EP0971744A2 - 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

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Publication number
EP0971744A2
EP0971744A2 EP98910075A EP98910075A EP0971744A2 EP 0971744 A2 EP0971744 A2 EP 0971744A2 EP 98910075 A EP98910075 A EP 98910075A EP 98910075 A EP98910075 A EP 98910075A EP 0971744 A2 EP0971744 A2 EP 0971744A2
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Prior art keywords
iso
butyl
propyl
pentyl
ethyl
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EP98910075A
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German (de)
English (en)
French (fr)
Inventor
Robert E. Manning
Kevin C. Glenn
Bradley T. Keller
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GD Searle LLC
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GD Searle LLC
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Application filed by GD Searle LLC filed Critical GD Searle LLC
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Classifications

    • 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

Definitions

  • 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.
  • cholestyramine binds the bile acids in the intestinal tract, thereby interfering with their normal enterohepatic circulation (Reihner, E. et al, in "Regulation of hepatic cholesterol metabolism in humans: stimulatory effects of cholestyramine on HMG- CoA reductase activity and low density lipoprotein receptor expression in gallstone patients", Journal of ioid Research. Volume 31, 1990, 2219-2226 and Suckling el al, "Cholesterol Lowering and bile acid excretion in the hamster with cholestyramine treatment", Atherosclerosis. 89(1991) 183-190).
  • the ileal bile acid transport system is a putative pharmaceutical target for the treatment of hypercholesterolemia based on an interruption of the enterohepatic circulation with specific transport inhibitors (Kramer, et al, "Intestinal Bile Acid Absorption” The Journal ' of Biolo g ical Chemistr y . Vol. 268, No. 24, Issue of August 25, pp. 18035-18046, 1993).
  • 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 .
  • Selected benzothiepines are disclosed in world patent application number W093/321146 for numerous uses including fatty acid metabolism and coronary vascular diseases .
  • 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.
  • HMG Co- A 3-hydroxy-3-methylglutaryl-coenzyme A
  • This enzyme catalyzes the conversion of HMG Co-A to mevalonate, which is an early and rate- limiting step in the biosynthesis of cholesterol .
  • Benzothiazepine anti-hyperlipidemic agents are disclosed in WO 94/18183, WO 94/18184, WO 96/05188, WO 96/16051, AU-A-30209/92, AU-A-61946/94 , AU-A-61948/94 , and AU-A- 61949/94.
  • the present invention furthers such efforts by providing novel pharmaceutical compositions and methods for the treatment of hyperlipidemic conditions.
  • R and R are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl, and cycloalkyl optionally are substituted with one or more substituents selected from the group consisting of OR ,
  • R , R , and R w are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, heteroaryl, ammoniumalkyl , alkylammoniumalkyl, and arylalkyl; or
  • R and R are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, , NR 9 R 10 , SR 9 , S(0)R 9 ,
  • R and R are independently selected from the group consisting of H, alkyl, alkenyl, alkenylalkyl , alkynylalkyl , heterocycle, ⁇ ca ⁇ >xyalkyl , carboalkoxyalkyl , ' cycloalkyl, cyanoalkyl, OR 9 , NR 9 R 10 , SR 9 , S(0)R 9 ,
  • R and R cannot be OH, NH and S ' or R 11 and R12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring;
  • R and R are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl,
  • alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl ⁇ heterocycle, ⁇ 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, eteroaryl arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR 13 , NR 13 R 14 , SR 13 , S(0)R 13 ,
  • a ⁇ is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation
  • said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, h eterocyc l e and h eteroaryl can be further substituted with one or more substituent groups selected from the group consisting of OR ,
  • alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, eterocycle and heteroaryl can optionally have one or more carbons replaced by 0,
  • R 13 , R 14 , and R 15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heteroaryl, heterocycle, A and polyalkyl optionally have one or more carbons replaced by 0, NR J , N + R 9 R 10 A-, S, SO, S ⁇ 2 ,
  • R , R , and R are optionally substituted with one or more groups selected from the group consisting of sulfoa kyiTA quaternary heterocycle, quaternary heteroaryl, OR 9 , NR 9 R 10 , N + R 9 R 1:L R 12 A " , SR 9 , S(0)R 9 ,
  • R 16 and R17 are independently selected from the substituents constituting R and M; or R 14 and R15 , together with the nitrogen atom to which they are attached, form a cyclic ring;
  • R 7 and R8 are independently selected from the group consisting of hydrogen and alkyl; and one or more R x are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl polyether, quaternary heterocycle, quaternary heteroaryl, OR 13 , NR 13 R 14 , SR 13 , S(0)R 13 , S(0)2R 13 ,
  • alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryli polyalkyl, heterocycle,y acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR 9 , NR 9 R 10 , N + R 9 R 11 R 12 A " , SR 9 , S(0)R 9 , S0 2 R 9 , S03R 9 , oxo, C0 2 R 9 , CN, halogen, CONR 9 R 10 , SO2OM, S ⁇ 2NR 9 R 10 , P0(0R 1S )0R 17 , P + R 9 R 11 R 12 A ⁇ , S * R 5 R 10 A " , or C(0)OM, and wherein R 18 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alky
  • P P(0)R 13 p R R A- phenylene, amino acid, peptid.e, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by 0, NR 9 , N+R9R10A-,
  • quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycT ⁇ afylalkyl , halogen, oxo, OR 13 , NR 13 R 14 , SR 13 , S(0)R 13 , S02R 13 , S03R 13 ,
  • NR 13 OR 14 NR 13 NR 14 R 15 , N02 , C02R 13 , CN, OM, S020M,
  • R 13 R 14 R 15 A _, P(OR")OR 14 , S * R 13 R 14 A ⁇ and N+RW , provided that both R and R cannot be hydrogen, OH, ojrr SSHH-,, aanndd wwhheenn RR 5 iis OH, R 1 , R 2 , R 3 , R 4 , R 7 and R 8 cannot be all hydrogen; provided that when R or R is phenyl, only one of R 1 or R 2 is H; provided that when q 1 and R x is styryl, anilido, or anilinocarbonyl, only one of R 5 or R ⁇ is alkyl ; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • R and R can independently be selected from the group consisting of H, aryl, heterocycle ⁇ quaternary heterocycle, and quaternary heteroaryl, wherein said aryl, heterocycle, heteroaryl, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl aryl, haloalkyl, cycloalkyl, heter cyS'e ⁇ arylalkyl, halogen, oxo, OR 13 , NR 13 R 14 , SR 13 , S(0)R 13 , S02R 13 , S03R 13 , NR 13 OR 14 , NR 13 NR 14 R 15 , N02 , C02R 13 , CN, OM, SO2OM,
  • R s or R ⁇ has the formula:
  • t is an integer from 0 to 5;
  • R 5 or R 6 has the formula (II) :
  • the invention is further directed to a compound selected from among:
  • R 1 ' is selected from the group consisting of alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide, wherein alkane diyl, 'alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can optionally have one or more carbon atoms replaced by O, NR 7 , N + R 7 R 8 , S, SO, S0 2 , S + R R ,.
  • alkane diyl alken ⁇ diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, heteroaryl, arylalkyl, halogen, oxo, OR 13 , NR 13 R 14 , SR 13 , S(0)R 13 ,
  • R -,1* further comprises functional linkages by which R" is bonded to R a ⁇ R J1 , or R M in the compounds of Formulae DII and Dill, and R M in the compounds of Formula Dili.
  • R , ⁇ , R", or R M and R M comprises a benzothiepine moiety as described above that is therapeutically ' effective in inhibiting ileal bile acid transpor .
  • the invention is also directed to a compound selected from among Formula DI, Formula DII and Formula Dili in which each of R al , R M and " comprises a benzothiepine moiety corresponding to the Formula:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R ⁇ , R 7 , R ⁇ R x , q, and n are as defined in Formula I as described above, and R 55 is either a covalent bond or arylene.
  • each of R 20 , R 21 , and R 22 in Formulae DII and Dili, and R 23 in Formula Dili be bonded at its 7- or 8-position to R 1 '.
  • R 5S comprise a phenylene moiety bonded at a m- or p-carbon thereof to R 19 .
  • Formula DI examples include:
  • benzothiepine compounds of the present invention can be used' alone or in various combinations .
  • R 1 and R 2 can be ethyl/butyl or butyl/butyl.
  • 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.
  • 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.
  • 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 .
  • the present invention also provides processes for the preparation of compounds of the present invention.
  • the present invention provides a combination therapy comprising the use of a first amount of an ileal bile acid transport inhibitor and a second amount of a HMG Co-A reductase inhibitor useful to treat hyperlipidemic disorders, wherein said first and second amounts together comprise an anti- hyperlipidemic condition effective amount of said compounds .
  • HMG Co-A reductase inhibitor- compounds useful in the present invention are shown in Appendix B.- Further scope of the applicability of the present invention will become apparent from the detailed description provided below. However, it should be
  • Alkyl alkenyl
  • alkynyl unless otherwise noted are each straight chain or branched chain hydrocarbons of from one to twenty carbons for alkyl or two to twenty carbons for alkenyl and alkynyl in the present invention and therefore mean, for example, methyl, ethyl, propyl, butyl, pentyl or hexyl .and ethenyl, propenyl, butenyl, pentenyl, or hexenyl and ethynyl, propynyl, butynyl, pentynyl, or hexyriyl respectively and isomers thereof.
  • Aryl means a fully unsaturated mono- or multi- ring carbocyle, including, but not limited to, substituted or unsubstituted phenyl, naphthyl, or anthracenyl .
  • Heterocycle means a saturated or unsaturated mono- or multi-ring carbocycle wherein one or more carbon atoms can be replaced by N, S, P, or 0. This includes, for example, the following structures:
  • Z, Z', Z" or Z"' is C, S, P, 0, or N, with the proviso that one of Z, Z', Z" or Z" ' is other than carbon, but is not 0 or S when attached to another Z atom by a double bond or when attached to another 0 or S atom.
  • the optional substituents are understood to be attached to Z, Z', Z" or Z"' only when each is C.
  • 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.
  • 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.
  • 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.
  • halogen means a fluoro, chloro, bromo or iodo group.
  • haloalkyl means alkyl substituted with one or more halogens .
  • cycloalkyl means a mono- or multi- ringed carbocycle wherein each ring contains three to ten carbon atoms, and wherein any ring can contain one or more double or triple bonds .
  • diyl means a diradical moiety wherein said moiety has two points of attachment to molecules of -interest.
  • oxo means a doubly bonded oxygen.
  • 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.
  • 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.
  • 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.
  • cycloaklylidene means a mono- or multi- ringed carbocycle wherein a carbon within the ring structure is doubly bonded to an atom which is not within the ring structures.
  • 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.
  • peptide means polyamino acid ' containing up to about 100 amino acid units.
  • polypeptide means polyamino acid containing from about 100 amino acid units to about
  • 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.
  • 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.
  • sulfoalkyl means an alkyl group to which a sulfonate group is bonded, wherein said alkyl is bonded to the molecule of interest.
  • active compound means a compound of the present invention which inhibits transport of bile acids .
  • alkylaryl or “arylalkyl,” the individual terms listed above have the meaning indicated above.
  • 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.
  • combination therapy refers to the administration of an ileal bile acid transport inhibitor and a HMG Co-A reductase inhibitor to treat a hyperlipidemic condition, for example atherosclerosis and hypercholesterolemia.
  • Such administration encompasses co-administration of these inhibitors in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each inhibitor agent.
  • such administration also encompasses use of each type of inhibitor in a sequential manner.
  • 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.
  • 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.
  • 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 .
  • the compounds of the present invention can be prepared by the procedures described below.
  • 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).
  • keto-aldehyde VI which can be cyclized with the reagent, prepared from zinc and titanium trichloride in refluxing ethylene glycol dimethyl ether (DME) , to give a mixture of 2 , 3-dihydrobenzothiepine VII and two racemic steroisomers of benzothiepin- (5Jf) -4-one VIII when R 1 and R 2 are nonequivalent .
  • Optically active compounds of the present invention can be prepared by. using optically active starting material III or by resolution of compounds X with optical resolution agents well known in the art as described in J". Org. Chem. , 39, 3904 (1974), ii>id. , 42, 2781 (1977), and ijbid., 44, 4891 (1979).
  • keto-aldehyde VI where R 2 is H can be prepared by reaction of thiophenol V with a 2- substituted acrolein.
  • Benzothiepin- (5H) -4-one VIII can be oxidized with MCPBA to give the benzothiepin- (5H) -4-one-l, 1-dioxide XII which can be reduced with sodium borohydride to give four racemic stereoisomers of X.
  • the two stereoisomers of X, Xa and Xb, having the OH group and R s on the opposite sides of the benzothiepine ring can be converted to the other two isomers of X, Xc and Xd, having the OH group and R 5 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) .
  • PTC phase transfer catalyst
  • the transformation can also be carried out with potassium t-butoxide in THF.
  • R 5 is OR, NRR' or S(0) n R and R * is hydroxy
  • R 5 is OR, NRR' or S(0) n R and R * is hydroxy
  • R 5 OR, NRR 1 , S(0)R
  • 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) .
  • phenol XVI is first reacted with dimethyl thiocarbamoyl chloride and triethylamine to give thiocarbamate XVII which is thermally rearranged at 200-300 °C, and the rearranged product is hydrolyzed with sodium hydroxide to yield the thiophenol XVIII.
  • Thiophenol V can also be prepared from 2- acylphenol XIX via the intermediate thiocarbamate XX.
  • Scheme 4 shows another route to benzothiepine-1, 1- dioxides Xc and Xd starting from the thiophenol XVIII.
  • Compound XVIII can be reacted with mesylate IV to give the sulfide-aldehyde XXI.
  • Oxidation of XXI with two equivalents of MCPBA yields the sulfone-aldehyde XIV which can be cyclized with potassium t-butoxide to a mixture of Xc and Xd.
  • Cyclyzation of sulfide-aldehyde with potassium t-butoxide also gives a mixture of benzothiepine XXIIc and XXIId.
  • Examples of amine- and hydroxylamine-containing compounds of the present invention can be prepared as shown in Scheme 5 and Scheme 6.
  • 2-Chloro-5- nitrobenzophenone is reduced with triethylsilane and trifluoromethane sulfonic acid to 2-chloro-5- nitrodiphenylmethane 32.
  • Reaction of 32 with lithium sulfide followed by reacting the resulting sulfide with mesylate IV gives sulfide-aldehyde XXIII.
  • Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone- aldehyde XXIV which can be reduced by hydrogenation to the hydroxylamine XXV.
  • Protecting the hydroxylamine XXV with di-t-butyldicarbonate gives the N, 0-di-(t-
  • Scheme 7 describes one of the methods of introducing a substituent to the aryl ring at the 5- position of benzothiepine.
  • Iodination of 5-phenyl derivative XXX with iodine catalyzed by mercuric triflate gives the iodo derivative XXXI, which upon palladium-catalyzed carbonylation in an alcohol yields the carboxylate XXXII.
  • R 1 and R s can be selected from among substituted and unsubstituted C x to C 10 alkyl wherein the substituent (s) can be selected from among alkylcarbonyl, alkoxy, hydroxy, and nitrogen-containing heterocycles joined to the C L to C 10 alkyl through an ether linkage.
  • Ethyl, n-propyl, n-butyl, and isobutyl are preferred.
  • substituents R l and R J are identical, for example n-butyl/n-butyl, so that the compound is achiral at the 3-carbon. Eliminating optical isomerism at the 3-carbon simplifies the selection, synthesis, separation, and quality control of the compound used as an ileal bile acid transport inhibitor.
  • substituents (R * ) on the benzo- ring can include hydrogen, aryl, alkyl, hydroxy, halo, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkyl, haloalkoxy, (N) -hydroxy- carbonylalkyl amine, haloalkylthip, haloalkylsulfinyl, haloalkylsufonyl, amino, N-alkylamino, N,N- dialkylamino, (N) -alkoxycarbamoyl, (N) - aryloxycarbamoyl , (N) -aralkyloxycarbamoyl, trialkyl- ammonium (especially with a halide counterion) , (N) - amido, (N) -alkyl, hydroxy, halo, alkoxy, alkylthio, al
  • 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.
  • substituents can be advantageously present on the 6, 7, 8, and/or 9- positions of the benzo ring, including, for example, guanidinyl, cycloalkyl, carbohydrate (e.g., a 5 or 6 carbon monosaccharide) , peptide, and quaternary ammonium salts linked to the ring via poly (oxyalkylene) linkages, e.g., - (OCH 2 CH 2 ) X -N * R"R"R 15 A " , where x is 2 to 10.
  • Exemplary compounds are those set forth below in Table 1.
  • 2-thiophene indicates a bond in the 2 position of the thiophene ring.
  • a similar convention is used for other heterocyclic substituents.
  • PEG 3400 molecular weight polyethylene glycol polymer chain
  • PEG 3400 molecular weight polyethylene glycol polymer chain
  • PEG 3400 molecular weight polyethylene glycol polymer chain
  • R 5 and R* are independently selected from among hydrogen and ring-carbon substituted or unsubstituted aryl, thiophene, pyridine, pyrrole, thiazole, imidazole, pyrazole, pyrimidine, morpholine, N-alkylpyridinium, N- alkyl-piperaziniu , N-alkylmorpholinium, or furan in which the substituent (s) are selected from among halo, hydroxyl, trihaloalkyl, alkoxy, amino, N-alkylamino, N,N-dialkylamino, quaternary ammonium salts, a C x to C t alkylene bridge having a quaternary ammonium salt substituted thereon, alkoxycarbonyl , aryloxycarbonyl , alkylcarbonyloxy and arylcarbonyloxy, (0,0)- dioxyalkylene, -[0(CH 2 )
  • the aryl group of R ! or R ⁇ is preferably phenyl, phenylene, or benzene triyl, i.e., may be unsubstituted, mono-substituted, or di- substituted.
  • the species which may constitute the substituents on the aryl ring of R 5 or R s are fluoro, chloro, bromo, methoxy, ethoxy, isopropoxy, trimethylammonium (preferably with an iodide or chloride counterion) , methoxycarbonyl, ethoxycarbonyl, for yl, acetyl, propanoyl, (N) -hexyldimethylammonium, hexylenetrimethylammonium, tri (oxyethylene) iodide, and tetra(oxyethylene) trimethylammonium iodide, each substituted at the p-position, the m-position, or both of the aryl ring.
  • R ! or R 6 is selected from phenyl, p-fluorophenyl, m-fluorophenyl, p- hydroxyphenyl , m-hydroxyphenyl , p-methoxyphenyl, - methoxyphenyl, p-N,N-dimethylaminophenyl, m-N,N-
  • IH2 dimethylaminophenyl I " p- (CH,),-N * -phenyl, I " m- (CH,),-N “ - phenyl. I " m- (CH,),-N * -CK-CH I -(OCH-CH.).-0-phenyl, I " p- (CH-) .-N “ -CH.CH-- (OCH.CH,) a -0-phenyl, I " ra- (N,N-dimethyl- piperazinium) - (N' ) -CH.- (0CH j CH,) 3 -0-phenyl, 3-methoxy-4- fluorophenyl, thienyl-2-yl, S-cholorothienyl-2-yl, 3, 4-difluorophenyl, I * p- (N,N-dimethylpiperaziniuai)- (N- )-CH a -(0CH J CH a
  • Preferred compounds include 3- ethyl-3-butyl and 3-butyl-3-butyl compounds having each of the above preferred R' substituents in combination with the R m substituents shown in Table 1. It is particularly preferred that one but not both of ' and R * is hydrogen.
  • R' and R* be hydrogen, that R 1 and R' not be hydrogen, and that R 1 and ' be oriented in the same direction relative to the plane of the molecule, i.e., both in ex- or both in ⁇ -configuration. It is further preferred that, where R* is butyl and R l is ethyl, then R 1 has the same orientation relative to the plane of the molecule as R 1 and R'.

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EP98910075A 1997-03-11 1998-03-10 COMBINATION THERAPY EMPLOYING ILEAL BILE ACID TRANSPORT INHIBITING BENZOTHIEPINES AND HMG Co-A REDUCTASE INHIBITORS Withdrawn EP0971744A2 (en)

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NO994390L (no) 1999-11-04
AU730024C (en) 2004-08-05
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