United States Patent
`
`.19.
`
`|11| Patent Number:
`
`5,827,875
`
`Dickson, Jr. et al.
`
`|4s] Date of Patent:
`
`Oct. 27, 1998
`
`US005827875A
`
`54]
`
`75]
`
`INHI11.I'I‘()RS ()l" MICROSUMAI.
`'l"RIGI.YCI£RIl)lC TRANSl‘l€R PROTIEIN AND
`ME'l'H()1)
`
`Inventors: John K. Dickson, .Ir., Eastampton,
`N,J.; .Iefl'rey A. Robl, Ncwtown, 1’a.;
`Scott A. Billet‘, Ilopewell, N.J.
`
`73] Assignee: Bristol-Myers Squibb Company,
`Princeton, NJ.
`
`21] Appl. No: 842,132
`
`2.2]
`
`Filed:
`
`Apr. 23, 1997
`
`Int. CLO ....................... .. /\6lK 31140; C071) 207,126
`51]
`52] U.S. CI.
`........................ .. 5147424; 5483528; 5481518;
`548,r"550; 548,557; 5'14./422; 5141426
`58] Field of Search ___________________________________ __ 5481523, 550,
`548.3557, 518, 525, 527; 5141422, 424,
`42.6
`
`56]
`
`References Cited
`U.S. PATENT UOCUIVIENTS
`
`................... .. 260:'293.62
`1011975 Cavalla ct al.
`..
`.. 260526.55
`611976 Cale. Jr. et al.
`911981 Bengtsson et al.
`424.-"26?
`1,-‘I983 Boix-Igleasias et al.
`424.-"267
`3,-‘I986 Tahara et :11.
`....... ..
`514.3212
`4,-‘I981: Tahara e1 :11.
`.
`514.-“Z12
`8.31986 Pierce .......... ..
`514E323
`511989 Picciola et al.
`544,891
`671991 Vega—N0verola et at
`54f:i.-“Z24
`771991 Desai et al.
`......... ..
`514,821
`711991 Baldwin et :11.
`514.8 18
`311992, Desai et al.
`514E324
`711992 Pan et al.
`.... ..
`514E460
`231993 Peglion et al.
`514.1319
`5,-“I993 Musscr ct al.
`514.-1314
`6.91993 Baldwin et al.
`514E252
`3,-‘I994 Martin el al.
`......................... .. 546.-"2111
`611996 Masuda et al.
`....................... .. 5141255
`
`
`
`
`
`.
`
`3,910,931
`3,963,745
`4,289,781
`4,367,232
`4,576,941]
`4,581,355
`4,607,042
`4,826,975
`5,026,858
`5,028,616
`5,032,598
`5,098,915
`5,130,333
`5,189,045
`5,212,182
`5,215,989
`5,292,883
`5,527,801
`
`FOREIGN P15i1‘EN'[‘ []()(.‘UM1:';N'1'S
`
`0584-4-at-6E
`06430571-'\l
`W()‘J3{f}5 778
`\-'1-I096,/4-064(.|
`
`liuropean Pat. Off. _
`3,-‘I994
`liuropean Pat. O11’.
`.
`3,-‘I995
`4,-‘I993 WIPO .
`12;‘ 1996 WIPO .
`
`()'I'IIl_-'.R PU11[.[(?A'l'I()NS
`
`Bullcid & Freedman, Nature 335, 649-651 {I988}. "Defec-
`tive co—translational formation of disulphide bonds in pro-
`tein disulphideisomerase—deficient microsomes”.
`Koivu ct al., J. Biol. Chem. 262, 6447-6449 (1987). "A
`Single Polypeptide Acts both as the B Subunit of Prolyl
`4»-Ilydroxylase and as a Protein l)isulfide-lsomerase”.
`Katie & IIavel in the Metabolic Basis of Inherited Disease,
`Sixth Edition, 1139-1 164 (1989). “Disorders of the I1iogen-
`esis and Secretion of Lipoproteins Containing the B Ap0li-
`poproteins”.
`Schaefer et al., (Tlin. (Them. 34, 119-1112 (1988). “Genetics
`and Abnormalities in Metabolism of Lipoproteins”.
`Drayna et al., Nature 327, 632-634 (1987). "Cloning and
`sequencing of human cholesteryl ester
`transfer protein
`el)N.u"\”.
`
`Pihlajaniemi et al., EMBO J. 6, 643-649 (1987). "Molecular
`cloning of the [3-subunit of human prolyl—4-hydroxylase.
`This subunit and protein disulphide isomerase are products
`of the same gene”.
`Yamaguchi el al., Iiioehem. Biophys. Res. Comm. 146,
`1485-1492 (1987). “Sequence of .VIembrane-A-ssocietted
`Thyroid Hormone Binding Protein From Bovine Liver: Its
`Identity with protein Disulphide Isomerase”.
`ljdman et al., Nature 317. 267-270 (1985). Sequence of
`protein disulphide isomerase and implications of its rela-
`tionship to thioredoxin.
`Kao et al., Connective Tissue Research 18, 157-174 (1988).
`“Isolation of CDNA Clones and Uenomic DNA Clones of
`
`[1-Subunit of Chicken Prolyl 4»-IIydroxylase"'.
`Wetterau, J. et al., Biochem 30, 9728-9735 (1991). "Protein
`Disulfide Isomerase Appears Necessary To Maintain the
`Catalytically Active Structure of the Microsomal '1‘riglyccr—
`ide Transfer Protein”.
`
`Morton, R.E.. et al., J. Biol. Chem. 256, 1992-1995 (1981).
`“A Plasma Inhibitor of Triglyceride and (Thloesteryl Ester
`Transfer Activities”.
`
`Wetterau, J. et al., Biochem. 30. 4406-4412 (1991). “Struc-
`tural Properties of the Microsomal Triglyeeride-'l‘r:tnsfer
`Protein Complex”.
`Wetterau, .1. ct al., J. Biol. Chem. 265, 9800-9807 (1990).
`“Protein Disultide lsomerase Is
`a Component of
`the
`Microsomal '1‘riglyceride Transfer Protein Complex".
`Wetterau,.l . and Zilversmit, D,B., Chem. and Phys. of Lipids
`38, 205-22. (1985). “Purilication and Characteri7.ation of
`Microsomal Triglyceride and Cholesteryl Ester Transfer
`Protein From Bovine I.iver Microsomes".
`
`(List continued on next page.)
`
`Prirmir_v Exariiinw John Kight
`;4.s:s'rLs'trir.=t Exmni'neJ'—(Iharanjit S. Aulakh
`Attorney, /tgem‘, or Fr}*m—Burton Rodney
`
`[57]
`
`ABSTRACT
`
`Compounds are provided which inhibit microsomal triglyc-
`eride transfer protein and thus are useful for lowering serum
`lipids and treating atherosclerosis and related diseases. The
`compounds have the structure
`
`R
`
`R3
`
`R"
`
`0
`
`N
`
`X
`
`/
`
`\
`
`U1"
`
`.\'—Rl
`
`Q
`1&5’ \
`/N
`
`R6
`
`N—1{1
`
`wherein R1 to R5, 0, W and X are as defined herein.
`
`16 Claims, No Drawings
`
`I ofll-4
`
`PENN EX. 2211
`
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`lPR20l5-01836
`
`

`
`5,827,875
`Page 2
`
`OTHER PUBLICATIONS
`
`Wetterau, J. and Zilversmit, D.B., Bioehimica et Biophysica
`Acta 875, 610-61? (1986). “localization of intracellular
`lriacylglycerol and cholesteryl ester transfer activity in rat
`tissues”.
`Wetterau, J. and Zilversmit, D.B., J. Biol. Chem. 259,
`10863-10866 (1984). “A Triglyceride and (‘holeslcryl Ester
`Transfer Protein Associated with Liver Microsomes”.
`Wetterau, J., Grant Application entitled: "Intracellular '1‘ryg—
`lyceride Transport and Metabolism".
`Presentation Materials, Aspen Bile /\eid,=’Cho|esterol Con-
`ference, Aug. 15, 1992.
`
`Wetterau, J. R., et al., Science, vol. 258, 999-1001, Nov. 6,
`I992, "Absence of Microsomal Triglyceride Transfer Pm-
`toin in Individuals with Ahetalipoproteinemia”.
`Archibald, J. J.., et al., Journal of Medicinal Chemistry, vol.
`I4, No. 1], pp. 1054-1059 (1991).
`Corlizo, L. el al., J. Med. Chem, 34, pp. 2242-2247, 1991.
`Hall, I. II. el al., Pharmaceutical Research, vol. 9, _\lo. [0, pp.
`1324-1329, 1992.
`Hall, I. H., cl a1., Pharlliacological Research Communica-
`tions, vol. 19, No. 12, pp. 839-858, 1987.
`Murthy et al.. Eur. J. Med. Chem. Chim. Ther., vol. 20, No.
`6, pp. 547-550, 1985.
`
`2 ol'l14
`
`PENN EX. 2211
`
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`lPR20l5-01836
`
`

`
`5,827,875
`
`1
`INHIBITORS OF MICROSOMAI.
`TRIGLYCERIDE TRANSFER PROTEIN AND
`METHOI)
`
`FIEID OF THE INVENTION
`
`This application is based on provisional application No.
`60f017,253 filed May '10, 1996.
`This invention relates to novel compounds which inhibit
`microsomal triglyceride transfer protein, and to methods for
`decreasing serum lipids and treating atherosclerosis employ-
`ing such compounds.
`BACKGROUND OF THE INVENTION
`
`The microsomal triglyceride transfer protein (MTP) cata-
`lyzes the transport of triglyceride (TG), cholesteryl ester
`(CE), and phosphatidylcholine (PC) between small unila-
`mellar vesicles (SUV). Wetterau & Zilversmit, Chem. Piiyx.
`Lipids 38, 205 22 (1985). When transfer rates are expressed
`as the percent of the donor lipid transferred per time, MTP
`expresses a distinct preference for neutral lipid transport
`(TE and CE), relative to phospholipicl transport. The protein
`from bovine liver has been isolated and characterized.
`
`Wetterau & Zilversmit, Chem. Pltys. Lipids 38, 205-22
`(1985). Polyacrylamide gel electrophoresis (PAGE) analysis
`of the purified protein suggests that the transfer protein is a
`complex of two subunits of apparent molecular weights
`58,000 and 88,000, since a single band was present when
`purified MTP was electrophoresed under nondenaturing
`condition, while two bands of apparent molecular weights
`58,000 and 88,000 were identified when electrophoresis was
`performed in the presence of sodium dodeeyl sulfate (SDS).
`These two polypeptides are hereinafter referred to as 58 kDa
`and 88 kDa, respectively, or the 58 kDa and the 88 kDa
`component of MTP, respectively, or the low molecular
`weight subunit and the high molecular weight subunit of
`MTP, respectively.
`Characterization of the 58,000 molecular weight compo-
`nent of bovine MTP indicates that
`it
`is the previously
`characterized multifunctional protein, protein disulfide
`iso11ierase(PDl).Wetterau et al.,J. Biol. Cirem. 265, 9800-7
`(1990). The presence of PDI
`in the transfer protein is
`supported by evidence showing that (1) the amino terminal
`25 amino acids of the bovine 58,000 kDa component of
`MTP is identical to that of bovine PDI, and (2) disullide
`isomerase activity was expressed by bovine MTP following
`the dissociation of the 58 kDa-88 kDa protein complex. In
`addition, antibodies raised against bovine PDI, a protein
`which by itself has no TC} transfer activity, were able to
`immunoprecipitate bovine TG transfer activity from a solu-
`tion containing purified bovine M'l't’.
`PDI normally plays a role in the folding and assembly of
`newly synthesized disulfide bonded proteins within the
`lumen of the endoplasmic reticulum. Bulleid & Freedman,
`Nature 335, 649-51 (1988). It catalyzes the proper pairing
`of cysteine residues into disulfide bonds, thus catalyzing the
`proper folding of disulftde bonded proteins. In addition, PDI
`has been reported to be identical
`to the beta subunit of
`human prolyl 4-hydroxylase. Koivu et al., J. Biol’. Chem.
`262, 6447-9 (1987). The role of PDI in the bovine transfer
`protein is not clear.
`It does appear
`to be an essential
`component of the transfer protein as dissociation of PD]
`from the 88 kDa component of bovine MTP by either low
`concentrations ofa denaturant (guanidine IICI), a chaotropic
`agent (sodium perchlorate), or a nondenaturing detergent
`(octyl glucoside) results in a loss of transfer activity. Wet-
`terau et al., Biocitemist‘r'y 30, 9728-35 (1991).
`Isolated
`
`10
`
`I5
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`bovine PDI has no apparent lipid transfer activity, suggest-
`ing that cithcr the 88 kDa polypeptide is the transfer protein
`or that it confers transfer activity to the protein complex.
`The tissue and subcellular distribution of MTP activity in
`rats has been investigated. VVcttcrau S; Zilversmit, Bioclrem.
`Hiopitys. Acta 875, 610-7 (1986). l.ipid transfer activity was
`found in Liver and intestine. Little or no transfer activity was
`found in plasma, brain, heart, or kidney. Within the liver,
`MTP was a soluble protein located within the lumen of the
`microsomal fraction. Approximately equal concentrations
`were found in the smooth and rough mierosomes.
`Abetalipoproteinemia is an autosornal recessive disease
`characterized by a virtual absence of plasma lipoproteins
`which contain apolipeproleirt B (apoB). Kane & Havel in
`The Metabrflic Brrsis of Irrlrwited Di.sea.s'e_, Sixth Edition,
`"I 139-64 (1989). Plasma TG levels may be as low as a few
`mgld]., 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 of very low density lipoproteins (Vl.DI.) in
`the liver and chylomicrons in the intestine. The molecular
`basis for this defect has not been previously determined. In
`subjects examined, triglyceride, phospholipid, and clinics-
`terol synthesis appear normal. At autopsy, subjects are free
`of atherosclerosis. Schaefer et al., Clin. Cfi|'£’J'.*l'. 34, ]39-12
`(1988). A link between the apoB gene and abetalipopro-
`teincmia has been excluded in several families. Talmud et
`
`iff.'lJ‘t”$f. 82, 1803-6 (1988) and Huang et al.,Am.
`al.,J. C.'iir.=.
`J’. Htmt. Genet. 46, 1141-8 (1990).
`Subjects with abetalipoproteinemia are afflicted with
`numerous maladies. Kane & Havel, supra. Subjects have fat
`malabsorption and TG accumulation in their enterocytes and
`hepatocytcs. Due to the absence of TG—rich plasma
`lipoproteins, there is a defect in the transport of fat—soluble
`vitamins such as vitamin E. This results in acanthocytosis of
`erythrocytes, spinoecrebellar ataxia with degeneration of the
`fascieulus curieatus and graeilis, peripheral neuropathy,
`degenerative pigmentary retinopathy, and ceroid niyopathy.
`Treatment of abetalipoproteinemie subjects includes dietary
`restriction of fat
`intake and dietary supplementation with
`vitamins A, E and K.
`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, Biocircrtr. Bioplrys.
`Item 875, 610-7 (1986). The ability of MTP to catalyze the
`transport of TC: 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.
`
`Ulofsson and colleagues have studied lipoprotein assem-
`bly in HcpG2 cells. Bostrom ct al., J. Biol. Client. 263,
`4434-42 (1988). Their results suggest small precursor lipo-
`proteins become larger with time. This would be consistent
`with the addition or transfer of lipid molecules to nascent
`lipoproteins as they are assembled. MTP may play a role in
`this process.
`In support of this hypothesis, Howell and
`Palade, J. Cflff Biol. 92, 833-45 (1982),
`isolated nascent
`lipoproteins from the hepatic Golgi fraction of rat
`liver.
`There was a spectrum of sizes of particles present with
`varying lipid and protein compositions. Particles of high
`
`3 ufll4
`
`PENN EX. 2211
`
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`lPR20l5-01836
`
`

`
`5,827,875
`
`3
`density lipoprotcin (HDL) density, yct containing apoB,
`were found. Higgins and Hutson, J. Lipid Res. 25,
`1295-1305 (1984),
`reported lipoproteins isolated from
`Golgi were consistently larger than those from the endo-
`plasmic reticulum. again suggesting the assembly of lipo-
`proteins is a progressive event.
`
`Recent reports (Science, Vol. 258, page 999, 1992; D.
`Sharp et. al.. Nature, Vol. 365, page 65, 1993) demonstrate
`that the defect causing abetalipoproteinemia is in the MTP
`gene, and as a result,
`the MTP protein. Individuals with
`abetalipoproteinemia 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 lipoprotcins, such as
`VIDL,
`the precursor to lDl__ It
`therefore follows that
`inhibitors of MTP would inhibit the synthesis of VLDI. and
`LDL, thereby lowering V[_[)[. levels, IDI. levels, choles-
`terol levels, and triglyceride levels in animals and man.
`
`Canadian Patent Application No. 2,091,102 puhlishcd
`Mar. 2, 1994 (corresponding to U.S. application Ser. No.
`117,362, filed Sep. 3, 1993 (file [)(I2lb)) reports M'l‘l’
`inhibitors which also block the production of apoB contain-
`ing lipoproteins in a human hepatic cell line {HepG2 cells).
`This provides further support for the proposal that an MTP
`inhibitor would lower apol3 containing lipoprotein and lipid
`levels in vivo. This Canadian patent application discloses a
`method for iderltiiying the MTP inhibitors
`
`QQCN:
`
`the name 2—[l—(3,3—dipltenylpropyl)—4—
`which llas
`piperidinyl]-?.,3-dihydro-3-oxo-l ll-isoindole hydrochloride
`
`which has the name 1—[3—(6—fluoro—1—tetralanyl)melhyl]—4—
`U—methoxypI1enyl piperazine
`El’ 0643057/\l published Mar. 15, "[995, discloses MTP
`inhibitors of the structure
`
`4
`—eontinued
`
`0
`R-‘/( V
`/INRI‘:
`
`()1
`
`0
`
`R}
`
`R3
`
`R
`
`when: X is: {.'HR"_.—[.'H—(.'I-l or —(.‘=(.‘—:
`I
`I
`I
`I
`R9
`RJI
`R9 Rlfl
`
`[II
`
`R8, R9 and R10 are independently hydrogen, alkyl, alkcnyl,
`alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
`cycloalkyl, or cycloalkylalkyl;
`
`Y is —(CHg),,.,—or —C—
`I I0
`
`where m is 2 or 3;
`
`R1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalleyl
`(wherein alkyl has at
`least 2 carbons), diarylalkyl,
`arylalkenyl. diarylalkenyl, arylalkvnyl, diarylalkvnyl,
`diarylalkylaryl, heteroarylalkyl (wherein alkyl has at least 2
`carbons), cycloalkyl, or cycloalkylalkyl (wherein alkyl has
`at
`least 2 carbons); all of the aforementioned R1 groups
`being optionally substituted through available carbon atoms
`with 1, 2, or 3 groups selected [rom halo, haloalliyl, alkyl,
`alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmereapto,
`arylmercapto, cyeloalkyl, eycloalkylalkyl, hetcroaryl,
`Iluorenyl, heteroarylalkyl, hydroxy or oxo; or
`
`R1 is a group of the structure
`
`
`
`1U
`
`I5
`
`30
`
`35
`
`4U
`
`45
`
`SU
`
`55
`
`
`
`M
`
`N_Rl:
`
`R” is a bond, alkylene, alkenylene or alkynylcne of up to
`6“ 6 carbon atoms, arylene (for example
`
`as
`
`4 "T114
`
`1.
`
`PENN EX. 2211
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`lPR20l5-01836
`
`

`
`5,827,875
`
`5
`or mixed arylene—alkylene (for example
`
`(C11-:J.=— J
`
`to 6;
`where n is l
`R13 is hydrogen, alkyl, alkenyi, aryl, heteroaryl,
`haloalkyl, arylalkyl, arylalkenyl, cycloalkyl, aryloxy,
`alkoxy, arylalkoxy, heteroarylalkyl or cycloalkylalkyl;
`Z is a bond, 0, S, N-alkyl, N-aryl, or alkylene or alk-
`enylene of from 1
`to 5 carbon atoms;
`R“, R”, R”, and R1” are iiidependenlly liydrogeii, alkyl,
`halo, haloalkyl, aryl, cycloalkyl, cyeloheteroalkyl, alkenyl,
`alkynyl, hydroxy, alkoxy, nitro, amino, thio, alkylsulfonyl,
`arylsulfonyl, alkylthio, arylthio, carboxy, aminocarbonyl,
`alkylcarlmiiyloxy, alkylczirboiiylamino, arylalkyl,
`heleroaryl, heteroarylalkyl, or aryloxy;
`or R1 is
`
`RI‘.
`
`— (("lI3)!, —<
`
`R18
`
`to 8 and R” and Rm are each independently
`wherein p is '1
`II, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
`cycloalkyl or cycloalkylalkyl, at least one of R” and Rm
`being other than II;
`or R’ is
`
`R30
`
`_R19_< REI
`
`wherein
`
`R19 is aryl or heteroaryl;
`Rm is aryl or heteroaryl;
`R31 is II, alkyl, aryl, alkylaryl, arylalkyl, aryloxy,
`arylalkoxy, hcteroaryl, heteroarylalkyl, hcteroarylalkoxy,
`eycloalkyl, cycloalkylalkyl or cycloalkylalkoxy;
`R2, R3, R’: are independently hydrogen, halo, alkyl,
`haloalkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl,
`alkylmercapto, arylmcrcapto, cycloalkyl, cyeloalkylalkyl,
`heteroaryl, heteroarylalkyl, hydroxy or haloalkyl;
`R5 is alkyl of at least 2 carbons, alkenyl, alkynyl, aryl,
`heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl,
`eycloalkylalkyl, polycycloalkyl, polyeycloalkylalkyl,
`cycloalkenyl, eycloalkenylalkyl, polyeycloalkenyl,
`polycycloalkenylalkyl, heteroztrylcarbonyl, all of the R5 and
`R“ substituents being optionally substituted through avail-
`able carbon atoms with 1, 2, or 3 groups selected from
`hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy,
`alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,
`cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl,
`arylalkyl, arylcycloalkyl, arylalkynyl, aryloxy, aryloxyalkyl,
`arylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl,
`heteroarylalkenyl, heteroaryloxy, hydroxy, nitro, cyano,
`amino, substituted amino (wherein the amino includes "l or
`2 substituents which are alkyl, or aryl or any of the other aryl
`compounds mentioned in the definitions), lhiol, alkylthio,
`aryllhio, heteroarylthio, arylthioalkyl, alkylcarbonyl,
`arylcarbonyl, arylaminocarbonyl, alkoxycarbonyl,
`arninocarhonyl, alkynylaminocarhonyl, alkyl-
`aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy,
`arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamirto,
`arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl,
`
`rm
`
`1U
`
`I5
`
`30
`
`35
`
`4U
`
`5U
`
`55
`
`til]
`
`6
`arylsulfonylamino; with the proviso that when R’ is CH_-,, R”
`is not H; and where R5 is phenyl, the phenyl preferably
`includes an ortlio hydrophobic substituent such as alkyl,
`haloalkyl, aryl, aryloxy or arylalkyl;
`R“ is hydrogen or C1434 alkyl or C1434 alkenyl;
`R7 is al.kyl, aryl or arylalkyl wherein alkyl or the a|.k.yl
`portion is optionally substituted with 0x0; and
`including pharmaceutically acceptable salts and anions
`thereof.
`
`In the formula 1 cornpounds, where X is CH: and R3, R3
`and R4 are each H, R1 willbe otherthan 3,3—diplienylpropyl.
`In the formula III compounds, where_one of R‘, R" and R"
`is fi—lluoro, and the others are II, R’ will be other than
`4—0—methoxyphenyl.
`U.S. application Ser. No. 472,067, liled Jun. 6, 1995 (file
`I)(f2le] discloses compounds of the structure
`
`
`
`R]
`l
`N
`
`,
`
`or
`
`0
`11="\
`/.\'
`
`R6
`
`R;
`
`0
`
`Rs
`
`R4
`
`/R1
`
`K\ N
`/N X)
`
`Y
`
`0
`0
`ll
`ll
`wlIeI'cQi.s' —C_'.— or —S—
`ll
`0
`
`X ISICIIR“, —C—_. —CII—CII— O1‘ —C‘:C—'.
`ll
`l
`l
`l
`l
`0
`Ru
`R10
`R0 Rm
`
`R5, R" and R1” are independently hydrogen, alkyl, alkenyl,
`alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
`cycloalkyl, or cycloalkylalkyl;
`Y is
`
`—(CH2)...-
`
`or
`
`—C—
`I
`
`I0
`
`wherein m is 2 or 3;
`R1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl
`wherein alkyl has at least 2 carbons, diarylalkyl, arylalkenyl,
`
`5 ufll4
`
`PENN EX. 2211
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`diarylalkertyl, arylalkynyl, diarylalkynyl,
`
`5,827,875
`
`rliarylalkylaryl,
`
` 7
`
`R16
`
`‘R" *3‘
`
`RI2_z2
`
`R13
`
`R”
`
`—R”—Z'
`
`R”—Z1
`
`R13
`
`R15
`
`Z
`
`or
`
`R14
`
`R”
`
`a
`
`Z
`
`@
`
`Rte;
`
`0,
`
`R'
`
`is an indenyl-type group of the structure
`
`R13
`
`R1,,
`
`‘R"‘Z1
`
`0‘
`
`Rm"
`
`Rl2—z3
`m
`
`R
`
`(CH1)
`
`4
`
`(F2-30I4)
`
`Z‘ and Z: are the sanie or diiferent and are independently
`30 a bond, (J, S,
`
`(_
`
`35
`
`fi.
`
`0
`
`0 3
`
`,
`
`-N11
`
`0-
`
`,
`
`alkyl 0
`
`E .
`
`1‘|~
`
`H
`
`"3
`
`on
`
`E
`
`0
`
`Or
`
`D
`
`E
`
`with the proviso that with respect to fl, at least one of Z‘ and
`Z3 will be other than a bond; R" is :1 bond, alkylene,
`alkenylene or alkynylene of up to "[0 carbon atoms; arylene
`or mixed arylene—alkylene; R” is hydrogen, alkyl, alkcnyl,
`40 aryl, haloalkyl, Irihaloalkyl,
`trihaloalkylalkyl, heteroaryl,
`heteroarylalkyl, arylalkyl, arylalkenyl, eyeloalkyl, aryloxy,
`alkoxy, arylalkoxy or cycloetlkylalkyl, with the provisos that
`(1) when R12 is ll, aryloxy, alkoxy or arylalkoxy, then Z3
`
`—Nn—c—, —.\'—c—_. —c—
`II
`i
`ll
`||
`0
`alkyl 0
`0
`
`5” or a honrl and
`
`(2) when Z2 is a bond, R” cannot be hetcroaryl or
`heteroarylalkyl;
`2. ishond, O, S, N-alkyl, N-aryl, or alkylene or alkenylene
`55 [rum 1
`to 5 carbon atoms; R”, R”, R”, and RN’ are
`independently hydrogen, alkyl, halo, haloalkyl, aryl,
`cycloalkyl, cycloheteroalkyl, alkcnyl, alkynyl, hydroxy,
`alkoxy, nitro, amino,
`thio, alkylsulfonyl, arylsullonyl,
`alkyllhio, aryllhio, arninocarbonyl, alkylcarbonyloxy,
`6“ Ell’)-'l(.‘i1]'b(Jl'l)(l3.1'l'1l1'10, alkylcarbonylamino, arylalkyl,
`heteroaryl, heteroarylalkyl or arvloxy;
`R15" and I-11“ are independently hydrogen, alkyl, halo,
`haloalkyl, aryl, cyeloalkyl, cyclohctcroalkyl, alkcnyl,
`alkynyl, alkoxy, alkylsulfonyl, arylsulfonyl, alkylthio,
`65 arylthio, aminoearbonyl, alkylcarbonyloxy,
`arylcarbonylarnino, alkylcarbonylarnino, arylalkyl,
`heteroaryl, heteroarylalkyl, or aryloxy;
`
`6 0””
`
`PENN Ex. 2211
`CFAD V. UPENN
`lPR20l5-01836
`
`least 2 carbons,
`heteroarylalkyl wherein alkyl has at
`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, arylmercapto, cycloalkyl, cyeloalkylalkyl,
`heleroaryl, Iluorenyl, heteroarylttlkyl, hydroxy or oxo;
`or R1 is a lluorenyl-type group ol‘ the structure
`
`5
`
`1U
`
`I5
`
`En
`
`15
`
`A
`
`”
`
`8
`_¢0m{m1¢d
`
`l__
`R )
`
`H
`
`R
`
`_l
`H
`_R _L
`Rl,_z3
`
`RI!
`
`_Rn_Z1
`
`R15“
`
`"I
`
`R”*‘
`
`R14
`
`m.
`
`[69
`
`“'2 (cm.
`R154:
`
`RI!
`
`R14
`
`$
`
`Elsa
`
`;
`
`R164:
`
`_R11_Z1
`
`R“—Z3
`
`F
`
`G
`
`H
`
`

`
`5,827,875
`
`9
`or R1 is a group of the structure
`1:!-
`
`—[('Il:lp—<
`
`R18
`
`10
`—continued
`
`and
`
`wherein p is 1 to 8 and R” and R13 are each independently
`ll, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
`cycloalkyl or eyeloalkylalkyl at least one of R” and R18
`being other than H;
`or R‘ is a group of the structure
`
`R30
`_R19_< R.’I
`
`are the same or different and are independently selected from
`heteroaryl containing 5- or 6-ring members; and
`N—oxides
`
`1U
`
`o
`
`N/
`\R,
`
`thereof; and
`pharmaceutically acceptable salts thereol‘;
`with the provisos that where in the lirst formula X is (TI [3,
`and R3, R3 and R4 are each H, then R1 will be other than
`3,3-diphenylpropyl, and in the Iilth Formula, where one oi‘
`R3, R3 and R“ is 6-iiuoro. and the others are H, R7 will be
`other than 4-{2-rriethoxyphenyl).
`U.S. application Ser. No. 548,811 filed Jan. 11, 1996 (tile
`I)(T2lh), discloses compounds having the structure
`XI
`
`0 |
`
`11
`|
`(T—N—(IH3—(Tt~‘;
`
`2
`
`(CIIg),,—N
`
`tr
`N—(T—R5
`
`X3
`
`including the piperidine N—oxide thereof or a pharmaceuti-
`cally acceptable salt thereof, wherein Z is a bond, 0 or S;
`X1 and X2 are independently selected from II or halo;
`3: is an integer from 2 to 6;
`R5 is heteroaryl, aryl, hetcroeycloalkyl or cycloalkyl, each
`R5 group being optionally substituted with 1, 2, 3 or 4
`substituents which may be the same or diilerent.
`SUMMARY OF THE INVENTION
`
`invention, novel com-
`In accordance with the present
`pounds are provided which are inhibitors of MTP and have
`the structure
`
` \l—Rl',
`
`W
`
`or
`
`wherein
`
`R19 is aryl or heteroaryl;
`R3” is aryl or heteroaryl;
`R3‘
`is 11, alkyl, aryl, alkylaryl, arylalkyl, aryloxy,
`arylalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy,
`cycloalkyl, cycloalkylalkyl or cycloalkylalkoxy;
`R2, R3, R" are independently hydrogen, halo, alkyl,
`alkenyl. alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto,
`arylrnercapto, cycloalkyl, cyclrtalkylalkyl, heteroary],
`heteroarylalkyl, hydroxy or haloalkyl;
`R5 is independently alkyl, alkenyl, alkynyl, aryl, alkoxy,
`aryloxy, arylalkoxy, heteroaryl, arylalkyl, heteroarylalkyl,
`cycloalkyl, eycloalkylalkyl, polycycloalkyl,
`pnlycyeloalkylalkyl, cycloalkenyl, cycloheteroalkyl,
`heteroaryloxy, cycloalkenylalkyl, polycycloalkenyl,
`polycyeioalkenylalkyl, heteroarylcarbonyl, amino,
`alkylamino, arylamino, heteroarylamino, cycloalkyloxy,
`cycloalkylamino, all optionally substituted through avail-
`able carbon atoms with l, 2, 3 or 4 groups selected from
`hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy,
`alkenyl, alkynyl, cycloalkyl, eycloalkylalkyl,
`eyeioheteroalkyl, cycloheteroalkylalkyl, aryl, hetcroaryl,
`arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy,
`aryloxyalkyl, arylall-zoxy, arylazo, heteroaryloxo,
`heterourylalkyl, heleroarylalkenyl, heteroaryloxy, hydroxy,
`nitro, eyano. amino, substituted amino,
`thiol, alkylthio,
`arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl,
`arylcarbonyl, arylatninocarhonyl, alkoxycarbonyl,
`aminoearbonyl,
`alkynylaminocarbonyl,
`alkylaminoearbonyl, alkenylaminocarbonyl,
`alkylcarbonyloxy, arylcarbonyloxy, alkylcarboriylarrtino,
`arylearbonylamino, arylsulfinyt, arylsulfinylalkyl,
`arylsulfonyl,
`rtlkylsulfonyl, arylsulfonylamino,
`heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio,
`heteroarylsullonyl, alkylsullinyl;
`RE‘
`is hydrogen or C,—C,, alkyl or C,—C,, alkenyl; all
`optionally substituted with 1, 2, 3 or 4 groups which may
`independently be any of the substituents listed in the deli-
`nition of R5 set out above;
`R7 is alkyl, aryl or arylalkyl wherein alkyl by itself or as
`part of arylalkyl is optionally substituted with mm
`
`0
`
`(H ):
`
`‘
`
`30
`
`35
`
`4U
`
`45
`
`SU
`
`55
`
`6“
`
`as
`
`W is Il,Il or 0;
`
`7 0””
`
`Q
`
`R‘/ X‘?
`
`R‘
`
`It
`
`N—1{l
`
`w
`
`PENN EX. 2211
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`11
`
`5,827,875
`
`CIIR3,
`
`ill‘
`0
`
`_.
`
`fll
`R‘!
`
`fll
`R10
`
`or
`
`fztlf
`R9 RIG
`
`R”, R9 and Rm are independently hydrogen, alkyl, alkcnyl,
`alkynyl, aryl, arylalkyl, hcteroaryl, hcteroarylalkyl,
`cycloalkyl, or cycloalkylalkyl;
`
`—continucd
`
`R15
`
`R16
`
`_Rll_z1
`
`R12—Z2
`
`Z
`
`;or
`
`R13
`
`R14
`
`5
`
`1”
`
`'5
`
`R1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl
`(wherein alkyl preferably has at
`lcast 2 carbons, more
`preferably at
`leasl 3 carbons), diarylalkyl, arylalkunyl,
`diarylalkenyl, arylalkynyl, Lliarylalkynyl, diarylalkylaryl,
`heleroarylalkyl (wherein al.k.yl preferably has at
`least 2
`carbons, more preferably at least 3 carbons). cycloalkyl, or
`3“
`cycloall-1ylal.kyl (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, alkuxy,
`aryloxy, aryl, arylalkyl, alkyl—mcrcapto, arylmcrcapto,
`cycloalkyl, cycloalkyl-alkyl, heleroaryl,
`Iluorenyl,
`heteroarylalkyl, hydroxy or oxo; or
`
`15
`
`30
`
`35
`
`40
`
`45
`
`su
`
`A
`
`15
`
`C
`
`R1 is a flnorcnyl—typc group of the structure
`
`R15
`
`0|‘
`
`R]-I
`
`
`
`R15
`
`0|‘
`
`R”
`
`R15
`
`Z
`
`of
`
`R16
`
`_Rn_z]
`
`1212-22
`
`R13
`
`R14
`
`D
`
`Ii
`
`F
`
`rr
`
`H
`
`R1 is an in(lenyl—type group of the structure
`
`R13
`
`R14
`
`_R11_Z1
`
`312-32
`Risa
`
`(CH2):
`
`R15“
`
`or
`
`
`
`R”
`
`Rm"
`
`0:
`
`R13
`
`R14
`
`_R1|_z1
`
`R12_z2
`R153
`
`(CH2)-
`
`R13
`
`R16:
`
`or
`
`RH
`
`3
`_R11_Z1 Q R169
`
`313‘?
`
`R154:
`
`;
`
`Z1 and Z3 are the same or ditfcrcnt and are independently
`55 a bond, 0, 8,
`
`5,
`5
`n(II)
`0 0
`
`_,
`
`H
`,—‘~.H—(_— —1\:f_‘— —c— or —C—,
`II
`I
`II
`II
`I
`0
`alkyl 0
`0
`OH
`
`an
`
`65
`
`with the provis.o that with respect to Q, at least one of Z1 and
`22 will be other than a bond;
`
`R” is a bond, alkylene, alkenylene or alkynylene of up lo
`10 carbon atoms, arylene [for example
`
`3 0””
`
`PENN Ex. 2211
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`5,827,875
`
`13
`
`or mixed arylene-alkylene (for example
`
`(C11:)..—J
`
`where n is 1 to 6;
`R12 is hydrogen, alkyl, alkenyl, aryl, haloalkyl,
`Irihaloalkyl,
`trihaloalkylalkyl, hctcroaryl, hctcroarylalkyl,
`arylalkyl, arylalkenyl, cycloalkyl, aryloxy, alkoxy, aryla—
`lkoxy or eycloalkylalkyl; with the provisos that (1) when
`R13 is H, aryloxy, alkoxy or arylalkoxy, then Z3 is
`
`—\n—c—, —rx—C—, —K_—
`H
`|
`H
`II
`0
`alkyl 0
`0
`
`or a bond;
`and (2) when Z3 is a bond, R” cannot be heteroaryl or
`heleroarylalkyl;
`Z is a bond, 0, S, N-all-tyl, N-aryl, or alkylene or alk-
`enylene of from 1 to 5 carbon atoms;
`R”, R”, R", and R“; are independently hydrogen. atkyl,
`halo, haloalkyl, aryl, eycloalkyl, cyclohctcroalkyl, alkenyl,
`alkynyl, hydroxy, alkoxy, nitro, amino, thio, alkylsulfonyl,
`arylsulfonyl, alkylthio, arylthio, aminocarbonyl,
`alkylcarhonyloxy, arylcarhonylamino, alkylcarbonylamino,
`arylalkyl, hctcroaryl, hctcroarylalkyl, or aryloxy;
`Rm’ and Rm" are independently any of the R15 or R”
`groups except hydroxy, nitro, amino or thio;
`or R1 is
`
`—EC[1:Jp —<
`
`R"
`
`R18
`
`wherein p is "l to 8 and R” and R” are each independently
`H, alkyl, alkenyl, aryl, arylalkyl, hctcroaryl, hctcroarylalkyl,
`cycloalkyl or cycloalkylalkyl, at least one of R” and Rm
`being other than H;
`or R‘ is
`
`Rm
`_R19< RZI
`
`wherein
`
`R19 is aryl or heteroaryl;
`R30 is aryl or hctcroaryl;
`R11 is H, alkyl, aryl, alkylaryl, arylalkyl, aryloxy,
`arylalkoxy, heteroaryl, heteroarylalkyl, hcteroarylalkoxy,
`cycloall-tyl, cycloalkylalkyl or cyeltnalkylalkoxy;
`R3, R3, R4 are independently hydrogen, halo, alkyl,
`alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmcrcapto,
`arylmcrcapto, cycloalkyl, cycloalkylalkyl, hctcroaryl,
`heleroarylalkyl, hydroxy or haloalkyl;
`R5 is alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy,
`arylalkoxy, heteroaryl, arylalkyl, heteroarylalkyl,
`cycloalkyl, cycloheteroalkyl, heteroaryloxy,
`cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl,
`
`14
`cycloalkenyl, cycloalkenylalkyl, polycycloalkenyl,
`polycycloalkcnylalkyl, hcteroarylcarbonyl, amino,
`alkylamino, arylamino, heteroarylamino, cycloalkyloxy,
`cycloalkylamino, all of the R5 substitucnts and R5 substitu-
`ents (set out hereinafter) being optionally substituted
`through available carbon atoms with 1, 2, 3 or 4 groups
`selected from hydrogen, halo, alkyl, haloalkyl, alkoxy,
`haloalkoxy, alkcnyl, alkynyl, cyeloalkyl, eyeloalkylalkyl,
`cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl,
`arylalkyl, arylcyclozdkyl, arylall-tcnyl, arylalkynyl, aryloxy,
`aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroary1—
`alkyl, 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, alkylearhonyl, arylcarbonyl,
`arylaminocarbonyl, alkoxycarhonyl, aminocarbonyl,
`alkynylaminocarhonyl, alkylaminocarhonyl,
`aIkenylaminocarhonyl, alkylcarbonyloxy, arylcarhonyloxy,
`alkylcarbonylamino, arylcarbonylamino, arylsultinyl,
`arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl,
`arylsulfottylamino, heteroarylcarbonylamino,
`heteroarylsultinyl, heteroarylthio, heteroarylsulfonyl, or
`alkylsullinyl. Where R5 is phenyl, aryl, heteroaryl or
`cycloalkyl, this group preferably includes an ortho hydro-
`phobic substitucnt such as alkyl, haloalkyl (with up to 5 halo
`groups], al.koxy, haloalkoxy (with up to 5 halo groups), aryl,
`aryloxy or arylalkyl;
`R" is hydrogen or C1-C4 alkyl or C1-C4 alkcnyl;
`
`«-
`
`are the same or ditferent and are independently selected from
`hctcroaryl containing 5- or 6-ring members; and
`including N-oxides of the formulae I and II compounds,
`that is
`
`K6(J;N/
`
`\R1
`
`1U
`
`I5
`
`30
`
`35
`
`4U
`
`45
`
`SU
`
`and
`
`55
`
`till
`
`65
`
`including pharmaceutically acceptable salLs thereof such
`as alkali metal salts such as lithium sodium or potassium,
`alkaline earth metal salts such
`calcium or magnesium, as
`well as zinc or aluminum and other cations such as
`
`ammonium, choline, diethanolamine, ethylenediamine,
`t-butylamine, I-octylamine, dehydroabietylamine, as well as
`pharmaceutically acceptable anions such as chloride,
`bromide,
`iodide,
`tartrate, acetate, me