United States Patent
`
`[L9]
`
`[11] Patent Number:
`
`6,066,653
`
`Gregg ct al.
`
`[45] Date of Patent:
`
`May 23, 2000
`
`US[JU606t3t353A
`
`[54] METHOD OF TREATING ACID LIPASE
`DEFICIENCY DISEASES WITH AN MTP
`INHIBITOR AND CHOLESTEROL
`LOWERING DRUGS
`
`FOREIGN PATENT DOCUMENTS
`
`643(JS?A1
`WO96,=’262D5
`
`J.-‘uropcan Pat. Off. .
`3i‘l99:'i
`8,0996 WIPO.
`
`OTHER PUBLICATIONS
`
`[75'
`
`_
`
`[73
`
`Inventors: Richard E. Gregg, Pennington, N..l.;
`-1011“ R» Wettemus H. L3-HETIUTUC’ Piiv
`_
`_
`1
`_
`Agglgnccj Br15t0]'M}'em Sqmhh C0” P""Ccm"=
`N--la
`"woos 437
`’
`Jam 10’ 1993
`
`0':
`
`P1, A 1 N
`“ -
`Pp '
`[33
`Filed:
`
`'
`
`Related U.S. Application Data
`Provisional application No. 6UtU36,183, Jan. 1?, 1997.
`|60
`Int. Cl.7 ......................... AGIK 3'li’445; /\61K 31;’2l
`[5l'
`L52‘ U.S. C].
`........................... 5141325; 514x510; 514x824
`[58' Field of Search ................................... .. 514E325, 510,
`514F324
`
`56‘
`
`References Cited
`
`U5 PATENT DOCUMENTS
`8;'l982 Terahara et al.
`...................... .. 56(I/119
`4_.34I‘J_.227
`5_It12_.2?.¢J M1998 Biller et a1.
`........................... ..
`:'i14i'252
`
`Seriver el al “The Metabolic and Molecular Bases of Inher-
`ited Disease”, Seventh Edition, vol. II, Chapter 82, “Acid
`Ijpasue l)t:lleieney: Wolman l)iscase and Cholesleryl Ester
`Storage Disease”, pp. 2563-2587, (1995).
`Scriver et al “The Metabolic and Molecular Bases of Inher-
`ited Disease”, Seventh Edition, vol.
`II, Chapter 85,
`"Niemann—Pick Disease Type C: A Cellular Cholesterol
`l.ipidosis”, pp. 2625-2639, {"1995}.
`
`Primary E.raimTn'er—Kimberly Jordan
`‘:I"mrm'y’ Agem’
`“T h””_Bumm Rmmyt Rmald 5‘
`°""°"a"
`[57]
`
`ABSTRACT
`.
`,
`,
`.
`,
`.
`.
`,
`A method is provided for inhibiting or treating diseases
`associated with acid lipase deficiency by administering to a
`patient an MTP inhibitor, alone or optionally, in combination
`with another cholesterol lowering drug, such as pravastatin.
`
`27 Claims, No Drawings
`
`1 of 22
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`PENN EX. 2095
`CFAD V. UPENN
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`6,066,653
`
`1
`METHOD OF TREATING ACID LIPASE
`DEFICIENCY DISEASES WITH AN MTP
`INHIBITOR AND CHOLESTEROL
`LOVVERING DRUGS
`
`This application claims the benefit of U.S. Provisional
`Application Ser. No. 60/036,183, filed Jan.
`'17, 1997.
`
`FIELD OF THE INVENTION
`
`The present invention related to a method for inhibiting or
`treating diseases associated with acid lipase deficiency,
`including Wolman disease andfor cholesteryl ester storage
`disease, by administering an MTP inhibitor alone or in
`combination with another cholesterol lowering drug, such as
`pravastatin.
`
`BACKGROUND OF THE INVENTION
`
`Wolman disease and cholesteryl ester storage disease are
`characterized by a dellciency in activity of lysomal acid
`lipase which results in massive accumulation of cholesteryl
`esters and triglycerides in most tissues of the body. Choles-
`teryl esters and triglycerides are derived from plasma lipo-
`proteins taken up by the cells and are substrates for acid
`lipase. Acid lipase is responsible for
`the hydrolysis of
`cholesteryl esters and triglycerides in the lysosomes.
`If plasma cholesterol levels are lowered sufliciently, then
`cholesteryl ester and triglyceride accumulation in the lyso—
`somes and the consequences of the accumulation could be
`minimized.
`Wtnlman disease is the more severe oi" the two diseases
`
`and is almost always fatal before the age of 1 year. In
`contrast, cholesteryl ester storage disease may go undetected
`until adulthood by which time lipid deposition is wide-
`spread. Hyperbctalipoproteinemia is common in cholesteryl
`ester storage disease, and premature atherosclerosis may be
`severe.
`
`To date, there has been no specific therapy for acid lipase
`deficiency other than attempts at suppression of cholesterol
`synthesis and apolipoprotein B production by 3—hydroxy—3—
`methylglutaryl coenzyme A reductase inhibitors in combi-
`nation with cholestyramine treatment and a diet excluding
`foods rich in cholesterol and triglycerides. The above appar-
`ently provided improvement in only one or two cases of
`cholesteryl ester storage disease. Thus, for the most part,
`Wtrlman disease and cholesteryl ester storage disease have
`been untreatable.
`
`10
`
`20
`
`30
`
`40
`
`50
`
`See Scriver, C. R. et al “The Metabolic and Molecular
`Bases of Inherited Disease”, Vol. II (1995), Chap. 82, "Acid
`Lipase Deficiency: Wolman Disease and Cholesteryl Ester
`Storage Disease", pp. 2563-2587.
`Until now, there have not been any therapeutic agents
`available which could lower plasma cholesterol levels suf-
`ficiently to minimize cholesteryl ester and triglyceride accu-
`mulation in the lysosomes.
`The microsomal triglyceride transfer protein (MTP) cata-
`lyzes the transport of triglyceride (TG), cholesteryl ester
`(CE), and phosphatidylcholine (PC) between small unila-
`mcllar vesicles (SUV). Wetterau & Zilvcrsmit, Chem. Pi1_y.s'.
`Lr'p.id.s 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
`thereby
`microsomal triglyceride transfer protein from bovine liver 65 would inhibit the synthesis of VI.DI. and I.DI.,
`has been isolated and extensively characterized (1). This has
`lowering VLDL levels, LDL levels, cholesterol levels, and
`led to the cloning of cDNA expressing the protein from
`triglyceride levels in animals and man.
`
`2
`MTP is composed of
`several species, including humans
`two subu nits, The small subunit is the previously character-
`ized multifunctional protein, protein disulllde isomerase.
`This is supported by biochemical analysis of the protein (3)
`as well as co-expression studies performed in insect S19
`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).
`1: Wetterau, J. R. and Zilversmit, D. B. (1985) Chem. Phys.
`Lipids 38, 205-222.
`Wetterau, J. R., et al,
`9800-9807.
`
`(1990) J. Biol. Chem. 265,
`
`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.
`
`4.
`
`ts.)
`
`DJ
`
`Jamil, 11., et al, (1995) J. Biol. Chem. 270, 6549-6554.
`. Sharp, I). et al, (1993) Nature 365, 65-69.
`Lin, M. C. M., et al, J. Biol. Chem. 269, 29138-29145.
`Nakamuta, M., et al, (1996) Genomics 33, 313-316.
`Wetterau, J. R., et al,
`(1990) J. Biol. Chem. 265,
`9800-9807.
`Wetterau, J. R., et al, (1991) Biochemistry 30, 9728-9735.
`Ricci, B., et al, (1995) J. Biol. Chem. 270, 14281-14285.
`In vitro, MTP catalyzes the transport of lipid molecules
`between phospholipid 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 distribution (liver and intestine) of MTP
`have led to speculation that it plays a role in the assembly of
`plasma lipoproteins, as these are the sites of plasma lipo-
`protein assembly. Wetterau & Zilversmit,B.i0cIrem. Biophys.
`Acm 875, 610-7 (1986). The ability of MTP to catalyze the
`transport of TG between membranes is consistent with this
`hypothesis, and suggests that MTP may catalyze the 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 autosomal recessive disease
`characterized by a virtual absence of plasma lipoproteins
`which contain apolipoprotein B (apoB). Kane & Havel in
`Tire McIrrboi"r'c Brrsi.s' of IrrhcJ'r'tcrr'
`IJr'.s'crr.s'c, Sixth edition,
`1139-64 (1989). Plasma 'l'(} levels may be as low as a few
`mgt‘dL, and they fail
`to rise after fat
`ingestion. Plasma
`cholesterol levels are often only 20-45 mg.»’dI.. These abnor-
`malities are the result of a genetic defect in the assembly
`andfor secretion ol‘ very low density lipoproteins (VI.[)I.) 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 free
`of atherosclerosis. Schaefer et al,, Clm. Chem. 34, B9-12
`(1988). A link between the apoll gene and abetalipopro-
`teinemia has been excluded in several families. Talmud et
`
`al.,.I. Clirr. Irtwzst‘. 82, 180%6 (1988) and Huang et al.,Am.
`J. Hwu. Genet. 46, 1141-8 (1990).
`Recent reports (5) demonstrate that the defect causing
`abetalipoproteinemia is in the MTP gene, and as a result, the
`MTP protein. When examined, individuals with abetalipo-
`proteinemia have no MTP activity, as a result of mutations
`in the MTP gene, some of which have been characterized.
`These results indicate that MTP is required for the synthesis
`of apoB containing lipoproteins, such as VLDL, the precur-
`sor to LDL.
`It
`therefore follows that inhibitors of MTP
`
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`6,066,653
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`3
`5. Wetterau, J. R., et al, (1992) Science 258, 999-1001.
`Sharp, D., et al, (1993) Nature 365, 65-69.
`Ricci, 13., et al, (1995) J. Biol. (Them. 270, 14281-14285.
`Shoulders,
`(T.
`(7., et al, (1993) Ilum. Mol. Genetics 2,
`2109-2116.
`
`Narcisi, "I". M. 15., et al, (1995) Am. J. Ilum. Genet. 57,
`1298-1310.
`
`Rehberg, E. 15., et al, J. Biol. Chem (in press).
`Canadian Patent Application No. 2,091,102 published
`Mar. 2, 1994 (corresponding to U.S. application Ser. No.
`117,362, llled Sep. 3, 1993 (file [)(T2lh)) which is incorpo-
`rated herein by reference), reports MTP inhibitors which
`also block apoB containing lipoprotein secretion in a human
`hepatic cell line (IIepG2 cells). This provides further support
`for the proposal that an MTP inhibitor would lower apoll
`containing lipoprotein and lipid levels in vivo. This (fana-
`dian patent application discloses a method for identifying
`the MTP inhibitors.
`
`triglyceride transfer protein
`The use of microsomal
`(MTP)
`inhibitors for decreasing serum lipids including
`cholesterol and triglycerides and their use in treating
`atherosclerosis, obesity, hyperglycemia, and pancreatitis is
`disclosed in WO 96196205, published Aug. 29, 1996, U.S.
`application Ser. No. 472,067, filed Jun. 6, 1995 (file DC21e),
`US. application Ser. No. 548,811, filed Jan. 11, 1996 (file
`DC21h), U.S. provisional application Ser. No. 60;“0t7,224,
`filed May 9, 1996 (file HX7"9a*), U.S. provisional applica-
`tion Ser. No. 601017.253. filed May 10, 1996 (file HX82*),
`US. provisional application Ser. No. 60,-017,254, May 10,
`1996 (file HX84*) and U.S. provisional application Ser. No.
`6U.'(028,;-.l.6, filed Oct. 1, 1996 (file HX86*).
`All of the above U.S. applications are incorporated herein
`by reference.
`
`DESCRIPTION OF THE INVENTION
`
`invention, a method is
`In accordance with the present
`provided for inhibiting or treating a disease associated with
`acid lipase deficiency,
`including Wolman disease andior
`cholesteryl ester storage disease (CESD),
`in mammalian
`species, wherein a therapeutically elfective 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.
`
`10
`
`20
`
`30
`
`40
`
`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.
`
`50
`
`In accordance with the present invention, the MTP inhibi-
`tor lowers plasma cholesterol (LDL—cholesterol) to at least
`about 50% of normal I.DI. blood level, preferably down to
`less than about 25% of normal, and most preferably down to
`less than about 15% 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 thereby
`minimizes cholestcryl ester and triglyceride accumulation in
`the lysosomes.
`
`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 methods of the
`invention include MTP inhibitors disclosed in Canadian
`
`4
`Patent Application Ser. No. 2,()91,102 described hereinbe-
`fore (corresponding to U.S. application Ser. No. 1'17,362),
`W() 92126205 published Aug. 29, 1996, U.S. application
`Ser. No. 472,067, filed Jun. 6, 1995 (file DC21e), U.S.
`application Ser. No. 548,811,
`filed Jan. 11, 1996 (file
`DC21h), U.S. provisional application Ser. No. 60;’017,224,
`filed May 9, 1996 (file HX79a*), US, provisional applica-
`tion Ser. No. 60;’017,253, filed May 10, 1996 (file IIX82"‘),
`US. provisional application Ser. No. 60;’U'l7,254, filed May
`10, 1996 (file IIX84‘ ), and U.S. provisional application Ser.
`No. 60,028,216, filed Oct. 1, 1996 (file HX86*). Preferred
`are each of the preferred MTP inhibitors disclosed in each of
`the above applications.
`All of the above U.S. applications are incorporated herein
`by reference.
`The MTP inhibitors disclosed in U.S. Application Ser. No.
`472,067, filed June 6, 1995 [file DC2'1e) are piperidine
`compounds ol‘ the structure
`
`where Q is
`
`x is: CHR3,
`
`0
`
`or TST
`1!
`or
`
`—Tn—Tt1
`R9
`R10
`
`R9
`
`R10
`
`R3, R9 and R10 are independently hydrogen, alkyl,
`alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,
`heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;
`
`Y is
`
`(013),,
`
`C)‘ ?C?
`
`0
`
`wherein m is 2 or 3;
`R1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl
`wherein alkyl has at
`least 2 carbons, diarylalkyl,
`
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`6,066,653
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`5
`arylalkenyl, diarylalkenyl, arylalkynyl, diarylalkynyl,
`diarylalkylaryl, heteroarylalliyl wherein alkyl has at
`least 2 carbons, cycloalkyl, or cycloalkylalkyl wherein
`alkyl has at least 2 carbons, all optionally substituted
`through available carbon atoms with 1, 2, 3 or 4 groups
`selected from halo, haloalkyl, alkyl, alkenyl, alkoxy,
`
`aryloxy, aryl, arylalkyl, alkylmercapto, arylmereapto,
`eyeloalkyl, eycloalkylalkyl, heteroaryl,
`fluorenyl,
`heteroarylalkyl, hydroxy or oxo;
`.
`or R! is a Iluorenyl-type group of the structure
`
`10
`
`20 25
`
`6
`
`_,_-Uminued
`
`R"‘g/;/ R”
`\ /
`
`01'
`
`TEWTY.
`
`a
`
`5
`
`R16,
`
`R15“
`
`
`
`F
`
`(‘
`I
`
`Rlfsa
`
`:P-“*7-I
`R,,_Z,
`
`I
`‘
`
`0'
`
`/ \
`/_\ .
`R” \:/ R”
`
`30
`
`Z‘ and Z: are the same or different and are independently
`a bond, 0, S,
`3,
`s
`_. —m11—c— —1x—c— —c— or
`I
`II
`I
`II
`I
`0
`0 ,
`0
`altkyt o
`0
`
`(
`
`35
`
`ifOII
`
`')
`
`"3
`
`40 with the proviso that with respect to B, at least one of Z‘ and
`Z3 will be other than a bond; R“ is a bond, alkylene,
`alkenylene or alkynylene of u
`to 10 carbon atoms; arylene
`or mixed arylene—a1kylene; R 7' is hydrogen, alkyl, alkenyl,
`aryl, haloalkyl,
`trihaloalkyl,
`lrihaloalkylalkyl. heteroaryl,
`heteroarylalkyl, arylalkyl, arylalkenyl, eyeloalkyl, aryloxy,
`45 alknxy, arylalkoxy or cycloalkylalkyl, with the provisos that
`preferably
`(1) when R13 is II, aryloxy, alkoxy or arylalkoxy, then Z2
`IS
`
`50
`
`N[I
`
`or a bond and
`
`Oi”)
`
`O1’)
`
`alkyl
`
`01!")
`
`(2) when Z3 is a bond, R” cannot be heteroaryl or
`heleroarylalkyl;
`Z is :1 bond, 0, S, N-alkyl, N-aryl, or alliylene or alk-
`enylene from 1
`to 5 carbon atoms; R13, R14, R15, and
`Rm are independently hydrogen, alkyl, halo, haloalkyl,
`aryl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl,
`hydroxy, alkoxy, nilro, amino,
`thio, alkylsulfonyl,
`arylsulfonyl, alkylthio, arylthio, aminoearbonyl,
`alkylcarbonyloxy,
`arylcarbonylamino,
`alkylcarbonylarnino, arylalkyl, heteroaryl, heteroaryla—
`lkyl or aryloxy;
`R”" and R””' are independently hydrogen, alkyl, halo,
`haloalkyl, aryl, eycloalkyl, cycloheteroalkyl, alkenyl,
`
`50
`
`65
`
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`7
`alkynyl, alkoxy, alkylsulfonyl, arylsulfonyl, alkylthio,
`arylthio, arninocarbonyl, alkylcarhonyloxy,
`
`arylcarbonylarnino, alkylcarbonylamino, arylalkyl,
`
`heteroaryl, heteroarylalkyl, or aryloxy;
`or R3 is a group of the structure
`
`8
`
`O
`
`3
`
`T((7H2}p%
`
`Rlr
`
`R”
`
`wherein p is 1 to 8 and R” and R13 are each independently
`”= 3lkYl= alkcnyla “W15 ‘“3’1a1kYlr h"l°m‘”3’l= h"l‘”"‘”Y]3lkYlv
`cycloalkyl or cycloalkylalkyl at least one of R” and R13
`being other than H;
`or R1 is a group of the structure
`
`:1}l9%
`
`R20
`R21
`
`m
`
`U:
`
`2”
`
`_. @ and @
`
`are the same or different and are independently selected from
`heteroaryl containing 5- or 6-ring members; and
`N-oxides
`
`0
`
`K\ _\_‘<
`2:) R1
`
`R [berm]-; and
`wherein Rm is aryl or heteroaryl;
`R30 is aryl or heteroaryl;
`pharmaceutically acceptable salts thereof; with the pro-
`R31 is H, alkyl, aryl, alkylaryl, arylalkyl, aryloxy,
`visos that preferably where in the first formula X is
`arylalkoxy, heteroaryl, heteroarylalkyl,
`(TII3, and R3, R3 and R4 are each II, then R3 will he
`heteroarylalkoxy, eyeloalkyl, cycloalkylalkyl or
`othenthan 3,3-diphenylpropyl, and preferably in the
`eyelnalkyhnkexy;
`hfth tormula,where one of R“, R’ and R 15 6—fluoro,
`R: R3 R4 are independently hydmgcn’ halo’ alkyl’ an
`and the (“hers are Us R7 will he mher than 4'(2'
`alkenyl,alkoxy,aryloxy,aryl,arylalkyl,alkylmercapto,
`m°[h0XYPh‘-"n3'l)-
`arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl,
`The MTP inhibitors disclosed in US, application Ser. No.
`heteroarylalkyl, hydroxy or haloalkyl;
`R5 is independently alkyl, alkenylj alkyl-W1, aryl, ajkuxy, H 548,811 filed Jan. 1], 1996 [llle DC2lh), have the structure
`aryloxy, arylalkoxy, heteroaryl, arylalkyl,
`'-
`heteroarylalkyl, cycloalkyl, cycloalkylalkyl,
`polycycloalkyl, polycycloalkylalkyl, cycloalkenyl,
`cycloheteroalkyl, heteroaryloxy, cycloalkenylalkyl,
`polycycloalkenyl, polycycloalkenylalkyl, 40
`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,
`
`25
`
`X‘
`
`I
`/‘
`
`0
`fl_;lJ_FH _CF
`'
`'
`3
`'
`
`3
`
`0
`
`(C-'H2}x
`
`5'
`
`E‘C‘R3
`
`alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl,
`
`4__‘ g
`
`‘
`
`cycloalkyl, cycloalkylalkyl, cycloheteroalkyl,
`cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl,
`arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy,
`aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo,
`_
`.
`_
`_
`_
`_
`_
`‘O _
`heteroarylalkyl, heteroarylalkenyl, heteroaryloxy,
`"
`Including the ptpendme N-oxide thereol or a pharmaceuti-
`hydmxy, 1-fin-Q, Cyglng, aming, 5uI_)5[i[u[¢d aming’ [hi0],
`cally acceptable salt thereof, wherein Z is a bond, 0 or S;
`alkylthio, arylthio, hctcroarylrhio, arylthioalkyl,
`X1 and X3 are independently selected from H or halo"
`alkylcarbonyl’ Mylcarbonyl’ arylamiflmarboflyl’
`_
`,
`,’
`._
`alkoxyearbonyl,
`aminocarbonyl,
`,3; X? an mmgcr from ‘ to 0’
`alkynylaminocarbonyl, alkylaminocarbotlyl,
`a 1kg n 3;] am 1' n 0 c Mb 3 n y 1 ,
`3 1k 3;] c a lb 3 n 3- [0 x Y, "
`R‘
`is heteroaryl, aryl, heterocycloalkyl or cycloalkyl, each
`arylcarI_)ony]oxy_
`alkylcarbonylamino,
`Rsgroup beingoptionally Sl.1bSliIL1lC(l with 1,2,3or4
`arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl,
`substituents which may be the same or different.
`arylsulfonyl, alkylsulfonyl, arylsulfonylamino,
`The MTP inhibitors disclosed in US. provisional appli-
`Eeleroafivllearlhtwnylarililfin,
`fllcllckrtiarlyirilstilfinyl, G0 cation Ser. No. (j0i’017,224_ filed May 9,1996(fi1e HX79a*)
`ClCl‘D('ll‘yI 10, ClCI'Oc'll'y S11 0(1)’ , a
`Y SU Hy;
`have [he glruclurc
`R“ 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 R5 set out above;
`R7 is alkyl, aryl or arylalkyl wherein alkyl by itself or as
`part of arylalkyl is optionally substituted with oxo
`
`xi
`
`55
`
`0
`L: )l\
`123/ \A
`
`Ll
`Is/ \R1 or
`
`[
`
`5 of 22
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`6,066,653
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`9
`
`-continued
`
`ta
`I.‘
`R3
`5
`\\L2/ KKBX \Rl or
`O[I
`
`IA
`
`[I5
`
`Rj\
`
`I3
`
`RX
`
`/LL».
`
`is
`
`R1
`
`ll)
`
`including pharrnaceutically acceptable salts thereof, wherein
`q is U,
`l or 2;
`A is (1) a bond;
`(2) —()—; or
`
`—.\'—:
`
`RS
`
`(3
`
`20
`
`where R5 is II or lower alkyl or R5 together with R2 forms
`a carbocyclic or heterocyclic ring system containing 4 to 8
`members in the ring.
`B is a i‘luorenyl—type group of the structure:
`
`R‘
`
`10
`is alkyl, alkenyl, alkynyl, alkoxyl, (alkyl or aryl)3Si
`(where each alkyl or aryl group is
`independent),
`cycloalkyl, cycloalkenyl, substituted alkylamino, sub-
`stituted arylalkylamino, aryl, arylalkyl, arylamino,
`aryloxy, heteroaryl, heteroarylamino, heteroaryloxy,
`arylsulfonylamino, heteroarylsulfonylarnino, arylthio,
`arylsulfinyl, arylsulfonyl. alkylthio, alkylsulfinyl,
`alkylsulfonyl, hcteroarylthio, heteroarylsulfinyl,
`hetcroarylsulfonyl, —PO (R13) (R14), (where R13 and
`R1“ are independently alkyl, aryl, alkoxy, aryloxy,
`heteroaryl, hcteroarylalkyl, heteroaryloxy,
`heteroarylalkoxy,
`cycloheteroalkyl,
`cycloheteroalkylalkyl, cyeloheteroalkoxy, or
`cycloheteroalkylalkoxy); R1 can also be aniinocarbonyl
`(where the amino may optionally be substituted with
`one or two aryl, alkyl or heteroaryl groups); cyano,
`l,l-(alkoxyl or aryloxy)2alkyl (where the two aryl or
`alkyl substituents can be independently delined, or
`linked to one another to form a ring, such as 1,3-
`dioxane or 1,3—dioxolane, connected to L‘ (or L2 in the
`case ol‘ R2) at
`the 2-position); 1,3-dioxane or 1,3-
`dioxolane connected to L’ (or L2 in the case of R2) at
`the 4—position.
`The R1 group may have from one to four substituents,
`which can be any ofthe R3 groups or R‘ groups, and any of
`the preferred R1 substituents set out below.
`R‘ may be substituted with the following preferred sub-
`stituents: alkylcarbonylamino, cycloalkylcarbonylamino,
`arylcarbonylamino, heteroarylcarbonylamino,
`alkoxycarbonylarnino, aryloxycarbonylamino,
`heteroaryloxylcarbonylamino, uriedo (where the uriedo
`nitrugens may be substituted with alkyl, aryl or heteroaryl),
`heterocyclylcarbonylamino (where the heterocycle is con-
`nected to the carbonyl group via a nitrogen or carbon atom),
`alkylsulfonylarnino,
`arylsullonylamino,
`heteroarylsulfon yla rnino,
`
`()
`
`where J is: CIIR1‘, —(?—, —cH—cH— , 01'
`
`0
`jczcj;
`
`R24
`
`R15
`
`R24 R15
`
`R37’, R3" and R25 are independently hydrogen, alkyl,
`alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,
`heteroarylalkyl, cycloalkyl, or eyeloalkylalkyl;
`R20, R21, R22 are independently hydrogen, halo, alkyl,
`alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto,
`arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl,
`heteroarylalkyl, hydroxy or haloalkyl; and these pre-
`ferred substituents may either be directly attached to
`R1, or attached via an alkylene chain at an open
`position.
`R3 is the same or different from R‘ and is independently
`any ol‘ the groups set out for R1, II, polyhaloalkyl (such
`as CF_,CH:, CF3CF:CH2 or CF_.,) or cycloheteroalkyl,
`and may be substituted with one to four of any of the
`groups defined for R7’, or any of the substituents pre-
`ferred for R1.
`
`to 10 carbons in
`I.‘ is a linking group containing from 1
`a
`linear chain (including alkylene, alkenylene or
`
`6 of 22
`
`PENN EX. 2095
`CFAD V. UPENN
`
`lPR2015-01836
`
`30
`
`40
`
`50
`
`R3
`
`R4’
`-,
`
`R"
`
`RT
`
`X
`
`R‘
`
`Fluo1'cnyl- type ring or moiety)'.nr
`
`(the above B is also referited to as a
`
`B is an ir1denyl—type group of the structure
`
`R3
`
`‘.
`
`/ “X”
`T 01'
`
`I
`R- /:\/R3’
`\ /
`
`Dr
`
`\
`[CI I2la
`
`R3b
`
`isR.
`
`(:1 : 2, 3 or 4)
`
`R3
`
`R3‘
`
`R}:
`
`R3
`
`Rh
`
`or Q
`
`R3”
`
`\
`[C-112).‘
`R3“
`(The ahox-‘c I5 is also referred to as
`an indcnyl-type ring or moiety}:
`
`R3’
`
`R.\L>
`
`R‘ is lI, alkyl or aryl;
`
`

`
`11
`alkynylene), which may contain, within the linking
`chain any of the following: one or two alkenes, one or
`two alkynes, an oxygen, an amino group optionally
`substituted with alkyl or aryl, an oxo group; and may be
`substituted with one to live alkyl or halo groups
`(preferably F).
`from I.‘ and may
`I.2 may be the same or different
`independently be any of the I.’ groups set out above or
`a singe bond.
`R3, R3‘, R’: and R"' may be the same or different and are
`independently selected from II, halogen, C153,
`haloalkyl, hydroxy, alkoxy, alkyl, aryl, alkcnyl,
`alkenyloxy, alkynyl, alkynyloxy, alkanoyl, nitro,
`amino,
`thiol, alkylthio, alkylsulfinyl, alkylsulfonyl,
`carboxy, alkoxycarbonyl, aniinocarbonyl,
`alkylcarbonyloxy, alkylcarbonylamino,
`cycloheteroalkyl, cycloheteroalkylalkyl, eyano, Ar,
`Ar-alkyl, Ar-O, Ar-amino, Ar-thio, Ar-sullinyl,
`Ar—sulfonyl, Ar—carbonyl, Ar—carbonyloxy or
`Ar-carbonylarnino, wherein Ar is aryl or heteroaryl and
`Ar may optionally include 1, 2 or 3 additional rings
`fused to Ar;
`R3" and R35’ are the same or different and are indepen-
`dently any of the R3 groups except hydroxy, nitro, amino or
`thio;
`
`W
`
`@
`
`are the same or different and independently represent a 5 or
`6 membered heteroaryl ring which may contain 1, 2, 3 or 4
`heteroatoms in the ring which are independently N, S or (J;
`and including N-oxides.
`X (in the fluorenyl type ring) is a bond, or is one of the
`following groups:
`
`6,066,653
`
`12
`
`lower alkyl, aryl, —C([))—R” or —C (O)
`R6 is II,
`—O—R”;
`
`R7 and R3 are the same or ditferent and are independently
`II, alkyl, aryl, halogen, —O—R13, or
`R7 and R” together can be oxygen to form a ketone;
`R9, Rm, R9’ and Rm’ are the same or different and are
`independently II, lower alkyl, aryl or —()—R”;
`R9“ and Rm“ are the same or different and are indepen-
`dently H, lower alkyl, aryl, halogen or —O—R”;
`R“ is alky or aryl;
`R‘: is II, alkyl or aryl.
`The following provisos apply to formula I preferred
`compounds:
`(:1) when R1 is unsubstituted alkyl or unsubstituted
`arylalkyl, L1 cannot contain amino;
`(b) when R1 is alkyl, L1 cannot contain amino and oxo in
`adjacent positions (to form an amide group);
`(C) when R2L:A— is HZN , R'L‘ cannot contain amino;
`(d) when R‘ is cyano, L‘ must have more than 2 carbons;
`(e) R‘I.‘ must contain at least 3 carbons.
`With respect to cornpounds IA and H3, R21} cannot have
`an 0 or N atom directly attached to S=[()),, or (.'R"'(()II),
`and for IA, R31; cannot be I].
`With respect to preferred compounds of formula IA and
`IB, where R1 is cycloheteroalkyl, R1 is exclusive of
`l-piperidinyl,
`l-pyrrolidinyl, 1-azetidinyl or
`l-(2-oxo-
`pyrrolidinyl).
`The MTP inhibitors disclosed in US. provisional appli-
`cation Ser. No. 6{l,=‘0]7,253,
`filed May 10, 1996,
`(file
`HX82*) are pyrrolidine compounds and have the structure
`
`10
`
`20
`
`30
`
`_S_
`
`I
`[OLE
`
`_O_
`
`T1?Rs
`
`_C_
`
`R4’ \Rs
`
`_ 7
`I \
`R9
`
`(_
`\
`R10 R9'/ R10’
`
`R9’ Rltl”
`
`1’
`R9 \Rll]
`
`40
`
`(‘I1
`
`(2)
`
`(3)
`
`(4)
`
`(5)
`
`(6)
`
`U)
`
` N—R‘
`
`W
`
`[[
`
`1&5/Q\N
`
`R5
`
`w
`
`N—1<‘
`
`0
`or :91?
`||0
`
`50
`
`0
`
`whereOis
`
`W is II,II or ();
`
`Xis:(THR3_.
`
`_. :TH__(|:”—_ 0,
`R9
`R10
`
`0
`
`R9
`
`R10
`
`wherein
`
`Y is 0, N—R° or S;
`n‘ is I),
`1 or 2;
`
`R”, R9 and Rm are independently hydrogen, alkyl,
`alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,
`heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;
`
`7 of 22
`
`PENN EX. 2095
`CFAD V. UPENN
`
`IPR2015-01836
`
`

`
`6,066,653
`
`R‘ is an indenyl-type group of the structure
`
`14
`
`OT
`
`,1 R11
`RN
`\ X
`
`\ /
`
`0,
`
`_.Rl1:_Z
`
`RI2jZ2
`
`Rlfia
`
`R13
`
`R14
`
` ll
`
`of
`
`R12
`
`32 A
`R‘-"9
`(CH3),
`
`R15‘
`
`R13
`
`R14
`
`_R11_Z Q .
`
`R12_. '2
`
`Rm
`
`R [52
`
`Z1 and Z3 are the same or dilfercnt and are independently
`a bond, 0, S,
`
`H.
`silky] o
`
`I
`
`s I
`
`C ) —\'n——fi—
`0 '3.
`0
`
`s |
`
`|-O
`
`—c— —l:‘—-
`"
`or
`|
`O
`OH
`
`with the proviso that with respect to B, at least one of Z‘ and
`Z: will be other than a bond;
`
`R” is a bond, alkylene, alkenylene or alkynylene of up to
`10 carbon atoms, arylene [for example
`
`.@-
`
`J
`
`80f22
`
`PENN EX. 2095
`
`CFAD V. UPENN
`
`lPR2015-01836
`
`13
`R1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl
`[wherein alkyl preferably has at least 2 carbons, more
`preferably at least 3 carbons], Lliarylalkyl, arylalkenyl,
`diarylalkenyl, arylalkynyl, diarylalkynyl,
`diarylalkylaryl, heteroarylalkyl (wherein alkyl prefer-
`ably has at least 2 carbons, more preferably at least 3
`carbons), cyeloalkyl, or eycloalkylalkyl (wherein alkyl
`preferably has at least 2 carbons, more preferably at
`least 3 carbons); all of the aforementioned R' 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, alkylmercapto, arylmercapto, cycloalkyl,
`eyeloalkylalkyl, heteroaryl, fluorenyl, hcteroarylalkyl,
`hydroxy or oxo; or
`R1 is a Iluorenyl-type group of the structure
`
`2
`
`01'
`
`Z
`
`01'
`
`I)
`
`10
`
`20
`
`to"J1
`
`30
`
`40
`
`50
`
`55
`
`

`
`6,066,653
`
`15
`or mixed arylene-alkylene (for example
`
`/\ CH2}? 3Q ‘
`
`where n is 1 to 6;
`
`R12 is hydrogen, alkyl, alkenyl, aryl, haloalkyl,
`trihaloalkyl,
`trihaloalkylalkyl, heteroaryl,
`heteroarylalkyl, arylalkyl, arylalkenyl, eycloalkyl,
`aryloxy, alkoxy, arylalkoxy or cyeloalkylalkyl; with the
`provisos that (1) when R13 is H, aryloxy, alkoxy or
`arylalkoxy, then Z2 is
`
`—_\:r1—c— .-
`
`—_\.'—c— —c—
`
`0
`
`alkyl 0
`
`0
`
`or a bond;
`
`and (2) when Z2 is a bond, R12 cannot be heteroaryl or
`heteroarylalkyl;
`Z is a bond, 0, S, N-alkyl, N-aryl, or alkylene or alk-
`enylene of from 1
`to 5 carbon atoms;
`R13, R14, R15, and R15 are independently hydrogen, alkyl,
`halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl,
`alkenyl, alkynyl, hydroxy, alkoxy, nitro, amino, thio,
`alkylsulfonyl, arylsulfonyl, alkylthio, arylthio,
`aniinocarbonyl, alkylcarbonyloxy, arylcarbonylamino,
`alkylcarbonylaniino, arylalkyl, heteroaryl,
`heteroarylalkyl, or aryloxy;
`R15" and RN" are independently any of the R15 or R”
`groups except hydroxy, nitro, amino or thio;
`or R1 is
`
`R1‘?
`T((7H2);% R18
`
`wherein p is 1 to 8 and R17 and R18 are each independently
`H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
`cyeloalkyl or eycloalkylalkyl, at least one of R" and R13
`being other than H;
`or R1 is
`
`Rm
`TR19< R21
`
`10
`
`20
`
`30
`
`4t
`
`45
`
`50
`
`wherein R19 is aryl or heteroaryl;
`R2“ is aryl or heteroaryl;
`R31 is H, alkyl, aryl. alkylaryl, arylalkyl, aryloxy,
`arylalkoxy, heteroaryl, heteroarylalkyl,
`heteroarylalkoxy, eyeloalkyl, eyeloalkylalkyl or
`eyeloalkylalkoxy;
`R2, R7’, R4 are independently hydrogen, halo, alkyl,
`alkenyl, alkoxy, aryloxy. aryl, arylalkyl, alkylmereapto,
`arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl,
`heteroarylalkyl, hyclroxy or haloalkyl;
`R5 is alkyl
`, alkenyl, alkynyl, aryl, alkoxy, aryloxy,
`arylalkoxy, heteroaryl, arylalkyl, heteroarylalkyl,
`eycloalkyl, eycloheteroalkyl, heteroaryloxy,
`
`16
`cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl,
`cycloalkenyl, cycloalkenylalkyl, polycycloalkenyl,
`polycycloalkenylalkyl, heteroarylcarbonyl, aniino,
`alkylamino, arylamino, heteroarylaniino,
`cycloalkyloxy, cycloalkylarnino, all of the R5 substitu-
`ents and R“ substituents (set out hereinafter) being
`optionally substituted through available carbon atoms
`with 1, 2, 3 or 4 groups selected from hydrogen, halo,
`alkyl, haloalkyl, alkoxy, haloallioxy, alkenyl, alkynyl,
`cyeloalkyl, eyeloalkylalkyl, cycloheteroalkyl,
`cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl,
`aryleyeloalkyl, 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, arylearbonyl, arylaminoearbonyl,
`alkoxycarbonyl,
`arninocarbonyl,
`alkynylaminocarbonyl, alkylaminocarbonyl,
`alkenylaminocarbonyl, alkylearbonyloxy,
`arylcarbonyloxy,
`alkylcarbonylamino,
`arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl,
`arylsulfonyl, alkylsulfonyl, arylsulfonylamino,
`heteroarylcarbonylamino, heteroarylsulfinyl,
`heteroarylthio, heteroarylsulfonyl, or alkylsulfinyl.
`Where R5 is phenyl, aryl, heteroaryl or cycloalkyl; this
`group preferably includes an ortho hydrophobic sub-
`stituenl such as alkyl, haloalkyl [with up to 5 halo
`groups), alkoxy, haloalkoxy [with up to 5 halo groups),
`ary], aryloxy or arylalkyl;
`R6 is hydrogen or (T,—(I,, alkyl or C1—(.',, alkenyl;
`
`*6
`
`are the same or different and are independently selected from
`heteroaryl containing 5- or 6—ring members; and
`
`including N—0xid-es of the formulae I and II eompounds,
`that is
`
`including pharmaeeutically acceptable salts thereof.
`The M'I'P inhibitors disclosed in US. provisional appli-
`cation Ser. No.
`(j0f017,254,
`filed May '10,
`"1996,
`(file
`IIX84*) are azetidine compounds which have the structure
`
`/
`
`N—(cn3),,
`
`N—R‘: or
`
`90f22
`
`PENN EX. 2095
`
`CFAD V. UPENN
`
`lPR2015-01836
`
`

`
`17
`-continuecl
`
`6,066,653
`
`H
`
`Q-so
`
`_
`
`R’/
`
`0
`
`- T -
`Rs
`
`O
`
`2.11
`
`(CH 1405:
`
`T 1
`
`R
`
`w|1ereQis
`
`or L.’
`||0
`
`x is:(THR3_.
`
`—?I—‘?H—-0],
`R9
`Rl[|
`
`()
`
`R9
`
`RH]
`
`R”, R9 and Rm are independently hydrogen, alkyl,
`alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,
`heteroarylalkyl, cycloalkyl, or eycloalkylalkyl;
`R1 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 (wher