PCT
`woii;.o··OOE.l.ECTUAL PRO~ER1Y ORGANlZA TION
`•
`lntemalional Bureau
`INfERNATIONAL APPLICATION PUBLISHED UNDER. rnE PATENT COOPERATION TREA1Y. (PCI)
`
`(51) lnfel'DllUonal Patent Classlllcadoa 6 :
`C07D 401A>4, 401M, 401112, 405AM,
`~' 405/12, 409AM, 409.m6, 409n2,
`211/S8, A61K 31/445
`
`Al
`
`(II) International Publication Number:
`
`WO 961.26205
`
`(43) lnternationaJ Publication Date:
`
`29 August, 1996 (29.08.96)
`
`(21) International Application Number:
`
`PCr/US96/00824
`
`(22) lnternationaJ Flllng Date:
`
`1 February 1996 (01.02.96)
`
`1
`
`(JO) Priortty Data:
`081391,901
`081472,067
`
`21 February 199S (21.02.9S)
`6 June l99S (06.o6.9S)
`
`us
`us
`
`BRJSTOL-MYERS SQUIBB COMPANY
`(71) AppUCIUlt:
`[US/US); P.O. Box 4000, Princeton, NJ 08543-4000 (US).
`
`(72) Inventors: WEITERAU, John, R.· n; 190 Rugby Drive.
`Langhorne. PA 19047 (US). s~. Daru, Young; 893
`Perrinevillc Road, Perrincville, NJ 08S3S (US) .• GREGG,
`Richard, E.; 7 Linden Lane, Pennington. NJ 08S34 (US).
`Bll.LER, scOu, A.; 31 Second Street, Hopewell. NJ 08S2S
`(US). DICKSON, John, A.; JOS Dawn Drive, Moiint Holly.
`NJ 08060 (US). LAWRENCE, R., Michael; 48 W. Crown
`Tenace, Yardley, PA 19067 (US). MAGNIN, David, R.; 40
`Cottage Court, Hamilton, NJ 08690 (US). POSS, MichSel,
`A.; IS Valerie Lane, La~vllle,: NJ 08648 (t1S). ROBL
`Jeffrey, A.; 7 TuJip Drive, Ne~own, PA 18940 (US).
`SUI.SKY, Richard, B.; 71 Gregory Lane, Franklin Plirk.
`NJ 08823 (US). TINO, Joseph,. A.; 11 · Chapin Lane,
`Lawrenceville, NJ 08648 (US). LAWsON, John, E.; S Old
`Pasture Court, Wallingford, CT 06492 (US). HOLA VA.
`Henry, M.; 13 Meadow Way, Meriden, CT 064SO (US).
`PARTYKA, Richard, A.; 618 Van Liew Coun, Ncshanic,
`NJ 08853 (US).
`
`(74) Aaenls: RODNEY, Burton et al.; Brislol"Myers Squibb Com(cid:173)
`pany, P.O. Box 4000, Princeton, NJ 08543-4000 (US).
`
`(81) Designated States: AU, BG, CA, CN, CZ. EE, Fl, GE, H:lJ,
`JP, KR, LT, LV, MX, NO, NZ, PL, RO. RU, SG, SK, UA.
`European patent CAT, BE, CH, DE. DK, ES, FR, GB. GR.
`IE. IT, LU, MC, NL, PT, SE).
`.
`.
`
`Published
`With international search report . .
`
`(54) 11tle: INHIBITORS OF MICROSOMAL TRIGLYCERIDE TRANSFER PRO'IEIN AND MEmOD
`
`~
`
`0
`
`R'-~~N-R'
`~x~~ (a)
`R'
`
`(c)
`
`tco
`.-0
`
`'~
`R'·I·
`, .6 x
`A4
`
`~·
`N
`
`(b)'
`
`(d)
`
`(57) Abstract
`
`"'
`
`Compounds are provided which inhibit microsomal triglyceride transfer protein and thus are useful for lowering serum llpids and
`treating alhcrosclerosis and related diseases. The compounds have the slructure (a, b, c or d) wherein RI to R'. Q, arid X arc as ·defined
`herein.
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`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify Stares party to the PCI' on the front pages of pamphlets publishing intemati~
`applications w11ler the PCI'.
`
`AM
`Almmla
`AT
`Aallria
`AU
`Awihlil
`BB
`Bart.dcl
`BE
`Belllum
`BF
`BmklDa Puo
`Bulpria
`BG
`BmlD
`BJ
`Brull
`BR
`BY
`Belmm
`CA
`c....i.
`Caitnl Africa Republic
`CF
`CG
`Ccago
`Swbcrlmd
`CH
`a
`CCle d'l'IOR
`CM c -
`Oilaa
`CN
`cs
`Cacbaolovakia
`CZIOCh Republic
`CZ
`DE
`Gc:rmaDy
`DK
`Demnut
`EE
`Elloaia
`Spain
`ES
`Fl
`Fmlmd
`n
`fnDce
`GA
`Oaboa
`
`Ullllcd Klnadam
`GB
`GB
`Gecrgia
`Guinea
`GN
`GR
`Girse
`HU
`H1111P7
`IE
`ln:lmd
`llal7
`IT
`IP
`Japu
`KB
`Kai)'&
`KG IC~
`Democndc ~1c·1 Republic
`KP
`ofltaru
`llcpullllc of Koru
`Kazakhlw1
`Lia:lllcamill
`Sri Lant&
`Llbcri&
`Udmania
`LUlanbomg
`Llrvia
`MoolCD
`Republic of Moldova
`Mldapacar
`Mali
`Moogotia
`M&Urilania
`
`KJl
`KZ
`u
`LK
`LR
`LT
`w
`LV
`MC
`MD
`MG
`ML
`MN
`MR
`
`MW
`Mallllri
`Me:lico
`MX
`NB
`Niau
`NL
`Nedlr:rludl
`NO N-7
`NZ
`N11wZalmd
`PL
`Po1IDd
`Pl'
`Portlapl
`RO
`Rommia
`RU
`Rlllllm Fedenl.ion
`SD
`S1ldD
`Sllltldcn
`SE
`SG
`Sill~
`Slovmla
`SI
`SknU::ia
`51(
`SN
`Salepl
`sz
`Swuilaad
`Qad
`TD
`Togo
`TG
`TJ
`T1jitiaum
`Trinidad ud TCJblio
`Tr
`UA
`\lkniDe
`UC
`Upnda
`us
`Ulliled S1a1a of~
`uz
`Uzbctisl.m
`Viel Nmi
`VN
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`PCTIUS96/0082~
`
`-1-
`
`INHIBITORS OF MICROSOMAL TRIGLYCERIDE TRANSFER
`PROTEIN AND METHOD
`
`This invention relates to novel compounds
`5 which· inhibit microsomal triglyceride transfer·
`.
`protein, and to methods for decreasing serum lipids :
`and treating atherosclerosis employing such
`compounds.
`
`.
`
`10
`
`20
`
`The mic~osomal triglyceride transfer procein
`(MTP) catalyzes the transport of triglyceride (TG),
`cholesteryl ester <CE), and phosphatidylcholine <PC)
`between small unilamellar vesicles (SUV) . Wetcerau &
`Zilversmit, Chem Phys Lipjds .J.a, 205-22 (1985).
`15 When transfer rates are expressed as the percer.t 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
`0 hys
`Lipjds .J.a, 205-22 {1985). Polyacrylamide gel
`electrophoresis <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 app3.rent
`molecular weights 58,000 and 88,000 were identi:ied
`when electrophoresis was performed in the pres.ence of
`sodium dodecyl sulfate (SOS). These two polypeptides
`are hereinafter referred to as 58 kDa and 88 kDa,
`respectively, or the 58 kDa and the 88 kDa component
`of MTP, respeccively, or the low molecular weigr.t
`
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`.
`
`5
`
`10
`
`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.· protei~,
`protein disulfide isomerase (POI). Wetterau,et al ,
`J Biol chem
`.2..[5, 9800-7 (1990). The presence·of
`POI in the transfer protein 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 POI, and (2) disulfide isomerase
`activity was expressed by bovine MTP following the
`dissociation of the 58 kDa - 88 kOa protein complex.
`In addition, antibodies raised against bovine POI, a
`15 protein which by itself has no TG transfer activity,
`were able to immunoprecipitate bovine TG transfer
`activity from a solution containing purified bovine
`MTP.
`
`20
`
`POI normally plays a role in the folding and
`assembly of newly syr.thesized disulfide bonded
`proteins within the lwnen of the endoplasmic
`reticulum. Bulleid & Freedman, Natyre .J..lS, 649-51
`(19BB).
`It catalyzes the proper pairing of cysteine
`residues into disulfide bonds, thus catalyzing.the
`25 proper folding of disulfide bonded proteins: · In
`addition, POI has been reported to be identical to
`.
`.
`the beta subunit of hwnan prolyl 4-hydroxylase.
`Koivu et al , J Biol Chem 2..§2, 6447-9 (1987). The
`role of POI in the bovine transfer protein is not
`30 clear. It does appear to be an essential component
`of the transfer protein as dissociation of POI :rom
`the BB kOa component of bovine MTP by either low
`.
`.
`concentrations of a denaturant (guanidine HCl), a
`chaotropic agent (sodium perchlorate). or a
`
`.
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`
`5
`
`15
`
`nondenaturing detergent (octyl glucoside) results in
`a loss of transfer activity. Wetterau et ~l ~ ·
`Bjpchemjstry .lQ, 9728-35 (1991).
`Isolated bovine.POI
`has no apparent lipid transfer activity, suggesting
`that either the 88 kDa polypeptide is the transfer
`protein or that it confers transfer activity to the
`protein complex.
`The tissue and subcellular distribution of MTP
`activity in rats has been investigated. Wetterau &
`10 Zilversmit, Bjochem Biophys Acta .B.1.5, 610-7 (1986).
`Lipid transfer activity was found in liver and
`intestine. Little or no transfer activity was found
`in plasma, brain, heart, or kidney. Within the
`liver, MTP was a soluble protein located within the
`lumen of the microsomal fraction. Approximately
`equal concentrations were found in the smooth and
`rough microsomes.
`Abetalipoproteinemia is an autosomal recessive
`disease characterized by a virtual absence of plasma
`lipoproteins which contain apolipoprotein B .tapoB) .
`Kane & Havel in The Metabolic Bas;s oF Tpherited
`Disease, Sixth edition, 1139-64 {1989). Plasma TG
`levels may be as low as a few mg/dL, and they fail to
`rise after fat ingestion. Plasma cholesterol levels
`are often only 20-45 mg/dL. These abnormalities are
`the result of a genetic defect in 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
`30 previously determined.
`In subjects examined,
`triglyceride, phospholipid, and cholesterol sy~thesis
`appear normal. At autopsy, subjects are free of
`atherosclerosis. Schaefer et al , Clin Chem
`.1,1,
`89-12 (1988). A link between the apoB gene and
`
`20
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`J
`
`abetalipoproteinemia has been excluded in s:evera1 ·
`families. Talmud et al ,
`IU. 1803-6
`,J Clin
`Inyest
`(1988) and Huang et al , Arn·
`Hum Genet . .4.fi,•1141.;..
`8 (1990).
`Subjects with abetalipoproteinemia are
`afflicted with numerous maladies. Kane & Havel,
`'
`.
`supra. Subjects have fat malabsorption arid. 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, 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 .
`.In yjtro, MTP catalyzes the transport.of lipid
`20 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 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,
`Biochem Bjophys Acta .B.15, 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 synthesis in the endoplasmic
`reticulum (ER) membrane to nascent lipoprotein
`particles within the lumen of the ER.
`
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`
`10
`
`20
`
`Olofsson and colleagues have studied
`lipoprotein assembly in HepG2 cells. Bostrom: e- al ·,
`J Biol Chem 2...6..l, 4434-42 (1988). Their resuits
`suggest small precursor lipoproteins become larger
`5 with time. This would be consistent with the
`addition or transfer of lipid molecules to nascent
`lipoproteins as they are assembled. MTP may pl,ay a
`role in this process.
`In support of this hypothesis,
`.i,2, 833-45 (1982),
`Howell and Palade, J
`eel l Biol
`isolated nascent lipoproteins from the hepatic Golgi
`fraction of rat liver. There was a spectrum c: sizes
`of particles present with varying lipid and prc~ein
`compositions. Particles of high density lipopr·:::>tein
`(HDL) density, yet containing apoB, were found.
`15 Higgins and Hutson, J Lipid Res 2..5, 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.
`Recent reports !Science, Vol. 258, page 999,
`1992; D. Sharp et. al., Nature, Vol. 365, page ES,
`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 is required for the synthesis of apoB contai.ning
`lipoproteins, such as VLDL,
`the precursor to LD:.. 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.
`
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`PCT/US96/0082~
`
`Canadian Patent Application No. 2, 091. 102
`published March 2, 19 9 4 (corresponding to U :~ S .
`application Serial No. 117. 362, filed September 3. ·
`1993 (file DC2lb)) reports MTP inhibitors whi.ch. also
`block the production of apoB containing lipoproteins
`in a hwnan hepatic cell line (HepG2 cell.s)., ~his
`provides further support for the proposal that an MTP
`inhibitor would lower apoB containing lipoprotein and.,
`lipid levels in vivo. This Canadian patent
`application discloses a method for identifying the
`MTP inhibitors
`
`5
`
`10
`
`CX{N-CN
`
`0
`which has the name 2-11-(3, 3-diphenylpropyl)~4-
`15 piperidinyl)-2, 3-dihydro~3-oxo-1H-isoindole
`hydrochloride and
`
`F
`which has the name l-[3-(6-fluoro-1-
`tetralanyl)methyl]-4-0-methoxyphenyl piperazine
`
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`PCTIUS9610082~
`
`In accordance with the present inventionr
`novel compounds are provided which are inhibitors of :
`MTP and have the structure
`I
`
`or
`
`or
`
`or
`
`J:i
`
`10
`
`J:I
`
`J::Ii
`
`R2
`
`0
`
`~ 1
`
`n·OC-0
`
`R4
`
`R'" Q.. r.-CN- R1
`
`R'
`
`R'
`I
`Rs_..0,~-0
`Rg
`
`15
`
`20
`
`0
`0
`"
`"
`where Q Is -c- or -s-
`II
`0
`
`-C: C-;
`I
`I
`R9 R10
`
`X Is: CHR8, -C- -~CH- or
`..
`' I
`I
`0
`R'
`R'o
`Ra, R9 and R10 are independently hydrogen, alkyl,
`alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,
`heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;
`Rl is a fluorenyl-type group of the structure
`
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`
`-- R11
`
`- Z1
`
`_ R11.z1
`
`or
`
`or
`
`-R11 -Z'
`R12 __ z2
`
`5
`
`12
`Rl is an indenyl-type group of the structure
`
`; or
`
`or
`
`or
`
`E
`
`(a= 2,3 or 4}
`
`E
`
`or
`
`- R11 -Z1
`
`R''-
`
`10
`
`.G
`
`zl and z2 are the same or different and are
`independently a bond, o, S,
`
`s
`" 0
`
`, -NH-C-
`0
`
`II
`
`,
`
`-N--C- I
`I
`II
`alkyl O
`
`-c--
`11
`0
`
`or
`
`H
`-~­
`OH
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`PCT/US96/0082.&
`
`5
`
`10
`
`with the proviso that with respect to ~, at least one
`of zl and z2 will be other thari a bond;
`Rll is a bond, alkylene, alkenylene or
`alkynylene of up to 10 carbon atoms, arylene (for
`example
`
`-0-
`~ -rg- (CHz>n-
`
`or mixed arylene-alkylene (for example
`
`where n is 1 to 6;
`Rl2 is hydrogen, alkyl, alkenyl, aryl, halo-
`alkyl, trihaloalkyl, trihaloalkylalkyl, heteroaryl,
`heteroarylalkyl, ary lalkyl·, arylalkenyl, cycloalkyl,
`aryloxy, alkoxy, arylalkoxy or cycloalkylalkyl; with
`the provisos that (1) when Rl2 is H, aryloxy, alkoxy
`-NH-C-
`,
`II
`o
`
`•
`
`15 or arylalkoxy, then z2 is
`-N-c-
`-c-
`ti
`..
`or a bond;
`alkyl O
`O
`and (2) when z2 is a bond, Rl2 cannot be
`heteroaryl or heteroarylalkyl;
`Z is a bond, 0, S, N-alkyl, N-aryl, or
`alkylene or alkenylene of from 1 to 5 carbon atoms;
`Rl3, Rl4, RlS, and Rl6 are independently
`hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl,
`cycloheteroalkyl, alkenyl, alkynyl, hydroxy, alkoxy,
`nitre, amino, thio, alkylsulfonyl, arylsulfonyl,
`alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy,
`arylcarbonylamino, alkylcarboriylamino, arylalkyl,
`heteroaryl, heteroarylalkyl, or aryloxy;
`RlSa and Rl6a are independently any of the RlS
`or Rl6 groups except hydroxy, nitre, amino or ti":.io;
`R2, Rl, R4 are independently hydrogen, haio,
`alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl,
`
`20
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`
`5
`
`15
`
`20
`
`alkylmercapto, arylmercapto, cycloalkyl,
`cycloalkylalkyl, heteroaryl, heteroarylalkyl; hydroxy
`or haloalkyl;
`R5 {s alkyl • alkenyl, alkynyl, acyl; alkoxy,
`aryloxy, arylalkoxy, heteroaryl, arylalkyl,,
`heteroarylalkyl, cycloalkyl, cycloheteroalkyl,
`heteroaryloxy, cycloalkylalkyl, polycycloalkyl,
`polycycloalkylalkyl, cycloalkenyl, cycloalk~nyl­
`alkyl, polycycloalkenyl, polycycloalkenylalkyl,
`10 heteroarylcarbonyl, amino, alkylarnino, arylamino.
`heteroarylarnino, cycloalkyloxy. cycloalky~amino. all
`of the RS substituents and R6 substituents (set out
`hereinafter) being optionally substituted through
`available carbon atoms with l, 2, 3 or 4 groups
`selected from hydrogen, halo, alkyl. haloalkyl,
`alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl,
`cycloalkylalkyl, cycloheteroalkyl,
`cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl,
`arylcycloalkyl, arylalkenyl, arylalkynyl, a·ry loXy,
`aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo,
`heteroaryl-alkyl, heteroarylalkenyl, heteroaryloxy,
`hydroxy, nitre, cyano, amino, substituted amino
`(wherein the amino includes 1 or 2 substituents.which
`are alkyl, aryl or heteroaryl, or any of the other
`.
`.
`aryl compounds mentioned in the definitions), thiol,
`alkylthio, arylthio, heteroarylthio, arylthioalkyl,
`alkylcarbonyl, arylcarbonyl, arylamino-carbony 1.,
`alkoxycarbonyl, aminocarbonyl, alkynylarninocarbonyl,
`alkylaminocarbonyl, alkenylamino-carbonyl,
`alkylcarbonyloxy, arylcarbonyloxy, alkyl(cid:173)
`carbonylamino, arylcarbonylamino·, arylsulfinyl,
`arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl ..
`arylsulfonylamino, heteroarylcarbonylamino,
`heteroarylsulfinyl, heteroarylthio. heteroaryl-
`
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`sulfonyl, or alkylsulfinyl. Wher.e Rs is phenyl,
`aryl, heteroaryl or cycloalkyl; this group pr:eferably
`includes an ortho hydrophobic substituent .such as··
`alkyl, haloalkyl (with up to 5 halo groups),· alkoxy ,: ·
`haloalkoxy (with up to 5 halo groups), aryl, arylbxy ·
`or arylalkyl;
`R6 is hydrogen or C1-C4 alkyl or C1-C4
`alkenyl;
`
`and
`
`are the same or different and are independently
`selected from heteroaryl containing 5- or 6-ring
`members; and
`including N-oxides of the formulae I, Ii, II
`and IIi compounds, that is
`
`s-o<· and
`
`including pharmaceutically acceptable salts
`thereof such as alkali metal salts such as lithium
`sodium or potassium, alkaline earth metal salts· such
`as calcium or magnesium, as well as zinc or aluminum
`and other cations such as anunonium, choline,
`diethanolamine, ethylenediarnine, t-butyl-amine, t(cid:173)
`octylamine, dehydroabietylamine, as well as
`pharmaceutically acceptable anions such as chloride,
`bromide, iodide, tartrate, acetate, methanesulfonate,
`maleate, succinate, glutarate, and salts of naturally
`occurring amino acids such as arginine, lysine,
`alanine and the like, and prodrug esters thereof.
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`Thus, the compounds of formulae I and II of.
`the invention encompass compounds of the. structure
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`5
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`..
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`'Ii
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`10
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`0
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`ze 1
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`5
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`In addition, in accordance with the present
`invention, a method for preventing, inhibiting or
`treating atherosclerosis, pancreatitis or obesity is
`provided, wherein a compound of formula I,· IL II, or
`IIi as defined hereinbefore, is administered ·1n an·
`amount which decreases the activity of microsomal ·
`triglyceride transfer protein.
`Furthermore, in accordance with the present.
`invention, a method is provided for lowering serum
`lipid levels, cholesterol and/or triglycerides, or
`inhibiting and/or treating hyperlipemia, hyper(cid:173)
`lipidemia, hyperlipoproteinemia, hypercholes(cid:173)
`terolemia and/o.r hypertriglyceridemia, wherein a
`compound of formula I, Ii, II, or IIi as defined
`15 hereinbefore, is administered in an amount which
`decreases the activity of microsomal triglyceride
`transfer protein.
`
`10
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`20
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`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,~.), can be isolated from the
`25 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
`30 which is distinct from the cholesterol ester transfer
`protein [Drayna et al , Nature .l.21. 632-634 (1987)]
`which may have similar catalytic properties.
`However, the MTP molecules of the present inven~ion
`do not necessarily need to be catalytically active.
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`For example, catalytically inactive MTP or fragments
`thereof may be useful in raising antibodies:to:the
`protein.
`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 •causing the regression of•
`atherosclerosis as used in the present application
`refers to reducing and/or eliminating atherosclerotic
`lesions.
`Unless otherwise indicated, the term a}ower
`alkyl•, •alkyl• or •alk• as employed herein alone or
`as part of another group includes both straight and
`branched chain hydrocarbons, containing 1 to 40
`carbons, preferably 1 to 20 carbons, more preferably
`1 to 12 carbons. in the normal chain, such as methyl,
`ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl,
`pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl,
`20 octyl, 2,2,4-trimethyl-pentyl, nonyl. decyl, undecyl,
`dodecyl, the various branched chain isomers thereof,
`and the like as well as such groups including 1 to 4
`substituents such as halo, for example F. Br, Cl 'or I
`or CF3, alkoxy, aryl, aryloxy, aryl{aryl) or diaryl,
`arylalkyl, arylalkyloxy, alkenyl, cycloalkyl,
`cycloalkylalkyl, cycloalkylalkyloxy, amino, hydroxy,
`acyl, heteroaryl, heteroaryloxy, hetero-arylalkyl,
`heteroarylalkoxy, aryloxyalkyl, aryloxyaryl,
`alkylarnido, alkanoylamino, arylcarbonylamino, nitro.
`cyano, thiol, haloalkyl, trihaloalkyl and/or
`alkylthio, as well as any of the other substituents
`as defined for Rs and R6.
`Unless otherwise indicated, the term
`•cycloalkyl" as employed herein alone or as part of
`
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`another group includes saturated or partially
`unsaturated {containing l.or 2 double bonds) cyclic
`hydrocarbon groups containing 1 to 3 rings, including
`monocyclicalkyl, bicyclicalkyl and tricyclicalkyi,:
`containing a total of 3 to 20 carbons forming the
`rings, preferably 4 to 12 carbons, forming the ring
`and which may be fused to 1 or 2 aromatic rings as.
`described for aryl, which include cyclopropyl,
`cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
`cyclooctyl, cyclodecyl and cyclododecyl,
`cyclohexenyl,
`
`5
`
`10
`
`co
`
`any of.which groups may be optionally substituted
`15 with 1 to 4 substituents such as halogen, alkyl,
`alkoxy, hydroxy, aryl, aryloxy, arylalkyl,
`cycloalkyl, alkylamido, alkanoylamino; . oxo, acyl·,
`arylcarbonylamino. amino, nitre, cyanci, thiol and/or
`alkylthio, as well as any of the other subs.tic.uents
`as defined for Rs or R6.
`The tenn •cycloalkenyl" as employed'.herein
`alone or as part of another group refers to' cyclic
`hydrocarbons containing 5 to 20 carbons, preferably 6
`to 12 carbons and 1 or 2 double bonds. Exemplary
`cycloalkenyl groups include cyclopentenyl, cyclo(cid:173)
`hexenyl, cycloheptenyl, cyclooctenyl, cyclohexa(cid:173)
`dienyl, and cycloheptadienyl, which may be optionally
`substituted as defined for cycloalkyl.
`The term •polycycloalkyl• as employed herein
`alone or as part of another group refers co a bridged
`multicyclic group containing 5 to 20 carboris an·d
`containing 0 to 3 bridges, preferably ~ to lt c~rbons
`
`20
`
`25
`
`30
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`SUBSTITUTE SHEET (RULE 26)
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`5
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`15
`
`and 1 or 2 bridges. Exemplary polycycloalkyl groups:
`include (3.3.0J-bicyclooctanyl, adamantanyl, [2.2.11:(cid:173)
`bicycloheptanyl, (2. 2 .2 J -bicyclooctanyl and ·th~· like'
`and may be optionally substituted as defined for
`cycloalkyl.
`The term "polycycloalkenyln as employed
`herein alone or as part of another group refeis .to a.
`bridged multicyclic group containing 5 to 20 carbons
`and contaifiing 0 to 3 bridges and containing i or 2
`10 double bonds, preferably 6 to 12 carbons and 1 or 2
`bridges. Exemplary polycycloalkyl groups include
`[ 2. 2 .1 J -bicycloheptenyl, ·
`[ 3. 3. 0] -bicyclooctenyl,
`(2.2.2)-bicyclooctenyl and the like and may be
`optionally substituted as defined for cycloalkyl.
`The term •aryl• or •Ar• as employed herein
`alone or as part of another group refers to
`monocyclic and bicyclic aromatic groups containing 6
`to 10 carbons in the ring portion (such as phenyl or
`naphthyl) and may optionally include one to three
`additional rings fused to Ar (such as aryl,
`cycloalkyl, heteroaryl or cycloheteroalkyl rings) and
`may be optionally substituted thro~gh available
`carbon atoms with 1, 2, 3 or 4 groups selected from
`hydrogen, halo, haloalkyl, alkyl, haloalkyl, alkoxy,
`haloalkoxy, alkenyl, trifluoromethyl,
`trifluoromethoxy, alkynyl, cycloalkylalkyl, cyclo(cid:173)
`heteroalkyl, cycloheteroalkylalkyl, aryl, hetero(cid:173)
`aryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy,
`arylthio, arylazo, heteroarylalkyl, heteroaryl-
`alkenyl, heteroarylheteroaryl, heteroaryloxy,
`hydroxy, nitro, cyano, amino, substituted amino
`wherein the amino includes 1 or 2 substituents 1which
`are alkyl, aryl or any of the other aryl compounds
`mentioned in the definitions), thiol, alkylthio,
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`20
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`SUBSTITUTE SHEET {RULE 26)
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`'.
`
`arylthio, heteroarylthio, arylthioalkyl,
`alkoxyarylthio, alkylcarbonyl, arylcarbonyl>
`alkylaminocarbonyl, arylaminocarbonyl,
`alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy,
`arylcarbonyloxy, alkylcarbonylamino, arylcarbonyl- ·
`amino, arylsulfinyl, arylsulfinylalkyl, :arylsul":"
`fonylamino or arylsulfonaminocarbonyl, or any. of the
`substituents as defined for the Rs or R6 gro,ups set
`out above.
`The term •aralkyl", aaryl~alkyl• or
`•aryllower alkyl• as used herein alone or a:s paft. of
`another group refers to alkyl groups as dis.cussed
`above having an aryl substituent, such as benzyl or
`phenethyl, or naphthylpropyl, or an aryl as defined
`above.
`
`The term • 1ower alkoxy", •alkoxy", •aryloxy•
`or •aralkoxy• as employed herein alone or as part of
`another group includes any of the above alkyl,
`aralkyl or aryl groups linked to an oxygen atom.
`The term •amino• as·employed herein alone or
`as part of another group may optionally be
`substituted with one or two substituents such as
`alkyl and/or aryl.
`The term •lower alkylthio•, alkylthl.6•,
`•arylthio• or •aralkylthio• as employed herein alone
`or as part of another group includes any of the above
`alkyl, aralkyl or aryl groups linked to a sulfur
`atom.
`
`The term •1ower alkylarnino•, •alkylamino•,
`•arylamino•, or •arylalkylarnino• as employed herein
`alone or as part of another group includes any of· the
`above alkyl, aryl or arylalkyl groups linked to a
`nitrogen atom.
`
`5
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`10
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`15
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`20
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`SUBSTITUTE SHEET {RULE 26).
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`The term "acyl" as employed herein by itself
`or part of another group as defined herein, refers to
`
`an organic radical linked to a carbonyl ( ~ )
`
`5
`
`.
`
`10
`
`15
`
`20
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`25
`
`group, examples of acyl groups include alkanoyl,
`alkenoyl, aroyl, aralkanoyl, heteroaroyl,
`cycloalkanoyl and the like.
`.
`.
`.
`:
`The term 0 alkanoyl" as used herein alone or·
`as part of another group refers to alkyl linked to'a
`carbonyl group.
`Unless otherwise indicated, the term "lower
`alkenyl" o:::- •alkenyl" as used herein by itsel'f·or as
`part of another group refers to straight or branched
`chain radicals of 2 to 20 carbons, preferably 3 to 12
`carbons, and more preferably 1 to 8 carbons in the
`normal chain, which include one to six double bonds
`in the normal chain, such as vinyl, 2-propenyl, 3-
`butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2- ·
`hexenyl, 3-hexenyl, 2-heptenyl; 3-heptenyl, 4-.
`heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-
`undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and
`the like, and which may be optionally substituted
`with l to 4 substituents, namely, halogen, haloalkyl,
`alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl,
`cyclo-alkyl, amino, hydroxy, heteroaryl, cyclohet_ero- ·
`alkyl, alkanoylamino, alkylamido, arylcarbonylamino,
`nitro, cyano, thiol and/or alkylthio, as well as any
`of the other substituents as defined ~or Rs or R'.
`Unless otherwise indicated, the term •1ower
`alkynyl" or •alkynyl" as used herein by itself or as
`30 part of another group refers to straight o:::- branched
`chain radicals of 2 to 20 carbons, preferably 2 to 12
`carbons and more preferably 2 to 8 carbons in the
`normal chain, which include one triple bond in the
`normal chain, such as 2-propynyl. 3-butynyl, 2-
`
`SUBSTITUTE SHEET (RULE 26)
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`.
`
`butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, .3-
`hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl;. 3-
`octynyl, 3-nonynyl, 4-decynyl,3-undecynyl, 4~
`dodecynyl and the like, and which may be optionally
`substituted with 1 to 4 substituents, namely,:
`..
`halogen, haloalkyl, alkyl, alkoxy, alkenyL 'aikjrny'l·~
`aryl, arylalkyl, cycloalkyl, amino, heteroacyl,
`cycloheteroalkyl, hydroxy, alkanoylarnino, alkylarnido,
`arylcarbonyl-amino, nitre, cyano, thiol, and/or
`alkylthio, as well as any of the other substituents
`as defined for Rs or R6.
`.
`The term "alkylene• as employed herein alone
`or as part of another group lwhich·a1so encompasses
`"alkyl" as part of another group such as arylalkyl or
`15 heteroarylalkyl) refers to alkyl groups as defined
`above having single bonds for attachment to other
`groups at two different carbon atoms and may
`optionally be substituted as defined above for
`•alkyl". The definition of alkylene applies to an
`alkyl group which links one function to another, such
`as an arylalkyl substituent.
`Ther terms "alkenylene• and "alkynyie~e· as
`employed herein alone or as part of another group
`(which also encompass •alkenyl" or "alkynyl." as part
`25 of another group such as arylalkenyl or arylalkynyi),
`refer to alkenyl groups as defined above and alkynyl
`groups as defined above, respectively, having single
`bonds for attachment at two different carbon atoms.
`Suitable alkylene, alkenylene or alkynylene
`groups or ( CH2) n or ( CH2) p (which may inc 1 ude
`alkylene, alkenylene or alkynylene groups) as defined
`herein, may optionally include 1,2, or 3 alkyl,
`alkoxy, aryl, heteroaryl, cycloheteroalkyl, alk.enyl,
`alkynyl, oxo, aryloxy, hydroxy, halogen substituents
`
`20
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`30
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`10
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`15
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`20
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`as well as any of the substituents defined fo~ Rs or
`R6, and in addition, may have one of the carbon atoms
`in the chain replaced with an oxygen atom, N-H, N(cid