WORLD INTELLECTUAL PROPERTY OROANIZA TION
`International Bui;eau
`
`PCT
`INTERN A TI ON AL APPLICATION PUBLISHED UNDER THE PA TENT COOPERATION TREATY (PCT)
`(51) International Patent ClasmficaU~n 6 :
`WO 98/27979
`A61K 31/24, 31144, 31/47, 31/415,
`31/445, 31/495, C07D 211/58, 233n8,
`401/06, 401/08, 401n2, 403/08, 405104,
`471/04, 47tn0
`
`(11) International Publication Number:
`
`Al
`
`(43) International Publication Date:
`
`2 July 1998 (02.07.98)
`
`(21) lnternaUonal Application Number:·
`
`PCTIUS97121950
`
`(22) International Filing Date:
`
`2 December 1997 (02.12.97)
`
`(30) Priority Data:
`60/033,899
`
`20 December 1996 (20.12.96)
`
`US
`
`BRISTOlr-MYERS SQUIBB COMPANY
`(71) Applicant:
`[US/US]; P.O. Box 4000, Princeton, NJ 08543-4000 (US).
`
`(81) Designated States: AL. AM, AT, AU, }.z, BB, BG,:BR, BY,
`CA, CH, CN, CZ, DE, DK, EE, ES, FI, GB, GE, HU,
`IL, IS, JP, KE, KG, KP, KR, KZ, LK,. LR, LS, LT, LU,
`L V, MD, MG, MK, MN, MW, MX, NO, NZ. PL; PT, RO,
`RU, SD, SE, SG, SI, SK, n. TM, TR; TT, ·uA,;uG, uz.
`VN, ARIPO patent (GH, KE, Ls,.MW,.SD, sz. UG, zw).
`Eurasian patent (AM, Az, BY; KG, Kz; MD0 RU, TJ, TM),
`European patent (AT, BE, CH, DE, DK, ES, FI, FR, GB,
`GR, IE, IT, LU, MC, NL, PT, SE), OAPI p11tent (BF., BJ,
`CF, CG, Cl, CM, GA, ON, ML, MR, NE, Sl':J, ID, TG).
`
`(72) Inventor: TINO, Joseph, A.; 11 Chopin Lane, Lawrenceville, Published
`NJ 08648 (US).
`With international search report.
`
`(74) Agents: RODNEY, Burton et al.; Bristol-Myers Squibb Com(cid:173)
`pany, P.O. Box 4000, Princeton, NJ 08543-4000 (US).
`
`(54) Title: HETEROCYCLIC INHIBITORS OF MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN AND METHOD
`
`r ..
`
`(IV)
`
`-T-
`
`..
`
`{V)
`
`(Q ;r· (U) ~~ (Ill)
`C(5cr ~ w. /::~~ ~,,
`;;:; ~ J: .re ....
`
`.....................
`a
`"'
`
`ii..&'
`, ,
`
`1l<e
`11•
`
`(VI)
`
`(VU)
`
`(VIII)
`
`(XII)
`
`(XUI)
`
`.r'S ....
`....
`
`(XIV)
`
`11•
`
`I
`
`...
`
`~A'" (X)
`.r"-8 ....
`.....
`
`(XV)
`
`ii"
`
`(57) Abstract
`Novel compounds are provided which are inhibitors of MTP and thus are useful for lowering serum lipids and treating atherosclerosis
`and related diseases, and have structure (I), including pharmaceutically acceptable salts thereof, or prodrug esters thereof, A is (II) or (III)
`where Z is Nor CH, or where Z is (IV) or CH2 when== is a single bond; Q is (I) -0-; (2) -S-; or (3) (V); B is (VJ) or (VII) or (VIII)
`or (IX) wherein a - 2, 3 or 4 or (X) or (XI) or (XII); and wherein L', R, R 1, Rl, R3', R3a, Rlb, R4, R4', R'. R'"· X, (XIII), (XIV) and (XV)
`are as defined herein.
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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
`DC
`HJ
`BR
`DY
`CA
`CF
`cc
`CH
`Cl
`CM
`CN
`cu
`CZ
`DE
`DK
`EE
`
`Albania
`Armenia
`Austria
`Auslnllla
`Aurbnijan
`Bomia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Cen1n1I African Republic
`Congo
`Switu:rland
`COie d'Ivoire
`Cameroon
`China
`Cuba
`Cuch Republic
`Germany
`Denmark
`l!s1onia
`
`ES
`Fl
`Flt
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KC
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Spain
`l'"mland
`France
`Gabon
`Uniled Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democrnlic People• s
`Republic of Korea
`Republic of Korea
`Kazalstan
`Saint Lucia
`Licchlenste;n
`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
`SC
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaa>
`Republic of Moldova
`Madagaacar
`Tiie fonner Yugoslav
`Republic of Macedonia
`Mall
`Mongolia
`Mauritania
`Malawi
`Mel<ico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Ruuian Federation
`Sudan
`Sweden
`Singapore
`
`SI
`SK
`SN
`sz
`TD
`TC
`TJ
`TM
`TR
`Tr
`UA
`UC
`us
`uz
`VN
`YU
`zw
`
`Slovenia.
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikis1an
`1Urlnnenisl8n
`TuJkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United SIBICS of Amttica
`Uzbekistan
`Vici Nam
`Yugoslavia
`Zimbabwe
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`HETEROCYCLIC INHIBITORS OF
`MICRQSQMAL TRIGLYCERIDE TBANSFER PROTEIN AND METHOD
`
`5
`
`Field of the Invention
`This invention relates to novel heterocyclic
`compounds which inhibit microsomal triglyceride transfer
`protein, and to methods for decreasing serum lipids and
`treating atherosclerosis employing su.ch compounds.
`
`IO
`
`15
`
`Background of the Invention
`The microsomal triglyceride transfer protein (MTP)
`catalyzes the transport of triglyceride (TG), cholesteryl
`ester (CE) , and phosphatidylcholine (PC) between small
`unilamellar vesicles (SUV). Wetterau & Zilversmit, Chem
`Phys. Lipids 38, 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 transP,ort ..
`The protein from bovine liver has been isolated and
`characterized. Wetterau & Zilversmit, Chem. Phys. Lipids
`38, 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
`25 was present when purified MTP was electrophoresed under
`nondenaturing condition, while two bands of apparent
`molecular weights 58,000 and 88,000 were identified when
`electrophoresis was performed in the presence of sodium
`dodecyl sulfate (SDS) .. These two polypeptides are
`30 hereinafter referred to as 58 kDa and 88 kDa, respectively,
`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 protein, protein disulfidt?
`isomerase (PDI). Wetterau et al., J. Biol. Chem.~.
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`9800-7 (1990). The presence of PDI 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 PDI, and (2)
`5 disulfide isomerase activity was expressed by bovine MTP
`following the dissociation of the -58 kDa - 88 kDa protein
`complex.
`In addition, antibodies raised against bovine
`PDI, a protein which by itself has no TG transfer activitx,
`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..§.1, 6447-9
`(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 ~8 kDa
`component of bovine MTP by either low concentrations qf 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., Biochemistry .lQ., 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 activity 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).
`35 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
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`protein located w1thin the lumen of the microsomal
`fraction. Approximately equal concentrations were found in
`the smooth and rough microsomes.
`Abetalipoproteinemia is an autosornal recessive
`5 disease characterized by a virtual absence of plasma
`lipoproteins which contain apolipoprotein B (apoB) . Kane &
`Havel in The Metabolic Basis of Inherited Disease, Sixth
`
`10
`
`15
`
`20
`
`25
`
`edition, 1139-64 (1989). Plasma TG l.evels may be as lo.w 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 previously determined.
`In subjects examined,
`triglyceride, phospholipid, and cholesterol synthesis
`appear normal. At autopsy, subjects are free of
`atherosclerosis. Schaefer et al., Clin. Chem. H, B9-12
`(1988). A link between the apoB gene and
`abetalipoproteinemia has been excluded in several families.
`Talmud et al., J. Clin. Inyest. 82, 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
`30 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 vitro, MTP catalyzes the transport of lipid
`molecules between phospholipid membranes. Presumably, it
`plays a similar role in viyo, and thus plays some role in
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`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. 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 synthesis in
`the endoplasmic reticulum (ER) membrane to nascent
`lipoprotein particles within the lumen of the ER.
`Olofsson and colleagues have studied lipoprotein
`assembly in HepG2 cells. Bostrom et al., J. Biol. Chem·
`2.2,J, 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 ~y
`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
`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
`25 Hutson, J. Lipid Res. 25, 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
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`have been characterized. These results indicate that MTP
`is required for the synthesis of apoB containing
`It
`lipoproteins, such as VLDL,
`the precursor to LDL.
`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 published
`March 2, 1994 (corresponding to U.S. application Serial No.
`117,362, filed September 3, 1993 (file DC2lb)) which is
`incorporated herein by reference), reports MTP inhibitors
`which also block the production of apoB containing
`lipoproteins in a human hepatic cell line (HepG2 cells).
`This provides further support for the proposal that an MTP
`inhibitor would lower apoB containing lipoprotein and lipid
`levels in Y.iJ!Q. This Canadian patent application discloses
`a method for identifying the MTP inhibitors
`
`5
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`CQN-CN
`
`0
`which has the.name 2-[l-(3, 3-diphenylpropyl)-4-
`20 piperidinyl J -2, 3-dihydro-3-oxo-lH-isoindole hydrochloride
`and
`
`F
`which has the name 1- [3- (6-fluoro-1-tetralanyl)-methyl.J-4-
`0-rnethoxyphenyl piperazine.
`EP 0643057Al published March 15, 1995, discloses MTP
`inhibitors of the structure
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`I
`
`II
`
`5
`
`Ill
`
`or
`
`or
`
`t60
`
`'-..;;:::
`R3· I-
`I...-:;.
`R4
`
`r .Fi!
`
`N
`I
`,,N-...../
`y
`
`10
`
`15
`
`where X is: cHRB,
`
`-CH-CH
`I
`I
`B.10
`
`R!I
`
`or
`
`Ra, R9 and Rio are independently hydrogen, alkyl, alkenyl,
`alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
`cycloalkyl, or cycloalkylalkyl;
`
`Y is -(CB2 ).,.- or -e-n
`0
`
`where m is 2 or 3;
`Rl is alkyl, alkenyl, alkynyl, aryl, heteroaryl,
`arylalkyl (wherein alkyl has at least 2 carbons),
`20 diarylalkyl, arylalkenyl, diarylalkenyl, arylalkynyl,
`diarylalkynyl, diarylalkylaryl, heteroarylalkyl (wherein
`alkyl has at least 2 carbons), cycloalkyl, or
`cycloalkylalkyl (wherein alkyl has at least 2 carbons); all
`of the aforementioned Rl groups being optionally
`substituted through available carbon atoms with l, 2, or 3
`groups selected from halo, haloalkyl, alkyl, alkenyl,
`alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto,
`arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl,
`fluorenyl, heteroarylalkyl, hydroxy or oxo; or.
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`Rl is a group of the structure
`
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`20
`
`25
`
`R12 f ~
`>"'="
`Rll is a bond, alkylene, alkenylene or alkynylerie of
`up to 6 .carbon atoms, arylene (for example
`
`R13
`
`R14
`
`-©-
`
`or mixed arylene-alkylene (for example
`~
`-g-(CH:z)n-
`
`where n is 1 to 6;
`R12 is hydrogen, alkyl, alkenyl, aryl, heteroaryl,
`haloalkyl, arylalkyl, arylalkenyl, cycloalkyl, aryloxy,
`alkoxy, arylalkoxy, heteroarylalkyl or cycloalkylalkyl;
`Z is a bond, 0, S, N-alkyl, N-aryl, or alkylene or
`alkenylene of from 1 to 5 carbon atoms;
`R13, Rl4, R15, and R16 are independently hydrogen,
`alkyl, halo, haloalkyl, aryl, cycloalkyl, cyclohetero(:llkyl,
`alkenyl, alkynyl, hydroxy, alkoxy, nitro, amino, thio,
`alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, carboxy,
`aminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino,
`arylalkyl, heteroaryl, heteroarylalkyl, or aryloxy;
`or Rl is
`
`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 R18 being other than H;
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`or Rl is
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`R20
`
`-R19 - (
`R21
`
`wherein R19 is aryl or heteroaryl;
`R20 is aryl or heteroaryl;
`R21 is H, alkyl, aryl, alkylaryl, arylalkyl,
`aryloxy, arylalkoxy, heteroaryl, heteroarylaikyl,
`heteroarylalkoxy, cycloalkyl, cycloalkylalkyl or
`cycloalkylalkoxy;
`R2, R3, R4 are independently hydrogen, halo, aikyl, ·
`haloalkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyi,
`alkylmercapto, arylmercapto, cycl~alkyl, cycloal~lalkYl;
`heteroaryl, heteroarylalkyl, hydroxy or haloalkyl;
`Rs is alkyl of at least 2 carbons, alkenyl, alkynyl,
`aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl,
`cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, •
`cycloalkenyl, cycloalkenylalkyl, polycycloalkenyl,
`polycycloalkenylalkyl, heteroarylcarbonyl, all of the Rs
`and R6 substituents being optionally substituted through
`available carbon atoms with l, 2, or 3 groups selected from
`hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy,
`alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,
`cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl,
`arylalkyl, arylcycloalkyl, arylalkynyl, aryloxy,
`aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo,
`heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy,
`nitro, cyano, amino, substituted amino (wherein the amino
`includes 1 or 2 substituents which are alkyl, or aryl or
`any of the other aryl compounds mentioned in the
`definitions), thiol, alkylthio, arylthio,· heteroarylthiC>,
`arylthioalkyl, alkylcarbonyl, arylcarbonyl,
`arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl,
`alkynylaminocarb~nyl, alkylaminocarbonyl,
`alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,
`alkylcarbonylamino, arylcarbonylamino, arylsulfinyl,
`arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl,
`
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`arylsulfonylamino; with the proviso that when Rs is CH3 , R6
`is not H; and where Rs is phenyl, the phenyl preferably
`includes an ortho hydrophobic substituent such as alkyl,
`haloalkyl, aryl, aryloxy or arylalkyl;
`R6 is hydrogen or C1-C4 alkyl or C1-C4 alkenyl;
`R7 is alkyl, aryl or arylalkyl wherein alkyl or the
`alkyl portion is optionally substituted with oxo; and
`including pharmaceutically acceptable salts and
`anions thereof.
`In the formula I compounds, where X is CH2 and R2
`R3 and R4 are each H, Rl will be other than 3,3-
`diphenylpropyl.
`In the formula III compounds, where one of R2, R3
`and R4 is 6-fluoro, and the others are H, R7 will be other
`than 4-0-methoxyphenyl.
`U.S. Application Serial No. 472,067, filed June ·5,
`1995 (file DC2le) discloses compounds of the structure
`R2
`0
`
`,
`
`n'~No-()-R'
`~x·
`R4
`
`5
`
`10
`
`15
`
`20
`
`25
`
`or
`
`or
`
`or
`
`or
`
`0:2
`R3·!-~ .-0
`
`0
`
`x
`
`--~
`,
`R4
`
`~1
`
`N
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`0
`II
`where Q is -c-
`
`II
`
`0
`or -s-
`11
`0
`
`X is: CHR8, - C-
`II
`0
`
`-CH- CH- or
`• I
`I
`R9
`R10
`
`-C= C-;
`I
`I
`R9 R10
`
`5 Rs, R9 and RlO are independently hydrogen, alkyl, alkenyl,
`alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
`cycloalkyl, or cycloalkylalkyl;
`
`JO
`
`JS
`
`20
`
`25
`
`Y is -(CB2>m- or -fi-
`0
`wherein m is 2 or 3;
`Rl is alkyl, alkenyl, alkynyl, aryl, heteroaryl,
`arylalkyl wherein alkyl has at least 2 carbons,
`diarylalkyl, arylalkenyl, diarylalkenyl, arylalkynyl,,
`diarylalkynyl, diarylalkylaryl, heteroarylalkyl wherein
`alkyl has at least 2 carbons, cycloalkyl, or
`cycloalkylalkyl wherein alkyl has at least 2 carbons, all
`optionally substituted through available carbon atoms with
`1, 2, 3 or 4 groups selected from halo, haloalkyl, alkyl,
`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
`
`or
`
`or
`
`R12-z2 r ~
`R1i<- ~R14
`
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`or
`
`; or
`Rl is an indenyl-type group of the structure
`
`- R11-z1
`
`R12_z2 X
`(CH2 a
`
`R16a
`
`R1&a
`
`or
`
`R13
`
`R14
`
`·z
`
`_ R11_ z1
`
`or
`
`R -z
`12
`2
`
`168
`
`R
`
`R1sa
`
`.6
`
`5
`
`(a= 2,3 or 4)
`
`RS"
`
`- R11_ z
`R -z
`12
`2
`R16a
`
`168
`
`R
`
`(CH2)a
`
`f
`
`R13
`
`R14
`
`or
`
`-R11_z1
`
`R12_ z2
`
`R16a
`
`10
`
`15
`
`~
`
`H
`
`R1sa
`
`zl and z2 are the same or different and are.
`independently a bond, 0, S,
`
`-c-11
`0
`
`'
`
`'
`
`H
`s
`S
`-N--C- '
`-Nu....c-
`or -~-
`" 0
`u
`( ")
`n
`u
`I
`o
`OH
`02
`alkyl O
`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
`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 that
`
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`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`(1) when Ri2 is H, aryloxy, alkoxy or arylalkoxy,
`-c-
`-NH-C-
`, -N--C-
`u
`u
`I
`11
`alkyl 0
`or a bond and
`O
`then z2 is
`O
`(2) when z2 is a bond, R12 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, arylsulfonyl,
`alkyl thio, aryl thio, aminocarbonyl, alkylcarbonyloxy,
`arylcarbonylamino, alkylcarbonylamino, arylalkyl,
`heteroaryl, heteroarylalkyl or aryloxy;
`RlSa and R16a are independently hydrogen, alkyl,
`halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl,
`alkenyl, alkynyl, alkoxy, alkyfsulfonyl, arylsulfonyl,
`alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy,
`arylcarbonylamino, alkylcarbonylamino, arylalkyl,
`heteroaryl, heteroarylalkyl, or aryloxy;
`or Rl is a group o.f the structure
`
`R17
`
`-(CH2)p-<
`RlB
`
`wherein p is 1 to 8 and R17 and R18 are each independently
`H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl,
`heteroarylalkyl, cycloalkyl or cycloalkylalkyl at least one
`of R17 and R18 being other than H;
`or Rl is a group of the structure
`
`R20
`
`-Rte--<
`ff21
`
`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;
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`5
`
`10
`
`15
`
`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, aiyl,
`alkoxy, aryloxy, arylalkoxy, heteroaryl, arylalkyl,
`heteroarylalkyl, cycloalkyl, cycloalkylalkyl,
`polycycloalkyl, polycycloalkyl~lkyl, cycloalkenyl,·
`cycloheteroalkyl, heteroaryloxy, cycloalkenylalkyl,
`polycycloalkenyl, polycycloalkenylalkyl,
`heteroarylcarbonyl, amino, alkylarnino, arylamino,
`heteroarylamino, cycloalkyloxy, cycloalkylamino, all
`optionally substituted through available carbon atoms with
`1, 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, aryloxy,
`aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo,
`20 heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy,
`nitro, cyano, amino, substituted amino, thiol, alkylthio,
`arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl,
`arylcarbonyl, arylarninocarbonyl, alkoxycarbonyl,
`aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl,
`alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,
`alkylcarbonylamino, arylcarbonylamino, arylsulfinyl,
`arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl,
`arylsulfonylamino, heteroarylcarbonylamino,
`heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl,
`alkylsulfinyl;
`R6 is hydrogen or C1-C4 alkyl or C1-C4 alkenyl; all
`
`25
`
`30
`
`optionally substituted with 1, 2, 3 or 4 groups which may
`independe~tly be any of the substituents listed in the
`definition of Rs set out above;
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`R7 is alkyl, aryl or arylalkyl wherein alkyl by
`itsel~ or as part of arylalkyl is optionally substituted
`with oxo ( ~ ) ;
`
`5
`
`10
`
`15
`
`20
`
`25
`
`and
`
`are the same or different and are independently selected
`from heteroaryl
`containing 5- or 6-ring members; and
`0
`
`µ,-~ 1 V R
`
`thereof; and
`N-oxides
`pharmaceutically acceptable salts thereof; with
`the provisos that where in the first formula X is CH2, and
`R2, R3 and R4 are each H, then Rl will be other than 3,3-
`diphenylpropyl, and in the fifth fonnula, where one of R2,
`R3 and R4 is 6-fluoro, and the others are H, R7 will be
`other than 4-(2-methoxyphenyl).
`U.S. application Serial No. 548,811, filed January
`11, 1996 (file DC2lh), discloses compounds having the
`structure
`
`including the piperidine N-oxide thereof or a
`pharmaceutically acceptable salt thereof, wherein Z is a
`bond, O or S;
`xl and x2 are independently selected from H or halo;
`x is an integer from 2 to 6;
`RS is heteroaryl, aryl, heterocycloalkyl or
`cycloalkyl, each RS group being optionally substituted with
`1, 2, 3 or 4 substituents which may be the same or
`different.
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`U.S. Provisional Application No. 60/017,253, filed
`May 10, 1996 (file HX82*) discloses compounds which are
`inhibitors of MTP and have the structure
`
`l:
`
`or
`
`5
`
`IO
`
`:r:r
`
`R5/°'N--n
`~6 ~N-R1
`w
`where W is H, H or O; and X, Q, Rl, R2, R3, R4, Rs and;R6
`are essentially as defined in U.S. Application Serial No.
`472, 067 (file DC2le) .
`U.S. Provisional Application No. 60/017,254, filed
`May 10, 1996 {file HX84*) discloses compounds which are
`inhibitors of MTP and have the structure
`
`J:
`
`15
`
`l: :r
`
`or
`
`20
`
`25
`
`where n is O or 1 and X, Q, Rl, R2, R3, R4, Rs and R6 are
`essentially as defined in U.S. Application Serial No.
`472,067 (file DC2le).
`U.S. Provisional Application No. 60/017,224 (file
`HX79a*) filed May 7, 1996, discloses compounds which are
`inhibitors of MTP and have the structure
`
`or
`
`or
`
`J:B
`
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`
`..
`including pharmaceutically acceptable salts thereof,
`wherein q is 0, 1 or 2;
`A is
`(1) a bond;
`(2) -0- ; or
`
`5
`
`10
`
`-N -
`I
`5
`(3)
`R
`where Rs is H or lower alkyl or Rs together with R2 forms a
`carbocyclic or heterocyclic ring system containing 4 to 8
`members in the ring.
`B is a fluorenyl-type group of the structure:
`
`R~./:. .._,
`n4'
`I j
`~
`x ~
`R4
`
`Het
`
`3'
`R
`
`or
`
`(the above B is also referred to as a
`fluorenyl- type ring or moiety); or
`
`15
`
`B is an indenyl-type group of the structure
`
`or
`
`or
`
`(a= 2,3 or 4)
`R3
`
`R3b
`
`(the above B is also referred to as
`an indenyl-type ring or moiety);
`
`R3a
`
`Rx is H, alkyl or aryl;
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`R1 is alkyl, alkenyl, alkynyl, alkoxyl, (alkyl or
`aryl)3Si (where each alkyl or aryl group is independent),
`
`5
`
`10
`
`15
`
`cycloalkyl, cycloalkenyl, substituted alkylamino,
`substituted arylalkylamino, aryl, arylalkyl, arylamino,
`aryloxy, heteroaryl, heteroarylamino, heteroaryloxy,
`arylsulfonylamino, heteroarylsulfonylamino, arylthio,
`arylsulfinyl, arylsulfonyl, alkylthio, alkylsulfinyl,
`alkylsulfonyl, heteroarylthio, heteroarylsulfinyl,
`heteroarylsulfonyl, -PO(Rl3) (Rl4),
`(where Rl3 and Rl4 are
`independently alkyl, aryl, alkoxy, aryloxy, heteroaryl,
`heteroarylalkyl, heteroaryloxy, heteroarylalkoxy,
`cycloheteroalkyl, cycloheteroalkylalkyl, cycloheteroalkoxy,
`or cycloheteroalkylalkoxy); Rl can also be aminocarbonyl
`(where the amino may optionally be sllbstituted with one or
`two aryl, alkyl or heteroaryl groups); cyano, 1,1-(alkoxyl
`or arylox:y)2alkyl (where the two aryl or alkyl substituents
`can be independently defined, or linked to one another to
`form a ring, such as l,3-dioxane or 1,3-dioxolane,
`connected to Ll (or L2 in the case of R2) at the 2-
`20 position); 1,3-dioxane or 1,3-dioxolane connected to Ll (or
`L2 in the case of R2) at the 4-position.
`The Rl group may have from one to four substituents,
`which can be any of the R3 groups or Rl groups, and certain
`preferred Rl substituents as disclosed.
`R2 is the same or different from Rl and is
`independently any of the groups set out for Rl, H,
`polyhaloalkyl (such as CF3CH2, CF3CF2CH2 or CF3) or
`cycloheteroalkyl, and may be substituted with one to four
`of any of the groups defined for R3, or any of. the
`subs ti tuents preferred for Rl ·
`Ll is a linking group containing from 1 to 10
`carbons in a linear chain (including alkylene, alkenylene
`or alkynylene), which may contain, within the linking chain
`any of the following: one or two alkenes, one or two
`alkynes, an oxygen, an amino group optionally substituted
`with alkyl or aryl, an oxo group; and may be substituted
`with one to five alkyl or halo groups (preferably F).
`
`25
`
`30
`
`35
`
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`L2 may be the same or different from Ll and may
`independently be any of the Ll groups set out above or a
`singe bond.
`R3, R3', R4 and R4' may be the same or different and
`are independently selected from H, halogen, CF3, haloalkyl,
`hydroxy, alkoxy1 alkyl, aryl, alkenyl, alkenyloxy, alkynyl,
`alkynyloxy, alkanoyl, nitro, amino, thiol, alkylthio,
`alkylsulfinyl, alkylsulfonyl, carboxy, alkoxycarbonyl~
`aminocarbonyl, alkylcarbonyloXy, alkylcarbonylamino,
`cycloheteroalkyl, cycloheteroalkylalkyl, cyano, Ar, Ar(cid:173)
`alkyl, Aro, Ar-amino, Ar-thio, Ar-sulfinyl, Ar-sulfonyl,
`Ar-carbonyl, Ar-carbonyloxy or Ar-carbonylamino, wherein Ar
`is aryl or heteroaryl and Ar may optionally include l, 2 or
`3 additional rings fused to Ar;
`R3a and R3b are the same or different and are
`independently any of the R3 groups except hydroxy, nitro,
`amino or thio;
`
`5
`
`IO
`
`15
`
`and
`
`20
`
`25
`
`are the same or different and independently represent a 5
`or 6 membered heteroaryl ring which may contain l, 2, 3 or
`4 heteroatoms in the ring which are independently N, S or
`O; and including N-oxides.
`X (in the fluorenyl type ring) is a bond, or is one
`of the following groups:
`
`(1) - s -
`1
`(O)n•
`-o-
`
`(2)
`
`(3) -N -
`I
`R6
`
`30
`
`(4) - c -, '
`
`R7
`
`R8
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`(5) - · c
`Rg
`
`, '
`
`/
`RlOR9'
`
`~
`.
`R10•
`
`(6) - c= c -
`I
`I
`R10•
`R9•
`
`(7) -,c,---Y-
`R9
`RlO
`
`wherein
`y is 0, N-R6 or S;
`n' is 0, 1 or 2;
`R6 is H,
`lower alkyl, aryl, -C(O)-Rll or
`-C (0) -o-Rll;
`R7 and RB are the same or different and are
`independently H, alkyl, aryl, halogen, -o-R12, or
`R7 and RB together can be· oxygen to form a ketone;
`R9, RlO, R9' and RlO' are the same or different·and
`are independently H, lower alkyl, aryl or -o-Rll;
`R9" and Rio· are the same or different and are
`independently H,
`lower alkyl, aryl, halogen or
`-O-Rll;
`
`Rll is alky or aryl;
`R12 is H, alkyl or aryl.
`The following provisos apply to formula I compounds:
`(a) when Rl is unsubstituted alkyl or unsubstituted
`arylalkyl, Ll cannot contain amino;
`(b) when Rl is alkyl, Ll cannot contain amino and
`oxo in adjacent positions (to form an amido group) ;
`(c) when R2L2A- is H2N~, RlLl cannot contain amino;
`
`(d) when Rl is cyano, Ll must have more than 2
`carbons;
`(e) RlLl must contain at least 3 carbons.
`With respect to compounds of the invention IA and
`IB, R2L2 cannot have an 0 or N atom directly attached to
`S=(O)q or CRX(OH), and for IA, R2L2 cannot be H.
`
`5
`
`IO
`
`15
`
`20
`
`25
`
`30
`
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`With respect to compounds of the invention I, IA and
`IB, where Rl is cycloheteroalkyl, Rl is exclusive of