l||||||||||||||||||l|||||||||||||||||||||||||||||||||||||||||||||||||||||||
`
`US()[)6(l57_'-l39A
`
`United States Patent
`
`.19.
`
`[in Patent Number:
`
`6,057,339
`
`Gregg
`
`[45] Date of Patent:
`
`May 2, 2000
`
`[S4 ME'l‘H()ll 01" lNHllll'l'll‘-IG (DR 'l'Rl‘L/\'I‘lN[}
`PHY'[‘()S'I“EROI.EMIA WI'l‘H AN MTI’
`[NHlBl'l‘()R
`
`[?5'
`
`Inventor: Richard E. Gregg, Pennington, NJ.
`
`[73
`
`Ase-'.igI1ee: Bristol-Myers SquihI1Cumpan_v,
`Princeton, NJ.
`
`[21‘ Appl. NLL: 09:"0l|5,-130
`
`22'
`
`Filed:
`
`Jan. 10, 1993
`
`Related U.S. Application Data
`Provisional application No. 60,-'U35_.59L, Jan. 17, 1.097.
`
`[6U‘
`
`Int. Cl.7 ....................... .. A6lK 311445; A61K 31;’21
`[51'
`[ST U.S. Cl.
`......................... .. 514E325; 514E510; 514E824
`[S8'
`Field nf Search ................................... .. 514,825, 510,
`5 I4/824
`
`[56
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`3/1'éJ§J6 Miettinen et al.
`5,5n2_t.L45
`5,7|2_279 M1993 Tiiller el -.11.
`FOREIGN P/ULNT DOCUMENTS
`
`5145182
`5143252
`
`[}'l‘H ER l’UB[ .l(.‘A'l'l(JNS
`
`Scriver et al, "The Metabolic and Molecular Bases of
`Inherited Disease". Seventh Edition. vol. II. Tljorkhern et al,
`"inborn Errors in Bile Acid l-Biosynthesis and Storage of
`Slerols. ()llIern Than (.‘l1ole.~;lerol“. pp. 2(l73—2(}99, (1995).
`
`of
`bflecls
`“SiIosterolemia—Upposing
`al,
`et
`(.‘ol)l)
`Clinlealylamine and Lovaslalin on Plasma Sterol Levels in 21
`Ilornozygous. Girl and Her lleterozygous. l-Either", (Rock-
`efeller Univ.. Bioehem. Genet & Belah Lab, New York,
`NY). Abstract No. 96:43-1984, Metabolism—Clini<.‘al and
`Experimental, vol. 45, No. 6, pp. 673-679, Jun. 1996.
`CA: 124:1?4453, Parsons et al., 1995.
`CA 125:‘! 32403, Ilidaka et al., 1995.
`
`Prirririry L'xrimL'r.=e.r—Ki111berly Jordan
`AII()rm’J1.-‘, Agent, or Firm—Burlon Rodney; Ronald S.
`Herincnau
`
`[57]
`
`AHSTRACI"
`
`A method is provided for inhibiting onset of or treating
`phytosterolemia by administering to a patient an MTP
`‘
`_
`_
`_
`_
`_
`‘
`_
`Inhlhllnr. alone 0r Optltmlly. In Uomblnailvn Wllh another
`cholesterol lowering drug. such as pravastatin.
`
`w()96,-'2ra2[J5
`
`8x1<.J95 WIPO .
`
`25 Claims, No Drawings
`
`1 of 22
`
`PENN EX. 2094
`CFAD V. UPENN
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`
`6,057,339
`
`1
`METHOD OF INHIBITING OR 'I"RI§A'l"IN(I
`PI-IY'I‘OSTER0l.l7.MIA WITH AN MTP
`IN HIBITOR
`
`This application claims benefit to U.S. Provisional Appli-
`cation 6t'l,"(l35,59l, tiled Jan. 17, 1997.
`
`FIELD OF TI IE INVENTION
`
`The present invention related to a method for inhibiting
`onset of or treating pliytosterolcrnia, by administering an
`MTP inhibitor alone or in combination with another cho-
`
`lesterol lowering drug, such as pravastatin.
`
`IBACTKEEROUNIJ OI’ TIIL7. [NVI_-lN'l'l()N
`
`10
`
`15
`
`As indicated in Scriver, C. R. et al “Metabolic Basis of
`Inherited Diseases" Vol. II (1995), Chap. 65, lnhorn Errors
`in Bile Acid Biosyritliesis and Storage of Sterols Other than
`Cholesterol, Bjorkhem,
`I. and Boberg, K. M., pp.
`2[l73—2U99, 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 charac-
`
`terized by "tendon and tuberous xanthomas and by a strong
`predisposition to premature coronary Ellht:l'():-iCll)t'('!.*-31!-3 .
`.
`.
`.
`Increased amounts of phytosterols (plant sterols), such as
`sitosterol and campesterol and their 5o.—stanols, are [ou nd in
`blood, plasma, erythrocytes, and different tissues, especially
`in the xanlhomtts and arteries ofatlectcd subjects. Increased
`serum cholesterol and cholesterol have also been found in
`
`many patients." (p. 3073)
`
`Patients afflicted with phytosterolemia have been found to
`have an increased iticitletice of coronary heart tliscase at all
`early age most likely due to early development of athero-
`sclerosis at an early age. Bjorkhem et al, supra, indicate at
`page 2090 that “the mechanism behind the atherosclerosis is
`uiiexplttitied, but a high cuiilctit of plant sterols iii
`the
`circulating lipoproteins might promote their deposition in
`the arterial wall.”
`
`The microsomal triglyceride transfer protein (MTP) cata-
`lyzes the transport of triglyceride (TO), cholesleryl ester
`(Cl.-'.), and phosphatidylcholine (PC) between small unila-
`_
`I
`_
`_
`mauar V°51"J“"S(5Uv)' Wellerau & Zllversmllv C‘J""m' P‘l‘3"""
`Lip-'-ids 38- 205‘23 (19851 when l“”'15feT “*l"v’5 are "37‘Pl""3‘-*5“-"'~l
`as the percent of the donor lipid transferred per time, MTP
`expresses a distinct preference for neutral lipid transport
`
`30
`
`40
`
`4-5
`
`so
`
`2
`1: Wetterau, J. R. and Zilversmit, D. B. (1985) Chem. Phys.
`Lipids 38, 205-222.
`Wetterau, J. R., et al,
`9R(|0—9R07_
`Wetterau, .l. R., et al, (1991) Biochemistry 31], 4406-4412.
`Alzcl, A., and Vlietterati, J. R. (1993) Biochetiiislry 32,
`l(I444—l U451}.
`
`(19911) J. Biol.
`
`(Them. 265,
`
`Atzel, /\., and Wetterau, J. R. (1994) Biochemistry 33,
`15382-15388.
`
`Jantil, Il.. et al. (1995) J. Biol. Chem. 370, 6549-6554.
`2. Sharp, I). et al, (1993) Nature 365, 65-69.
`Lin, M. (T. M., et al, .1. Biol. (Them. 269, 29138—29l45.
`Nakamuta, M., et al, (1996) (ienomies 33, 313—316.
`3. Wettcrau, J. R., ct al.
`(1990) J. Biol. Chem. 265,
`98t)0—98(I7.
`Wettcrau,.l. R., et al, (1991) Bioclieniistry 30, 97%—9735.
`4. Ricci, IL, et at, (1995) J. Biol. Chem. 270, 14281-14135.
`ln vitro, MTP catalyzes the transport of lipid molecules
`between pliospholipid membranes. Presumably,
`it plays a
`similar role in vivo, and thus plays some role in lipid
`metabolism. The subcellular (lumen of the microsomal
`fraction) and tissue distributioii [liver and iiitestiiie) of MTP
`have led to speculation that it plays a role in the assembly of
`plasma lipoproteins, as these are the sites of plasma lipo-
`protein assemlily. Wette rau & Zilversmit, Iiiociieiit. Iiiopltys.
`Acra 875, 610-7 (1986). The ability of MTP to catalyze the
`transport oli TG between membranes is consistent with this
`hypothesis, and suggests that MTP may catalyze the trans-
`port 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 aulosomal recessive disease
`characterized by a virtual absence of plasma lipoproteins
`which contain apolipoprotein B (apoB). Kane & llavel in
`Ute Membot't'c Brrsis of InIte.I'r'i‘eri Dt'sert.5'e, Sixth edition,
`1139—64 (1989). Plasma TG levels may be as low as a few
`mgfdL, and they fail
`to rise after fat
`ingestion. Plasma
`cholesterol levels are often only 20-15 mgjd L. These abnor-
`malities are the result of a genetic defect in the assembly
`andfor 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 choles-
`terol synthesis appear normal. At autopsy, subjects are [rec
`of atherosclerosis. Schacler ct al., Ciin. Chem. 34, B9—l2
`(1988). A link between the apol3 gene and abetalipopro—
`teinemia has been excluded in several families. Talmud et
`
`al.,.I. Clirt. l'm’e.s“I. 82, 1803-6 (1988) and lluang et al.,Am.
`J. Htmt. Genet. 46, 1141-8 (1990).
`the defect causing
`Recent reports (5) demonstrate that
`abetalipoproteinemia is in the MTP gene, and as a result, the
`MTP protein. When examined, individuals with abeLalipo—
`proteinemia have no MTP activity, as a result of mutations
`in the MTP gene, some of which have been characterized.
`
`'11_iese results indicate that M'1Pis required for the synthesis
`(TU and CL), relative to phospholipid transport. The 55
`0l "P013 C0l'11ii1l'11T1}% 11P0PT0l51D-‘is -‘$1-‘Ch «'15 VLDL. “'13 PIC‘-‘UT’
`microsomal triglyceride transfer protein from bovine liver
`5”’
`'0
`It
`'h°“’f°r° follnws that 'nh1h”m""‘ “f M”
`has been isolated and extensively characterize(|(1). This has
`would inhibit the synthesis of VI.[)[. and [.l)I.,
`thereby
`ha [0 the cloning of CDNA expressing [ha pmlcin [mm
`lowering \rI.|)I. levels, [.13]. levels, cholesterol levels, and
`.
`.
`.
`.
`_
`.
`.
`.
`.
`.
`several species, including humans (2). M I P is composed of
`so triglyceride levels in animals and man.
`‘
`I
`_
`,
`_
`I
`_
`, _
`_
`_
`I
`‘
`1
`_
`_
`3 wcncrau’ ]_ R_’ at “I, (I 992) Science 253, 99g_mm_
`two siibitnits. The small sttbunit is the previoitslycharat.ter-
`Sharp’ D’! C‘ al, (1993) Nature 365’ 65 69_
`ized rnultifunctional protein,‘ protein disulhde isomerase.
`Ricci, 3” m 3]’ (1gt)5) _]_ may (11-]cm_ 2701 1423]_14_'_)g5_
`This is supported by biochemical analysis of the protein (3)
`ghoutdm-5,
`('j_ (“__,
`.31 31, (-1993) ]—[um_ MOL Genetics 2,
`as well as eo—expression studies performed in insect Sf‘)
`cells using the baculovirus expression system. Expression of (,5. g1[]t;_3] ]5_
`soluble active M'l'I’ requires the co—expression of PIJI and
`Nareisi, T. M. E., et al, (1995) Am. J. Hum. Genet. 57,
`the unique large subunit of MTI’ (4).
`l29Fi—l 310.
`
`2 of 22
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`

`
`6,057,339
`
`3
`Rehherg, E. F., et al, .1. Biol. Chem (in press).
`Canadian Patent. Application No. 2,091,102 published
`Mar. 2, [994 (corresponding to US. application Ser. No.
`117,362, filed Sep. 3, 1993 (file [)CT2lb)) which is incorpo-
`rated herein by reference), reports M'[‘I’ inhibitors which
`also block apoB containing lipoprotein secretion in a human
`hepatic cell line (I IepG2 cells). Thisprovides further support
`for the proposal that an MTP inhibitor would lower apoT§
`containing lipoprotein and lipid levels in vivo. This Cana-
`dian patent application discloses a method for identifying
`the MTP inhibitors.
`triglyceride transfer protein
`The use of mierosomal
`(M'l'I’)
`inhibitors for decreasing serum lipids including
`cholesterol and triglycerides and their use in treating
`atherosclerosis, obesity, hyperglycemia, and pancreatitis is
`disclosed in W0 96.326205, published Aug. 29, "I996, U.S.
`application Ser. l\'o. 412,067, filed Jun. 0, 1995 (file DC21e),
`US. application Ser. No. 548.811, liled Jan. "ll, 1996 (lile
`[)C2lh), U.S. provisional application Ser. No. 60;/Ul7,224,
`filed May 9, 1996 (file HX".’9:1*), US. provisional applica-
`tion Ser. No. 6U,l(l'l7,253, filed May ‘[0, 1996 {file HX82*),
`US, provisional application Ser. No. 60,l0'|7,25-1, May 10,
`1996 [file HXt-34*) and US. provisional application Ser. No.
`ti0rU28,2'1(:, filed Oct.
`'1, 1996 (tile llX8(i*).
`All ofthe above U.S. applications are incorporated herein
`by reference.
`])l:'.S(Il{Il"l‘[()N OF 'l‘H1:‘. [NVEN'l'l(lN
`
`invention, a method is
`In accordance with the present
`provided for inhibiting onset of or treating phytosterolemia,
`in mammalian species, wherein a therapeutically effective
`amount of a microsomal triglyceride transfer prole in [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 transdernially,
`to patients in need of treatnztent.
`In accordance with the present invention, the M11’ inhibi-
`tor lowers plasma cholesterol (l,l)l.—el1olesterol) to at least
`about 50% of normal LDL blood level, preferably down to
`less than about 25% of nornial, and lowers triglycerides to
`at least about 50% of normal triglyceride blood level, and
`preferably down to about 25 "0 or less of normal, and thereby
`reduces plasma cholesterol and resulting atherosclerosis.
`The terms “another cholesterol lowering drug or agent” or
`“another delipidating drug" will be employed interchange-
`ably herein.
`MTP inhibitors to be employed in the ntethods of the
`invention include M11’ inhibitors disclosed in Canadian
`Patent Application _\lo. 2,091,102 described hereinbefore
`(corresponding to US. application Ser. No. 117,362), W0
`92Q62[l5 published Aug. 29, 1996, U.S.applit:ationSer.N(1.
`472,067, filed Jun. 6. 1995 (file l_)C21e), US. application
`Ser. No. 548,811, filed Jan. 11, 1996 (file DC21h), US.
`provisional application Ser. No. 6Ur'U17,224, filed May 9,
`1996 (lile HX79a*), US. provisional application Ser. No.
`ti[l,»'U'l"i',253, filed May '10, I996 (file I-lX82*), U.S. provi-
`sional application Ser. No. 6{l:’017,254, filed May 10, 1996
`(file HX84*), and U.S. provisional application Ser. No.
`6Ut’[l%,216, filed Oct. 1, 1996 (file HX86‘). Preferred are
`each ofthe preferred MTP inhibitors disclosed in each ofthe
`above applications.
`All ofthe above U.S. applications are incorporated herein
`by reference.
`
`10
`
`15
`
`30
`
`40
`
`4-5
`
`50
`
`SS
`
`hf‘!
`
`4
`The MTP inhibitors disclosed in US. application Ser. No.
`472,067, Iiled Jun. 6, 1995 (file DC21e) are piperidine
`compounds of the structure
`
`0
`
`_
`where Q is
`
`II
`TC T or
`
`o
`
`II
`TST
`ll0
`
`x is: C1114“,
`
`0
`
`R9
`
`R10
`
`or
`
`R9
`
`R10
`
`R“, R9 and R1” are independently hydrogen, alkyl, alkenyl,
`alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
`eyeloalkyl, or cyeloalkylalkyl;
`
`Y is
`
`T[:{'HgJ,,,
`
`or
`
`ll0
`
`wherein m is 2 or 3;
`
`R1 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 cyeloalkylalkyl wherein alkyl has at least 2
`carbons, all optionally sulistituted through available carllon
`atoms with 1, 2, 3 or4 groups selected from halo, haloalkyl,
`alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl,
`alkylmercapto, arylmercaplo, eycloalkyl, cycloall-zylatkyl,
`lreleroaryl, fluorenyl, lteleroarylalkyl, ltydroxy or onto;
`
`30122
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`PENN EX. 2094
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`
`6,057,339
`
`5
`or R; is a l‘1uorenyl—type group of the structure
`
`R16
`‘\{’
`
`R15
`
`\/‘
`
`
`
`
`
`R1 is an indenyl-type group of the structure
`
`R1)
`
`//
`
`\
`
`R]-I
`
`TRHT;-1
`
`‘\ .
`/
`Rizjfi-‘2R15u\((_,H:)'/‘
`Rim
`[.7 =?._.3 CI4)
`
`R1.‘
`\‘_a*/
`/
`
`R14
`
`\Z\
`\
`
`_:R1J_71
`
`0?
`
`or
`
`R1'_=:l2
`
`Rm‘
`
`R15:
`
`I.-L
`
`F
`
`0
`
`or
`
`[I
`
`Z.’ and 2.: are the same or dilferent and are independently
`a bond, 0, S,
`
`10
`
`15
`
`30
`
`40
`
`4-5
`
`50
`
`55
`
`E1?!
`
`with the proviso that with respect to H, at least one of Z‘ and
`Z2 will be other than a bond; R“ is a bond, alkylene,
`alkenylene or alkynyl-.:ne of up to 10 carbon atoms; arylcne
`or mixed arylene—alkylene; R13 is hydrogen, alkyl, alkenyl,
`aryl, haloalkyl,
`lrihaloalkyl,
`lrihalloalkylalkyl, heteroaryl,
`heteroarylalkyl, arylalky], arylalkenyl, eycloalkyl, arylnxy,
`alkoxy. arylalkoxy or cycloalkylalkyl, with the provisos that
`preferably
`(1) when R” is H, aryloxy, alkoxy or arylalkoxy, then Z3
`LS
`
`~
`
`II
`
`__
`
`.
`
`II
`
`I
`
`L
`
`II
`
`or a bond and
`(2) when Z2 is a bond, R” cannot be heteroaryl or
`heteroarylalkyl;
`Z is a bond, 0, S, N-alkyl, N-aryl, or alkvlene or alk-
`enylene from 1 to 5 carbon a1oms;R”, R”, Rig, and R” are
`independently hydrog-.:r1, all-iyl, halo, haloalkyl, aryl,
`eycloalkyl, eyeloheteroalkyl, alkenyl, alkynyl, hydroxy,
`alkoxy, nilro, amino,
`lhio, alkylsulfonyl, arylsulfonyl,
`alkyllllio, aryllhio. aminocarbonyl, alliylearbenyloxy,
`arylcarbonylamino, alkylcarbonylarnino, arylalkyl,
`hetcroaryl. heteroarylalliyl or aryloxy;
`R15" and R15“ are independently hydrogen, alkyl, halo,
`haloalkyl, aryl, cycloalkyl. cyclohetcroalkyl, alkenyl,
`alkynyl, alkoxy, alkylsulfonyl, arylsulfonyl, alkyllhio,
`aryllhio, aniinocarbonyl, all-tylcarbonyloxy,
`arylcarbonylamino, alkylcarbonylarnino, arylalkyl,
`heleroaryl, heleroarylalkyl. or aryloxy;
`or R1 is a group of the structure
`
`R17
`fc.‘1I;‘_a,.4<R15
`
`wherein p is 1 to 8 and R” and R” are each independently
`II, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
`eycloalkyl or eycloalkylalkyl at least one of R” and R”
`being other than II;
`or R‘ is a group of the structure
`
`R30
`_R19% R11
`
`wherein R” is aryl or heleroaryl;
`R2“ is aryl or hetcroary];
`R11 is II, alkyl, aryl, alkylaryl, arylalkyl, aryloxy,
`arylalkoxy, heleroaryl, heleroztrylalkyl, heteroarylalkoxy,
`eyeloal.kyl, eyeloalkylalkyl or cycloalkylalkoxy;
`R2, R3, R" are independently hydrogen, halo, alkyl,
`alkenyl, alkoxy, aryloxy, ary], arylalkyl, alkylmcreapto,
`arylmercaplo, cycloalkyl, cycloalkylalkyl, heleroaryl,
`heteroarylalkyl, hydroxy or hnloalkyl;
`
`40f22
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`6,057,339
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`7
`R5 is independently alkyl, alkenyl, alkynyl, aryl, alkoxy,
`arylnxy, arylalkoxy, hereroaryl, arylalkyl, hcteroarylalkyl,
`cyeloalkyl. cyeloalkylalkyl, polycyeloalkyl,
`polycycloalkylalkyl, cycloalkenyl, eycloheteroalkyl,
`heteroaryloxy, eycloalkenylalkyl. polycycloalkenyl,
`polyeycloalkenylalkyl, heteroarylearbonyl, amino,
`alkylamino, arylamino, heteroarylamino, eycloalkyloxy,
`cycloalkylamino, all optionally substituted through avail-
`able carbon atoms with 1, 2, 3 or 4 groups selected from
`hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy,
`alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,
`cycloheteroalkyl, eyelohcteroalkylalkyl, aryl, heteroaryl,
`arylalkyl, arylcycloalkyl. arylalkenyl, arylalkyttyl, aryloxy,
`aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo,
`heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy,
`nitro, cyano, amino, substituted amino,
`lhiol, alkylthio,
`aryllhio, heteroarylthio, arylthioalkyl, alkylcarbonyl,
`arylcarhonyl, arylaminocurhonyl, alkoxycarbonyl,
`aminocarbonyl.
`alkynylaminocarbonyl,
`alkylaminocarbony], alkenylarnirtocarhnnyl,
`alkylcarlaonyloxy, arylearbonyloxy, alkylcarbonylamino,
`arylearbonylamino, arylsulfinyl, arylsulfinylalkyl,
`arylstllfonyl, alkylsulfonyl, arylsulfonylamino,
`hcteroarylcarbonylamino, hcteroarylsulfinyl, hcteroarylthio,
`heteroarylsulfonyl, alkylsulllnyl;
`
`R5 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 dell-
`nition of R5 set out above;
`
`R? is alkyl, aryl or arylalkyl wherein alkyl by itself or as
`part of ztrylalkyl is optionally substituted with oxo
`
`(ill a
`
`are the same or different and are independently selected from
`heteroaryl containing 5- or 6—ring members; and
`
`N—oxides
`
`lhereo I‘; and
`
`pharrnaceutically acceptable salts thereo[; with the pro-
`visos that preferably where in the First Formula X is CH2, and
`R3, R3 and R4 are each II,
`then R1 will be other than
`3,3—dipl1enylpropyl, and preferably in tltc Ilflh fomtula,
`where one of R2, R3 and R4 is t')—l1uoro, and the others are
`H, R7 will be otlter than 4—(2—t11ctl1o.xyplteuyl).
`
`'l'he M'l'l-‘ inhibitors disclosed in US. application Ser. No.
`548,811 llled Jan. 11, 1996 (file DC21h), have the structure
`
`10
`
`15
`
`—
`
`30
`
`40
`
`50
`
`55
`
`E1?!
`
`including the piperidine N-oxide thereol" or a pl1artnaceLtti-
`eally acceptable salt thereof, wherein Z is a bond, 0 or S;
`X1 and X3 are independently selected from H or halo;
`3: is an integer from 3 to I5;
`R5 is heteroaryl, aryl, heterocycloalkyl or Lycloalkyl, each
`R‘ group being optionally substituted with 1., 2, 3 or 4
`substituents which may be the same or dillerent.
`The MTP inhibitors disclosed in US. provisional appli-
`cation No. 6U;’0l7,224, filed May 9, 1996 (file HX79a“}
`have the structure
`
`0
`L3 /lL L1
`n3/ ‘A
`13/ “R1 °'
`
`t<3\
`
`1.3
`
`(ojq
`,ii
`
`I.‘
`“'15/F “R1
`on
`
`or
`
`rt?
`\“J_"
`
`1.1
`
`13/
`
`R‘
`
`RX
`
`IA
`
`In
`
`including pharmaceulically acceptable salts thereof, wherein
`q is 0,
`l or 2;
`A is
`
`(L) a bond;
`(2) —O—; or
`
`(3)
`
`:11:
`
`l,.t{'
`
`where R5 is H or lower alkyl or R5 together with R2 forms
`at carbocyclic or hcterocyclic ring systetti cutitainittg, 4 to 8
`members in the ring.
`B is .1 l.luorenyl—type group of the structure:
`
`R3
`
`R1‘
`
`t\ ““
`
`( / X
`33
`
`l “J
`
`I ’
`R‘
`
`S0f22
`
`PENN EX. 2094
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`6,057,339
`
`-continued
`
`
`
`(the above l-3 is also referred to as a fiuorenyl—type ring or
`moiety); or
`B is an indenyl—type group of the structure
`
`R-‘
`
`
`
`R-‘ — R-"
`\I‘
`/\
`
`Of
`
`R31:
`
`R3:
`
`10
`
`__/it-‘
`[let
`
`it”
`
`it“
`
`(the above B is also referued to as an inclenyl-type ring or
`moiety);
`R’ is ll, alkyl or aryl;
`R1 is alkyl, alkenyl, alkynyl, alkoxyl, (alkyl or aryl)3Si
`(where each al.kyl or aryl group is independent), cycloalkyl,
`eyeloalkenyl, substituted alkylamino, substituted
`arylalkylarnino, aryl, arylalkyl, arylamino, aryloxy,
`heteroaryl, heteroarylamino, heteroaryloxy,
`arylsulfonylarnino, heleroarylsulfonylamino, arylthio,
`arylstiltinyl, arylsulfonyl, alkylthio, alkylsullinyl,
`alkylsulfonyl, heteroarylthio, heteroarylsulfinyl,
`heteroarylsnlfonyl, —P0(R”) (R”), (where R17’ and R”
`are independently alkyl, aryl, alkoxy, aryloxy, heteroaryl,
`heteroarylalkyl, heteroaryloxy, heteroarylalkoxy,
`cyeloheI.eroalkyl, eyelohe1.eroalkylalkyI, eyeloheleroalkoxy,
`or cycloheteroalkylalkoxy); R1 can also be aminocarbony]
`(where the amino may optionally be substituted with one or
`two aryl, alkyl or heteroaryl groups]; cya no, 1,1-(alkoxyl or
`aryloxy):alkyl [where the two aryl or alkyl suhstituenk; can
`be independently defined, or linked to one another to form
`a ring, such as 1,3-dioxane or 1,3-dioxolane, connected to L1
`(or L3 in the ease of R‘) at the 2-position); 1,3-dioxane or
`1,3-dioxolane connected to L] (or L3 in the case of R2) at the
`4—position.
`The R1 group may have from one to [our substittlents,
`which can be any of the R3 groups or R‘ groups, and any of
`the preferred R1 suhstituents set out below.
`R1 may be substituted with the following preferred sub-
`stituents: alkylearbonylamino, eycloalkylearhonylamino,
`
`10
`arylearbonylamino,
`heteroarylearbonylamino,
`alkoxycarbonylamino, aryloxycarbonylatnino,
`heteroaryloxylearbonylamino, uriedo (where the uriedo
`nitrogens may be substituted with alkyl, aryl or heteroaryl],
`heteroeyelylearhonylaminn (where the heteroeyele is con-
`neeled to the carbonyl group via a nitrogen or carbon atom],
`alkylsulfonylamino,
`arylsulfonylamino,
`heteroarylsulfonylamino,
`
`t<3‘—
`
`R3"\
`
`1
`R22
`
`o
`
`t<— .
`/
`
`I
`
`wheieJis:CHRn_.
`
`0
`
`—(‘.n—(:n—— or —C=(|‘.—;
`R9‘
`R35
`R“ R1‘
`
`R23, R1" and R35 are independently hydrogen, alkyl, alkenyl,
`alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
`cycloalltyl, or cyclual.kylal.lLyl;
`R20, R2‘, 112* are independently hydrogen, halo, alkyl,
`alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmereapto,
`arylmereapto, eyeloalkyl, eycloalkylalkyl, heleroaryl,
`heteroarylalkyl, hydroxy or haloalkyl; and these preferred
`substituenls may either be directly attached to R‘, or
`attached via an alkylcne chain at an open position.
`R2 is the same or different from R1 and is independently
`any of the groups set out for R1, II, polyhaloalkyl (such as
`(TI~‘3(_‘H:, (fl~‘3(.‘[-'_,_{.‘H_, or (F3) or eyeloheteroalkyl, and may
`be substituted with one to four of any of the groups defined
`for R3, or any of the substituetits preferred for R‘.
`I.‘ is a linking group containing from 1 to 10 carbons in
`linear chain {including alkylene, alkenylene or
`a
`alkynylene), which may contain, within the linking chain
`any ofthe following: one or two alkertes, 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).
`I? may he the same or different
`from I,’ and may
`independently be any oi‘ the [.1 groups set out above or a
`sillge hond.
`R3, R3‘, R4 and RE may be the same or ditlerenl and are
`independently selected from ll, halogen, Cl"-3, haloalkyl,
`hydroxy, alkoxy, alkyl, aryl, alkenyl, alkcnyloxy, alkynyl,
`alkynyloxy, alkanoyl, nitro, amino,
`thiol, alkylthio,
`alkylsulfinyl, alkylsulfonyl, earboxy, alkoxycarbonyl,
`atniltoearbottyl, alkylcarbonyloxy, alkylcalrbottylzllrlillo,
`cycloheteroalkyl, cyeloheleroalkylalkyl, cyano, Ar,
`Ar—a|.kyl, ArO, Ar—amino, Ar—thio, Ar—sulfit1yl, Ar—sulfonyl,
`Anearbonyl, Ar—cart)onyloxy or Anearbonylamino, wherein
`Ar is aryl or heteroaryl and Ar may optionally include I, 2
`or 3 additional rings fused to Ar;
`R3" and R3” are the same or different and are indepen-
`dently any oi" the R3 groups except hydroxy, nitro, amino or
`thin;
`
`10
`
`15
`
`30
`
`40
`
`4-5
`
`50
`
`S5
`
`er
`
`of‘!
`
`are the same or diflerent and independently represent a 5 or
`(1 membered heteroaryl ring which may contain 1, 2, 3 or 4
`heleroatoms in the ring which are independently N, S or 0;
`and including N—oxides_
`
`60f22
`
`PENN EX. 2094
`CFAD V. UPENN
`IPR2015-01836
`
`

`
` R-”—
`
`R‘
`
`/
`
`-
`
`N
`
`J
`-
`ts—R :or
`
`W’
`
`II
`
`11
`X [in the fluorenyl type ring) is a bond, or is one of the
`following groups:
`
`6,057,339
`
`(1)
`
`3)
`
`(3:
`
`(4)
`
`(5)
`
`(6)
`
`(7)
`
`— (0}..v
`
`_0_
`
`1:‘
`
`_((_
`I \
`R’
`1:3
`
`/
`
`R9
`
`\Rlfl R9'/ ‘\RIfI‘
`
`jclce
`
`I|{l{|
`IL?"
`_C Y-_
`/ \
`it”
`is“
`
`wherein
`
`Y is o, N—R° or s;
`n' is U, l or 2;
`
`3&5 is H, lower all<yl, aryl, —C(l'))—R” or —C(O)—O—
`R ;
`
`R7 and R“ are the same or different and are independently
`H, alkyl, aryl, halogen, —U—R"', or
`R7 and R” together can be oxygen to form a ketone;
`
`R9, R10, R5’ and Ric" are the same or diJIerent and are
`independently II. lower alkyl. aryl or —O—R“;
`
`Roi and Rmi are the same or different and are indepen-
`dently I-l, lower alkyl, aryl, halogen or —O—R“;
`
`R“ is alky or aryl;
`R12 is H, £ll.l{§'l or aryl.
`The following provisos apply to formula I preferred
`compounds:
`tinsilhstitutecl alkyl or unsul).-ailtited
`is
`(at) when R1
`arylalliyl, L1 cannot contain amine;
`(b) when R1 is alkyl, 1.1 cannot contain amino and mm in
`adjacent positions {to form an amido group);
`
`(C) when R:I_:A— is HSN , R11} cannot contain amino;
`(cl) when R‘ is eyano, I.1 must have more than 2 carbons;
`
`(e)R1l.must contain at least 3 carbon:-'..
`With respect to cornpounds IA and IB, R21? cannot have
`an 0 or N atom directly attached to S=(O)q or (".R"‘(0I-l),
`and for IA, R21} cannot be ll.
`
`With respect t.o preferred compounds of formula IA and
`IB, where R1 is cycloheteroalkyl, R1 is exclusive of 1- pipe r-
`iclinyl,
`l—pyrrolidinyl,
`l—.'i7.cliiliny| or
`"I —('2—oxn—
`pyrrolidinyl).
`The .\1‘lTPinhihilors disclosed in US. provisional appli-
`cation No. 60,017,253, tiled May 1U, 1996, (tile IIX82"‘) are
`pyrrolidine compounds and have the structure
`
`10
`
`15
`
`30
`
`40
`
`4-5
`
`50
`
`SS
`
`bf‘!
`
`115/O\~‘1\'
`llgs
`
`w
`
`o
`
`rx'—R‘;
`
`II
`_
`whereO1.s TET or
`
`o
`
`II
`
`o
`
`W is H,H or 0;
`
`x is:c1IR“_. —i|‘—, —r|‘H—r|‘H— or —:|‘=(|-—:
`()
`R9
`Rltl
`R9
`R10
`
`R”, R9 and R” are independently hydrogen, alkyl, alkenyl,
`alkynyl, aryl, arylalkyl, hcleruaryl,
`liclcroarylalkyl,
`cycloalkyl, or cycloalkylalkyl;
`R1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl
`(wherein alkyl preferably has at
`least 2 carbons, more
`preferably at
`least 3 carbons), diarylalliyl, arylalkenyl,
`diarylalkcnyl, arylalkynyl, diarylalkynyl, diarylalkylaryl,
`hetcroarylalkyl (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
`aforcrnenlinnerl R1 groups‘. being optionally stihstituterl
`through available carbon atoms with '1, 2, 3 or 4 groups
`selected from halo, haloalkyl, alkyl, alkenyl, alknxy,
`aryloxy, aryl, arylalkyl, alkylmercapto, arylmcrcapto,
`eycloalkyl, czycloalkylalkyl, heteroaryl,
`iluorenyl,
`heteroarylalkyl, hydroxy or oxo; or
`R1 is a lluorenyl-type group of the structure
`
`
`
`70f22
`
`PENN EX. 2094
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`6,057,339
`
`14
`
`13
`
`-continued
`
`\g \/
`
`‘
`
`5
`ll.
`0
`
`S
`(||).~
`0,
`
`:1\H—r_‘: —h—c—
`ll
`..
`|
`ll
`o
`alk}'10
`
`He or 4;
`II
`I
`(J
`011
`
`“
`
`20
`
`10 with the proviso that with respect to B, at least one of Z‘ and
`Z3 will be other than a bond;
`
`D
`
`15
`
`R" is a bond, alkylcne, alkenylene or alkynylene ofup to
`10 carbon atoms, arylcnc (for example
`
` j ]
`V .-
`
`or mixed arylcnc—alkylcnc (for example
`
`:01’
`
`R1 is an indcnyl—lypc group of the structure
`
`35
`
` ((ll['2J‘l-1 I
`
`|{l_i
`|_\\
`/ {
`
`R1-I
`
`TR“:71 :
`\\
`_,
`2
`R :‘l”R1aa ‘(cH3,;/
`[:2 = 2, 3 or 4)
`
`R‘““
`
`0'
`
`
`
`Rm \({,H2)=./\‘];16n
`
`Rn
`|_‘/ti“
`net
`
`TRHTZ1
`
`R1;_z-
`
`R1“
`
`RIS:
`
`F
`
`"T
`
`H
`
`Z1 and Z3 are the same or different and are independently
`a bond, 0, S,
`
`to 6;
`where n is "l
`30 R” is hydrogen, alkyl, nlkcnyl, aryl, haloalkyl,
`trihaloalkyl,
`trihaloalkylalkyl, heteroaryl, heleroarylalkyl,
`arylalkyl, arylnlkcnyl, cycloalkyl, aryloxy, alkoxy, aryla—
`lkoxy or cycloalkylalkyl; with the provisos that (1) when
`35 R12 is H, arylnxy, alkmty or arylalkoxy, than 73° is
`_
`:_\—r_‘: : A
`I
`II
`,
`II
`alkyl 0
`0
`
`:NH—(_‘:
`ll
`(J
`
`.-
`
`40
`
`or a bond;
`
`45
`
`and (2) when Z3 is a bond, R12 cannot be heleroaryl or
`heleroarylalkylg
`Z is a bond, 0, S. N-alkyl. N-aryl. or alkylene or alk-
`enylene of from 1 to 5 carbon atoms;
`Rm’, R”, R”, and R” are independontly hydrogen, alkyl,
`halo, haloalkyl, aryl, Lycloalkyl, cycloheleroalkyl, alkenyl,
`50 alkynyl, hydroxy, alkoxy, nitro, amino, thio, alkylsulfonyl,
`arylsulfonyl, alkylthio, arylthio, aminoa.'arhonyl,
`alkylcarbonyloxy, arylcarbonylamino, alkylcarbonylamino,
`arylalkyl, heteroaryl, heleroarylalkyl, or aryloxy;
`.
`R15“ and R1°"’ are independently any o[ the R15 or R”
`V
`55 groups except lzydlm-ry, nitro, amino or thin;
`or R1 is
`
`an
`
`(,5.
`
`(t:H;ju,./<
`
`R”
`
`R15
`
`wherein p is 1 to 8 and R” and R1” are each independently
`[1, alkyl, alknnyl, aryl, arylalkyl, hcteroaryl, hcleroarylalkyl,
`cycloalkyl or cycloalkylalkyl, at leasl one of R” and Rm
`boillg, other than H;
`
`3 of 22
`
`PENN EX. 2094
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`or R; is
`
`6,057,339
`
`including pharmaeeutically acceptable salts thereof.
`The MTP inhibitors disclosed in US. provisional appli-
`cation No. 60/017,254. filed May 10, 1996, [file IIX84*] are
`azetidine compounds which have the structure
`
` 0
`
`R5’, KT—{L:H3;$x—R1
`
`Re
`
`0
`
`O
`
`_
`ll
`II
`when: Q15 T T or {ST
`||0
`
`X is: CHRS,
`
`TC“-l—(|TH
`_I
`0
`R9
`Rm
`—c:=c— :
`
`or
`
`R‘
`ls:
`
`R
`Iiu
`
`n is U or 1;
`R“, R9 and R” are independently hydrogen, alliyl, alkenyl,
`alkynyl, aryl, arylalkyl, heteroaryl. heteroarylalkyl,
`cycloalkyl, or cycloalkylztlkyl;
`R‘ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl
`(wherein alkyl preferably has at
`least 2 carbons, more
`preferably at
`least 3 carbons), diarylalkyl, arylalkenyl,
`(liarylalkenyl, arylalkynyl, diarylalkynyl, diarylalkylaryl,
`heteroarylalkyl (wherein alkyl preferably has at
`least 2
`carbons, more preferably at 1:: asl 3 carbons), cycloalkyl, or
`eycloalkylalkyl (wherein alky] preferably has at
`least 2
`carbons, more preferably at
`least 3 carbons); all of the
`aforementioned R1 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. alkylrnercapto. arylmercapto,
`cycloalkyl, cycloalkylalkyl, heteroaryl,
`fluorenyl,
`heteroarylalkyl, hydroxy or oxo; or
`R1 is a Iluorenyl—typc- group of the structure
`
`Of
`
`wherein R” is aryl or heteroaryl;
`Rm is aryl or hetcroaryl;
`R31 is H, alkyl, aryl, alkylaryl, arylalkyl, aryloxy,
`arylalkoxy,
`lieteroaryl,
`litzteroarylalkyl,
`lictcroarylalkoxy,
`cyeloalkyl, eycloalkylalkyl or cycloalkylalkoxy;
`R3, R3, R4 are independently hydrogen,
`Iialo, alkyl,
`alkenyl, alkoxy. aryloxy, aryl, arylalkyl, alkylmercapto,
`arylmercapto, cycloalkyl, cycloalkylalkyl, heleroaryl,
`heteroarylalkyl, hydroxy or haloalkyl;
`
`10
`
`15
`
`R5 is alkyl, alkenyl. alkynyl, aryl, alkoxy, aryloxy,
`arylalkoxy, heteroaryl, arylalkyl, heteroarylalkyl,
`eyeloalkyl, cycloheteroalkyl, heteroaryloxy,
`cycloalkylall-tyl, polycyeloalkyl, polyeycloalkylalkyl,
`cycloalkenyl, eyeloalkenylalkyl, polyeycloalkenyl,
`polycycloalkenylalkyl, hetcroarylcarbnnyl, amino,
`alkylaniino, arylatnino,
`lieleroarylarnino, eycloalkyloxy,
`cycloalkylaniino, all of the R5 substiluents and R” substitu-
`ents (set out hereinafter) being optionally substituted
`through available carbon atoms with I, 2, 3 or 4 groups
`selected from hydrogen, halo, alkyl, haloalkyl, alkoxy,
`haloalkoxy, alkenyl, alkynyl, cycloalkyl, cyeloalkylalkyl,
`cycloheteroalkyl, cyc]oheteroall-iylalkyl, aryl, heteroaryl,
`arylalkyl, arylcycloalkyl. arylalkenyl, arylalkynyl, aryloxy,
`aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo,
`heteroarylalkyl, hete-roarylalkenyl, heteroaryloxy, Iiydroxy,
`nitro, cyano, amino, substituted arnino (wherein the amino
`includes '1 or 2 substituents which are alkyl, aryl or
`heteroaryl. or any ofthe other aryl compounds mentioned in
`the definitions),
`thiol, alkylthio, arylthio, heteroarylthio,
`arylthioalkyl, alkylcarbonyl, arylcarbonyl,
`arylarninoearbonyl, alkoxyearbonyl, aininoearbonyl,
`alkynylaminocarbonyl, alkylarninocarbonyl,
`alkenylanainocarbonyl, alkylcarbonyloxy, arylearbonyloxy,
`alkylearbonylamino, arylcarbonylamino, arylsulfinyl,
`arylsnltinylalkyl, arylsulfonyl, alkylsulfonyl,
`arylsulfonylamino, hetcroarylearbonylamino,
`heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl, or
`alkylsullinyl. Where R5 is phenyl, aryl, heteroaryl or
`cyeloalkyl; this group preferably includes an ortho hydro-
`phobic substituent such as alkyl, haloalkyl (with up to 5 halo
`groups}. alkoxy. halo alkoxy (with up to 5 halo groups), aryl,
`aryloxy or arylalkyl;
`R5 is hydrogen or (f1—(I,L alkyl or (T141, alkenyl;
`
` and
`
`are the same- or difle-rent and are independently selected from
`heteroaryl containing 5- or 6-ring members; and
`including N-oxides of the formulae I and I] compounds,
`that is
`
`30
`
`40
`
`4-5
`
`50
`
`SS
`
`60
`
`bf‘!
`
`90f22
`
`PENN EX. 2094
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`17
`-con