`INTERNATIONAL APPLICATION PUBLISHED UNDER TIIB PATENT COOPERATION TREATY (PCI')
`WO 98131225
`
`WORLD INTELLECJlJAL PROPERTY ORGANIU l:rON
`International Bureau
`
`(Sl) International Patent Classlftcatlon 6 :
`AOIN 43/40, A61K 31/445
`
`Al
`
`(11) International Publication Number:
`
`(43) International Publication Date:
`
`23 July 1998 (23.07.98)
`
`(21) International Application Number:
`
`PCT/US98J00618
`
`(22) International Filing Date:
`
`13 January 1998 (13.01.98)
`
`(30) Priority Dale:
`60/035,591
`
`17 January 1997 (17.01.97)
`
`us
`
`BRISTO~MYERS SQUIBB COMPANY
`(71) Applicant:
`[US/US); P .0. Box 4000, Princeton, NJ 98543-4000 (US).
`
`(81) Designated States: AL, AM, AT, AU, AZ, BB, BG, BR, BY,
`CA, CH, CN, CZ. DE, DK, EE, ES, Fl, GB, GE, HU, IL,
`IS, JP, KB, KG, KP, KR, KZ, LK, LR, LS, LT, LU, LV,
`MD, MG, 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, KE, LS, MW, SD, SZ. UO, ZW),
`Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European patent (AT, BB, CH, DE, DK, ES, Fl, PR, GB,
`GR, IE, IT, LU, MC, NL, PT, SE), OAPI patent (BF, BJ,
`CF, CG, Cl, CM, GA, GN, ML, MR, NE, SN, ID, TG).
`
`(72) Inventor: GREGG, Richard, B.; 7 Linden Lane, Pennington, Published
`With international search report.
`NJ 08534 (US).
`·
`·
`
`(74) Agents: RODNEY, Bunon et al.; Bristol-Myers Squibb Com-
`pany, P.O. Box 4000, Princeton, NJ 08543-4000 (US).
`
`·
`
`(54) Title: A METHOD OF INHIBITING OR TREATING PHYTOSTEROLEMIA WITH AN MTP INHIBITOR
`
`(57) Abstract
`
`A method is provided for inhibiting onset of or treating phytosterolemia by administering 10 a patient an MTP inhibitor, alone or
`optionally, in combination with another cholesterol lowering drug, such as pravastatin.
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`Codes used to identify Slates pany to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`FOR THB PURPOSES OF INFORMATION ONLY
`
`AL
`AM
`AT
`AV
`AZ
`BA
`BD
`BE
`Bl'
`BC
`DJ
`DR
`BY
`CA
`CF
`CG
`CH
`Cl
`CM
`CN
`cu
`CZ
`DE
`DK
`EE
`
`Albania
`Anncnia
`Auslria
`Auslmlia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burtina Faao
`Bulgaria
`Benin
`Brnil
`BclBJUS
`Canada
`Cenlral African Republic
`Congo
`Swilzerland
`COcc d'Ivoire
`Cameroon
`China
`Cuba
`Czech Republic
`Gennany
`Denmark
`Estonia
`
`ES
`l'J
`l'R
`GA
`GB
`GE
`CH
`CN
`CR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Spain
`f"mland
`France
`Gabon
`United Kingdom
`GcOfllia
`Ghana
`Guinea
`Greece
`Hung my
`Ireland
`Israel
`Iceland
`l1aly
`Japan
`Kenya
`Kyrgyzstan
`Democm1ic People'•
`Republic of Korea
`Republic of Korea
`Kazalc&lan
`Sainr Lucia
`Liech1ens1eiii
`Sri Lanka
`Liberia
`
`LS
`LT
`LV
`LV
`MC
`MD
`MC
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SC
`
`Lesotho
`Lltiniania
`Luembourg
`l.alvla
`Monaco
`Republic of-Moldova
`Madqaacar
`The former Yugoslav
`Republic of Mscedonla
`Mall
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Nctherlandl
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Fedcraiion
`Sudan
`Sweden
`Singapore
`
`SI
`SK
`SN
`sz
`TD
`TG
`TJ
`TM
`TR
`Tr·
`UA
`VG
`us
`vz
`VN
`YU
`zw
`
`Slom.ia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikislan
`Tutkmeniston
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbeki11an
`Viel Nam
`Yugoslavia
`Zimbabwe
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`A METHOD OF INHIBITING OR TREATING PHYTOSTEROLEMIA wrrn AN MTP INHIBITOR
`
`Field of the Inyention
`The present invention related to a method for
`inhibiting onset of or treating phytosterolemia, by
`administering an MTP inhibitor alone or in combination with
`another cholesterol lowering drug, such as pravastatin.
`
`5
`
`10
`
`Background of the Invention
`As indicated in Scriver, C.R. et al "Metabolic Basis
`of Inherited Diseases" Vol. II (1995), Chap. 65, Inborn
`Errors in Bile Acid Biosynthesis and Storage of Sterols
`15 Other than Cholesterol, Bjorkhem, I. and Boberg, K.M., pp.
`2073-2099, phytosterolemia (also referred to as
`sitosterolemia) is a rare inherited sterol storage disease
`involving increased intestinal absorption of phytosterol or
`shellfish sterols and decreased fecal secretion. It is
`characterized by "tendon and tuberous xanthomas and by a
`strong predisposition to premature coronary
`atherosclerosis ....
`Increased amounts of phytosterols
`(plant sterols), such as sitosterol and campesterol and
`their Sa-stanols, are found in blood, plasma, erythrocytes,
`
`20
`
`25
`
`30
`
`35
`
`and different tissues, especially in the xanthomas and
`arteries of affected subjects.
`Increased serum cholesterol
`and cholesterol have also been found in many patients."
`(p. 2073)
`Patients afflicted with phytosterolemia have been
`found to have an increased incidence of coronary heart
`disease at an early age most likely due to early
`development of atherosclerosis at an early age. Bjorkhem
`et al, supra, indicate at page 2090 that "the mechanism
`behind the atherosclerosis is unexplained, but a high
`content of plant sterols in the.circulating lipoproteins
`might promote their deposition in the arterial wall."
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`The microsomal triglyceride transfer protein (MTP)
`cata_lyzes the transport of triglyceride (TG), cholesteryl
`ester (CE), and phosphatidylcholine (PC) between small
`unilamellar vesicles (SUV). Wetterau & Zilversmit, Chem.
`5 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 transport.
`The microsomal triglyceride transfer protein from bovine
`liver has been isolated and extensively characterized (1).
`This has led to the cloning of cDNA expressing the protein
`from several species, including humans (2). MTP is
`composed of two subunits. The small subunit is the
`previously characterized multifunctional protein, protein
`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) .
`
`10
`
`15
`
`20
`
`Wetterau, J.R. and Zilversmit, D.B. (1985) Chem.
`l:
`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.-
`
`4412.
`
`Atzel, A., and Wetterau, J.R. · (1993) Biochemistry
`32, 10444-10450.
`Atzel, A., and Wetterau, J.R. (1994) Biochemistry
`33, 15382-15388.
`Jamil, H., et al, (1995) J. Biol. Chem. 270, 6549-
`
`25
`
`30
`
`6554.
`
`35
`
`2.
`
`(1993) Nature 365, 65-69.
`Sharp, D. et al,
`Lin, M.C.M., et al, J. Biol. Chem. 269, 29138~29145.
`Nakamuta, M., et al, (1996) Genomics 33, 313-316.
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`Wetterau, J.R., et al, (1990) J. Biol. Chem. 265,
`3.
`9800-9807.
`Wetterau, J.R., et al, (1991) Biochemistry 30, 9728-
`
`5
`
`9735.
`
`4.
`14285.
`
`Ricci, B., et al, (1995) J. Biol. Chem. 270, 14281-
`
`IO
`
`In vitro, MTP catalyzes the transport of lipid
`molecules between phospholipid membranes. Presumably, it
`plays a similar role in yiyo, and thus plays some role in
`11pid metabolism. The subcellular (lumen of the microsomal
`fraction) and tissue distribution (liver and intestine} of
`15 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 JU.5., 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.
`Abetalipoproteinemia is an autosomal recessive
`disease characterized by a virtual absence of plasma
`lipoproteins which contain apolipoprotein B (apoB) . Kane &
`Havel in The Metabolic Basis 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.
`30 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 had not
`been previously determined.
`In subjects examined,
`triglyceride, phospholipid, and cholesterol synthesis
`appear normal. At autopsy, subjects are free of
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`atherosclerosis. Schaefer et al., Clin. Chem. 34, 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. 1 Am· J Hurn· Genet. 46, 1141-8 ( 1990) .
`Recent reports (5) demonstrate tha.t the defect
`causing abetalipoproteinemia is in the MTP gene, and as a
`result, the MTP protein. When examined, individuals with
`abetalipoproteinemia have no MTP activity, as a result of
`IO 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.
`
`15
`
`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-
`
`5.
`
`14285.
`
`Shoulders, C.C., et al, (1993) Hum. Mol. Genetics
`2, 2109-2116.
`, T.M.E., et al, (1995) Am. J. H~. Genet.
`Narc.i.s
`57, 1298-1310.
`Rehberg, E.F., et al, J. Biol. Chem (in press).
`
`1i
`
`20
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`25
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`30
`
`Canadian Patent Applica.tion 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 apoB containing lipoprotein secretion in a
`human hepatic c~ll line {HepG2. cells). This provides
`further support for the proposal that an MTP inhibitor
`35 would lower apoB containing lipoprotein and lipid levels in
`viyo. This Canadian patent application discloses a method
`for identifying the MTP inhibitors.
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`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
`No. 60/017,224, filed May 9, 1996 (file HX79a*), U.S.
`10 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 1, 1996 (file HX86*).
`All of the above U.S. applications are incorporated
`herein by reference.
`
`15
`
`Description of the Invention
`In accordance with the present invention, a method
`is provided for inhibiting onset of or treating
`phytosterolemia, in 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
`delipidating agent.
`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 cholesterol (LPL-cholesterol} to at
`least about 50% of normal LPL blood level, preferably down
`to less than about 25% of· normal, and lowers triglycerides
`to at least about 50% of normal triglyceride blood level,
`and preferably down to about 25% or less of normal, and
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`thereby reduces plasma cholesterol and resulting
`atherosclerosis.
`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.
`Application Serial No. 548,811, filed January 11, 1996
`(file DC2lh), U.S. provisional application No. 60/017,224,
`filed May 9, 1996 (file HX79a*), U.S. provisional
`application No. 60/017,253, filed May 10, 1996 (file
`HX82*), U.S. provisional application No. 60/017,254, filed
`May 10, 1996 (file HX84*), and U.S. provisional application
`No. 60/028,216, filed October 1, 1996 (file HX86*).
`Preferred are each of the preferred MTP inhibitors
`20 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) are
`piperidine compounds of the structure
`R2
`0
`R3-~N-CN- R1
`Vlx.
`
`25
`
`R4
`
`'
`
`or
`
`or
`
`or
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`or
`
`5
`
`10
`
`0
`II
`where Q is -c- or
`
`0
`II
`-S-
`11
`0
`
`Xis: CH. R8, - C-
`..
`0
`
`-CH- CH- or
`' I
`I
`R9
`R10
`
`-C= C- i
`I
`I
`Rs R10
`
`Rs; R9 and RlO are independently hydrogen, alkyl, alkenyl,
`alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
`cycloalkyl, or cycloalkylalkyl;
`Y is -(CH2)m- or -rr-
`
`15
`
`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
`20 optionally substituted through available carbon atoms with
`l, 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
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`- R11-z1
`
`or
`
`or
`
`or
`
`5
`
`~
`Rl is an indenyl-type group of the structure
`
`or
`
`or
`
`or
`
`(a= 2,3 or4)
`
`f
`
`or
`
`_ R11_ z1
`
`R16a
`
`H
`
`10
`
`zl and z2 are the same or different and are
`independently a bond, 0, S,
`
`s II
`0
`
`15
`
`-Ntt-C-
`"
`0
`
`·•
`
`-N -C -
`I
`11
`alkyl O
`
`-c-11
`0
`
`or
`
`H -y-
`OH
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`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 preferably
`(1) when.R12 is H, aryloxy, alkoxy or arylalkoxy,
`-Ntrc- . -N--c-
`-c-
`"
`I
`II
`alkyl 0
`or a bond and
`then z2 is
`O
`O
`(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, Rls, 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,
`20 heteroaryl, heteroarylalkyl or aryloxy;
`RlSa and R16a are independently hydrogen, alkyl,
`halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl,
`alkenyl, alkynyl, alkoxy, alkylsulfonyl, arylsulfonyl,
`alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy,
`arylcarbonylamino, alkylcarbonylamino, arylalkyl,
`heteroaryl, heteroarylalkyl, or aryloxy;
`or Rl is a group of the structure
`
`II
`
`25
`
`.a17
`
`-(CB;i)p-<
`au
`30 wherein p is 1 to B 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;
`or Rl is a group of the structure
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`Jf O
`-n1e--<
`ff21
`
`5
`
`10
`
`15
`
`wherein R19 is aryl or heteroaryl;
`R20 is aryl or heteroaryl;
`R21 is H, alkyl, aryl, alkylaryl, arylalkyl,
`ar)rloxy, arylalkoxy, heteroaryl, heteroarylalkyl,
`heteroarylalkoxy, cycloalkyl, cycloalkylalkyl or
`cycloalkylalkoxy;
`independently hydrogen, halo, alkyl,
`R2, R3, R4 are
`alkenyl, alkox}r, 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,
`heteroarylamino, cycloalkyloxy, cycloalkylamino, all
`20 optionally substituted through available carbon atoms with
`1, 2, 3 or 4 groups selected from hydrogen, halo, alkyl,
`haloalkyl, qlkoxy, haloalkoxy, alkenyl, alkynyl,
`cycloalkyl, cycloalkylalkyl, cycloheteroalkyl,
`cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl,
`arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy,
`aryloxyalkyl, arylalkoxy, arylp.zo, heteroaryloxo,
`heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy,
`nitro, cyano, amino, substituted amino, thiol, alkylthio,
`arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl,
`arylcarbonyl, arylaminocarbonyl, alkoxycarbonyl,
`aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl,
`alkertylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,
`alkylcarbonylamino, arylcarbonylamino, arylsulfinyl,
`arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl,
`arylsulfonylamino, heteroarylcarbonylamino,
`
`25
`
`30
`
`35
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`
`heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl,
`alkylsulfinyl;
`R6 is hydrogen or C1-C4 alkyl or C1-C4 alkenyl; all
`optionally substituted with l, 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
`( ~ ) .
`
`with 0X0
`
`I
`
`5
`
`10
`
`Het
`
`and
`
`./:.~~
`'
`are the same or different and are independently selected
`from heteroaryl
`containing 5- or 6-ring members; and
`0
`~~Rt
`N-oxides
`thereof; and
`pharmaceutically acceptable salts thereof; with
`the provisos that preferably 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 preferably in the fifth
`fo:r:mula, where one of R2, R3 and R4 is· 6-fluoro, and the
`20 others are H, R7 will be other than 4- (2-methoxyphenyl).
`The MTP inhibitors disclosed in U.S. application
`Serial No. 548,811 filed January 11, 1996 (file DC2lh),
`have the structure
`
`15
`
`25
`
`x2
`including the piperidine N-oxide thereof or a
`pharmaceutically acceptable salt thereof, wherein z is a
`bond, O or S;
`
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`
`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.
`The MTP inhibitors disclosed in U.S. provisional
`application No. 60/017,224, filed May 9, 1996 (file HX79a*)
`have the structure
`
`or
`
`:IA
`
`or
`
`J:B
`including pharmaceutically acceptable salts thereof,
`wherein q is 0, 1 or 2;
`A is
`(1) a bond;
`; or
`(2) -0-
`
`5
`
`10
`
`15
`
`(3)
`where Rs is H or lower alkyl or Rs together with R2 forms a
`carbocyclic or heterocyclic ring system containing 4 to 8
`20 members in the ring.
`B is a fluorenyl-type group of the structure:
`
`~~·
`
`R3'
`
`X
`
`R4
`
`(the above B is also referred to as a
`fluorenyl- type ring or moiety); or
`
`or
`
`25
`
`B is an indenyl-type group of the structure
`
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`
`3
`
`R,UR
`
`3'
`
`or
`
`or
`
`,)~R3b
`
`R3a
`
`(the above B Is also referred to as
`an lndenyl-type ring or moiety);
`
`(a= 2,3 or 4)
`R3
`
`R3a
`
`5
`
`10
`
`15
`
`20
`
`25
`
`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 arylalkylamino, aryl, arylalkyl, arylamino,
`aryloxy, heteroaryl, heteroarylamino, heteroaryloxy,
`arylsulfonylamino, heteroarylsulfonylamino, arylthio,
`arylsulfinyl, arylsulfonyl, alkylthio, alkylsulfinyl,
`alkylsulfonyl, heteroarylthio, heteroarylsulfinyl,
`heteroarylsulfonyl, -PO(R13) (R14),
`(where R13 and R14 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 substituted with one or
`two aryl, alkyl or heteroaryl groups); cyano, 1,1-(alkoxyl
`or aryloxy)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 l,3-dioxolane,
`connected to Ll (or L2 in the case of R2) at the 2-
`position); l,3-dioxane or 1,3-dioxolane connected to L1 (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 any of
`the preferred Rl substituents set out below.
`
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`Rl may be substituted with the following preferred
`substituents: alkylcarbonylamino, cycloalkylcarbonylamino,
`arylcarbonylamino, heteroarylcarbonylamino,
`alkoxycarbonylamino, aryloxycarbonylamino,
`5 heteroaryloxylcarbonylamino, uriedo (where the uriedo
`nitrogens may be' substituted with alkyl, ,aryl or
`heteroaryl}, heterocyclylcarbonylamino {where the
`heterocycle is connected to the carbonyl group via a
`nitrogen or carbon atom), alkylsulfonylamino,
`arylsulfonylamino, heteroarylsulfonylamino,
`
`10
`
`R21-1-
`
`-~
`.0
`
`0
`. N-
`.
`J
`
`tc.20
`
`I
`
`R22
`
`15
`
`20
`
`25
`
`30
`
`where J is: CBR:.i3 , -c- -CH-CH- or -C=C- ;
`' I
`I
`I
`I
`II
`~· ~5
`~·~5
`0
`R23, R24 and R25 are independently hydrogen, alkyl, alkenyl,
`alkynyl, aryl, ary'lalkyl, heteroaryl, heteroarylalkyl,
`cycloalkyl, or cycloalkylalkyl;
`R20, R21, R22 are
`independently hydrogen, halo,
`alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl,
`alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl,
`heteroaryl, heteroarylalkyl, hydroxy or haloalkyl; and
`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
`substituents 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
`
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`
`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) .
`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, nitre, amino, thiol, alkylthio,
`alkylsulfinyl, alkylsulfonyl, carboxy, alkoxycarbonyl,
`aininocarbonyl, alkylcarbonyloxy, alkylcarbonylamino,
`cycloheteroalkyl, cycloheteroalkylalkyl, cyano, Ar,
`Ar~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
`
`10
`
`15
`
`20
`
`and
`
`are the same or different and independently represent a 5
`25 or 6 membered heteroaryl ring which may contain 1, 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:
`
`30
`
`(1) - s -
`1
`(0)11•
`-o-
`
`(2)
`
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`
`5
`
`(3) -N -
`I
`R6
`
`(4)
`
`(5)
`
`(6) - c= c -
`1
`I
`Rg•
`a10•
`
`(7)
`
`,cc,---Y-
`Rg
`RlO
`
`l5
`
`10 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-R11 ;
`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 form a ketone;
`R9, Rio, 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
`-0-R11 ;
`
`20
`
`25
`
`30
`
`Rll is alky or aryl;
`R12 is H, alkyl or aryl.
`The following provisos apply to formula I preferred
`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.
`
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`5
`
`. With respect to compounds 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.
`With respect to preferred compounds of formula IA
`and IB, where Rl is cycloheteroalkyl, Rl is exclusive of
`1-piper-idinyl, 1-pyrrolidinyl, 1-azetidinyl or
`1-(2-oxo-pyrrolidinyl).
`The MTP inhibitors disclosed in U.S. provisional
`application No. 60/017,253, filed May 10, 1996, (file
`10 HX82*) are pyrrolidine compounds and have the structure
`:I
`
`15
`
`0
`0
`"
`whereQls -c- or -s-
`II
`it
`0
`
`W is H,H or O;
`
`X is· CHR8
`.
`•
`
`- C-
`..
`0
`
`-CH- CH- or
`• I
`I
`Re
`R10
`
`-C= C-;
`I
`I
`R9 R10
`
`20 Rs, R9 and RlO are independently hydrogen, alkyl, alkenyl,
`alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
`cycloalkyl, or cycloalkylalkyli
`Rl is alkyl, alkenyl, alkynyl, .aryl, heteroaryl,
`arylalkyl (wherein alkyl preferably has at least 2 carbons,
`25 more preferably at least 3 carbons) , diarylalkyl,
`arylalkenyl, diarylalkenyl, arylalkynyl, diarylalkynyl,
`diarylalkylaryl, heteroarylalkyl (wherein alkyl preferably
`has at least 2 carbons, more preferably at least 3
`carbons), cycloalkyl, or cycloalkylalkyl (wherein alkyl
`30 preferably has at least 2 carbons, more preferably at. least
`3 carbons); all of the aforementioned Rl groups being
`
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`
`optionally substituted through available carbon atoms with
`l, 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
`
`_ R11_ z1
`
`R12_ z2
`
`I/
`
`or
`
`y_~
`R13~ R14
`
`~
`
`5
`
`IO
`
`or
`
`-R11-z1
`
`R12_z2
`
`R13
`
`; or
`
`~
`Rl is an indenyl-type group of the structure
`
`or
`
`or
`
`15
`
`(a= 2,3 or4)
`
`f
`
`or
`
`-n11_z1
`
`H
`
`R1sa
`
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`
`zl and z2 are the same or different and are
`independently a bond, 0, S,
`
`·'
`
`0
`
`,
`
`II
`
`H
`s ..
`-c-11
`or -'-C-
`-N--C- I
`( ~) , -NH-C-
`' OH
`I
`· 11
`0
`0
`alkyl O
`0
`2
`5 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 exami:>le
`~
`-g(CH2)-0
`
`where n is 1 to 6;
`R12 is hydrogen, alkyl, alkenyl, aryl, haloalkyl,
`trihaloalkyl, trihaloalkylalkyl, heteroaryl,
`15. heteroarylalkyl, arylalkyl, arylalkenyl, cycloalkyl,
`aryloxy, alkoxy, arylalkoxy or cycloalkylalkyl; with the
`provisos that (1) when R12 is H, aryloxy, alkoxy or
`-c-
`-NH-C-
`,
`-N -C -
`I
`..
`II
`11
`O
`alkyl O
`O
`
`or a
`
`arylalkoxy, then z2 is
`bond;
`
`20
`
`25
`
`and (2) when z2 is a bond, R12 cannot be heteroaryl
`or heteroarylalkyl;
`Z is a bond, 0, S, N-alkyl, N-ar)fl, or alkylene or
`alkenylene of from 1 to 5 carbon atoms;
`Rl3, R14, R15, and R16 arl;! 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,
`30 or aryloxy;
`R15a and R16a are independently any of the R15 or R16
`groups except hydroxy, nitro, amino or thio;
`or Rl is
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`
`R17
`
`-(CB:z)p-<
`·1tl8.
`
`wherein p is 1 to 8 and R1 7 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
`
`5
`
`10
`
`15
`
`ff20
`-R19~
`.
`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;
`R2, R3, R4 are independently hydrogen, halo, alkyl,
`alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylrnercapto,
`arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl,
`heteroarylalkyl, hydroxy or haloalkyl;
`Rs is alkyl , alkenyl, alkynyl, aryl, alkoxy,
`aryloxy, arylalkoxy, heteroaryl, arylalkyl,
`20 heteroarylalkyl, cycloalkyl, cycloheteroalkyl,
`heteroaryloxy,. cycloalkylalkyl, polycycloalkyl,
`polycycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl,
`polycycloalkenyl, polycycloalkenylalkyl,
`heteroarylcarbonyl, amino, alkylamino, arylamino,
`heteroarylarnino, cycloalkyloxy, cycloalkylarnino, 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, haloalkox