AP804A - APO-B-secretion/MTP inhibitory amides. - Google Patents

APO-B-secretion/MTP inhibitory amides. Download PDF

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AP804A
AP804A APAP/P/1997/001145A AP9701145A AP804A AP 804 A AP804 A AP 804A AP 9701145 A AP9701145 A AP 9701145A AP 804 A AP804 A AP 804A
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inhibitors
compounds
crc10
alkyl
crc4
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APAP/P/1997/001145A
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AP9701145A0 (en
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George Chang
George J Quallich
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Pfizer
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
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    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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Abstract

This invention is directed to compounds of the formula or the stereoisomers, pharmaceutically-acceptable salts and hydrates thereof. The compounds are Apo B/MTP inhibitors and are useful in the treatment of various disorders and conditions such as atherosclerosis, pancreatitis, obesity, hypercholesteremia, hypertriglyceridemia, hyperlipidemia, and diabetes. The compounds of this invention are also useful in combination with other pharmaceutical agents including cholesterol biosynthesis inhibitors and cholesterol absorption inhibitors, especially HMG-CoA reductase inhibitors and HMG-CoA synthase inhibitors; HMG-CoA reductase gene expression inhibitors; CETP inhibitors; bile acid sequestrants; fibrates; cholesterol absorption inhibitors; ACAT inhibitors, squalene synthetase inhibitors, ion-exchange resins, anti-oxidants and niacin. This invention is also directed to intermediates and processes useful in the preparation of compounds of formula (I).

Description

Apo B-SECRETION/MTP INHIBITORY AMIDES
Field Of The Invention
This invention relates to compounds which are inhibitors of microsomal triglyceride transfer protein (MTP) and/or apolipoprotein B (Apo B) secretion and which are, accordingly, useful for the prevention and treatment of atherosclerosis and its clinical sequelae, for lowering serum lipids, and in the prevention and treatment of related diseases. The invention further relates to pharmaceutical compositions comprising these compounds and to methods of treating atherosclerosis, obesity, and related diseases and/or conditions with said compounds, either alone or in combination with other medicaments, including lipid lowering agents. Further still, the invention relates to certain processes and intermediates related thereto which are useful in the preparation of the compounds of the instant invention.
Background Of The Invention
Microsomal triglyceride transfer protein catalyzes the transport of triglyceride, cholesteryl ester, and phospholipids and has been implicated as a putative mediator in the assembly of Apo B-containing lipoproteins, biomolecules which contribute to the formation of atherosclerotic lesions. Specifically, 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. The ability of MTP to catalyze the transport of triglyceride between membranes is consistent with this speculation, and suggests that MTP may catalyze the transport of triglyceride from its site of synthesis in the endoplasmic reticulum membrane to nascent lipoprotein particles within the lumen of the endoplasmic reticulum.
Compounds which inhibit MTP and/or otherwise inhibit Apo B secretion are accordingly useful in the treatment of atherosclerosis and other conditions related thereto. Such compounds are also useful in the treatment of other diseases or conditions in which, by inhibiting MTP and/or Apo B secretion, serum cholesterol and triglyceride levels may be reduced. Such conditions may include, for example, hypercholesterolemia, hypertriglyceridemia, pancreatitis, and obesity; and hypercholesterolemia, hypertriglyceridemia, and hyperlipidemia associated with pancreatitis, obesity, and diabetes. For a detailed discussion, see for example, Wetterau et al„ Science, 258, 999-1001, (1992), Wetterau et al., Biochem. Biophys. Acta., 875, 610-617 (1986), European patent application publication No. 0 584 446 A2, and European patent application publication No. 0 643 057 A1 the latter of which discloses certain compounds of the generic formulae
which have utility as inhibitors of MTP.
Summary Of The Invention
The instant invention relates to compounds which are Apo B-secretion/MTP inhibitors represented by the structural formula (I), including the stereoisomers and the pharmaceutically acceptable salts and hydrates thereof,
wherein G is selected from:
(a) a phenyl or heterocyclic ring wherein said heterocyclic ring contains a total of from 3 to 14 ring atoms, wherein said heterocyclic ring incorporates a total of from 1 to 4 ring heteroatoms selected independently from oxygen, nitrogen, and sulfur, wherein the individual rings of said heterocyclic ring may be independently saturated, partially saturated or aromatic, and wherein each of said phenyl or heterocyclic rings may have optionally from 1 to 4 substituents selected independently from halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (CrC10)alkyl, (Cr C4)perfluoroalkyl, (C1-C10)alkoxy, (Ci-C4)perfluoroalkoxy, {C1-C50)alkoxycarbonyl, (Ct-CuOalkylthio, (Ci-C10)alkylamino, di(C1-Ci0)alkylamino, (Cr C10)alkylaminocarbonyl, di(CrC10)alkylaminocarbonyl, diiCrCioJalkylaminoiCr C10)alkoxy, (CrC10)acyl, (C^-C^perfluoroacyl, (CrCi0)acyloxy, (CrC-ioJacyloxyiCr C10)alkyl, (C-rCeJacylamino and (CrCeJperfluoroacylamino; (b) -CH2CN,
(d) (C2-C12)alkyl or (C2-C12)perfluoroalkyl wherein each of said (C2-Ci2)alkyl and (C2-C12)perfluoroalkyl is substituted optionally with from 1-3 substituents selected independently from: (1) phenyl, halogen, nitro, cyano, hydroxy, -NR1R2, -OCOR3, (Ci-C4)alkoxy, (CrC4)perfluoroalkoxy, (CrC4)thioalkoxy or (CrC^perfluorothioalkoxy, where R1 and R2 in the definition of -NR1R2 are each selected independently from hydrogen, formyl, phenyl, benzyl, benzoyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl, (CrC4)alkyl, (C1-C4)perfluoroalkyl, (CrC10)alkoxycarbonyl, (Cr C6)acyl, (C-|-C6)perfluoroacyl, aminocarbonyl, (CrC10)alkylaminocarbonyl, di(Cr C10)alkylaminocartx3nyl, aminosulfonyl, (CrC^alkylaminosulfonyl, di(Cr C4)alkylaminosulfonyl, (CrCJperfluoroalkylaminosuIfonyl, (Cr
C4)perfluoroalkylaminosulfonyl, difCrC^alkylsulfonyl, and (C-|- C4)perfluoroalky!sulfonyl, or where R1 and R2, taken together with the nitrogen atom to which they are attached, form a saturated, partially-saturated or aromatic heterocyclic ring, wherein said heterocyclic ring contains a total of from 3 to 14 ring atoms and incorporates optionally an additional 1 to 4 ring heteroatoms selected independently from oxygen, nitrogen and sulfur, wherein said heterocyclic ring may have optionally from 1 to 4 substituents selected independently from halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (Ci-C10)alkyl, (CvCJperfluoroalkyl, (CrCio)alkoxy, (Cr C4)perfluoroalkoxy, (CrCi0)alkoxycarbonyl, (CrCio)alkylthio, (CrC10)alkylamino, di(CrCio)alkylamino, (CrC10)alkylaminocarbonyl, di(Ci-Ci0)alkylaminocarbonyl, diiCrC^alkylaminoiC-j-CicOalkoxy, (CrC10)acyl, (Ci-C10)perfluoroacyl, (Cr C10)acylamino, (CrC10)acyloxy, and (C1-Ci0)acyloxy(C1-C10)alkyl, where R3 is selected from -NR1R2, phenyl, (CrC10)alkyl, (Cr C4)perfluoroalkyl, (CrC6)alkoxy and (CrC^perfluoroalkoxy, f (2) (C3-C8)cycloalkyl or (C3-C8)cycloalkenyl wherein each of said (C3-C8)cycloalkyl and (C3-C8)cycloalkenyl may have optionally from 1 to 4 substituents selected independently from halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C-i-Ci0)alkyl, (CrC4)perfluoroalkyl, (C1-C10)alkoxy, (CrC4)perfluoroalkoxy, (Cr Ci0)alkoxycarbonyl, (C1-C10)alkylthio, (CrC10)alkylamino, di(C1-C10)alkylamino, (Cr C10)alkylaminocarbonyl, di(CrC10)alkylaminocarbonyl, diiCrCioJalkylaminofCr C10)alkoxy, (CrCi0)acyl, (C-,-C10)perfluoroacyl, (C1-C10)acylamino, (Cr Cio)perfluoroacylamino, (CrC10)acyloxy, and (CrC^JacyloxyCC-i-CioJalkyl, and (3) a saturated, partially-saturated or aromatic heterocyclic ring containing a total of from 3 to 14 ring atoms, wherein said heterocyclic ring incorporates a total of from 1 to 4 ring heteroatoms selected independently from oxygen, nitrogen and sulfur, wherein said heterocyclic ring may have optionally from 1 to 4 substituents selected independently from halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C-,-C10)alkyl, (CrC4)perfluoroalkyl, (CrCio)alkoxy, (CrC4)perfluoroalkoxy, (Cr C10)alkoxycarbonyl, (Ci-C10)alkylthio, (CrC10)alkylamino, di(Ci-C10)alkylamino, (Cr C10)alkylaminocarbonyl, di(CrC10)alkylaminocarbonyl, di(Ci-C10)alkylamino(C-i-C10)alkoxy, (CrCi0)acyl, (CrC^perfluoroacyl, (Οι·Όιο)3εΥΐθπιϊηο, (Cr C10)perfluoroacylamino, (CrC10)acyloxy, and (C1-C10)acyloxy(C1-C10)alkyl, provided that (C2-C12)alkyl does not include unsubstituted allyl; (e) (C3-C8)cycloalkyl or (C3-C8)cycloalkenyl wherein each of said (C3-C8)cycloalkyl and (C3-C8)cycloalkenyl may have optionally from 1 to 4 substituents selected independently from halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (Ci-C10)alkyl, (Cr C4)perfluoroalkyl, (C1-C10)alkoxy, (C^C^perfluoroalkoxy, (CrC10)alkoxycart)onyl, (CrC10)alkylthio, (CrC^Jalkylamino, di(CrC10)alkylamino, (Cr
Cio)alkylaminocarbonyl, di(Ci-C10)alkylaminocarbonyl, di(C1-C50)alkylamino(C1-Ci0)alkoxy, (CrC10)acyl, (CrC10)perfluoroacyl, (CrC10)acylamino, (Cr C10)perfluoroacylamino, (CrC10)acyloxy, and (C1-C10)acyloxy(C1-C10)alkyl; and (f) -(CH2)nCOR4, where R4 is selected from hydroxy, phenyl, -NR1R2, (CrC4)alkyl, (Ci-C4)perfluoroalkyl, (CrC4)alkoxy, (C^-C^perfluoroalkoxy, (C3-C8)cycloalkyl, and (C3-C8)cycloalkenyl, where n is an integer from 1 to 4. A preferred subgroup of the compounds of formula (I) and the stereoisomers, pharmaceutically acceptable salts and hydrates thereof, includes those compounds wherein G is selected from: (a) a phenyl or heterocyclic ring wherein said heterocyclic ring contains a total of from 3 to 7 ring atoms, wherein said heterocyclic ring incorporates a total of from 1 to 4 ring heteroatoms selected independently from oxygen, nitrogen, and sulfur, wherein said heterocyclic ring may be saturated, partially saturated or aromatic, and wherein each of said phenyl or heterocyclic rings may each have optionally from 1 to 4 substituents selected independently from halogen, hydroxy, phenyl, benzyl, benzoyl, benzyloxy, (CrCio)alkyl. (CrC4)perfluoroalkyl, (CrC-t0)alkoxy, (Cr C4)perfluoroalkoxy, (C-|-e10)alkoxycarbonyl, (CrC10)alkylthio, (CrC10)alkylamino, di(CrCi0)alkylamino, (CrC10)alkylaminocarbonyl, di(CrC10)alkylaminocarbonyl, dKCrC^alkylaminoCCrC^alkoxy, (CrC10)acyl, (Ci-C10)perfluoroacyi, (C-r Ce)acylamino, (CrCe)perfiuoroacylamino, (C1-C10)acyloxy, and (CrCioJacyloxyiCr Cio)alkyl; (b) (C2-C12)alkyl wherein said (C2-Ci2)alkyl is substituted optionally with from 1-3 substituents selected from: (1) phenyl, halogen, cyano, hydroxy, -NR1R2, -OCOR3, (Ci-C4)alkoxy, or (Ci-C4)perfluoroalkoxy, where R3 is selected from -NR1R2, (CrC4)alkyl and (C1-C4)perfluoroalkyl, (2) (C3-C6)cycloalkyl or (C3-C6)cycloalkenyl wherein each of said (C3-C6)cycloalkyl and (C3-C6)cycloalkenyl may optionally have from 1 to 4 substituents selected independently from hydroxy, (CrC4)alkyl, (CrC4)alkoxy, and (C-|-C4)alkoxycarbonyl, and (3) a saturated, partially-saturated or aromatic heterocyclic ring containing a total of from 3 to 6 ring atoms, wherein said heterocyclic ring incorporates a total of from 1 to 4 ring heteroatoms selected independently from oxygen, nitrogen and sulfur, wherein said heterocyclic ring may have optionally from 1 to 4 substituents selected independently from halogen, hydroxy, phenyl, benzyl, benzoyl, benzyloxy, (Cf-C10)alkyl, (CrC4)perfluoroalkyl, (C1-C10)alkoxy, (CrCioJalkoxycarbonyl, (Cr C10)alkylthio, (Ci-Cio)alkylamino, di(CrC10)alkylamino, (C1-C10)alkylaminoci3rbonyl, di(C-,-Cio)alkylaminocarbonyl, di(Ci-C1o)alkylamino(C1-C10)alkoxy, (Cr C4)perfluoroalkoxy, (C-i-Cio)acyl, (CrC10)acylamino, (C1-C10)perfluoroacylamino, (Cr C10)acyloxy, and (C1-C10)acyloxy(C1-C10)alkyl; provided that (C2-C12)alkyl does not include unsubstituted allyl, (c) (C3-C6)cycloalkyl or (C3-C6)cycloalkenyl wherein each of said (C3-C6)cycloalkyl and (C3-C6)cycloalkenyl may have optionally from 1 to 4 substituents selected independently from hydroxy, (CrC4)alkyl, (CrC4)alkoxy, (CrCwJacylamino, (Cr C10)perfluoroacylamino and (CrC4)alkoxycarbonyl; and (d) -(CH2)nCOR4, where R4 is selected from hydroxy, phenyl, -NR1R2, (CrC4)alkyl, (CrC^perfluoroalkyl, (CrC4)alkoxy, (C-,-C4)perfIuoroalkoxy, (C3-C6)cycloalkyl, and (C3-C6)cycloalkenyl, where n is an integer from 1 to 4.
More particularly preferred of the compounds of formula (I) including the stereoisomers, pharmaceutically acceptable salts and hydrates thereof, are those compounds of the subgroup wherein G is selected from: (a) (C2-C12)alkyl, wherein said (C2-C12)alkyl is substituted optionally with a group selected from phenyl, halogen, cyano, hydroxy, (CrC4)alkoxy, or a saturated, partially-saturated or aromatic heterocyclic ring selected from thienyl, pyrazolyl, pyrrolidinyl, pyrrolyl, furanyl, thiazolyl, isoxazolyl, imidazolyl, triazolyl, tetrahydropyranyl, pyridyl, and pyrimidyl, wherein each of said heterocyclic rings may have optionally from 1 to 3 substitutents selected independently from halogen, (CrC4)acyl, (CrC4)perfIuoroacyl, (CrC4)alkyl, (CrCJperfluoroalkyl, (CrC4)alkoxy, (Ci-C4)alkylaminocarbonyl, and (C1-C4)acylamino; provided that (C^-C^Jalkyl does not include unsubstituted allyl; (b) -(CH2)nNR1R2, where n is an integer from 2 to 4; and (c) -(CH2)nCOR4, where n is 1 or 2.
The following compounds of formula (I), including the stereoisomers and the pharmaceutically acceptable salts and hydrates thereof, listed hereinbelow together with their corresponding IUPAC chemical names, are especially preferred wherein G is selected from: -CH2COOH, (6-i(4’-Trifiuoromethvlbiphenvl-2-carbonvn-amino]-3.4-dihvdro-1H-isoauinolin-2-viy-acetic acid: -(CH2)4CH3, 4,-Irifluoromethylbiphenyl-2-carboxylic acid-(n-pentyl-1.2.3.4-tetrahydroisoauinolin-g-yl)-amide; -(CH2)3OCH3, 4,-Trifluoromethylbiphenyl-2-carboxylic acid-r2-f3-methoxypropyl)-1.2.3.4-tetrahvdroisoquinolin-6-yi]-amide: -(CH2)2OCH3, 4’-Trifluoromethylbipheny[-2-carboxylic acid-[2-(2-methoxvethvl)-1.2.3.4-tetrahvdroisoquinolin-6-yQ-amide: -(CH2)2OCH2CH3, 4’-TrifluoromethylbiDhenyl-2-carboxylic acid-r2-I2-ethoxyethvl)-1.2.3.4-tetrahydroisoquinolin-6-yl]-aro!de: -(CH2)2CN, 4’-Trifluoromethylbiphenyl-2-carboxylic acid-[2-(2-cvanoethyl)-1.2.3.4-tetrahydroisoauinolin-6-yll-amide: -(CH2)2OCOCH3,
Acetic acid 2-(6-[f4’-trifluoromethylbiphenyl-2-carbonyl)-amino]-3.4-dihydro-1 H-isoquinolin-2-yl}-ethyl ester: -(CH2}2OCON(CH3)2,
Dimethvlcarbamic acid 2-{6-[(4’-trifluoromethylbiphenyl-2-carbonvl)-amino]-3jL· dihvdro-1 H-isoauinolin-2-yl}-ethyl ester; -(CH2)2NH2, t 4’-Trifluoromethylbiphenyl-2-carboxylic acid-[2-(2-aminoethyn-1.2.3.4-tetrahydroisioquinolin-6-yl]-amide: -(CH2)2NHCOCH3, 4.’-Trifluoromethylbiphenyl-2-carboxylic acid-[2-(2-acetylaminoethyl)-1.2.3,4-tetrahydroisoauinolin-6-yn-amide; -(CH2)2CON(CH3)2, 4’-Trif1uoromethvlbiphenvl-2-carboxviic acid-[2-(2-dimethytcarbamoylethyl)-1.2.3.4-tetrahydroisoquinolin-6-yQ-amide: -CH2CON(CH3)2, 4’-TrifluorQmethylbiphenyl-2-carboxylic acid-f 2-dimethylcarbamoylmethvl-1.2.3.4-te.trahvdroisoauinolin-6-yl)-amide: -CH2CON(CH2CH3)2,

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  1. Original document published without claims.
APAP/P/1997/001145A 1996-11-27 1997-11-20 APO-B-secretion/MTP inhibitory amides. AP804A (en)

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US3230796P 1996-11-27 1996-11-27
PCT/IB1997/001368 WO1998023593A1 (en) 1996-11-27 1997-11-03 Apo b-secretion/mtp inhibitory amides

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AP9701145A0 AP9701145A0 (en) 1998-01-31
AP804A true AP804A (en) 2000-01-28

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