WORLD INTELIBC'JUAL PROPl!RTY ORGANIZATION
`International Bureau
`
`'<111
`
`PCT
`INTERNATIONAL APPLICATION PUBUSHED UNDER TIIE PATENT COOPERATION TREATY (PCT)
`: WO 00138725
`
`(51) Intematlonal·Patent Classlftcatlon 7 ;
`A61K 45/06, 31/55, 31/585, A61P 9/00,
`A61K 31/575
`
`Al
`
`(11) International Publication Nwnber:
`
`(43) International Publication Date:
`
`6 July 2000 (06.07 .00)
`
`I
`(21) International Application Number:
`
`PCT/US99/27946
`
`(22) International FDlng Date:
`
`17 December 1999 (17.12.99)
`
`(30) Priority Data:
`60/1 I3,9SS
`
`23 December 1998 (23.12.98)
`
`US
`
`(71) Applicant (for all designated States except US): G.D. SEARLE
`& CO. [US/US]; Corporate Patent Dept., P.O. Box SI 10,
`Chicago, ll. 6068~5 I JO (US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): KELLER. Bradley, T.
`[US/US); 1780 Canyon View Court, Chestemeld, MO
`63017 (US). REITz, David, B. [US/US); 14814 Pleas·
`ant Ridge Court, ChcstedieJd, MO 63017 (US). SCHUH,
`Joseph, R. [US/US]; 20SS Rurline, SL Louis, MO 63146
`(US). SIKORSKI, James, A. [US/US); 2313 Bast Royal
`Court, St. Louis, MO 63131 (US). TREMONT, Samuel, J.
`[US/US); 729 Berqucst Drive, St. Louis, MO 63011 (US).
`LAPPE, Rodney, W. (USIUSJ; 1S69 WildhOTBe Parlcway
`Drive, Chesterfield, MO 63005 (US).
`
`(74) Agents: Wll.LIAMS, Roger, A. et al.; G.D. Searle & Co.,
`Corporate Patent Dept., P.O. Box SJIO, Chicago, IL
`60680-S 110 (US).
`
`(81) Designated States: AE, AL, AM, AT, AU, AZ, BA~ BB, BG,
`BR, BY, CA, CH, CN, CR, CU, CZ, DE. DK, :DM, EE,
`ES, Fl, GB, GD, GE. OH, GM, HR, HU, ID,,Il., IN,'IS, ~.
`KE, KG, KP, KR, KZ, LC, LK, LR, LS,'LT;LU,.LV, MA,
`MD, MG, MK, MN, MW, MX, NO, NZ, PL, PTi RO, RU,
`SD, SB, SG, SI, SK, SL, TJ, TM, TR, TI, 1Z, UA, UG,
`US, UZ. VN, YU, ZA, ZW, ARIPO patent (GH, GM, KE,
`LS, MW, SD, SL, SZ, TZ, UG, ZW), Eurasian patent (AM,
`AZ., BY, KG, KZ, MD, RU, TJ, TM), European patent (AT,
`BE, CH, CY, DB, DK. ES, Fl, FR, GB, GR, rE, ·rr, LU,
`MC, NL, PT, SE); OAPI patent (BP, BJ, CF, CG; Cl, CM,
`GA, ON, OW, ML, MR, NE. SN, 1D,,TG).
`
`Published
`With in1ema1ional search report.
`Before the expiration of the t~ limit for amending the
`claims and to be republished in the event of the receipt of
`·
`amendments.
`
`(54) Title: COMBJNA TIONS FOR CARDIOVASCULAR INDICATIONS
`
`(57) Abstract
`
`The present · invention provides combinationB of cardiovalicular therapeutic compounds for the prophylaxis or treatment of
`cardiovascular disease including hypercholesterolemia and _atherosclerosis. Combinations disclosed include an Hear bile acid transport
`inhibitor combined with a cholesteryl ester transport protein (CETP) inhibitor, a fibric acid derivative, a nicotinic. acid derivative, ·a
`microsomal triglyceride transfer protein inhibitor, a cholesterol absorption antagonist, a phytostero1, a stanol, an antihypertensive_ agent, or
`othen;. Further combinations include a CETP inhibitor with a fibric acid derivative, a nicotinic acid derivative, a bile acid scquestrant, a
`microsomal triglyceride transfer protein inhibitor, a cholesterol absorption antagonist, or others.
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`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`CJ
`CM
`CN
`cu
`C'L
`DE
`DK
`RE
`
`Albania
`Armenia
`Allllria
`Auslnlla
`Azerbaijan
`Boanla and Hcnegovlna
`Bmbadcl
`Belgium
`Bmtina Paso
`Bulgaria
`Benin
`Brazil
`Bel11111
`Canada
`Ccmral Africm Republic
`Congo
`Swiu.erlaDd
`COO: d'JvoiJe
`Cameroon
`Cllna
`Cuba
`Cuoch Republic
`Oennany
`Denmarlr:
`Bslonia
`
`FS
`Fl
`FR
`CA
`CB
`CE
`CH
`CN
`CR
`HU
`IE
`IL
`IS
`· IT
`JP
`KE
`KC
`KP
`
`KR
`KZ
`LC
`u
`LK
`LR
`
`Spain
`F'mland
`Prance
`Oabon
`Un~Klllgdom
`Georgia
`Ghana
`Ouinca
`Oiuce
`Hungary
`hcland
`laraei
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyz:aan
`DemDCnlic People'•
`Republic of ICorQ
`RepubliC of "-a
`Kazablln
`Saini Lucia
`Lieclneftltdn
`Sri Lanka
`Uberia
`
`LS
`LT
`·w
`LV
`MC
`MD
`MC
`MK
`
`l.aolho
`Udluanla
`Luumbaurg
`l.Mvia
`Monaa>
`Republic of Moldova
`Madagucar
`1be former Yugoslav
`Republic of Macedonia
`ML
`Mali
`MN
`Monaofia
`MR
`Mamilanla
`MW Malawi
`MX
`Mexico
`Niger
`NE
`NL
`Ncthcrtanda
`NO·
`Norway
`NZ
`New Zealand
`PL
`Poland
`PI'
`Ponugal
`RO
`Rmnanla
`RU
`Rusalan l'cdenlion
`so
`Sudan
`SE
`Sweden
`Singapcm
`SC
`
`SI
`SK
`SN
`sz
`m
`TC
`TJ
`TM
`TR
`TT
`UA
`UC
`us
`uz
`VN
`YU
`zw
`
`SloYcnia
`Slovakia
`Senegal
`Swaziland
`Olllll
`Thso
`Tajitmm
`Turbnenlswl
`Tmtey
`'lmldad Biid Tobago
`UbBloe
`Uguda
`United SllllCI of America
`Uzbekistan
`Viet Nam
`Yugoslavia
`Zimbabwe
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`Combinations for Cardiovascular ~ndications
`
`This application claims priority of U.S. provisional:
`
`application Ser. No. 60/113,955 filed Dec. 23, 1998.
`
`5
`
`BACICGROUNP OF THE I:NVENTI:ON
`
`Field of the 'Invention
`
`The present invention relates to methods of t~~ating.
`
`10 cardiovascular diseases, and specifically relates to
`
`combinations of compounds, compositions, and methods for
`their use in medicine, particularly in the prophylaxis and
`treatment of hyperlipidemic conditions such as are
`associated with atherosclerosis, hypercholesterolemia, and
`15 other factors in coronary artery disease in mammals
`including hypertension. More particularly, the invention
`relates to ilea! bile acid transporter {IBAT) inhibitors,
`cholesteryl ester transfer protein {CETP) activity
`inhibitors, fibric acid derivatives {fibrates), nicotiriic
`20 acid derivatives, microsomal triglyceride transfer protein
`{MTP) inhibitors, cholesterol absorption antagonists,
`stanols, phytosterols, or antihypertensive agents.
`
`25
`
`Description of Related Art
`It is well-settled that hyperlipidemic conditions
`associated with elevated concentrations of total
`
`cholesterol and low-density lipoprotein {LDL).
`
`cholesterol are major risk factors for coronary heart
`disease and particularly atherosclerosis; Numerous
`
`30 studies have demonstrated that a low plasma
`concentration of high density lipoprotein (HDL)
`
`cholesterol is a powerful risk factor for the
`development of atherosclerosis (Barter and Rye,
`Atherosclerosis, ..l..£l, 1-12 (1996)). HDL is one of the
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`:i..
`major classes of lipoproteins that function in the
`transport of lipids through the blood. The major lipids
`
`found associated with HDL include cholesterol,
`
`cholesteryl ester, triglycerides, phospholipids and
`5 fatty acids. The other classes. of lipoproteins fol.ind in
`the blood are low density lipoprotein (LDL),.
`intermediate density lipoprotein (IDL), and very low
`density lipoprotein (VLDL) . Since low levels of HDL
`
`cholesterol increase the risk of atherosclerosis,
`
`10 methods for elevating plasma HDL cholesterol would be
`therapeutically beneficial for the treatment of
`
`atherosclerosis and other diseases associated with
`accumulation of lipid in the blood vessels. These
`diseases include, but are not limited to, coronary heart
`15 disease, peripheral vascular disease, and stroke.
`Atherosclerosis underlies most coronary artery
`disease (CAD), a major cause of morbidity and mortality in
`modern society. High LDL cholesterol (above about 180
`mg/dl) and low HDL cholesterol (below·35 mg/dl) have been
`20 shown to be important contributors to the development of
`atherosclerosis. Other diseases or risk factors, such as
`peripheral vascular disease, stroke, and
`
`25
`
`hypercholesterolaemia are negatively affected by adverse
`HDL/LDL ratios.
`Interfering with the recirculation of bile acids from
`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
`30 atherosclerosis. Stedronsky, in "Interaction of bile
`acids and cholesterol with nonsystemic agents having
`
`hypocholesterolemic properties," Biochimica et Biophysica
`
`Acta, ~. 255-287 (1994) discusses the biochemistry,
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`3
`physiology and known active agents surrounding bile acids.
`
`and cholesterol.
`
`Transient pathophysiologic alterations are shown to
`
`be consistent with interruption of the enterohepatic
`
`5 circulation of bile acids in humans with an inherited lack
`
`of !BAT activity, as reported by Heubi, J.E., et al. See
`
`"Primary Bile Acid Malabsorption:· Defective in' Vitro
`
`804-11 (1982) .
`
`Ileal Active Bile Acid Transport", Gastroenteroiogy, . .§.l,
`•
`In another approach to the reduction of recirculation
`of bile acids, the ileal bile acid transport system is a
`
`10
`
`putative pharmaceutical target for the treatment of
`
`hypercholesterolemia based on an interruption of the
`
`enterohepatic circulation with specific transport
`
`1.5
`
`inhibitors (Kramer, et al., "Intestinal Bile Acid
`Absorption" The Journal of Biological Chemistrv, Zfil! (2.4),
`18035-46 (1993).
`
`In several individual patent applications, Hoechst
`.
`Aktiengesellschaft discloses polymers of various naturally
`20 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 effec-t.ive as--pharrnaceuticals and, in particular for use
`
`25 as hypocholesterolemic agents. The individual Hoechst
`patent applications which disclose such bile acid
`
`transport inhibiting compounds are each separately "listed
`below.
`
`30
`
`Rl. Canadian Patent Application No. 2, 025 ,·294.
`R2. Canadian Patent Application No. 2, 078 ,·s9a:.
`R3. Canadian Patent Application No. 2,085,782.
`R4. Canadian Patent Application No. 2,085,830.
`RS. EP Application No. 0 379 161.
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`R6. EP Application No. 0 549 967.
`R7. EP Application No. 0 559 064.
`RS. EP Application No. 0 563 731.
`
`PCT/US99/27946
`
`5
`
`Selected benzothiepines are.disclosed in world patent
`
`_application number WO 93/321146 for numerous uses
`including fatty acid metabolism and coronary vascular
`
`diseases.
`
`Other selected benzothiepines are known for use as.-
`
`10 hypolipaemic and hypocholesterolaemic agents, espec.ia:lly
`for the treatment or prevention of atherosclerosis as
`disclosed in application No. EP 508425. A French patent
`
`application, FR 2661676 discloses additional
`
`benzothiepines for use as hypolipaemic and
`
`15 hypocholesterolaemic agents. Furthermore, patent
`application no. WO 92/18462 lists other benzothiepines for
`
`use as hypolipaemic and hypocholesterolaemic agents. U.S.
`
`Patent No. 5,994,391 (Lee et al.) Each of the
`benzothiepine hypolipaemic and hypocholesterolaemic agents
`20 described in these individual patent applications is·
`limited by an amide bonded to the carbon adjacent the
`
`phenyl ring of the fused bicyclobenzothiepine ring.
`
`· Further benzothiepines useful for the treatment of
`
`hypercholesterolemia and hyperlipidemia are disclosed in
`
`25 patent application no. PCT/US95/10863. More
`
`benzothiepines useful for the prophylaxis and treatment of
`
`hyperc·holesterolemia and hyperlipidemia as well as
`
`pharmaceutical compositions of such benzothiepines are
`
`described in PCT/US97/04076. Still further benzothiepines
`
`30 and compositions thereof useful for the prophylaxis and
`
`treatment of hypercholesterolemia and hyperlipidemia are
`
`described in U.S. Application Serial No. 08/816,065.
`
`In vitro bile acid transport inhibition is disclosed
`to correlate with hypolipidemic activity in The Wellcome
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`b
`Foundation Limited disclosure of the Patent Application
`No. WO 93/16055 for ,."Hypolipidemic Benzothiazepine
`Compounds." That publication describes a number of
`hypolipidemic benzothiazepine compounds. Additional·
`5 hypolipidemic benzothiazepine compounds (particularly
`
`2,3,4,5-tetrahydrobenzo-l-thi-4-azepine compounds) ~re
`disclosed in Patent Application No. WO 96/05188:. A
`particularly useful benzothiazepine disclosed in WO ·
`96/05188 is the compound of formula B-2. Further
`10 hypolipidemic benzothiazepine. compounds are described in
`Patent Application No. WO 96/16051.
`
`"--o
`
`B-2
`
`(3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-
`7,8-dimethoxy-5-phenyl-l-4-benzothiazepine
`1,1-dioxide
`
`~ther benzothiazepine compounds useful for control of
`cholesterol are 2,3,4,5-tetrahydrobenzo-1-thi-5-azepine
`IBAT inhibitor compounds described in PCT Patent
`Application No. WO 99/35135.
`Included in that.description
`is the compound of formula B-7.
`
`15
`
`20
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`B-7
`
`Further IBAT inhibitor compounds include a class 9f
`
`naphthalene !BAT inhibitor compounds, described by: T.
`Ichihashi et al. in J. Pharmacol. Exp. Ther., 284(1), 43-
`In this class, S-8921 (methyl 1-(3,4-
`
`5 50 (1998).
`
`dimethoxyphenyl) -3- (3-ethylvaleryl) -4-hydroxy-6, 7, 8.(cid:173)
`trimethoxy-2-naphthoate) is particularly useful. The
`
`structure of S-8921 is shown in formula B-20. Further
`naphthalene compounds or lignin derivatives useful for the
`
`10 treatment or prophylaxis of hyperlipidemia or
`
`atherosclerosis are described in PCT Patent Application
`
`No. WO 94/24087.
`
`0
`
`0
`
`15
`
`Another class of lipid-lowering drug is an anti-
`obesity drug. An example of an antiobesity drug is
`orlistat. Orlistat is described in European Patent No.
`EP 0 129 748.
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`Inhibition of cholesteryl ester transfer protein
`(CETP) has been shown to effectively modify plasma
`
`PCT/US99/27946
`
`HDL/LDL ratios, and is expected to check the progress
`
`and/or formation of certain cardiovascular diseases.
`
`5 CETP is a plasma protein that facilitates the m9vement
`of cholesteryl esters and triglycerides between. the
`various lipoproteins in the blood (Tall, J. Lipid Re~.,'·
`~. 1255-74 (1993)). The movement of cholesteryl ester
`· from HDL to LDL by CETP has the effect of lowering HDL
`
`It therefore follows that inhibition.of
`10 cholesterol.
`CETP should lead to elevation of plasma HDL cholesterol
`and lowering of plasma LDL cholesterol, thereby
`
`providing a therapeutically beneficial plasma lipid
`profile. ·Evidence of this effect is described in
`15 McCarthy, Medicinal Res. Revs., l..J., .139-59 (1993).
`Further evidence of this effect is described in Sitori,
`Pharmac. Ther., 67, 443-47 (1995)). This phenomenon was
`first demonstrated by Swenson et al., (J. Biol. Chem.,
`~. 14318 (1989)) with the use of a monoclonal antibody
`20 that specifically inhibits CETP.
`In rabbits, the
`antibody caused an elevation of the plasma HDL
`cholesterol and a decrease in LDL cholesterol·. Sori et
`
`al. (Biochim. Biophys. Acta,~. 743-480 (1984))
`describe proteins from human plasma that inhibit CETP.
`25 U.S. Patent 5,519,001, herein incorporated by reference,
`issued to Kushwaha et al., describes a 36 amino acid
`peptide derived from baboon apo C-1 that inhibits CETP
`
`activity. Cho et al. (Biochim. Biophys. Acta 1391, 133-
`144 (1998)) describe a peptide from hog plasma that
`30 inhibits human CETP. Bonin et al. (J; Peptide Res., 51,
`216-225 (1998)) disclose a decapeptide inhibitor of
`
`CETP. A depspeptide fungal metabolite is disclosed as a
`CETP inhibitor by Hedge et al. in Bioorg. Med. Chem.
`Lett., 8, 1277-80 (1998).
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`There have been several reports of non-peptidic
`
`PCT/US99/27946
`
`compounds that act as CBTP.inhibitors. Barrett et al.
`(J. Am. Chem. Soc., l,ll, 7863-63 (1996)) describe
`cyclopropane-containing CETP inhibitors. Further
`5 cyclopropane-containing CETP inhibitors are described by
`Kuo et al. (J. Am. Chem. Soc., ll.1., 10629-34 (1995)).
`Pietzonka et al. (Bioorg. Med. Chem. Lett., .§., 1951-54
`
`(1996)) describe phosphonate-containing analogs· of
`
`cholesteryl ester as CBTP inhibitors. Coval et, al~
`
`10
`
`15
`
`(Bioorg. Med. Chem. Lett., !2,, 605-610 (1995).) describe
`Wiedendiol-A and -B, and related sesquiterpene compounds
`as CETP inhibitors. Lee et al. (J. Antibiotics, il,
`693-96 (1996)) describe CETP inhibitors derived from an
`insect filngus. Busch et al. (Lipids, 25, 216-220,
`(1990}) describe cholesteryl acetyl bromide as a CETP
`inhibitor. Morton and Zilversmit (J. Lipid Res., .l.S,,
`836-47 (1982)) describe that p-chloromercuriphenyl
`
`20
`
`sulfonate, p-hydroxymercuribenzoate and ethyl
`mercurithiosalicylate inhibit CETP. Connolly et al.
`(Biochem. Biophys. Res. Comm., rn, 42-47 (1996))
`describe other cysteine modification reagents as CETP
`inhibitors. Xia et al. describe 1,3,5-triazines as
`CETP inhibitors (Bioorg. Med. Chem. Lett., .§., 919-22
`(1996)}. Bisgaier et al. (Lipids, ~. 811-8 (1994)}
`25 describe 4-phenyl-5-tridecyl-4H-l, 2, 4-triazole-thiol as
`a CETP inhibitor. Additional triazole CETP inhibitors
`are described in U.S. Patent Application Serial No.
`09/153,360, herein incorporated by reference. Sikorski
`et al. disclosed further novel CETP inhibitors in PCT
`
`30 Patent Application No. WO 9914204.
`Substituted 2-mercaptoaniline amide compounds can
`be used as CETP inhibitors and such therapeutic
`compounds are described by H. Shinkai et al. in PCT
`
`Patent Application No. WO 98/35937.
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`Some substituted heteroalkylamine compounds are
`known as CETP inhibitors.
`In European Patent
`
`PCTIUS99/27946
`
`Application No. 796846, Schmidt et al. describe 2-aryl(cid:173)
`
`substitµted pyridines as cholesterol ester transf~r
`5 protein inhibitors useful as cardiovascular agents. One
`substituent at c3 of the pyridine ring can .be an
`hydroxyalkyl group. In European Patent Application No.
`
`801060, Dow and Wright describe heterocyclic derivatjves
`
`substituted with an aldehyde addition product of an
`10 alkylamine to afford l-hydroxy-1-amines. These,are
`
`reported to be ~3-adrenergic receptor agonists useful
`
`for treating diabetes and other disorders. In Great
`Britain P~tent Application No. 2305665, Fisher et al.
`disclose 3-agonist secondary amino alcohol substituted
`is pyridine derivatives useful for treating several
`disorders including cholesterol levels and
`atherosclerotic diseases.
`In European Patent
`
`Application No. 818448 (herein incorporated by
`reference), Schmidt et al. describe tetrahydroquinoline
`20 derivatives as cholesterol ester transfer protein
`inhibitors. European Patent Application No. 818197,
`Schmek et al. describe pyridines with fused heterocycles
`as cholesterol ester transfer protein inhibitors.
`Brandes et al. in German Patent Application No. 19627430
`25 describe bicyclic condensed pyridine derivatives as
`cholesterol ester transfer protein inhibitors.
`In PCT
`Patent Application No. WO 9839299, Muller-Gliemann et
`
`al. describe quinoline derivatives as cholestery1 ester
`
`30
`
`transfer protein inhibitors.
`Polycyclic compounds that are useful as CETP
`inhibitors are also disclosed by A. Oomura et al. in
`Japanese Patent No. 10287662. For example, therapeutic
`compounds having the structures C-1 and C-8 were
`prepared by culturing Penicillium spp.
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`Cycloalkylpyridines useful as CETP inhibitors are
`
`PCT/US99/27946
`
`disclosed by Schmidt et al. in European Patent No~ EP
`
`818448. For example, the therapeutic compound having
`
`the structure C-9 is disclosed as being particularly
`
`5 effective as a CETP inhibitor.
`Substituted tetrahydronaphthalene compounds us.eftil
`
`as CETP inhibitors are described in PCT Patent
`
`Application No. WO 9914174. Specifically described in
`
`that disclosure as.a useful CETP inhibitor is (8s»-3-
`10 cyclopentyl-l-{4-fluorophenyl)-2-[{S)-fluoro(4~
`trifluoromethylphenyl)methylJ-8-hydroxy-6- ·
`spirocclobutyl-5,6,7,8-tetrahydronaphthalene.
`Some 4-heteroaryl-tetrahydroquinolines useful as
`CETP inhi°bitors are described in PCT.Pa~ent Application
`
`15 No. WO 9914215. For example, that disclosure describes
`3-{4-trifluoromethylbenzoyl)-5,6,7,8-tetrahydroquinolin(cid:173)
`s-one as a useful CETP inhibitor.
`In another approach to the reduction of total
`cholesterol, use is made of the understanding that HMG CoA
`20 reductase catalyzes the rate-limiting step in the
`biosynthesis of cholesterol (The Pharmacological Basis of
`Therapeutics, 9th ed., J.G. Hardman and ~.E. Limberd, ed.,
`McGraw-Hill, Inc., New York, pp. 884-888 (1996), herein
`incorporated by reference).
`HMG CoA reductase inhibitors
`25 {including the class of therapeutics cormnonly called
`"statins") reduce blood serum levels of LDL cholesterol by
`competitive inhibit·ion of this biosynthetic step (M. S.
`
`Brown, et al., J. Biol. Chem,~' 1121-28 (1978), herein
`incorporated by reference). Several.statins have been'
`30 developed or commercialized throughout the world.
`Mevastatin was among the first of the statins to be
`developed and it is described in U.S. Patent No. 3,983,140
`(herein incorporated by reference) . Lovastatin, another
`important HMG CoA reductase inhibitor, is described in ·
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`It
`U.S. patent no. 4,231,938 (herein incorporated by
`
`reference). Simvastatin is described in U.S. patent no.
`
`4,444,784 (herein incorporated by reference). Each of·
`
`these HMG CoA reductase inhibitors contains a six-membe.red
`
`5
`
`lactone function which apparently mimics the structure of
`HMG CoA in competition for the reductase·. · The HMG· CoA: ·
`
`reductase inhibitor class of cholesterol-lowering drugs is
`
`further exemplified by a group of drugs which contain ~,4-
`
`dihydroxyheptanoic acid functionalities rather than the
`
`10 lactone. One member of this group is pravastatin,:
`described·in U.S; patent no. 4,346,227 (herein
`
`incorporated by reference). Another HMG CoA reductase
`
`inhibitor which contains a 2,4-dihydroxyheptanoic acid
`group is ·fluvastatin, described in U.S. patent no.
`
`15 5,354,772 (herein incorporated by reference). Warnings of
`side effects from use of HMG CoA reductase inhibitors
`
`include liver dysfunction, skeletal muscle myopathy,
`
`rhabdomyolysis, and acute renal failure. Some of these
`
`effects are exacerbated when HMG CoA reductase inhibitors·
`20 are combined with fibrates or nicotinic acid.
`
`Fibric acid derivatives comprise another class of
`
`drugs which have effects on lipoprotein levels. Among the
`
`first of these to be developed was clofibrate, disclosed
`in U.S. patent no. 3,262,850. Clofibrate is the ethyl
`
`25 ester of p-chlorophenoxyisobutyric acid. A widely used
`
`drug in this class is gemfibrozil, disclosed in U.S.
`
`patent. no. 3,674,836. Gemfibrozil frequently is used to.
`
`decrease triglyceride levels or increase HDL cholesterol
`concentrations (The Pharmacological Basis of Therapeutics·,
`
`30 p. 893). Fenofibrate (U.S. patent no. 4,058,552) has a·n
`
`effect similar to that of gemfibrozil, but additionally
`
`decreases LDL levels. Ciprofibrate (U.S. patent no.
`
`3,948,973) has similar effects to that of fenofibrate.
`
`Another drug in this class is bezafibrate (U.S. patent no.
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`3,781,328). Warnings of sid~2effects from use of fibric
`acid derivatives include gall bladder disease
`
`(cholelithiasis), rhabdomyolysis, and acute renal' failure.
`
`Some of these effects are exacerbated when f ibrates are
`
`5 combined with HMG CoA reductase .inhibitors.
`
`Probucol is a powerful antioxidant which has shown
`
`the ability to lower serum cholesterol levels and cause
`
`regression of xanthomas in patients having homozygous
`familial hypercholesterolemia (A. Yamamoto, et al. I Am;. J·.
`10 Cardiol., fil, 29H-35H (19~6)) .
`-However, treatment· with
`probucol alone sometimes shows erratic control of LDL and
`
`frequent lowering of HDL (The Pharroacological Basis of
`
`Therapeutics, p. 891) . Probucol is contraindicated for
`
`patients with progressive myocardial damage and/or,
`15 ventricular arrhythmias.
`
`A class of materials which operates by another
`mechanism to lower LDL cholesterol comprises bile acid
`sequestering.agents. Such agents are typically anion
`
`exchange polymers administered· orally to a patient.
`
`'As
`
`20 the agent passes through the gut, anions of bile acids are
`
`sequestered by the agent and excreted. Such sequestering·
`
`has been speculated to prevent reabsorption by the gut,
`
`for example the ileum, thereby preventing conversion of
`
`the bile acids into cholesterol. One such bile acid
`25 sequestering agent is cholestyramine, a styrene(cid:173)
`
`divinylbenzene copolymer containing quaternary ammonium'
`
`cationic groups capable of binding bile acids. It is
`
`believed that cholestyramine binds the bile acids i'n the
`
`intestinal tract, thereby interfering with their normal
`
`30 enterohepatic·circulation. This effect is described by
`
`Reihner 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
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`patients 11
`(1990) .
`
`J3
`Journal of Lipid Research, 3,l., 2219-2226
`Further description of this effect is found in
`Suckling et al. in "Cholesterol Lowering and bile acid.
`
`excretion in the hamster with cholestyramine treatinent",
`
`5 Atherosclerosis, §.2., 183-90 (1991). This results in an.
`
`increase in liver bile acid synthesis because of 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.
`
`10
`
`Another bil.e acid sequestering agent is colestipol, a
`
`copolymer of diethylenetriamine and i-chloro-2,3-
`epoxypropane. Colestipol is described in U.S. Patent No.
`
`15
`
`3,692,895. A frequent side effect of colestipol and of
`cholestyr.amine is gastric distress~
`Additional bile acid sequestering agents are
`described in U.S. Patent No. 5,703,188, assigned to Geltex
`Pharmaceuticals Inc. For example, one such bile acid
`sequestering agent is 3-
`methacrylarnidopropyltrimethylammonium chloride
`20 copolymerized with ethylene glycol dimethacrylate to yield
`a copolymer.
`Yet another class materials proposed as bile acid
`.sequestering agents comprises particles comprising
`amphiphilic copolymers having a crosslinked shell domain
`25 and an interior core domain (Patent application no.· PCT/US
`
`97/11610). Structures and preparation of such crosslinked
`amphiphilic copolymers are described in PCT/US97/11345.·
`
`Such particles have been given the common name of
`"knedels" (K.B. Thurmond et al., J. Am. Chern. Soc., .!ll
`(30) I 7239-40 (1996)) •
`
`30
`
`Nicotinic acid (niacin) is a B-cornplex vitamin
`
`reported as early as 1955 to act as a hypolipidemic agent
`(R. Altschl, et al., Arch. Biochem. Biophys., ~, 558-9
`(1~55)). It is sometimes used to raise low HDL levels and
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`lower VLDL and LDL levels.
`
`J~eful commercial formulations
`of nicotinic acid include Niacor, Niaspan, Nicobid,
`
`Nicolar, Slo-Niacin. Nicotinic acid is contraindi~ate9
`
`for patients having hepatic dysfunction, active peptic
`
`5 ulcer, or arterial bleeding. Another compound in this·
`
`class useful for cardiovascular indications is niceritrol
`
`(T. Kazumi et al., Curr. Ther. Res.,.~. 546-51). __ J.
`Sasaki et al. (Int. J. Cl in. Pharm. Ther., ll (_7), · 420-'26'
`(1995)) describes a reduction in cholesterol es~er'
`
`10 transfer activity by niceritrol monotherapy. Acipimox-(5~
`
`methyl pyrazine-2-carboxylic acid 4-oxide, U.S. Patent No.
`
`4, O 02, 750). is structurally similar to nicotinic acid and
`
`has antihyperlipidemic activity.
`A st.udy by Wetterau et al. (Science, 6..ftA, 751-54
`(1998)) describes a number of alkylpiperidine compounds,
`
`15
`
`isoindole compounds, and fluorene compounds useful 'for
`
`inhibiting microsomal triglyceride transfer protein (MTP
`
`inhibitors) . Rodents and Watanabe-heritable
`hyperlipidemic rabbits treated with these compounds show
`
`20 decreased production of lipoprotein particles.
`Cholesterol absorption antagonists may also be useful
`for the treatment of prophylaxis of cardiovascular
`
`diseases such as hypercholesterolemia or atherosclerosis.
`For example, azetidinones such as SCH 58235 ([3R-
`
`25
`
`[3a (S*) , 4(3]] -1- (4-fluorophenyl) -3- [3- (4 -fl uorophenyl) -3-
`
`hydroxypropyl] -4- (4-hydroxyphenyl) -2-azetidinone) (_formula
`
`A-1), ·described in J. Med.· Chem., il(6), 973-980 (1998) ·,
`
`SCH 58235
`are useful cholesterol absorption antagonists.
`is further described by Van Heek et al. in J. Pharmacol.
`
`30 Exo. Ther., ~(l), 157-163 (1997). Further azetidinone
`
`compounds useful for treatment or prophylaxis of
`
`cardiovascular disease are described in U.S. Patent No.
`
`5,767,115.
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`F
`
`N
`
`s
`R
`•• ,'-=--.l\..
`.....
`#
`
`0
`
`A-1
`
`OH
`
`[3R-[3a(S*),4b]]-l-(4-fluorophenyl)-3-
`[3-(4-fluorophenyl)-3-hydroxypropyl]-4-
`(4-hydroxyphenyl)-2-azetidinone
`
`Phytosterols, and especially stanols have been shoWn
`'s to effectively inhibit cholesterol absorption from the
`gastrointestinal tract, and to negatively affect
`cholesterol synthesis. Phytosterols are expected to slow
`or inhibit the progress and formation of certain
`
`cardiovascular conditions, including hyperlipidemic
`
`10 conditions such as hypercholesterolemia and
`
`atherosclerosis. Stanols are Sa saturated derivatives of
`
`phytosterols.
`
`(Straub, U.S. Patent No. 5,244,887). It
`
`has been suggested that phytosterols lower blood
`
`cholesterol levels by reducing the absorption of
`
`15 cholesterol from the intestine (Ling and Jones,
`
`"Mini:i;-eview Dietary Phytosterols: A Review of Metabolism,
`
`Benefits and Side Effects," Life Sciences, 57 (3), 195-206
`
`(1995)) .
`
`Sitostanol, clionastanol, 22,23-dihydrobrassica-
`
`20 stanol, campestanol, and mixtures thereof contained in
`
`food additives intended to reduce cholesterol absorption
`
`from foods and beverages containing cholesterol are
`
`described by Straub in U.S. Patent Number 5,244,887.
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`I '4 .
`A beta-sitostanol fatty acid ester or fatty acid
`ester mixture which lowers cholesterol in serum is
`
`described by Miettinen et al. in U.S. Patent Number
`5,502,045.
`
`5
`
`A stanol composition containing in sitostanol and
`campestanol which effectively lowers serum cholesterol·
`
`levels when incorporated into edibles is described by
`Wester et al. in WO 9806405.
`A ther~peutic composition of one or more o)cysterols
`
`10 and a suitable carrier to inhibit cholesterol absorption
`from the diet is described by.Haines in U.S. Patent .Number
`. 5 I 929 I 062 o
`
`Cardiovascular disease is also caused or aggravated
`by hypert"ension. Hypertension is defined as per.sistently
`15 high blood pressure. Generally, adults are classified as
`being hypertensive when systolic blood pressure is
`persistently above 140 mmHg or when diastolic blood
`pressure is above 90 mmHg. Long-term risks for
`cardiovascular mortality increase in a direct relationship
`20 with persistent blood pressure (E. Braunwald, Heart
`Disease, 5th ed., W.B. Saunders & Co., Philadelphia, :1997,
`pp. 807-823). Various mechanisms have been advantageously
`exploited to control hypertension. For example, useful
`
`antihypertensive agents can include, without limitation,
`25 an andrenergic blocker, a mixed alpha/beta andrenergic
`
`blocker, an alpha andrenergic blocker, a beta andrenergic
`blocker, an andrenergic stimulant, an angiotensin
`converting enzyme (ACE) inhibitor, an angiotensin II
`
`receptor antagonist, a calcium channel blocker, a
`30 diuretic, or a vasodilator. A particularly useful·
`
`antihypertensive agent is eplerenone (see, for example,
`
`U.S. Patent No. 4,559,332). Eplerenone lowers blood
`pressure by functioning as a· diuretic. Eplerenone was
`
`formerly called epoxymexrenone.
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`Some combination the:tapie·s for the treatment :of·
`cardiovascular disease have been described in th