PCT
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`WORLD IN7ELLECTllAL PROPERTY ORGANIZATION
`International 8ul'Cau
`
`(Sl) International Patent Clas.o;iftcation 6:
`AOIN 43116, 43118, 43/40, A61K 31135,
`31138, 31/445
`
`Al
`
`(11) lnt~mational Publication Number:
`
`WO 98/03069
`
`(43) International Publication Date:
`
`29 January 1998 (29.01.98)
`
`(21) lnternallonal Application Number:
`
`PCT/US97/12229
`
`(22) International Filing Date:
`
`14 July 1997 (14.07.97)
`
`(30) Priority Data:
`60/022,866
`
`24 July 1996 (24.07.96)
`
`us
`
`BRISTOL-MYERS SQUIBB COMPANY
`(71) Applicant:
`[US/US]; P.O. Box 4000, Princeton, NJ 08543-4000 (US).
`.
`
`(72) lnvenlors: GREGG, Richard, E..; 7 Linden Lane, Pennington,
`NJ 08543 (US). POULEUR, Hubert, G.; 43 Woodlane
`Road, Lawrenceville, NJ 08648 (US). WETI'ERAU, John,
`R .• 11: 190 Rugby Drive, Langhorne, PA 19047 (US).
`
`(74) Agents: RODNEY. Burton el al.; Bristol-Myers Squibb Com(cid:173)
`pany, P.O. Box 4000, Princeton, NJ 08543-4000 (US).
`
`(81) Designated States: AL, AM, AT. AU, AZ, BB, BG, BR, BY,
`CA, CH, CN, CZ. DE, DK, EE, ES, Fl, GB, .GE; HU,
`IL. IS, JP, KE, KG, KP,:KR, KZ, LK,:LR_:Ls; LT, LU,
`LV, MD, MG, MK, MN, MW, MX, NO, NZ;·PL, PT, RO,
`RU, SD, SE, SG, SJ, SK, TJ, TM; TR, T:f, UA, UG, UZ,
`VN, ARIPO patent (GH, KE, LS, MW, SD. SZ, UG, ZW),
`Eurasian patent CAM, AZ,.BY, KG; K7., MD, .RU, TJ,"TM).
`European patent (AT, BE; CH, l>E, DK, cS, 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).
`
`Publi.'ihed
`With interna1ional search report.
`
`(54) Title: METHOD FOR LOWERING SERUM LIPID LEVELS EMPLOYING AN MTP INHIBITOR IN COMBINATION WITH
`ANOTIIER CHOLESTI.lROL LOWERING DRUG
`.
`.
`
`(57) Abstr11ct
`
`A method is provided for lowering serum lipids, cholesterol and/or lriglyccrides and thereby inhibiting atherosclerosis by administering
`to a patienl an MTP inhibitor, in combination with a cholesterol lowering drug, such as pravastatin.
`·
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`Codes used 10 identify Slates pany to 1he PCT on the front pages of pamphlets publishing inrcmational applications under !he PCT.
`
`FO.R THE PURPOSES OF INFORMATION ONLY
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`BE
`Bl'
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`Cl
`CM
`CN
`cu
`CZ
`DE
`DK
`EE
`
`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia Ind Herzegovina
`Barbados
`Belgium
`Bwtina Faso
`Bulgaria
`Bellin
`Bruit
`Belarus
`Canada
`Cen1ral Arrian llcpublic
`COil go
`Switzerland
`COie d·lvoirc
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmai:k
`iisJonia,
`
`E.S
`l'I
`FR
`GA
`GB
`GE
`Gii
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`K7.
`LC
`u
`LK
`LR
`
`Spain
`Pin land
`Prance
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greta
`Hun guy
`.Ireland
`ls noel
`Iceland
`llaly
`Jepui
`Kenya
`Kyrgyuian
`Dcmocra1ir Ptople••
`Republic or Korea
`Republic of Korea
`Kaubtan
`Saint l.ucia
`Liechlens1cin
`Sri Lanka
`Liberia
`
`u;
`.LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NF.
`NL
`NO
`NZ
`PL
`Yr
`RO
`RU
`SD
`SE
`SC
`
`Laolho
`Lilhuania
`Luocmbourg
`La!Yia
`Monaa>
`Republic or Moldova
`Madagascar
`The ronllCf Yugotlav
`Republic of Macedonia
`Mali
`MC?11golla
`Mlllrilan!a
`Malawi
`Mexico
`Niger
`Nerberlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian t-"cdcraiion
`Sudan
`Sweden
`Singapore
`
`SI
`SK
`SN
`sz
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UC
`us
`uz
`VN
`YU
`zw
`
`Slovenia
`Slovakia
`Senesal
`Swuilllld
`Chad
`Togo
`Tafitlsran
`T\ntmeni.stan
`Turtey
`Trinidad and Tobf&o
`Ukraine
`Uganda
`Unlled SlalCS or Americe
`Uzbekislan
`Viet Nam
`Yugoslavia
`Zimbah...,
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`METHOD FOR LOWERING SERUM LIPID LEVELS
`EMPLOYING AN MTP INHIBITOR IN COMBINATION WITH
`ANQTHER CHOLESTERQL LQWERING DRUG
`
`5
`
`10
`
`Field of the Inyention
`
`The present invention relates to a method·
`for lowering serum lipids, cholesterol and/or
`triglycerides in mammalian species by administering
`an MTP inhibitor in combination with another
`cholesterol lowering drug, for example, an HMG CoA
`reductase inhibitor, such as pravastatin,
`lovastatin or simvastatin.
`
`15
`
`Background of the Invention
`The use of microsomal triglyceride transfer
`protein (MTP) inhibitors for decreasing serum
`lipids including cholesterol and triglycerides and
`their use in treating atherosclerosis, obesity,and
`pancreatitis is disclosed in Canadian Patent
`20 Application No. 2,091,102 (corresponding to U.S.
`Application Serial No. 117, 362.>, U.S. Application
`Serial No. 472,067, filed June 6, 1995 (file
`DC2le), U.S. Application Serial No. 548,811. (file
`DC2lh), U.S. provisional application No.
`60/017,224, (file HX79a*), U.S. provisional
`application No. 60/017,253, (file HX82*) and U.S.
`provisional application No. 60/017,254, (file
`HX84*).
`All of the above U.S. applications are
`incorporated herein by reference.
`
`25
`
`30
`
`Description of the Inyention
`In accordance with the present invention,. a
`method for preventing, inhibiting or treating
`atherosclerosis, pancreatitis or obesity is
`provided, wherein an MTP inhibitor in combination
`
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`15
`
`with another cholesterol lowering drug is
`administered in therapeutically effective amounts
`to lower LDL cholesterol and triglycerides.
`Furthermore, in accordance with the present
`invention, a method is provided for lowering se~
`lipid levels, cholesterol and/or triglycerides, or
`. inhibiting and/or treating hyperlipemia,
`hyperlipid-emia, hyperlipoproteinemia,
`hypercholesterolemia and/or hypertriglyceridemia,
`10 wherein a combination of an MTP inhibitor and
`another cholesterol lowering drug is administered
`in therapeutically effective amounts.
`In addition, in accordance with the present
`invention, a novel combination of cholesterol
`lowering agents is provided which includes an MTP '
`inhibitor and another cholesterol lowering drug.
`Cholesterol lowering drugs or drugs which
`are inhibitors of cholesterol biosynthesis which
`may be used in the method of the invention in
`combination with the MTP inhibitor include HMG CoA
`reductase inhibitors, squalene synthetase
`inhibitors, fibric acid derivatives, bile acid
`sequestrants, probucol, niacin, niacin derivatives,
`neomycin, aspirin, and the like.
`It is believed that the combination of MTP
`inhibitor and other cholesterol lowering drug,
`which works by a mechanism other than inhibiting
`MTP, is a surprising and unique concept in treating
`diseases involved with elevated cholesterol and/or
`triglycerides and atherosclerosis, obesity and/or
`pancreatitis, in that the combination may provide.
`additional anticholesterolemic effects over that
`which may be obtained using each of the components
`of the combination alone.
`It is expected that
`reduced levels of each of the MTP inhibitor and
`other cholesterol lowering drug may be employed to
`
`20
`
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`
`30
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`achieve desired results, albeit with reduced side
`effects.
`
`Detailed Description of the Invention
`
`5
`
`I 0
`
`The following definitions apply to the
`terms as used throughout this specification, unless
`otherwise limited in specific instances.
`The term "MTP" refers to a polypeptide or
`protein complex that (1) if obtained from an
`organism ( e. g. , cows, humans, etc. ) , can be
`
`20
`
`25
`
`30
`
`isolated from the microsomal fraction of
`homogenized tissue; and. (2) stimulates the
`transport of triglycerides, cholesterol esters, or
`phospholipids from synthetic phospholipid vesicles,
`15 membranes or lipoproteins to synthetic vesicles,·
`membranes, or lipoproteins and which is distinct
`from the cholesterol ester transfer protein [Drayna
`et al., Nature 327, 632-634 (1987)] which may have
`similar catalytic properties.
`The phrase "stabilizing" atherosclerosis as
`used in the present application refers to slowing
`down the development of and/or inhibiting the
`formation of new atherosclerotic lesions.
`The phrase "causing the regression of"
`atherosclerosis as used in the present application
`refers to reducing and/or eliminating
`atherosclerotic lesions.
`The combination of the MTP inhibitor and
`other cholesterol· lowering drug will be employed
`in
`a weight ratio to each other of within the range
`of
`from about 1000:1 to about 0.001:1 and preferably
`from about 0.05:1 to about 100: 1.
`MTP inhibitors to be employed in the
`methods of the invention include MTP inhibitors
`disclosed in Canadian Patent Application No.
`2,091,102 (corresponding to U.S. Application Serial
`
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`No. 117,362), U.S. Application Serial No. 472,067,
`filed June 6, 1995 (file DC2le), U.S. Applicatibn·
`Serial No. 548,811 (file DC2lh), U.S. provisional
`applicati<m No. 60/017,.224, (file HX79a*), U.S ..
`5 provisional application No. 60/017,253, (file
`HX82*) and U.S. provisional application No.
`60/017,254, (file HX84*).
`All of the above U.S. applications are
`incorporated herein by referel'\ce ..
`The MTP inhibitors disclosed in U.S.
`Application Serial No. 472, 067, filed June 6, 199:5
`(file DC2le) are piperidine compounds of the
`structure
`
`10
`
`R2
`
`0
`
`n3-~ N-GN-R1
`~x
`R4
`
`•
`
`15
`
`or
`
`20
`
`25
`
`Rs .. a.r-C · N- R1
`
`6
`R
`
`•
`
`or
`
`or
`
`or
`
`where Q is
`
`0
`II -c-
`
`II
`
`0
`or -s-
`11
`0
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`x is: CHR 8, - c- -CH- CH-
`"
`' I
`I
`R' Rto
`0
`
`or
`
`-C: C-;
`I
`I
`Rg Rto
`
`Ra, R9 and Rio are independently hydrogen, alkyl,
`alkenyl, alkynyl, aryl, arylalkyl, heteroaryl ,,
`heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;
`Y is -(CH2>m- or -:r-
`
`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,
`arylal·kynyl, 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 l,
`2, 3 or 4 groups selected from halo, haloalkyl,
`alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl,
`alkylmercapto, arylmercapto, cycloalkyl, cyclo(cid:173)
`alkylalkyl, heteroaryl, fluorenyl, heteroarylalkyl,
`hydroxy or oxo;
`or Rl is a fluorenyl-type group of the
`structure
`
`-R11-z1
`
`or
`
`or
`
`.5
`
`10
`
`15
`
`20
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`or
`
`or
`
`.Q
`
`Rl is an indenyl-type group of the structure
`
`or
`
`or
`
`5
`
`(a= 2,3 or 4)
`
`E
`
`or
`
`- R11- z1
`
`R12_ z2
`
`R16a
`
`. J::I
`
`n1sa
`
`zl and z2 are the same or different and are
`independently a bond, 0, S,
`
`JO
`
`s
`"
`0
`
`(;f)
`
`H
`or -c;:-
`, -NH-~- • -~-- ~- •
`o
`0 2
`alkyl. 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;
`Rl2 is hydrogen, alkyl, alkenyl, aryl, haloalkyl,
`trihaloalkyl, trihaloalkylalkyl, heteroaryl,
`heteroarylalkyl, arylalkyl, arylalkenyl, cycle-
`
`-c-
`11
`0
`
`15
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`alkyl, aryloxy, alkoxy, arylalkoxy or cycloalkyl(cid:173)
`alkyl, with the provisos that
`(1) when Rl2 is H, aryloxy, alkoxy or
`-NH-C-
`-N -C -
`"
`I
`II
`o
`alkyl O
`
`-C-
`II
`o
`
`,
`
`arylalkoxy, then z2 is
`or a bond and
`(2) when z2 is a bond, Rl2 cann~t be
`heteroaryl or heteroarylalkyl;
`Z is bond, 0, S, N-alkyl, N-aryl, or
`alkylene or alkenylene from 1 to 5 carbon atoms;
`10 Rl3, Rl4, 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, heteroaryl,
`heteroarylalkyl or aryloxy;
`RlSa and Rl6a are independently hydrogen,
`alkyl, halo, haloalkyl, aryl, cycloalkyl, cyclo-
`20 heteroalkyl, alkenyl, alkynyl, alkoxy, alkyl-
`sulf onyl, arylsulfonyl, alkylthio, arylthio, amino(cid:173)
`carbonyl, alkylcarbonyloxy, arylcarbonylamino,
`alkylcarbonylamino, arylalkyl, heteroaryl,
`heteroarylalkyl, or aryloxy;
`or Rl is a group of the structure
`
`5
`
`15
`
`25
`
`Rl7
`
`-(CH2)p-<
`alB
`
`wherein p is 1 to 8 and R17 and RlB are each
`independently H, alkyl, alkenyl, aryl, arylalkyl,
`30 heteroaryl, heteroarylalkyl, cycloalkyl or
`cycloalkylalkyl at least one of Rl7 and RlB being
`other than H;
`or Rl is a group of the structure
`
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`ft20
`-R1s--<
`ff21
`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,
`R2, R3, R4 are
`halo, alkyl, 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, cycloalkyl(cid:173)
`alkyl, polycycloalkyl, polycycloalkylalkyl,
`cycloalkenyl, cycloheteroalkyl, heteroaryloxy,
`cycloalkenylalkyl, polycycloalkenyl, polycyclo(cid:173)
`alkenylalkyl, heteroarylcarbonyl, amino,
`alkylamino, 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, arylcyclo-alkyl,
`arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl,_
`arylalkoxy, arylazo, heteroaryloxo, hetero-
`arylalkyl, heteroarylalkenyl, heteroaryloxy,
`hydroxy, nitro, cyano, amino, substituted amino,
`thiol, alkylthio, arylthio, heteroarylthio,
`arylthioalkyl, alkylcarbonyl, arylcarbonyl,
`arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl,
`alkynylaminocarbonyl, alkylaminocarbonyl,
`
`5
`
`JO
`
`15
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`20
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`25
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`
`alkenylaminocarbonyl, alkylcarbonyloxy,
`arylcarbonyloxy, alkylcarbonylamino,
`
`arylcarbonylarnino, arylsulfinyl, arylsulfinylalkyl;
`arylsulfonyl, alkylsulfonyl, arylsulfonylarniho,
`heteroarylcarbonylamino, heteroarylsulfinyl,
`heteroarylthio, heteroarylsulfonyl, alkyls~lfinyl;
`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 oxo
`
`( ~ ) .
`
`,
`
`and
`
`are the same or different and are independently
`selected from heteroaryl containing 5- or 6-ring
`members; and
`
`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 formula, where one of R2 , R3 and R4 is
`6-f luoro, and the 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
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`0
`II B
`C- N- CH:z- CF3
`
`(CH:z)x-N'J-:-g-Rs
`
`x2
`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 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
`
`I
`
`or
`
`IA
`
`or
`
`IB
`
`including pharmaceutically acceptable salts
`thereof, wherein q is 0, 1 or 2;
`(1) a bond;
`A is
`(2) -0- ; or
`
`( 3)
`where Rs is Hor 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:
`
`5
`
`10
`
`15
`
`20
`
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`._,
`
`R~f....
`n4'
`I j
`~
`x ~
`A4
`
`Het
`
`3•
`R
`
`or
`
`(the above B is also referred to as a
`fluorenyl· type ring or moiety); or
`
`5
`
`B is an indenyl-type group of the structure
`
`or
`
`or
`
`(a= 2,3 or 4)
`R3
`
`(the above B is also referred to as
`an indenyl-type ring or moiety);
`
`IO
`
`15
`
`20
`
`Rx is H, alkyl or aryl;
`Rl is alkyl, alkenyl, alkynyl, alkoxyl,
`(alkyl or aryl)3Si (where each a:lkyl or aryl group
`
`is independent), cycloalkyl, cycloalkenyl,
`substituted alkylamino, substituted arylalkylamino,
`aryl, arylalkyl, arylamino, aryloxy, heteroaryl,
`heteroarylamino, heteroaryloxy, arylsulfonylarnino,
`heteroarylsulfonylamino, arylthio, arylsulfinyl,
`arylsulfonyl, alkylthio, alkylsulfinyl,
`alkylsulfonyl, heteroarylthio, heteroarylsulfinyl,
`heteroarylsulfonyl, -PO(Rl3) (R14),
`(where Rl3 and
`R14 are independently alkyl, aryl, alkoxy, aryloxy,
`heteroaryl, heteroarylalkyl, heteroaryloxy,
`
`SUBSTITUTE SHEET (RULE 26)
`
`13 of 60
`
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`
`W098/03069
`
`PCT/US97/12229
`
`- 12 -
`
`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 1,3-"-.
`dioxane or 1,3-dioxolane, connected to Ll (or L2in
`the case of R2) at the 2-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 any of the preferred Rl substituents
`set out below.
`Rl may be substituted with the following
`preferred substituents: alkylcarbonylamino, cyclo-
`alkylcarbonylamino, arylcarbonylamino, heteroaryl(cid:173)
`carbonylamino, alkoxycarbonylamino,
`aryloxycarbonylamino, 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,
`arylsulfonylarnino, heteroarylsulfonylamino,
`
`5
`
`IO
`
`15
`
`20
`
`25
`
`30
`
`where J is: CRR2l,
`
`- c- -CB- CH- or
`I I
`I
`II
`0
`R24 R25
`
`SUBSTITUTE SHEET (RULE 26)
`
`14 of 60
`
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`

`
`W098/0J069
`
`PCT/US97/12229
`
`- 13 -
`
`5
`
`15
`
`R23, R24 and R25 are independently hydrogen. alkyl,
`alkenyl, alkynyl, aryl, arylalkyl, 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
`subs ti tuents may either be directly attached to R1 ,:
`10 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 R1 ·
`Ll is a linking group containing from l:to
`10 carbons in a linear chain (including alkylene,
`alkenylene or alkynylene), which may contai~,
`within the linking chain any of the following: one
`or two alkenes, on·e 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
`30 different and are independently selected from H,
`halogen, CF3, haloalkyl, hydroxy, alkoxy, alkyl,
`aryl, alkenyl, alkenyloxy, alkynyl, alkynyloxy,
`alkanoyl, nitro, amino, thiol, alkylthio, alkyi(cid:173)
`sulfinyl, alkylsulfonyl, carboxy, alkoxycarbonyl,
`aminocarbonyl, alkylcarbonyloxy,
`alkylcarbonylamino, cycloheteroalkyl,
`
`20
`
`25
`
`35
`
`SUBSTITUTE SHEET (RULE 26)
`
`15 of 60
`
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`
`

`
`W098/03069
`
`PCTiuS97/lll29
`
`.- 14 -
`
`cycloheteroalkylalkyl, cyano, Ar, Ar-alkyl, Aro,
`Ar-amino, Ar-thio, Ar-sulfinyl, Ar-sulfonyl, A,r(cid:173)
`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 RJ groups except
`hydroxy, nitro, amino or thio;
`
`5
`
`JO
`
`.and
`
`are the same or different and independently
`represent a 5 or 6 mernbered.heteroaryl ring which
`may contain l, 2, 3 or 4 heteroatoms in the ring
`15 which are independently N, s or 0; and including N(cid:173)
`oxides.
`X (in the fluorenyl type ring) is a bond,
`or is one of the following groups:
`
`20
`
`25
`
`30
`
`( 1) - s -
`1
`(Oln•
`
`(2)
`
`-o-
`
`(3) -N -
`I
`R6
`
`(4) - c -,, '
`
`R7
`
`aB
`
`(5)
`
`(6)
`
`(7) - c y -
`, '
`Rll
`RlO
`
`SUBSTITUTE SHEET (RULE 26)
`
`16 of 60
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`
`W098/03069
`
`PCT/US97/lll29
`
`- 15 -
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`wherein
`y is 0, N-R6 or S;
`n• is 0, 1 or 2;
`R6 is H, lower alkyl,
`-C (0) -O-Rll;
`R7 arid RB are the same
`independently H, alkyl, aryl,
`R7 and RB together can
`
`aryl, -C(O)-Rll or
`
`or different and are
`halogen, -o-R12, or
`be oiygen to•foima
`
`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 a~d
`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) ;
`(cl when R2L2A- is H2N-, RlLl cannot
`contain amino;
`(d) when Rl is cyano, Ll must have ~ore
`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 compounds IA and IB, where
`Rl is cycloheteroalkyl, Rl is exclusive of l-piper-
`idinyl, 1-pyrrolidinyl, 1-azetidinyl or 1-(2-oxo(cid:173)
`pyrrolidinyl) .
`
`SUBSTITUTE SHEET (RULE 26)
`
`17 of 60
`
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`
`

`
`W098/03069
`
`PCTIUS97/llll9
`
`- 16 -
`
`The MTP inhibitors disclosed in U.S.
`provisional application No. 60/017,253, filed May.
`10, 1996, (file HX82*) are pyrrolidine compounds
`and have the structure
`x
`
`5
`
`x :r
`
`or
`
`..
`0
`0
`II
`where Q Is -c- or -s-
`II
`0
`
`w is H,H or 0;
`
`X is: CHR8
`
`•
`
`- C- -CH- CH-
`• I
`I
`II
`0
`Ag
`R10
`
`or -c: C-;
`I
`I
`Rs R10
`
`RB, 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 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 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 1,
`2, 3 or 4 groups selected from halo, haloalkyl,
`alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl,
`
`IO
`
`15
`
`20
`
`25
`
`30
`
`SUBSTITUTE SHEET (RULE 26)
`
`18 of 60
`
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`
`W098/03069
`
`PCTluS97/12229.
`
`- 17 -
`
`alkyl-rnercapto, arylrnercapto, cycloalkyl,
`cycloalkylalkyl, heteroaryl, fluorenyl,
`heteroarylalkyl, hydroxy or oxo; or
`Rl is a fluorenyl-type group of the
`structure
`
`5
`
`or
`
`R1s
`
`or
`
`_ R11_ zt
`
`R12_ z2
`
`10
`
`Ru
`R
`Rl is an indenyl-type group of the structure
`
`; or
`
`or
`
`or
`
`(a= 2,3 or4)
`
`f
`
`or
`
`- R11 - Z1
`R1Z_ z2
`
`15
`
`tl
`zl and z2 are the same or different and are
`independently a bond, O, S,
`
`R1sa
`
`SUBSTITUTE SHEET (RULE 26)
`
`19 of 60
`
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`

`
`, .
`
`W098/03069
`
`PCTIUS97112229
`
`- 18 -
`
`'
`
`-NH-C-
`11
`o
`
`, -N--C- ,
`I
`II
`alkyl O
`
`-c-
`11
`0
`
`or
`
`H:
`
`-~...,--.
`
`OH
`
`s
`" 0
`with the proviso that with respect to~. at least·
`one of zl and z2 will be other than a bond;
`Rll is a bond, alkylene, alkenylene o:r
`alkynylene of up to 10 carbon atoms, aryiene ffor.
`example
`
`5
`
`--©--
`
`.or mixed arylene-alkylene (for example
`~ -g(CH2>n-
`
`10 where n is 1 to 6 ;
`Rl2 is hydrogen, alkyl, alkenyl, aryl, halo(cid:173)
`alkyl, trihaloalkyl, trihaloalkylalkyl, heteroaryl,
`heteroarylalkyl, arylalkyl, arylalkenyl, cyclo(cid:173)
`alkyl,
`aryloxy, alkoxy, arylalkoxy or cycloalkyl-
`alkyl; with the provisos that (1) when Rl2 is H,
`aryloxy, alkoxy or arylalkoxy, then z2 is
`-NH-c-
`, -N -c -
`-c -
`I
`••
`u
`o
`alkyl O
`O
`
`II
`
`or a bond;
`
`15
`
`20
`
`25
`
`30
`
`and (2) when z2 is a bond, Rl2 cannot be
`heteroaryl or heteroarylalkyl;
`· Z is a bond, 0, s, N-alkyl, N-aryl, or
`alkylene or alkenylene of from 1 to 5 carbon atoms;
`Rl3, Rl4, Rl5, and Rl6 are independently
`hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl,
`cycloheteroalkyl, alkenyl, alkynyl, hydroxy,
`alkoxy, nitro, amino, thio, alkylsulfonyl, aryl(cid:173)
`sulfonyl, alkylthio, arylthio, aminocarbonyl,
`alkylcarbonyloxy, arylcarbonylamino, alkylcarbonyl(cid:173)
`amino, arylalkyl, heteroaryl, heteroarylalkyl, or
`aryloxy;
`R15a and R16a are independently any of the
`RlS or Rl6 groups except hydroxy, nitro, amino or
`thio;
`
`SUBSTITUTE SHEET (RULE 26)
`
`20 of 60
`
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`
`

`
`W098/03069
`
`PCT/US97/12l29
`
`or Rl is
`
`- 19 -
`
`.
`
`R17
`
`-(CB;z)p~
`Rl8
`
`wherein p is 1 to 8 and R17 and RlB are each
`independently H, alkyl, alkenyl, aryl, arylalkyl.,
`5 heteroaryl, heteroarylalkyl. cycloalkyl or
`cycloalkylalkyl, at least one of R17 and RlB be{ng ·
`other than H;
`or Rl is
`
`15
`
`20
`
`25
`
`ff20
`-R19--<
`R21
`10 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;
`R2, R3, R4 are independently hydrogen, halo,
`alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl,
`alkylmercapto, arylmercapto, cycloalkyl,
`cycloalkylalkyl, heteroaryl, heteroarylalkyl,
`hydroxy or haloalkyl;
`Rs is alkyl , alkenyl, alkynyl, aryl,
`alkoxy, aryloxy, arylalkoxy, heteroaryl, arylalkyl,
`heteroarylalkyl, cycloalkyl, cycloheteroalkyl,
`heteroaryloxy, cycloalkylalkyl, polycycloalkyl,
`polycycloalkylalkyl, cycloalkenyl, cycloalkenyl(cid:173)
`alkyl, polycycloalkenyl, polycycloalkenylalkyl,
`heteroarylcarbonyl, amino, alkylamino, arylamino,
`heteroarylamino, cycloalkyloxy, cycloalkylamino,
`all of the Rs substituents and R6 substituents (set
`out hereinafter) being optionally substituted
`through available carbon atoms with l, 2, 3 or 4
`groups selected from hydrogen, halo, alkyl,
`haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl,
`cycloalkyl, cycloalkylalkyl, cycloheteroalkyl,
`
`30
`
`SUBSTITUTE SHEET (RULE 26)
`
`21 of 60
`
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`
`

`
`WO 98/03069 .
`
`PCTIUS97/12229
`
`- 20 -
`
`5
`
`10
`
`15
`
`cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl,
`arylcycloalkyl, arylalkenyl, 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, aryl or heteroaryl, or any of the
`other aryl compounds mentioned in the definitions),
`thiol, alkylthio, arylthio, heteroarylthio,
`arylthioalkyl, alkylcarbonyl, arylcarbonyl,
`arylaminocarbonyl, alkoxycarbonyl, aminocarbOnyl,
`alkynylaminocarbonyl, alkylaminocarbonyl,
`alkeriylaminocarbonyl, alkylcarbonyloxy,
`arylcarbonyloxy, alkylcarbonylamino,
`arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl,
`arylsulfonyl, alkylsulfonyl, arylsulfonylamino,
`heteroarylcarbonylamino,·heteroarylsulfinyl,
`heteroarylthio, heteroarylsulfonyl, or
`alkylsulfinyl. Where Rs is phenyl, aryl,
`20 heteroaryl or cycloalkyl; this group preferably
`includes an ortho hydrophobic substituent such as
`alkyl, haloalkyl (with up to 5 halo groups),
`alkoxy, haloalkoxy (with up to 5 halo groups),
`aryl, aryloxy or arylalkyl;
`R6 is hydrogen or C1-C4 alkyl or C1-C4
`alkenyl;
`
`25
`
`../:~~
`.
`
`Hat
`
`and
`
`30
`
`are the same or different and are independently
`selected from heteroaryl containing 5- or 6-ring
`members; and
`including N-oxides of the formulae I and II
`compounds, that is
`
`SUBSTITUTE SHEET (RULE 26)
`
`22 of 60
`
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`
`

`
`W098/03069
`
`PCT/US97/12129
`
`- 21 -
`
`1 and
`
`including pharmaceutically acceptable salts
`thereof.
`The MTP inhibitors disclosed in U.S.
`5 provisional application No. 60/017,254, filed May
`10, 1996, (file HX84*) are azetidine compounds
`which have the structure
`I:
`
`or
`
`10
`
`I:I:
`
`0
`0
`u
`"
`where Q is -C- or -S -
`11
`0
`
`xis: CHR 8,
`
`15
`
`- c- ·CH- CH· or
`"
`• I
`I
`0
`Rg
`R10
`
`-C= C·;
`I
`I
`Ra R10
`
`n is 0 or 1;
`RB, R9 and RlO are independently hydrogen, alkyl,
`alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,
`heteroarylalkyl, cycloalkyl, or. cycloalkylalkyl;
`Rl is alkyl, alkenyl, alkynyl, aryl,
`20 heteroaryl, arylalkyl (wherein alkyl preferably has
`at least 2 carbons, 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 preferably has at least 2 carbons, more
`preferably at least 3 carbons); all of the
`
`25
`
`SUBSTITUTE SHEET (RULE 26)
`
`23 of 60
`
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`CFAD V. UPENN
`IPR2015-01836
`
`

`
`W098/03069
`
`PCTIUS97/12229
`
`- 22 -
`
`5
`
`JO
`
`15
`
`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_,
`alkylmercapto, arylmercapto, cycloalkyl,
`cycloalkylalkyl, heteroaryl, fluorenyl, heteroaryl(cid:173)
`alkyl, hydroxy or oxo; or
`Rl is a fluorenyl-type group of the
`structure
`
`-R11-z1
`
`or
`
`_ R11_ z1
`
`or
`
`R'2- z2
`
`If ~
`y_~
`R13~ R'4
`
`~
`
`or
`
`R13
`R
`Rl is an indenyl-type group of the structure
`
`; or
`
`or
`
`or
`
`(a= 2,3 or 4)
`
`E
`
`SUBSTITUTE SHEET (RULE 26)
`
`24 of 60
`
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`

`
`W098/03069
`
`PCTIUS97/12229
`
`- 23 -
`
`R13
`
`R14
`
`or
`
`- R11- z1
`n12_ z2
`
`;
`
`R16a
`
`R~"
`
`- R11_ z
`12
`2
`R - z
`R1sa (CH2)a
`
`R168
`
`g
`
`H
`zl and z2 are the same or different -and: are
`independently a bond, 0, S,
`
`R1Sa
`
`5
`
`10
`
`15
`
`20
`
`25
`
`-N--C-
`1
`II
`alkyl 0
`
`or
`
`H
`-~-
`OH
`
`-c-
`( ~) , -NH-~- •
`11
`0
`0 2
`0
`with the proviso that with respect to ~. at least
`one of zl and z2 will be other than a bond;
`Rll is a bond, alkylen