PCT
`WORLD INTELLECTUAL PROPERTY OROANIZATION
`International Bureau
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCf)
`
`tJ'/1
`
`(SI) International Patent CtaSsmcation 6 :
`A61K3l/445,31/235,3l/22
`
`Al
`
`-
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`(11) International Publication Number:
`
`WO 98131366
`
`(43) International Publication Date:
`
`23 July i998 :<23.07.98)
`
`(21) International Application Number:
`
`PCT/US98/00524
`
`(22) International ltiling Date:
`
`12 January 1998 (12.01.98)
`
`(JO) Priority Data:
`60/035,592
`
`17 January 1997 (17.01.97)
`
`us
`
`BRISTOL-MYERS SQUIBB COMPANY
`(71) Applicant:
`[US/US]; P.O. Box 4000, Princeton, NJ 08543-4000 (US).
`
`(81) Designated States: AL, AM, AT, AU: AZ. BB, BG, BR, BY,
`CA, CH, CN, CZ. DE, DK, BE, ES, Pl, GB, GE, HU, IL,
`IS, JP, KE. KG, KP, KR, KZ. LK, Lit. LS, LT. LU, LV,
`MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU,
`SD, SE, SG, SI, SK, TJ, TM, TR, ;TT. UA, UG, UZ, YN.
`ARIPO patent (GH, GM, KE, LS, MW, SD, SZ,. UG. ZW),
`Eurasian patent (AM, AZ, BY, KG,,KZ, MD, RU, TJ, TM),
`European patent (AT, BE, CH, DE, DK, ES, Fl, FR, GB,
`GR, IE, IT, LU, MC, NL, PT, SE), OAP! patent (BF, BJ,
`CF, CG, Cl, CM, GA, GN, ML, MR, NE, SN, TO,.ro):
`
`(72) Inventors: BEHOUNEK, Bruce, D.; 1405 . Bridle Court,
`Yardley, PA 19067 (US). MCGOVERN, Mark, E.; The
`flloridian, Penthouse #3, 650 West Avenue, Miami Beach,
`FL 33139 (US). BELDER, Rene; 62 Cherry Brook Drive,
`Princeton, NJ 08540 (US).
`
`Published
`With international search report.
`Before the expiraJion of the time li17Ut for amending the
`claims and to be republished in the event of the receipt of
`amendmenLS.
`
`(74) Agents: RODNEY, Burton et"itl.; Bristol-Myers Squibb Com(cid:173)
`pany, P.O. Box 4000, Princeton, NJ 08543-4000 (US).
`
`(54) TiUe: METHOD FOR TREATING ATHEROSCLEROSIS WITII AN MPT INHIBITOR AND CHOLESTEROL LOWERING
`-DRUGS
`.
`
`(57) Abstract
`
`A method is provided for preventing or reducing the risk of onset of a cardiovascular event by administering an MTP Inhibitor alone
`or in _combination with another cholesterol lowering drug such as an HMG CoA reductase inhibitor such as piavilsllltin, to a patient who
`may or may not have one or more risk factors for a coronary and/or cerebrovascular event such as hypercholesteroleinia. ·
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`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing intemat.ional applications under the PCT.
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`Cl
`CM
`CN
`cu
`CZ
`DE
`DK
`EE
`
`Albania
`Annenia
`Austria
`Australia
`Azerbaijan
`Bosnia 11J1d Herzegovina
`Barbados
`Betgiwii
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`Bulgaria
`Benin
`Brazil
`Belarus
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`Cen1111I Arri'8'1 Republic
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`· COie d' lvoire
`Cameroon
`China
`Cuba
`Cuch Republic
`Gcnnany
`Denmark
`Bstonia
`
`ES
`Fl
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IB
`IL
`IS
`IT
`JP
`KB
`KG
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Spain
`Pin land
`l'rlllla:
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hun guy
`Ireland
`Israel
`Iceland
`lcaly
`Japan
`Kenya
`KyigyDtan
`Democratic Ptople'a
`Republic or Korea
`Republic or Korea
`Kazalatan
`Saini Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MC
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic or Moldova
`Madagascar
`11lc fonner Yugoslav
`Republic or Maa:donia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mciico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Ponu&at
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`SI
`SK
`SN
`sz
`TD
`TG
`TJ
`TM
`TR
`IT
`UA
`UG
`us
`uz
`VN
`YU
`zw
`
`Slovenia
`Slovakia
`Senegal
`Swuil11J1d
`Chad
`Togo
`Tajikistan
`Turi:menislan
`Turtey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of Amcr«:a
`Uzbekistan
`Viet Nam
`Yugoslavia
`Zimbabwe
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`PCT/US98/00524
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`METIIOD FOR TREATING ATHEROSCLEROSIS WITII AN MPT INHIBITOR AND CHOLESTEROL LOWERING.
`DRUGS
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`Field of the Inyention
`The present invent.ion relates to a method for
`preventing.or reducing the risk of or onset of
`cardiovascular events employing an MTP inhibitor. alone or
`in combination with another cholesterol lowering drug, for
`example, an HMG CoA reductase inhibitor, such as
`·pravastatin.
`
`Background of the Invention
`
`Despite significant pr.ogress in reducing mo:i:::tality
`due to atherosclerotic coronary artery disease (CAD) over
`the last several years, cardiovascular disease remains the
`major cause of death in .most developed countries. : The
`relation between CAD and elevated concentrations of serum
`total cholesterol, particularly.low-density lipoprotein
`(LDL) cholesterol, is well documented.
`It is well established that lipid disorders are
`important factors in the development of coronary heart
`disease (CHD), Schettler, G., "The role of diet and drugs
`in lowering serum cholesterol in the postmyocardial
`infarction patient," Cardiovasc. Drugs Ther., 1989, 2/6
`(795-799) .
`Glatter, T.R., "Hyperlipidernia. What is 'normal•,
`who should be treated and how," Postgrad. Med., 1984, 76/6
`(49-59), states that "As the Coronary Primary Prevention
`Trial has recently shown, a 1% reduction in cholesterol
`level produces a 2% reduction in risk of myocardial
`infarction. "
`Goldstein, J.L., et al, "The LDL receptor defect in
`familial hypercholesterolemia.
`Implications for
`pathogenesis and therapy," Med. Clin. North Am., 1982, 66/2
`(335-362) indicate that "familial hypercholesterolemia was
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`the first genetic disorder recognized to cause myocardial
`infarction. To this day, it remains the outstaridipg
`example of a single-gene mutation that causes both
`hypercholes-terolemia and coronary atherosclerosis."
`Satler, L.F., et al, "Reduction in coronacy heart.
`disease: Clinical and anatomical considera-tions I:.. Cl in.
`Cardiel., ·1989; · 12/8 (422-426) disclose that "the higher
`the total plasma cholesterol and low density lipoprotein
`cholesterol (LDL-C), the greater the_risk that•coronary
`artery disease will develop. Recently, clinical trial$
`including the Coronary Drug Project, the Lipid Research
`Clinics Coronary Primary Prevention Trial (LRC-CPPT), and
`the Helsinki Heart Study provided evidence that lowering
`cholesterol reduces the frequency of fatal and nonfatal
`coronary events."
`In addition, Satler et al disclose that
`other studies "demonstrated that lowering of cholesterol
`was associated with a decreased incidence of progression of
`coronary disease, as well as with the potential for
`reduction in the atherosclerotic plaque."
`Wilhelmsen, L., "Prac~ical guidelines for drug
`therapy after myocardial infarction!" Drugs, 1989, 38/6
`(1000-1007) discloses that it is advisable to correc_t blood
`lipid disturbances in effective management of the
`postinfarction patient.
`Yamamoto, A., et al, "Clinical features of familial
`hypercholes terolemia, " Ar·teriosclerosis, Jan. -Feb. 1989, 9
`(1 Suppl.) p 166-74, disclose that "in addition to the low
`density lipoprotein (LDL) cholesterol level, higher
`triglyceride and lower high density lipoprotein (HDL)
`cholesterol levels correlate with an increased risk of
`ischemic heart disease.
`Other references disclosing the relation between CAD
`and elevated concentrations of serum total cholesterol
`include
`1. Canner P.L. et al, "Fi£teen year mortality in
`Coronary Drug Project patients:
`-long-terin benefi~ with
`niacin", J. Am. Coll. Cardiel. 1986; 8:1245-1255.
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`2. Frick, M.H. et al, "Helsinki Heart Study:
`primary-prevention trial with gemfibrozil in middle-aged
`men with dyslipidemia. Safety of treatment, changes in
`risk factors, and incidence of coronary heart disease," N.
`5 Engl. J. Med. 1987; 317:1237-1245.
`3 . Kannel I w. B .. et al I
`n Serum cholesterol;,
`lipoproteins, and the risk of coronary heart disease:. the
`Framingham Study," Ann. Intern. Med. 1971; 74:1-12:
`4.
`"The Lipid Research Clinics Program.
`.The Lipid
`IO Research Clinics Coronary Primary Prevention Trial·• results .... ·
`I:
`reduction in incidence of coronary heart disease," JAMA
`1984; 251-351-364.
`5. Martin, M.J. et al, "Serum cholesterol, blood
`pressure, and mortality:
`implications from a cohort of
`361,662 men," Lancet 1986; 2:933-936.
`Efforts to further reduce the mortality rate from
`CAD should benefit from appropriate screening for, and
`treatment of, hypercholesterolemia. Primary
`hypercholesterolemia is initially treated with a low-
`If
`cholesterol low-fat diet and lifestyle modification.
`t.hese mea~ures are inadequate, lipid lowering drugs are
`then added. Agents currently available for the treatment
`of hypercholesterolemia include bile acid-binding resins,
`nicotinic acid, probucol, fibrates, and 3-hydroxy-3-
`25 methylglutaryl coenzyrne A reductase inhibitors.
`Pravastatin, a member of the latter class, in doses up to
`40 mg/day, reduces serum LDL cholesterol an average of 32
`to 34% and total cholesterol an average of 24 to 26% in
`patients with primary hypercholesterolemia. Hunninghake,
`30 D.B. et al, "Efficacy and safety of pravastatin inpatients
`with primary hypercholesterolemia, I:
`a dose-response
`study." Atherosclerosis 1990; 85:81-89.
`European Patent Application 0461548A2 discloses use
`of an HMG CoA reductase inhibitor for preventing a second
`35 heart attack.
`Pending U.S. Application Serial No. 08/424,984 filed
`April 19, 1995, discloses use of an HMG CoA reductase
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`inhibitor for preventing a second heart attack in patients
`having normal cholesterol.
`U.S. application Serial No. 08/212,470 filed March
`11, 1994, disclosed use of pravastatin to slow progression
`of coronary artery atherosclerosis.
`u.s .. application Serial No. 08/182,471 filed January
`18, 1994; discloses a method for preventing or reducing ·
`risk of or onset of cardiovascular events employing an HMG
`CoA reductase inhibitor.
`The microsomal triglyceride transfer protein (MTP)
`catalyzes the transport of triglyceride (TG), cholesteryl
`ester (CE), and phosphatidylcholine (PC) between smali
`unilamellar vesicles (SW) . Wetterau & Zilversmit, Chem.
`Phys. Lipids J.a, 205-22 (1985). When transfer rates are
`eXpressed as the percent of the donor lipid transferred per
`time, MTP eXpresses a distinct preference for neutral lipid
`transport (TG and CE), relative to phospholipid transport.
`The protein from bovine liver has been isolated and
`characterized. Wetterau & Zilversmit, Chem. Phys. Lipids
`38, 205-22 ( 1985) . Polyacrylamide gel electrophore.sis
`(PAGE) analysis of the purified protein suggests that the
`transfer protein is a complex of two subunits of apparent
`molecular weights 58,000 and 88,000, since a single band
`was present when purified MTP was electrophoresed under
`nondenaturing condition, while two bands of apparent
`molecular weights 58,000 and 88,000 were identified whe~
`electrophoresis was performed in the presence of .sodium
`dodecyl sulfate (SDS). These two polypeptides are
`hereinafter referred to as 58 kDa and 88 kDa, respectively,
`30 or the 58 kDa and the 88 kDa component of MTP,
`respectively, or the low molecular weight subunit and.the
`high molecular weight subunit of MTP, respectively.
`Characterization of the 58,000 molecular weight
`component of bovine MTP indicates that it is the previously
`characterized multifunctional pre>teih, protein disulfide
`isomerase (PDI). Wetterau et al., J. Biol. Chem. ill,
`9800-7 (1990). The presence of PDI in the transfer protein
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`is supported by evidence showing that (1) the amino
`terminal 25 amino acids of the bovine 58,000 kDa component
`of MTP is identical to that of bovine PDI, and (2)
`disulfide isomerase activity was expressed by bOvine MTP.
`follpwing the dissociation of the 58 kDa - 88 kDa proteip
`complex.
`In addition, antibodies raised against bovine
`PDI, a protein which by itself has no TG transfer activity,
`were able to immunoprecipitate bovine TG transfer: activity
`from a solution containing purified bovine MTP.
`PDI normally plays a role in the folding and
`assembly of newly synthesized disulfide bonded proteins
`within the lumen of the endoplasmic reticulum. Bulleid ~
`Freedman, Nature.335, 649-51 (1988).
`It catalyzes the
`proper pairing of cysteine residues into disulfide bonds,
`thus catalyzing the proper folding of disulfide bonded
`proteins.
`In addition, PDI has been reported to be
`identical to the beta subunit of human prolyl
`4-hydroxylase. Koivu et al., J. Biol. Chem. 2.§2.,· G447-9
`(1987). The role of PDI in the bovine transfer protein .is
`not clear. It does appear to be an essential component of
`the transfer protein as dissociation of PDI from the 88 kDa
`component of bovine MTP by either low concentratio~s of a
`denaturant (guanidine HCl), a chaotropic agent (sodium
`perchlorate), or a nondenaturing detergent (octyl
`glucoside) results in a loss of transfer activity.
`Isolated
`Wetterau et al , Biocheroistrv 30, 9728-35 (1991).
`bovine PDI has no apparent lipid transfer activity,
`suggesting that either the 88 kDa polypeptide is .the
`transfer protein or that it confers transfer actiyity to
`the protein complex,
`The tissue and subcellular distribution of MTP
`activity in rats has been investigated. Wetterau &
`Zilversmit, Biochem. Biophys. Acta 875, 610-7 (1986).
`Lipid transfer activity was found in liver and intestine.
`35 Little or no transfer activity was found in plasma,. brain,
`heart, or kidney. Within the liver, MTP was a solu.ble
`protein located within the lumen of the microsomal
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`fraction. Approximately equal concentrations .were found in
`the smooth and rough microsomes.
`Abetalipopreteinemia is an autosomal recessive·
`disease characterized by a virtual absence of plasma
`lipoproteins which contain apolipoprotein B (apoB). Kane &
`Havel in The Metab9lic Basis of Inherited Disease·, Si::i:cth ·.
`edition, ·1139~64 (1989). Plasma TG levels may be as iow as
`a few mg/dL, and they fail to rise after fat ingestion.
`Plasma cholesterol levels are often only 20-45 mg/dL.·
`to These abnormalities are the result of a genetic defect i.n
`the assembly and/or secretion of very low density:
`lipoproteins .(VLDL) in the liver and chylomicrons in the
`intestine. The molecular basis for this defect has not
`been previously determined.
`In subjects examined,
`triglyceride, phospholipid, and cholesterol synthesis.
`appear normal. At autopsy, subjects are free of
`atherosclerosis. Schaefer et al., Clin Chem. J,!, B9-12
`(1988). A link between the apoB gene and
`abetalipoproteinemia ha.s been excluded in several· families.
`Talmud et al., J. Clin. Invest. _az, 1803-6 (1988) and Huang
`et al., Am· J Hum. Genet.~. 1141-8 (1990).
`Subjects with abetalipoproteinemia are afflicted
`with numerous maladies. Kane & Havel, supra. Subjects
`have fat malabsorption and TG accumulation in their
`enterocytes and hepatocytes. Due to the absence of TG-rich
`plasma lipoproteins, there is a defect in the transport of
`fat-soluble vitamins such as vitamin E. This results.in
`acanthocytosis of erythrocytes, spinocerebellar ataxia with
`degeneration of the fasciculus cuneatus and gracilis,
`30 peripheral neuropathy, degenerative pigmentary retinopathy,
`and ceroid myopathy. Treatment of abetalipoproteinemic.
`subjects includes dietary restriction of fat intake and
`dietary supplementation with vitamins A, E and K.
`1Il vitro, MTP catalyzes the transport of ·lipid
`35 molecules between phospholipid membranes. PresUmably, it
`plays a similar role in yiyo, and thus plays some role in
`lipid metabolism. The subcellular (lumen of the microsomal
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`fraction) and tissue distribution (liver and intestine) of
`MTP have led to speculation that it plays a role in the
`assembly of plasma-lipoproteins, as these are the sites of
`plasma lipoprotein assembly. Wetterau & Zilversmit,
`5 Biochem. Biophys. Acta 875, 610-7 (1986). The ability of
`MTP to.catalyze the transport of TG between membranes is
`consistent with this hypothesis, and suggests that·MTP may
`catalyze the transport of TG from its site of syn°thesis in
`the endoplasmic reticulum (ER) membrane to nascent
`lipoprotein particles within the lumen of the ER .•
`Olofsson and colleagues have studied lipo~rotein
`assembly in HepG2 cells. Bostrom et al., J. Biol .. Chem.
`ZQJ., 4434-42 (1988). Their results suggest small precursor
`lipoproteins become larger with time. This would be
`consistent with the addition or transfer of lipid molecules
`to nascent lipoproteins as they are assembled: MTP may
`play a role.in this process.
`In support of this
`.
`hypothesis, Howell and Palade, J. Cell Biol. ~. 833-45
`(1982), isolated nascent lipoproteins from the hepatic
`20 Golgi fraction of rat liver. There was a spectrum of sizes
`of particles present with varying lipid and protein
`compositions. Particles of high density lipoprotein (HDL)
`density, yet containing apoB, were found. Higgins and
`Hutson, J. Lipid Res 2.2,, 1295-1305 (1984), reported
`lipoproteins isolated from Golgi were consistently larger
`than those from the endoplasmic reticulum, again suggesting
`the assembly of lipoproteins is a progressive event.
`However, there is no direct evidence in the prior art
`demonstrating that MTP plays a role in lipid metabolism or
`the assembly of plasma lipoprotein.
`Recent reports (Science, Vol. 258, page 999.. 1992;
`D. Sharp et al, Nature, Vol. 365, page 65, 1993)
`demonstrate that the defect causing abetalipoproteinemia is
`in the MTP gene, and as a result, the MTP protein.
`Individuals with abetalipoproteinemia have no MTP activity,
`as a result of mutations in the MTP gene, some of which
`have been characterized. These results indicate that MTP
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`is required for the synthesis of apoB containing
`lipoproteins, such as VLDL,
`the precursor to LDL.: It·
`therefore follows that inhibitors of MTP would inhibit the
`synthesis of VLDL and LDL, thereby lowering VLDL levels,
`LDL levels, cholesterol levels, and triglyceride levels· in
`animals and man.
`Canadian Patent Application No. 2,091,102 publ:j.shed
`March 2, 1994 (corresponding to U.S. application S~rial No.
`117,362, filed September 3, 1993 (file DC21b)) which is
`incorporated herein by reference), reports MTP inhibitors
`which also block the lipoproteins in a human hepatic cel·l
`line (HepG2 cells). This provides further support for the
`proposal that an MTP inhibitor would lower apoB containing
`lipoprotein and lipid levels in Y!YQ~ This Canadian patent
`application discloses a method for identifying the MTP
`inhibitors.
`The use of microsomal triglyceride transfer protein
`(MTP) inhibitors for decreasing serum lipids including
`cholesterol and triglycerides and their use in treating
`atherosclerosis, obesity, hyperglycemia, and pancre~titis
`is disclosed in WO 96/26205, U.S. Application Serial No.
`472,067, filed June 6, 1995 (file DC2le), U.S. Application
`Serial No. 548,811, filed January 11, 1996 (file DC2lh),
`U.S. provisional application No. 60/017,224, filed May 9,
`1996 (file HX79a*), U.S. provisional application No.
`60/017,253, filed May 10, 1996 (file HX82*), U.S.:
`provisional application No. 60/017,254, filed May 10, 1996
`(file HX84*) and U.S. provisional appication No.
`60/028,216, filed October l, 1996 (file HX86*).
`All of the above U.S. applications are incorporated
`herein by reference.
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`Description of the Invention
`In accordance with the present invention, patients
`35 who may have (and preferably will have) one or more risk
`factors for a coronary and/or cerebrovascular even~ such as
`hypercholesterolemia and/or coronary heart disease
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`including previous myocardial infarction, who are. treated
`with an MTP inhibitor alone or optionally in combination
`with another cholesterol lowering drug, for example, an HMG
`CoA reductase inhibitor, such as pravastatin, experience a
`rapid marked and significant reduction in cardiovascular
`events. Thus, although a certain number of patients having
`one or more risk factors for coronary or cerebrovascular
`events are expected to suffer a cardiovascular incident,
`such as a myocardial infarction and/or unstable angina
`and/or stroke, such patients when treated with an: MTP
`inhibitor, alone or in combination with another cholesterol
`lowering drug, have a rapid and sizable reduction in such
`cardiovascular events.
`Thus, in accordance with the present invention, a
`15 method is provided for preventing onset of or reducing risk
`of a cardiovascular event in a patient, which patient may
`have one or more risk factors for a coronary and/or
`cerebrovascular event, wherein a therapeutically effective
`amount of an MTP inhibitor by itself or optionally in
`combination with another cholesterol lowering drug such as
`an HMG CoA reductase inhibitor, is administered
`systemically, such as orally or parenterally or
`transdermally.
`Preferred HMG CoA reductase inhibitors for use in
`combination with the MTP inhibitor are pravastatin,
`lovastatin, simvastatin, atorvastatin, cerivastatin and
`fluvastatin, more preferably pravastatin.
`The term "risk factors for a coronary and/or
`cerebrovascular event." as employed herein refers· t~ risk
`factors such as hypercholesterolemia, mixed hyperlipidemia,
`hyperlipoproteinemia, hypertriglyceridemia, coronary heart
`disease (CHD), coronary artery disease (CAD), family
`history of coronary artery disease, hypertension, diabetes,
`cigarette smoking, cerebrovascular disease and/or male
`gender.
`The term "coronary heart disease" (CHD) as employed
`herein refers to diseases including atherosclerosis of the
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`coronary arteries, previous myocardial infarction, angina
`pectoris and/or heart failure.
`The term "cerebrovascular disease" as employed
`herein refers to diseases including atherosclerosis of the
`intracranial and/or extracranial arteries, stroke, and
`transient ischemic attacks.
`The terin "cardiovascular event(s)" or "serious
`cardiovascular adverse event(s)" as employed herein refers
`to coronary and/or cerebrovascular event(s} including
`primary myocardial infarction, secondary myocardial
`infarction, angina pectoris (including unstable angina),
`congestive heart failure, sudden cardiac death, Cerebral
`infarction, syncope, transient ischemic attack and the
`like.
`
`In accordance with the method of the invention,
`where the risk factor in patients to be treated.is
`hypercholesterolemia, the serum total cholesterol
`concentrations will be at least 5.2 mmol/liter (at least
`200 mg/dl) . The patients may also have other risk factors
`for atherosclerotic coronary artery disease such as
`hypertension, previous myocardial infarction, smoker and
`the like, with or without hypercholesterolemia or elevated
`cholesterol.
`The method of the invention applies to treatment of
`patients with normal cholesterol (that is less than 200
`mg/dl} to prevent or inhibit onset of a first myocardial
`infarction or to prevent or inhibit onset of a second
`myocardial infarction.
`The method of the invention applies to patients with
`one or more of the above risk factors to prevent or inhibit
`onset of a first myocardial infarction or a second
`myocardial infarction or angina or a cerebral infarction or
`TIA·or sycope.
`The method of the invention also applies to
`inhibition or regression of coronary artery atherosclerosis
`in patients with or without risk factors.
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`Notwithstanding the above, it will be appreciated
`that in accordance with the present.invention, the MTP.
`inhibitor alone or -in coi:nbination with another cholestero.l
`lowering drug may be administered to patients irrespective
`of cholesterol levels and other risk factors to achieve .the
`reduction in cardiovascular events.
`Other cholesterol lowering drugs or drugs which are
`inhibitors of cholesterol biosynthesis which may be used in·
`the method of the invention in .combination with the MTP
`inhibitor include HMG CoA reductase inhibitor?, squalene
`synthetase inhibitors, fibric acid derivatives, bile acid
`sequestrants, probucol, niacin, niacin derivatives;
`neomycin, aspirin, and the like.
`It is believed that the combination of MTP inhibitor
`and other cholesterol lowering drug, which works by a
`mechanism other than inhibiting MTP, is a surprising and
`unique concept in treating diseases involved with elevated
`choiesterol and/or triglycerides and a.therosclerosis, in
`that the combination may provide additional anticholes-
`terolemic effects over that which may be obtained using
`each of the components of the combinatio~ alone. It is
`expected that reduced levels of each of the MTP inhibitor
`and other cholesterol lowering drug may be employed to
`achieve desired results, albeit with reduced side effects.
`
`Detailed Pescription of the Inyention
`The following·definitions apply to the terms as used
`throughout this specification, unless otherwise limited in
`specific instances.
`The term "MTP" refers to a polypeptide or protein
`complex that (1) if obtained from an organism. (e .• g., cows,
`humans, etc.), can be isolated from the microsomal fraction
`of homogenized tissue; and (2) stimulates the transport of
`triglycerides, cholesterol esters, or phospholipids from
`synthetic phospholipid vesicles, ·membranes or lipoproteins
`to synthetic vesicles, membranes, or lipoproteins and which
`is distinct from the cholesterol ester transfer protein
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`[Drayna et al., Nature 327, 632-634 (1987)] which· may.have
`simiiar catalytic properties.
`The phrase "stabilizing" atherosclerosis as used in
`the present application refers to slowing down the
`development of and/or inhibiting the formation of new
`atherosclerotic lesions·.
`The phrase ncausing the regression of"
`atherosclerosis as used in the present application ref er·s.
`to reducing and/or eliminating atherosclerotic lesions.
`The combination of the MTP inhibitor and other
`cholesterol lowering drug will be employed in a weight
`ratio to each other of within the range of from about
`1000:1 to about 0.001:1 and preferably from about 0.05:1 to
`about 100:1.
`MTP inhibitors to be employed in the methods of the
`invention include MTP inhibitors disclosed in WO 96/26205
`published August 29, 1996, Canadian Patent Applica~ion ~o.
`2,091,102 (corresponding to ·u.s. Application Serial No.
`117,362), U.S. Application Serial No. 472,067, filed June
`6, 1995 (file DC2le), U.S. Application Serial No. 548,811,
`filed January 11, 1996 (file DC2lh), U.S. provisional
`application No. 60/017,224, filed May 9, 1996 (file
`HX79a*), U.S. provisional application No. 60/017,253, filed
`May 10, 1996 (file HX82*), U.S. provisional application No.
`60/017,254, filed May 10, 1996 (file HX84*) and U.S.
`provisional application No. 60/028,216, fil~d October l,
`1996 (file HX86*).
`All of the above U.S. applications are incorporated
`herein by reference.
`The MTP inhibitors disclosed in U.S. Application
`Serial No. 472,067, filed June 6, 1995 (file DC2le) are
`piperidine compounds of the structure
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`tco
`• u_r N\
`
`~,
`
`x ""'--/
`
`A3· i-' """=
`
`, b
`A4
`
`I.
`
`or
`II.
`
`or
`III.
`
`or
`IV.
`
`or
`
`v.
`
`whereQ is
`
`0
`II -c- or
`
`II
`
`0
`-S-
`11
`0
`
`X Is: CHR8
`
`'
`
`- C- -CH- CH-
`• I
`I
`II
`0
`Ag
`A10
`
`or
`
`-C=C-;
`I
`I
`Ag A10
`
`Ra, R9 and RlO are independently hydrogen, alkyl, alkenyl,
`alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
`cycloalkyl, or cycloalkylalkyl;
`. Y is -(CH:z)m- or -:r-
`wherein m is 2 or 3;
`Rl is alkyl, alkenyl, alkynyl, aryl, heteroaryl,
`arylalkyl wherein alkyl has at least 2 carbons,
`
`0
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`diarylalkyl, ar}rlalkenyl, diarylalkenyl, arylalkynyl,
`diarY"lalkynyl, diarylalkylaryl, heteroarylalkyl wperein
`alkyl has at least-2 carbons, cycloalkyl, or
`cycloalkylalkyl wherein alkyl has at least 2 carbons, alT
`optionally substituted through available carbon atoms.with
`l, 2, 3 or 4 groups selected from halo, haloalkyl',
`alky-1,
`alkenyl, · alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, ·
`arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl;
`fluorenyl, heteroarylalkyl, hydroxy or oxo;
`or Rl is a fluorenyl-type group of the structure
`
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`
`or
`
`_ R11_ z1
`
`or
`
`or
`
`15
`
`; or
`
`I!
`Rl is an indenyl-type group of the structure
`
`or
`
`or
`
`(a= 2,3 or4)
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`or
`
`_ R11_ z1
`
`R13
`
`R14
`
`R16a
`
`Ji
`
`R1sa
`
`zl and z2 are the same or different and are
`independently a bond, 0, S,
`
`s It
`0
`
`S
`11
`)
`0 2
`
`(
`
`'
`
`-N--e- ,
`I
`II
`alkyl 0
`
`"
`
`5
`
`15
`
`H
`-e-11
`or -e- ·
`-NH-e-
`'• ·oH
`u
`o
`0
`with the proviso that with respect to~, at least· one of zl
`and z2 will be other than a bond; Rll is a bond, alkylene,
`alkenylene or alkynylene of up to 10 carbon atoms; arylene
`10 or mixed arylene-alkylene; R12 is hydrogen, alkyl,·
`alkenyl, aryl, haloalkyl, trihaloalkyl, trihaloalkylalkyl,
`heteroaryl, heteroarylalkyl, arylalkyl, arylalkenyl,
`cycloalkyl, aryloxy, alkoxy, arylalkoxy or cycloalkylalkyl,
`with the provisos in preferred compounds that
`(1) when Rl2 is H, aryloxy, alkoxy or arylalkoxy,
`-NH-e- • -N--e-
`-e-
`I
`. o
`alkyl O
`o
`
`then z2 is
`
`ll
`
`U
`
`tt
`
`or a bond and
`
`(2) when z2 is a bond, Rl2 cannot be heteroaryl or
`heteroarylalkyl;
`z is bond, 0, S, N-alkyl, N-aryl, or alkylene or
`alkenylene from 1 to 5 carbon atoms; R13, R14, RlS, and R16
`are independently hydrogen, alkyl, halo, haloalkyl, aryl,
`cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, hydroxy,
`alkoxy, nitro, amino, thio, alkylsulfonyl, ar}Tlsulfonyl,
`alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy,
`arylcarbonylamino, alkylcarbonylamino; arylalkyl,
`heteroaryl, heteroarylalkyl or aryloxy;
`RlSa and R16a are independently hydrogen,· alkyl,
`halo, haloalkyl, aryl, cycloalky~, cycloheteroalkyl,
`alkenyl, alkynyl, alkoxy, alkylsulfonyl, arylsulfonyl',
`alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy,
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`arylcarbonylamino, alkylcarbonylamino, arylalkyl, :
`heteroaryl, heteroarylalkyl, or aryloxy;
`or Rl is a gxoup of the structure
`
`a17
`-(CB2)p~
`·
`R18
`
`wherein p is 1 to 8 and R17 and RlB are each independently
`H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl,
`heteroarylalkyl, cycloalkyl or cycloalkylalkyl at.least one
`of R17 and RlB being other than H;
`or Rl is a group of the structure
`
`5
`
`IO
`
`ff20
`-R1B--<
`ff21
`
`15
`
`20
`
`wherein R19 is aryl or heteroaryl;
`R20 is aryl or heteroaryl;
`R21 is H, alkyl, aryl, alkylaryl, arylalkyl,
`aryloxy, arylalkoxy, heteroaryl, heteroarylalkyl,
`heteroarylalkoxy, cycloalkyl, cycloalkylalkyl or
`cycloalkylalkoxy;
`independently hydrogen, halo, alkyl,
`R2, R3, R4 are
`alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto,
`arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl,
`heteroarylalkyl, hydroxy or haloalkyl;
`Rs is independently alkyl, alkenyl, alkynyl, aryl,
`alkoxy, aryloxy, arylalkoxy, heteroaryl, arylalkyl,
`25 heteroarylalkyl, cycloalkyl, cycloalkylalkyl,
`polycycloalkyl, polycycloalkylalkyl, cycloalkenyl,
`cycloheteroalkyl, heteroaryloxy, cycloalkenylalkyl,
`.polycyc