US006066650A
`[ii] Patent Number:
`[45] Date of Patent:
`
`6,066,650
`May 23,2000
`
`5/1993 Peglion et al
`5,208,243
`5/1993 Musser et al
`5,212,182
`6/1993 Baldwin et al
`5,215,989
`5,262,418 11/1993 Van Daele et al
`5,527,801
`6/1996 Masuda et al
`5,571,832 11/1996 De Costa et al
`5,578,611 11/1996 Gluchowski et al
`
`514/309
`514/314
`514/252
`514/258
`514/255
`514/408
`514/318
`
`FOREIGN PATENT DOCUMENTS
`
`3/1994 European Pat. Off. .
`0584446A2
`3/1995 European Pat. Off. .
`0643057Al
`4/1993 WIPO .
`WO 9305778
`WO96/40640 12/1996 WIPO .
`
`OTHER PUBLICATIONS
`
`Archibald et al., Benzamidopiperidines. 3. Carbocyclic
`Derivatives Related to Indoramin, Journal of Medicinal
`Chemistry, vol. 17, No. 7, pp. 739-744, Jul. 1974.
`
`(List continued on next page.)
`
`Primary Examiner—Richard L. Raymond
`Assistant Examiner—Brenda Coleman
`Attorney, Agent, or Firm—Burton Rodney
`
`[57]
`
`ABSTRACT
`
`Compounds are provided which inhibit microsomal triglyc(cid:173)
`eride transfer protein and thus are useful for lowering serum
`lipids and treating atherosclerosis and related diseases. The
`compounds have the structure
`
`N
`
`R1,
`
`United States Patent [19]
`Biller et al.
`
`[54]
`
`[75]
`
`INHIBITORS OF MICROSOMAL
`TRIGLYCERIDE TRANSFER PROTEIN AND
`METHOD
`
`Inventors: Scott A. Biller, Hopewell; John K.
`Dickson, Eastampton, both ol N.J.; R.
`Michael Lawrence, Yardley, Pa.; David
`R. Magnin, Hamilton, N.J.; Michael A.
`Poss, Lawrenceville, N.J.; Richard B.
`Sulsky, Franklin Park, N.J.; Joseph A.
`Tino, Lawrenceville, N.J.; John E.
`Lawson, Wallingford; Henry M.
`Holava, Meriden, both of Conn.;
`Richard A. Partyka, Neshanic, N.J.
`
`[73] Assignee: Bristol-Myers Squibb Company,
`Princeton, N.J.
`
`[21] Appl. No.: 08/898,303
`
`[22] Filed:
`
`Jul. 21, 1997
`
`Related U.S. Application Data
`
`[63] Continuation of application No. 08/472,067, Jun. 6, 1995,
`Pat. No. 5,739,135, which is a continuation-in-part of appli(cid:173)
`cation No. 08/391,901, Feb. 21, 1995, abandoned, which is
`a continuation-in-part of application No. 08/284,808, Aug.
`5, 1994, abandoned, which is a continuation-in-part of
`application No. 08/117,362, Sep. 3, 1993, Pat. No. 5,595,
`872.
`
`Int. CI.7
`
`[51]
`
`A61K 31/445; A61K 31/47;
`A61K 31/52; A61K 31/495; C07D 211/00;
`C07D 217/00; C07D 215/38; C07D 401/00
`514/248; 514/252;
`514/315
`[52] U.S. CI
`514/318; 514/320;
`514/266; 514/307; 514/314
`514/324; 514/326;
`514/321; 514/322; 514/323
`544/277; 544/407;
`514/329; 544/235; 544/238
`546/146; 546/169; 546/194
`546/196; 546/197;
`546/198; 546/199; 546/201
`546/202; 546/208;
`546/209; 546/211; 546/213
`546/214; 546/223;
`546/224
`[58] Field of Search
`514/248, 252,
`514/266, 307, 314, 315, 318, 320, 321,
`323, 322, 324, 326, 329; 544/235, 238,
`277, 407; 546/146, 169, 194, 196, 197,
`198, 199, 201, 202, 208, 209, 211, 213,
`214, 224, 223
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,910,931 10/1975 Cavalla et al
`4,289,781
`9/1981 Bengtsson et al
`4,367,232
`1/1983 Boix-Igleasias et al
`4,563,466
`1/1986 Archibald et al
`4,576,940
`3/1986 Tahara et al
`4,581,355
`4/1986 Tahara et al
`4,607,042
`8/1986 Pierce
`4,826,975
`5/1989 Picciola et al
`4,918,073
`4/1990 Ruger et al
`5,026,858
`6/1991 Vega-Noverola et al
`5,028,616
`7/1991 Desai et al
`5,032,598
`7/1991 Baldwin et al
`5,098,915
`3/1992 Desai et al
`5,130,333
`7/1992 Pan et al
`5,189,045
`2/1993 Peglion et al
`
`260/293.62
`424/267
`424/267
`514/319
`514/212
`514/212
`514/323
`544/391
`514/255
`546/224
`514/321
`514/318
`514/324
`514/460
`514/319
`
`wherein R1 to R7, Q, X and Y are as defined herein.
`
`2 Claims, No Drawings
`
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`
`OTHER PUBLICATIONS
`
`Bulleid & Freedman, Nature 335, 649-651 (1988). "Defec(cid:173)
`tive co-translational formation of disulphide bonds in pro(cid:173)
`tein disulphideisomerase-deficient microsomes".
`Koivu et al., J. Biol. Chem. 262, 6447-6449 (1987). "A
`Single Polypeptide Acts Both as the (3 Subunit of Prolyl
`4-Hydroxylase and as a Protein Disulfide-Isomerase*".
`Kane & Havel in the Metabolic Basis of Inherited Disease,
`Sixth Edition, 1139-1164 (1989). "Disorders of the Biogen(cid:173)
`esis and Secretion of Lipoproteins Containing The B Apo-
`lipoproteins".
`Schaefer et al, Clin. Chem. 34, B9-B12 (1988). "Genetics
`and Abnormalties in Metabolism of Lipoproteins".
`Drayna et al, Nature 327, 632-634 (1987). "Cloning and
`sequencing of human cholesteryl ester transfer protein
`cDNA".
`Pihlajaniemi et al., EMBO J. 6, 643-649 (1987). "Molecular
`cloning of the (B-subunit of human prolyl 4—hydroxylase.
`This subunit and protein disulphide isomerase are products
`of the same gene".
`Yamaguchi et al., Biochem. Biophys. Res. Comm. 146,
`1483-1492 (1987). "Sequence of Membrane-Associated
`Thyroid Hormone Binding Protein From Bovine Liver: Its
`Identity with Protein Disulphide Isomerase".
`Edman et al, Nature 317, 267-270 (1985). Sequence of
`protein disulphide isomerase and implications of its rela(cid:173)
`tionship to thioredoxin.
`Kao et al., Connective Tissue Research 18,157-174 (1988).
`"Isolation of cDNA Clones and Genomic DNA Clones of
`P-Subunit of Chicken Prolyl 4-Hydroxylase*".
`Wetterau, J. et al, Biochem 30, 9728-9735 (1991). "Protein
`Disulfide Isomerase Appears Necessary To Maintain the
`Catalytically Active Structure of the Microsomal Triglycer(cid:173)
`ide Transfer Protein".
`Morton, R.E. et al., J. Biol. Chem. 256, 1992-1995 (1981).
`"A Plasma Inhibitor of Triglyceride and Chloesteryl Ester
`Transfer Activities".
`
`Wetterau, J. et al:, Biochem: 30, 4406-4412 (1991): "Struc(cid:173)
`tural Properties of the Microsomal Triglyceride-Transfer
`Protein Complex".
`Wetterau, J. et al., J. Biol. Chem. 265, 9800-9807 (1990).
`"Protein Disulfide Isomerase Is a Component of the
`Microsomal Triglyceride Transfer Protein Complex".
`Wetterau, J. and Zilversmit, D.B., Chem. and Phys. of Lipids
`38, 205-222 (1985). "Purification and Characterization of
`Microsomal Triglyceride and Cholesteryl Ester Transfer
`Protein From Bovine Liver Microsomes".
`Wetterau, C. and Zilversmit, D.B., Biochimica et Biophysica
`Acta 875, 610-617 (1986). "Localization of intracellular
`triacylglycerol and cholesteryl ester transfer activity in rat
`tissues".
`Wetterau, J. and Zilversmit, D.B., J. Biol. Chem. 259,
`10863-10866 (1984). "ATriglyceride and Cholesteryl Ester
`Transfer Protein Associated with Liver Microsomes".
`Wetterau,.J., Grant Application entitled: "Intracellular Trig(cid:173)
`lyceride Transport and Metabolism", 1987.
`Presentation Materials, Aspen Bile Acid/Cholesterol Con(cid:173)
`ference, Aug. 15, 1992.
`Wetterau, J. R., et al, Science, vol. 258, 999-1001, Nov. 6,
`1992 "Absence of Microsomal Triglyceride Transfer Protein
`in Individuals with Abetalipoproteinemia".
`Archibald, J. L., et al., Journal of Medicinal Chemistry, vol.
`14, No. 11, pp. 1054-1059, 1971.
`Cortizo, L. et al., J. Med. Chem., 34, pp. 2242-2247, 1991.
`Hall, I. H. et al., Pharmaceutical Research, vol. 9, No. 10, pp.
`1324-1329 1992.
`Hall, I. H., et al., Pharmacological Research Communica(cid:173)
`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.
`Derwent Abstract No. 93-117225/14, 1993.
`
`2 of 162
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`INHIBITORS OF MICROSOMAL
`TRIGLYCERIDE TRANSFER PROTEIN AND
`METHOD
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`5
`
`This is a continuation of application Ser. No. 08/472,067,
`filed Jun. 6, 1995 now U.S. Pat. No. 5,739,135, which is a
`continuation-in-part of application Ser. No. 08/391,901,
`filed Feb. 21, 1995, now abandoned, which
`is a
`continuation-in-part of application Ser. No. 08/284,808,
`filed Aug. 5,1994, now abandoned, which is a continuation-
`in-part of application Ser. No. 08/117,362, filed Sep. 3,
`1993, now U.S. Pat. No. 5,595,872.
`
`15
`
`FIELD OF THE INVENTION
`
`This invention relates to novel compounds which inhibit
`microsomal triglyceride transfer protein, and to methods for
`decreasing serum lipids and treating atherosclerosis employ- 20
`ing such compounds.
`
`BACKGROUND OF THE INVENTION
`
`The microsomal triglyceride transfer protein (MTP) cata(cid:173)
`lyzes the transport of triglyceride (TG), cholesteryl ester
`(CE), and phosphatidylcholine (PC) between small unila(cid:173)
`mellar vesicles (SUV). Wetterau & Zilversmit, Chem. Phys.
`Lipids 38, 205-22 (1985). When transfer rates are expressed
`as the percent of the donor lipid transferred per time, MTP
`expresses a distinct preference for neutral lipid transport
`(TG and CE), relative to phospholipid transport. The protein
`from bovine liver has been isolated and characterized.
`Wetterau & Zilversmit, Chem. Phys. 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 dodecyl 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(cid:173)
`nent of bovine MTP indicates that it is the previously
`characterized multifunctional protein, protein disulfide 50
`isomerase (PDI). Wetterau et al.,/. Biol. Chem. 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) disulfide 55
`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 TG transfer activity, were able to
`immunoprecipitate bovine TG transfer activity from a solu- 6Q
`tion containing purified bovine MTP.
`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 353, 649-51 (1988). It catalyzes the proper pairing 65
`of cysteine residues into disulfide bonds, thus catalyzing the
`proper folding of disulfide bonded proteins. In addition, PDI
`
`has been reported to be identical to the beta subunit of
`human prolyl 4-hydroxylase. Koivu et al., /. 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 PDI
`from the 88 kDa component of bovine MTP by either low
`concentrations of a denaturant (guanidine HC1), a chaotropic
`agent (sodium perchlorate), or a nondenaturing detergent
`(octyl glucoside) results in a loss of transfer activity. Wet(cid:173)
`terau et al, Biochemistry 30, 9728-35 (1991). Isolated
`bovine PDI has no apparent lipid transfer activity, suggest(cid:173)
`ing that either 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. Wetterau & Zilversmit, Biochem.
`Biophys.Acta 875, 610-7 (1986). Lipid 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 microsomes.
`Abetalipoproteinemia is an autosomal recessive disease
`characterized by a virtual absence of plasma lipoproteins
`which contain apolipoprotein B (apoB). Kane & Havel in
`The Metabolic Basis of Inherited Disease, Sixth edition,
`1139-64 (1989). Plasma TG levels may be as low as a few
`mg/dL, and they fail to rise after fat ingestion. Plasma
`cholesterol levels are often only 20-45 mg/dL. These abnor(cid:173)
`malities are the result of a genetic defect in the assembly
`and/or secretion of very low density lipoproteins (VLDL) in
`the liver and chylomicrons in the intestine. The molecular
`basis for this defect has not been previously determined. In
`subjects examined, triglyceride, phospholipid, and choles(cid:173)
`terol synthesis appear normal. At autopsy, subjects are free
`of atherosclerosis. Schaefer et al., Clin. Chem. 34, B9-12
`(1988). A link between the apoB gene and abetalipopro(cid:173)
`teinemia has been excluded in several families. Talmud et
`al.,/. Clin. Invest. 82, 1803-6 (1988) and Huang et al.,Am.
`/. Hum. 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
`hepatocytes. 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, spinocerebellar ataxia with degeneration of the
`fasciculus cuneatus and gracilis, peripheral neuropathy,
`degenerative pigmentary retinopathy, and ceroid myopathy.
`Treatment of abetalipoproteinemic 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(cid:173)
`protein assembly. Wetterau & Zilversmit, Biochem. Biophys.
`Acta 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(cid:173)
`port of TG from its site of synthesis in the endoplasmic
`reticulum (ER) membrane to nascent lipoprotein particles
`within the lumen of the ER.
`Olofsson and colleagues have studied lipoprotein assem(cid:173)
`bly in HepG2 cells. Bostrom et al., /. Biol. Chem. 263,
`
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`4434-42 (1988). Their results suggest small precursor lipo(cid:173)
`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. Cell Biol. 92, 833^5 (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
`density lipoprotein (HDL) density, yet containing apoB,
`were found. Higgins and Hutson, /. Lipid Res. 25,
`1295-1305 (1984), reported lipoproteins isolated from
`Golgi were consistently larger than those from the endo(cid:173)
`plasmic reticulum, again suggesting the assembly of lipo(cid:173)
`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 lipoproteins, such as
`VLDL, the precursor to LDL. It therefore follows that
`inhibitors of MTP would inhibit the synthesis of VLDL and
`LDL, thereby lowering VLDL levels, LDL levels, choles(cid:173)
`terol levels, and triglyceride levels in animals and man.
`
`Canadian Patent Application No. 2,091,102 published
`Mar. 2, 1994 (corresponding to U.S. application Ser. No.
`117,362, filed Sep. 3, 1993 (file DC21b)) reports MTP
`inhibitors which also block the production of apoB contain(cid:173)
`ing lipoproteins in a human hepatic cell line (HepG2 cells).
`This provides further support for the proposal that an MTP
`inhibitor would lower apoB containing lipoprotein and lipid
`levels in vivo. This Canadian patent application discloses a
`method for identifying the MTP inhibitors
`
`SUMMARY OF THE INVENTION
`In accordance with the present invention, novel com(cid:173)
`pounds are provided which are inhibitors of MTP and have
`the structure
`
`30
`
`35
`
`40
`
`45
`
`50
`
`R5^
`
`^ N-
`
`N
`
`R'
`
`or
`
`O
`II
`C—
`
`c—
`II II
`o
`
`or
`
`,
`
`o
`II
`s
`II
`CH CH
`o
`1
`1
`R10
`R"
`
`;
`
`where Q is
`
`X is: CHR8,
`
`- c = c-
`
`which has the name 2-[l-(3,3-diphenylpropyl)-4-
`piperidinyl]-2,3-dihydro-3-oxo-lH-isoindole hydrochloride
`and
`
`,,
`
`R8, R9 and R10 are independently hydrogen, alkyl, alkenyl,
`alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
`cycloalkyl, or cycloalkylalkyl;
`
`60
`
`Yis
`
`(CH2)m
`
`or
`
`C
`
`0CH3
`
`which has the name l-[3-(6-fluoro-l-tetralanyl)methyl]-4-
`O-methoxyphenyl piperazine
`
`65 where m is 2 or 3;
`R1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl
`(wherein alkyl has at least 2 carbons, preferably at least
`
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`3 carbons), diarylalkyl, arylalkenyl, diarylalkenyl,
`arylalkynyl, diarylalkynyl, diarylalkylaryl, heteroaryla-
`Lkyl (wherein alkyl has at least 2 carbons, preferably at
`least 3 carbons), cycloalkyl, or cycloalkylalkyl
`(wherein alkyl has at least 2 carbons, preferably at least
`3 carbons); all of the aforementioned R1 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, alkyl- w
`mercapto, arylmercapto, cycloalkyl, cycloalkyl-alkyl,
`heteroaryl, fluorenyl, heteroarylalkyl, hydroxy or oxo;
`or
`R1 is a fluorenyl-type group of the structure
`
`6
`-continued
`
`, 12
`
`s/
`
`Z2-
`R
`(a = 2, 3 or 4)
`
`y RI'
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`R is an indenyl-type group of the structure
`
`Z1 and Z2 are the same or different and are independently
`a bond, O, S,
`
`s
`,s.
`o VoJ2
`
`\
`
`\)
`
`••
`
`\
`
`\>
`
`,
`
`NH
`
`O
`II
`o
`
`-N
`
`C-
`
`alkyl O
`
`or
`
`— c—
`II
`o
`
`H
`C
`
`1
`
`OH
`
`with the proviso that with respect to B, at least one of Z1 and
`Z2 will be other than a bond;
`
`R11 is a bond, alkylene, alkenylene or alkynylene of up to
`10 carbon atoms, arylene (for example
`
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`or mixed arylene-alkylene (for example
`
`(CH2)n
`
`)
`
`where n is 1 to 6;
`R12 is hydrogen, alkyl, alkenyl, aryl, haloalkyl,
`trihaloalkyl,
`trihaloalkylalkyl, heteroaryl,
`heteroarylalkyl, arylalkyl, arylalkenyl, cycloalkyl,
`aryloxy, alkoxy, arylalkoxy or cycloalkylalkyl; with the
`provisos that (1) when R12 is H, aryloxy, alkoxy or
`arylalkoxy, then Z2 is
`
`- N H — c-
`
`alkyl O
`
`and (2) when Z2 is a bond, R12 cannot be heteroaryl or
`heteroarylalkyl;
`Z is a bond, O, S, N-alkyl, N-aryl, or alkylene or alk-
`enylene of from 1 to 5 carbon atoms;
`R13, R14, R15, and R16 are independently hydrogen, alkyl,
`halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl,
`alkenyl, alkynyl, hydroxy, alkoxy, nitro, amino, thio,
`alkylsulfonyl, arylsulfonyl, alkylthio, arylthio,
`aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino,
`alkylcarbonylamino, arylalkyl, heteroaryl,
`heteroarylalkyl, or aryloxy;
`R15fl and R16" are independently any of the R15 or R16
`groups except hydroxy, nitro, amino or thio;
`or R1 is
`
`-(CH2),
`
`wherein p is 1 to 8 and R17 and R18 are each independently
`H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
`cycloalkyl or cycloalkylalkyl, at least one of R17 and R18
`being other than H;
`or R1 is
`
`R
`
`8
`is alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy,
`arylalkoxy, heteroaryl, arylalkyl, heteroarylalkyl,
`cycloalkyl, cycloheteroalkyl, heteroaryloxy,
`cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl,
`cycloalkenyl, cycloalkenylalkyl, polycycloalkenyl,
`polycycloalkenylalkyl, heteroarylcarbonyl, amino,
`a l k y l a m i n o, a r y l a m i n o, h e t e r o a r y l a m i n o,
`cycloalkyloxy, cycloalkylamino, all of the R5 substitu-
`ents and R6 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, haloalkoxy, alkenyl, alkynyl,
`cycloalkyl, cycloalkylalkyl, cycloheteroalkyl,
`cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl,
`arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy,
`aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo,
`heteroaryl-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,
`alkylcarbonyl, arylcarbonyl, arylaminocarbonyl,
`a l k o x y c a r b o n y l,
`a m i n o c a r b o n y l,
`alkynyl aminocarbonyl, alkyl aminocarbonyl,
`a l k e n y l a m i n o c a r b o n y l,
`a l k y l c a r b o n y l o x y,
`a r y l c a r b o n y l o x y,
`a l k y l c a r b o n y l a m i n o,
`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-
`stituent such as alkyl, haloalkyl (with up to 5 halo
`groups), alkoxy, haloalkoxy (with up to 5 halo groups),
`aryl, aryloxy or arylalkyl;
`R6 is hydrogen or C1-C4 alkyl or C1-C4 alkenyl;
`R7 is alkyl, aryl or arylalkyl wherein alkyl or the alkyl
`portion is optionally substituted with oxo; and
`
`( Het )
`
`( H e t l)
`
`( n et
`
`l)
`
`are the same or different and are independently selected from
`heteroaryl containing 5- or 6-ring members; and
`including N-oxides of the formulae I, li, II and Hi
`compounds, that is
`
`S0
`N
`
`; and
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`wherein R19 is aryl or heteroaryl;
`R20 is aryl or heteroaryl;
`R21 is H, alkyl, aryl, alkylaryl, arylalkyl, aryloxy, 60
`a r y l a l k o x y, h e t e r o a r y l,
`h e t e r o a r y l a l k y l,
`heteroarylalkoxy, cycloalkyl, cycloalkylalkyl or
`cycloalkylalkoxy;
`R2, R3, R4 are independently hydrogen, halo, alkyl,
`alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, 65
`arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl,
`heteroarylalkyl, hydroxy or haloalkyl;
`
`including pharmaceutically acceptable salts thereof such
`as alkali metal salts such as lithium sodium or
`potassium, alkaline earth metal salts such as calcium or
`magnesium, as well as zinc or aluminum and other
`cations such as ammonium, choline, diethanolamine,
`ethylenediamine,
`t-butylamine,
`t-octylamine,
`dehydroabietylamine, as well as pharmaceutically
`acceptable anions such as chloride, bromide, iodide,
`tartrate, acetate, methanesulfonate, maleate, succinate,
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`glutarate, and salts of naturally occurring amino acids
`such as arginine, lysine, alanine and the like, and
`prodrug esters thereof.
`In the formula I compounds, where X is CH2 and R2, R3 5
`and R4 are each H, R1 will be other than 3,3-diphenylpropyl.
`In the formula III compounds, where one of R2, R3 and R4
`is 6-fluoro, and the others are H, R7 will be other than
`4-(2-methoxy)phenyl.
`
`10
`
`Thus, the compounds of formulae I and II of the invention
`encompass compounds of the structure
`
`30
`
`35
`
`10
`-continued
`
`N R1
`
`X.
`
`N-
`
`R=
`
`u
`
`R
`
`II N-
`
`N R1
`
`N R1
`
`N R1
`
`R6
`
`||
`O
`
`NT-
`I
`R'
`
`11
`
`40
`
`R=
`
`45
`
`The compounds of formula III of the invention encompass
`compounds of the structure III"
`
`50
`
`55
`
`60
`
`65
`
`(CH2)^
`
`Ilf
`
`In addition, in accordance with the present invention, a
`method for preventing, inhibiting or treating atherosclerosis,
`pancreatitis or obesity is provided, wherein a compound of
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`12
`be fused to 1 or 2 aromatic rings as described for aryl, which
`include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
`cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl,
`cyclohexenyl,
`
`11
`formula I, li, II, Hi or III as defined hereinbefore wherein R1
`also includes arylmethyl, heteroarylmethyl and cycloalkyl-
`methyl and Y also includes —CH2—, is administered in an
`amount which decreases the activity of microsomal triglyc(cid:173)
`eride transfer protein.
`Furthermore, in accordance with the present invention, a
`method is provided for lowering serum lipid levels, choles(cid:173)
`terol and/or triglycerides, or inhibiting and/or treating
`hyperlipemia, hyperlipidemia, hyperlipoproteinemia, hyper(cid:173)
`cholesterolemia and/or hypertriglyceridemia, wherein a
`compound of formula I, li, II, Hi or III as defined herein(cid:173)
`before wherein R1 also
`includes arylmethyl,
`heteroarylmethyl, and cycloalkylmethyl, and Y also includes
`—CH2—, is administered in an amount which decreases the
`activity of microsomal triglyceride transfer protein.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`The following definitions apply to the terms as used
`throughout this specification, unless otherwise limited in
`specific instances.
`The term "MTP" refers to a polypeptide or protein
`complex that (1) if obtained from an organism (e.g., cows,
`humans, etc.), can be isolated from the microsomal fraction
`of homogenized tissue; and (2) stimulates the transport of
`triglycerides, cholesterol esters, or phospholipids from syn(cid:173)
`thetic phospholipid vesicles, membranes or lipoproteins to
`synthetic vesicles, membranes, or lipoproteins and which is
`distinct from the cholesterol ester transfer protein [Drayna et
`al., Nature 327, 632-634 (1987)] which may have similar
`catalytic properties. However, the MTP molecules of the
`present invention do not necessarily need to be catalytically
`active. For example, catalytically inactive MTP or fragments
`thereof may be useful in raising antibodies to the protein.
`The phrase "stabilizing" atherosclerosis as used in the
`present application refers to slowing down the development
`of and/or inhibiting the formation of new atherosclerotic
`lesions.
`The phrase "causing the regression of atherosclerosis as
`used in the present application refers to reducing and/or
`eliminating atherosclerotic lesions.
`Unless otherwise indicated, the term "lower alkyl",
`"alkyl" or "alk" as employed herein alone or as part of
`another group includes both straight and branched chain
`hydrocarbons, containing 1 to 40 carbons, preferably 1 to 20
`carbons, more preferably 1 to 12 carbons, in the normal
`chain,such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl,
`isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl,
`octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl,
`the various branched chain isomers thereof, and the like as
`well as such groups including 1 to 4 substituents such as
`halo, for example F, Br, CI or I or CF3, alkoxy, aryl, aryloxy,
`aryl(aryl) or diaryl, arylalkyl, arylalkyloxy, alkenyl,
`cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino,
`hydroxy, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl,
`heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, alkylamido,
`alkanoylamino, arylcarbonylamino, nitro, cyano, thiol,
`haloalkyl, trihaloalkyl and/or alkylthio, as well as any of the
`other substituents as defined for R5 and R6.
`Unless otherwise indicated, the term "cycloalkyl" as
`employed herein alone or as part of another group includes
`saturated or partially unsaturated (containing 1 or 2 double
`bonds) cyclic hydrocarbon groups containing 1 to 3 rings,
`including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl,
`containing a total of 3 to 20 carbons forming the rings,
`preferably 4 to 12 carbons, forming the ring and which may
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`any of which groups may be optionally substituted with 1 to
`4 substituents such as halogen, alkyl, alkoxy, hydroxy, aryl,
`aryloxy, arylalkyl, cycloalkyl, alkylamido, alkanoylamino,
`oxo, acyl, arylcarbonylamino, amino, nitro, cyano, thiol
`and/or alkylthio, as well as any of the other substituents as
`defined for R5 or R6.
`The term "cycloalkenyl" as employed herein alone or as
`part of another group refers to cyclic hydrocarbons contain(cid:173)
`ing 5 to 20 carbons, preferably 6 to 12 carbons and 1 or 2
`double bonds. Exemplary cycloalkenyl groups include
`cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,
`cyclohexadienyl, and cycloheptadienyl, which may be
`optionally substituted as defined for cycloalkyl.
`The term "polycycloalkyl" as employed herein alone or as
`part of another group refers to a bridged multicyclic group
`containing 5 to 20 carbons and containing 0 to 3 bridges,
`preferably 6 to 12 carbons and 1 or 2 bridges. Exemplary
`polycycloalkyl groups include [3.3.0]-bicyclooctanyl,
`adamantanyl,
`[2.2.1]-bicycloheptanyl,
`[2.2.2]-
`bicyclooctanyl and the like and may be optionally substi(cid:173)
`tuted as defined for cycloalkyl.
`The term "polycycloalkenyl" as employed herein alone or
`as part of another group refers to bridged multicyclic group
`containing 5 to 20 carbons and containing 0 to 3 bridges and
`containing 1 or 2 double bonds, preferably 6 to 12 carbons
`and 1 or 2 bridges. Exemplary polycycloalkyl groups
`include [3.3.0]-bicyclooctenyl, [2.2.1]-bicycloheptenyl,
`[2.2.2]-bicyclooctenyl and the like and may be optionally
`substituted as defined for cycloalkyl.
`The term "aryl" or "Ar" as employed herein alone or as
`part of another group refers to monocyclic and bicyclic
`aromatic groups containing 6 to 10 carbons in the ring
`portion (such as phenyl or naphthyl) and may optionally
`include one to three additional rings fused to Ar (such as
`aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings) and
`may be optionally substituted through available carbon
`atoms with 1, 2, 3 or 4 groups selected from hydrogen, halo,
`haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl,
`trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkylalkyl,
`cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl,
`arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylthio,
`a r y l a z o, h e t e r o a r y l a l k y l,
`h e t e r o a r y l a l k e n y l,
`heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro, cyano,
`amino, substituted amino wherein the amino includes 1 or 2
`substituents (which are alkyl, aryl or any of the other aryl
`compounds mentioned in the definitions), thiol, alkylthio,
`arylthio, heteroarylthio, arylthio alkyl, alkoxyarylthio,
`alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl,
`arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl,
`alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino,
`arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfo-
`nylamino or arylsulfonaminocarbonyl, or any of the sub(cid:173)
`stituents as defined for the R5 or R6 groups set out above.
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`The term "aralkyl", "aryl-alkyl" or "aryllower alkyl" as
`used herein alone or as part of another group refers to alkyl
`groups as discussed above having an aryl substituent, such
`as benzyl or phenethyl, or naphthylpropyl, or an aryl as
`defined above.
`The term "lower alkoxy", "alkoxy", "aryloxy" or
`"aralkoxy" as employed herein alone or as part of another
`group includes any of the above alkyl, aralkyl or aryl groups
`linked to an oxygen atom.
`The term "amino" as employed herein alone or as part of
`another group may optionally be substituted with one or two
`substituents such as alkyl and/or aryl.
`The term "lower alkylthio", alkylthio", "arylthio" or
`"aralkylthio" as employed herein alone or as part of another
`group includes any of the above alkyl, aralkyl or aryl groups
`linked to a sulfur atom.
`The
`term "lower alkylamino", "alkylamino",
`"arylamino", or "arylalkylamino" as employed herein alone
`or as part of another group includes any of the above alkyl,
`aryl or arylalkyl groups linked to a nitrogen atom.
`The term "acyl" as employed herein by itself or part of
`another group as defined herein, refers to an organic radical