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WO1999021564A1 - Inhibiteurs phosphonate ester cyclique de proteine microsomale de transfert des triglycerides et procede associe - Google Patents

Inhibiteurs phosphonate ester cyclique de proteine microsomale de transfert des triglycerides et procede associe Download PDF

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Publication number
WO1999021564A1
WO1999021564A1 PCT/US1998/021750 US9821750W WO9921564A1 WO 1999021564 A1 WO1999021564 A1 WO 1999021564A1 US 9821750 W US9821750 W US 9821750W WO 9921564 A1 WO9921564 A1 WO 9921564A1
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Prior art keywords
aryl
alkyl
amino
oxo
trifluoroethyl
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Richard B. Sulsky
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Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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Priority to CA002307889A priority Critical patent/CA2307889A1/fr
Priority to JP2000517722A priority patent/JP2001521001A/ja
Priority to EP98953531A priority patent/EP1039915A4/fr
Priority to AU10876/99A priority patent/AU753520B2/en
Publication of WO1999021564A1 publication Critical patent/WO1999021564A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/657163—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom
    • C07F9/657181—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • This invention relates to novel cyclic phosphonate esters which inhibit microsomal triglyceride transfer protein, and to methods for decreasing serum lipids and treating atherosclerosis employing such compounds .
  • MTP microsomal triglyceride transfer protein
  • TG triglyceride
  • CE cholesteryl ester
  • PC phosphatidylcholine
  • Polyacrylamide gel electrophoresis 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) .
  • SDS sodium dodecyl sulfate
  • 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.
  • 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 disulfide bonded proteins.
  • 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.
  • MTP 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.
  • VLDL very low density lipoproteins
  • Subjects with abetalipoproteinemia are afflicted with numerous maladies. Kane & Havel, vide 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.
  • 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 lipoprotein assembly.
  • MTP may catalyze the transport of TG from its site of synthesis in the endoplasmic reticulum (ER) membrane to nascent lipoprotein particles within the lumen of the ER.
  • HDL high density lipoprotein
  • R 8 , R 9 and R 10 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;
  • Y is - ( E 2 ) m - or —C— ⁇ O where m is 2 or 3;
  • R 1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl (wherein alkyl has at least 2 carbons) , diarylalkyl, arylalkenyl, diarylalkenyl , arylalkynyl, diarylalkynyl, diarylalkylaryl, heteroarylalkyl (wherein alkyl has at least 2 carbons) , cycloalkyl, or cycloalkylalkyl (wherein alkyl has at least 2 carbons) ; all of the aforementioned R 1 groups being optionally substituted through available carbon atoms with 1, 2, or 3 groups selected from halo, haloalkyl, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, fluorenyl
  • R 11 is a bond, alkylene, alkenylene or alkynylene of up to 6 carbon atoms, arylene (for example
  • n 1 to 6;
  • R 12 is hydrogen, alkyl, alkenyl, 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 alkenylene of from 1 to 5 carbon atoms;
  • R 13 , R 14 , R 15 , and R 16 are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, hydroxy, alkoxy, nitro, amino, thio, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, carboxy, aminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl, or aryloxy; or R 1 is
  • R 17 and R 18 are each independently H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl, at least one of R 17 and R 18 being other than H; or R 1 is R 20 R « ⁇
  • R 21 wherein R 19 is aryl or heteroaryl; R20 i s aryl or heteroaryl;
  • R 21 is H, alkyl, aryl, alkylaryl, arylalkyl, aryloxy, arylalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, cycloalkyl, cycloalkylalkyl or cycloalkylalkoxy;
  • R 2 , R 3 , R 4 are independently hydrogen, halo, alkyl, haloalkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl;
  • R 5 is alkyl of at least 2 carbons, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl , polycycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, heteroarylcarbonyl, all of the R 5 and R 6 substituents being optionally substituted through available 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, arylcycl
  • R 6 is hydrogen or C 1 -C 4 alkyl or C 1 -C 4 alkenyl
  • R 7 is alkyl, aryl or arylalkyl wherein alkyl or the alkyl portion is optionally substituted with oxo; and including pharmaceutically acceptable salts and anions thereof or esters thereof.
  • R 1 will be other than 3,3- diphenylpropyl .
  • R 7 will be other than 4-O-methoxyphenyl.
  • X is: CHR 8 , ' - C II— ⁇ CH— CH- or -C_ C- ; o I
  • R 8 , R 9 and R 10 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;
  • Y is -(CHa), or -C-
  • n 2 or 3
  • R 1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl wherein alkyl has at least 2 carbons, diarylalkyl, arylalkenyl, diarylalkenyl, arylalkynyl, diarylalkynyl, diarylalkylaryl, heteroarylalkyl wherein alkyl has at least 2 carbons, cycloalkyl, or 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, cycloalkylalkyl, heteroaryl, fluorenyl, heteroarylalkyl, hydroxy or oxo; or R
  • R 1 is an indenyl-type group of the structure
  • Z 1 and Z 2 are the same or different and are independently a bond, 0, S,
  • R 11 is a bond, alkylene, alkenylene or alkynylene of up to 10 carbon atoms; arylene or mixed arylene-alkylene;
  • R 12 is hydrogen, alkyl, alkenyl, aryl, haloalkyl, trihaloalkyl, trihaloalkylalkyl, heteroaryl, heteroarylalkyl, arylalkyl, arylalkenyl, cycloalkyl, aryloxy, alkoxy, arylalkoxy or cycloalkylalkyl, with the provisos that (1) when R 12 is H, aryloxy, alkoxy or arylalkoxy,
  • R 12 when Z 2 is a bond, R 12 cannot be heteroaryl or heteroarylalkyl;
  • Z is bond, 0, S, N-alkyl, N-aryl, or alkylene or alkenylene from 1 to 5 carbon atoms;
  • R 13 , R 14 , R 15 , and R l ⁇ 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;
  • R 15a and R 16a are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl, or aryloxy; or R 1 is a group of the structure
  • R 18 wherein p is 1 to 8 and R 17 and R 18 are each independently H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl at least one of R 17 and R 18 being other than H; or R 1 is a group of the structure
  • R 21 wherein R 19 is aryl or heteroaryl; R 20 is aryl or heteroaryl;
  • R 21 is H, alkyl, aryl, alkylaryl, arylalkyl, aryloxy, arylalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, cycloalkyl, cycloalkylalkyl or cycloalkylalkoxy;
  • R 2 , R 3 , R 4 are independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl;
  • R 5 is independently alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, arylalkoxy, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalky
  • R 6 is hydrogen or C 1 -C 4 alkyl or C 1 -C 4 alkenyl; all optionally substituted with 1, 2, 3 or 4 groups which may independently be any of the substituents listed in the definition of R 5 set out above;
  • R 7 is alkyl, aryl or arylalkyl wherein alkyl by itself or as part of arylalkyl is optionally substituted with oxo ( ⁇ °
  • R 5 where R 5 is H or lower alkyl, or R 5 together with R 2 forms a carbocyclic or heterocyclic ring system containing 4 to 8 members in the ring;
  • B is a fluorenyl-type group of the structure
  • B is an indenyl-type group of the structure
  • R x is H, alkyl or aryl
  • R 1 is alkyl, alkenyl, alkynyl, alkoxyl, (alkyl or aryl) 3 Si (where each alkyl or aryl group is independent), cycloalkyl, cycloalkenyl, substituted alkylamino, substituted arylalkylamino, aryl, arylalkyl, arylamino, aryloxy, heteroaryl, heteroarylamino, heteroaryloxy, arylsulfonylamino, heteroarylsulfonylamino, arylthio, arylsulfinyl, arylsulfonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, heteroarylthio, heteroarylsulfinyl, hetero- arylsulfonyl, -PO(R 13 ) (R 14 ) , (where R 13 and R 14 are independently alkyl, aryl
  • J is: CHR 23 , —C— -CH— CH- or -C__C- ;
  • R 23 , R 24 and R 25 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;
  • R 20 , R 21 , R 22 are independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl; and these substituents may either be directly attached to R 1 , or attached via an alkylene at an open position;
  • R 2 is independently any of the groups set out for R 1 , H, polyhaloalkyl, or cycloheteroalkyl, and may be optionally substituted with one to four of any of the groups defined for R 3 or substituents defined for R 1 ;
  • L 1 is a linking group containing from 1 to 10 carbons in a linear chain including alkylene, alkenylene or 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, an oxo group, and may be substituted with one to five alkyl or halo groups;
  • L 2 may be the same or different from L 1 and may independently be any of the L 1 groups set out above or a singe bond;
  • R 3 , R 3 ', R 4 and R 4 ' may be the same or different and are independently selected from H, halogen, CF 3 , haloalkyl, hydroxy, alkoxy, alkyl, aryl, alkenyl, alkenyloxy, alkynyl, alkynyloxy, alkanoyl, nitro, amino, thiol, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, cycloheteroalkyl, cycloheteroalkylalkyl, cyano, Ar-, Ar- alkyl, ArO, Ar-amino, Ar-thio, Ar-sulfinyl, Ar-sulfonyl, Ar-carbonyl, Ar-carbonyloxy or Ar-carbonylamino, wherein Ar is aryl
  • R 3a and R 3b are the same or different and are independently any of the R 3 groups except hydroxy, nitro, amino or thio;
  • X is a bond, or is one of the following groups: (1) —s—
  • R 6 is H, lower alkyl, aryl, -C(0)-R 1:L or -C (0) -0-R 11 ;
  • R 7 and R 8 are the same or different and are independently H, alkyl, aryl, halogen, -0-R 12 , or
  • R 7 and R 8 together can be oxygen to form a ketone
  • R 9 , R 10 , R 9 ' and R 10 ' are the same or different and are independently H, lower alkyl, aryl or -0-R 11 ;
  • R 9 " and R 10 " are the same or different and are independently H, lower alkyl, aryl, halogen or -0-R 11 ;
  • R 11 is alky or aryl
  • R 12 is H, alkyl or aryl
  • novel compounds are provided which are inhibitors of MTP and have the structure
  • R 5 where R 5 is H or lower alkyl or R 5 together with R 2 forms a carbocyclic or heterocyclic ring system containing 4 to 8 members in the ring.
  • B is a fluorenyl-type group of the structure:
  • B is an indenyl-type group of the structure
  • R a and R b may be the same or different and can be hydrogen, alkyl, aryl, arylalkyl or heteroaryl (linked to the ring via a carbon atom) ;
  • R 5a is H, lower alkyl or aryl
  • R 1 is independently alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, arylalkoxy, heteroaryl, heteroarylalkoxy, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloheteroalkyl, heteroaryloxy, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl , heteroarylcarbonyl, amino, alkylamino, arylamino, heteroarylamino, cycloalkyloxy, cycloalkylamino, all optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl
  • R 1 and R 5a can be joined to form a ring of the structure
  • J is: CHR 23 , — ;
  • R 23 , R 24 and R 25 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;
  • R 20 , R 21 , R 22 are independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl; and these preferred substituents may either be directly attached to R 1 , or attached via an alkylene chain at an open position.
  • R 2 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, (alkyl or aryl)3Si (where each alkyl or aryl group is independent) , cycloalkyl, cycloalkenyl, substituted alkylamino, substituted arylalkylamino, aryl, arylalkyl, arylamino, aryloxy, heteroaryl, heteroarylamino, heteroaryloxy, arylsulfonylamino, heteroarylsulfonylamino, arylthio, arylsulfinyl, arylsulfonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, heteroarylthio, heteroarylsulfinyl , heteroarylsulfonyl, cycloheteroalkyl, cycloheteroalkyl,
  • the R 2 group may optionally have from one to four substituents, which include any of the R 1 substituents, and any of the preferred R 2 substituents set out below.
  • Preferred R 2 group when L 2 and A are each a single bond include the following: haloalkyla ino, (where halo includes CF 3 ), alkylamino, cycloalkylamino, arylamino, heteroarylamino, alkoxyamino, aryloxyamino, heteroaryloxyamino, heterocyclyla ino (where the heterocycle is connected to the carbonyl group via a nitrogen or carbon atom) .
  • L 1 is a linking group containing from 1 to 10 carbons in a linear chain (including alkylene, alkenylene or 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 five alkyl or halo groups (preferably F) .
  • L 2 may be the same or different from L 1 and may independently be any of the L 1 groups set out above or a single bond.
  • R 3 , R 3 ', R 4 and R 4 ' may be the same or different and are independently selected from H, halogen, CF 3 , haloalkyl, hydroxy, alkoxy, alkyl, aryl, alkenyl, alkenyloxy, alkynyl, alkynyloxy, alkanoyl, nitro, amino, thiol, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, cycloheteroalkyl, cycloheteroalkylalkyl, cyano, Ar, Ar- alkyl, ArO, Ar-amino, Ar-thio, Ar-sulfinyl, Ar-sulfonyl, Ar-carbonyl, Ar-carbonyloxy or Ar-carbonylamino, wherein Ar is aryl or
  • R 3a and R 3b are the same or different and are independently any of the R 3 groups
  • X in the fluorenyl type ring is a bond, or is one of the following groups:
  • R 7 and R 8 are the same or different and are independently H, alkyl, aryl, halogen, -0-R 12 , or
  • R 7 and R 8 together can be oxygen to form a ketone;
  • R 9 , R 10 , R 9 ' and R 10 ' are the same or different and are independently H, lower alkyl, aryl or -0-R 11 ;
  • R 9 " and R 10 " are the same or different and are independently H, lower alkyl, aryl, halogen or -0-R 11 ;
  • R 11 is alky or aryl;
  • R 12 is H, alkyl or aryl; with the proviso that when A is a (1) bond, R 2 L 2 cannot be hydrogen.
  • the pharmaceutically acceptable salts of the compounds of formula I include 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-butyl-amine, t- octylamine, dehydroabietylamine, as well as pharmaceutically acceptable anions such as chloride, bromide, iodide, tartrate, acetate, methanesulfonate, maleate, succinate, glutarate, and salts of naturally occurring amino acids such as arginine, lysine, alanine and the like, and prodrug esters thereof.
  • alkali metal salts such as lithium, sodium or potassium
  • alkaline earth metal salts such as calcium or magnesium
  • other cations such as ammonium, choline, diethanolamine, ethylenediamine, t-butyl-amine, t- o
  • a method for preventing, inhibiting or treating atherosclerosis, pancreatitis, hyperglycemia or obesity wherein a compound of formula I, IA or IB as defined hereinbefore is administered in an amount which decreases the activity of microsomal triglyceride transfer protein.
  • a method for lowering serum lipid levels, cholesterol and/or triglycerides, or inhibiting and/or treating hyperlipemia, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, atherosclerosis, hyperglycemia, pancreatitis, obesity, hypertriglyceridemia, Type II diabetes (NIDDM) wherein a compound of formula I as defined hereinbefore is administered in an amount which decreases the activity of microsomal triglyceride transfer protein.
  • NIDDM Type II diabetes
  • 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 synthetic phospholipid vesicles, membranes or lipoproteins to synthetic vesicles, membranes, or lipoproteins and which is distinct from the cholesterol ester transfer protein
  • stabilizing atherosclerosis as used in the present application refers to slowing down the development of and/or inhibiting the formation of new atherosclerotic lesions .
  • causing the regression of" atherosclerosis as used in the present application refers to reducing and/or eliminating atherosclerotic lesions.
  • lower alkyl 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 which may be any of the R 3 groups, or the R 1 substituents set out herein.
  • 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 be fused to 1 aromatic ring as described for aryl, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl,
  • cycloalkenyl as employed herein alone or as part of another group refers to cyclic hydrocarbons containing 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 .
  • 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,
  • polycycloalkenyl 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 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 .
  • aryl 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, or 3 groups selected from hydrogen, halo, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl , arylalkoxy, arylthio, ary
  • aralkyl refers to alkyl groups as discussed above having an aryl substituent, such as benzyl or phenethyl, or naphthylpropyl, or an aryl as defined above.
  • lower alkoxy 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.
  • amino as employed herein alone or as part of another group may optionally be substituted with one or two substituents such as alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and/or cycloalkyl.
  • lower alkylthio alkylthio
  • arylthio arylthio
  • 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.
  • lower alkylamino alkylamino
  • alkylamino alkylamino
  • arylamino arylalkylamino
  • 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.
  • acyl as employed herein by itself or part of another group, as defined herein, refers to an organic radical
  • alkanoyl as used herein alone or as part of another group refers to alkyl linked to a carbonyl group.
  • lower alkenyl or “alkenyl” as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to
  • 1 to 8 carbons in the normal chain which include one to six double bonds in the normal chain, such as vinyl, 2- propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2- hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3- octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4, 8, 12-tetradecatrienyl, and the like, and which may be optionally substituted with 1 to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamino, alkylamido, arylcarbonylamino,
  • lower alkynyl or “alkynyl” as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons and more preferably
  • 2 to 8 carbons in the normal chain which include one triple bond in the normal chain, such as 2-propynyl, 3- butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3- hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3- nonynyl, 4-decynyl,3-undecynyl, 4-dodecynyl and the like, and which may be optionally substituted with 1 to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, heteroaryl, cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido, arylcarbonylamino
  • alkylene as employed herein alone or as part of another group refers to alkyl groups as defined above having single bonds for attachment to other groups at two different carbon atoms and may optionally be substituted as defined above for "alkyl”.
  • alkenylene and alkynylene as employed herein alone or as part of another group refer to alkenyl groups as defined above and alkynyl groups as defined above, respectively, having single bonds for attachment at two different carbon atoms.
  • Suitable alkylene, alkenylene or alkynylene groups or (CH 2 ) ⁇ rw ( H 2 ) n or (CH 2 ) P (which may include alkylene, alkenylene or alkynylene groups) as defined herein, may optionally include 1, 2, or 3 substituents which include any of the R 3 groups, or the R 1 substituents set out herein.
  • alkylene, alkenylene and alkynylene include
  • halogen or "halo” as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine as well as CF 3 , with chlorine or fluorine being preferred.
  • metal ion refers to alkali metal ions such as sodium, potassium or lithium and alkaline earth metal ions such as magnesium and calcium, as well as zinc and aluminum.
  • heterocyclyl refers to “cycloheteroalkyl” groups and “heteroaryl” groups as defined herein.
  • cycloheteroalkyl refers to a 5-, 6- or 7-membered saturated or partially unsaturated ring which includes 1 to 2 hetero atoms such as nitrogen, oxygen and/or sulfur, linked through a carbon atom or a heteroatom, where possible, optionally via the linker (CH 2 ) P (which is defined above) , such as and the like.
  • the above groups may include 1 to 4 substituents such as alkyl, halo, oxo and/or any of of the R 3 groups, or the R 1 substituents set out herein.
  • any of the above rings can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.
  • cycloheteroalkoxy refers to a 4-, 5-, 6- or 7- membered saturated or partially saturated ring which includes at least one oxygen atom in the ring and at least 1 or 2 other hetero atoms in the ring such as nitrogen, oxygen and/or sulfur, linked through a carbon or heteroatom, where possible, optionally via the linker
  • the above groups may include 1 to 4 substituents such as alkyl, halo, oxo and/or any of of the R 3 groups, or the R 1 substituents set out herein.
  • any of the above rings can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.
  • heteroaryl refers to a 5- or 6- me bered aromatic ring which includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygen or sulfur, and such rings fused to an aryl, cycloalkyl, heteroaryl or cycloheteroalkyl ring (e.g. benzothiophenyl , indolyl) , and includes possible N-oxides, such as
  • Ar may be either aryl or heteroaryl as defined above.
  • R 7a is H, lower alkyl, aryl, -C(0)R 7b , -C(0)0R 7b ' ' R 7b is alkyl or aryl.
  • the heteroaryl groups including the above groups may optionally include 1 to 4 substituents such as any of the R 3 groups, or the R 1 substituents set out herein.
  • any of the above rings can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.
  • cycloheteroalkylalkyl as used herein alone or as part of another group refers to cycloheteroalkyl groups as defined above linked through a C atom or heteroatom to a (CH 2 ) P chain.
  • heteroarylalkyl or “heteroaryl-alkenyl” as used herein alone or as part of another group refers to a heteroaryl group as defined above linked through a C atom or heteroatom to a -(CH 2 ) p - chain, alkylene or alkenylene as defined above.
  • polyhaloalkyl refers to an "alkyl” group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl, preferably F, such as CF 3 CH 2 , CF 3 ' or CF 3 CF 2 CH 2 .
  • X is a bond, oxygen or sulfur; R 3 and R 4 are independently H or F.
  • Preferred R 2 groups are alkyl, polyfluoroalkyl (such as 1, 1, 1-trifluoroethyl) , alkenyl, aryl, heteroaryl or heteroarylalkyl, such as 2-pyridylmethyl (preferably substituted with one of the preferred R 2 substituents above) .
  • L 1 contains 2 to 7 atoms in the linear chain and L 2 is a bond or lower alkylene.
  • the preferred L 2 group is alkylene such as CH 2 or a bond.
  • the preferred A group is -NH- .
  • Preferred R 1 groups are as set out in the preferred compounds shown in the following Table.
  • the compounds of formula I may be prepared by the exemplary processes described in the following reaction schemes . Exemplary reagents and procedures for these reactions appear hereinafter and in the working Examples . Methods for preparing starting materials useful in preparing cyclophosphonates in accordance with the present invention, are shown in the folowing reaction schemes.
  • serinol derivative (2) can be acylated via carbodiimide coupling directly to 3..
  • 2. can be acylated with acid chlorides to tri-acylated 4..
  • Subsequent solvolysis provides diols 3_.
  • the diols 3_ could also be prepared from bis-O-trimethylsilylated amine 5., acylation with acid chlorides and subsequent methanolysis to provide 3_.
  • fluorenyl-type moieties including all fluorenyl-type groups and all indenyl-type groups are collectively referred to as "fluorenyl-type" moieties.
  • the use of the first fluorenyl-type group (as set out in the previous paragraph) in the Reaction Schemes is for purposes of illustration only; any of the 3 fluorenyl groups or 4 indenyl groups as set out above may be employed in any of the Reaction Schemes set out herein in place of
  • the compounds of formula I of the invention may be prepared as shown in Reaction Scheme 2.
  • dialkyl phosphonate ester Im is treated with bromotrimethylsilane and then is treated with oxalyl chloride and dimethylformamide (employing conventional procedures) to give a diphosphinyl dichloride intermediate which (without purification) is reacted with diol 3_ (which may be chiral or achiral) (as formed in Scheme IA, IB or IC) and an amine base such as triethylamine to give a mixture of the 7-trans and 7-cis isomers (lo and Ip, respectively) of the invention.
  • the 7- trans and 7-cis isomers may be separated by conventional chromatographic techniques .
  • R 1 ' is an lo' arylmethyloxy or (7-trans) heteroarylmethyloxy
  • R 1 ' OCH 2 C 6 H 5
  • R 1 C ⁇ 2 H may be made to undergo hydrogenolysis to form an amine intermediate which can be reacted with R 1 C ⁇ 2 H to prepare other acyl derivatives in accordance with the invention.
  • the starting material I may be prepared according to the following Reaction Schemes 4 and 4A.
  • PG is an oxygen protecting group, such as t-Bu (CH3 ) 2Si or tBu (Ph) 2Si -
  • Q 1 is alkyl, triorganosilyl (such as trimethylsiiyi or t-butyldimethylsilyl), H, the latter in the presence of base such as butyllithium, sodium hydride, or sodium bis-(trimethylsilylamide) Reaction Scheme 4A (Alternative Method for Making Ih)
  • Protected alcohol XlVa can be converted into a wide variety of functional groups through the intermediacy of a halide Ih.
  • the alcohol Ig can be converted to the halide Ih of the invention by either activation through the sulfonate ester (tosyl chloride, or mesyl chloride) and iodide displacement (Nal or KI in acetone or 2-butanone) , or by reaction with triphenylphosphine, I 2 and imidazole.
  • the halide Ih can undergo an Arbuzov reaction to form phosphonates, phosphinates and phosphine oxides of the invention Im.
  • the Arbuzov reaction can be accomplished with phosphites, phosphinites , and phosphonites (for example, (alkylO) 3 P or (alkylO) 2 POSi (alkyl) 3 or (alkyl0) 2 P0H, the latter being in the presence of a base such as butyllithium, sodium hydride or sodium bis (trimethylsilylamide) ) at temperatures within the range from about -20°C to about 180°C.
  • a base such as butyllithium, sodium hydride or sodium bis (trimethylsilylamide)
  • the starting material VIIIA for compound Im may be prepared as shown in Reaction Scheme 5.
  • the amide VIIIA may be formed by treating II with thionyl chloride or oxalyl chloride in an inert organic solvent such as dichloromethane (optionally in the presence of dimethylformamide (DMF) ) to form the acid chloride IIA
  • Acid chloride IIA without separation from the reaction mixture, is treated with amine (R 2 L 2 )R 5 NH at a reduced temperature within the range from about -40°C to about room temperature, to form the amide VIIIA.
  • Amide VIIIA may be converted to compounds of formula I employing the procedure set out in Reaction Scheme 4/4A.
  • the amine will be employed in a molar ratio to acid chloride IIA within the range from about 4:1, to about 1:1, optionally in the presence of a tertiary amine base or other acid scavenger.
  • an acid such as H 2 SO 4 or p-toluene-sulfonic acid
  • an alcohol such as allyl alcohol, ethanol or methanol.
  • activation of the acid II to the acid chloride followed by treatment with an alcohol optionally in the presence of a tertiary amine base or other acid scavenger, gives compounds of formula VIIIB.
  • Compounds Im may be modified by the various transformations set out in Reaction Scheme 8.
  • the compounds of the invention may be employed in preventing, stabilizing or causing regression of atherosclerosis in a mammalian species by administering a therapeutically effective amount of a compound to decrease the activity of MTP.
  • the compounds of the invention can be tested for MTP inhibitory activity employing the procedures set out in U.S. application Serial No. 117,362 filed September 3, 1993 , employing MTP isolated from one of the following sources :
  • He G2 cells human hepatoma cells
  • the compounds of the invention may also be employed in lowering serum lipid levels, such as cholesterol or triglyceride (TG) levels, in a mammalian species, by administering a therapeutically effective amount of a compound to decrease the activity of MTP.
  • the compounds of the invention may be employed in the treatment of various other conditions or diseases using agents which decrease activity of MTP.
  • compounds of the invention decrease the amount or activity of MTP and therefore decrease serum cholesterol and TG levels, and TG, fatty acid and cholesterol absorption and thus are useful in treating hypercholesterolemia, hypertriglyceridemia, hyperlipemia, hyperlipoproteinemia, hyperlipidemia, pancreatitis, hyperglycemia, atherosclerosis, non-insulin dependent diabetes (Type II diabetes) and obesity.
  • the compounds of the present invention are agents that decrease the activity of MTP and can be administered to various mammalian species, such as monkeys, dogs, cats, rats, humans, etc., in need of such treatment. These agents can be administered systemically, such as orally or parenterally.
  • the agents that decrease the activity or amount of MTP can be incorporated in a conventional systemic dosage form, such as a tablet, capsule, elixir or injectable formulation.
  • a conventional systemic dosage form such as a tablet, capsule, elixir or injectable formulation.
  • the above dosage forms will also include the necessary physiologically acceptable carrier material, excipient, lubricant, buffer, antibacterial, bulking agent (such as mannitol) , anti-oxidants (ascorbic acid or sodium bisulfite) or the like.
  • Oral dosage forms are preferred, although parenteral forms are quite satisfactory as well.
  • the dose administered must be carefully adjusted according to the age, weight, and condition of the patient, as well as the route of administration, dosage form and regimen, and the desired result.
  • the dosage forms described above may be administered in amounts of from about 5 to about 500 mg per day in single or divided doses of one to four times daily.
  • flash chromatography refers to chromatography performed on EM Industries Silica Gel 60 (catalog #9385-9), 230-400 mesh under 10-20 psi of nitrogen pressure.
  • the combined aqueous layers were extracted with ethyl ether (800 mL) .
  • the aqueous layer was made acidic with HC1 solution (IN, 500 mL) , then extracted with dichloromethane (3 x 750 mL) .
  • the combined organic layers were dried over MgS0 4 - Evaporation gave title compound (71 g, 85%) as a white solid.
  • Example 1 Part B compound To a stirred solution of 699 mg (1.45 mmol) of Example 1 Part B compound in 5 mL of dichloromethane at room temperature under argon was added 0.63 mL (4.8 mmol) of bromotrimethylsilane. After 1 h, the reaction mixture was evaporated to provide a thick oil . The oil was dissolved in 3 mL of dichloromethane at room temperature under argon and treated with 0.26 mL (3.0 mmol) of oxalyl chloride and 50 ⁇ L of DMF. After 2 h, the reaction mixture was evaporated and redissolved in 3 mL of dichloromethane .
  • Example 3 Part B compound was added 283 mg (1.45 mmol) of Example 3 Part B compound and 0.6 mL . (4.3 mmol) of triethylamine. After 2 h, the reaction was diluted with ethyl acetate and washed once with 10% citric acid solution, dried (MgS ⁇ 4 ) and evaporated. Purification by flash chromatography on silica gel (5 x 15 cm column, ethyl acetate) provided title compound, white solid, mp 166-168°C, 245 mg, 29% yield.
  • Example 4 trans-9-[5-[2-Oxo-5-[[[4 , -(trifluoromethyl)[1 ,1'-biphenyl]-2-yl]carbonyl]amino]- 1 ,3,2-dioxaphosphorinan-2-yl]pentyl]-N-(2,2,2-trifiuoroethyl)-9H-fluorene-9- carboxamide.
  • Example 5 cis-9-[5-[2-Oxo-5-[[[4'-(trifluoromethyl)[1,1'-biphenyl]-2-yl]carbonyl]amino]- 1,3,2-dioxaphosphorinan-2-yl]pentyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene- 9-carboxamide.
  • the combined aqueous layers were extracted with ethyl ether (160 mL) .
  • the aqueous layer was made acidic with HC1 solution (IN, 100 mL) , then extracted with dichloromethane (3 x 150 mL) .
  • the combined organic layers were dried over MgS0 4 . Evaporation gave title compound as a white solid.
  • Example 1 Part B compound To a stirred solution of 1.76 g (3.64 mmol) of Example 1 Part B compound in 5 mL of dichloromethane at room temperature under argon was added 1.65 mL (12.6 mmol) of bromotrimethylsilane. After 1 h, the reaction mixture was evaporated to provide a thick oil. The oil was dissolved in 20 mL of dichloromethane at room temperature under argon and treated with 1.2 mL (13.8 mmol) of oxalyl chloride and 100 ⁇ L of DMF. After 2 h, the reaction mixture was evaporated and redissolved in 5 mL of dichloro- methane.
  • Example 8 trans-9-[4-[2-Oxo-5-[[2-(2-pyridinyl)benzoyl]amino]-1,3,2-dioxaphosphorinan- 2-yl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, hydrochloride.
  • Part A(l) compound 850 mg, 5.0 mmol
  • potassium permanganate 1.9 g, 12.0 mmol
  • the hot reaction mixture was filtered, and the filtrate was evaporated to dryness.
  • the solid residue was dissolved in water (5 mL) and acidified with acetic acid to pH 4-5.
  • the resulting precipitate was isolated by filtration and rinsed with water to give a white solid (800 mg) which was recrystallized from hot ethanol (12 mL) to give title compound as a white solid (453 mg, 45% yield) .
  • Part A compound is a commercial compound supplied by Maybridge Chemical Company.
  • Example 6 compound An argon-purged slurry of 371 mg (0.60 mmol) of Example 6 compound and 90 mg of 10% palladium-on-charcoal in 10 mL of methanol at room temperature was partially evacuated and subjected to hydrogenation from a filled balloon. After 4 h, the reaction mixture was purged with argon and filtered through a 0.45 ⁇ nylon filter.
  • Example 10 trans-9-[4-[5-[[2-(4-M ⁇ holinyl)benzoyl]amino]-2-oxo-1 ,3,2-dioxaphosphorinan- 2-yl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide.
  • Example 6 compound An argon-purged slurry of 359 mg (0.582 mmol) of Example 6 compound and 100 mg of 10% palladium-on-charcoal in 15 mL of methanol at room temperature was partially evacuated and subjected to hydrogenation from a filled balloon. After 16 h, the reaction mixture was purged with argon and filtered through a 0.45 ⁇ nylon filter.

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Abstract

Nouveaux inhibiteurs phosphonate ester cyclique de MTP de structure (I) dans laquelle R2, L2, A, B, L?1, R1 et R5a¿ sont tels que décrits dans le descriptif. Ces composés sont utiles pour abaisser le taux sérique de cholestérol et de triglycérides.
PCT/US1998/021750 1997-10-28 1998-10-14 Inhibiteurs phosphonate ester cyclique de proteine microsomale de transfert des triglycerides et procede associe Ceased WO1999021564A1 (fr)

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CA002307889A CA2307889A1 (fr) 1997-10-28 1998-10-14 Inhibiteurs phosphonate ester cyclique de proteine microsomale de transfert des triglycerides et procede associe
JP2000517722A JP2001521001A (ja) 1997-10-28 1998-10-14 ミクロソーム・トリグリセリド転移たんぱくの環式ホスホネートエステル抑制剤および抑制方法
EP98953531A EP1039915A4 (fr) 1997-10-28 1998-10-14 Inhibiteurs phosphonate ester cyclique de proteine microsomale de transfert des triglycerides et procede associe
AU10876/99A AU753520B2 (en) 1997-10-28 1998-10-14 Cyclic phosphonate ester inhibitors of microsomal triglyceride transfer protein and method

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Publication number Priority date Publication date Assignee Title
US4952740A (en) * 1984-04-10 1990-08-28 Societe Nationale Elf Aquitaine Cyclic phosphonites

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BR9707607A (pt) * 1996-01-16 1999-07-27 Bristol Myers Squibb Co Inibidores aromáticos conformacionalmente restringidos da proteína de transferéncia de triflicerídeos microssomal e processo
US5760246A (en) * 1996-12-17 1998-06-02 Biller; Scott A. Conformationally restricted aromatic inhibitors of microsomal triglyceride transfer protein and method

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US4952740A (en) * 1984-04-10 1990-08-28 Societe Nationale Elf Aquitaine Cyclic phosphonites

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