereof.
A-2 A compound of formula ,vwher-cn R I is methyl or ethyl, pR 2 is1 methyl, c.-hy'l or iby;
R
4 is pheInyl; R: a and R~d aLc re gI and RSc. arc the- s.,me or difecrent an-d are each hy droqcn, ,rechyl, me::hoxy.
hydroxy, tiTooehlor halo; R6and R 7 are the same or diFFerent and are each hydro~cn, metvhyl, chy or i-butyl; X is CH-) or C=O; I is 2; or a salt, solvate, or physiologic-aly functional derivative threarct.
A-3 A compound of formula seed rom the group consisting of (±)-3-n-Buyl-3-ethyl-2,3-dihydro-5phenyl- I,5-b'cnzot&hazcpin-4-one; -n-Butyl.J -ethy(-2,3-dihydro-S-phenyl- I, -berzoz Liaze:)n n-4one-l,1-dioxidc; (±)-J-n-Buyl-3--cthyl-2,3 .4,5-tetrahydroc-5-phenyl- I, -bea-zothiaze -ine,,; (--)-3-n-Butyl-3-ethyl-2,3,4,S-tetrahvdro-5-phenyl-1, 5-b-ertzoLichiepine-I, I-dioxide; -n-But-yl-2-isobutyl-3-c yl-23,45- -rahydro-5-pheny.. 1, 1 -dioxide; 3 3 -Dicthyl-2,3-dihydro-5.phciyl. I .5-benzotLhizepin-4.-once 3,J-Diethyl-2,J-ihydro-5-pheniyll ,S-be zotl~iz.-in-4--one 1,1-dioxide; -3.3'-Diethyl-2 .3,4 ,5-tetrahydro-S-phenyl-1I, -benzothiiazepine; 3 3 -Diethyl-2,3,4.5-tctrahydro-5phenyl-1I bcnzothiizepine- 1,1 -dioxide; SHEEt 32-11 be-,zothiazcvine- I, I1-dioxide; 3,3 3 D iethyl-2, 3,4,5 -ztrahydro-7, 9 -L-ncthoxy 5 -phcriYI -I 5-bcrzoti azc m. c-ij dioxi~de; r. vr-- eh x phenyl[-1I,5-bcnz-o&JaZ t-inc 1, 1-dioxide;, ity-,,,-er-vro8,rchx 'n-il 1, 5 -be othiazc .1.Ic-1 -dioxide: o-1-dioxide; ,,3-.Djcthyt.2,3.,S~erhdoSp~I I 5o'.ota~f-S-iaz 8-olde, c--dioxide 37'~r-o--u-Dithl- 2 .,45dr yo ,3,7,5-ethoxydro-e8- l,5.onzottacrLfl-SO bcrzothiazcpIfc- 1. 1 -dioxide; 7-bromno- ,3 -Diethyl-2,3 ,4,5-tet.-ahydro-8-ncthoxy-5-phe-yl 1,5-.zo t'aZCpIfle 1, 1 -ioxide; (-3-nBtI3ChI2 .4 ~crhdoSPelII,~ tIZzcpn7Sdo I, dioxide;, ity-.345 ~ahyr--'in l1,5-benzot.h-i2zepin/ -diol-1l, -ioxide:, uy---ty ,,,5t~aido8m hx--hni-,5-bernzothiazepi1e-
I-
monoxiade; 3',3-Diethyl-2,3 ,4,S-teL-hydro-8-mc noxy-5-pflenyI-l .5 -benzLothiaZeptnC- 1-monoxide; (=-)-3-n-ButA.-3-ethy1-2,J.
4 Stetr~.hyd(ro-5-phenl- 1,5-benzoflhiazC-i--ll1monoxide; 3,3-Diethyl-2,J ,4',5-tctrahydro-5-pIhemyI 1,5-benZOEth2aZ-e-if- 8 -11-monoxide; (z----uy-,thl23dhd mthx--hnl1, 5-benotiLfl)i0A oe- (±:)-3-n-ButyI-3 -ethyl-2,3 Stetranydro-8-mcthoxy-5-ph--iyl-l ,S-bc-Zoa~Lr 2-C)L.
-n-Butyl-3-cthyi-2.J ,4,5-ttabydro-8-mctfoxy- 5-phenyl- 1, S-ben.!otE1zepiflc- 1, 1-dioxide; -n-B uryI-3 -ethyl -2,J 5-tetrzhydro-8 hydroxy- phenyl- 11, -benzo ,hdlazpir.c- 1,1-dioxide; AMENDED
SHEET
32 4-one; 7 -Bromo-3-n-butyl-3-ethyl.2-,2,4, 5-tc:rahydro- -c-enoy-,-bcnewiI.-c'n olzcpae 1n,1, -dioxide (*)-3-nbromol-3--utl-23,4ect2hIvr--ahos-f--.ey ,S1-oen-othj',-p~n--.
ol1,1 -dioxide; -n-bu tyl-3 -thyl-2, 3, 4,5- tcc rahydro 8-dime thoxv- 5-p henyi- I, 5 -bezo Chi aze ofne 1, 1 -dioxide; ()3-n-butyl-3 -ethvI-2,3,4,5 terrahy~dro-5pheny- 1, 5-beazot iazcptie-7,8-diol 1, 1 dicxide; romo-3 -n-buty-3 -chvl-2,3 -dihydro-S5-phtny- 1,5.-benzotriazpin A4oe 1I1-dioxide; and dioxide.
A-4 A compound of fo rmu!a sci-cte.d lorn: -)-3-n-butyI-~y-,,45-crhdr--ehxv-3- -nl 1,5-boe orh'azpin-8ol 1. 1-dioxide; and 1, 1-dioxide or a salt, solvatc, or physiolocalv -iincrW denvauive ihcreof.
AMENDED SHEET 32b .4 5 ,I -n-Butvl-2- sobury1-3 -cthyl-23,4,5 cc:-ahydro- -ph cnvl- 1. 5 -be cnot~'jaztpnc- 1,1 dioxide-, 3,3 -D I thy-2,3 -dihydro-5-phen-fy 5 -beracthiain-oe 3 ,3-Dierhvi-2,3 -dilhydro-5-phenyl- 1, 5-beazotliaz. :In-4-on-c 1, 1-dioxidc-; 3,3 -Dic:hyl-2.3, 4,5c.S-_e:hydro-S-phenyI- 1, 5-benzothi=. c pne: 3,3 -Die~hvl-2.,3.'4.5-t ctrahydro-5-phc.-yI-1I 5-ben~zoijaze-ie- 1.1-dioxide; 3 ,3-Dimeth.vl-2,3,4',S-cecrahiydro-5-phenvl- I,-ezcuzpre 3,3-Dim,-tiyI-2,3,4,5-,,-,rahydro-5-phenvyi- I .5-benzothiazepinc- i. I -dioxide..
)-3-n-Buryi-3 -ethyI-2,3,4,S-ce-rahydro-7,8-dimenthox-5--phcn,- i eac>zei-,dioxide; 3. 3-Diethyl-?,3,4.S-cet.rahydro-7,8-dmethon,-5-phcnyl- l 5baohizpr.-1, 1-dioxi;de; dioxide; 3,3 -Diethyl-2,3,4,5-c S-erahvdo-S-me,.ox-S -oheinyl- c- ,5b~oI.eInc- 1. 1 -dioxide: -n-Buryl-3 -ethyl-2,3.4, 5-Ece,,ahydro-5 -ph cryl- I, 5-beazoc'i-.ia.e:)in-8-ol- i, 1-dioxide;, -n-Buryl- 3-ethyl -2,3,4,5-tetrhydro-7-meci'oxy- 5- phery- 1, enzothiz' 'eoin-S -oI- dioxide; 3,3 -Diet hyl-2 .3 ,4,5-retrahydr-o-7-methox---ohcnyl-1,5-bc': ohiaze-pn-S-oi-1, [-dioxide: (--)-7-bromo-3-n-Buy-3--thyi-2,3,4,5-cetrahydr-8-nehox-5-p-icnyi- benzothiaze--.ine- 1, 1 -dioxide: 7-bromo-3,3 -DicthvI-2,3,4,S-ctrahydro-8-mneLhoxy-S-phewiy- I ,5-benzoc1 aze-cuen- 1, 1 dioxide; -n-Buryl-3 -ethyl-2,3,4,5-teu-a-hydro-5-phenyl- 1 ,5-berzothiaz:pin-7,8-diol- 1, 1 -dioxide; 3,3 -Diethyl-2-,3,4,5-tectrahydro-5-phenlyl- I ,S-benazothiazcpi-7,8-diol- 1, 1 -dioxide; -n-BLryI-3-ethyl-2,3 S-tecahydro-8-methoxy/-5-pheny- 1, 5-benzothiazepine- 1 monoxide; 3, 3-Diethyl-2,3,4,5-teahydro-8-methoxy-5-phcnyl- l, 5-b-_nzocthiazepinie- -monoxide; -)-3-n-Buryi-3--chy-23,4,5-tcrahydro-5-pheny-1,5-benzcthiazcpin-8-o-1I-monoxidc; 3,3 -Dicthyl-2,3 ,4,5-tcu-ahydro-5-phe-nyi- I, 5-bcnzothiazcpin-8-oI -monoxide; ('->-3-n-ButyI-3-ethyI-2,3-dihydro-8-methoxy-5-phenyI- I ,S-b.-azothiaepin-4-one;, (±>-3-n-Buty-3-ethyl-2,3 ,4,5-cctrahydro-8-mcthoxy-S-phenyl- 1 ,S-benzodhiaZeopine; AMENDED SHEET, _2'7 dioxide-, (±)-7-Brcrno-3-n-buryl.3-thy-2,3-dihvdro-8-mthoxf-5-pheflyi- I,-ezcuzpn4oe (-)7Boo3nbrl3chl2345tcyr--ehx--hnl beazothiaze~pinc 1,1-dioxide-; rm uyl3ch 2345t.,ay r--hn i-,5-benL--otiua-z-i-S-oI dioxide; dioxide; (_)3nb 5-erhdo78dr.!,x h-y-15-beazo-zia 2z epine C dioxide: (=:-)-7-nButyi-3-e hvtl-3,-ceyl2,rahydo--phyl- ,5-bero~hi' 'zcin .1 4_done -nuty-3-ehyI-2,4,5-ihydro--phoxy-,5-phenzti-5a)zp az-On dioxide: and -n-buty-3 -ethy 5 -etrahydro- 5-p.fyk- 1, 5-be aoihazc 7-oi 1.1 -dioxidt.
Particulaily preferred compounds include.: e thI~23,45.ttrahdro7-mthoy-5-h~f~f-I ,-benothazein--oI1,1 dioxide; aid Bri--ty t34,-crahydro-8-hydroxyf-5-p',icenyl-1I be.-zoch-tnazeine-l 1dioxide.
e% t ICtT 32,P 3 .3-Diethyi-2,3,4S-,,etrahydr-o- 1, 1 -dioxo-5-phenyI- I ,4-bc~th.:ziepin-8-vl aspaae.
(3 P, 5R) 3-B ury-3 ethylI-2,3,4, 5 -t ttadhydro- 7,8 5- phenyl 1, 4-benzoL '_zt::ine- 1, 1 -dioxide; (3 R, 5R)-3 -ButyI-3 -e~hy'-2,3,4,-ttahydro-7,8-me thox-5-?hc.-iy- 1,4-be.-zothi'azcpi'n-4 ol 1, 1-dioxide; Tas3'uy- rhd,-,8d-. oy :bc;l 1, ,4-benzoth~zzepinc- 1, 1-dio)6dc; -bury1-3 -thyI-2,3,4,5reahyrc-.78diD.-e:oxy-5phenyl. -beohavn 4-ol 1, 1-dio.xide; rorno-3 -bLuyI-3 -e'IyI-2,3,4.5-tc ahydr-o-8-mthoxy-5-phcnyl- ben-izothiazepine 1,1 -dioxide; (3 P, 5R)-7-Bromo-3 -butyl-3'-ethyl-2,3 5-tetr-ahydiro-8 -m.-thoxy-5-phenyI- 1,4benzothizpin-4--ol 1,1-d~ioxide; 5R)-3-Buryl-3-cthyl-2,3,4,5-rtexahydro-5-phcnyl-1I,4-benzothia-zepine-7,8-diol 1,1dioxi~de; (3 SR)-3-Buryl-3 -ethyl-2,3,t, 5-tetra-hydro-8-methoxy-5-phenyl-1I,4-ber.ZoLtiazeir-7-oi 1, 1 -dioxide; AMENDED SHEET J2~ -buryl-3 -ethyl-2,3,4, 5 -Ltahydr- -menoy- l,-PbcuothzIn.-8'oi 1,1 -iie, (+-)-Trpans-3 -butyl-3 -cthyl-2, ,14,S5-t *.mydro- 5-phecnyl- 1 ,4-b cnzot,.azcp ine-4, 8 -dial -buyl-3 hyl-2,3,4,5 -t -r2.hydro-8 -rnthoxy'-5-c1,yl I -bcazochdaz:pI'ne-7 carbaldehyde 1,1-dioxide: 7-yi)mcthoxy) ethanol S,S-dioxidce; Tas br ra.,do8-,yof-5-cnl 1, -berizthi'z inen-7carbaldehyde 1,.1 -dioxi'de; dioxide; )-butyl -3 -ethyl -2,3 ,4,5 -smyd.,o-5 -phenyl- 1, 4-beazohiaz p in- suiforuic acidbenzothiazcepinc (--)-Trans-3-buryI-3 -cthyl-2,3 ,4,5-tea-ahydro-8,9-dinethoxy-5-pheflyl-1I,4-benzot&hazepiLne- 1, 1 -diioxa'de; (3 R, 5R)-3 -butyl-3 -crthyl--5-(4-fluoropherlyl)- 2 ,J 5-ccerahydro-7, 8-dirnethoxy- 1,4beazo thiazo~in-4-ol 1,1-dioxide; -bry ehl ,,,-e-tyr-8-cho-5-enl1,4-benzothiazepine- 7 mnethanol S,S-dioxide; AMENDED SHEET 32D bc.-zothi2zzccne- I, 1-dioxid-e; beaizothiazcpinc 1,1 -dioxide; (3P.SR).3JbutyI-3-thyI-23,45tcj--ydro-s..phcyil, 1 ,-.zotiazpin-7,g-dyI diacetare- 1, 1 -dioxide; (8FR 1 OR)-8-Butyfl-8-cethyl-2,3,7,8,9, I O-h-iehvd~ro- 10- 1 4-d[cxono1(2. 1,4)bco-.zothiiazcpinc 6,6-dioxidde; (3P.SR)-3-out-yl-7,8-die-thoxv--,,,-erhyr-:''c- ,4l,-benzohiaet- L'e 1,1-dioxide; (+-)Trans3buyl-8eU.oxy3cthyl2,3,45-rhydro-s..oh:,y[i-1 4 -berL-othi azc.:ine- 1,1 dioxide; -bury[ -3 -ethyl -2,3,4,5 5-t trakwdro- 8 1soro 0oXY- 5 -ph enyl 4bceizozhiiazepi 1, 1 -dioxide hydrochior-de; (-}-Trans-3 -butyl-3 -ethyl-2,3 5-itrahydro-5-ohenyl i- I ,4-berzothiaze-in-8-carba6ehyde- 1, 1 dioxidc; 3,3.-Diethyl-2,3,4,5-etrhyro-7,8-dinethoxy-5-phenyl- I,4'-,bezoth-iazepine 1, -dioxide: 3 ,3-Diethyl-5 -Q-f!uorochenvl)-2 ,3,4,5-te,%-Ahydr--rnetchoxv-- I -be,-zothiaL;zepine 1,1dioxidc; 3,3-Diethyi-2,3 ,4,5-teo-ahydro-8-mehoxy-S-phcnyl-1 ,4'-b-crzothiaz-,p'n- 1,1 -dioxide; 3, 3-DiethyI-2,3,4T,S-tetrahydro-5-phcny[- 1,4-benzothiaz=in4, 8-dioll,1-dio.xde: (S)-3,3-Dihy-23,4.5-ehydro-4-hydroxy-7,..dinehoXy-5ph.-nyl 1,4benzod-iiazepine 1,1 -dioxide; (+->-Trans-3 -bu ryl -8-thoxy.3 -ethyl -2,3 5-tetrahydro-5 -phenyl- 1. 4-benzoti-i a~zein-4-oI- 1, 1 -dioxide;
)AI'AFNDEDSHE
33/4 (---Trns--buvt--e 1 v-2,3,4, C.I c-x-zz5-iazz:H-I (+-)-Trans-3..butyl-3 -ethylI2,J4, 5-t etrahydro S,9-crlic M Cy-5-chenyl- 1,4bcnzothiazepin-4-ol 1.1-dioxide; 3 3 R,5R>-3-butyl-3)-cthyl-2,3,4,5-terahydro-S-phcny- 1,4-bca--othiazpin-,7,8-r,,iol 1,1 dioxide; (+-)-Trans-3-butyl-e~y-2,3,4,-trhydro47stnrnc.oxy5-phcnyl. 1,4berizo&uazcpinc 1, 1 -ioxidc; (+-)-Trans -3 -butyl-3-e, hyl-5-phenvi.2,3,4,5 -tetrahyd ro. 7, -dlmetlhovy- 1 ,4-ezt~zr 4 yI acetc S,S-dioxidc; 3 ,3-Dicthyl-2,3,4,5-tectrahydro-5-phenv,,i-l I 4-bcaiotruaz,,l n-8-oI1 ,1-dioxidt-, 3,-it hyI-- ,'txf5oc,-'oeniotazcpi'n-8-oI 1, 1-dioxide; 3,3-Diburyi-2,3,4,5-teurahydr-o-5-pheny!-1,4-beaizothi azec-i-8-oI 1,1 -dioxide; (±-)-Trans-3 -Butyl-3 -ethy[-2,3,4,5-tetr-ahydr-o- 1, -dioxo-5-phenvl-1I,4-benzaothi azp--S-yI hydrogen sulfate; -Butyl-3-ethyi-2,3,4,5-teo-ahyd.ro- 1, 1-dioxo-5-phe- I ,4-b-,azo&iia-zepn-8-vI dihydroge-n phosphate; 2 ,3-Diethyl-2,3,4,5-te-tra.hydro- 1,1-dioxo-5-phcnyl- 1 .4-benzothiazcpin-9-yl hydrogen 3,3-Dicthyl-2,3,4,5-tet-rahydro-1, 1-dioxo-5-phenyl- 1 ,4-bea-zotiiaZepin-3-yIdihydrogen phosphate; (+-)-Trans 3-B uyI3 -thy 1 2,3 ,4,5 -t ccahyd ro-]1, I -dioxo-5-phe-nyl- 1,4ben~zothiazepin-8-y[ asparuttc; and A;NDED
SHEET
332 Tr?_s-3-ut-l-3 cc h I 2,3,,5-ttraydro8-meuh xv- -rh-ny benizodiazpne-7-m-hfloL S,S-dioxidc, ma 122-1230 C (JR. SR)-3-butyl-3 -ethyl-2,3,4, 5-tetrahydro-8-rncth oxY-7-rntr---hc-l.-1 4 beaizothiazcpine 1,1-dioxide 0.40 hydrate, trp 122-1230 C (+-)-Trans-3 -burl-3-ethyl-2,3, 4,S-tcuhydro-8 met hoxy- 71-(m.-thoX) phenyl- 1,4-bcnzohiazcptLen 1,1i-dioxide, mp 118-1190 C (-'-)-Tranis-7-bror-no-J -butyl-3-ct'hyl-2,3,4 5 -tetr-ahyd-ro-5 -pheryl- 1,4beazodlhiazepini-8-ol 1, 1 -dioxide 0.4Q hydrate, mp 137-1380 C )T &t--uy--eh l2345tt-ay r h .ll 1,bcazothizpine 1, 1 -dioxide. mp 169-1 700 C (3R,5R>-3 -butyl-3-ethyl-2,3 ,4,5-tetrahydro-5-pheri- I ,4-benzothiazepin-7,8-diyl diaceta.-e 1 1 -dioxide, mp 79-8 10 C 1 OR)-8-Butyl-8-ethyl-2,3, 7
.S,
9 1 0-hex;zhydrc- 10-1 l,'T-dioxono(2,3 4.
benzothiazcpine 6,6-dioxide, mp 820 C -,e-.,d45phnt14bno~zpn 1.1 dioxide 0.20 hydrate, trp 110-1110 C AMENDED SHEET 333 ben~zothiaezpine-ciod. mo 5-544 benzothiazeoine 1, 1 -dioxici hydrochl oride, rnp 194- 1970 C (+-)-Tras-3-butyl-3-ethyl-2, 3 ,4,5 -tctrahydro-8-isopropoxy-5-phcl- 1,4benzoth-iazecpinc 1, 1-dioxide hydrocloride. ni~p 178-18 10 C (-Tas3-uy- -chl2345ttayr- pey-14-ben-zotlazepin-Scarbaldchydc 1, 1-dioxidc, mp 165-1700 C 3 ,3-Diethyl-2,3 ,4,5-tct ydro-7,8-dL,,c,,hox- 5 -ohenyl-1I,4-beaLzofia.Zep'fLre- 1,1 dioxide, mp 163-1640 C 3,3 ichy1-S.(4-luorooheriyi)- 2 5 -*etr2.hyd70- 8-met ho'y-1,4'D =oI A-OeZ7t.InZCtl 1, 1-dioXide 101 -1030 C 3,3-Dicthyl-2,3,4, S-tetrahydiro-8-troxy- 5 -phenyl- I ,4-bc.7o&azzzp'.c- 1,.
dioxide, nip 132-1330 C 3,3-Dicthyl-2,3 ,4,S-cttrahydro-S-phefylYi .4beizothiaze-pifl4,8-diolI 1,1-dioxide, rnp 225-2270 C (RS)-3,3D hl234,--t?-yr--~do,78d.Ectoy--hnii4 benzothiaz-epine 1, 1-dioxide, mp 205-2060 C (+-)-Tras-3butyl-8CLhoxy-3-thyI- 2 3 4 5-teta.ydro-5-flcflyl-1,4bcenzotl-iazzpin- 4 -ol 1, 1-dioxide, rop 149-1500 C (-4-)-Trans-3 -butyl-3 -ethyl-2,3 Strahydro-8-iso pro o5-pOX hnyl<- 1,4bcavtlkdipi-4-ol 1,1-dioxide, arp 109-1 150 C (+-)-Tras-3-butyl-3-Cthyl-2.i -Ectra-hydiro-7,8,9-L imethoxy-S-pherIyi-l berizothia.zcpin-4-ol 1, 1 -dioxide, nip 84-960 C AMEMDFD SHEET Js (3 R,5 -bur,11-3-ethy1 -273,44.5,,eiathydo- I,-dioxic, m 2 15-1100 C (+-)-Trans-3-buty-3-ethyl2,3,,5.cet.ahvdro.4,7, 8-tineth-oxyf-5-orenyl- benzothiazepine 1, 1-dio~dde, mp 169-1870 C (+-)-Trars-3-butyl-3-cthyl.$.ph-enyl-2,3 S-tctrahydro-7, S -dirnec.hoxy- 1,4bceizoL~hazepin-4-_yi acetate S,S-dioxide, np, 154-156c) C 3,3-Die-thyI-2,3,4,5-tec-ahydro-5-phenyi-l ,4-bcrazotr-azEoIin-8-o 1,1 -dioxide, rnp 177-1780 C 3, 3-Di ethyl-2,3,4,5-te~rahydro-7-methoxcy-5-phe'.vl-1I,4-beaizothi;azepin-8-oI dio,,de 3, 3-Dibutyl-2,3,4,5-te-r-hvdro-5-phenwI. I,'4-ben~zo-th'iazcpin-8-oI 1,1-dioxide (-+-)-Tranis-3-Buty-3-ethy-2,3,4,5-te-rahydro- 1, 1 -dIoxo-5-phcnv!- benazo.hi?_aepin-8-yl hydrogen suifate, mo 196.5-200'C (-4-)-Trans-3-Butyl-3-cthyl-2,3,4,S-tetra-hydro-I, 1 -dioxo-5-phcnyI-] ,4benzothiazci)*n-8-yl dihydrogcn phosphate 3, 3-D I ethyl[-2,3 ,4,5 t cu-hydro- 1, 1-dioxo-5-pheny[- 1,4 -ber,-othiazep:in-8 -yihiydrogen su Lfatec 3, 3- D i th y I-2, 3,4, 5- t ctrah ydr o- 1, 1 di oxo p h n yI- I 4 -b cnzothi.Zcp In 8y~dihydrogen phosphatze -3 -Buryl -3 -ethyl tet rahyd ro- 1, I -dioxo-S-phenyl- ,4bemothiazcpin-8-yl aspartate A~4~U)FD SHFET ,335 A-6 The compounds of the formula R 1
S
a 6 wherein RI is a straig.ht cha-;ied C 1 6 -iy .op 2 is a trihtcaindC alkyl group; R 3 is hydrogen or a groulp OR' 1 in %which R 1 1 is hydrogen, optionaliy substituted
C
1 6 alkyl or a C 1 6 alkylcarbonyl grou:-p4 pAi yidyl or optionally subs-tituted phenyl; pR 5 pR 6
R
7 adRaetesame or diferentc and ech is selece-d fr-om hydrogen, halogen, cyano, R15-acctyLide,
OR
15 option1ally substituted C 1 6 alkyl, C0R 15
CH(OH)RI
5
S(O),R
15 p(O)(0R 15
OCOR
1 5, OC 3
CN,
SOIN, NHCN, CH-7ORI 5 CHO, (CH-) 0 o-N, CCNRI 2
R
1 (CH,_)pCC27R 1
(CH
2
CCR
1 Ir-COCF 3 NHS02R 1 5, CCHICRI 5, CCH=C{ 1 O(CHjC H 2 C)nR 1
OC
2 0 CR Cc 2
~R
2 1 and
C(C
2 1
R
1 3R 1 -4 wherein p is an integer f-rm 1-4, n is an integer from0and p, 12 p,13, R 14 and R 15 are *independently selected hydrogen and optionalliy substituted C 1 6 alkyli; or R 6 and? arlnedt form a group -0 (CR I 2 RI3) wheeinR 1 2 and R 13 are a-s hereinbefore de~ned and mn is 1 or 2; and R 9 and R &re the same or different and each is hydrogen or C 1 6 alkyl; v.4th the proviso that when R 3 is hydrogen either R 7 is not hydrogen or at leaLst twio of R 5 R, R'and R8are not hydrogen; and salts, solvates and physiolo ically 5±nctiona1 derlivatives Lhereof.
!140V Pf I F H I- -3 b A-7 Thei c o moL.un ds as A- n hi-'bc i are of Fh r rulIa
R
6 3 R H wherein RI to RIO are as hereinbefobre de5ned a-id i 0o ioge~i cyano, R 1 5 a cryl id c, OR 1 5 o:),:onajly s-ubstitutedC 6 ailCRS CH(Om)RI' S(O)nR 1 5 p(OX(OR',1 0C0R 1 5 O~,ON C,~'N
CO-,R
5
M-COCF
3 NHSO2,Ri 5 OC:-i OR 15, o~c-? O(CHCH2)O),R' O(CHI-9pSO 3 R' 5, O(CI-{7)pNR 2 R 13 and O(CH )pN--Rl 2
R
1
-'RI
4 wherein ra, p a-nd R 12 to R 1 5 are as hecneoedc4=ed: and salts, solvates or physiolo;6ally 5..ncrional dcrivatives thereof.
-S The cornounds as dec'e in A- are of the FormuLa S
R
R
wherein~ R 1
-R
1 aae ,LiiA6;ad salts, solvates and hvsioio 'c.ailv rum= aonal decvtie thereof.
A-9 Tne compounds as ~r-iie n -A-6 w~hc are of the Formula (V 01 4 OH wherein RI-RIO are as 6ec-j:e in a-nd szlts, solvates and physioloically functionai derivatives thereof.
i; I I i: if) H P 33a 0 R
R
R 4 (IVa) hr In RR 10 are a-s in p,-6 and salts, solvates and pflVsicioCCiIy ftincticnal deiivarive-s thcrceof.
A- Ihic comoounds in A-S whercein: RI andRp 2 ar zcchae d C 1-aByl; R3 is hydroge-n or hydroxy;,
R
4 is un-subs iruted phenyl;
R
5 is hydrogcn
R
9 and IR 0 arc both hyd rogen; a-nd either R' s sece frm hoghydroxy, C) _6 aikoxy, cot:o:ai subsr _,Cd C 1 6 alkyl, -S(O),nR 15
-OC(OD)R
15 and -CF.&OR 15 whereiLn ,R.15 is hvogno 0 1-6 alk'A; and
R
6 and R8~ arc irtdcpeidendiY sc!ezed from hydrogeni and those zrous lisrt th e dcEridton ofRI; or R8 is hydrogen.- and R6 and R 7 ar.- Linked to for a goup 2 ~O WLnCf m Is 1 or2; and salts, solvaics, and physiologically 5=tciona1 derlivatives therecof A- 12 A compound a=cording to any of A- t I whcr-in R 6 and pR 7 arc both mct.noxy.
A-13 A compound sected,,- from the group coasisi'ng of: (3.,5R)-3-ButYi-3 -ehyI-2,3,4,5-te2hdro-7,-imetb ox-YSPC1ny[- 1,4 benzo-,hiazepinc 1,1 -dioxide; 33e: rars-3 -uzy~i-3-c Ihyi-2,3 45t'vdo73 -)-Trnris-3)-burl-3-hyl-2,3,,5t-T+hyd-o-7, 8-dirme,-hoxy-5-cphenyi-1,bnzothiazepin-4-ol 1, i-dioxide; R5R>Q-7-B rornoc-3 -buryl-3 -ethyl -2,3 1,5-e niydro-meo'ShrI 1beo-.Zhi',-circ 1, 1-dioxide, ozo~haze~n-4-1 ,1-dioxi'dc; (3R, SR)-2-Butyl-3-ethyl-2,3,4,5-t raiydro-5-ph'ienyl-I,4 octon-zenLre-7.8-dioI 1, 1 -dioxide; (3R,SR)-3 -Bu, y-3-thyi-2,3,4,5-t ,-aydro-8-me-Lhoxy.,-5-ohcny1- 1,4benzo thia-zep in-7- ol 1,1-diox*ide; (3 R, SR)-3-Buryi-3 -ethyl-2,3 ,4,S-tet,-ahYdr-7-mr.ethoxyf-5-pheny1- 1,4benizothiaz-pine 1, 1-dioxidc; )-Tras-3 -butyi-3 -eihyl-2,3 5-tet-ahydro-5-phr.- I -,4-oe-nzothiazepin.-S-ol 1, 1 -dioxide; -bu vi1-3 -cthy1-2,3,4,5- ce-.ahydro-S-phcm yI I ,4bcrzotJiazcpII&,-3 iaL 1 -3 -buryl-3 thy-2,3,4,5-tctzhyd ro-8 methxy 5- pheiy- 1, 4bemzothiia.zc-pine-7-carbalde-hyde 1, 1 -dioxide; AMENDED SHEET 33J 2-(b3unty 3 y[ 5rah rc-hcy ,4bot, c 11, -d-dioxdde sui~foric acid 1, 1-doX2'dc; (7,9)-7BurI-7e~hI-67,S9-t.r~ydr-9-h:~ 1I,3-dioxolIo(4,5--{( 1,4A)_ bcnzcL!iazcp'Ln (+-)-Trans-3 -buryl -3 -ethyl 3 5-t etrahydro-9, ech oxy- 5- p hcnyl 1, 4berizoth.a4cpine 1,1 -dioxide; bczotbuiaznin-4-oI 1,1-dioxide;- (-+-)-Trns-3)-butyI-3-ethyI-2,3-,4,5-tetahydro-8-m.,choxy--phefly[I- ,4bc-LzoLhi3a-eoin-7-ncttanol S,S-dioxidcc; (3R,5Ry-3-buryI-3-ehyI-2,3,4,5-Ectr-hydro--reth -oxy-7-rtro-5-ph--flyl- 1,4bcrtzothiazeinc 1,1 -dioxide; -butyi-3-ethyl-2,3 ,4,5-terahydro--mhoxy-7-(net±0cyrr~ethyl)- 5 phcrryI- 1,4-bcnzotliiazepirne 1,1-dioxide; (3R.,5R)-3-butyI-3-cthy-2,3),4 ,5-t -ahyXo-5-henl- 1 ,4-benlZothL2azeC'n-7,S-dV'I diacetate 1, 1 -dioxide; (SR. IOR)-S-Buryi-S-ethyi-2.3 1 0 eix.hdr- 10-I ,4'-dioxono(2-,3 1,4)benzothiazcpine 6,6-dioxide; AMENDED SHEET bcz tiz-ii 1,1-io iehy rcloie -Trans-3 -butyl-3 hyl-2,3,4, 5-tctrahydro- 5-ispcpyl- -phefl,'Il- 1,--;In8 cztiazenie 1,1-dioxide hdohoie 3, -DI-thyl3- yle~-2,3,4,5 -tectahydro-S hx-5- Dhe nyl- 1, 4- be nzod& z=:Int,dioxide; 3,3 -Diethyl-5-(4-Ouorophny-2,3,,5-cetahyd-o--mlt-ioxy-1 ,4-beazothia.Zepine 1, 1 -diocdec; 3 ,3-Diethy1-2,3,4,5-tetra.hydro-8-mehoxy-5-phenl- I,4-'oe.nzoth:iazepLle !Iidioxide; 3,3 -Di ethyl ttrahydro- -phenl- ,4-bcnzothia-7.in-4,8-diol doie berizothiazepine 1, 1 -dioxi'de; benzothiazepin-4-oll1, 1 -dioxide; bet'.zothiazcpi~n-4-oI 1,1I-dioxide; bcizotiazepir-4-ol 1, 1-dioxide; (3,R--uy--ty-,,45trayr--hnl I,4-benzotiiazpin-4,7,3-tiol 1, 1 -dioxide; NODED 'HEE., ,4.5 ccttyro7SdmthoXYi benzothiazepin-4-yj ac'etate S,S-dioxidc; 3 ,3-Diethyl-2,3,4,5et-hydro--i~hoxY'S-ohfl-ii-,4-oe-.zoth iaezpin-8-oI 11 dioxide; 3, 3-Diu t1s34,5tetahyr-2,,,-tahefydro,-b ~Iazpf8oI-dioxide;cnl-, bcanzothiaze-pin-8-yI hydrogen sulfate; (+;-)-Trans-3-Butyl1- 3 -ethyl-2,3 ,4,5-tctrahydiro-1, 1 -dIoxo-5-phenyf-l ,4 bc.-zothiazepin--YI dihydrogen phosphatE; 3, 3-Diethyi-2,3,4,5 -tet-ahydro- 1,1I -dioxo-5-phenyl- I ,4-benzohiaZepifl-8-yI hydrogen sulfate; 3, 3-Diet.hyl-2.3 ,4,5-tc..ydro-1, 1-dioxo-S-ohen.yl-1I,4-benz-o.-LaZ-epil-8-yI dihydrogen phos-phate; 1 -dioxo-5-phcnyi- 1,4bc-nzothia~pIfl- 8 -yl aspartate; ind 3,3-Diethy-2,3,4,5-tctr3.fydroI 1-dioxo-5-phcfll- 1 ,4-boeaothizepi-ln--~yI aspartate.
(3F,S5R)-3 -Burty1-3--thyl- 2,3 ,4,5 -tetraihydrOc--/, 8-dimecthoxy-5-phcoyl-1,.bcazoth=z.pife 1,1-dioxide, or a sal1t, solvate. or physioloic-lily f~coa OcrivatvC thereot.
*'~Nf)Ffl 3'/2 A- 14 Cornpou-nds havirq cxccutio~ta1 hypolipidaeraic propcnts inci-.1e:- 1 -ethyl -2,3 ,4,5 -ict.hyd.o- 8 -mthoxy- 5- phly I-4 l,4-bca1zotbaz-:.in- 3yli-2 (R)-2-butanol S,S-dioxicit; 1-(3 -e~hyI-2,3 ,4,5-ccaahyd-o-8-mthoxy--ph'el- 1 ,4t-be)r~od--th n-_3yi)-3-butanol S,S-dioxide; +trais 1 thy 1 2,3,4,5 -tet hydro- 7 -rrho xy- 5-;h--ly I o.beazobazzoI r.-3 yvI)-2(R)-2-butaoi S,S-dioxide; 3eI-5(-l~~C~lI- I 4_-eanro-rith l, 4beaizothiazepion -3-yI)-2(R)-2-butanoI S,S-dioxide; )-trans- I-(3-ethvl.5-(4-hydroxypheflyl)-2,.3 ,4,5-t.--trahy',dro- 1,4-bearzothiazc~in-.,yI)-2(R)-2-bucanol S,S-diaxidt 0.5 hydrate: AMENDED 'SHEET '113 Ic 1, 1 -dioxidenhydrcchrijnd; bcnzothuiazcpi'ne 1,i -dioxide; benzothiaztpine 1,1 dioxide; trifluoro-(2S)-2-butanol- S,S-dioxide; 1-(3 -ethyl-,3 Lrhdro- 7- mctho xy 5 -p-erny I- I,"4-ea1zoL,1i' z:L- (++)trans-3 Ethyl-2.3 ,4,5 -te trahydro- 3 droxv 'yb 1) 3- phevlt- 1,4be~zo hiazcpime 1,1 -dioxide; hy'droxyphcnyl)-I ,4'-beazothiaze:;ine 1,1-dioxide; I -(3.-Ethvl-5-(4-fhocrophcnyl)-2,3,4,5-tetrhydro- bertz-othiazeoin-3-yI)-2(R)-2-butanoI S,S-dioxidc; (--)-trans-l-(3-Ethyl-2,3,4,5-te trahydro-7-nethoxy..Spi-henyl1,4 bea-zotiazeoi*n-3-yl)-4,4,4-t-ifluoro-2(S)-2--butanoI 3,3-dioxide; bcenzotb3iazeoin-3-yi)-4,4,4 -trirluoro-2(S)-butan-oI S ,S-dioxide-; 3-yI -N2R)-2-bucanol S,S dioxide; (++)trans- 1 -E-thvl-2,3, ,5,-c.trahydro-7.8-dime.-thoxy--ohenvI- 1,4benzothiazeiln -3-yl)-4,4,4-trifluoro-'-buaoI S,S-dioxidc; 1 -(3-EZy-2,3,4,5-tet-hydro-7,3-diethoR \'-i-hnyl-i,4ben~zothi aze-pin-3-y[)-3,3,4,4,4-pentafiuoro-2-butan-ol S,S-dioxid-.; tram -3 -eth v -2,3,4,S-tetrahydro- 5-phen y I- 4-r-ifluoro-2 hydroxybutyl)- 1, 4-benzothiazepin-8- yI)oxy)propoanesuifonic acid 1,1I-dioxide; (--)-trans )-ethy 1-2 .3,4,5 -tetrahydro-3 -hydrox vbut-l)- 5-phenyl benzothiazepin-8-y)oxyehylL-imeL~ya onilum iodide 1, 1 -dioxide; (++)trans- I -(3-E~hvl-2,3,4',5-tetra v do-7,-dicL.oxy-5-phe nvl-lI,'" ben-zothiazepin-3-y)-4..4,4-trifluoro-2-buarnol S.S-dioxide; +rans -e thy I-2,3.4.5.-ietrahyd ro- 5-phenvl -3 (4,4,4 Miluo ro-2 hy'droxv but 1,4-benzothiazeoiln-3)-Yl)oxv)ethvitr-imnethylarnrnonu= iodide 1. 1-dioxide,
CO)
Z)
LL
()-trans- 1 -tyl -2,3,4,5 -thdro-7, 8-d hox- 5 p be~zoIi:azr~n-S)-v tan-riol 2-butnox S,-doxi-; I~ -3(,,-riruhooel) -ix2,2,-eayr-,-i~o~ phenyi -l ,p-bn othia inol)4,,-riiuoo2bu.nl ,-;ixi 'DC ZO [hiaze7p'ri-3-yl)--4,4,4--trifluoro-2-'oULnOI S,S-diioxide; 'oenzothiaze o-in-3-yi)-2-butanl ,-doia*c; (-)zLia-ti-a n-3-yi)-2,R)2 u,,-tohvro,S-ihYdro'--oe\1btn~zohiaepi)-l-2-butano SS-d dioxide oenzotze4--l),-iuoro- 1-butanol not S,S-dioxid e; c--oe Othp'L~in-3-yl)-2, -btnilone SS-o ,,iISSdix;c yl-2,-(4-fluorphnyl-,,,-teayd07-fCmOYoeazothiazeoi-l-()2ba n ol SS-dioxide; Z'.4: 31 3,4, 5-TetLrahyd:Lo-3 -me chvi-5-phenvl- I,-eaebrnethzriol 1, 1-dioxide, mo 79-S0 0
C;
methanol 1, 1-dioxide hydrochloride 0.25 hydrate mcp 222-224 C; -Butyl-3 -ethyl-23,,,-tetrahydo- 1 yllphen,-oi hydrochrloride, np 234-235 PcC(dec.); (+)=-5-(-Bei--foxypeny)-3-cthyi-2,3 ,4,5-cezahvdro- 1,4- DoenzotriazeotfLPe-3-metanol, ma 138-143'C; _4-)Trn, -3-Ethyl-2,3,4,-terahyro-5-pcny- I ,4-beaz.-ozete methanol 1.1 -dioxide, rnp 134-137'C; 3- E thy 1-2,3,4, 5-teo-hdr--(3 -'h-ydro xy butyl)- 5 -hernyl- benzothiaztpine 1,1 -dioxide, mro 151-1 Ethy 1-2,3,5 e~ahydro- 3-butyI -'hydroxy-S-(3 pyridyl)- 1,4 benzothiazeoine 1, 1-dioxide, mp 202-205'C; yl)ph.-nol hydrochloride, mp 236-237 0 C(dcc.); Buty- 3 -e thy te trahydro- 5-4h ydroxvp htnyl)- 1, 4benizothiazepi n 1, 1-dioxide, mp 163-165'C; 5-tetrahydro-3-(3-hy-doxybut,,)5Dhnl 1,4be'.zodiiaztpine 1. 1 -dioxide hydrochloridc. rnp 206-209 0
C;
hvd roxyhey) I.-berzothiaztpine 1.1 phni-14L -dioxide, r-ip 197-1 98'C; sI/i -ldoit -p 173170 medhaol, mp 104-106'C; 'ocazotlhiazeoine-3-methanol, mo 123-12800; be rtzo th azeoi n-3-yi)-2(R)-2-boutariol S,S-dioxide, -rp 130-132'C; -(3-Ethyi-2,3,4,5-t ,',dr-o-5-ophenyl- I ,4-benzothiaz-:L--3yl)-4,4,4- -fluoro-2(R)-2-buaoI S,S-dioxice, 140-1 I -(3-Et~hyl-2,3 ,4,5-t-e-ahy dro-5-pety- I ,4-ber..zo&iazepin-3ylI)-4-fluoro-2-(RS-2buzan S§S-ioxide- 0.50 n\'cjaie, rnp 131i47'C; I -(3-Et hyI-2,3,4,5.te- -ahydro-5-phenryl- I ,4-b.-n-zta~Lyi)-4,4,4trifl.uoro-2(S)-2-buraoI Soxidc, mp 159-16 100; beazo thiazep i-3-yi}-4,4,4-tLrifILuoro-2(S)-2-butanol S,S-dioxidc, mp 163- 17000; (+).Trans. 1 -Ethyl -2,3 ,4,5 -te.rahydro- 8- m thoxy-5 -ph cnyI- 1, 4 benizothiazeo pin-3-yi)--4, 4 Fuoro-2(S)-2-boutazo! S,S-dioxide-, mp 175-179 0
C;
(+-)-TrasI-3-ety-, 1_5 r~doSj~toy5oiI 1,4bcn-zotiazeoin,-3-yl-2(R)-2-outar~ol S,S-dioxide-, mo 156-1 570C; be.-zothiazep in,-3-yi)-.4,4,4-triWuoro-2-ouaoI S,S-dioxide:; -Ethyl -te Lrahydro- 8 mcthoxy-5 -phenyl- 1,4ben~zothiazeo in-3-yi)-3,3,4,4,4-pentafluoro-2-butanoI S,S-dioxide; -(3-Ethyl-2.3,4,5-ctr-ahiydro-7.oS-dimethoxy-5-phenyl- 1,bcrnzo thiazeo in-3-yl)-3,3 ,4,4,4-rpenuailuoro-2-butaoI SS-dioxide, hy droxybutyl)- I .4-beizothiaz:o-in--7-yl)oxy)pm-opa.ne suLforic acid 1, 1 -aiioxidt; (-..)-Trmn;-3-((3-ethyv..3,4.5-tetrahydro-5-phenyI-3-(4,4,4-trifluoro-2r be'Zothiaztpi n_3-yI)-4 _P-.zifuoro-2-butaiol S,S-dioie I1,1-dioxide hiydroxybutylf)- 1,4-'oeri-oui-azeoin,-8 y~x~~ytLn~ha- iodide 1, ,1-dioxide; -e thy i-2,3, 4, 5-tenhydro-3 hydroxybu 5-phemy 1 1,4benzothiaze o in-S-v!)oxy)propanesuLfoni'c acid 1, 1 -dioxide; be.-izothiazet in-7-yi)oxi )proD2aresuIfoaic acid 1, 1-,diloxide; benzoth.iaze-pin-3-yi)-2-butanoI S,S-dioxidc; hapn3- 1)-3(.,--fureh e luo ro- 7 ui ,S-detoxy-o-c 'cen--z i,-otazzeo3- 4,4,--fuoo-2c ,-buuoI 3S-io I-(3-(2,yl2,3,triuorethyd) -2,,-tehanyd-5-rnethox''-5 pr-.enyol- ,iiazeazothiaein-3-yI)--4,I SS-diflorThtso SS-ixi 1-(3'-Ethy1-2,3 ,4,5-tetrahydr-o-9,-etyox-5-he nyl-,-- 'cc -zothi azzi in-3-yi)-41,4,4'-trif7iuoro-2-bu~aoI S,S-dioxidt; 1 -(3-ethyl-2,3,4,S-tetrahydro-9-rnethoxv-5-ohe nyi-l,benzothiazcpin-3-yI)-l-butanoi SS-dioxide; 14 -3ehi -2.3,4 ,5 -t t:rahyd-o 7,3-.i5i-x v; Denztnaz~ir-3-i)4,4,4-Lrifiuoro- I-but~aoi S,S-dio.xidc; (-+)Trans 1 -ethyl -2,3,4,5 -zc ahydxo-7, 9 -dirn cho xy- 5 -phcny ben~zoti-iiazepiLn-3-yi)-2--butanonet S,S-dioxid-.
AN
co: A- 3. A cm cun ,d o f for=. u;a k 1: (O)n
S
(R)p R1 I is an iate2er of from-' 0 to 4; n is an intreger of from 0 to 2; R is an atom or group seleczed from halogen, c,,ano, hyL-cxy, a-'Iv a.1koxy, airyl, heteroaxyl, aryloxy, arylalkoxy, araikylI, alkar/l, -O(CH- )pSO 3
R
1 1
-O(C~
2 0 Nl lI2, O(C~t_\Th 0
R
1 1
R
2
R
1 -CORII~ _C-C02 1 1 _C0N-R 1
IR
12 -CH-)ORI 1 -N,,Ri IR 12 -Ni-{CORI 1, -NH50 2 Rl 1, -SRI 1, -S02)R 1 1 -SO2)NR' 1 Rp 12 and -S0 3
R
1 1 or R is a group -OC-20- whch forrns a fu~rthr r,-g attached to X wherein a is an intcger of from 1 to 4, RI 1 R 12 ar Lidependtntly seiczted fromn hydrogen, C 1 6 aikyl and ph.-nyl. and RI 4 is hydrogen Or C 1- alkyl, wvhceen said alkyl, alkoxy, a.-yl, hetcroaryl, a:-yloxv, arvlaLkoxy, akyl anid al'karyl groups are ocuonally su'ostintetd by one or miore atoms or zou~s sclezted from halogen, hydroxy, nir itrl, c aikoxy, -COR 1 11, -COj R I!, -SOtRl 1 wherein RI is as hereinibefore defined and -NRl 4 RI5 Wherein Rl"' is as ht=; Zz-efore- defiEned and R 1 5 is hydrogen or C 1 6 MLkCI RI is hydrogen Or C 1 6 alkyl;
R
2 is an atom or group selected from hydrogen, 01.6 alkyl (including cycloal-kyl and cycloalkylalkyl), CI-4 aikoxy, pyrrl, thienyl, pyridvi, 1,3-benzodioxolo, phe-nvl and naphthyl, which groups are optionally substitute-d by one or more atoms or groups independently selected from halogen, cyano, hydroxy, nin-o, cxarboxyl, phenyl, phenoxy, benzvloxy, -CORI 1 -CO2)R1 1, -CONRI 1
R
1 2
-CH
2
ORI
1 -NRl R 12 -NHCORI 1 -NHS0-)R 1
-SRI
1 -SO-R 1 -S0 3 Rt 1 (wherein;, .01 and R 12 are as hereinibefore defineci). -OCH-))pNRI 1
R
12 0O(C-H-) N R 1
IR
12 R 13 p
I
36'0 and 1 R p I a- RIZ a-t as he'necedf n 'zs ri'C, g hv cn o r C: is hdragn. hd~wx Cu~a~c~i, akcxv i 6 Ac
R
4 is a g-ouo indezen6:nt:, set!cA -'rom C 1-6 ai icuigcy'cloal ikiad cyc loalk-ylalkyl), C-2 6 alk~oyl, and C--6 alk Yy, whaich groups are ontiona-Ily substituted by one or more atoms or groups independently selected from halogen, oxo, -OR 14 -COaRl', NRl 4 Rb5, -SR 14
-S(O)C
1 6 aLkyl, -SO-,R 14 and -SO-R1 4 (wherein R 1 4 and RI 5 as her-tinbeforc define-d) R) is a group LIndependently selected from C-2 6 aikyl (includig cycloaIc~'i an'd cycloalkvlalkyl), alkenyl and C 2 6 aknlwhich -10u. s are ooiona subst ituted by one or m-ore atoms or =ru-ns indeoendenti',' selected from halogen.
ox, OR 4
,-CO-R
4
N
1 R~ -SR' -S(O)CI-6 alkylI, -SO-R 1 Ln -S0 3
RI"
(whereiLn R 14 and R 15 are as hercinibcfore defined); or R 4 and R5, together w ith the carbon atom to whirch the;' are attched, formn aC3' spiro cycloa.lkyl group which is optionally substituted by one or more atomrs or groups in deenddy slcte,d from haliogen, -OR 14 -CO RI 4
,-SR
1 d 5.R 4 1 (wherin R 4 and R 1 are a-s herecinefrdfnd) R6 an-d o 7 2-c independecntly seetdfrom hydrogen and C 1 6 aik yl; anid X is an aromatic or non-a-romatic monoccyclic or bicyclic In g s-yste-m having from 5 to 10 carbon atoms (including the two carbon atoms formmg par, of the thiazepinc t11cg) wherein oodional-ore or more of the carbon atorns is/are reprlaced by hecteroatom(s) independently selected from nizogen, oxygen and sulphur; with the proviso that at least one of t. R 2
R
4 and R 5 is hydroxy or a group containing hydroxy; an-d salts. solvates and physiologically fuunctional det-ivatives there-of.
-16 A compound as de~ie in A-15 wherctn: AMENDED
SHEET
I is 0, 1, or 2; n is I or 2; and RI, R6 and R 7 are all hydrogen; and R' is hydrL:oge:n or hyorLoxy/ A- 17 A compound as de=I~ in AJ- which is a tran-s isomer wherein: I is 0or 1; ri is 2; and
R
4 and R 5 aegroups indepedetly selected frm 1 ak (including cycioa-lkyi and cycioalk-ylalkyl), 6 alkenyl and C2 6 alkYn1Yl, wber-ein said ai1kyl1, aLkenyl, or alkynyl grouip may be substituted by one or more hydroxy groups, or R 4 an-d together with the carbon atom to which they' arc attached, form a C3- 7 s-piro cycloalkyl group which can be substituted by one or mnore hydroxy gos;or Ilis 0ori1; n is 2;
R
2 is a phenyl group which may be subs-tituted by one or more atoms or groups independently selccte-d from halogen, cyano, hydroxy, nro, carboxyl, phen'i1.
phenoxy, berzyloxy, -CoRp 11, -COR 1
-CONR
1 f Ri 12 -CH)ORI 1, -NRI IR 12 -NHCORI 1 .NT1HSO)R1 1, -SRI 1 -S02)RI 1 -S0 3
R
11 I (wherein R 11
I
and RI 2 are independently selected firom hydrogen, C 1 6 alkyl and phenyl), -O(CH-2) NR 11
R
12 NR+ 1
R
12
R
1 3 an OC )S0R 1 wh: 1 i s an Lieger of from 1 to 4, RPI I and RI 1 2 are a-s hecreinibefore defined and R 1 3 is hydrogen or C 1 6 alkyl);
R
4 and R 5 are groups independenitly selected From C 1 6 alk-yl (including cycloalk-.' and cycloalkvlalkyl), C-2 6 alkenyl an-d C-2- 6 alky-nyl, wherein said alkyl, alkenyl, or aikynyl group may be substituted by one or more hydroxy groups, or p 4 and R 5 AMENDED
SHEET
352 to v'erwih tht cabon atom to :io are a cne, aC cvcioalkyj group wh =hna' be sbitedby' o7t or- More 'nYC~roxy ~o ;or s 0 or 1: n is 2;
R
2 is a phenyl group which may be substituted by cne or more atomns or z~ours inde- endentlv selected from halogen, cyano, hydroxy, nitro, carboxyl, r'hv, prteroxy, benzyloxv, -CORI 1, -CO--R 1 1, -CINTR 1
IR
12
-CHTOR
1 1.
-NR I R 12 -NHCORI I, -NH3QSO-Rll 1 Sa 1
-O
3 1 (w rinR' and R 12 are- independently selected from hydroge.-i C 1 6 aLikvl and hrl) RI R 1
TR+
1
R'R
1 andz S0 3 CO (where*ips ani integ.er or from I to 4, P 1 and R 12 are as htreiibcrore ~d and 1 Is hydro gen Or C 1 -6 alkyl): and R 5 are groups ind.eoendently selected &omn C 1 6 aLky (inicluding cycloalkyl and cycloalkylalkyI), C- 2 6 alkenyli and C2- aky-nyl, which groups can bc subsciruted by one or more hydroxy groups; and X is a frsed ph enyl, naphthyl, pyrr,'l, thienyl, or :oyridyl group; A-18 A compound as 62~~z in A-LIvhich is: (-+trans-3-e thy-2,3,4, 5 -te -ahvd.-o-3 -((2R)-2-hydroxvbDutvl)- 5 -phenyI -1,4benizothliaze-p ia: 1,1-dioxide; (+-)-trans-l1 -ethyl -2,3,4,5-tetrahydro-8 -rnetoxy- 5 -reyivi ,4-beazo Lhiaze:pin-3yi-2(R)-2-butanol S.S-dioxide; yI)-3-butanol S,S-dioxide; -)-tran.s-lI-(3-echyl-2,3,4,5-tetahvdro-7-me-thoxy- 3-phen-y l-1, 4 -benL-zothiazepi)n-SyI)-2(R)-2-butaol (-4---rrais-l1 -ethyl- 5-(4 -fluo rophenyl)-2_3,4, 5-tetrahydro-7-methoxy 1,4benizothiaze:)In-3-vi)-2(R)-2-butaznoI S,S-dioxide; (--trans- I -(3-ethvl.-5-(4-hydroxvphenv)-2.3,4,5-te--hydro-lI, 4 +-ben~zothiazep:in-3yl)-2(R)-2-butanol 3.3-dioxide 0.5 hydrate: AW4NDED
.SHE-'
3 3 beizthaz-p~rc1,1-dioxide;h~cine 'benzothiazeoine 1,1-dioxide; -ethyl -2,3,4,5 -ze-aydro-5-phenvl- I 4bztiae yi)-4,4,4ifluoro-(23)-2-butanioI- S,S-di*oxide; y I4,4,4-urifluoro-(2S)-2 -butanoI S-dlox idt; (--)trans-3 -Ethyl -2,3 tetrai-wdro- 3- (3-'hydro xvbcuctvi)- 5 -,henY! locaizothLiazcuiric 1,1-dioxide; (-+tran-3 -Ethyl -tetrahydro-3- (2 ydro hyd.roxypheriyl)-1I,4-benz-oth'azepDire 1,1 -dioxide; bca:zothiaze pi.ri-3-yl)-2(R)-2-butanoI S,S-dioxide; (-r-)-trars- 1 -Ethyl -2,3 ,4,5 -tetrahydro-7-mc-thoxy- 5-phmyl- 1 ,4 benzotiazepi-3-yl)-4',4,4-tri'fluoro-2(S)-2.)butan-,ol 3,S-dioxide;- (-ans 1-(3 -Ethy1-2,3,4, 5-tetrahydro- 8-rnehoxy- 5-ohel-i,4benzo chiaz-,pi1n-3 -y rifluo ro -2(S)-buio I S,S-dioxide; (+-)+trans 1-(3 -d ch'1-23 ,4,5 cvrahydro- 7.S8-dim, ethoxy-3-pheny1-1, 4 benzothi aze-pin-3 -yl-2-(R)-2--butanol S,S diox-ide:; (--trams- 1 -(3-Eth ylI-2,3,4,5-zetahydro- 7, S-dime ho xy- 3 -ohenyl- 1,4 benothazpin3-y)-,4-.rifluoro-2-butanoI S,S-dioxIdt; 'oen-zoLthiazec in-3 -yI)-3,3,4,4,4-penitafiuoro-2-butanoI 3.3-dioxidc; hvdroxybutyl)-I1, 4-benizothiazep~in-8-yl)oxy )propanesuifoaic acid 1, 1-dioxYide; (-+--)-trans-3-((3-ethyl-2,3-,4,5-tctrabhydro-3-('2-hydroxybutryi)-5-cphernyl- 1,4benzothiazcp in- 8-yI)oxy)e thy itrie thyl arnoni urn iodide 1, 1 -dioxide; I -(3-Ethyl-2,3,4,5-tecrahvdro-7.S-dieho-y--iherny- 1,4benzothiozepin-3-vI)A14,4-tr-iiluoro-2-but--.oI 3,3-dioxide; (+-)-traris-3-((3-ethyl-2.3 ,4.5-(cerahvdro-5-ohenvl, -trliluoro-2hydroxv'obuvl)- I .4-benizothiazei-~Ioyehhireh~mnf~-r iodide 1. 1-dioxide: Sglt (+-)-trans-3 -ethy1-2, 3 rt-ayroS(>yrzyutl-5pey IA, be-oLLazcpr-3-y1)-2-bu=an01 SS-diox' ce; -(3-(2,2,2-t-ifiuoroethyD-2,3 ,4,5-tet-hyro-7,-i ,meth phenyl- 1,4-beazothiaz-epin-3 -,yi)4-',4,4-triiuoro-2-bu.noI S ,S-dioxide; -Ehy-2, ,,5tetrahydro-7,8-d' htdoxv->phel- 1,4b.-nzothiaze:pin -3-yl)-4,I-trbu~oro2ba S,S-dioxid; be~nzothiazepinr-3-yl)-2-butanoI S,S-dioxide; -)-tians-l1 (3 -ehyl-2,3,4,5-te y),do-8-mcinyo.-y--pny-,4be az-o thiaze in- 3-yl)-4',4,4--tr-ifluoro- I-butaniol S,S-dioxide-; or (--)-rrans-l1-(3-ethyl-2,3 ,4,5-*Lt ahydro-7,3-dLhydcLoxy-5-phef-il-1,4oenzo thiazepLi- 3 .yl.2-butanone- S,S-dioxide A-19 A compoud. as de2ba n A-)-5of the formula Ga) (O)n 7
S
x p
R
whnerein
R
2 R3 I is an integer of from 0 to 4; n is an integer of from 0 to 2; R is an atom or group selcced from halogen, cyanmo, hydroxy, nicro, aiky1, alkoxy, aryl, heteroaryl, aryloxy,arylalkoxy, araikyl, aiLkaryl, -CORI 1, -CO- R 1 and -S0 3
R
1 where-in RI and R 12 are indepecndcentiy selected from hydrogen, C 1 6 alk%.l and phenvi, wherein said alkyl, alkoxy, aryl, heceroaryl, aryloxy, arylalkoxy, alralkvl and alkaryl groups are optionally substituted by one or more atoms or goups sciec:ed from halogen, hydroxy. nitro. niL-rlie, alkyl, aikoxy, -CORI 1, -CO-RI 1,
_)AN
ToU
SO?
1 Iwherein RI I;s -as herteinbef-orc oeuint, -Nl4 I W R4aeas hcreinbef-ort nd .RI is hydrogen ior Cl- 6 ak
.R
2 is an atom or group selected from hydrogen, C 1 6 alkyl (including cycloalkyl and cycloalkylalIkyl), CI- alkoxy, pyrryl, thienyl, pyr-idyl, 1,3-ctrizodioxoio, phenyi and naphthyl, which goups optionally substituted by one or more atoms or groups independently sel-cte-d from halogen, cyanio, hydrx, nioro, carboxyl, heny,I phen-oxy, benzvlxc, -COR 1 1, -CO-)RI 1, -CO,-fRI I 1 2 -CH,.ORI I, N 1 1 2 -N}{HC0R 1 1
-MHSO
2
,R
1 -SRII, -SO-,RII, -S0 3 RII (wherei1n RI 1 and R I a-r indepeaddendy selected from hydrogen, C 1 6 alkyl and phenyl), -0(01-in) N 1 ii p N Rl IRI, 2 RI3 and -0(CHI S0 3 RI I (wherein p is ant integer or Eon I to 4, R 1 1pand R 12 axe as he-ribefore depThed and R 1 3 is hy drogen or Cl..-6 ay) R-I is selected:57rm hydrogen, hydroxy and C 1 6 al-kyl
R
4 is a group indtpendcrntly selected from 01.-6 a.I'kyl' (including cycloalkyl and cycloalkylalkyl), 02.6 alken-,yl and C2-6 aikynyl, which goups are optionaly subs-tituted by onec or more atoms or groups indeojende-nty selected f-rm halogeni,
-O
1 ,-C0 2
R
1
,-RR
5 and -S0 3
R
1 (hein R I and R 1 5 are id.-cendendy selected from hydrogen and C1.-6 alkyl);
R
5 is a group independently sel-cte.d frlom C-2 6 alkyl (Including cyclozilkyl and cycloalkylaLkyl), C-2.6 alke:nyl and C-2-6 alky -nyl, which goups ootionally substituted by one or more atoms or groups independently selected from h1-alogenr,
-OR
14
-CO-)R
1 4
-NR
14 R!5 a.nd -S0 3
R
14 (whereini k 1 and R 15 are in-dependently selected from hydrogen and 0 1-6 alkyl); or R 4 and R 5 together with the carbon atom to which they are attached, form aC-7 spiro cycloalkyl group which is optionally substituted by one or more atoms or groups independently selected from halogen, -OR, 14
-CO-)RI
4 -S0 3 R 14 anrd -NPIR 1
P
(where R 14 and R 1 5 are as here-inbefore defined;
R
6 and R 7 are independently selected from hydrogen and 01.6 alkyl; and X is an aromatic or non-aromaiic monocyclic or bi cyclic ring system AMENDED SHE,7T 36-b nav1n i.m to 10 car-on atorris -Lvo 7Zic thiazepri z'winerring opuon ally one or mcre or- the c~c !rtlaced bv ht,eoatcrn(s) e. vee:d ,vithl the proviso tha~ at least one of R 2 and F.5 i yroxy or a grroucp containing hydroxy; and salts, solvatcs and physiologically fnctional derivatives thereof.
A-0 A compound of formi-ula gI):.
(O)n 7 (R~p N wherein Iis an int eger of from 0 to 4; ni is an initeg er of flrm 0 to'2; Ris an atom or group selezed -romn halogen, c,.ano,hydoxy, aikyl, alkox, any, heteroaryl, ar;[oxy, azrylatttoxy, aralkyl1, alkaryl, -O(CH2 )pSO-R 1
I,
-O(CH
2 )PNR 1 1
R
12 -O(CH-a))N+R IR 1 2
RI
4 -CORI 1, -COa)RI 1
-CONR
1 1
R
12 -CTI-bORI 1, ,NR 1
R
12 -N-ICORI 1,_-NHSO2)Rl 1, -SRI 1, -S0 2
R
1 1-SO-,NR' IR 12 and -S03RI 1 or R is a group -OCHibO- which formns a attached to X wherein p is an inte-ger of from 1 to 4, RI I and R 12 art independently selected from hydrogen, C 1 6 alkyl and pheinyl and R1 4 is hydrogen or C 1 6 alkyl, wherein said alkyl, alkoxy, aryl, heteroarf l, aryloxy, arylalkoxy, ar-alkyl and alkarvyl groups are optionally substituted by one or more atoms or groups independently selected from halogen. hydroxy, n1itro. niti-ile, alkyl, alkoxy, -cop" 1
-CO-,RI
1 -S0 3 RI I wherein RI I is as hereinoefort defined and -NRI 4
R
15 wherein R 1 is as hercinbefore defind and R 1 5 is hydrogen Or C 1 -6 alkyl; AMENDEG 21K 357 PLis hvdro~trn or C 1 6 aki and cycloaikylaikyi), Cl_ aikoxy, pyrr-yi, thienyi, pyri1dyl, 1,3-'oenzodjoxoio, phe.ny arnd naohthyl, which grouos a-re optionally substinated by on-- or more atom or groups inctntly selected from halogen, cyano, hydroxy, 7_it*ro, carb-oxy, phcenvl, ohenoxy, bcenzyloxy, -CORI 1, -COa)RI 1, -CO.NR 1
IR
12
-CH
2
OR
1 1,
-NRIIR
12
-NHCOR
11
-HI
1 -SRII, -S02?RII, -S0 3 RII (wherein2 R 1 1 andc R 12 are ind-edetly se-;ectea -om hydrogen, C; -6lkyl anid phenyl), *O(CH-2) NR 1 lR 1Z-, N R I IR I 2
.,Z
1 3 and~ -O0(CH SOR 0 p isan initeger or fErm 1 to 4, R?1 anid R 12 are as '-ereLnbore1 oeimed and R 13 is hydrogen Or C 1 6 al]<yl);
R
3 is hydrogen, hydroxy C 1 6 alkyl, alk-ox Or -O-C 1 Acyl;
R
4 is a goup inoecetndoetly selected frOm CI- 6 akl(in1cludIng cycloalkyI and cycloaLk-Yla.Lkyl), C-2 6 alke-ny[ and C2 6 alky-nyl, which grou s are optionally siubstituted by one or more atoms or grcucs Lndeperidzntly sec_cted ifrom halogen, oxo -O 14
,-COR
14
->R
14 1
~,-SR
4
,-S(O)C
1 6 aik',i -SO R 1 and -SOR 1 (whercLn R 14 and R 1 5 are as hceeinbefore defined); is a group indovience tly sel-cte-d from C-2- 6 aLkyt (including c yloalk-'l and cycloaikylalkyl), C-2.
6 at'ke-nYi and C-2 6 aikynyl, whi;ch grou-,s aret o:tionaillv substituted by one or more atoms or groups independently selected from~ halogen.: oxo, -OR 14 -C0 2 R 1 4 _\Nr, 14 RI5, _SR 1 4 1 a ?R 4 n 3 3 1 (wher:Ln R 1 -ad R 1 5 aite as her-eirbefore ceined);or R 4 and R 5 togethe- wit nn ,abnao owur hey are antached, form a C> 7 spiro cycloa~kyl group which is optionally substituted by one or more atomns or groups independently selected from halogen, -OR 1 4
-CO-?R
1 4 -S0 3
R
1 4 and -NRp 1 4 R 1 5 (where R 14 2,1d R 1 5 2re as hertinbe.fore de-fined; R6 a-nd R 7 are independent!,,, selctdrm hydrogen an-d C1..6 alkyl; and X is an aromatic or non-aromatic monocyclic or bicyclic ring system A A41ENDE SHEET 36?' having from 5 to 10 carbon atoms (including the two carbon atoms forming part of the thiazepine ring) wherein optionally one or more of the carbon atoms is/are replaced by heteroatom(s) independently selected from nitrogen, oxygen and sulphur; with the proviso that at least one of R, R 2
R
4 and R 5 is hydroxy or a group containing hydroxy; and salts, solvates and physiologically functional derivatives thereof, for use in the prophylaxis or treatment of clinical conditions for which a bile acid uptake inhibitor in indicated.
AI.
_00
AT
AMENDED
SHEET,
A-21 Corncound-s cifformla having exccptiona1 hypoiipidaeriC ooete n~d (-)-(RR)-3-butyl-3-ethyl-2,3,4,5-teLtrihydro-5-phenvl-1I,4-hezti~pn doie +tas 3 ,crhdo-5-h y ,4-bc.-zohi'aztpine 1, 1 dioxide; 1, 1-dioxidc; I-)tans -(3-ethyi-2,3 ,4,5-tetrahy)d.-o-5-phenlyl- 1,-eztIzp,- -Y)2bt-,oSS dioxide; (-+)trans- 1I(-tv-, 45ttayr~~ehX-.f~liI,-onoha i--yi)-2butarionc S,S-dioxide_ hydrochloride 1. 1 hydrate; (-+trans T3-(I 5-hnl 1, 4-beaz-odiiazepirc 1, -dioxideZ hyd-oc'aloride 0.4? hydrate; (+'-)-transu-3-(ethoxvehyl)-3-Cthyl- 2 -,tetrahydro-5-pheflyIl-1 4enohizpn dioxide hydrochloride- hemihydratc; (+)t;.s3(Loy-Ly)3ehl2345tr~do5o-nl 1,4-benzothi azc)Le 1 1 dioxide hydrochloride; +trans-cthvl 3-(3.-ethyl 5-tetrzhydro -5 PhcnyII -,4-bcr~zo thiazzepi-3 -y I)propiioratc 1, 1-dioxide; -ethyl 2 ,3 5-cetrahydro-5 1 ,4-benzothi zzepin-3 YI> 3 -buterim-2 one 1,1-dioxide; -cahdo8mchx--hyspo1,4-benzotnhazep)"Ine- 3 ,1 -cyclohexane) 1,1-dioxide; ayo5( prdl-,4-be-azoth azepiLne 1,-~oie -i---uy--ehl2345tcavr-?hd-x--4oiy) l,d-be-azothazz:ire 14l-dioxide; (+)tas3btl3e.y-,,45t my~o5(-~nl-,4-benrzotlhiazepilne 1,1-dioxidei; (+)ta~--uyl3ehl2 45tc--~y~o5(H-pyrrol- 1-yl)-1 ,4-boenzothiazczepjne 1,1 dioxide; (+tzrns -3 -buryl-3 -ethyl -2,3,4T,5 -tetrahydro-5 -phenylpyri do(4 ,3 I ,4-bernzo thiaze-oine 1, 1-dioxide; (++)trans-3 -butyl-3-cthyl-3 4,,-eryr-- hnl2-yrl(-,t-r-)- 1,4benizothiazc-ine 1,1-dioxide 0.1 hydrate; -buyl-3-et.hyl1- 4 5-tetrahydro-5 -phflylhicflo( 2 3 1, ,4-berizcthiazeine 1, 1 dioxide; AMENDED SHEE7 ,34D 23.5-r __:hvL-1 isooy- tn rflurohuvI'-' d Icx Idc 0.2 5 1 0; -2 3,4, 5- Ttrahydro- 3- iso orooYI-3 -rethyl1-5 phny I- 1,4-berao chi azc ine 1,1-dioxide 0.66 (+-).traris-3-(3-Ethx'1-2,3,4 n ,Sttayr--hni- 4bnohae -3 -yl)prooa_-ol 1,1 dioxide; E thy I- 5 Flu oro ph ny 1) 4, 5- ze ahy dro 7 m t ho xy 3-(3 -me th ox -ro c1)- 1, ,-bcenzothiaz::pine 1, 1 -dioxide hvdroch ,lride; 1, 1-dioxide; 1 -Ehyl-2,3,41,5-terrahvdo-7,-mzthox-5-her~iv- 1,-_oraez- y) butanrin S,S-dioxide- hydrochloride; 1,i1-dioxide; 2-butanonec S,S-dioxide; bcaothiaz~Le 1,1 -dioxide; 3-butarione SS-diox~ide; butarion: S,S-dioxicic; l-'outanone S,S-dioxide; -(3-ethyl-2,3 ,4,5-tcn-ahy'dro-7,S-dirn:.h oxy-5-D~henyi- I ,4-benzoth'iazet!-in--y,l> 4 4 ,4-trifluoro-1-butanonc S,S-dioxide; 1-(3-ethyl-2.3 ,4,5-te -ahydro-7,S-dimethoxy-5-phcnyl- 1,4'-boe-zothidaze-: in-3-vl)- 3 3 ,4,4,4-pentafluoro-2--butanone S,S-dioxide; 1 -ethyl -2,3 ,4,5 -te=hydr-o-7,.3 -d ict-hoxy-5 -ph cny I bcnzo LiiazeLpin--'-vl)- 4 ,4,4-Lriiluoro-2-butanonez S,S-dioxide; beanzothaztpine 1,1-dioxide; -(,22-tri fluoro ethyl) -2 3,4,3 -zeLahydro- 7.8-dime .o x y- 5-phen vlI- 1,4ber2oLiiaz-cpin-3-yl)-2-butaone S.S-dioxide;
AMENDED
d. 4bvztaz:n: b utancnc ioie y1)OXY)'z -ansul folli c acid1, ioc; ,,5t~ravdo3-(2-oxobutvi)-5-phe.nvi- I __-izLiat'm8 yi)oxy)Cehylt-imerl-ylarnmoniurn iodide 1.1-dioxide; -buy- -3 e hyll-2,3,4, talh,do-- eh cnxy- i-he-tzch a4~rz:hia L~ n 1,-dio )-2 burtanone S,S-dioxide- hydroch-loride 1.1 hydrate; ,5-Te~rahydW-o-3-isooro pyl-3-rner-hvl-5-Tjhe:ny-I 1,1-dioxid.- 0.66 (-+)trans- -E hyi- I3 In -erh~do7Sdrehx--h~114bno.e 2-butaone S,S-dioxide; A.A. EIND 2 22 cycohe-xan.) 1,1-dioxide, mp 177-179OC; oer-zotn~iaztplrne 'I.1.dioxidz 0.25 np 1 0-1320C; cyc lohexane) 1, 1-dioxide. mu 210-211 OC; cyc~ohcxanc) t,1I-diioxidc, mp 2 10-2 1 OC; beazothuazeclnc hvd~ochloidc, o 211-27130C; beazoLhPaz-pne iydoc''Jrded rn 268-20 0
C;
cvclotpenxan) hydrocloie 0.25 rau 224-226c)C; (+-)-2,3,4,5-Tca-ahydro-5-phenvlsp oiro(1,4-oenzotmiaztrn rie-3, I'cyctohcxane) hydrochloridc 1,-i2. mo 167-169 0 C yl)propionic acid 1. 1-dioxide 0.5 mo, 132-13 OC: A.ME Nnmf 3 3 cerizoLHiaztp:ine, mp 69-740C; bnzotdhiaze pinle 1, 1-dioxid:, rzp 116-1 13CC; bznzouhizzoiri I -oxidt, trno 91-93 0
C;
benz:o tiazze ic 1,1 -dioxi"d.. rrip 14 9-15 i C; b.-rzothia.eine 1oIce MO 92.930 C; beaz=r iaze'- in 1,1-dioxide, mo 101-103 0
C;
(-)-C-3-Butyl-3-ethvl-2,3,4,5-teay..ro-5-(3 -oyridylt)-I .4benzoLhiazc-jine 1,7"-dioxide, mo 60-61CC; carbaldehyde 1 1 -dioxide, mo 162-164CC; bcra.othi azzinc 1,1-dioxi-de- 0.66 ?E20O, rrio 1 19-120OC; bceazothiazc-pinc 1,1-dioxide, mp 121-124C, benzothiiazcpinec 1, 1-dioxide, rnD I150 1 52C; berizothiazep inc 1,1-dioxide. tri 20 2205cC; flpropanoi 1,1-dioxidc rnp 164.165;CC; 17 9 -18100C: benzothiazzpinte Li-dioxid, mp 50-520C; 3 B u-3 I 3 -ehv I 5t e rah v ro ohnv I :Io~c) o o F) 1,+4thiazcpirc 1.I1-dioxide- 0. 125 H-20, -no 75-77 0
C;
3, 1 -cycloh'exane) 1,.1 -dioxidt. rnc 142-1i43 OC; oezotnian-3-Li-vl)-2-buanoie S,S-diox:'dc pioc2re mo75- I ,4-ber-LotLEia~pLn 1, 1-dioxidc, mo 123-131 0
C;
-Burui1-3 nhyI-2,3,.-.5-cc:.-hvdro-5-(2 -0,-ndy I)-I1,4benzothiaze inc 1,1-dioxide, IMP 50-330C.; benzothiazepine! 1;PI:dioxide 0.25 'hvd.-ate, mp 153-! 5500; be'.zot.iazeo)*In-3-vI)-2.,buaione- S.S-cdioxid-, ,no 142. 14J60 C; -1,4t-be-izoL--iaz!:ijn- 1,1-a-locd.phc-nyl -1,4_-enzoth-iaz:pinc 1,1-dioxyide bcnzochiiazcpi*n-3 -yi)-3-but2anon-e S,S-dioxide be-izothiaze o'in-3-vi)-3-outa-none S.S-d4ioxide oenztazpin- I-bun~one S.S-dioxide 1-(3 EchI2..-Lea-ahvdro- 7. 8-dim cthox.v- 5-ahtmvk 1.4- AMENDED SH-EET 365 Der-= 'on- v).44~fuz--o~o~ S.S-dioxidt I -thv y!-2,1 ,45 0 rhr-7 -Idimenxi 1 c henv-1,4 oea~tnazeL1--y1-3,,4 4,4~en 'or-2-U2.Sdone Sao~ (-i-)-Tans-I -3-etvl-.3 ,,S-ehvdo-7S-di~thxv--oivi- ~eaotm az £n3-l)-.4,-trfio~a2-btann~S.s-dioxidt 1 -ethyli-27-',4,5 ccahy'&o- 8-rneuovv- 5- p -nyl i- ~enz &iz~pL-~3-y)-44,4-ifloro2-btzraneS,S-:Ioxide 4- 7ifiuoroburyi)-1I,4-berzot.hiaze-,inc 1,1 -dioxide (--)-Trar~s-3-ethyi-2,J ,4,5 -tec-ahvdro-7,-dir-,*-ne.xy-pe nyl-3'-(4.4,I 4- -ifluorobut'I)-I A roezodi~azepjine 1,1-dioxidel phnenyi-lIA- be-izothiazec:in-3-yI)-2-outznone- S,S-dioxide 1 S(-222~fureh1-., .S-i-no.O dretxc'> be hcr azco n- 7oizi--y Iox )propaeut2oi ci S,S-dioxidc oenzo thiazep in-3-yl)-2-butaron, SS-dioxide I-czoiazn--yix)propbuanoesioc aci 1,-dioxide -ethyl -2.3 ,4,5 5-teuzihvdro-7, -o xto v-i5 hen 'e.i.otiazep in-8-vI)oxv~rhropanesifionic acid 1.1 -dioxide AM FN oF_ n~P~ ~~arn* 0 A-23 c c rmpcur of f.ul a (O)n R 1 is an- L t cg c o f fr om 0 t o 4; ni is an integer ofC from 0 to 2; R is an atom or group selcc::d fr-om- halogen, cyano, laito, a-Lkyl, aikoxy, az-vl, ne~eroaryi, aryloxy, arylaiLlkoxy, arailkyl, aLkaryl, -O(CH2i-)DSO3R' 0(CH2))PNRI 1
R
12
-O(CH-)
0
N-'R
1
IR
12 RI 4
CORI
1 _C02R 1 1, CONRI IR 12 -CHiOR 1 1 -NT! IR 12 -NHCORI 1 -NHSO-)tl 1
-SRI
1 -SO-iRl 1, -SO-)NRl lR 12 _SO.R 1 wherin pis anintcger irom Ito 4, RI I and RI 2 iLrdeperidently selce---d Erom hydrogen. C 1 6 alkyl =nd phernyl, and R 14 is h','dzogeri Or C 1 6 ailkyl or P, is a group -OCH2O- which formas a fuirther ring attached X, whe--rei said ailkyl aLkox' aryl, h:eor',aruloxv, az 1 'laikoxy, iazLkyl and aikarzyl groups a-e o otionaily subs-ditcd by one or more- atoms or groups see:dfroM halogenr, clzo, alitilk alkyl, aLkcx-,,, -CORI 1 -CO.-7R 1 1
-SO
3
R
1 Ihri R, I is as hc7:einbcfor- defined and -NRI "RI 5 wherei' p 1 4 is as her-einbefore detned RI 5 is hydrogen or C 1- 6 alkyfl; R I is Ihydro gen or C 1 alkyl; P!is an atom or group sel.ct.-d from hyidroge:n. CI- 6 aly icluding c),ci-caikvlI and cvcloalkylaLkvl), CI-4 alkov., py-myl, thienyl. pviv,1,3-benzodioxoto, phenyl and riaphthyl, which goups are opotiontally substituted_ by one or more aioms or L-ouzs ;ndcoendently selcc-ed from haiogen. c'.,ano. ruoo, ccarboxyl, clhcn'i.
phenoxy, benzvloxv,, -C0RII, -CO-)RI 1 -CONRI 1
R'I
2 -CH-,0RII. -NRl 1
R
12 -NHCOR'l 1. -NIHSO)IP 1 -5R 1 l -S02Y S .0 3 R (-eri R 1 ad- rea2 3
R
1 (wht.-cin c, R and R 1 art astrc:___;or dI hydrogen or C 1 6 alkvi); R3 is hydrogen, OH, C 1 6 alkvl. C 1 6 alkoxy 07 -0C I aCVl;
R
4 is a group independently selected from C 1 6 (including cycloalky1 cycloalkylalkyl), C2.
6 alkenyl and C2- 6 aikvn-,yl, which groups are cotionall., substituted by one or more atoms or crouos indtencient ly selected from haloge.
oxo, Cl ai'koxy,,_COIRl 4
>TR
4 Rb, -qR 1 4
-S(O)CI
1 6 -S0)PI' _S0 3
R
1 4 (wAhereinr 1 p 4 and R15 are hercinbef-rore define-d);
R
5 is a group indepe-ndently selected f"romn C-7- aikyl (Including~ cycloalkvi an cycloalkyialkyl), C2- 6 aLkenyl, and C-2 6 alkynyl, which groups a-re ootionaily substituted by one or more atoms or groups independently selected from halozen, oxo, Cl_ 4 aikox -CO-)R 1 4
NR
1 4
R
1 5 -S Rl 4 C 1 6 alkyl, -SO0) RI 4 -S0 3 R 14 (wvherei n R I and RI 5 arc hereinbefore defined); or p 4 and R5, toget,--r with the carbon atom to wh~ich zthey are attached, formo a C3..7 s-p~ro cvcloalkA-- group wrnch is optionally substituted by one or m~ore atoms or zroups independently selected from halogen, C 1 6 aloy .ORL,-0Rl 4 -d -NR1 4 whcre p,4and Rl are asheeneo etrd) p 6 and R 7 a-re indepe-ndently selected from hydroen. and C 1 6 allkvl; and X is an aromatic or non-aromnatic monocyclic or bityciic ring system to 10 carbon atomrs (including the two carbon atomns f-or rni part of the_ thazeoine ring) wherein optionally one or more of thez carbon atoms islare re.Jlaccd by heteroatom(s) independently selected from nitrogen, oxygen and sulphur; with the uroviso that wvhen I is an Integer of f.rorn 0 to 4, R 3 r 3 or OH, R 2 unsubstiruted phenyl or pheny'l substiitd by one or more atoms or groups independently selected from halogen. nitro. phenvialkoxy, C 1 -4l1oxY, C 1 6 alkyl and 0(CH-))pSO-,R' wherein p and RI I are as hereinbefore defined. wher=eri said phenylalkoxy, alkoxv and alkyl groups art optionally substituted by one or more halogen atoms. and X isa fused oheny.)l Lig hen. R 4 is othe.r tha a, AMENDED
SHEET
szraiczht aik.' -roL:c Znd R' :s outncr :riani a ta2:2K; I is 0, 1 or 2; n is I or 2; RI, R 6 and R7 all :'vdrogen; R3 is hydrogen or hy'drxy; and X is a fused phenyl. naph&hyI, pv'r-'l, t hicnyl or pynniyl, oup.
A como~ound as d-1_,s in Ai-23 A-24 wnerc:n Ilis 0 or 1; n Is 2; and
R
2 is pyryl),, thienyl, pyridyl, phenyl or naphthyl, such groups bngoptio naily.
substLituted by one or more atoms or groups indepecndenitly sele=ced from halogzen, c'vano, nito,. caroboxyl, ohc.-yl, chenoxy, benzylioxy, -CORI 1, -COa)RI 1, -CONRI lRi 2
-C,,.CR
1 1, NrRI IP 12 -N'-HCORI 1,
-NSO-,R
1 1 -SRI 1, -SOiRl 1, -S 0 3 R' 1 (wherein R 1 I and R 12 arineedtl selected f',r :ihyd.-ogen, C1- 6 al:<Yl anId 0*hnYlD, -O(CH-7)'NrR1IIR1 2 -O(C'.;.)WR1IR1 2 RI3 and -O(CH-))pSO 3 Rl I (wherein p is an iteger of from I to 4, TO I and R 12 are as hetr:inbcfore definedc and R 1 3' is hydrogen or C 1- alkyl).
AM4wENDED SHEET, 3 7D 2 c. OM P 0 UI---I s'I des= dioxi de; benzothi azcr inc I.j -dioxide;, (--trans-3 -ethyl-2.3 ,4 5 -etrahydro-3 -methaoxy 01.y1)- 5~~rs-1 bcrizothiaz-pirie ,,I-diioxidc; butanontS.S-dioxide: yl)-2-buranione S.S-dioxide hydrocl iLIde 1.1 hydatc; (-4-)-rans 3-(1 -butt:nyl)-3 -ethyl- 273,4.5 t eahydr-o- 5- phcnyl -I .4b~ohaz:njine tI.Idioxide hydrochloride 0.4 hydrate; benzo&_h;aze-oine 1, 1 -dioxide hvdroclor-ide he-mIhy&ate-; oerizothiazepirne I,1I -dioxidec hydrocloridie; (++)-raxis-ethyl 3 -(3-ethvl1-2_3,4_-tezahydL-o-5 -ohnvi-1 4 b~e~o ;7 I' yl)propionate 1,1 -dioxide; butca-2-onec 1,1 -dioxidec; cyclohexane) 1,1-dioxide; diioxide- -bury 1-3 -ethyl -2,3,4,-;--etrydro-4-hydroxy;-5-(4 -pyndy)-I ,4benzothiazepLnc 1,1-dioxide; +trans- 3-butylI- 3-cthyl -2.3 5-teL-avdro-5 L-hi ny1) -be r.zot c p, 1 dioxide; benrzothiazepine 1,1i-dioxide: (+-)-trans-3-but '1-3-ethvl1-2.3,4-tahd-5heyyro(,F)lberizothiazepine 1.1-dioxide; (-+trarns- 3-but),lI- 3-ethvl -3.4.5.7-tetrah vdro- 3-chc ny 1-2 H- pyrro lo(3, 4-7)-l4 benzothiazepiric 1.1-dioxide- 0.1 hydrate: A AFNILED '13HEF 937/1 (+trans c Iehvi2.3 4>~fYP'~ ic *e-nzoth iazetine I 1 ioxi"' t 1,1-dioxide 0.25 benzothIaz.-rinc; dioxidc 0.66 1.1 dioxide; e x~ r oy)-],4-oeaothazeine1-dioxide' 'hvdzochiorid:e; cyclohexane) 1,1-dioxide.; yI)-2-butanonc S,S-dioxide hydrochlor-ide,; -b r 13 eh l2 ,45-tcayr-5-phe np 1,4benzothiaztoirie 1,1-dioxide; b rothiazcpin-3-yl)-2-bunfonc S.S-dioxide-; benizothnazcpie IJ.-dioxude; I -(3--Ethyl-2,3,4,5-tezahydo-7,-dieLioxy--fel~fY- 14 be.-zothiazepin-3-yl)-3-butanorie S,S-dioxidt; (3Eyi23,.-eahd--mho h1-,-b'oh zm yl)- I-butarione S,S-di*oxide; I -(3-Ethyi-2,3 ,4",5-terrahydr-o-7,S- dimethoxy-5-oheflvi- 1,4benzothiazcpin-3-yl)--butfoflc S,S-dioxide; 1 -ethyl-223,4I,5-tetrayd-o-7,-diLt-foxy- -phl- 1,4ben-zothiazepin-3-yi)-,4,4-rifrluoroI -butanone S ,S-dioxidc; (+&-)-trans-lI (3-ethyl-2.3,4,5-tetr- -ydro-7.S-dime ,oxy-5-pheflI- 1,4ben-zothiazzepin-3-yl)-3.3.4,,4-)CfltafluorO--?but-afloflC S,S-dioxidt; (-+trans- 1 -ethyl -2.3.4,5-tetraydro-7, -dImc!hoxy-5-f~li 1,4bezothiaz.eon-3-l)-,.,4-riluo-o-'OI-utffofl S,S-dioxide; &fubu')- az .4ben--tmaze- iue I, -vl)-2-btrtaonz S,S-ciioxide; boenzothiaze- in-8-y1)oxy)prooanesuLfoai.c acid 1, -dioxie; (+--~ans2-(3-ethy1-2,J,4 ,5-tehvro-3-(2-oxobur-A)-5-phny1-1,4ber~othaz~nn-8yl~oy~ehyI&ethlarnoniim odide 1 -dioxid:; A-27 A compoound as in A-21f the formula q) (O)n R -r0
S
(a)
N
(R)
1
R
2 R3 I is an integer of -Eom 0 to n is an integer of from 0 to 2; R is an atom or sLc!tcttd from halager, cyn, -ao, allkvl ailkoxy, 2-I, b e te-oaryl1, ar-ylIoxy arylIalko x, aralkyl aLKaryt, C0R 1 1 I, C0-) R"I -CONR I 1 2 -C-ORII, -NR 11
R
12 -N,-HCORII, *NHFSO-), 11
-SR
11
-SO-,RI
1 -S0 3
R
1
II
wherein R 11 and R 12 axe indep,=dcritiy selected Efrm hydrogen, CI6 aLky and phenyl, whereinl said aik-'I, alkoxy, aryl, hete-oaryi, aryjioxy, aryiaikoxy, a-ralvi and alkarylgroups are optioaaily stbs-,4-ute,,d by one or More atoms or groups selccted.
ftrom halogen. nitro.rdile. ailcy'i, aikoxy, -OR 11
-CO-,R
1 -S0 3
R
11 weri R is as herei;nbefore defined and -RR 1 whein R14~ 'id R 15 are as heretinbefort d cEl aned, RI and R 3 are. independently sciecced from hydrogen and C 1 6 alkyl: 373 7.
2 is an atom or group selected from hvdrogtem Ci alkyl (inciuding c,.ccI~ n cycloalkylailkyl), Cl-, alkoxy, pyrril, thienyli, pV-dylj2-b.p'odiooio na~l hthyl, which S _'Itsar oct onally substitutad' b-V ont Or M-0rt atOMS -7 zr~S independently selected from halogen, cyano, nitro, ca-boxyl, phenyl, pnenoxy, benzyloxy, -CORI 1 -COiR 1 1, -CONRI IR 12 -CHa)ORI 1 -NRl lR12' _NHCOR 1
-NHSO
2 RI 1 -SRI 1 -S02_Rl 1 -S0 3 Rl I (wherein RI I and R 12 are independently selected from hydrogen, CI..
6 alkyl and phenyl), -O(CH- 2
NR
1
R
12 -O(CH) N~ 1 1
R
2
R
1 ~and S0 3 RI I (wherein p is an integer Of from 1 to 4, RI lpand R 12 are as hereLibefore de~nned and RI 3 is hydrogen or C 1 6 aikyl);
R
4 is a group independently selected from C 1 6 alk-yl (including cycloaikyl ano.
cvcloalkylalkyl), C2- 6 alkenyvl and C2..6 alkynyl, which groups are opoinaiiv substituted by one or more atoms or groups indepe-ndently selected from halogen, Cl alkoxy, -C02-RI 4
-NR
14
R
15 pS 3 14 (wherein p 14 and R15 are independently selected from hydrogen and C 1 6 aLlkyl) and R 16 COR1 7 where R 16 is a C 0 1- aLkylene group and RI 7 is a C 1 4 alkyl group;
R
5 is a group independently selected from C2..
6 alkyl (including cycloalkyl and cycloaikylalkyl,), C-2- 6 aL.nyl and C 2 6 aikYnylI, which groups are octionally substituted b y one or more atoms or groups independently selected from halogen,
C
14 a~kxy,-C0R 1
R
14
RI
5 -S0 3
R
14 (henR 4 and R 1 5 r independently selected from hydrogen and C 1 6 alkyl) and -R 16 00RI 7 where R1~6 is a C 1 4 aRikylenec group) and R 17 is a C 1 4 aLkyl zroup; or R 4 and .R 5 together with the carbon atom to wh ich they are attached, form 3 7 spiro cycloalkyl group) which is optionally subst ituted by one or more atoms or groups inder~cndentlv selecte-d from halogen, C 1 6 alkoxy, -C02-R 1 4 S0 3
RI
4 and ,'aR 14
RI.
5 (where R JA and R 15 are as nereinbefort defined;
R
6 and R 7 arc independently selected from hydrogen and C 1 6 aikyl; and X is an aromatic or non-aromatic monocyclic or bicyclic ring system having from 5 t.o carbon atoms (including the two carbon atoms forming part of the thiazepine ring) wherein optionally one or more of the carbon atoms is/are replaced by heteroatomn(s) independently selected from nitrogen, oxygen and sulphur;
'U.
3714 ,tri the proviso ihat wrn s an Mut.c.: o 0 to 4. R' R' 6 'astst;imia ohenvi or- ohetvl sti:bszirtd by one. or more t: r~ r~c~ indenecnd.-ntly seiezcd from hL-,oc::n r..no. phnrylaikoxy, aikox'. C -0 ai k, j and -O(CH-i) S 0 R 1 w io and RII are as> ME -oi P h cn v I 1k 0x P a-)k-oxy and a2<-i groups are optio:oaily substttdb n rrtr halogen atomns, and X is a fuse-d phenyi ringy, then R 4 is other- thani a C 1 -6 3=2i, alkyl group and R? is Other tham a C2 5 straight aLkyl group; and salts, solvates and zhysioiogicaIly funtlndrivatives tr.ereor.
A-23 AcomUound of formula (O)n
R
S
P,
I is an Liteger of fiom 0 to 4: n is an inte~er of from 0 to 2; R is an atom or group secotec-d from bLaiogen., ovano, rlito, alkyl, alkon., arvi, hetcroaryl, aryloxy, arylalkoxy, araLkyl aLkaryl, -O(CFj1PS03RI 1, -CObfRI 1
R
12
-CH
2 ORI 1, ,,RI 1
R
12
CORI
1
-NHSO
2
R
1 1, -SRl 1,
-SO-JR
1 1, -SO 2 NR IRI 2 S0R 1 wherein p is an integer, of from I to 4, _RII and
R
12 are independently selecte-d from hydrogen. CI- 6 alkyl and phenyl, and R 14 is hydrogen or CI- alkyl1, or R is a group whicnh forms a further rn attached to X, wherein said alkl loxy, arylI, h:,roary!, arvioxyf, aryflaikoxy, ara.lkyl and allkaryl groups are opionally subsituted by one or more atoms or grouos sc!cted from halogen ioo, nililt. alkyl, alkoxv -CORI I, *CO-,RI I, -SO-.Rl I wherein. RI I is as hereinbefore defined and _\NR 14 RI5 whe.rein R 14 is as hereixibefore defiried and RI 5 is hdrogcn orC 1-6alkyl: ~i p2 isdogn
R
2 is an atom or QrounO seiete!1 frm-~oe.C li iz~igccoL and cycloaikyialkvi), C 1 -4 alkox, yy, thienyl, p)ry, 2zGcJAxolo, phi.
and naohthyl, which groups are optionally substituted by one or more atoms or, groups indeednl elcced from halogen, cyano. nitro, carboxyl, phenyl, pherioxy, ber,--yloxy, -COR[ 1 ,I -CO-R 1 1, -CONR 1 1
R
12 -CH-7ORI 1, -YR 1
IR
12
-NTHCO
1
,NHOR
1
SR
1 -S0 3 RI I (wherei;n RI I and R 12 ar a hereinbefore de-fined), -O(C"-)pNRI IR 12 -O(CF-2)pN Rl IRI 2 RI3 and -O(CH,)pSOJRl (wherecin p, RI and R 12 are as 'here inoe fort: detllnec _13 is hydirogen Or C 1 6 alkyl);
R
3 is hydrogen, OH, Cl.
6 alkyl, C 1 6 aikoxy Or -0CI 1 6 acyl;
R
4 is a group independently selected from Cj- 6 alkyl (including cycloalk-yi and cycloalkylalkyl), C-2 6 a.Lkenyl and C2- 6 alky nyl, which groups are optionally substituted by one or more atoms or groups independently selected from halogen, oxo, C 1 4 alkoxy, -C02)R 1 4 -NRl 4
R
1 5, -SR 14
-S(O)C
1 6 aikyfl, -S02)R 1 4 -S0 3 R 14 (wherein R 14 and R 15 are as hereiriberore- descrlibed); is a group indepenidently selected from C2- 6 aLkylI (including cy.cloalkyfl and cyc loalkylalkyl), C2- 6 aLke<nyl, and C2- 6 alky-nyl, waivrch groups are optionally substituted by one or m-ore atoms or groups inoepenritnly selected "-rm halogen.
oxo, C 1 4 alkoxy, -CORk, -NR 14 RI5, -SR 14
-S(O)CI-
6 alkyl, -SO-)R 1 4 -S0 3
RI
4 (wherein R 14 and R 15 are as here-inbefort defind) or p 4 and R 5 together with the carbon atom to wrui-b thecy are attached, form a C3-7 spiro cycloalkyl group which is optionally substituted by one or more atoms or g-roups inde-pendently selected f~omn halogen. Cl..6 alkoxy, -C02)R 1 4 pS0 3 14 and
-NR
14
RI
5 (where R 14 and R 15 are as hereinbefore defined;
R
6 and R 7 are independertly selected fr om hydrogeni andC 6 alIkyl; and X is an aromatic or non-aromnatic monocyclic or bicyciic ring systemn having from to 10 carbon atoms (including the two carbon atomns forming part of the thiaztpine ring) wherein optionally one or more of the car-bon atoms islare- replaced by heteroatom(s) independenitly selected from nitrogen, oxygen and sulphur, AMENDED SHEET, wvith the oraviso that whie' I is arn r t fra-. 0 to RR7 H, R or OH., -2 =u-sbt::dpev r~::is:s~e yo~o ~ra groups independently selected from haloizen, nitro, phenylalkoxy, C 1 alkox', C 1 alky-,l arnd -0(C.Hi)-SO 3 Rl Iwhertin p and Rl I art as herecinbefarc de-fined, whter said phenylalkoxy, alkoxy' and alkyl groups are- optionally substituted by one or more hailoqen atoms, and X is a fused phenyi ring, then R-1 ig other than a C16 straight alkyl group and R 5 Is othe-r than a sraidght alkyl groupJ, and salts, solvates and physiologically ft-ictional derivatives theZreof for use in thtrapy, AMENDEDSHr =124-125 C.
3Die zh-yl 3 5~ 3- ce aydro 5 pen 1 I ':e-ozhae !,!-dioxide, mo 100-1024 0
C;
33- uz), 1-2 3. 5- -rahvdr-m5"y5-o phenyl.- Ie-bzaia Ze-p thae1,1-dioxide, r) 103-0 0 40 G be~oheie1,1-dioxide, mp 120-130 0
C;
1,1-dioxi-de.:io 101-103'C 3-E-zhyl-2,3,4,5-cetr:ahvidro- 3-metc'y-5-pheniv1-l.-4-bemz.-o:hi*azeo-ne hydrochlotride 0.25H 0, ,no 162-164 0 C (e ff.) 33-Dihl-2,3,4, 5--eydro--5v-3jerv-he'v-1.-bcezo-ize~ hydrochloride, mo 211-214 0 C AHME~flD ;Pj J7pf 0en o101-103 C ?infe, Fo- 72-74 0
C;
hydrochnlocide 0.25H,0, mo 205-207 0
C
3 Ethyl-2 .5 -tecrahvd-ro ohanvI' Droovi I ,4-ez~i~o hydrochloride, 209-2L 0
C;
3 -Echl 2..345 -cecrahydro- 5 -phenyl 3 ro :yl I-beflzo r-azevL'.e 1.1 -dioxide hydrochlo ridie 0 3 H,0 206 -209 0c.
2 3 5 .Te c:ahyd-.o -5 -penL 3 3 -i)ov L 4 belzo zhia e n 3 ,3 -Dibuly- 2 3, 4 5 e craydro 5 -heny1- i .4 -ben.-o :hi~aze:o ire hydrochlorioe, no209-212 0
C;
4-ydrochloride, mp 2-03-205OC: hydrochloride. mp 205-207 0 1,1-dioxide 'hydrochloride. o 209-21?0r; 2.3 .4.5.Terrahydro-3-methyl-3-peltY- maleace. mp 182-1830OC l,4-benzor-hiazepine 1,1-dioxide, 113 3-11.0 0
C;
-Butyl 3- e thl 2 ,3 5 zerahydro 7 me zoxv-5- nyI- 1, 4 -'oenzochiaZepine, Lighc yellow oi; I ,4-benzotchiazep)ine, light yellow- oil; 1,4-'enzozhiazeoine 1,1-dioxide, ttp L13-115 0C; 3 -Buzv-3 -erhy1-2, 3i5- erahdro-7-nechoxy- l.4-benzothiazeoi.e 1-oxide, ma~ 103-L05 C; (+-)-Trans 3-3u:yl 3- e hy L- 2 ,3.4 5 crahdro 7-me chox-5Pheny1 1,t4-ber-zo:";azeoine 1,1-dioxide hydiroch-Loride, rp 199-120l 0
C;
(+-)-Trarns-3-3ur-y1-3-ethiyl-5-chen.yl-2,3.4-,5-tetr-a'nv;dro-L.4benzochiazepine I-oxide, mo 98-1~ 0
'C:
'ce7zochiazepine 1-oxide, ro133-12-6 0C;_ -C;s-7-Chloro- 3-butvl- 3-echyl- 2.3. 4,5- cetrahnvcr-o 1,4-benzochiazeoine 0.4 coluene, light yellow oil; 1,&-benzothiaze~ine 0.3 coluene, light yellow o;i: 1.4oenothazeine 1.1-dioxide. mo 100-1020C -7 be z oth ia7-e p i ne ,-di oxi de I ydroc ch cr;- 2 0 4. 0 6 00 benzochiazepine 1,1-dioxide, m'D 1553-56C; 1,4-'berzoiazeLoine, mo 75-77 0 C 1~.oe~ohizeire ,1-dicxide. rnp 109-11-- 0C: 1,4-benzochiazeLrne, mp 76-78a 0
C;
hydro-1,4.-benzochaze~ine o 98- OC: 1,.-benzochiaZe-oine 1. 1-dioxide 0c M10r d a 0.3 H:i,.
MDv 178-180 0C; 1,4-'benzochiazeoine 1,1-dioxide hvd-:ocn.torice, no 18613800; benzothiazenine 1.1--dioxide. mr, 139-L.2 0
C:
benZochiazepirie 1,1-dioxide, ma 139-L.1,2 0
C:
i) -25 4 3en~vLox:,henyl) -,-ehl 3 -az hydro-1,4-benzochiaze-jine 1,4-dioxide, mv 137-138%C; hydro-1,4-benzo-chiazevine, mn 97-98 C :',iazeoz4n- -5-yI)phenoxy~prouanesulohonic ac id 1, 1-dicxide, rnp 2700C (dec.) (+-)-Trarns-3-Bucyl-3-echyl-2,3 cezra',id-o- -(3--Fluoroohenyl)- 1, 4 -benzochazepine 1.!-dioxide, hymp Loie op 194-190 C; ,benthazeine 1,1-dioxide, 1-1 C benzothiazevine 1,1-dioxide, rnp 11-113 0
C:
)-Cias-3-3uyl- 3-ey -2 3.-15 5erhvr rfucmcnl phenyl)-1,4-bernzochiazeoine 1.1-dioxide, 64-65 0
C
o-echylphertyl)-1.4-benzochi-azeuine 1.1-dioxide, mo 110-L12 0C pheni)-L.4-'oenzochiazepine 1.L-dioxide. mo 205-213 0
C:
A IL ~,it 2J'Z ?'I-enyi)-1 4 -ben .za hia::e: ine I. benzothiazepine 1,1-dioxide, mo 86-87 0 ;and -(ency-3-bu:'4l-23tv2 L, 5--ac-.ah dro- chiazetine 1.1-dioxide. mp 98-100O0 C; -Trans -3-Me chyl orooyl -2 .3 eA ce :rahvd.o 5-onenvl I benzochiazeoine 1,1-dioxide, mo L29-1300 C AMENDED SHEET 3 e3 A ccouno~'d olf forr~ia (1) is an (R)..offom0co2 P. and are atoms or groups indece rde n:ly selected firom h-alogen, :'icroj hniloy C alkoxy, C, and Il- 4 p 3" -nee~ o s n nceger of iro 1 oJan s hvdrogen orC alkyl, wherein said phenylalkoxy, alk<oxy and alkyl. groups are cocionalIy substitutced by one or moehalogen atonms; R. is a C 1 -,straight alkyl grouu; and is a C-6 straight alky! group; and salts, solvates and physiologicaLly functional d erivatZve s c.hereof.
AMENDED SHEET 3Jlfr A 31 A rom:rouno ot formula ()as v~~ R is anethyl, erchyl, n-nronvl or n-bucyl; and R 5is ethyl, n-oropyl. or n-buzyL; and salts. soivates and physiologically functional deriva:4ves thereot.
7k-33 A connourid of f:rrula as de~bdi A-31 which co-.Do-,.
is in the crans tonfiguracion as here;-n defin-ed, or a saltr, solvace. or physiologicaLly functional derivative :hereof.
A-34 A compound of formula as de=_J~ in A-32 hni ch compound is c-as3bcl3ecy12 345 chiazepine 1.1-dioxide, or a salt, solvatea, or ohv siolosicaiL.; functional derivati-ve tnereof.
The compound of formula 6eib'd ir A-33 which compound is in the or (RR.,SS)-Eorn.- or is a salt., solvate. or hyiLogically functional derivacive cf any chereof.
thiazepire !,1-dioxide or a saL:, soLy:,ate, or onvsioLogicaly functional derivative thereof.
thiazeoine 1,1-dioxide oenzozhiazeuine !,!-dioxide or1 a salt. soivate. or physiolozically functional thiereof.
i~Th. berzzzhepine I,L-iz~ A-36 A polymeric or oligomeric bile acid, prepared by polymerisation of a monomeric bile acid of the formula I G-X-A
(I)
in which G is a free bile acid or its alkali metal salt or a bile acid having rings A, B, C, D esterified on ring D and which is bonded via its ring A, B or C, to the group X, X is a bridge group and A is a polymerizable, ethylenically unsaturated group, or by copolymerisation with a monomer containing a polymerizable, ethylenically unsaturated double bond, or by copolymerisation with N-vinylpyrrolidone or its derivatives, and/or by copolymerisation with ethylenically unsaturated dicarboxylic anhydrides and ethylenically unsaturated dicarboxylic acids each having 2 to 6 carbon atoms; their esters or half esters, esters being understood as alkyl esters having 1-6 carbon atoms, 0.0. cycloalkyl esters having 5 to 8 carbon atoms, benzyl esters or phenyl esters.
A-37 A polymer or oligomer as described in A-36 wherein G is a free bile acid or its alkali metal salt or a bile acid esterified on ring D and which is bonded via its ring A, B or C, to the group X, to which the formula II applies in which Y is adjacent to G and is -NR' C 2Q *:o or is (Ci.Cl2)-alkylene or (C7-C 13 )-aralkylene, where individual methylene groups in the alkylene chain of the alkylene or aralkylene radical can be replaced by one or more groups selected from -NR' o I II II 0 0 o 386a o and p independently of one another are zero or 1, where o and p are not simultaneously zero, A is an ethylenically unsaturated group of the formula o
II
C N- or CH-C-R--.
II
o in which R' is hydrogen or CH 3 and
R
2 is 0 0 II II -NR- or a single bond, where the carbonyl groups are adjacent to the C-C double bond, R' and R" independently of one another are hydrogen or (Ci-C 6 )-alkyl.
A-38 A polymer or oligomer s described in A-37 wherein G corresponds to the formula I :n
R
3 to R 8 independently of one another are hydrogen, OH, NH2 or an OH group 3 6 protected by an OH protective group and one of the radicals R 3 to R 6 is a bond to the group X, where this bond starts from the positions 3 (R 3 or R 4 or 7 (R 5 or R 6 and the other position 7 or 3 in each case carries an OH group or a protected OH group, B is -OH, -0-alkali metal, -0-alkaline earth metal, -O-(C-Cl 2 )-alkyl, -Oallyl or -O-benzyl where alkyl is either n-alkyl or iso-alkyl and where the ester group formed o
II
386b is an ester which can be saponified both by acid and by base, Y is 0 o !1 II or -NR Z is (Ci-C 12 )-alkylene, (C 7
-C
13 )-aralkylene, where 1 to 3 methylene groups in the alkylene chain are replaced by the groups -NR-, or -NR'-C-N- II II II 0 0 0 and o and p independently of one another are zero or 1, where o and p are not simultaneously zero, A is 0 N- or CH=C-R where S. R' is hydrogen or CH 3 and R is
NR'-C-.
.5 -NIl- or a single bond, in which R' and R" independently of one another are hydrogen or (Ci-C 6 )-alkyl.
A-39 The polymeric or oligomeric bile acid of A-36 wherein said monomer S. containing a polymerizable, ethylenically unsaturated double bond is a monomer of formula IV 20 Hc=C--R 1 in which
R
9 is hydrogen or methyl and R' is o o o II II- II -C-0-RI. RIK.
386c -CN, -O-R 1 5 hydrogen halogen -SO 3 H, or -O-(CH 2
CH
2 0),R 16 in which R" is hydrogen, (CI-Clo)-alkyl, (Ci-Cio)-monohydroxyalkyl or-(CH2CH2-O-),R 16
R'
2
R
13
R
15 and R 16 are identical or different and are (Ci-Clo)-alkyl,
R'
4 is (Ci-Ci 8 )-alkyl and n is 1 to A polymer or oligomer as described in A-36 wherein the weight-average molecular weight is up 250,000 g/mol.
A-41 A polymer or oligomer as described in A-36 wherein in the case of copolymers the molar ratio of bile acid units to copolymerised monomer units is between 300:1 and 1:300.
A-42 A polymer or oligomer as described in A-36 wherein the crosslinking is carried out by means of copolymerization with ethylenically polyunsaturated monomers.
A-43 A polymer or oligomer as described in A-42 wherein the crosslinking is carried out with ethylenically polyunsaturated acrylic acid and methacrylic acid 15 derivatives.
A-44 A polymer or oligomer as described in A-42 wherein the crosslinking is Scarried out with acid amides of the formula V R' 0 0 v I I II I H2C=C-C-NH-D-Nn-C-CCH 2 in which 20 R 9 is hydrogen or methyl and D is where m is 1 to 10 and E is hydrogen or OH.
A-45 A pharmaceutical composition comprising a compound of A-36 and a pharmaceutically acceptable carrier.
386d A-46 The polymer or oligomer as described in A-40 wherein the weightaverage molecular weight is between 2,000 and 100,000 g/mol.
A-47 The polymer or oligomer as described in A-40 wherein the weightaverage molecular weight is between 3,000 and 60,000 g/mol.
A-48 The polymer or oligomer as described in A-38 wherein B is -OH, -0alkali metal, -O-(Ci-C 6 )-alkyl, -0-allyl or -O-benzyl.
A-49 The polymer or oligomer as described in A-38 wherein R 3 to R 8 independently of one another are hydrogen, OH, NH 2 or an OH group protected by an OH protective group and one of the radicals R 3 to R 6 is a bond to the group X, where this bond starts from the positions 3(R 3 or R 4 or 7 (R 5 or R 6 in the P-position, and the other position 7 or 3 in each case carries an OH group or a protected OH group.
The polymer of oligomer as described in A-37 wherein G is a free bile acid or its alkali metal salt or a bile acid esterified on ring D which is bonded via its ring A to the group X.
A-51 A polymer or oligomer as described in A-39 wherein the monomers are compounds according to the formula IV (meth)acrylic acid, (meth)acrylic acid esters, acrylamide and its derivatives, carboxylic acid vinyl esters having 3-20 carbon atoms or N-vinylpyrrolidone and its derivatives.
A-52 The polymeric or oligomeric bile acid of A-39 wherein said halogen is chlorine, bromine, or iodine.
A-53
I
H*
IHO' OH
H
OCHO
OiCO* 386e 48 g (122 mmol) of 3a,7a,12a-trihydroxy-24-nor-23-cholanic acid (=norcholic acid), 200 ml of formic acid and 1 ml of perchloric acid are stirred at 50 0 C for hours, the mixture is cooled to room temperature, 160 ml of acetic anhydride are added and the mixture is stirred for a further 15 minutes. It is poured onto 1.5 1 of water and the solid constituents are filtered off with suction and washed with 1 1 of water. The residue is dissolved in 700 ml of ether and washed three times with water. The organic phase is dried (MgSO 4 and concentrated. Yield 52 g of Example 1.
MS (FAB, 3-NBA/LiC1) C 26
H
38 0 8 (478), 485 (M+Li-) EXAMPLE 2
OH
oco o
H
T
T
H H O CO'' OC O O o, o 14\ coOHCO'' H'H OCO H g (10.4 mmol) of Example 1 are dissolved in 20 ml oftrifluoroacetic acid/5 ml of trifluoroacetic anhydride at 0°C. 840 mg (12 mmol) of sodium nitrite are added in portions in the course of one hour. The mixture is subsequently stirred at 0°C. for a further hour then at 40 0 C. for 2 hours. The solution is cooled to 0°C. again, neutralized 15 with 5N NaOH and extracted with dichloromethane. The organic phase is dried S (MgSO 4 and concentrated. Chromatography of the residue over silica gel (cyclohexane/ ethyl acetate=2:1) gives 3.1 g of Example 2.
MS (FAB, 3-NBA/LiCl) C 25
H
35 N0 6 (445), 452 (M+Li) 386f EXAMPLE 3
OHCO
OC
5
S
S g (3.37 mmol) of Example 2 and 5 g of KOH are dissolved in 50 ml of ethanol/water and the solution is heated under reflux. When the reaction has ended (monitoring by thin layer chromatography), the ethanol is stripped off and the residue is washed with ether. The aqueous phase is acidified with 2N HCI and extracted three times with ethylacetate. The combined organic phases are dried (MgSO 4 and concentrated 1.25g of Example 3 are obtained.
MS (FAB, 3-NBA/LiC1) C 22
H
36 0 5 (380), 387 (M+Li) EXAMPLE 4
S
S
H
N QOH 500 mg (12.87 mmol) of 3a,7a,12a-trihydroxy-24-nor-23-cholanic acid and 370 mg (36 mmol) of N-methylmorpholine are dissolved in 20 ml of THF. 0.34 ml (36 mmol) of t hyl chloroformate is added at 10 0 C. After 15 minutes, a solution of 270 mg (36 mmol) 387 of glycine in 5 ml of IN NaGH is added dropwise. The mixture is subsequently stirred at room temperature for 18 hours. The reaction mixture is concentrated and the residue is chromatographed over silica gel (dichloromethane/methanol= 320 mg of Example 4 are obtained.
MIS (FAB/3-NBA) C 25
H
41 N0 6 (451), 452 EXA VfPLE .4.
*9 9 4 9 5 4 U 4 9 9 9 9494 9 444*94 4 4
S
4 4
HOH
0
T
F
H14 340 mg of Example 5 are obtained from 500 mng (12.67 mmol) of norcholic acid and 450 mng (836 mmol) of taurine by the process described for Example 4.
MIS (FAB, 3-NBA) C 2 5
H
4 3 N0 7 S (501), 502 FX.A.,Pl 7 6 0 H'C-S -0" 0 g (25.3 mmol) of norcholic acid are dissolved in 50 ml of pyridine. 2.6 ml of riethanesulfonyl chloride are added drop.wise at 0 0 C. The reaction mixture is then 388 stirred at room temperature for 3 hours. It is poured onto ice-water and extracted three times with ethyl acetate. The organic phase is dried (MgSO 4 and concentrated. The crude product is crystallized from diisopropyl ether, filtered off with suction and then dried in vacuo. 11.2g of Example 6 are obtained.
MS (FAB, 3-NBA/LiCl)) C 24
H
40 0 7 S (472), 485 (M+2Li+-H EXAMPLE 7 o H H
II
H
3 C-S-O' OH II H 0 CMc
HOOM
0
T
H H G e H 000 38.7 g (81.9 mmol) of Example 6 and 6.9 g (106 mmol) of sodium azide are stirred in 350 ml ofdimethylformamide at 130C. for 2.5 hours. After cooling, the mixture is poured onto 1.5 1 of ice-water and extracted three times with ethyl acetate. The organic phase is dried (Mg SO 4 and concentrated. The crude product is esterified in a methanolic hydrochloric acid solution, prepared from 100 ml of methanol and 14 ml of acetyl chloride, at room temperature for 2 hours. For working up, the mixture is partly soo. concentrated and the product is poured onto 1 1 of water and extracted three times with ethyl acetate. After drying and concentration of the organic phase, the crude product is chromatographed over silica gel (cyclohexane/ethyl acetate=6:4). 9.0 g of Example 7 are obtained.
MS (FAB, 3-NBALiCl) C 24
H
39
N
3 0 4 (433), 440 (M+Li 389 EXAM?'LE 8 OMe (18.5 mmol) of Example 7 are hydrogenated with hydrogen in 220 ml of ethyl acetate in the presence of about 50 mg of 10% Pd/C. When the reaction has ended, the catalyst is filtered off and the filtrate is concentrated. Chromatography of the residue (methanol/triethylamine=95:5) gives 6.0 g of Example 8.
MS (FAB, 3-NBA/LiC1) C 24
H
41
NO
4 (407), 414 (M+Li+) 9 9* EXALE 9 oH o HzC--S--O II 0
COOCH,
0 4.3 g (8.6 mmol) of the mesylate (cf. EP-A-0 489 423) are heated at 100 to 110 0 C. in ml of dry DMF with 0.42 g (8.6 mmol) of sodium cyanide for 3 hours. The mixture is poured onto ice-water and extracted with ethyl acetate, and the residue from the organic phase is filtered over silica gel. (Ethyl acetate/heptane=2:l). 890 mg of nitrile are obtained.
390 MS (FAB, 3-NBA/LiC1) C 35
H
41 N0 4 (431), 438 (M+Li EXAM\PE g (3.48 mmol) of the nitrile from Example 9 are hydrogenated in 100 ml of methanol with addition of 10 ml of concentrated ammonia solution and 1 g of strength rhodium-on-A1 2 0 3 under 140 bar at 50 0 C. for 24 hours. The catalyst is filtered off with suction, the filtrate is concentrated and the residue is purified over silica gel (CH2C1 2 /MeOH/concentrated NH 3 solution=100:15:2). 1.1 g of amine (Example are obtained.
MS (FAB, 3-NBA/LiC1) C 26
H
45 N0 4 (435), 442 (M+Li 10 r EXAMPLE 11A OSLc 1 S 270 mg of dry zinc iodine are added to 9 g (21.4 mmol) of ketone (see equation 4) under argon in 50 ml of dry dichloromethane, and 10 ml (3.5 equivalents) of trimethylsilyl cyanide are added in portions, while cooling with ice. After about 1.5 hours, the reaction has ended. The residue which remains after concentration is purified with nheptane/ethyl acetate=l0:1 over silica gel. 12.1 g of the product are obtained as a colorless oil which predominantly comprises one stereoisomer.
SiRA MS (FAB, 3-NBA/LiCl) C 35
H
6 5
NO
5 Si 3 (664), 671 (M+Li EXA.MPLE 11B Mc3SiO
COOCH)
ci COO.Li °SM OSL J COOC
OH
2.1 ml (27.4 mmol) oftrifluoroacetic acid are first added to a suspension of 1.036 g (827.4 mmol) of sodium borohydride in dry THF, the mixture is stirred for 15 minutes and 12.1 g (18.2 mmol) of the nitrile from Example 11A in 40 ml of dry THF are then added, while cooling with ice. After 24 hours at room temperature, the mixture is worked up by addition of water and ether, the organic phase is extracted by shaking with hydrogen-carbonate solution and the residue is purified by chromatography with
CH
2
CL
2 /Ch 3 OH/concentrated NH 3 solution=100:10:15. 7.83 g of the amine are obtained.
0 MS (FAB, 3-NBA/LiC1) C 32
H
61 N05Si 2 (596), 603 (M+Li EXA.MPLE 12A 0 H o oc*
ATO
TT
H H A:0' OAc
H
392 g (42 mmol) of methyl ketone (cf. equation 2) are dissolved in 400 ml of methanol, 2.48 g (64 mmol) of sodium borohydride are added and the mixture is stirred at room temperature for 45 minutes. After addition of 400 ml of water, 2N HC1 is carefully added until the pH reaches 3. The mixture is concentrated, water is added again and the mixture is extracted with EA. The organic phase is dried and concentrated, and the residue is chromatographed over silica gel (cyclohexane/ethyl acetate 1:1).
Yield 15.1 MS (FAB, 3-NBA/LiC1) C 27
H
42 07 (478), 485 (M+Li EXAMPLE 123'
OH
H H AcO' OAc
H
0 0 o-s-C.x SAcO I
H
o AO OAc and the mixture is stirred at room temperature for 2 hours. For working up, water is e 1o° i0 15.g (31.5 mol) of alcohol (Example 12A) are dissolved in 250 ml ofdichloro- 393
HOH
HOH
2. g(.0 mo)of3tc~lc-tiydoy-4-o-2-hoaicaid .l 4.8mm0 of metyl 3j-amin-7ct~~ci-dhydrox-24-colanae (cf E-A0 775,13 1 mmol) ofhdoyezTriz n ml fdccoeycrojmd r in 1 0 m fd yt ta y ro u a tr o e p r t r f r2 o r. T e r a to mitue s onetrte ad h rsiueiscroatgrphdovr ilcagl chorfom H~j X
HO
0.4 14ol ofNO (5.42).tizlead104g(. m o)o dccoexlabdim r MS3 (FAB 3-(M/iI)C879li(9) 85(M L t33HS 0Oint\,3V4V 11,1 LON~ Ho H 0
HH
(-M-YO 16i 19H)DION11F."D (o.rvyp-N-CsY:D 7, zO-x-
H
HO, T
H
0 7Ak3LS 2 0 X-G2
T
I 08 -X-G2 M S ?B3 -T3 iC O H 21 HO 335C (NI U 0 Q.Mc
HI
1 22 Cs:4.NO.
0 T 0 ONI c
I
2.3 C- O. (334), HOi 0 391 C U*)
H
24 C~iHin..,C (768).
MAFNC~FD ~-4E
JPL
l: 0H GX 0 'Z (FAB. C.
C Hi,:OC (S812).
T T 0
OM'C
H
-6 HO 'OH(Vt TO !2i
CY.'
T
TABLE NI A. -1"
HOI
I I Om aH ,63 C(U* Ho c
T
HO
F T- ~-X-G2 M FA3
ONIC
T
OH
.9HO 35! M P
HI
T OHO%(
H
T
H
OR
C--1 (3 5 1 i~~n 398
HO
H OH 'HO I O H K
H
S(HO
i mehy HOe (Table OH
*T*
water and dried in vacuo. 2.5 g of Example 32 are obtained.
MS (FAB, 3-NBAiLiC1) C47H77NOs (784), 791 (M+Li Examples 33 to 50 of Tables 4 to 6 are obtained analogously to Example 32 from the 10 methyl esters (Tables 1-3).
«J H TA31 400 G-_7 33 Ms 37kB. AaC X -02 000H
HO
0
OH
HI
T H
OH
C,,H,NO
1 379 (MU) (763). 775 (~i AMENDED
SHEET
AMENDED
SHEET
T. 3LR -cz.E .O jX -C: 0 C i o E X- G2 3-S'3A/UC) OH H TABL E S 0 LX -02
HO
T
HO
H
OH
H
AMENDED
SHEET
4IOf 0 41
C.-!.NO
0 (USS).
HO
FO
0 OH 0 OH C,4,NC,(7) 7 ML (75-4).755 CH,,NO. (793). 905(,U (30) 907 (MU-1 4AE-NPQED -l i0' H -X-G2 M (FX3 -AtC
HO
T 0 aOH
H
0 0
HO
T 0 OH 0' H
H
01 H H (830).1937 MU C,.,NO (75).733(M- 747 Examvles 51 to 54 from Table 7 are obtaincd analogously to Ex~ample 5 ftom thse acids decsc-ibed above.
4v-3 1 7 i Oh -X-G2 M.S (FA.B >-NBA.ILO) T 0 '~Sv H H L 0 H 52 CHYOS(935). 92(Nt+H1
HOH
*I H-1
H
HO
0HOH
HI
T
HO
Examples 55 to 57 of Table 3 am- obu~aied antalogously to Ea~plc 4.
AMENDED SHEET TIk3LE 3 0 I
H
HO I 342 (NIH*)
HI
T
OR
HH
F O 09 cM+U).-
OH
HH
H H IH I OR Exa~uics 58 to 63 of Tab[- 9 obtzicd 1anaioguslY to Exalxmok 13.
AMENDED SHEET TA-BLE_ 9 HO H
H
(in fcflo-s.= t -ix oi Gkr If Cis zoc jio-m).
EIL GI-MS (TA. 58 9~N ,S9).
T 0 H IH 59 C.Em{,NO, 789 (N,-ui 0~ Ho"=CH
H
CHNO
H
H
61 C ,HNO 1 (798') HO 705 (NMtU') Ho" OH
H
IMENOME -SHEET, TABLE 9-continued
HH
HH
H0 H H G IS-' H
H
Ex Cpes6 tzfowi9 ofTabule 10 e obtc ak of IL a no on F-x- TBL 10B -NAU2
H
HOO H71(MU C 7HrNG7 (768).
775 (M+Ui') ~C~jflpfl ~l-tEET 1/07 TABLE
HH
(Th f~ a1e~ o C i 0o~nu n e e~~n f0M LL Cl- MS(FAB 3.NA/UH H6H CH,0 7 (6 Tie H 7 MU
C.,H
7 ,N0 3 (784).
791 (ML-)
C.
6
H-,NO
1 (77O).
771(+U C. 1 rInXO 1 s(6 763 QOI+LU) The sodium salts of Example 32 and all the examples of Tables 4 to 8 and 10 can be prepared. The compounfd is dissolved in methanol, an equimolar amount of IN aqueous NaOH is added and the mix=ir is then evaporated in vauo.
,I N iN *F n H FF 408 A54 A bile acid derivative of the formula I 2 wherein Gi is linked via the side chain on atom No. 17 with the bonding member X to atom No. 3 of G 2 and Gi is a radical of the formula II 0.
R(3) Z I CH] C -L H I H H in which Z is one of the following radicals H3C HiC CH- CH-CHi-.
H
I
C
or a single bond, 10 R(1) is H, an alkyl radical having 1 to 10 carbon atoms or an alkenyl radical having 2 to 10 carbon atoms, R R(5) are independently H, OH or R(2) and or R(4) and R(5) together form the oxygen of a carbonyl group, X is a single bond or a bridge member of the formula III O 0 II II C I i L4.. L L) in which A is an alkylene chain, which is branched or unbranched, and which is optionally interrupted by or phenylene, the linkage of the phenyl ring being in the ortho-, meta- or para-position and the chain comprising 2 to 12 chain members.
408 a B is an alkylene chain which is branched or unbranched and which is optionally interrupted by or phenylene, the linkage of the phenyl ring being in the ortho-, meta- or para-position and the chain comprising 2 to 12 chain members, L(2) and L(3) are identical or different and are selected from H, an alkyl radical or alkenyl radical having up to 10 carbon atoms, a cycloalkyl radical having 3 to 8 carbon atoms, a phenyl radical, which is unsubstituted or mono- to trisubstituted by F, Cl, Br, (Ci-C4)-alkyl or (Ci-C 4 )-alkoxy, or a benzyl radical, which is unsubstituted or mono- to trisubstituted by F, Cl, Br, (C 1
-C
4 )-alkyl or (C 1
-C
4 )-alkoxy, q is 0 to r is 0 or 1; s is 0 or 1; and t is 0 or 1,
G
2 is a radical of the formula IV 0 RC7) R(6) Z
T
I a 1
R()
15 in which Z is one of the following radicals t i C C C *or a single bond, with the proviso that Z may be 409 in only one of formulas II and IV; V is or or t when W is H or, V is -CH 2 or -CH 2
CH
2 when W is H or OH, Y is -OL, NHL,
-N
L.
or an amino acid or amino-sulfonic acid bonded via the amino group, selected from the group consisting of -NH-CH 2 -COOH, -NH-CH 2
-CH
2
SO
3
H,
-N-CH
2 -COOH =d -N-CH--CHi-SCH.
I I in which L is H, an alkyl radical or alkenyl radical having up to 10 carbon atoms, a cycloalkyl radical having 3 to 8 carbon atoms, a phenyl radical, which is unsubstituted or mono- to trisubstituted by F, Cl, Br, (Ci-C 4 )-alkyl or (Ci-C 4 )-alkoxy, or a benzyl radical, which is unsubstituted or mono- to trisubstituted by F, Cl, Br, (Ci-C 4 )-alkyl or (C 1
-C
4 alkoxy, and R(9) are independently H, OH or and R(7) or R(8) and R(9) together form the oxygen of a carbonyl group.
The bile acid derivative of the formula I, as described in A-54, wherein L is an 20 alkenyl radical having 2 to 10 carbon atoms.
A-56 The bile acid derivative of formula I, as described in A-54, wherein one or more of L(2) or L(3) is an alkenyl radical having 2 to 10 carbon atoms.
14on-absorba -Ie, i-lsolub 1 i- Ihasic, crosslinked polymers have been used for many years ior binding bile acids and utilized therapeutically Bile acid derivatives described ~n Patent Aoolicatiofl EP-A-O. 489 423 have a high affinity for the AMENDED "'-EE intestinal bile acid transportation system and therefure allow specific inhibition of the enterohepatic circulation.
A-58 dimeric bile acid derivatives of the formula G1-X-G2 in which G1 and G2 are linked in positions 3, 7 or 12 or by the side chain via the linker X. Bile acid derivatives in which G1 is bonded to X via positions 7 or 12 and G2 Sis bonded to X via positions 3, 7 or 12 or the side chain AMENC
S~NE
are no', described in T-he examoles of the Euzo'ea~i Patent _bil acidz deri'vatives of the f-r-ula
I
G! X G2 72 in which Gi is a radical of the fo=.ula II ~n which Y has the following meaning: O-Ka, in which Ka is an alkali metal, alkaline earth metal or quaternarry amonium ion, -CL, -NHL, -NL 2 an amnino acid or' arinosulfonic acid bonded via the amino group, such as, for exa-mple NH CH 2 COOH,
-NHCH
2
CH
2
SO
3 H, -NCH 2 000H, -NCH 2
CH
2
SO
3
H
I
I
CH
3
CHM
3 and (C,-CJ-alkyl esters, alkali metal and alkaline earth metal salts and quaternary a~oni= salts thereof, and in which L is H, an alkyl or alkenyl radical -having up to carbon atoms, which is branched or unbranched, a LI.4; cycloalkyl radical having 3 to 8 carbon atoms or a Uj phenyl or benzyl radical, which are unsubstituted or mono- tot4sbtttdb Cl, Br, (C,-C,)halkyl or (C-C)-alkoxy, R i Han lky oraiknvlradical havi ng up to carbon atoms, which is branched or unbrancheAd, a cycloalkyl radical having 3 to 8 car'zon a-cr-s, a oenzyl radical, a bi;phenYlo=ethyi or atre methyl radical, in which the nuclei are unsubstituted or minn- t~o trisubstituted by F Cl, 3r, (C -C)-alk,,l or -alkoxy, or a radical o 0 -P-OL -S-OL or o 0 in which L has the abovementioned meaning,
R
2 to R 5 R' and R' or R' and R' in each case together being the oxygen of a carbonyl group, or mndividually and in each case independently of one another being C C 0 CL 0 H, -OT, -ST, NT HOT -C-P-CT, -C-S-CT, -T' in which T has the meaning of L or is a free valency for bonding the group X, and in which in total only one free valency starts from G1 for bonding the group X, X is a single bond or a group of the formula III 0 0 L~ L L 3 in which A and B are alkylene chains, which are branched or unbranched, it being possible for the chains to be cotionallv interrupted by or L L 2 and L' are identical or different and have the meaning of L and a is zero to r is zero or 1, s is zero or 1. and t is zero or 1 and G2 is a radical of the formula IV R9 R 0 H (IV) H H H R in which Z is a free valency to the group X or has the meaning given under Y, R' is a free valency to the group X or has the meaning given under R' and
R
7 to R 10 have the meaning given under R' to and in which in total only one free valency starts from G2 to the group X.
Particularly preferred compounds of %the formula 'I are those in which Gi is a radical of the zfo~ula !I in which Y OH, O-(C,-C 4 )-Alkyl, .NHCH 2 C00H,
-NCH
2 000OH, -NHCH 2
CH
2
SO
3 H, -NCH 2
CH
2
SO
3
H
CH 3 OH1 3 R' is R, benzyl, biphenylrnethyl, fo~ryl or acetyl, R' to R' and R' or R' and R' in each case together being the oxygen of a carbonyl group, or individually and in each case independently of one another being o 0 H, -OT, -NHT, -NHlC-T,
-T
O in which T is H, a br anched, or unbranched
(C,-C
4 alkyl. radical or .1 a free valency to bridge. group X, and ;in kz a total of one free valency starts from G-1 for bZondi.no t'-e croup X, is a bond, -CH CH 2
NH-
-CH
2
C.H
2
CH
2
NH
[1
I
-(H
2 2
-C-N-(CH
2 H H where n is 2 or 3, m is 1 to 4 andz o is 2 or 3, and G2 is a radical of the fo-=.ula IV
RY
RH
LA~
15
LL
IN I I n which Z is a free valency to group X or has the meaning given above under Y, R' is9 a free valency to group) X or has the meaning given above under R' and R7 to R" have the meaning given above under R-7 to and in which only one free valency starts from G2 to the S group X.
The process for the preparation of compounds of the f orula 1, comprises a) in the case where X is a single bond, reacting suitable forms of Gl and G2 with one ancther by crocesses which are known in principle, or b) in the case where X is a bri-de group, reacting a) reactive forms of Gl-X with G2 or p) reactive forms of G2-X with GL by processes which are known in principle, or c) preparing compounds of the formula I (G1-X-G2) frcm G1-X1 and X2-G2 by processes which are known or, where they are not known, by the processes described below in more detail, X being formed from X1 and X2 by formation of a covalent bnc., in part cular within a condensation or substitution reaction.
a) X is a single bond The bile acids G1 are employed either in the free form or in protected form. After linking with G2, which is likewise present in a free or protected form, the protective groups are split off, if appropriate, and the C-24 carboxyl function is converted into a derivative, if appropriate. Suitable protective groups for the alcohol groups are expediently formyl, acetyl, tetrahydropyranyl or t-butyldimethylsilyl. Various alkyl or benzyl esters, and also, for example, orthoesters, are suitable protective groups Ior the C-24 carboxyl group.
For example, bile acid preferentially reacts at position 3, but also at position 7, with activated forms of carboxylic acids, such as acid chlorides or mixed anhydrides, with addition of bases, such as trialkylamine or pyridine, but also NaOE, at room temperature in suitable solvents, such as tetrahydrofuran, methylene chloride or ethyl acetate, but also dimethylformamide (DMT) or dimethoxyethane
(DME).
AMENDED SHEET The various isomers can semarated, for exazmole -by cn-roratocranhy. The r-eaction can be carried out selectively by usiLng suiltahle -:rozec-tve croucs.
The corre spc nding ammin-bi4le acid~s can be converted the reaction can be carried out either with protect.ed or with free bile acids.
Other compounds can be linked analogously by known standard processes.
.0 b) X is a bridge group The p~rocesses specified under a) are also used to carry out the linking of Gl-X with G2 or G1 with X-G2. Here also, the bile acid portion is expediently emoloyed either in rotected or in unorotected form.
A preferred preparation process compirses reacting reactive forms of 01 with reactive forms of X-G2. I~f appropriate, the linking reaction is followed by spilit ting-off of protective groups and conversi-on of C-24 carboxyl into derivatives.
The preparation of reactive bile acid units GI-X and X-G2 is shown in the following ecuation.
0
~H
R 0
(Y)
AMENED r_ 8 2 C o 0oV c
CH
2 YI (V I 8 R 0 0Ce v It Ix -AWNiiFfl SHEE o-~ H 0 RH (x R =Hformyl or acetyl, R' or OH, Rl for-my2. or acetyl yI I
R
H 0 0 0V x 0 H 0 R (x I I) (x I II) 192/1 x or XI I H H
CH
R 0V xI or X I t R 0 (x Y 0 1 C H 2) 0 0 V 10W 4 0
OH
H 0 (XY X'iY II R E, fornTyl or acetyl, RI or OE, n =2 or 3 Compounds of the typme V in which the 3-oosition s protected are reacted with ally1 brom-ide/Eiinig base cr triethyl&mine. If the compound V has one OE group, the alkylation is un&mbi;guous; if two free OE groups are present, monoalkylation takes place at positiJons 7 and 12 in approxi-mately equal proportions and only traces of the dialkylated product are formed. The protective group in the 3-position can either be so2lit off with sodi;uz wU Smethylate or retained for further reactions. The A4-NPMFf ;H F- 1122 monoalkylated compounds and VIcan1 be -41*-it oone or wth.s0 IN a 4C 4 t ve the aldehdes V an' X. The 7-and I12-hvdr-oxyet-hl com-pounds X and A are ad;L-Y accessible from these byi si-mole reduction, f examzple with NaBH,. The correspon"Jing 7- and propyl derivatives XII and XIII can be synthesized from the ally! compounds 'KI7 and VII by hydroboration. The aminoalkyl derivatives XIV and 'KV can be prepared fromn the hydroxyalkyl compounds of the type X to XIII by a reaction sequence which is known in principle (mesylation Of the primary OH group with methanesulfonyl chloride! pyridine, azide exchange with NaN, in dimethylformam'de, reduction of the azide function with hydrogen under catalytic conditions) Further reaction of the amino functions of these compounds with succinic anhydride gives bile acid units of the type XCVIT and XVII. Suitable bile acid units furthermore are described in EP-A- 0 489 423.
Exa-moles 1 and 2 0 W0
W
HH
OH A .0II 1 H 150 g (0.32 mol) of methyl 3-acetyl-cholate, 500 ml of dimethylforma-mide, 125 mi of N-ethyl-diisooropylamine and ml of allyl bromide are heated uinder reflux for 16 hours. New ally 1 bromide (25 ml) is added every 2 hours.
The reacti;on solution is evaporated on a rotary evaporator. The residue is partitioned between water /me thylene chloride and the organic phase separated off a nd dried with magnesium sulfate. After coluzrn chromatography (ethyl acetate/cyclohexane 1:2, silica-gel 70-200 the product fractions are evaporated on a rotary evaporator.
Yield =92.2 g of 7-/12-ally 1 mixture.
AMENDED SHEET C i 4 8 0 5 0 4 M S 5 1 1 M L i r Te m 4xture was se-ara-ed by rac.- la- ~sal~t~ wit n-hentane.
Ex (az.pL 3 0 0 HO0
HO
rH H H O~ c~ H H O(e H H 0 So g (0.1 mol) of Example 1, 250 mi of diethyl. ether and 250 ml of water are initially introduced into the reaction vessel, while stirring vigorously. 503 mg (0.002 mol) o-f osmium tet-roxide are added. The mixture is stirred at room temperature for 15 minutes. 53 g (0.25 mol) of sodium periodate are ad~ded in portions over the course of 1 hour, and the mixture is subsequently stirred for 8 hours, while stirring vigorously. The ether phase is separated off, dried with magnesi=r sulfate and evamorated on a rotar/ evaporator.
Yield: 7 g of crd
FC
1 46 0, (506) HS 513 (M Li) Examp-le 3 is further reacted without additional rirficat-;on.
Ex=, ple 4 HO
HO
H 0 O0 V(H 0 Owl4 A C A~ C 00C
H
H
H.
LU 4.2 g (0.12. mol) of sodium borohydride are added in 2, 6 portions to 47 g (0.093 mol) of Example 3 and 250 m-1 of AUAFNIFDI SHEFr methanol at 0°C. After 2 hours at 0'C, the reactlon.
solution is poured onto saturated ammonium chloride solution, the mixture is extracted 3 ties with ethyl acetate and the combined organic phases are dried with magnesium sulfate and evaporated on a rotary evaporator.
After column chromatography (ethyl acetate/cyclohexane 1.5:1, silica gel 35 70 m) the product fractions are evaporated on a rotary evaporator and the residue is crystallized with diisopropyl ether. Yield: 25 g of C,,HB,0, (508), MS 515 Li') Example HO uHO H H 2
H
Ac 0 0 A c 0 H 0 H
H
g (0.02 mol) of Example 1 and 250 ml of tetrahydrofuran were initially introduced into a reaction vessel at room temperature, and 40 ml (0.04 mol) of borane-tetrahydrofuran complex (1 molar) were added dropwise at room temoerature. The mixture was subsequently stirred at room temperature for 2 hours, and 25 ml of water, 25 ml of 2 N sodium hydroxide solution and 25 ml of 35% strength hydrogen peroxide solution were added dropwise in succession. The mixture was subsequently stirred at room temperature for a further 15 minutes. The reaction solution was poured onto water, the mixture was extracted 3 times with diethyl ether and the combined organic phases were dried with magnesium sulfate and evaporated on a rotary evaporator.
Yield: 8.5 g of C 3 ,,0007 (522), MS 529.(M Li') Example 5 was further reacted without additional purification.
'M NOFI IHH- Example 6 H0 0 H0 -e H"
H
g (0.02 mol) of Example 4 and 100 ml of pyridine are initially introduced into a reaction vessel at O°C.
1.7 ml (0.022 mol) of methanesulfonyl chloride are added droowise at 0 C and the mixture is subsequently stirred at 0°C for a further 30 minutes and at room temperature for 2 hours. The reaction solution is poured onto water, the mixture is extracted 3 times with ethyl acetate, and the combined organic phases are dried with magnesium sulfate and evaporated on a rotary evaporator. The residue is dissolved in 100 ml of dimethylformamide, 1.4 g (0.022 mol) of sodium azide are added and the mixture is stirred at 80°C for 2 hours. The reaction solution is poured onto water and the mixture is worked up as described above. The residue is dissolved in 100 ml of methanol, 100 mg of palladium-on-charcoal are added and hydrogenation is carried out under normal pressure for 2 hours. The catalyst is filtered off and the filtrate is evaporated on a rotary evaporator. After column chromatography (ethyl acetate/ MeOE/EtN 10:1:1, silica gel 70-200 pm), Example 6 is obtained.
Yield 7.3 g of C,,B 4 ,NO, (507), MS 514 (M Li') Examole 7 HO HO H H H H 0 ic0O 0 H H A H L co C1 HcM 0 H 98.6 mg (0.001 mol) of succinic anhydride are added to 500O Mg (0.001 mcI) ofg amino comLoound, 20 m. of tetrahydrofuran and It ml of triethylaimife at room temoeratulre.
The =mi-xt-ure is subsecuently stirr---ed at- room teinoerature zor 1 hour. The reaction solution is poured onto 2% srength s odium- di4hydrogen phosphate solutinth U m-L,-xture is extracted 3t;es with thl acetate c te organic phase ;s dried with magnesium sulfate and evaoorated on a rotary evaporator.
Yield: 580 mg of C, 3 H,,N0, (607), MS 614 (M Li*) Example 7 was further reacted without additional purlication.
Examiples 8 to 12 were prepared analogously to Examples 3 to 7.
Examles 8-12
H
H ZExamole 13 c holic aci H t- H H H
HH
300 mg (0.73 mxnol) of cholic acid, 330 mg (0.78 ntmol) ofI methyl 70-amino3a,12dihydroxy-5pcholanate (Redel, Bull. Soc. Chim. Fr., page 877, 1949), 240 mg (0.97 mmol) of EEDQ and 0.25 ml of diisopropylethyla-mine are stirred in 20 ml of DMF at 90*C for 4 hours. After cooling, the reaction mixture is concentrated and the residue is chromatographed over silica gel (CH 2 Cl 2 /MeOll 8 COs, 1 N09 (812) 819 (M The two bile acid derivatives can also be linked with triethyla-mine ain methylene chloride or with dicyclohexylcarbodiimide hydroxybenzotriazole ortrie-thyla-mine in tetrahydrofLuran.
The compounds of Table 1 were prepared analogously to Exa-mple 13.
Table 1
HO
H H I-
H
A4 ?Qflr"Ii k2.9 ExapleR 12 R MS(F, 3-11.A/Li, 14 a-O H i -OB C 4 50, (796) 803 (y i-) ~-OH1B -OH C 4
,S
1 N0, (796) 803 (M Li-) F16 13 H -OCEO- C 5
,E,
1 NO, (808.5) 809.5 The examples of Table 2 were obtained analogously tc Example 13 from Exa-mples 7 and 8.
~hm4<j ;;.414 '1'iillo 2 0 110 m 0 Ac0o "V 7 2 0 Hi 0 OR.3 E~xample X] HS (FAI3, 3-NI3A/LiC1) 17 C11-I C 5 311 (898) 905 (Mj 4- Li 4 1-f-ll- diphenylmethyl C6(I 1 911 1 0 (1064) 1071 (M Li 4 19 -1IIICO (C'1 2 2 CONII (C113) 3 1111- 11 C6 0 1l,,NO12 (1054) 1061 (M Li") -11IICO (Cl! 2 2 CONhl (CIII) )1111- diplienylinetihyl C7 3 11 10
,N
3 0,2 (1220) 1227 (H 4- Id' The examples of Tables 3 and w,.ere lkwse cbta e,analogously to Example 1.
Table 3 HO0 O~e Ac 0\\ I II
I
N I 0 Examole R 6MS 3-NBA/LiCl) 21 HO 0 C6 2 3, 00
,N,O
4 (1097) 1104
HO
H
HH
220 (1055) 1104 22 0 0 "0 -13,2 Table 4 A~ c o" 0 ~I4 Example R7MS (FAB, 3-NB.A/LiCl) 23 0 ~EN~ (898) 905
HO
HO 6 k
H
24 0 x ~EONOA1097) 1104 0 C6 0 ,O(1055) 1062 AMENDED
SHEET
133 Exaole26
H
H 0\\ 250 mg (0.21 mamo1) of E-xample 12 are ciSsolved in 20 mof ethanol, 2 ml, of IN NaO.H solution are added and the mixture is stirred at room temperature -for 16 hours. For ,.orking up, t"he mixture is concentrated, the residue ;s dissolved in B2O, the pB is brought to 1-2 with 2N B21 and the mixture is concentrated again. The residue is chromatographed over silica gel (CECl 3 /MeOE 220 Mg ofL free acid are obtained MS (B,3-NBA/LiCl)
C
4 1 ,1 9 0, (798) 805 Li-) The exa-mples of Tables 5 to 8 are otai'ned analogously, to Example 26.
Table H AMENDFI-r;- #/31/ 28O B CASE,,N0 7 (782) 789 29 HHCASH-,NO., (766) 773 (HM+L-i) T~)1e r6 0 HOi H \1"1 1 SN H x0 1*1 Y c r j f fl' Examlple( x'H
MS
-II IC~olen,,o (860) 867 (M Li 4 31 -l-diphienylmethyl C6,!1, 5 NOI, (1026) 1033 Li*) 32 -11Ico (C11 2 2 CON11I(C11 2 31111- HI C5 1 97130. (.1016) 1023 (M Li 4 33 -11IICO (eli 2 2 C011Il (C11 2 3 N11- dliphenylme Uiyl C1 0 11 10 1 1'I30 1 118 2 118 9 (M Li4) Table7 H0
H
HH
o H
HU
Table 8
H
R
'4
H
T lo owing glycine conjugates and taurine conjugates were obtained analogously to synthesis processes which AL/-q,,kbave already been described (EP 489 422).
K?~
4 o~AMENDED CyHEET H 0 7so O 1101
C
LUj ilIC ti s 0 3
H
c 1 2 cH 2-x3 0il ExarnoJle 47 H 0 H 0S0 16H MS (FA3, 3-111A/LiC1) Cla7 10 1
N
3 0 1 4 S (1092) 1099 (M +L) Exarnple 48 0 3
H
H0\\ 0 eH
H
00 MS 3-NBA/LiC1)
C
7 2H, 1
ON
4 0 1 3 (1239) 1246 (M Li-) Table 11 shows measurement values for the inhibition of the uptake of [IH]-taurocholate in brush border membrane vesicles from the ileum of rabbits. The quotients of the
IC
0 and IC 50 Na values of the reference substance taurochenodeoxycholate (TCDC) and of the particular test substance are stated.
*r4 Ta!ble 11 0.12 0.29 A bile acid de-rivative of the form',la. i G1 x 027 4n which GI. is a ra(cical of thne 77~ S in which Y has t%-he following meaning: O: a, in which Ka is an alkali metal, alkaline earth metal or quaternary ammonium ion, -OL, -NHL, -NL 2 a amio aid or arinosulfonic acid bonded va ,the amino group, such as, for exam~ple -NHCH 2 COOH, -NHCH 2 CH2zSO 3 H, -NCHCOOH,
-NCH
2
CH
2
SO
3
H
kO M 3
CH
3 and (c,-cj)-alkyl esters, alkali metal and alkal ine eart-Ih metal salts and auaternary a-monium salts thereoff and in which L is Ban alkyl or alkenyJ- radical having up to carbon atoms, which is branched or unbranched, a cycloalkyl radical having 3 to 8 carbon atoms or a phenyl or benzyl radical, which are unsubsti4 tuted or mono- to trisubstituted by F, Cl, Br, (C-C)-alkyl or (Cj-C)-alkoxy( R' is E, an alkyl or alkenyl radical having up to carbon atoms, which is branched or unbranched, a cycloalkyl radical having 3 to 8 carbon atoms, a AMENDED SKET benzyl radical, a biphenylmethyl or a t-r-)henylmethyl radical, in which the nuclei; are unsubstituted or =zcno-to trisubstitutled by F, Cl, Br, (C,-C 4 -alky! or (c,-CJ)-alkoxy, or a radical o
C
11 0 -P-CL, -S-CL or
-C-L
o 0 in which L has the abovementioled meaning, RI to R1, RI and R' or R' and R 5 in each case together being the oxygen of a carbonyl group, individually and in each case independently of one another being 0 0 0 OL
C
H, -OT, S.*H0CT -S-CT, -NHH. -C-P-CT, .0-S-CT,
-T
II
I
in which T has the meaning of L or is a free valency for bonding the group X, and in which in total only one free valencY starts from GI for bonding the group X, X is a single bond or a group of the fo=-ula
IIT
0 0
L
1 L L0 in which A and B are alkylene chains, which are branched or unbranched, it being possible for the chains to be optionally interr-upted by or ,14, L' and L' are identical or dif'ferent and 'MENDED~ SHEET have the meaning of L and a is zero to r is zero or 1, s is zero or 1 and t is zero or 1 and G2 is a radical of the formula IV R R 0o FZ 0 I V H R7 in which Z is a free valency to the group X or has the meaning given under Y, R' is a free valency to the group X or has the meaning given under R' and R' to R" have the meaning given under R 2 to R 5 and in which in total only one free valency starts from G2 to the group X.
A-62 A bile acid derivative of the formula I as descrdIinA-61 Sin which G1 is a radical of the formula
II
II)
H1.F
T
in which Y is CH NC., CC, -NC'H-,CCOH,
-NHCH
2 C-H'SO3H,
-NCH
2
CHS)
.RI is H, benzyl, biphenylmethyl, fo--yl or acetyl, P.2 to R' and 21 or and R 5 in each case together being the oxygen of a carbon,,! group, or individually and in each case independently of one another being 0 0 H, -OT, -NHT. N-C-T,
-T
in which T is H, a branched or unbranched (C,-C,)-alky3- radical or a free valency to bridge group X, and in which a total of one free valency starts from G1 for bonding the group X, X is a bond,
H
-CH
2
CH
2
CH
2
NH
0 0 -(CH 2 H
H
where n is 2 or 3, m is 1. to 4 and o is 2 or 3, and G2 is a radical of the formula
!V
-R 3 1 0 o z R v R RH R in which Z is a free valency to group X or has the meaning given above under Y, R' is a free valency to group X or has the meaning given above under R' and
R
7 to R 1 have the meaning given above under R 2 to R', and in which only one free valency starts from G2 to the group X.
AMENDED
S.EI-T
447 A-63 monomeric bile acid derivatives of the formnula I
Z-X-GS
in which GS is a bile acid radical having an acid function in the side chain or a salt thereof, X is a covalent bond or a bridge group of the formula (CH 2 ),,where n= I to 10, in which the alkylene chain can contain 1 to 3 oxygen atoms, NH or 0 groups, and in which GS is bonded via X as desired, and Z is 100 0 II ~ii 0(C~ whr R isi ec csC-C-Nlklor(-.(C2)where the alkyl moiety is optionally substituted by a COOH group, 447a 0 MIC>,Gii
H'C
/i \3 0
CH)
C-NCH-
SC
COOH
H--suf i-CH. SO0 -g o AOChsr Sc tin i to in toat c o a e 5 Alkvad..ica- ca no tberih-hinoqr o. i CHOH Scompounds OHe formula D t e in i in oo* where A is in each case OH or NH(Ci-CIo) alkyl.
Preferred compounds of the formula I are those in which GS is linked to X in the 3position, linking taking place in the a- or O3-position.
o An acid function is understood as meaning, in particular, the COOH group or the sulfonic acid group.
Alkyl radicals are straight-chain or branched.
.The compounds of the formula according to the invention have a high affinity for the specific bile acid transportation system of the small intestine and inhibit bile acid absorption in a concentration-dependent and competitive manner.
By competitive inhibition, intervention in the enterohepatic circulation can be considerably more selective. Avitaminoses are not to be expected, and a qualitative \hange in the bile acid composition in the bile is just as unlikely. A controlled reduction 447b in the serum cholesterol level can be achieved with compounds according to the invention, without the known side effects being observed. Because of their high affinity for the bile acid transportation system, very much lower daily doses than with the commercially available polymers are sufficient; this also leads to a high acceptance by patient and doctor.
The compounds have valuable pharmacological properties and are therefore particularly suitable as hypolipidemic agents.
The invention thus also relates to medicaments based on the compounds of the formula and to the use of the compounds as medicaments, in particular for reducing the cholesterol level.
The compounds according to the invention were tested biologically by determination of the inhibition of 3 H] taurocholate uptake in the brush border membrane vesicles from the ileum of rabbits. The inhibition test was carried out as follows: 1. Preparation of brush border membrane vesicles from the ileum of rabbits.
Brush border membrane vesicles were prepared from the intestinal cells of the small intestine by the so-called Mg 2 precipitation method. Male New Zealand rabbits (2 to 2.5 kg body weight) were sacrificed by intravenous injection of 0.5 ml of an aqueous solution of 2.5 mg of tetracaine HC1, 100 T 61R and 25 mg of mebezonium iodide. The small intestine was removed and rinsed with ice-cold physiological saline solution. The 20 terminal 7/10 of the small intestine (measured in the oral-rectal direction, i.e. the terminal ileum, which contains the active Na -dependent bile acid transportation system) was used for preparation of the brush border membrane vesicle. The intestines were frozen in plastic bags under nitrogen at -80 0 C. For preparation of the membrane vesicles, the frozen intestines were thawed at 30 0 C. in a water bath. The mucosa was S 25 scraped off and suspended in 60 ml of ice-cold 12 mM Tris/HCl buffer (pH 7.1)/300 mM mannitol, 5 mM EGTA/10 mg/1 of phenylmethylsulfonyl fluoride/1 mg/1 of trypsin inhibitor from soybeans (32 U/mg)/0.5 mg/1 of trypsin inhibitor from bovine lung (193 U/mg)/5 mg/1 ofbacitracin. After dilution to 300 ml with ice-cold distilled water, the mixture was homogenized with an Ultraturrax (18-rod, IKA Werk Staufen, FRG) for 3 minutes at 75% of the maximum output, while cooling with ice. After addition of 3 ml oflM MgC1 2 solution (final concentration 10mM), the mixture was left to stand at 0°C.
for exactly 1 minute. The cell membranes aggregate by addition of Mg 2 and A, recipitate, with the exception of the brush border membranes. After centrifugation at 447c 3000x g (5000 rpm, SS-34 rotor) for 15 minutes, the precipitate was discarded, and the supernatant, which contained the brush border membranes, was centrifuged at 267000x g (15000 rpm, SS-34 rotor) for 30 minutes. The supernatant was discarded and the precipitate was rehomogenized in 60 ml of 12mM Tris/HC1 buffer (pH 7.1)/60 m M mannitol, 5 mM EGTA using a Potter Elvejhem homogenizer (Braun, Melsungen, 900 rpm, 10 strokes). After addition of 0.1 ml of 1 M MgCl 2 solution and an incubation time of 15 minutes at the mixture was centrifuged again at 3000x g for 15 minutes. The supernatant was then centrifuged again at 46000x g (15000 rpm, SS-34 rotor) for minutes. The precipitate was taken up in 30 ml of 10 mM Tris/Hepes buffer (pH 7.4)/300 mM mannitol and resuspended homogeneously by 20 strokes in a Potter Elvejhem homogenizer at 1000 rpm. After centrifugation at 48000x g (20000 rpm, SS- 34 rotor) for 30 minutes, the precipitate was taken up in 0.5 to 2 ml of Tris/Hepes buffer (pH 7.4)/280 mM mannitol (final concentration 20 mg/ml) and resuspended with the aid of a tuberculin syringe with a 27 gauge needle. The vesicles were either used immediately for transportation studies after preparation, or stored at -196 0 C. in portions of 4 mg in liquid nitrogen.
2. Inhibition of Na -dependent 3 H]-taurocholate uptake in the brush border membrane vesicles of the ileum.
The uptake of substrates into the brush border membrane vesicles described above was 20 determined by means of the so-called membrane filtration technique. 10 p1 of the vesicle suspension (100 [g of protein) were pipetted as drops onto the wall of a polystyrene incubation tube (11x70 mm) which contained the incubation medium with the corresponding ligands (90 The incubation medium contained 0.75 1l=0.75 p.Ci of 3 H(G)]-taurocholate (specific activity: 2.1 Ci/mmol)/0.5 pl of 10 mM taurocholate/8.75 [l of sodium transportation buffer (10 mM Tris/Hepes (pH 7.4)/100 mM mannitol/100 mM NaC1) (Na-T-P) or 8.75 pl of potassium transportation buffer (10 mM Tris/Hepes (pH 7.4/100 mM mannitol/100 mM KC1) and 80 pl of the inhibitor solution in question, dissolved in Na-T buffer or K-T buffer, depending on the experiment. The incubation medium was filtered through a polyvinylidene fluoride membrane filter (SYHV LO 4NS, 0.45 pmr, 4 mm4, Millipore, Eschbom, FRG). The transportation measurement was started by mixing the vesicles with the incubation medium. The concentration oftaurocholate in the incubation batch was 50 uM. After he desired incubation time (usually 1 minute), the transportation was stopped by 447d addition of 1 ml of ice-cold stopping solution (10mM Tris/Hepes (pH 7.4)/150mM KC1).
The mixture formed was immediately filtered off with suction over a membrane filter of cellulose nitrate (ME 25, 0.45 gm, 25 mm diameter, Schleicher Sshuell, Dassell, (FRG) under a vacuum of 25 to 35 mbar. The filter was rinsed with 5 ml of ice-cold stopping solution.
To measure the uptake of the radioactively labelled taurocholate, the membrane filter was dissolved with 4 ml of the scintillator Quickszint 361 (Zinsser Analytik GmbH, Frankfurt, FRG) and the radioactivity was measured by liquid scintillation measurement in a TriCarb 2500 measuring instrument (Canberra Packard GmbH, Frankfurt, FRG).
After calibration of the instrument with the aid of standard samples and after correction for any chemiluminescence present, the values measured were obtained as dpm (decompositions per minute).
The control values were in each case determined in Na-T-P and K-T-P. The difference between the uptake in Na-T-P and K-T-P was the Na -dependent transportation content. The concentration of inhibitor at which the Na -dependent transportation content was inhibited by 50%--based on the control-was designated as the IC5oNa The table shows the measurement values of the inhibition of the 3 H]-taurocholate :..uptake in brush border membrane vesicles from the ileum of rabbits. The quotients of 20 the IC5o and ICsoNa values of the taurochenodesoxycholate (TCDC) investigated as the standard in each vesicle preparation and the particular substance are stated.
S
S S 0
S
9 S:sta.-c ICA (TCDC TCW,. TCr~Q fro Ei. I-b: |Ca (Subs=C=) ICIs (SU61m=) 3 0.4 0.35 4 0.77 0.69 18 0.47 0.42 21 0.34 0.33 33 033 025 35 1.0 1.02 36 0.19 0.20 33 0.49 0.41 40 0.52 0.50 43 0.78 0.73 The invention furthermore relates to the use of the compounds according to the invention for the preparation of a medicine.
For this, the compounds of the formula I are dissolved or suspended in pharmacologically acceptable organic solvents, such as mono- or polyhydric alcohols, 447e such as, for example, ethanol or glycerol, or in triacetin, oils, for example sunflower oil or cod-liver oil, ethers, such as, for example, diethylene glycol dimethyl ether, or also polyethers, for example polyethylene glycol, or also in the presence of other pharmacologically acceptable polymeric carriers, such as, for example, polyvinylpyrrolidone, or other pharmaceutically acceptable additives, such as starch, cyclodextrin or polysaccharides. The compounds according to the invention furthermore can be administered in combination with other medicaments.
The compounds of the formula I are administered in various dosage forms, preferably orally in the form of tablets, capsules or liquids. The daily dose varies in the range from 3 mg to 5000 mg, but preferably in the dose range of 10 to 1000 mg, depending on the body weight and constitution of the patient.
The particular monoisotopic molecular weights calculated are stated in the following examples.
Unless stated otherwise, mass spectra were recorded by the FAB technique with addition of LiCl and 3-nitrobenzaldehyde [3-NBA].
Starting compounds which have the bile acid structure have already been described in some cases for example, EP-A-0 417 725, EP-A-0 489 423 and EP-A-0 548 793.
R
1 is defined in Example 6.
o
O'OH
EXAMPLE I
H
H
SCOOH
.*500 H 0 0 n 447f 1 g (1.96 mmol) of the methyl ester a is dissolved in 15 ml of tetrahydrofuran (THF) or 1,4-dioxane and the solution is stirred intensively with 10 ml of 2 N NaOH overnight at room temperature. It is then diluted with a large quantity of water and acidified with half-concentrated hydrochloric acid, while cooling with ice. Precipitation is brought to completion by subsequent stirring for 1 hour, while cooling with ice, and the precipitate formed is filtered off with suction and rinsed with cold water. Recrystallization from ethanol/water and drying in vacuo give 940 mg of Example 1.
C
29
H
50 0 6 (494) MS: 501 The following Examples 2 to 7 are prepared analogously to "Example 1" from the corresponding bile acid esters: EzuarpIc aS E.=pie- S:nrica NC. hac n a -Jl MW MS 2 6 c-0,I, 508 5IS U-) 3 8 C: 535 543 Gm 4 9 550 557 (M U') 10 CRJ.O. 55.' SI(N -U- EXAMPLE 6
*OH
*COOH
CuR.O(496) MS:0503 M+ HO O CuLo.
1 (540) MS: 503 (M Li 0- EXAMPLE 7 *oo *C (o3l-i 0) MS: 57 (M U 447g EXAMPLE 8 H
O
100 mg (0.2 mmol) of the methyl ester are dissolved in 10 ml of dioxane and the solution is stirred with 3 ml of half-concentrated sodium hydroxide solution at room temperature for 6 hours. The mixture is diluted with water and acidified with halfconcentrated hydrochloric acid to give, after filtration with suction and washing, the acid "Example 8" (50 mg, 5 1
C
29
H
47 N0 5 (489) MS: 496 (M+Li~) The following substance examples were prepared as for "Example 8": EXAMPLE 9 0 CZ,{.,NO(505) NtS: 512CM EXAMPLE C33HN06(561) 56S4 U*) 447h EXANMILE 12 0 0 Ci;,Hf7NzO' 0176) MS. 583 (M U-) EXA.MPLE 13 0 Cj-FC,,NO-Y (593) MS: 600 U, EXA MPLE 14 0 CnHFJNO 7 (57) NIS: 586C(M U') EXAMPLE 1S 0 CAR11-NO7 (537) .MS. 5"4 (M1 Li EXAmPLE 16
OH
COOC-i,
H
OM
0
T
H OH 0 0.84 ml of triethylamine is added to 3.14 g (6 mmol) of the primary alcohol a in 100 ml of dry methylene chloride and the mixture is cooled to -10 0 C. 0.4 ml (6 mmnol) of chiorosulfonic acid in 20 ml of dry methylene chloride is added to the solution at this temperature. After 1 hour at 0 0 C. and 1 hour at room temperature, water is added, the organic phase is separated off, the aqueous phase is extracted several times with ethyl R t acetate and the combined organic phases are dried and concentrated. The residue is 447i purified by chromatography (SiO 2 ethyl acetate/methanol=3:1). 1.45 g of "Example 16" are obtained.
C
3 1
H
54 0 9 S (602) MS: 631 (M-H +Li++Na) 615 (M-H+2Li EXAMPLE 17 0 o
II
0 0.5 g (0.83 mmol) of "Example 16 is stirred in 20 ml of dioxane with 7 ml of halfconcentrated sodium hydroxide solution at room temperature for 6 hours. The mixture is then acidified with half-concentrated hydrochloric acid, while cooling, and is concentrated in vacuo. The residue is purified by column filtration (SiO 2 ethyl acetate/ methanol=3:1). 254 mg of "Example 17" are obtained.
C
30
H
51 0 9 S (610) MS=617 (M+Li 601 (M-Na++2Li EXAMPLE 18 0
I
a---O--(CHzh-R' g (5.12 mmol) of "Example 2" in 20 ml of pyridine at 0 to 5 0 C. and the mixture is subsequently stirred at room temperature for 2 hours. It is poured onto 200 ml of ice- 15 water, about 15 ml of concentrated sulfuric acid are added, while stirring and cooling, and the mixture is extracted several times with ethyl acetate. The organic phase is dried and concentrated and the residue is purified by chromatography (SiO 2
CH
2 C1 2
*CH
3 OH=10:1). 1.78 g of "Example 18" are obtained.
C
42
H
6 1 0 9 P(740) MS: 747 (M+Li EXAMPLE 19
II
A I
OH
448 1 g (1.35 mmol) of "Example 18" is hydrogenated in 50 ml of glacial acetic acid with a spatula-tip of platinum-on-charcoal in a shaking vessel. When the reaction has ended (about 4 hours), the catalyst is filtered off with suction and the filtrate is concentrated.
The residue is purified by column filtration (SiO 2 ethyl acetate/CH 3 0H=2:1). 270 mg of "Example 19" are obtained.
C
30
H
53 0 9 P (588) MS: 601 (M-H'+2Li (M+Li) EXAMPLE
OH
HO
O COOC-) HIN9 X S-(CH-)t-O
OH
41.1 2.24 g (4 mmol) of amine h and 324 mg (4 mmol) of potassium cyanate are suspended in 60 ml of water and the suspension is heated to boiling point. A solution is formed, from which a solid precipitates after a short time. The mixture is stirred at boiling point for minutes and cooled, about 40 ml of water are added and the mixture is acidified with dilute hydrochloric acid. It is extracted several times with ethyl acetate, the organic phase is dried and concentrated in vacuo and the residue is purified by chromatography o.. (SiO 2 EtOAc/CH 3 OH=10:1). 520 mg of "Example 20" are obtained.
15 C 32
H
56
N
2 0 5 (564) MS: 571 (M+Li+) EXA.NLE 21 a0
II
450 mg (0.mmol) of "Example 20" are stirred in 10 ml of bioxane with 5 ml of halfconcentrated sodium hydroxide solution at room temperature for 6 hours. When the reaction has ended, the mixture is diluted with water, acidified with hydrochloric acid ,qand subsequently stirred in an ice-bath for 1 hour. The precipitate is filtered off with 449 suction and rinsed with water to give, after drying in vacuo, 430 mg of "Example 21".
C
3 1
H
54
N
2 0 6 (550) MS: 557 (M+Li EXAMPLE 22
COOCH
O INHf NH-(CHIt-O
,H
2 mmol ofphenyl isocyanate in 5 ml of methylene chloride are added to 1.04 g (2 mmol) of amine b (Example 20) in 50 ml of dry methylene chloride and 28 ml of triethylamine at 0°C. The mixture is subsequently stirred at room temperature for 6 hours and worked up as described under "Example 16", the aqueous phase being acidified. After column filtration (CH 2
C
2
/CH
3 0H=10:1), 6540 mg of "Example 22" are obtained.
C
38
H
60
N
2 0 6 (640) MS: 647 (M+Li g S EXAMPLE 23 *oo 0
C
37
H
58
N
2 0 6 MS: 633 (M+Li EXAMPLE 24 too.
S
(HSsc--(Ch--O heated at boiling point in 50 ml of acetonitrile for 2 hours. All the volatile constituents are removed in vacuo and the residue is purified by chromatography (SiO 2 *2C 2/CH3OH= 1.2 g of "Example 24" are obtained.
450
C
34
H
62 1N0 5 (691) MS (FALB, 3-NBA): 564 EXAN{PLE Compound Example 25 is prepared from Example 24 analogously to "Example 21" The crude product is purified by medium pressure chromatography over RP-8 silica gel
(CH
3 0HfH 2 0=7:3).
C
33
H
60 CIh40 5 (585) MS (FAB, 3-NBA): 550 (M-Cl-) -XAMPLE 26
COCR
1.04 g (2 mmol) of amine b and 276 mg (2 mmol) of pyrazole c are heated under reflux in 40 ml of dry acetonitrile for 10 hours. After cooling and addition of ether, a precipitate is formed, and is filtered off with suction and rinsed with dry ether. After drying, 450 mg of "Example 26" are obtained.
C
32
H
5 sBrN 3
O
5 (643) MS: 570 (M-HBr+Lil) 564 (M-Br-) EXA-MPLE 27 HIl~ MH-(C47)4 -R'
*C
is prepared analogously to "Example 2 1"
C
31
H
55 C11N 3 0 5 (585) MS: 556 (M-HCl+Li+) 550 (M-C1-) EXANIPLE 28
T
CU HI4 451 g (1.9 mmol) of amine b, 265 mg of NaBH 3 CN and 610 mg of heptanal are stirred in ml of dry methanol at room temperature for 48 hours. The mixture is concentrated in vacuo, the residue is partitioned between ethyl acetate and saturated bicarbonate solution and the residue of the organic phase is purified by chromatography. In addition to a small amount ofmonoheptylamino derivative, 650 mg, of "Example 28" are obtained.
C
45
H
83 N0 5 (718) MS: 725 (M+Li+) EXAMPLE 29 n-C-H:, N
CNCH:
iHC is prepared analogously to "Example 21". The aqueous phase is decanted off from the oily crude product after acidification, and the residue is extracted by stirring with ethyl acetate and then filtered off with suction and dried.
C
44
H
82 CIN0 5 (740) MS: 711 (M-HCl+Li 705
C
EXAMPLE is prepared analogously to "Example 28" and "Example 29" by reductive amination of olp cholanate and subsequent alkaline hydrolysis.
:C
4 1
H
55
N
4 (625) MS: 632 (M+Li+) EXAMPLE 31 ooo... is reare aaloouly o Example 28 Eape2"b rdcieaiaino 452 is prepared analogously to "Example 30" using cyclododecanone as the carbonyl component.
C
38 H1 87 N0 4 (602) MS: 609 (M+Li+) E XAM PL IE 3 2
COOP.
R =C-1 .1 *9 a 4 *4 a a a a a a a a a. a a a 1 0.38 g (2 mmol) of naphthoyl chloride in 5 ml of CH 2 Cl 2 is added to 0.9 g (2 mmol) of amine d and 0.6 ml of triethylamine in 20 ml of dry CH 2
CL
2 while cooling with ice.
The mixture is subsequently stirred at O'C. for 1 hour and left to stand overnight. Water is added, and the mixture is acidified and extracted several times with CH 2 Cl 2 The residue from the organic phase is purified by chromatography (SiO 2 EtOAc/cyclohexane=3:1). 1 g of "Example 32" is obtained.
C
3 gH 53 N0 5 (603) MS: 610 (M+Li+) EXAMPT 33 is prepared analogously to "Example 2 1"
C
37
H
51 N0 5 (589) MS: 596 (M+Li+) 5 EXAMPLE 34
COOH
\RA-*HCCH' ~O 453 is prepared analogously to "Example 32" and "Example 33" using anthracene-9carbonyl chloride.
C
41 H1 53 N0 5 (639) MIS: 646 (M±Li+) EXAMPLE prepared analogously to "Example 34" using p-toluenesulfonyl chl oride and amine b.
C
37
H
59 N0 7 S (661) MIS: 668 (M+Li+) EXAMPLE 36 HIC ~SO-tN-(CHX),-RI is prepared analogously to "Example 35". The methyl ester obtained as an intermediate product is methylated in dimethylformamide, after deprotonation by sodium hydride, with iodomethane at room temperature. The product is then subjected to alkaline hydrolysis analogously to "Example
C
3 8
H
6 1 N0 7 S (675) MS: 688 682 (M+Li+) P. EXAMPLE 37 0 11 454 is prepared analogously to "Example3 2"/"Ex ample 33" using amine b.
C
41
H
59 N0 5 (661) MS: 668 (M±Li+) EXAMPLE 39
CI
0 o C-NH-Ci7-Cl N- C4 A7 0041 0
HO
0 H OH 004) 426 mg (1 mmol) of urethane and 782mig (15 mmnol) of amine b are heated under reflux in 50 ml of dioxane for 4 hours. The mixture is then concentrated and the residue is purified by chromatography (SiO 2
CH
2 Cl 2
/CH
3 OH=10: 540 g of "Example 39" are obtained.
C
4
.H
7 0CIN 3
O
1 0S (915) MS: 922 (M±Li+) 0 0 ]soEXAMPLE 0 0 see 440. is prepared analogously to "Example 21" 47
H
6 8CTN 3 0 10 S (901) MS (electrospray): 902 *see EXAIMPLZ 41 s .0
*SOH
mg(..ml fdccoeycroimdeaeaddt ouino .6g( of amnS,56m 3mo)o hnaai n 9 g(36m )o 7 s:...noraoei 0 l fTF h itr ssire tro eprtr o 455 hours. The urea formed is filtered off, the solution is concentrated and the residue is taken up in ethyl acetate. The solution is washed with saturated NaHCO 3 solution, 2N citric acid, saturated NaHCO 3 solution and water. The residue from the organic phase is purified by chromatography (SiO 2 ethyl acetate/CH 3 0H=5:1). 1.2 g of"Example 41" are obtained.
C
38
H
65
NO.
1 0 (695) MS: 702 (M+Li EXAMPLE 42 0 ,o
OH
is prepared analogously to "Example 21".
C
37
H
63
NO
1 0 (681) MS (FAB, 3-NBA): 682 (M+H *0 OEXAMPLE 43 O NH-(CHh.)-R' H.o-- .,HO-C--H
.:.H-C-OH
H-C--OH
C-rOH
C
36
H
6 3
NO
1 (685) MS: 714 (M-H +Li+Na
S
EXAMPLE 44
HO
COOCH)
0 0 coa T T Ar io b 456 1.04 g (4 mmol) of acid chloride e, 2.1 g (4 mmol) of amine b and a spatula-tip of 4dimethylaminopyridine are stirred in 40 ml of dry pyridine at room temperature for 6 hours. After standing overnight at room temperature, the mixture is concentrated in vacuo. "Example 44" is isolated after purification by chromatography (SiO 2
CH
2 C1 2 Ch30H=20:1).
C
43
H
69 N0 9 (743) MS: 750 (M+Li EXAMPLE 0 I I
COOH
is prepared analogously to "Example 21".
C
42
H
67 N0 9 (729) MS: 742 (M-H++2Li 736 (M+Li EXAMPLE 46 c o o c 1 c o o c 0 H H 2.6 g (5 mmol) of amine b in CH 2
C
2 are added to 1.3 g (5 mmol) of acid chloride e and 0.8 ml of triethylamine in 50 ml of dry CH 2 C1 2 while cooling with ice, and the mixture is stirred at 0 0 C. for 1 hour. An excess of methanol is then added, the mixture is allowed to come to room temperature, water is added and the mixture is acidified with dilute hydrochloric acid. The aqueous phase is extracted several times by shaking with
CH
2 C1 2 After purification of the residue from the organic phase by chromatography (SiO 2
CH
2 Cl 2
/CH
3 0H=10:1), "Example 46" is obtained.
C
44
H
73 N0 0 o (775) MS: 783 (M+Li+) EXAMPLE 47
COOH
coa CO-NH-(CHi)-R' 457 is prepared analogously to "Example 21".
C
42
H
69
NO
10 (747) MS: 760 (M-H++2Li) 754 (M+Li EXAMPLE 48 3.14 g (6 mmol) of alcohol a are heated at 100 0 C. with 3 ml of ethyldiisopropylamine and 1.5 g of diphenylmethyl bromide in 50 ml of DMF for 8 hours. After aqueous working up and purification by chromatography (SiO 2
CH
2 Cl 2
/CH
3 0H=10:1), "Example 48" is obtained.
i C 44
H
64 0 6 (688) MS: 695 (M+Li o EXAMPLE 49
:C
43
H
62 0 6 (674) MS: 681 (M+L) The following compounds are prepared analogously to Example 1 from the corresponding bile acid esters by alkaline ester hydrolysis: EXA\MPLE EXAM PLE
C
2 8
H
4 6 0 6 MW: 478 MS: 485 (M+Li 458 EXAMPLE 51
C
28
H
46 0 5 MW: 462 MS: 469 (M+Li+) EXAMPLE 52
COOH
C
3 oH 53 N0 44 MW: 491 MS: 498 a EXAMPLE 53 is prepared from Example 44 and n-hexylamine analogously to Example 41 with a reaction time of 25 hours.
C
49
H
82
N
2 0 8 (827) MS: 834 (M+Li+) EXAMPLE 54 0 CH-(0q-{ 2
-R
0 170 mg of "Example 53" are dissolved in 5 ml of dioxane, 1.5 ml of half-concentrated sodium hydroxide and 25 ml of water are added, and the mixture is stirred at room A~.mperature for 12 hours.
459 A suspended solid is filtered off and the filtrate is acidified with dilute hydrochloric acid, stirring is continued for 1 hour, and the precipitate formed is filtered off with suction. After drying, 154 mg of "Example 54" are obtained.
C
4 8
H
82
N
2 0 9 (831) MS: 838 (M+Li EXAMPLE HO 0 0
SCOMH-(CH.).-R'
Prepared analogously to "Example 53" and "Example 54" from fluoresceine and amine b.
C
5 oH 53 N0 9 (821) MS: 828 (M+Li EXAMPLE 56 11 T"O Prepared analogously to "Example 55" from pivalic acid and amine b.
C
35
H
5 N0 6 (591) MS: 598 (M+Li EXAMPLE 57 o c I is prepared analogously to "Example 55" from 2-ethylhexanoic acid and amine b.
C
3 sH67NO 6 (633) MS: 640 (M+Li+) EXAMPLE 58 HC CHI *o 0 is prepared analogously to "Example 55" from clofibric acid and amine b.
C
4 0
H
62 CIN0 (703) MS: 710 (M+Li C4oH62CINO7 (703) MS: 710 (M+Li 460 EXAMPLE 59
O
is prepared analogously to "Example 55" from gemfibrocil and amine b.
C
45
H
73 N0 7 (740) MS: 747 (M+Li EXAMPLE
C
0 rC 0 IH
H
HIC
Prepared from 522 mg of amine b and 94.1 mg of di-n-propylmalonic acid in THF in the presence of DCC/HOBT. Isolated after 54 h. The yield is 69%.
C
40
H
69
NO
8 (690) MS: 697 (M+Li+) EXAMPLE 61 0
HC
HIC
250 mg of "Example 60" are hydrolyzed in dioxane using 2N NaOH. After aqueous work-up and purification by column chromatography (EtOAc/CH30H 10:1), 160 mg of compound 61 are obtained.
C
39
H
67
NO
8 (676) MS: 677 (M+1) 461 A-64 A monomeric bile acid derivative of the formula IA
LA
HH
wherein R is H, CH 3 or M and M is a metal capable of forming a salt, X is a bridge group of the formula (CH 2 where n=l to 3, in which 1 to 3 (CH 2 groups can be replaced by NH or
HC-
II
0 groups, or a bridge group of the formula (CH 2 where n=4 to 10, in which 1 to 3(CH 2 groups can be replaced by oxygen atoms, NH or *groups with the proviso that no neighboring (CH 2 )-groups are replaced by oxygen atoms and in which GS is bonded via X as desired; and Z is HO-c,-CX=e-CH 2 0 o
II
0 0 o 0 0 S HO-- HO -C ee *0 *O O (H)CdO-P-O-.
o NH
S
S
S
10
S
S
462 or -N(R) 3 where R is in each case C I-C 7 alkyl, or H 2
-N-(CH
2 6 0 11 where the alkyl moiety is optionally substituted by a COGH group, -L 0 0 0 NH0 0 0
C-NH{-.
HO 0 0
CONH-
0 If
LII
0 If 463
C
0 0 0 NH qH-(H-COH) 0 II COA N-or
COOH
o tCOA tCO-NHwhere A is in each case OH or NH (C I-C 10 alkyl.
5A-65 A bile acid derivative of the formula I as described in A-64, in which GS is linked to X in the 3-position, linking taking place in the a- or j3-position.
p2pZTD( B HMG CoA Reductase inhibitors
COMPOTJNDS
2-d COMPOUND CLASSES CAS NUMNIBERS for SPECIFIC and
REPRESENTATIVE
CONPO UINDS R E E:Esr F1 u vas ta 6 a L c Ll~--a FvLn S 'i' Lza'as 93937-5-4-1 2241173 3 1C9 37-0 ,3,302-63-9 1 3-2 A! -o r(:sma DE3122-99 E? 33538 3Z0392 i3017-01-7 123 29-03-4 BMfS 1S0431 135,0), 3 3 (11 2 932- 99.
(193) 2 0 1 I G- 14.175C-63-2 ls LlCudin- 5-522 14.396&-73-3. 133?93 139993- L39393-465-7, 139993-47-8, 139993-43-9, 1399 93-49-0, 139993- 50-3, 139993-51-4, 139993-52-5, 139993-53-6, 139393-54-7, 139993- 55-8, 139993-56-9_139 993-57-0, 139993-58-1. 139993-59-2, 139993- 60-5. 139993-61-6, 139993-62-7, 139993-63-8, 139993-4-9, 139993- 65-0, 139993-6&1, 139993-67-2, !39993-63-3; 139993-69-4, 13993- 70-7, 139993-71-8, 139993-72-9, 139993---0, 139993-74-1,139993- 75-2 139993--j3 139993-74, 139993-78-5, 139993-79-6, 139993- 80-9. 1,0110-63-0, 1412S--9, 140123-99-0. 140157-62-6 125394-01-1, 1258402-2, 12-594- 03-3. 12594-4-, 125894-05-5, 123894-08-3, 1:894-09-9, 125914- 96-7 i5763S-3-4, 157053-145, 157053- E orca.Anaogs of di- zr.d L 1 iptidz 'c ac-ds Socd, Scod.. 5ok14oga1, ?H-211. G 3 2270312 15-6, 157025-16-7, 137053-17-3, 1570-5--13-9, 157025-1-0- 2 N fv, 66 1 29829-0-4 C c 1 s c t 0 r t C-F-83 101 !307 1321C0-55-1 771-i7-:9-4
.T.
an wrz-A*:n (19'76). 934-9.
c -4;cp'
I
1 2 9 7 7iln(f Trn s hen, C-!az: e~ Chv 9 6 ~c~aio~ a: cl d&n gl ryasdm G R 9 5030 2cd.s azd LZzc~ca of 6&ph.e-cxy-3,S--6brydxxyi 222 15 7243-M-1-6 S5 3,16765E 13058i1-~2-9, i1305S1-43-0, 130-531- 41, 130581-452, 130531-46-3,' 130531-47+-4 i3053l-:Ls-5. 130581- 49 130531-SC-9.130531-51-0, 130581-52-1, 130619-07-7, 130619- 08-3. 130619-09 -9 1Z27502-48-1, 136cC6-66, 13603-4 04-3 -7369323 S- .achr, B-ldcr, B 3 c t al J Ch c -M PAIENDED
SHEET
c- S L 6536 9 L -11 '311 2 Rawsc c1 7 15 7 1-a- 33 -1370231-5 12.511 1-69-5 1.5 9 -6 9- 6 A nbiOL 1531), S ccziy(99), 3(j 291-7_19 c, all., c iotys Ac-a D P2 6 1 5-59 izl:'bicars izz-!ucL-. Na =(i SC 32-561 SC 45355 '76752-41-5 125793-76-2 133933-235-2 'uS 4 2 "1-52 6 conrtaining HM CoA r'.c~asc Iro iCludizz SQ 336CC pyt---~ca c.r)zyc aci-ds and szhs ztra--:a a~1cium (CT 81 US j:4'13 4 13 443 135052-71-6, 136215-32-2, 136215- 83-3, 136215-3--. 136215-35-5, 136315-18-9, 1363 15- 19-0, 1363 20-3, 136315-21-4,1363116-2C-6 134523-03- 3 L, Ll N, i zd Rc Ch.
'2 2203 27 DE 2,90-/0 F z Cr' L Bc=d7= 49562-29-9 815 9-67-0 31637-97-5 ~{v4ncUn 1 og.~
-S
I 2A-T. "Hdiz~-3,5-d3on~ us 371232-.5 E' -2450M03 US 49372.59 WO 19CO0897 16&443-2 9AiFnm1D-rC- OS -514 a,-,and y -lky '1 aii-oph noc anal'o 9.
p--OPQCIC d~opyi~~.-1co ;-dcuding 3- Eopt-vzyi77crz- -c or 9 (T 3 1:~s USS '~3 64-1696- J? 0- C3933 Y 2 ard HEJ td US:= 29().67586 Scvas a.
a orv at t 2 cer2-vastati 'e rv a- S t a in I~ 101 2 2 Ser%*. c a2.c s e A- 12 -2256 ace e cev a S t 7 rix p-Co 5 6 5io c R e du ct a se Ih -trS 5 eC; x~~eo ia G-CoPX ?eduictase -4 secooxysero H2G -CoA c as e I t~ors, tac e= ezxy 3, 5&hdxhXo20ac.is ln'po2.a~~s Wr.er-Lar:Ibezt L-6692 62 m~evas catin N- (2-.ethy2.propyl) ca~r~'y 2 AL 8- "o41.(Iayc c c-a 2-yl) e perhyd~roisc~qu.flO 2 2.fle Bayer Merck :-oa.
Ja'azi Tc*raco Merck Cc Sato Unvers i.v Mis-,LO;S72 C,-.ezi Cal E ave r n2.~2.S2 Xerck Co L-upo~n Merck Nissa2 Che'ica2 C. 1 a~x o Mr2.O -vvesse2 Merck CO~zr Merck &Co Sazrkyo -4 (2 4 S- 53753A u vcxuzc rcm 0c~z e ,13 C-2 56-1) zetrar'vao- 2 6 ez- 2 l to 6-me t'vl.e2.Y (4 Zcle =oe---r-nger Va rt Caro, 1, a univers: atzras

Claims (46)

1. A composition, comprising an ileal bile acid transport inhibitor and an HMG Co-A reductase inhibitor.
2. The composition of claim 1 wherein the HMG Co-A reductase inhibitor is selected from the group consisting of lovastatin, simvastatin, pravastatin and fluvastatin.
3. The composition of claim 1 wherein the HMG Co-A reductase inhibitor is atorvastatin.
4. A pharmaceutical composition, comprising: a first amount of an ileal bile acid transport inhibitor, and a second amount of an HMG Co-A reductase inhibitor, wherein said first and second amounts of said inhibitors together comprise an anti-hyperlipidemic condition effective amount of said inhibitors, and a pharmaceutically acceptable carrier. The pharmaceutical composition of claim 4 wherein the HMG Co-A reductase inhibitor is selected from the group consisting of lovastatin, simvastatin, pravastatin and fluvastatin. 2 20 6 The pharmaceutical composition of claim 4 wherein the HMG Co-A reductase inhibitor is atorvastatin.
7. The composition of any one of claims 1 to 6 wherein the ileal bile acid transport inhibitor is a compound of formula pR Y R1 9 2 4 4 (I) wherein: q is an integer from 1 to 4; n is an integer from 0 to 2; S L R' and R 2 are independently selected from the group i C ;'consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, 470 alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituents selected from the group consisting of OR 9 NR9R'o, N'R 9 RiOR"A-, SR 9 S'R 9 R'OA- SP'R 9 R'OR"A, S R 9 SO 2 R 9 SO 3 R 9 CO, 2 R 9 CN, halogen, oxo, and CONR 9 R' 0 wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or more carbons replaced by O, NR 9 NR 9 R'OA-, S, SO, SO 2 S'R 9 P'R 9 R'oA-, or phenylene, wherein R 9 R" 0 and R" are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, heteroaryl, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; or R1 and R 2 taken together with the carbon to which they are attached form C 3 -Cj 0 cycloalkylidene; R 3 and R 4 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, heteroaryl, OR 9 NR 9 SR 9 S(O)R 9 S0 2 R 9 ~and S0 3 R 9 wherein R 9 and R" 0 are as defined above; or R 3 and R' together form =NOR", =NNR11R 2 =NR 9 or =CR"R 2 wherein R 1 and R" are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, -arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, heteroaryl, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR 9 NR 9 R'o, SR 9 S(O)R 9 S0 2 R 9 S0 3 R 9 C0 2 R 9 CN, halogen, oxo, and CONR 9 R'O, wherein R 9 and R' 0 are as defined above, provided that both R 3 and R 4 cannot be OH, or SH, or R" and R1 2 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; R 5 and R 6 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, -Ft cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteraryl, SR 9 S(O)R 9 S0 2 R 9 and S0 3 R 9 wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR 13 NR1 3 R 14 SR 1 3 S(0)R 13 SO 2 R 13 SO 3 R 1 3 NR"OR" 4 NR 3 NR 4 R 1 5 NO2, CO 2 R 13 CN, OM, SOOM, SO 2 NR' 3 R 14 C(0)NRR" 4 C OM, COR 3 P R"R 14 P'R R'RsA-, P(OR 13 OR 14 S'R 3 R 4 and N'R 9 "R1R 2 A-, Wherein: A' is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can be further substituted with one or more substituent groups selected from the group consisting of OR, NR 7 R 8 SR 7 S(O)R 7 SOR 7 SO 3 R 7 CO 2 R 7 CN, oxo, CONRR 8 N RR 9 A, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, 70 heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R R 8 PR 7 RsR 9 and P (OR 7 )OR 8 and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether,.aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can optionally have one or more carbons replaced by O, NR 7 N'R 7 R 8 S, SO, SO, S'R 7 PR 7 P(O)R 7 PR 7 R 8 or phenylene, and R' 3 R 14 and R" 1 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, heteroaryl and polyalkyl optionally have one or more carbons replaced by O, NR 9 NR 9 S, SO, SO S S S+R 9 PR 9 PR 9 R'oA-, P R 9 phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R" 4 and R's are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR 9 NR 9 R' 0 N*R 9 R"R1 2 A-, SR 9 S R 9 S0 2 R 9 S0 3 R 9 oxo, C0 2 R 9 CN, halogen, CONR 9 R'O, SO 2 NR 9 R'O, PO(OR")OR 7 PRR'R"oA, SR 9 and C(0)OM, wherein R" and R" 7 are independently selected from the substituents constituting R 9 and M; or R14 and R15, together with the nitrogen atom to which they are attached, form a cyclic ring; R 7 and R 8 are independently selected from the group consisting of hydrogen and alkyl; and 100 one or more Rx are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR'-, 105 NRR SR' 3 S R" 3 S(0) 2 R1 3 SO 3 R SR1 3 RA NRO 3 0R 4 NR 3 NR1 4 R 5 NO 2 CO 2 1R' 3 CN, OM, SO 2 0M, SO 2 NR 13 '14, NR' 4 C(O)R R 3 C. C(0)NR' 3 R1 4 NR1 4 C(0)R1 3 C(0)OM, COR", OR", S(0)n NR 18 NR' 3 R' 8 NR 8 OR14, N-RR1R 12A-, P*R 9 R"R'1 2 A, amino acid, peptide, polypeptide, and carbohydrate, 110 wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, heteroaryl, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR 9 NR9Ro, N'RR 1 1 1 2 SR 9 S R 9 SO2R, SO3R9, oxo, COR9, CN, halogen, CONR 9 R10, SOOM, SO 2 NR 9 R' 0 PO(OR") OR PR 9 R1R 2 A, S'R'oA-, or C(O)OM, and wherein is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle and quaternary 120 heteroaryl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, 473 and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group 125 consisting of OR 9 NR 9 R1 0 N*R 9 R"R1 2 SR 9 S(O)R 9 SO 2 R 9 SO 3 R 9 oxo, CO 2 R 9 CN, halogen, CONR 9 R' 0 S0 3 R 9 SO 2 0M, SO 2 NR 9 R 10 PO(OR 1 6)OR 17 and C(0)OM, wherein in Rx, one or more carbons are optionally replaced by O, NR 13 N'R"R 4 S, SO, SO 2 S'RlA-, PR 1 3 130 P(O)R 3 P'R' 3 R 4 A phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by O, NR 9 N+R 9 S, SO, 135 SO 2 S'R 9 PR 9 P'R 9 R' 0 or P(O)R 9 wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, 140 cycloalkyl, heterocycle, heteroaryl, arylalkyl, halogen, oxo, OR 3 NR" 3 SR 3 S R SO 2 R 13 SO 3 R 13 NR 3 OR 4 NR- 3 NR' 4 Ri 5 NO 2 COR 13 CN, OM, SO20M, SO 2 NR13R 4 C(O)NR" 3 R 14 C(0)OM, COR" 1 P(0)R 3 "R 14 P+R' 3 R 4 RR 5 P(OR 1 3 )OR14, S1 3 RR14A-, and N'R9R"R12A provided that both Rs and R 6 cannot be hydrogen, OH or SH, and when R 5 is OH, R, R, R R 7 and R 8 cannot be all hydrogen; provided that when R 5 or R 6 is phenyl, only one of R 1 Sor R 2 is H; .150 provided that when q 1 and Rx is styryl, anilido, or anilinocarbonyl, only one of R' or R 6 is alkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
8. The composition of claim 7, wherein R 5 and R 6 are independently selected from the group consisting of H, aryl, heterocycle, heteroaryl, quaternary heterocycle, and quaternary heteroaryl, wherein said aryl, heterocycle, heteroaryl, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups Independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, halogen, oxo, OR" 3 NR 3 R 4 SR", S(0)R13, SO 2 R', SO 3 R' NR 3 OR" 4 NR" 3 NR' 4 R 5 N 2 CO 2 R 13, CN, OM, S0 2 NR 3 R 4 C NR 3 R 4 C OM, COR", P R 3 R' 4 P-R1R4R1SA-, P(OR 3 OR 4 S+R"4R"A-, and NR 9 R11Rl 2 A-, wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can optionally have one or more carbons replaced by O, NR', N'R 7 S, SO, SO2, S'R 7 PR P(O)R, P'*R 7 RsA, or phenylene, wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can be further substituted with one or more substituent groups selected from the group consisting of OR 7 NR 7 R, SR 7 S(O)R 7 SO 2 R 7 SO 3 R 7 CO 2 CN, oxo, CONR 7 N'R 7 R 8 R 9 alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R 7 R', P'R 7 R 8 R 9 A, and P(O) (OR 7 OR 8 A
9. The composition of claim 8, wherein RS or R 6 has the formula: -Ar- (RY), wherein: t is an integer from 0 to *Ar is selected from the group consisting of phenyl, thiophenyl, pyridyl, piperazinyl, piperonyl, pyrrolyl, naphthyl, furanyl, anthracenyl, quinolinyl, isoquinolinyl, quinoxalinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrimindinyl, thiazolyl, triazolyl, isothiazolyl, indolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, and benzoisothiazolyl; and one or more RY are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, quaternary 475 heterocycle, quaternary heteroaryl, OR 9 SR 9 S(O)R 9 SO 2 R 9 and S0 3 R 9 wherein said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, and heteroaryl can be substituted with one or more substituent groups independently.selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, halogen, oxo, OR", NR 3 R 4 SR", S(O)R 1 SO 2 R L SO 3 R 13 NR1 3 OR14, NR' 3 NR 4 R 1 i, NO 2 CO 2 R 1 3 CN, OM, SO 2 OM, SO 2 NR 3 R 14 C(0) NR3R 14 C(0)OM, COR 1 3 P(0)R 1 3 R 14 PR 3 R1 4 R 15 A-, P(OR 3 OR 1 4 S+R1 3 R 4 and N+R 9 R"R1 2 A-, wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can be further substituted with one or more substituent groups selected from the group consisting of OR 7 NR 7 R 8 SR 7 S(O)R 7 SO 2 R 7 S0 3 R 7 CO 2 R 7 CN, oxo, CONR 7 R 8 N'R 7 RSRA, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R 7 R 8 P'R 7 R R 9 and P(O) (OR 7 )ORa; and wherein said alkyl, alkenyl, alkynyl, polyalkyl, S polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can optionally have one or more carbons 40 replaced by O, NR 7 N'R 7 RA-, S, SO, SO 2 S*R 7 PR 7 P(0)R 7 PR 7 or phenylene.
10. The composition of claim 8, wherein R s or R 6 has the formula (II): o 9 *999 d r D 476
11. A combination therapy method for the prophylaxis or treatment of a hyperlipidemic condition in a mammal, comprising: administering to said patient a first amount of an ileal bile acid transport inhibitor, and administering to said patient a second amount of an HMG Co-A reductase inhibitor, wherein said first and second amounts of said inhibitors together comprise an anti-hyperlipidemic condition effective amount of said inhibitors.
12. The combination therapy method of claim 11 wherein the HMG Co-A reductase inhibitor is selected from the group consisting of lovastatin, simvastatin, pravastatin and fluvastatin.
13. The combination therapy method of claimllwherein the HMG Co-A reductase inhibitor is atorvastatin.
14. The method of any one of claims 11 to 13 wherein the ileal bile acid transport inhibitor is a compound of formula 0 t n S P 6 7z R* (I) wherein: q is an integer from 1 to 4; n is an integer from 0 to 2; and R 2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, *.alkylthio, (polyalkyl)aryl, and cycloalkyl, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkythio, (polyalkyl)aryl, and cycloalkyl optionally are1 to 4; n is an integer from 0 to 2; substitute and with one or more substituindependentl selected from he group the group consisting of ORH, alky, akenyl, alkynyl, haloalkySR, S alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituents selected from U the group consisting of OR 9 NRgR 1 N'RSR'R"A-, SR 9 S'RRL°A- P-PR9Ri'A', S R 9 SO SO 3 R9, C0 2 R9, CN, halogen, oxc, and CONR 9 R 10 wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or more carbons replaced by 0, NR9, N-R 9 R"OA, S, SO, SO, S-R 9 A-.'P-R 5 or phenylene, wherein R 9 and RW are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, heteroaryl, ammoniumalkyl, alkylammoniumalkyl, and arylalky; or R' and R 2 taken together with the carbon to which they are attached form C 3 -QC 0 cycloalkylidene; RI and R' are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, heteroaryl, OR 9 NR9R'O, SR 9 S(O)R 9 S0 2 R, and SO 3 R9, wherein R 9 and RIO are as defined above; or R' and R' together form =NOR", NNR"R' 2 =NR 9 or =CR1"2 wherein R" and R 12 are independently selected from the group consisting of H, alkyl, alkenyl, alkyrryl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, heteroaryl, carboxyalkyl, carboalkoxyalkyl, cycloalkyl. cyanoalkyl, OR 9 NR9R' 0 SR 9 S0 2 R 9 S0 3 R 9 C0 2 R9, ON, 40 halogen, oxo, and CONRR' 0 wherein R5 and R" 0 are as defined above, provided that both R 3 and R' cannot be OH, NPi 2 or SH, or R" and R' 2 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; R 5 and R6 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteraryl, SR9, S(O)R 9 SO,R9, and so wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, hecerocycle, heteroaryl, quaternary heterocycle, and quaternary heteroaryl can be subsituced with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR" 3 NR1 3 R1 4 SR' 3 S R11, S0 2 R' 3 SO 3 R' 3 NR1 3 0R' 4 NR' 3 NR' 4 R1 5 NO 2 CO 2 R' 3 CN, OM, So 2 OM, SO 2 NR1IR1 4 C NR1 3 R" 4 C (0)OM, COR"~, P 13 R1 4 P R 3 R"RA-, P OR' 4 S*R' 3 R'A and N*R 9 R"1R'A- Wherein: A- is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroary. can be further substituted with one or more substituent groups selected from the group consisting of OR 7 NR 7 R", S 7 S(0) R So0 2 R S0 3 R C0 2 R CN, oxo, CONR N'R 7 R 8 R 9 A, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P (0)R 7 R 8 P'R 7 RR 9 A, and P (OR 7 )0OR', and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can optionally have one or more carbons replaced by 0, NR N*R R 8 A, S, SO, SO 2 ,I SR A, PR 7 P .0,0..P*R 7 RaA, or phenylene, and R' 3 R' 4 and R" 5 are '000., independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, heteroaryl and polyalkyl optionally have one or more carbons replaced by 0, NR 9 N*R 9 R' 0 5, S0, SO 2 S*R 9 A, PR 9 P+R 9 R' 0 A, P (0)R 9 phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R1 3 R1 4 and R' 5 are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR 9 NR 9 R' 0 N*R 9 RR 1 2 A-, SR 9 S (0)R 9 S0 2 R 9 S0 3 R 9 oxo, C0 2 R 9 CN, halogen, CONR 9 R' 0 479 SO 2 M, S 2 ONR 9 RIo, PO (OR' 6 OR 7 P*R 9 R'oR"A S'R 9 and C OM, wherein R' 6 and R1 7 are independently selected from the substituents constituting R 9 and M; or and R 5 together with the nitrogen atom to which they are attached, form a cyclic ring; R 7 and R' are independently selected from the group consisting of hydrogen and alkyl; and 100 one or more Rx are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR" 3 105 NR'"R' 4 SR 3 S SO 3 R 3 S' 3 R' 4 NR' 3 0R 4 NR1 3 NR 4 R 5 NO 2 CO 2 R 1 3 CN, OM, SO 2 OM, SO 2 NR13R 14, NR1 4 C R 3 C(0)NR 3 R" NR1 4 C(0)R 3 C(0)OM, COR1 3 OR' 8 S(0) NR"', NR1 3 R' 8 NR' 8 0R' 4 N 9 R"R'RR 2 A PR 9 R11R 2 A, amino acid, peptide, polypeptide, and carbohydrate, 110 wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, heteroaryl, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR 9 NR 9 R'o 0 N'R 9 R"R 2 SR 9 S R 9 SO 2 R, S0 3 R 9 oxo, C0 2 R 9 CN, 115 halogen, CONR 9 R'o, SO 2 0M, SO 2 NR 9 R'1 0 PO(OR 6 OR' 7 P'R 9 R"R 2 A-, 0:* S'R 9 R'OA-, or C(O)OM, and wherein R" is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle and quaternary :120 heteroaryl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group 125 consisting of OR 9 NR 9 R' 0 N'R 9 R"R 2 A, SR 9 S R 9 S0 2 R 9 S0 3 R 9 oxo, C0 2 R 9 CN, halogen, CONRR'I 0 SO 3 R, SOOM, SO 2 NR 9 R' 0 PO(OR 6 )OR1 7 and C(O)OM, wherein in Rx, one or more carbons are optionally replaced by O, NR 3 N'R 3 R' 4 A, S, SO, SO 2 PR' 3 jL ~480 130 P(O)Rl", PR 3 R1 4 phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by O, NR 9 NR 9 R'oA S, SO, 135 SO,, S-R 9 PR 9 PR 9 R'iA-, or P(0)R 9 wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, 140 cycloalkyl, heterocycle, heteroaryl, arylalkyl, halogen, oxo, OR 13 NR'"R' 4 SR 13 S(0) SO 2 R" 1 SOR 13 NR" 3 OR' 4 NR' 3 NR1 4 R 1 S, NO 2 CO 2 R 13 CN, OM, S02OM, SO 2 NRR3 14 C(O)NR" 3 R1 4 C(0)OM, COR 13 P(0) R R' 4 P-R 3 RL 4 R'RA-, P(OR 3 OR 14 SR 3 R 4 A-, and N'R 9 R"RI 2 A-, 145 provided that both R 5 and R 6 cannot be hydrogen, OH or SH, and when R s is OH, R R, R 3 R 4 R 7 and R 8 cannot be all hydrogen; provided that when R 5 or R 6 is phenyl, only one of RI or R 2 is H; 150 provided that when q 1 and R x is styryl, anilido, or anilinocarbonyl, only one of R' or R 6 is alkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
15. The method of claim 14, wherein R 5 and R 6 are independently selected from the group consisting of H, S.aryl, heterocycle, heteroaryl, quaternary heterocycle, *.gee* and quaternary heteroaryl, 5 wherein said aryl, heterocycle, heteroaryl, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, halogen, oxo, OR 13 NR 3 R' 4 SR" 3 S(O)R" 3 SO 2 R 3 O SO 3 R 13 NR 3 OR14, NR' 3 NR 4 R 15 NO 2 COR 13 CN, OM, SO 2 OM, SO 2 NRI' 3 C (0)NR1 3 R C M, COR' 3 P R 3 R 14 P'R 1 3 R 1 4 R'A- P (OR 13 OR 1 4 S+R1 3 R1 4 A, and N'R 9 R"R1 2 A, wherein said alkyl,.alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can optionally have one or more carbons replaced by R 7 R 8 S, So, SO 2 S*R 7 PR 7 P(O)R 7 P'R 7 R 8 or phenylene, wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can be further substituted with one or more substituent groups selected from the group consisting of OR 7 NR R 8 SR 7 SSoR 7 S 2 R 7 So0 3 R C0 2 R CN, oxo, CONR 7 N*R 7 R 8 R 9 alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R 7 R 8 P*R 7 R 8 R 9 and P(O) (OR 7 )0OR".
16- The method of claim 15, wherein R' or R 6 has the formula: -Ar- MRY), wherein: t is an integer from 0 to Ar is selected from the group consisting of phenyl, thiophenyl, pyridyl, piperazinyl, piperonyl, pyrrolyl, naphthyl, furanyl, anthracenyl, quinolinyl, isoquinolinyl, quinoxalinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrimindinyl, thiazolyl, triazolyl, isothiazolyl, indolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, and benzoisothiazolyl; and 0 one or more Ry are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR 9 SR 9 S (0)R 9 S0 2 R 9 and S0 3 R 9 wherein said alkyl, alkenyl; alkyriyl, aryl, cycloalkyl, heterocycle, and heteroaryl can be substituted with one or more substituent groups independently selected Z-f IL q rmthe group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, halogen, oxo, OR 3 NR1 3 R1 4 SR 1 3 S R1 3 1 SO 2 R1 3 1 So S 3 R' 13 NR1 3 OR 14, NR1 3 NR14R's NO 2 CO 2 R1 3 CN, OM, SO 2 OM, SO 2 NR 3 C(O)NR' 3 C(O)OM, COR1 3 P(O)R1 3 R 4 P'R' 3 R' 4 R'1 5 A, P (OR1 3 OR' 4 S+R' 3 R 4 A- and N+R 9 RllR12A-, wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can be further substituted with one or more substituent groups selected from the group consisting of OR 7 NR 7 R 8 SR 7 S(O)R 7 S0 2 R 7 SO 3 R 7 C0 2 R 7 CN, oxo, CONR 7 R", N+R 7 R 8 R 9 alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R 7 P'R 7 R 8 R 9 and P(O) (OR 7 )OR 8 and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle and heteroaryl can optionally have one or more carbons replaced by 0, NR 7 N+R 7 R 8 S, SO, SO 2 S+R 7 A, PR 7 P(O)R 7 PR 7 R 8 A, *:40 or phenylene.
17. The method of claim 16, wherein R' or R 6 has the formula (II): *C a C" c pY 483
18. The use of a composition of claim 4 for the manufacture of a medicament for treatment of a hyperlipidemic condition in amammal.
19. The use according to claim 18 wherein the HMG Co-A reductase inhibitor is selected from the group consisting of lovastatin, simvastatin, pravastatin and fluvastatin. The use according to claim 18 wherein the HMG Co-A reductase inhibitor is atorvastatin.
21. The use according to any one of claims 18-20 wherein the ileal bile acid transport inhibitor is a compound of formula of claim 7.
22. The use according to claim 21 wherein R 5 and R 6 of said formula are as defined in claim 8.
23. The use according to claim 21 wherein R s and R 6 of said formula are as defined in claim 9.
24. The use according to claim 21 wherein R s and R 6 Of said formula are as defined in claim 84 484 C-3024/AU The composition of claim 1 wherein the HMG Co-A reductase inhibitor is pravastatin.
26. The pharmaceutical composition of claim 4 wherein the HMG Co-A reductase inhibitor is pravastatin.
27. The combination therapy method of claim 11 wherein the HMG Co-A reductase inhibitor is pravastatin.
28. The use according to claim 18 wherein the HMG Co-A reductase inhibitor is pravastatin.
29. The composition of claim 1 wherein the HMG Co-A reductase inhibitor is simvastatin.
30. The pharmaceutical composition of claim 4 wherein the HMG Co-A reductase inhibitor is simvastatin. c 31. The combination therapy method of claim 11 wherein the HMG Co-A reductase inhibitor is simvastatin. 15 32. The use according to claim 18 wherein the HMG Co-A reductase inhibitor is simvastatin.
33. The composition of claim I wherein the HMG Co-A reductase inhibitor is lovastatin. *o •34. The pharmaceutical composition of claim 4 wherein the HMG Co-A reductase inhibitor is lovastatin. The combination therapy method of claim 11 wherein the HMG Co-A reductase inhibitor is lovastatin.
36. The use according to claim 18 wherein the HMG Co-A reductase inhibitor is lovastatin. C-3024/AU
37. A pharmaceutical composition, comprising: a first amount of an Hleal bile acid transport inhibitor, and a second amount of an 11MG Co-A reductase inhibitor selected from the group consisting of lovastatin, simivastatin, pravastatin, fiuvastatin. and atorvastatin, and a pharmaceutically acceptable carrier, wherein said first and second amounts of said inhibitors together comprise an anti-hyperlipidemic condition effective amount of said inhibitors, and wherein the Hleal bile acid transport inhibitor is a compound of formula (LX): R 1 an 2 aeidpnetyslce rmakl R 5 s ubtiute penl;an 2 on rmr Xaeidpnetyslce rmtegopcnisigo ,ak amin ad peindeypepnde, nd slcerbodael Qeenalkyl, alkenyl, alicynyl, y caly, aryl, polyalkyl, h elgeeroakycycleak, ~heterocrycylo ,yly, haloalkyl, polyether, quaternary heterocycle, qutrayh rand, R" S(OR 9 R1, SOR, SPA", o, 0 2 R, SCN 1, halogen NR3 R 4, O 2 OMR RO 2 N, 9 R' 0 COO', C)ORO, PS0R 2 S2R 9 R 0 or C(O)M, a(Ond I R1 26 N~C(O)RK ARS, ORSO, S(R' 3 A, PR, (R 1, PVOR phenyleneA, amino11 a, aioipeptide, polypeptide, an carbohydrate, plehr rplakl wherein iaidpoyakyl, phe aknyln, lamino aci, peptidey, potypepycde,an C-3024/AU carbohydrate, one or more carbons are optionally replaced by 0, NR!, N+ 9 R' 0 S, so, SO 2 PR!, P+R R' 0 or and wherein quaternary heterocycle and quaternary heteroaryl. are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylallcyl, halogen, oxo, NR1 3 R 14 SR 1 3 S(O)R 1 3 SO 2 R' 3 S0 3 R 1 3 N RB OR 1 4 NR 13 NRI 4 NO 2 CO 2 R 1 3 CN, OM, SO 2 OM, sONRB R 1 4 C(O)NR1 3 R 1 4 C(O)OM, COR 1 3 P(O)R1 3 R 1 4 P+R 1 3 R1 4 R 15 P(OR 1 3 )0R 14 S+R1 3 R 4 A and N*R 9 RI]R 12 and wherein and R 0 are independently selected from the group consisting of H, ailkyl, alkenyl, alcynyl, cycloalkyl, aryl, acyl, heterocycle, heteroaryl, amrnoniumalcyl, alkylammoniunalcyl, and arylalkyl; and wherein R" and R" 2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl., aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, heteroaryl, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR!, NR 9 R' 0 SR 9 S(O)R 9 S0 2 S0 3 R 9 C0 2 CN, halogen, oxo, and CONR!R' 0 or R" and R 1 2 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; wherein R" 3 R' 4 and R" 5 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, qu~aternary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl, alkenyl, alkynyl., arylalkyl, heterocycle, heteroaryl and polyalkyl optionally have one or more carbons replaced by 0, NRW, N+R 9 R' 0 A7, S, So, SOD, S+RA, 25 PR 9 P'OA, phenylene, carbohydrate, amino acid, peptide, or polypeptide, and wherein R" 3 R' 4 and R" 5 are optionally substituted with one or more groups ~~**:selected from the group consisting of sulfoalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR', NR R' 0 NWRR' R' 2 SR 9 S0 2 R!, SOXR, oxo, C0 2 R 9 CN, halogen, CONRR, SO 2 OM, S0 2 NRR, PO(OR' 6 )OR 7 P+R 9 R' 0 S1R!R'OA:, and C(O)OM, or R" 4 and R" 5 together with the nitrogen atom to which they are attached, form a cyclic ring; and wherein R 6 and R" 7 are independently selected from the substituents constituting R' and M; and wherein RWB is selected from the group consisting of acyl, arylailcoxycarbonyl, arylailcyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle and quaternary C-3024/AU heteroaryl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group consisting of OR!, -NR 9 RW, N'+R 9 R' 1 R' 2 A, SW 9 S(OR, S0 2 R 9 SOXR, oxo, C0 2 CN, halogen, CONR 9 R' 0 S0 3 R 9 SO 2 OM, SO 2 NR 9 R' 0 PO(0R' 6 )OR' 7 and C(O)OM; and .wherein N is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
38. The composition of claim 37 wherein the H1MG Co-A reductase inhibitor is selected from the group consisting of lovastatin, simnvastatin, pravastatin and fluvastatin.
39. The composition of claim 37 wherein the HMVG Co-A reductase inhibitor is pravastatin. ~40. The composition of claim 37 wherein the H1MG Co-A reductase inhibitor is 15 simvastatin.
41. The composition of claim 37 wherein the HMG Co-A reductase inhibitor is .lovastatin.
42. The composition of claim 37 wherein the H1MG Co-A reductase inhibitor is atorvastatin.
43. The composition of claim 3 7 wherein R' and R' are independently selected from the group consisting of ethyl n-propyl, n-butyl and isobutyl.
44. The composition of claim 43 wherein one or more RW are independently selected from the group consisting of methyl, ethyl, isopropyl, t-butyl, hydroxy, methoxy, ethoxy, isopropoxy, methyltbio, iodo, bromo, fluoro, methylsulfinyl, methylsulfonyl, ethyltluo, amino, hydroxylamine, N-methylamino, N,N-dimethylamino, NN- diethylamino, (N)-benzyloxycarbomoyl, trimethylammonium -NHC(=O)CH 3 NHC(=O)C 5 H 11 -NHC(=O)C 6 H 3 carboXyethYlarnino, (N)-morpholinyl, (N)-azetidinyl, (N)-N-methylazetidinium (N)-pyrrolidinyl, pyrrolyl, RqZ(N)-N-methylpyridiniun (N-N-methylmorpholinium A N-N'-methylpiperazinyl, 488 C.3024/AU (N')-bromomethylaxnido, (N)-N-hexylamino, thiophene, -W(CH 3 2 C0 2 H -NCH 3 CJI 2 C0 2 H, -(N)-N'-dimethylpiperazinium I-, N-t-butyloxycarbamoyl, (N)-methylsulfonamido, (N)N'-methylpyrrolidinium and -(OCH 2 GH 2 31, wherein AN ic a pharmaceutically acceptable anion. A combination therapy method for the treatment or prophylaxis of a hypcrlipidemic condition in a mammal in need thereof, comprising: administering to said mammal a first amount of an ilea] bile acid transport inhibitor, and administering to said mammal a second amount of an HMG Co-A reductase inhibitor selected from the group consisting of lovastatin, simivastatin, pravastatin, fluvastatin and atorvastatin, wherein said first and second amounts of said inhibitors together comprise an anti-hyperlipidernic condition effective amount of said inhibitors, and wherein the ileal bile acid transport inhibitor is a compound of formula (LX): C C C C C C C C C CC.. C. 20 0 S 2 R 1 (R X 3 7 R' 4 OH (LX) wherein: R' and W 2 are independently selected from alkyl; RW is substituted phenyl; and one or more WX are independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyL, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR" 3 R' 3 R 1 4 SR 3 S(O)R 1 3 S(O) 2 R 3 SO 3 R' 3 s 4 R1 3 R1 4 A7, NR1 3 OR'1 4 N R'NR1 4 R' 3 NO 2 CO 2 R1 3 ON M OOSO 2 NR1 3 R' 4 NR' 4 C( 1R 3 C(O)NRI 3 R1 4 NR1 4 C( 1R 3 C(O)OM, CORD 3 OR', s(O)DR' 8 NR 1 3 R's, NRSOR 1 4 WR!R"R' 2 PR 9 R"1R'A amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, heteroaryl, acyloxy, arylalkyl, haloalicyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR?, NR 9 NWRR"R 2 SR!, 489 C-3024/AU SO 2 R, SOXR, oxo, COXR, CN, halogen, CONR!R', SO 2 OM, SO 2 NR!R' 0 PO(R1 6 )OR1 7 P+R 9 R"R'VA, SVR 9 1 A, or C(O)OM, and wherein in IV, one or more carbons are optionally replaced by 0, NR' 3 NR 1 3 R 4 A S, So, SO 2 S+R 3 A, PR'1 3 p(O)R 3 P+R' 3 R1 4 A phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by 0, NR!, N+R 9 S, SO, SO 2 S+R!A, PR!, P+R 9 R' 0 A, or P(O)R 9 and wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alcenyl, alkynyl, polyalkyl, polyether, aryl, haloalicyl, cycloalkyl, heterocycle, heteroaryl, arylailcyl, halogen, oxo, OR" 3 qR 3 R1 4 SR 1 3 S(O)R' 3 SO 2 R1 3 SO 3 R' 3 N R'0R1 4 NRI 3 NR' 4 R' 5 NO 2 CO 2 R1 3 CN, OM, SO 2 OM, SO 2 NRI 3 R' 4 G(O)NRt 3 R1 4 C(O)OM, COR 3 P(O)R 3 R 4 P+R 3 R 1 4 R' 5 P(OR' 3 )OR1 4 SIR1 3 R1 4 A, and N'RR"R 2 and wherein R? and R 0 are independently selected from the group consisting of H, alkyl, alkenyl, alcynyl, cycloallcyl, aryl, acyl, heterocycle, heteroaryl, ammoniumalkyl, alkylammoniuinalcyl, and arylalkyl; and wherein R and R' are independently selected from the group consisting of H, alkyL, alkenyL, alkynyl, aryL arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, 20 heteroaryl, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR!, Nr 9 R' 0 SR!, S(O)R 9 S0 2 S0 3 R 9 C0 2 CN, halogen, oxo, and CONRR' 0 or R" and R" 2 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; wherein R' 3 R" 4 and R" 5 are independently selected from the group consisting of hydrogen, ailkyl, alkenyl, alkynyl, polyalkyl, aryl, arylailcyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl, alkenyl, ailcynyl, arylakl, heterocycle, heteroaryl and polyalcyl optionally have one or more carbons replaced by 0, NR 9 N+R 9 R' 0 A7, 5, SO, SO,, S+R 9 A, PR!, P+R!R' 0 A, pheriylene, carbohydrate, amino acid, peptide, or polypeptide, and wherein R" 3 R 1 4 and R" 5 are optionally substituted with one or more groups selected from the group consisting of sulfoallcyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, ORe, NR!R' 0 NWRR'''A, SR!, SOXR, SONR, oxo, COXR, CN, halogen, CONR 9 R' 0 S0 2 OM, SO 2 NR 9 R' 0 PO(OR' 6 )OR 7 P 4 RWR'R"A S+R 9 R' 0 A7, and C(O)OM, or 490 C-3024/AU R' 4 and R' 1 together with the nitrogen atom to which they are attached, form a cyclic ring; and wherein R 1 6 and R" 1 are independently selected from the substituents constituting R 9 and M; and wherein R" 8 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle and quaternary heteroaryl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group consisting of OR 9 NR9R' 0 N'RR "R 2 SR 9 S(O)R 9 SO2R 9 S0 3 R 9 oxo, COR 9 CN, halogen, CONR 9 R'R, S0 3 R 9 SO 2 OM, SO 2 NR 9 R' 0 PO(OR 6 )OR 17 and C(O)OM; and wherein A is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
46. The combination therapy method of claim 45 wherein the HMG Co-A reductase inhibitor is selected from the group consisting of lovastatin, simvastatin, pravastatin and fluvastatin.
47. The combination therapy method of claim 45 wherein the HMG Co-A 20 reductase inhibitor is pravastatin.
48. The combination therapy method of claim 45 wherein the HMG Co-A reductase inhibitor is simvastatin.
49. The combination therapy method of claim 45 wherein the HMG Co-A reductase inhibitor is lovastatin.
50. The combination therapy method of claim 45 wherein the HMG Co-A reductase inhibitor is atorvastatin.
51. The composition of claim 45 wherein R' and R 2 are independently selected from the group consisting of ethyl, n-propyl, n-butyl and isobutyl.
52. The composition of claim 51 wherein one or more R" are independently C-3024/AU selected from the group consisting of methyl, ethyl, isopropyl, t-butyl, hydroxy, methoxy, ethoxy, isopropoxy, methyithia, iodo, bromo, fluoro, methylsul~finyl, methylsulfonyl, ethylthio, amino, hydroxylaxuine, N-methylamino, N,N-dimethylamino, NN- diethylammno, (N)-benzyloxycarbornoyl, trimethylammonium AN, -NHC&=O)CH 3 NI{C(=-O)C 5 H 1 -NHC(=O)C 6 1 3 carboxyethylamino, (N)-morpholinyl, (N)-azetidinyl, (N)-N-methylazetidinium AN, (N)-pyrrolidinyl, pyrrolyl, (N')-N-methylpyridiniuin (N)-N-methylmorpholinium AN, N-N' -methylpiperazinyl, (N')-bromomethylamido, (N)-N-hexylamino, thiophene, -N'(CH 3 2 CO 2 H -NCH 3 CHCQ 2 H, -dimethylpiperazinium I-, N-t-butyloxycarbamoyl, (N)-methylsulfonamido, (N)N'-methylpyrrolidiniuxn and -(OCH 2 CH 2 3L, wherein AN is a pharmaceutically acceptable anion.
53. The use of a composition of Claim 37 for the manufacture of a medicament for treatment of a hyperlipidemic condition in a mammal.
54. The use according to claim 53 wherein the HMG Co-A reductase inhibitor is selected from the group consisting of lovastatin, simivastatin, pravastatin and fluvastatin.
55. The use according to claim 53 wherein the HMG Co-A reductase inhibitor is prvastatin.
56. The use according to claim 53 wherein the H1MG Co-A reductase inhibitor is simvastatin. 2Q 576. The use according to claim 53 wherein the orM o-A arede in hibidetoryi sleatedfoahtropcnitn o ehl thlnspoy, -uyhd.xmtoy etoy spopxmtytio oo rmo loo egysliymehlufnl 492 C-3024/AU ethylthio, amino, hydroxylamine, N-methylamino, N,N-dimethylamino, N,N- diethylainino, (N)-benzyloxycarbomoyl, triinethylammoniuxn K, -NHC(=O)C1 3 NIIC(=0)C 5 Hj I, -IiHC(=O)C 6 H, 1 carboxyethylamino, (N)-morpholinyl, (N')-azetidinyl, (N)-N-methylazetidiniuni (N)-pyrrolidinyl, pyrrolyl, (N)-N-methylpyridiriium A (N)-N-methylmorpholinium A, N-N'-methylpiperazinyl, (N)-bromoniethylamido, (N)-N-hexylainino, thiophene, -N'XCH 3 2 CO 2 H -NCH 3 CII 2 CO 2 H, -(N)-N'-dixnethylpiperazinium 1-, N-t-butyloxycarbainoyl, (N)-methylsulfonamido, -methylpyrrolidinium and -(OCH 2 CH 2 31 wherein A: is a pharmaceutically acceptable anion. DATED this 30 day of October 2000 G. D. SEARLE CO., By its Patent Attorneys, E. F. WELLINGTON CO., By. 0O sees (BueWllntn 0:00 0*0 690 Osee 00* 0000 0*@ 0see. 66960 493
AU64408/98A 1997-03-11 1998-03-10 Combination therapy employing ileal bile acid transport inhibiting benzothiepines and HMG Co-A reductase inhibitors Ceased AU730024C (en)

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HUP0002395A3 (en) 2002-12-28
NO994390D0 (en) 1999-09-10
CN1255864A (en) 2000-06-07
JP2002500628A (en) 2002-01-08
BG103793A (en) 2000-07-31
NZ337830A (en) 2001-07-27
WO1998040375A3 (en) 1998-12-03
CA2283575A1 (en) 1998-09-17
BR9808013A (en) 2001-09-25
WO1998040375A2 (en) 1998-09-17
AU730024C (en) 2004-08-05
SK125099A3 (en) 2001-02-12
NO994390L (en) 1999-11-04
PL336415A1 (en) 2000-06-19
HUP0002395A2 (en) 2001-05-28

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