i\
`
`(~
`
`PCT
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`lntemational Bureau
`INTERNATIONAL APPLICATION PUBLISHED UNDER TIIE PATENT COOPERATION TREATY (PCT)
`WO 98/23593
`
`(51) International Patent Classi6caUon 6 :
`C07D 217/04, 405/06, 401/06, 409/06,
`A61K 31/47
`
`(11) International Publication Number:
`
`Al.
`
`(43) International Publication Date:
`
`4 June 1998 (04.06.98)
`
`(21) International Application Number:
`
`PCTIIB97/0l 368
`
`(22) International Filing Date:
`
`3 November 1997 (03.11.97)
`
`(30) Priority Data:
`60/032,307
`
`27 November 1996 (27.11.96) us
`
`(71) Applicant (for all designated States except US): PFIZER INC.
`[US/US]; 235 East 42nd Street, New York, NY 10017 (US).
`
`(72) Inventors; and
`(75) InventorsfApplicimts (for US only):
`CHANG, George
`I Winthrop Hill Road, lvoryton, CT 06442
`[US/US];
`(US). QUALLICH, George, joseph [US/US]; 349 Norwich
`Westerly Road, North Stonington, CT 06359 (US).
`
`(74) Agents: SPIEGEL, Allen, J. et al.; Pfizer Inc .. 235 East 42nd
`Street, New York, NY 10017 (US).
`
`(81) Designated States: AL, AM· AT, Au._ AZ, BA, BB, BG, BR,
`BY, CA, CH, CN, CU, CZ, DE, DK, EE, BS, Pl, GB, GE,
`HU, IL, IS, JP, KE, KG, KP, KR; KZ, LC,' LK, LR, LS,
`LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL.
`PT, RO, RU, SD, SE, SG, SI, SK; TJ, Thf, TR, TI, UA,
`UG, US, UZ, VN, YU, ARIPO patent (GH, KE, LS, MW,
`SD, SZ, UG, 'ZW), Eurasian patent (AM, AZ. BY, KG, KZ,
`MD, RU, TJ, TM), European patent(AT, BE, CH, DE, DK,
`ES, Fl, FR, GB, GR, IE, IT; LU, MC, NL, PT, SE), OAPI
`patent (BF, BJ, CF, CG, Cl, CM, GA, GN, ML, MR, NE,
`SN, TD, TG).
`.
`.
`.
`..
`
`Published
`With inJernational search report.
`
`(54) Titl~: APO B-SECRETION/MTP INHIBIToRY AMIDES
`
`m ,...o
`
`~
`
`(I)
`
`(57) Abstract
`
`This invention is directed to compounds of fonnula (I) or the stereoisomers, pharmaceutically acceptable salts and hydrates thereof.
`The compounds are Apo BIMTP 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; Cfil'P
`inhibitors; bile acid sequestrants; fibrates; cholesterol absorption inhibitors; ACA T inhibitors, squalene synthetase inhibitors, ion-exchange
`resins, anti-oxidants and niacin. This invention is also directed to intennediates and processes useful in the preparation of compounds of
`fonnula (I).
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`Codes used 10 identify States pany 10 the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Albania
`AL
`Armenia
`AM
`Austria
`AT
`Australia
`AU
`AZ
`Azerbaijan
`Bosnia and Hcrugovina
`BA
`Barbados
`BB
`Belgium
`BE
`Burkina Paso
`BF
`Bulgaria
`BG
`BJ
`Benin
`Br.u:il
`BR
`Bcluus
`BY
`Canada
`CA
`CF
`Cenual African Republic
`. Congo
`CG
`CH
`Swiuerland
`COie d'Ivoire
`Cl
`ciimeroon
`CM
`China
`CN
`cu
`Cuba
`CZ C~ Republic
`DE
`Oennany
`Denmarlc
`DK
`F.F.
`&Ionia
`
`ES
`Fl
`FR
`GA
`GB
`GE
`CH
`GN
`GR
`HU
`IE
`IL
`JS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Spain
`fTmland
`Prance
`Oabon
`United Kingdom
`Ocorgia
`Ohana
`Ouinea
`Oreece
`Hungary
`Ireland
`l&racl
`Iceland
`Italy
`Japau
`Kenya
`Kyrgyulan
`Democ:ralic People'•
`Republic of KOIQ
`Republic of Korea
`Kazablall
`Sahli Lucia
`Licchlcnsieln
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`l..csO(ho
`Lllhuania
`Luxembourg
`Lalvia
`Monaco
`Republic of Moldova
`Madagascar
`1be former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Maurilania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation.
`Sudan
`Sweden
`Singup<m
`
`SI
`SK
`SN
`sz
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UC
`us
`uz
`VN
`YU
`zw
`
`SloYalia
`Slovakia
`Senegal
`Swuiland
`Owl
`Togo
`Tajikistan
`Tuttmeniaran
`Twkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United StalCI of America
`Uzbekistan
`Viel Nam
`Yugoslavia
`Zimbabwe
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`-1-
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`Apo B-SECRETION/MTP
`INHIBITORY AMIPES .
`
`5
`
`Field Of The lnyentjoo
`
`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
`
`1 O
`
`related diseases. The invention further relates to phamiaceutical comp0sitions
`
`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
`
`15
`
`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 beer:i implicated as a putative mediator
`
`in the assembly of Apo_B-containing lipoproteins, biomolecules which contribute to
`
`20
`
`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'
`
`25
`
`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
`
`30
`
`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 hypertipidemia associated with
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`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. O 643 057 A 1 the latter of which
`
`5
`
`discloses certain compounds of the ·generic formulae
`
`N
`
`I
`x
`
`N-R'
`
`~~·:x)o-c
`R3 •••• : " I
`.
`~-
`/-:,...
`R4 ••
`
`.
`
`and
`
`which have utility as inhibitors of MTP.
`
`10
`
`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
`
`15
`
`the pharmaceutically acceptable salts and hydrates thereof,
`
`wherein G is selected from:
`
`(I)
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`(a) a phenyl or heterocyclic ring wherein said heterocyclic ring contains a tqtcil of
`
`from 3 to 14 ring atoms, wherein said heterocydic ring incorporates a total of from
`1 to 4 ring heteroatoms selected independently from oxygen, nitrogen, and:sulfur,
`
`wherein the individual rings of said heterocydic ring may be independently .
`
`5
`
`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, amlnosulfonyl,
`
`phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C1-C10)alkyl, (C1- •
`C4)perfluoroalkyl, (C1-C10)alkoxy, (C1-C4)perfluoroalkoxy, (C1-C10)alkoxycarbonyl,
`(CrC10}alkylthio, (C1-C10)alkylamino, di(CrC10)alkylamino, (C1-
`C10}alkylaminocarbonyl, di(C1-C10}alkylaminocarbonyl, di(C1-C10)alkylamino(C1-
`C10)alkoxy, (C1-C10)acyl, (C1-C10)perfluoroacyl, (C1-C10)acyloxy, (CrC1o)acyloxy(C1-
`C10)alkyl, (C1-C6)acylamino and (C1-C6)perfluoroacylamino;
`(b) -CH2CN, .
`
`10
`
`15
`
`(c)
`
`20
`
`(d} (CrC12}alkyl or (CrC12)perfluoroalkyl wherein each of said (CrC12)alkyl and
`(C2-C12}perfluoroalkyl is substituted optionally with from 1-3 substituents selected
`independently from:
`(1) phenyl, halogen, nitro, cyano, hydroxy, -NR1R2
`, (C1-C4)alkoxy,
`(C1-C4}perfluoroalkoxy, (C1-C4}thioalkoxy or (C1-C4)perfluorot1Jioalkoxy,
`where R1 and R2 in the definition of-NR1R2 are each selected independently
`from hydrogen, formyl, phenyl, benzyl, benzoyl, (CrC8)cydoalkyl, (C3-
`25 C8}cycloalkenyl, (C1-C4)alkyl, (C1-C4)perfluoroalkyl, (C1-C10)alkoxycarbonyl, (C1-
`C6}acyl, (C1-Cs)perfluoroacyl, aminocarbonyl; (C1-C10)alkylaminocarbonyl, di(C1-
`C10)alkylaminocarbonyl, aminosulfonyl, (C1-C4)alkylaminosulfonyl, di(C1-
`C4}alkylaminosulfonyl, (C1-C4)perfluoroalkylaminosulfonyl, (C1-
`
`, -OCOR3
`
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`C4)perfluoroalkylaminosulfonyl, di(C1-C4)alkylsulfonyl, and (Cr
`C4)perfluoroalkylsulfonyl,
`or where R 1 and R2
`
`, taken together with the nitrogen atom to which 'they are
`
`attached, form a saturated, partially-saturated or aromatic heterocyclic ring;
`
`5
`
`wherein said heterocyclic ring contains a total of from 3 to 14 ring.atoms arid.
`
`incorporates optionally an additional 1 to 4 ring heteroatoms selected
`
`10
`
`15
`
`independently from oxygen, nitrogen and sulfur, wherein said heterocyclic ring may
`
`have optionally from 1 to 4 substituents selected independently ·from halogen,
`
`hydro),Cy, cyano, nitre, oxo, thloxo, aminosulfonyl, phenyl, phenoxy, phenylthio,
`benzyl, benzoyl, benzyloxy, (C1-C10)alkyl, (C1-C4)perfluoroalkyl, (C1-C10)alkoxy, (C1-
`C4)perfluoroalkoxy, (C1-C10)alkoxycarbonyl, (C1-C10)alkylthio, (C1-C10)alkylamino,
`di(C1-C10)alkylamino, (C1-C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl,
`di(C1-C10)alkylamino(C1-C10)alkoxy, (C1-C10)acyl, (C1-C10)perfluoroacyl, (C1-:
`C10)acylamino, (C1-C1o)acyloxy, and (C1-C10)acyloxy(C1-C10)alkyl,
`where R3 is selected from -NR1R2
`, phenyl, (C1-C10)alkyl, (C1-
`C4)perfluoroalkyl, (C1-C6)alkoxy and (C1-Cs)perfluoroalkoxy,
`(2) (CrC8)cycloalkyl or (C3-C8)cycloalkenyl wherein each of said (Cr
`C8)cycloalkyl and (C3-C8)cycloalkenyl may have optionally from 1 to 4 substituents
`selected independently from halogen, hydroxy, cyano, nitro,.oxo, thioxo,
`
`20
`
`aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy~ (C1-'
`C10)alkyl, (C1-C4)perfluoroalkyl, (C1-C10)alkoxy, (C1-C4)perfluoroalkoxy, (Cr
`C10)alkoxycarbonyl, (C1-C10)alkylthio, (C1-C10)alkylamino, di(C1-C10)alkylamino; (C1-
`C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl, di(C1-C10)alkylamino(C1-
`C10)alkoxy, (C1-C10)acyl, (C1-C10)perfluoroacyl, (C1-C1o)acylamino, (C1-
`25 C10)perfluoroacylamino, (C1-C10)acyloxy, and (CrC10)acyloxy(C1-C10)alkyl, 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
`
`30
`
`selected independently from halogen, hydroxy, cyano, nitre, oxo, thioxo,
`
`aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C1-
`C1o)alkyl, (C1-C4)perfluoroalkyl, (C1-C10)alkoxy, (C1-C4)perfluoroalkoxy, (Cr ·
`C10)alkoxycarbonyl, (C1-C10)alkylthio, (C1-C10)alkylamino, di(C1-C10)alkylamino, (c1..:
`
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`5
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`10
`
`15
`
`C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl, di(C1-C10)alkylamino(C1-
`C10)alkoxy, (C1-C10)acyl, (C1-C10)perfluoroacyl, (C1-C10)acylamino, (C1-
`C10)perfluoroacylamino, (C1-C10)acyloxy, and (C1-C10)acyloxy(C1-C1o)alkyl, ·
`provided that (CrC12)alkyl does not include unsubstituted allyl; ·
`(e) (CrC8)cycloalkyl or (CrC8)cycloalkenyl wherein each of sa.ld (CrC8)cycloalkyl
`and (CrC8)cycloalkenyl may have optionally from .1 to 4 substituents selected
`independently from halogen, hydroxy, cyano, nitre, oxo, thioxo, aminosulfonyl,
`
`phenyl, phenoxy, phenylthlo, benzyl, benzoyl, benzyloxy, (C1-C10)alkyl, (C1-:
`C4)perfluoroalkyl, (C1-C10)alkox}t, (C1-C4)perfluoroalkoxy, (C1-C10)alkoxycarbonyl,
`(C1-C 10)alkylthio, (C1-C10)alkylamino, di(C1-C10)alkylamino, (C1-
`C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl, di(C1-C10)alkylamino(C1-
`C10)alkoxy, (C1-C10)acyl, (C1-C10)perfluoroacyl, (C1-C10)acylamino, (C1-
`C10)perfluoroacylamino, (C1-C10)acyloxy, and (C1-C10)acytoxy(C1-C1o)alkyl; and
`, where R4 is selected from hydroxy, phenyl, -NR1R2
`(f) -(CH2)0 COR4
`, (CrC4)alkyl,
`(C1-C4)perfluoroalkyl, (C1-C4)alkoxy, (C1-C4)perfluoroalkoxy, (CrC8)cycloalkyl, and
`(CrC8)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
`
`20
`
`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 heterocycllc ring may be saturated, partially saturated or aromatic,
`
`25
`
`and wherein each of said phenyl or heterocyclic rings may each have optionally
`from 1 to 4 substltuents selected independently from halogen, hydroxy, phenyl,
`
`benzyl, benzoyl, benzyloxy, (C1-C10)alkyl, (C1-C4)perfluoroalkyl, (C1-C10)alkoxy, (C1-
`C4)perfluoroalkoxy, (C1-C10)alkoxycarbonyl, (C1-C10)alkylthio, (C1-C10)alkylamino,
`di(C1-C10)alkylamino, (C1-C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl,
`di(C1-C10)alkylamino(C1-C10)alkoxy, (C1-C10)acyl, (C1-C10)perfluoroacyl, (Cr.;
`C6)acylamino, (C1-C6)perfluoroacylamino, (C1-C10)acyloxy, and (CrC10)acyloxy(C1-
`C1o)alkyl;
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`(b) (CrC12)alkyl wherein said (CrC12)alkyl is substituted optionally with from 1-3
`substituents selected from:
`(1) phenyl, halogen, cyano, hydroxy, -NR1R2
`, -OCOR3
`(C1-C4)perfluoroalkoxy,
`where R3 is selected from -NR1R2, (C1-C4)alkyl and (C1-C4)perfluoroalkyl,
`(2) (C3;.C6)cycloalkyl or (C3-C6)cycloalkenyl wherein each of said (C~­
`C6)cydoalkyl and (C3-Cs)cycloalkenyl may optionally have from 1 to 4 substituentS
`selected independently from hydroxy, (C1-C4)alkyl, (C1-C4)alkoxy, and (C1-
`1 O C4)alkoxycarbonyt, and
`(3) a saturated, partially-saturated or aromatic heterocyclic ring containing. a
`
`, (C1-C4)alkoxy, or
`
`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
`
`15
`
`selected independently from halogen, hydroxy, phenyl, benzyl, benzoyl, benzyloxy,
`
`(C1-C10)alkyl, (C1-C4)perfluoroalkyl, (C1-C10)alkoxy, (C1-C10)alkoxycarbonyl, (C1-
`C10)alkylthio, (C1-C10)alkylamino, di(C1-C10)alkylamino, (C1-C10)alkylaminocarbonyl,
`di(C1-C1o)alkylaminocarbonyl, di(CrC10)alkylamino(C1-C10)alkoxy, (C1-
`C4)perfluoroalkoxy, (C1-C10)acyl, (C1-C10)acylamino, (C1-C10)perfluoroacylarriino, (Cr
`20 C10)acyloxy, and (C1-C10)acyloxy(C1-C10)alkyl;
`provided that (CrC12)alkyl does not include unsubstituted allyl, ·
`(c) (C3-C6)cycloalkyl or (CrC6)cycloalkenyl wherein each of said (C3-C6)cycloalkyl
`and (C3-C6)cycloalkenyl may have optionally from 1 to 4 substituents selected
`Independently from hydroxy, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C10)acylamino, (C,-
`25 . C10)perfluoroacylamino and (C,-C4)alkoxycarbonyl; and
`(d)-(CH2)nCOR4, where R4 is selected from hydroxy, phenyl, -NR1R2, (C1-C4)alkyl,
`(C,-C4)perfluoroalkyl, (C1-C4)alkoxy, (C,-C4)perfluoroalkoxy, (C3-C6)cycloalkyl, and
`(C3-C6)cycloalkenyl,
`where n is an integer from 1 to 4.
`
`30
`
`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:
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`(a) (C2-C12)alkyl, wherein said (CrC12)alkyl is substituted optionally with a group
`selected from phenyl, halogen, cyano, hydroxy, (C1-C4)alkoxy, or a saturated,
`partially-saturated or aromatic heterocyclic ring selected from thienyl, pyrazolyl,
`
`pyrrolidinyl, · pyrrolyl, furanyl, thiazolyl, isoxazolyl, imidazolyl, trlazolyl,
`
`5
`
`tetrah.ydropyranyl, pyridyl, and pyrimidyl, wherein each of said heterocyclic rings .
`
`may have optionally from 1 to 3 substitutents selected independently from halogen,
`
`(C1-C4)acyl, (C1-C4)perfluoroacyl, (C1-C4)alkyl, (C1-C4)perftuoroalkyl, (C1-C4)alkoxy,
`(C1-C4)alkylaminocarbonyl, and (C1-C4)acylamino;
`provided that (C2-C12)alkyl does not include unsubstituted allyl;
`(b)-(CH2)0NR1R2, where n is an integer from 2 to 4; and
`(c) -(CH2)0COR4, where n is 1 or 2.
`The following compounds of formula (I), including the stereoisomers and the
`
`10
`
`pharmaceutically acceptable salts and hydrates thereof, listed herein below together .
`
`with their corresponding IUPAC chemical names, are especially preferred wherein
`
`15 G is selected from:
`
`-CH2COOH,
`
`IB-[(4'-Trifluoromethy!bjphenyl-2-carbonyD-aminoj-3 4-djhydro-1 H-jsooujno!in-2-yll(cid:173)
`
`acetic acid;
`
`20
`
`-(CH2)4CH3,
`
`4'-Trmuoromethylbiphenyl-2-carboxy!ic acid-lo-penM-1 2 3 4-tetrahydrOjsoqujriolin-
`
`6-yl)-amjde;
`
`-(CH2hOCH3,
`
`25
`
`4'-Tdf!uoromethylbjphenyl-2-carboxylic acid-[2-C3-methoxyprooyl)=1 2 3 4-
`
`tetrahydrojsoqyjnoljn-6-yl]-amjde;
`
`-{CH2hOCH3,
`
`4'-Trifluoromethy!bjphenyl-2-carboxylic acid-[2-C2-methoxyethyll-1 2 3 4-
`
`30
`
`tetrahydrojsoqujno!in-6-yl]-amjde;
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`4'-Tdf!uoromethy!bjpheoyl-2-carboxyUc acjd-£2-(2-ethoX)'ethyl)-1 2 3 4..:
`
`tetrahydrojsogujno!jn-6-yl]-amjde;
`
`5
`
`-(CH2hCN,
`4'-Trif!uoromethy!bjpheoy!-2-carboxylic acid-[2-(2-cyanoethyl)-l 2 3 4-
`tetrahydrojsogyjno!jn-6-yl]-amjde;
`
`-(CH2)iOCOCH3,
`
`Acetjc acid 2-{6-[(4'-trmyoromethy!bjpheoy!-2-carbonyll-amjool-3 4-djhydro=1 H-
`
`10
`
`jsogyjnolin-2-yO-ethyl ester;
`
`-(CH2hOCON(CH3)i,
`
`Dimethylcarbamic acid 2-{6-[<4'-trjf!uoromethylbjpheoyl-2-carbonyll-arDino]-3 4-
`
`djhydro-1 H-jsoqujno!in-2-yl}=ethyl ester;
`
`15
`
`-(CH2hNH2.
`4'-Trifluoromethylbjphenyl-2-carboxylic acid-[2-(2-amjnoetbyl)-1 2 3 4-
`tetrahydrojsjoqyjno!in-6-yD-amjde;
`
`20
`
`-(CH2hNHCOCH3,
`
`4 ·-Triflyoromethylbjphenyl-2-carboxy!jc acid-[2-(2-acety!amjnoethy!l-1 2 3 4-
`
`tetrahydrojsoqyjno!in-6-yl)-amjde;
`
`-(CH2)iCON(CH3)i,
`
`25
`
`4' -Trifluoromethylbjphenyl-2-carboxy!ic acid-£2-(2-djmethylcarbamoyletbyl)-1 2 3 4-
`
`tetrahydrojsoqujno!jn-6-yl)-amjde;
`
`-CH2CON(CH3}i,
`
`4'-nmuorometbylbjpheny!-2-carboxy!ic acjd-<2-djmethylcarbamoytmethy!-1 2 3 4-
`
`30
`
`tetrahydroisoqujno!jn-6-y!)-amjde;
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`4'-Trifluorometby!bjpbenyl-2-carbox,v!ic acid-C2-djetbylcarbamoylmetbyl-1 2 3 4-
`
`tetrahydrojsoqujoo!jo-6-yl)-amjde;
`
`-(CH2)2NHS(0)2CH3;
`
`5
`
`4 '-Icifluoromethylbiphenyl-2-carboxylic acid-[2-t2-methanesulfoaylamjooethvll-
`
`1 2 3 4-tetrahydrojsoqujnolin-6-yll-amjde;
`
`-(CH2hNHCOCF3,
`
`4'-Jrjf!uoromethy!bjphenyl-2-carbox,vlic acid-{2-[2-(2 2 2-trifluoroacetylamjoq)-ethyl)-
`
`10
`
`1 2 3 4-tetrahydrojsoqujno!in-6-y!}-amjde;
`
`-(CH2hNHCOCH2CH3,
`
`4'-Trif!uoromethylbjphenyl-2-carboxylic acid-[2-<2-propjooylamjnoethy!l-1 2 3 4-
`
`tetrahydrojsoqujnolin-6-yO-am!de;
`
`15
`
`..:ccH2hNHCOOCH3,
`
`C2-ffi·:M'-Trifluoromethylbjphenyl-2-carboayll-amjoo]-3 4-djhydro-1 H-jsoqujno!in-2-
`
`yl}-ethy!)-carbamjc acid methyl ester.
`
`20
`
`-(CH2hNHCHO,
`4'-Trif!uorometby!bjpheny!-2-cartmx,v!jc acid-C2-l2-formy!amjnoethyll-1 2 3 4-
`
`tetrahydrojsoqujno!in-6-y!l-amjde;
`
`· 25
`
`-(CH2hNHCONHCH3,
`4'-Difluoromethylbjphenyl-2-carbox,vlic acjd-{2-[2-<3-methylurejdo)-etbyQ-1 2 3 4-
`tetrahydrojsoquino!ia-6-yl}-amjde;
`
`-(CH,),-0
`N I
`
`c~
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`4' -Jrjf!uoromethylbiphenyl-2-carboxyHc acid-{2-[2-{1-methyl-1 H-pyrro!-2-y!lethyl]-
`
`1 2 3 4-tetrahydrojsoqujoo!in-6-y!l-amjde;
`
`N~
`-(CHVz~ ;N
`
`N
`H
`
`5
`
`4'-Tdfluoromethy!bjphenyl-2-carboxy!ic acid-{2-[2-C2H~[1 2 4]tdazol-3-y!-ethy!J.:.
`
`1 2 3 4-tetrahydrojsoqujnolin-6-yl}-amjde;
`
`4' -Triflyoromethylbiphenyl-2-carboxylic acjd-[2-(2 2-djphenylethyl)-1 2 3 4-
`
`10
`
`tetrahydrojsoqyjnolin-6-y!]-am!de;
`
`4'-Trifluoromethylbjpheoyl-2-carboxyliC acjd-{2-(2-pyrjdin-2-y!-ethyl}-1 2 3 4-
`tetrahydrojsoQujnolin-6-y!l-amjde;
`
`15
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`4'-Tcif!uoromethylbjphenyl-2-carboxy!ic acid-(2-phenylethyl-1 2 3 4-
`tetrahydrojsoayjnol!n-6-yl)-amjde;
`
`-CNH
`
`5
`
`4'-Trttlyoromethylbjphenyl-2-carbox,vlic acid-(2-pjperidjn-4-yl-1 2 3 4-
`
`tetrahydrojsoqujno!in-6-yl)-amjde; and
`
`4 '-Trifluorometby!bjphenyl-2-carbox,vfjc add-[2-(1-trifluoromethyfacetyl-pjperidjn+
`
`10
`
`y!}-1 2 3 4-tetrahydmjsoqujno!jn-6-y!l-amide.
`
`The following selected functional group definitions and examples thereof are
`
`employed throughout-the Instant specification and the appendant claims and are
`
`offered by way of illustration, and not by limitation.
`
`15
`
`The term "acyl" refers to either a straight or branched chain hydrocarbon
`
`moiety attached to a carbonyl group. Representative of such radicals are acetyl,
`
`propionyl, butyryl, and isobutyryl, and the like.
`
`Term "alkyl" includes both straight and branched chain hydrocarbon
`
`radicals, having optional unsaturation in the form of double or triple-bonded carbon
`
`20
`
`atoms. Representative of such radicals are methyl, ethyl, propyl, propylene,
`
`propynyl, isopropyl, isopropylene, butyl, isobutyl, isobutylene, tert-butyl, pentyl,
`
`hexyl, and so forth.
`The term "alkoxy" includes a straight or branched chain hydrocarbon radical
`attached to an oxygen atom. Illustrative of such radicals are metboxy, etboxy;
`
`25
`
`propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, hexoxy, heptoxy, and the like.
`
`Reference to the term "halogen° is inclusive of fluorine, chlorine, bromine,
`
`and Iodine unless noted otherwise.
`
`The term "perfluoro", when used in conjunction with a specified 'hydrocarbon
`
`radical, is meant to include a substituent wherein the individual hydrogen atoms
`
`30
`
`thereof may be substituted therefor with one or more and preferably from 1 to· 9
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`fluorine atoms. Exemplary of such radicals are trifluoromethyl, pentafluoroethyl,
`
`heptafluoropropyl and the like.
`
`Illustrative values for the term "(C1-C10)alkoxycarbonyl" include
`methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,
`
`5
`
`butoxycarbonyl, and the like.
`Illustrative values for the term "(C1-C10)alkylthion include the corresponding
`sulfur-containil;ig congeners of the term "alkoxy" as defined hereinabove, including
`
`methylthio, ethylthio, propylthio, isopropylthlo, butylthio, isobutylthio, pentylthio,
`
`hexylthio, heptylthio, and the like.
`
`10
`
`Illustrative values for the term "(C1-C10)alkylamino" include methylamino,
`ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, and so forth.
`
`Illustrative values for the term "di(C1-C10)alkylamino" include dimethylamino,
`diethylamino, dipropylamino, di-isopropylamino, and the like as well as N-methy!-N'(cid:173)
`
`ethylamlno, N-ethyl-N'-propylamino, N-propyl-N'-isopropylamlno, and the like.
`
`15
`
`Illustrative values for the term "(CrC10)acyloxy" include acetyloxy,
`propionyloxy, butyryloxy, and the like and also include such radicals which ·
`
`incorporate a cyclic substituent such as benzoyloxy.
`
`Illustrative values for the term "(C3-C8)cycloalkyin include cyclopropyl,
`cyclobutyl, cyclopentyl, cyclohexyl, and the like.
`
`20
`
`Illustrative values for the term "(CrC8)cycloalkenyl" include cyclopropenyl,
`cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.
`
`It is to be understood that the term "heterocyclic ring" as employed
`
`throughout the instant specification and appendant claims embraces heterocyclic
`
`radicals which may be either monocyclic and polycyclic in nature. Exemplary of
`
`25 monocyclic heterocyclic ring systems are radicals such as furanyl, thienyl,
`
`pyrazolyl, pyrrolidinyl, pyrrolyl, thiazolyl, isoxazolyl, imidazolyl, triazolyl;
`
`tetrahydropyranyl, pyridyl, pyrimldyl, and so forth. Exemplary of polycyclic
`
`heterocyclic ring systems are radicals such as indolyl, benzofuranyl,
`
`benzimidazolyl, quinolinyl, acridinyl, phthalazinyl, and the like.
`
`30
`
`It is to be understood further that if a carbocyclic or heterocyclic ring may be
`
`bonded or otherwise attached to a designated substrate, including eompound (I),
`
`through differing ring atoms without denoting a specific point of attachment, then all
`
`possible points are intended, whether through a carbon atom or a trivalent nitrogen
`
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`atom. For example, the term "pyridyl" means 2-, 3-, or 4-pyridyl, the term "thienyl"
`
`means 2-, or 3-thienyl, and so forth.
`
`The terms "treating" or "treatmenr as employed herein are meant to e('nbrace
`
`prophylactic as well as disease-remitive treatment.
`
`5
`
`The instant Invention further provides pharmaceutical compositions suitable for
`
`the treatment of conditions including atherosclerosis, pancreatitis, obesity,
`
`hypercholesterolemia, hypertriglyceridemia, hyperlipidemia and diabetes, which
`
`comprise a therapeutically effective amount of a compound of formula (I) shown and·
`
`defined hereinabove, including the stereoisomers, pharmaceutically acceptable Salts
`
`1 O
`
`and hydrates thereof, in combination with a pharmaceutically acceptable carrier or
`
`diluent.
`
`The compounds of the instant invention inhibit or decrease Apo B secretion,
`
`likely by the inhibition of MTP, although it may be possible that additional·
`
`mechanisms are involved. The compounds are useful In treating any of the disease
`
`15
`
`states or conditions in which Apo B, serum cholesterol, and/or triglyceride levels are
`
`elevated. Accordingly, the instant invention provides a method for inhibiting or
`
`decreasing Apo B secretion in a mammal in need thereof which comprises the ·
`
`administration of an Apo B secretion inhibiting or decreasing amount ofa
`
`compound of fori'nula (I) or a stereoisomer, pharmaceutically acceptable salt or
`
`20
`
`hydrate thereof. The invention further provides a method of treating a condition
`
`selected from atherosclerosis, pancreatitis, obesity, hypercholesterolemia,
`
`hypertriglyceridemia, hyperlipidemia, and diabetes which comprises administenng to
`
`a mammal, especially a human, in need of such treatment a therapeutically effective
`
`amount of compound (I) or a stereoisomer, pharmaceutically acceptable salt or•
`
`25
`
`hydrate thereof. A prefered subgroup of the conditions described hereinabove is·
`
`atherosclerosis, obesity, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia,
`
`and diabetes.
`
`The compounds of this invention may be used in conjunction with other
`
`pharmaceutical agents, including other lipid lowering agents. Such agents include,
`
`30
`
`for example, cholesterol biosynthesis inhibitors and cholesterol absorption inhibitors,
`
`especially HMG-CoA reductase inhibitors and HMG-CoA synthase inhibitors; HMG(cid:173)
`
`CoA reductase gene expresion inhibitors; CETP inhibitors; bile acid sequestrants;
`
`fibrates; cholesterol absorption inhibitors; ACA T inhibitors, squalene synthetase
`
`
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`inhibitors, ion-exchange resins, anti-oxidants and niacin. In combination therapy
`
`treatment, the compounds of the instant invention and the other drug therapies may .
`
`be administered to mammals {e.g. humans) by conventional methods.
`
`Specific cholesterol absorption inhibitors and cholesterol biosynthesis inhibitors
`
`5
`
`are described in detail hereinbelow. Additional cholesterol absorption inhibito~ are
`
`known to those skilled in the art and are described, for example, In PCT WO
`
`94/00480.
`
`Any HMG-CoA reductase inhibitor may be employed as the second
`
`compound in the combination therapy aspect of the instant invention. The tem'.l HMG-
`
`1 O CoA reductase inhibitor refers to a compound which inhibits the biotransforrnation of
`
`· hydroxymethylglutaryl-coenzyme A to mevalonic acid as catalyzed by the enzyme
`
`HMG-CoA reductase. Such inhibition may be determined readily by one of skill in the
`
`art according to standard assays (e.g., Methods of Enzymology, 1981; 71: 455-509
`
`and the references cited therein). A variety of these compounds are described and
`
`15
`
`referenced herelnbelow. U.S. Pat. No. 4,231,938 (the disdosure of which Is hereby
`
`incorporated by reference) discloses certain compounds isolated after cultivation of.a
`
`microorganism belonging to the genus Aspergillus, such as lovastatin. Also, U$; Pat.
`
`No. 4,444,784 (the disclosure of which is hereby incorporated' by reference) discloses
`
`synthetic denvatives of the aforementioned compounds, such as simvastatin. ;
`
`20
`
`Additionally, U.S. Pat. No. 4,739,073 (the disclosure of which is hereby incorporated
`
`by reference) discloses certain substituted indoles, such as fluvastatin. Further, U.S:
`
`Pat. No. 4,346,227 (the disclosure of which is hereby incorporated by reference)
`
`discloses ML-236B derivatives, such as pravastatin. In addition, EP 491,226 teaches
`
`certain pyridyldihydroxyheptenoic acids, such as rivastatin. Also, U.S. Pat. No.
`
`25
`
`4,647,576 (the disclosure of which Is hereby incorporated by reference) discloses
`
`certain 6-[2-(substituted-pyrrol-1-yl}-alky~-pyran-2-ones such as atorvastatin. Other
`
`HMG-CoA reductase inhibitors will be known to those skilled in the art.
`
`Any HMG-CoA synthase Inhibitor may be used as the second compou·nd in
`
`the combination therapy aspect of this invention. The term HMG-CoA synthase
`
`30
`
`inhibitor refers to a compound which inhibits the biosynthesis of
`
`hydroxymethylglutaryl-coenzyme A from acetyl-coenzyme A and acetoaeetyl- ·
`
`coenzyrne A, catalyzed by the enzyme HMG-CoA synthase. Such· inhibition may be ·
`
`determined readily by one of skill iil the art according to standard assays (e.g.,
`
`
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`Methods of Enzymology, 1975; 35: 155-160 and Methods of Enzymology, 1985;.110:
`
`19-26 and the references cited therein). A variety of these compounds are des.cribed:
`
`and referenced hereinbelow. U.S. Pat. No. 5, 120,729 (the disclosure of which is
`
`hereby incorporated by reference) discloses certain beta-lactam derivatives. U.S. ;Pat.
`
`5
`
`No. 5,064,856 (the disclosure of which is hereby incorporated by reference) discloses
`
`certain spiro-lactone derivatives perpared by culturing .the microorganism Mf 5253.
`
`U.S. Pat. No. 4,847,271 (the disclosure of which is hereby incorporated by reference)
`
`discloses certain oxetane compounds such as 11-(~hydroxymethyl-4-oxo-2-oxetayl):-
`
`3,5,7-trimethyl-2,4-undecadienoic acid derivatives. Other HMG-CoA synthase·
`
`1 O
`
`inhibitors will be known to those skilled in the art.
`
`Any compound that decreases HMG-CoA reductase gene expression may be
`
`used as the second compound in the combination therapy aspect of this invention.
`
`These agents may be HMG-CoA reductase transcription inhibitors that block the .
`
`transcription of DNA or tra