·~
`
`PCT···
`INTERNATIONAL APPLICATION PUBLISHED UNDER TIIE PATENT COOPERATION TREATY (PCT')
`
`WORLD INTELl..ECTIJAL PROPERTY ORGANIZATION
`International Bureau
`
`(51} International Patent Classlllcatlon 6 :
`A61K 31/445, 31/425, 31/22
`
`Al
`
`(11) International Publication Number:
`
`WO 98131367
`
`(43) International Publication Date:
`
`23 July 1998 (23.o7.98)
`
`(21) International Application Number:
`
`PCT/US98/00619
`
`(22} International Filing Date:
`
`13 January 1998 (13.01.98)
`
`(30) Priority Data:
`60/036,183
`
`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,.BO, BR, BY,
`CA, CH, CN, CZ. DE, DK, EE, ES, Fl, GB, OE; HU, ll.,
`JS, JP, KB. KG, KP, KR, KZ, LK; LR, LS. LT, LU, LV,
`MD, MO, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU,
`SD, SE, SO, SI, SK, TJ, TM, TR, TI, UA; UG, UZ, VN,
`ARIPO patent (GH, GM, ~ LS, MW, SD, SZ.· UG, ZW),
`Eurasian patent (AM, AZ, BY, KG, Kz, MD, RU, TJ, TM),
`European paterit (AT, BE, CH, DB, DK, ES, Fl, FR, GB,
`GR, IE, IT, LU, MC, NL, PT, SE), OAPI patent (BF, . .BJ,
`CF, CG, Cl, CM, GA, GN, ML, MR, NE, SN, TD, TG).
`
`(72) Inventors: GREGG, Richard, E.; 7 Linden Lane, Pennington, Published
`NJ 08534 (US). WHITERAU, John, R., ·n; 190 Rugby
`With international search report.
`Drive, Langhorne, PA 19047 (US).
`Before the expiration of the time "limit for amending the
`claims and to be republished in the evenl of the receipt of
`amendments.
`
`(74) Agents: RODNEY, Burton et al.; Bristol-Myers Squibb Com~
`pany, P.O. Box 4000, Princeton, NJ 08543-4000 (US).
`
`(54) Title: METiiOD FOR TREATING ACID LIPASE DEFICIENCY DISEASES WITH AN MTP INHIBITOR AND CHOLESTEROL
`LOWERING DRUGS
`
`(57) Abstract
`
`A method is provided for inhibiting or treating diseases associated with acid lipase deficiency by administering to a patient an MTP
`inhibitor, alone or optionally, in combination with another cholesterol lowering drug, such as pravastatin.
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`Codes used 10 identify Slates party to the PCT on the front pages of pamphlets publishing international applications under lhe PCT.
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`DE
`BF
`BG
`BJ
`DR
`UY
`CA
`Cl'
`cc
`CH
`Cl
`CM
`CN
`cu
`CZ
`DE
`DK
`EE
`
`Albanill
`Armenia
`AU!lria
`Australia
`A=baijan
`Bosnia and Hcrzc:govina
`Barbados
`Belgium
`Burkina Paao
`Bulgaria
`Benin
`Bruil
`llelaTUS
`Canada
`Central African Republic
`Congo
`Swilzerland
`COie d' lvoire
`Cameroon
`China
`Cuba
`Czech Republic
`Gcnnan:y
`Denmark
`Estonia
`
`ES
`F1
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Spain
`Finland
`l'nna:
`Osbon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hung&I')'
`Ireland
`Israel
`la: land
`llaly
`Japan
`Kenya
`Kyrgyutan
`Democ:ralic People• a
`Republic or Korea
`Republic or Komo
`Kazabtan
`Saini Lucia
`Liecluenstcin
`Sri Lanka
`Uberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`Pr
`RO
`RU
`SD
`SE
`SG
`
`Lesotho
`Lilhuanio
`Luxcmbowg
`Lal via
`Monaco
`Republic or Moldova
`Madllll8SC&r
`The former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Maori1ania
`Malawi
`Mexia>
`Niger
`Nethcrlanda
`Norway
`New Zealand
`Poland
`Ponugal
`Romani.a
`Rusaian Federation
`Sudan
`Sweden
`Singapore
`
`SI
`SJt
`SN
`sz
`TD
`TG
`TJ
`TM
`TR
`1T
`UA
`UC
`us
`uz
`VN
`YU
`zw
`
`Slovc1ila
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajitislan
`1'1rkmcnis1an
`Turkey
`Trinidad and Tobago
`Ulnainc
`Uganda
`United Slalel of America
`Uzbekistan
`Viet Nam
`Yugmlavia
`Zimbabwe
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`PCT/US98/00619
`
`ME'IlfOD FOR TREATING ACID LIPASE DEFICIENCY DISEASES wrm AN MTP INHIBITOR AND CHOLESTEROL
`LOWERING DRUGS
`
`s
`
`10
`
`Field of the Invention
`The preserit invention related to a method for ·
`inhibiting or treating diseases associated with acid.lipase
`deficiency, including Wolman disease and/or cholesteryl
`ester storage disease, by administering an MTP inhibitor
`alone or in combination with another cholesterol lowering
`drug, such as pravastatin.
`
`IS
`
`20
`
`Background of the Invention
`Wolman disease and cholesteryl ester storage disease
`are characterized by a deficiency in activity of lys~mal
`acid lipase which results in massive accumulation of
`cholesteryl esters and triglycerides in most tissues·of·the
`body. Cholesteryl esters and triglycerides are derived
`from plasma lipoproteins taken up by the cells and are
`substrates for acid lipase. Acid lipase is responsible for
`the hydrolysis of cholesteryl esters and triglycerides· in
`the lysosomes.
`If plasma cholesterol levels are lowered
`sufficiently, then cholesteryl ester and triglyceride
`accumulation in the lysosomes and the consequences of the
`accumulation could be minimized.
`Wolman disease is the more severe of the two
`diseases and is almost always fatal before the age of l
`30 year.
`In contrast, cholesteryl ester storage disease may
`go undetected until adulthood by which time lipid
`deposition is widespread. Hyperbetalipoproteinemia is
`common in cholesteryl ester storage disease, and premature
`atherosclerosis may be severe.
`To date, there has been no specific therapy for acid
`lipase deficiency other than attempts at suppression of
`cholesterol synthesis and apolipoprotein B production by
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`JO
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`15
`
`3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors
`in combination with cholestyramine treatment and a diet
`excluding foods rich-in cholesterol and triglycerides. The
`above apparently provided improvement in only one or two
`cases of cholesteryl ester storage disease. Thus, for the:
`most part, Wolman disease and cholesteryl ester stofage
`disease have been untreatable.
`See Scriver, C.R. et al "The Metabolic and Molecular
`.Bases of Inherited Disease", Vol. II (1995), Chap. 82,
`"Acid Lipase Deficiency: Wolman Disease and Cholesteryl
`Ester Storage Disease•, pp. 2563-2587.
`Until now, there have not been any therapeutic
`agents available which could lower plasma cholesterol
`levels sufficiently to minimize cholesteryl ester and
`triglyceride accumulation in the lysosomes.
`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 Jj!, 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 microsomal triglyceride transfer protein from bovine
`liver has been isolated and extensively characterized (1).
`This has led to the cloning of cDNA expr~ssing the protein
`from several species, including humans (2). MTP is
`composed of two subunits. The small subunit is the
`previously characterized multifunctional protein, protein
`30 disulfide isomerase. This is supported by biochemical
`analysis of the protein (3) as well as co-expression
`studies performed in insect Sf9 cells using the baculovirus
`expression system. Expression of soluble active MTP
`requires the co-expression of PDI and the unique large
`subunit of MTP (4) .
`
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`l:
`Wetterau, J.R. and Zilversinit, D.B.
`Phys. Lipids 38, 205-222.
`Wetterau, J.R., et al, (1990} J. Biol. Chem .. 265,
`9800-9807.
`Wetterau, J.R., et al, (1991} Biochemistry 30, 4406-
`
`(1985} Chem.
`
`4412.
`
`Atzel, A;, and Wetterau, J.R.
`32, 10444-10450.
`Atzel, A., and Wetterau, J.R. (1994) Biochemistry
`33, 15382-15388.
`Jamil, H., et al, (1995) J. Biol. Chem. 270, 6549-
`
`(1993.) Biochemistry
`
`6554.
`
`5
`
`10
`
`2.
`
`15
`
`Sharp, D. et al, (1993) Nature 365, 65-69.
`Lin, M.C.M., et al, J. Biol. Chem. 269, 29138-29145.
`Nakamuta, M., et al, (1996) Genomics 33, 313~3l6.
`
`Wetterau, J.R., et al, (1990) J. Biol. Chem. 265,
`3.
`9800-9807.
`Wetterau, J.R., et al, (1991} Biochemistry 30, 9728-
`
`9735.
`
`4.
`14285.
`
`Ricci, B., et al, (1995) J. Biol. Chem. 270, 14281-
`
`20
`
`25
`
`30
`
`.In yitro, MTP catalyzes the transport of lipid
`molecules between phospholipid memb~anes. 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. Biophys. Acta .e.22., 610-7 (1986). The ability of
`35 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
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`the endoplasmic reticulum (ER) membrane to nascent
`lipoprotein particles within the lumen of the ER.
`Abetalipoproteinemia is an autosomal recessive
`disease characterized by a virtual absence of plasma
`lipoproteins which contain apolipoprotein B (apoB). Kane &
`Havel in The Metabolic Ba.sis of Inherited 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.
`10 These abnormalities are the result of a genetic defeqt 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 had not
`been previously detennined.
`In subjects examined,
`triglyceride, phospholipid, and cholesterol synthesis
`appear normal. At autopsy, subjects are free of
`atherosclerosis. Schaefer et al., Clin .. Chem. 34, B9-12
`(1988). A link between the apoB gene and
`abetalipoproteinemia has been excluded in several families.
`20 Talmud et al., J Clin Invest. 82, 1803-6 (1988) and Huang
`et al, Am· J. Hum Genet
`.4..2,; 1141-8 (1990).
`Recent reports (5) demonstrate that the defect
`causing abetalipoproteinemia is in the MTP gene, and as a
`result, the MTP protein. When examined, individuals with
`abetalipoproteinernia 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 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.
`
`25
`
`30
`
`5.
`
`35
`
`Wetterau, J.R., et al, (1992) Science 258, 999-1001.
`Sharp, D., et al, (1993) Nature 365, 65-69.
`Ricci, B., et al, (1995) J. Biol. Chem. 270, 14281-
`
`14285.
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`
`Shoulders, C.C., et al, (1993) Hum. Mol. Genetics
`2, 2109-2116.
`Narcisi, T.M.E., et al, (1995) Am. J. Hum. Genet.
`57, 1298-1310.
`Rehberg, E. F. , et al, J. Biol . Chem (in press) ..
`
`5
`
`10
`
`20
`
`Canadian Patent Application No. 2,091,102 publisped
`March 2, 1994 (corresponding to U.S. application Sefrial No.
`117,362, filed September 3, 1993 (file DC2lb)) which is
`incorporated herein by reference), reports MTP inhibitors
`which also block apoB containing lipoprotein secretion 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
`15 Yi.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 pancreatitis
`is disclosed in WO 96/26205, published August 29, 1996,
`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
`25 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,
`May 10, 1996 (file HX84*) and U.S. provisional application
`No. 60/028,216, filed October l, 1996 (file HX86*).
`All of the above U.S. applications are incorporated
`herein by reference.
`
`30
`
`35
`
`Description of the Invention
`In accordance with the present invention, a method
`is provided for inhibiting or treating a disease associated
`with acid lipase deficiency, including Wolman disease
`and/or cholesteryl ester storage disease (CESD), in
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`10
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`15
`
`mammalian species, wherein a therapeutically effective
`amount of a microsomal triglyceride transfer protein (MTP)
`inhibitor is administered to a patient in need of
`treatment.
`The MTP inhibitor may optionally be administered in
`combination with another cholesterol .lowering drug or
`delipidatirig agerit.
`The MTP inhibitor alone or optionally in :combination
`with another cholesterol lowering drug is administered
`systemically, such as orally or parenterally or
`transdermally, to patients in need of treatment.
`In accordance with the present invention, the MTP
`inhibitor lowers plasma cholestero_l (LDL-cholesterol) to at
`least about 50% of normal LPL blood level, preferably down
`to less than about 25% of normal, and most preferably down·
`to less than about 15% of normal, and lowers trigly~~~ides
`to at least about 50% of normal triglyceride blood level,
`and preferably down to about 25% or less of normal, and.
`thereby minimizes cholesteryl ester and triglyceride
`accumulation in the lysosomes .
`The terms "another cholesterol lowering drug or
`agent" or "another delipidating drug" will be employed
`interchangeably herein.
`MTP inhibitors to be employed in the methods of the
`invention include MTP inhibitors disclosed in Canadian
`Patent Application No. 2,091,102 described hereinbefore
`(corresponding to U.S. Application Serial No. 117,362), WO
`92/26205 published August 29, 1996, U.S. Application Serial
`No. 472,067, filed June 6, 1995 (file DC2le), U.S.
`30 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
`35 May 10, 1996 (file HX84*), and U.S: provisional app~ication
`No. 60/028,216, filed October l, 1996 (file HX86*).
`
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`Preferred are each of the preferred MTP inhibitors·
`disclosed in each of the above applications.
`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) ·a.re
`piperidine ·compotinds of the structure
`R2
`0
`
`W·~N-CN-R1
`~x·
`R4
`
`,
`
`or
`
`or
`
`or
`
`or
`
`0
`"
`where Q Is -c- or
`
`ti
`
`0
`-S-
`11
`0
`
`Xis: CHR8, -c- -CH-CH- or
`• I
`I
`0
`Re
`R10
`
`II
`
`-C= C- ·
`I
`I
`'
`Rs Rto
`
`Ra, R9 and RlO are independently hydrogen, alkyl, alkenyl,
`alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
`cycloalkyl, or cycloaikylalkyl;
`
`Y is - (CB3 )m- or -~-
`0
`
`- 7 -
`
`5
`
`10
`
`15
`
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`
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`5
`
`10
`
`15
`
`wherein mis 2 or 3;
`Rl is alkyl, alke_nyl, 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 wherei~ 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, eye loalkylalkyl, heteroaryl ·,
`fluorenyl, heteroarylalkyl, hydroxy or oxo;
`or Rl is a fluorenyl-type group of the structure
`
`-.
`
`- R'1-z1
`
`or
`
`- R11-z1
`
`or
`
`~
`, ; . ~ 14
`R
`R
`
`~
`
`; or
`
`or
`
`_ R11_z1
`
`R12_ z2
`
`20
`
`R
`Rl is an indenyl-type group of the structure
`
`R13
`
`R14
`
`»'-:-...~
`
`or
`
`(a= 2,3 or4}
`
`-R11-z1
`R -z
`12
`2
`
`E
`
`- 8 -
`
`or
`
`R168
`
`. R15a
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`"~"
`
`R168
`
`(CH2}a
`
`- R11_z
`R -z
`12
`2
`Rtsa
`
`M
`
`or
`
`-R11-z1
`
`R13
`
`R14
`
`R1sa
`
`H
`
`R15a
`
`zl and z2 are the same or different and are
`independently a bond, 0, S,
`
`5
`
`IO
`
`15
`
`20
`
`25
`
`30
`
`, .
`
`s II
`0
`
`-NH-c-
`11
`o
`
`, -N - -c - ,
`I
`11
`alkyl 0
`
`or
`
`'.
`
`H
`-c-
`-~-
`" 0
`OH
`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, cyclo(cid:173)
`alkyl, aryloxy, alkoxy, arylalkoxy or cycloalkylalkyl, with
`the provisos that preferably
`(1) when R12 is H, aryloxy, alkoxy or arylalkoxy,
`-NH-C-
`, -N -C -
`-c -
`l
`I
`11
`II
`11
`or a bond and
`o
`alkyl O
`o
`then z2 is
`(2) when z2 is a bond, R12 cannot be heteroaryl or
`heteroarylalkyl;
`Z is a bond, 0, S, N-alkyl, N-aryl, or alkylene or
`alkenylene from 1 to 5 carbon atoms; R13, R14, R15, and R16
`are independently hydrogen, alkyl, halo, haloalkyl, aryl,
`cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, hydroxy,
`alkoxy, nitro, amino, thio, alkylsulfonyl, arylsulfonyl;
`alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy,
`arylcarbonylamino, alkylcarbonylamino, arylalkyl,
`heteroaryl, heteroarylalkyl or aryloxy;
`R15a and R16a are independently hydrogen, alkyl,
`halo, haloalkyl, aryl, cycloalkyl,_cycloheteroalkyl,
`alkenyl, alkynyl, alkoxy, alkylsulfonyl, arylsulfonyi,
`alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy,
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`arylcarbonylamino, alkylcarbonylamin6, arylalkyl,
`heteroaryl, heteroarylalkyl, or aryloxy;
`or Rl is a group of the structure
`
`R17
`
`-(CB;i)p-<
`· R18
`
`wherein p is 1 to 8 and Rl7 and RlS are each independently
`H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl,
`heteroarylalkyl, cycloalkyl or cycloalkylalkyl at least: one
`of Rl7 and RlS being other than H;
`or Rl is a group of the structure
`
`5
`
`IO
`
`15
`
`20
`
`wherein Rl9 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,
`heteroarylalkyl, cycloalkyl, cycloalkylalkyl,
`polycycloalkyl, polycycloalkylalkyl, cycloalkenyl,
`cycloheteroalkyl, heteroaryloxy, cycloalkenylalkyl,
`polycycloalkenyl, polycycloalkenylalkyl,
`heteroarylcarbonyl, amino, alkylamino, arylamino,
`30 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, alk~nyl, alkynyl,
`cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cyclohetero-
`alkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl,
`
`25
`
`35
`
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`
`5
`
`10
`
`15
`
`arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl,
`acylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl", .
`heteroarylalkenyl, heteroaryloxy, hydroxy, nitre, c}rano,
`amino, substituted amino, thiol, alkylthio, arylthio,
`heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl,
`arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl,
`alkynylaminocarbonyl, alkylaminocarbonyl,
`alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonylo:Xy,
`a;Lkylcarbonylamino, arylcarbonylamino, arylsulfinyl,·
`arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl,
`arylsulfonylamino, heteroarylcarbonylamino,
`heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl,
`alkylsulfinyl;
`R6 is hydrogen. or C1-C4 alkyl or C1-C4 alkenyl; all
`optionally substituted with·1, 2, 3 or 4 groups which may
`independently be any of the substituents listed in the
`definition of Rs set out above;
`R7 is alkyl, aryl or arylalkyl wherein alkyl by
`itself or as part of arylalkyl is optionally substituted
`
`20
`
`with oxo ( W ) ;
`
`./:8~
`
`Het
`
`I
`
`and
`
`25
`
`30
`
`are the same or different and are independently selected
`from heteroaryl
`containing 5- or 6-ring members; and
`0
`~i1
`thereof; and
`
`N-oxides
`pharmaceutically acceptable salts thereof; with
`the provisos that preferably where in the first fonnula X
`is CH2, and R2, R3 and R4 are each H,
`then Rl will be other
`
`"-./ R
`
`than 3,3-diphenylpropyl, and preferably 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).
`
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`
`The MTP inhibitors disclosed in U.S. application
`Serial No. S48,811 filed January 11, 1996 (file DC2lh),
`have the structure
`
`x:a
`including the piperidine N-oxide thereof or a
`pharmaceutically acceptable salt thereof, wherein Z is a
`bond, 0 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
`l, 2, 3 or 4 substituents which may be the same or
`different.
`The MTP inhibitors disclosed in U.S. provisional
`application No. 60/017,224, filed May 9, 1996 (file HX79a*)
`have the structure
`
`5
`
`10
`
`15
`
`20
`
`25
`
`or
`
`IA
`
`or
`
`IB
`including pharmaceutically acceptable salts thereof,
`wherein q is 0, 1 or 2;
`A is
`(1) a bond;
`; or
`(2) -0-
`
`(3)
`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.
`
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`
`B is a fluorenyl-type group of the structure.:
`
`./:
`
`......
`
`R~~1.n4' or
`~~v)l~)
`x
`
`~
`R
`
`~, 4
`R
`
`.A.
`
`.......
`
`R~n4' ~
`·1 .J
`.X ~4 R
`
`Het
`
`R3'
`
`or
`
`5
`
`(the above B Is also referred to as a
`fluorenyl- type ring or moiety); or
`
`B is an indenyl~type group of the structure
`
`3
`
`3'
`
`R,nR
`Hn3b
`
`R3a
`
`or
`
`or
`
`(a= 2,3 or4)
`R3
`
`(the above B Is also referred to as
`an indenyl-type ring or moiety);
`
`10
`
`15
`
`20
`
`Rx is H, alkyl or aryl;
`Rl is alkyl, alkenyl, alkynyl, alkoxyl, (alkyl or
`aryl)3Si (where each alkyl or aryl group .is independent),
`cycloalkyl, cycloalkenyl, substituted alkylamino,
`substituted arylalkylan\ino, aryl, arylalkyl, arylamino,
`aryloxy, heteroaryl, heteroarylamino, heteroaryloxy,
`arylsulfonylamino, heteroarylsulfonylamino, arylthio,
`arylsulfinyl, arylsulfonyl, alkylthio, alkylsulfinyl,
`alkylsulfonyl, heteroarylthio, heteroarylsulfinyl,
`heteroarylsulfonyl, -PO (R13) (Rl4), . (where R13 and R14 are
`independently alkyl, aryl, alkoxy, aryloxy, heteroaryl,
`heteroarylalkyl, heteroaryloxy, heteroarylalkoxy,
`
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`
`cycloheteroalkyl, cycloheteroalkylalkyl, cycloheteroalkoxy,
`or cycloheteroalkylalkoxy); Rl can also be aminocarbonyl·
`(where the amino may-optionally be substituted with one.or.
`two aryl, alkyl or heteroaryl groups); cyano, 1,1-(alkoxyl
`or aryloxy) 2a~kyl (where the two aryl or alkyl subs ti tuent·s
`can be independently defined, or linked to one another to
`form a ring, such as 1,3-dioxane or 1,3-dioxolane,
`connected to Ll (or L2 in the case of R2) at the 2-:
`.position); 1,3-dioxane or 1,3-dioxolane connected tp Ll (or
`L2 in the case of R2) at the 4-position.
`The Rl group may have from one to four subst'ituents,·
`which can be any of the R3 groups or Rl groups, and any of
`the preferred Rl substituents set .out below.
`Rl may be substituted with the following preferred
`substituents: alkylcarbonylamino, cycloalkylcarbonylamino,
`arylcarbonylamino, heteroarylcarbonylamino, alkoxycarbonyl(cid:173)
`amino, aryloxycarbonylamino, heteroaryloxylcarbonylamino,
`uriedo (where the uriedo nitrogens may be substituted with
`alkyl, aryl or heteroa.ryl) , heterocyclylcarbonylamino
`(where the heterocycle is connected to the carbonyl group
`via a nitrogen or carbon atom), alkylsulfonylamino,
`arylsulfonylamino, heteroarylsulfonylamino,
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`tc.20
`
`0
`
`N-
`.
`J
`
`21 -~
`R -1-
`h-
`,
`R22
`
`where J isz CHR2J, -c- -CH-CB- or -C=C- I
`' I
`I
`I
`I
`II
`~4 ~5
`~4~5
`0
`
`R23, R24 and R25 are independently hydrogen, alkyl, alkenyl,
`alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
`cycloalkyl, or cyclo.alkylalkyl;
`R20, R21, R22 are
`independently hydrogen, halo,
`alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl,
`alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl,
`heteroaryl, heteroarylalkyl, hydroxy or haloalkyl; and
`
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`
`5
`
`10
`
`these preferred substituents may either be directly
`attached to Rl, or attached via an alkylene chain at an
`open position.
`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
`suhstituents preferred for Rl·
`Ll is a linking group containing from 1 to 10.
`carbons in a linear. chain (including alkylene, alke~ylene
`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
`15 with alkyl or aryl, an oxo group; and may be substituted
`with one to five alkyl or halo groups (preferably F).
`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, alkoxy, alkyl, aryl, alkenyl, alkenyloxy, alkynyl,
`alkynyloxy, alkanoyl, nitro, amino, thiol, alkylthio,
`alkylsulfinyl, alkylsulfonyl, carboxy, alkoxycarbonyl,
`aminocarbonyl, alkylcarbonyloxy, alkylcarbonylarnino,
`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;
`
`20
`
`25
`
`30
`
`35
`
`and
`
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`
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`
`5
`
`10
`
`15
`
`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)
`
`(2)
`
`- s - .
`I
`(O)n•
`-o-
`
`(3) -N -
`I
`R&
`
`(4)
`
`(5)
`
`(6)
`
`(7) -,c,---y-
`R9
`RlO
`
`25
`
`20 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 {O) -O-Rll;
`R7 and Rs are the same or different and are
`independently H, alkyl, aryl, halogen, -O-R12, or
`R7 and Rs together can be oxygen to fonn 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;
`
`30
`
`Rll is alky or aryl;
`
`- 16 -
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`
`R12 is H, alkyl or aryl.
`The following provisos apply to formula I preferred
`compounds:
`(a) when Rl is unsubstituted alkyl or unsubsti t1,ited
`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 IA and IB, R2L2 cannot
`have an O or N atom directly attached to S=(O)q or CRX(QH),
`and for IA, R2L2 cannot be H.
`With respect to preferred compounds of fqrmula I~
`and IB, where Rl is cycloheteroalkyl, Rl is exclusi~e of 1-
`piperidinyl, 1-pyrrolidinyl, 1-azetidinyl or 1- (2-.oxo(cid:173)
`pyrrolidinyl) .
`The MTP inhibitors disclosed in U.S. provisional
`application No. 60/017,253, filed May 10, i996, (file
`HX82*) are pyrrolidine compounds and have the structure
`:I
`
`R3
`
`:I :I
`
`~·
`• i-· ~ ,N--D
`• ,,,,:; X
`R4
`
`N-R1
`
`W
`
`or
`
`RS/Q,~
`~R 1
`~6
`w
`
`0
`II
`whereQ is -c-
`
`0
`II
`or -s-
`11
`0
`
`W is H,H or O;
`
`Xis: CHR8, - C-
`11
`0
`
`-Ctt- CH-
`• I
`I
`R9
`R10
`
`or
`
`-C= C-;
`I
`I
`Re R10
`
`- 17 -
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
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`
`Ra, R9 and RlO are independently hydrogen, alkyl, alkenyl,
`alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
`cycloalkyl, or cycloalkylalkyl;
`Rl is alkyl, alkenyl, alkynyl, aryl, heteroaryl,
`arylalkyl (wherein alkyl preferably has at least 2 carbons,
`more preferably at least 1 carbons), diarylalkyl,
`arylalkenyl, diarylalkenyl, arylalkynyl, diarylalkyhyl,
`diarylalkylaryl, heteroarylalkyl (wherein alkyl .preferably
`has at least 2 carbons, more preferably at least 3
`carbons), cycloalkyl, or cycloalkylalkyl (wherein alk}rl
`preferably has at least 2 carbons, more preferably at least
`3 carbons); all of the aforementioned Rl groups being
`optionally substituted through available carbon atoms with
`l, 2, 3 or 4 groups selected from halo, haloalkyl, alkyl,
`alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmerc~pto,
`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
`~
`
`5
`
`10
`
`15
`
`20
`
`or
`
`-R11-z1
`
`R12_z2
`
`R13
`
`; or
`
`25
`
`~
`Rl is an indenyl-type group of the structure
`
`- 18 -
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`
`or
`
`E
`
`n12_z2 X
`R1sa (CH2 a
`
`g
`
`(a= 2,3 or4)
`
`of
`
`or
`
`zl and z2 are the same or different and are
`independently a bond, 0, S,
`
`5
`
`n15a
`
`0
`
`J
`
`II
`
`-N--C- I
`I
`II
`alkyl O
`
`-c-11
`0
`
`or
`
`H
`-~-
`OH
`
`s
`( ~} I -NH-C-
`" 0
`0
`2
`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 (for example
`
`10
`
`-©---
`
`or mixed arylene-alkylene (for example
`~ -v(CH2>n-
`
`1s where n is 1 to 6 ;
`R12 is hydrogen, alkyl, alkenyl, aryl, haloalkyl,
`trihaloalkyl, trihaloalkylalkyl, heteroaryl,
`heteroarylalkyl, arylalkyl, arylalkenyl, cycloalkyl,
`aryloxy, alkoxy, arylalkoxy or cycloalkylalkyl; with the
`20 provisos that (1) when R12 is H, aryloxy, alkoxy or
`-NH-c-
`• -N -c -
`-c -
`..
`I.
`u
`u
`alkyl 0
`o
`O
`
`or a
`
`arylalkoxy, then z2 is
`bond;
`
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`
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`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`.
`
`and (2) when z2 is a bond, R12 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;
`R13, R14, RlS, and Rl6 are independently hydrogen;
`.
`.
`alkyl, halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl,
`alkenyl, aikynyl, hyd