Ufllted States Patent
`
`[L9]
`
`[11] Patent Number:
`
`6,121,283
`
`Chang et al.
`
`[45] Date of Patent:
`
`Sep. 19, 2000
`
`US[JU6l 2] 283A
`
`[54_ APO B-SECRETI()N;’MTP INHIBITORY
`AMIDES
`
`/lttorrrey, Agent‘, or Fi'mi—Peter C. Richardson; Gregg C.
`Benson; Carl J. Goddard
`
`[75'
`
`Inventors: George Chang, Ivoryton; George
`Joseph Qualliehv North S‘°’““9:l‘3'“=
`h‘”h“f Cm";
`
`[73 Awgnwi Pfizer Inc’ New York’ NY‘
`'3]
`App]_ No_;
`()9;234.,45(,
`T1 ‘_
`P91 hlfldi
`l33
`86- PCFN _:
`0
`§37l Date:
`
`_
`
`I
`
`N0“ 3: 1997
`PCT [B97 ["368
`if
`I
`Apr. 20, "I999
`
`§ 102%) mm’: Apr‘ 20’ ‘[999
`[JCT pub, N0; w()93;23593
`
`[37]
`
`PCI1 P11h- D3133 -]u“- 4: 1998
`
`[fill]
`
`Related U'S' Applieatien Dal"
`Provisional application No. t‘:i0,."032,3fJ7, Nov. 27, I996.
`
`Int. Cl.’ ....................... .. C07D 2't7,t04; /\61K 31:47
`[51]
`[52] U.S. Cl.
`........................................... .. 514E307; 546E139
`[58] Field of Search ............................ .. 546E139; 5l4,=’3U7
`
`[56]
`
`References Cited
`
`U.S. P/¥l'l_7N'l‘ [)U(IUMl_il\l'l'S
`
`4_.U22_.9UU
`
`5;'1T-IT! Matltison .............................. .. 4244258
`
`l*()Rl_-'](}N P/XI‘ljN'l‘ [)()(IUMlJN'l‘S
`
`European Pal. (HT.
`2,-’l‘.J‘)4
`8,"1996 VVIPO .
`12;'1996 WIPO .
`
`.
`
`[if)43[]5'7'‘
`9626205
`9lf:'t4tJI5-’ltJ
`
`ABSTRACT
`[57]
`Thisinvention is directed to compounds of formula (I) or the
`stcreoisomcrs, pharmaceutically acceptable salts and
`hydrates thereof. The compounds are Ape B/Mil’ inhibitors
`and are useful in the treatment of various disorders and
`conditions such as atherosclerosis, pancreatitis, obesity,
`hypercholesteremia, hypertriglyceridcmia, hypcrlipidcmia,
`and diabetes. The compounds of this invention are also
`useful
`in combination with other pharmaceutical aocnts
`including cholesterol biosynthcsis inhibitors and cholceicrol
`absorption inhibitors,especially llM(3-(.'oA reductase
`inhibitors and HMG—CoA synthase inhibitors; HMG—CoA
`reductasc gene expression inhibitors; CETP inhibitors; bile
`acid sequestrants; fibrates; cholesterol absorption inhibitors;
`ACAT inhibitors, squalene synthetasc 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]
`
`(It
`
`G
`
`N/
`
`CF.‘
`
`®
`
`0
`
`N
`
`® 11
`
`Prrninrv E,\'rmi£riet‘—Zinna Northington Davis
`
`56 Claims, N0 Drawings
`
`1 of 37
`
`PENN EX. 2219
`CFAD V. UPENN
`
`lPR2015-01836
`
`

`
`6,121,283
`
`1
`
`APO B-SECRETIONIMTP INHIBITORY
`AMIDES
`
`CROSS-R1£I"IiRIiNC]_-L T0 RI.-"L/\'l'IjD
`APPLICATIONS
`
`This application is the National Stage filing under 35
`USC. §371 based on PCT;’lB97i’01368, filed internationally
`on Nov. 3, 1997, which claims priority from US. Provi-
`sional Application No. 60i’032,307, filed Nov. 27, 1996.
`
`10
`
`l-‘II.-'I_[) OI‘ 'l‘IIl_i INVI_-'N'I'I()N
`
`This invention relates to compounds which are inhibitors
`of microsomal triglyceride transfer protein (M'l‘l-’) andfor
`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 (lis-
`eases. The invention further relates to pharmaceutical com-
`positions comprising these compounds and to methods of
`treating atherosclerosis, obesity, and related diseases andfor
`conditions with said compounds, either alone or in combi-
`nation with other medicaments,
`including lipid lowering
`agents. Further still, the invention relates to certain pro-
`cesses and intermediates related thereto which are useful in
`
`20
`
`the preparation of the compounds of the instant invention.
`
`30
`
`BACKGROUNIJ ()1-‘ 'I"III_-' INVl_iN'l'[()N
`
`triglyceride transfer protein catalyzes the
`Microsomal
`transport oftriglyceride, cholesteryl ester, and phospholipids
`and has been implicated as a putative mediator in the
`assembly of Apo B—eontaining lipoproteins, biomolecules
`which contribute to the formation of atherosclerotic lesions.
`
`the subeellular (lumen of the mierosomal
`Specifically,
`fraction) and tissue distribution (liver and intestine) of MTP
`have led to speculation that it plays a role in the assembly of
`plasma lipoproteins, as these are the sites of plasma lipo-
`protein assembly. The ability of MTP to catalyze the trans-
`port 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 andfor otherwise inhibit
`Apo I3 secretion are accordingly useful in the treatment of
`atherosclerosis and other conditions related thereto. Such
`
`40
`
`50
`
`55
`
`compounds are also useful in the treatment of other diseases
`or conditions in which, by inhibiting M'['l-’ andfor Apo ll
`.
`.
`.
`secretion, serum cholesterol and triglyceride levels may be
`_
`.
`_
`_
`-
`.
`_
`1
`-
`_
`_
`reduced. Such conditions may include,
`for example,
`hypercholesterolemia, hypcrtriglyccridcmia, pancreatitis,
`and
`obesity;
`and
`hypereholesterolemia,
`hypertriglyceridemia, and hyperlipidemia associated with G0
`pancreatitis, obesity, and diabetes. For a detailed discussion,
`see for example, Wetterau et al., Science, 258, 999-100],
`(1992), Wetterau et al., Bioehem. Biophys. Acta., 875,
`610-617 (1986), European patent application publication
`No. 0 584 446 A2, and European patent application publi- 55
`cation No. 0 643 057A1 the latter ofwhich disclosescertain
`compounds of the generic formulae
`
` 0
`
`R3
`
`\
`
`R3. _ _: _ /
`
`R-1
`
`R7
`
`Nx
`Y/N\)
`
`which have utility as inhibitors of MTP.
`
`SUMMARY OF THE INVENTION
`
`The instant invention relates to compounds which are Apo
`ll-secretion;‘M'I'P inhibitors represented by the structural
`formula (I), including the stereoisomers and the pharmaceu-
`tically acceptable salts and hydrates thereof,
`
`{IF3
`
`(It
`
`G
`
`0 / N
`
`II
`
`wherein (i 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
`saru rated, partially saturated or aromatic, and wherein
`each of said phenyl or heterocyclie rings may have
`optionally from 1
`to 4 substituents selected indepen-
`_
`.
`dently lrom halogen, hydroxy, cyano, nitro, oxo,
`_
`_
`x
`‘
`‘mom’ ammosulfonyl’ phcnyl"ph""nOXy‘ phenylthfo’
`bcmyl’ hcnmyl’ bcm3:]‘”‘yj (('1_('10)alk5'1’ (1(‘1_(1"*)
`pcrfluurflalkyli H’ !_('1I))a1kC’x5'!
`(('1_('4)
`P°"flU0_"0aik0XY-
`(C-1—C1o)f11k0X}’°a1'b0“Yl= (C1_C_iJ.0)
`3]k}’]1h10» ((:1‘(:1o)3lk)"liim1Tl0a d1(c1‘cio)a1kY13im1l'l0,
`(C1—Cm)a1ky1amin0carbonylt di(C1_C10)
`a1k)'1amiI10C3fb0fl)'1. Cli(C;-C1o)a1kY1«'lmifl0(C1-Clo)
`alkoxy, ((71%: ,(,)acyl, [C,—C,[,)perIluoroacyl, (C,~Cm)
`acyloxy,
`(C1—C10)acyloxy[C,—C1D)alkyl,
`(C1-C6)
`acylamino and (C,,—C,,)peri‘luoroaeylamino;
`
`2 of 37
`
`PENN EX. 2219
`CFAD V. UPENN
`
`lPR2015-01836
`
`

`
`6,121,283
`
`10
`
`30
`
`so
`
`(h) —(TII2CN,
`
`—ctH
`
`4
`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,
`henzoyl, henzyloxy, (C1—Cu,)all<yl, [C,—C,,)perlluoroalkyl,
`(C,—C,,,)alkoxy,
`(C,—C,,)perl‘luoroalkoxy,
`(C,—C,[,)
`alkoxycarbonyl.
`(C,—C,,-,)alkylthio, (C,—Cm)alkylamino,
`di(C,—C”,)alkylarnio,
`(C,—C,,,)alkylaminoearbonyl,
`di(C,—C,0)alkylaminocarbonyl, di[C,—C,D)alkylamino
`(C,—Cm)alkoxy,
`(C,—Cu,)acyl,
`(C,—Cm)perlluoroacyl,
`(C,—C,0)acylammo,(C1-C10)perfluoroacylam1no,(C,—Cl0)
`aeyloxy, and (C,—Cm)acyloxy(C,—C,0)a1kyl,
`provided that (C2—C,3)alkyl does not
`include unsubsti-
`((73—Cl3]perIluoroalkyl wherein
`((T:,_—C1:,_)alkyl or
`(d)
`tuted allyl;
`each of said (C2—C13)alkyl and (C3—C,2)per[luoroalkyl
`(c) (C3—C,,)cycloalkyl or [C_,—C,,)eycloalkenyl wherein
`,
`is substituted optionally with from l—3 substituents 15
`each of Said (C3_C8)C_yCl0alkyl and (C3_C3)
`selected independently from:
`cycloalkenyl may have optionally from 1 to 4sul'.-smu-
`(1) phenyl, halogcn’ Him), CYMO’ hydmxy’ _NR1R2’
`ems Scl°“:l°(l mdcpcndfmlly frolin halogen‘ hydmxyv
`—()(I[)R3,
`[C1—C_,)alkoxy,
`(Cl—C4)per[luoroalkoxy,
`‘Wane’ mm)’ 0x0’_lh10x0’ ammosulfonylv ph°nyl=
`((I1—(I4)1hioalkoxy or ((71—(I4)perfluorothioalkoxy,
`phcn0xy' phcnyllhlm b°nzyl' b°nz0yl' b°nZyl0Xy=
`where R1 and R3 in the definition of —NR1R2 are each 20
`(C1_C10)alk‘yl' §Cl_C4)p°rflu0r0‘1lkyl'
`(F1_C:l0)
`selected independently from hydrogen,
`formyl, phenyl,
`alkoxy’
`((‘1_('4)pf:rlll:mr0alk0x¥’
`(('1l_(;10)
`benzyl, benzoyl, [(T3—(T,,)cycloalkyl, (C_,—C,,]cycloalkenyl,
`iill{()Xyt.Iiafl')()l'ly-l,
`‘{:(.1‘—(.m)2ill\'ylT.l'l10,
`((:1—(;10)
`(Cl_C4)alkyl’
`(C]_C':)pcrfluOroa1kyl’
`(Cl_CH])
`a1k)'l31T_'1“0- d1((~1'C_-1g)a1‘ky1am1“0-1 (C-1'(-10)
`alkoxycarbonyl,
`(C,—C.‘fi)acyl,
`(C,—Cfi)perlluoroacy],
`al‘ky‘lam‘1nocarbony_l, d1[:'(.,:(.10)alkylani1pocarbonyl,
`aminocarbonyl,
`[C1_Cm)a1ky1amin0Carb0nyL dim-I_Cm) 25
`d‘§('1f('1U)alkylamm"(('1f('19)alk‘”‘y1 (('1_('{0)a‘f3'l=
`alkylaminoearhonyl, aminosulfonyl, {C,—C,,)
`(('1_(‘10)pcrllu0T”aCyl‘ ‘(('1‘_C‘1D)aCylam1"0’ ((;1_(;l0)
`alkylaminosulfonyl, di(C1—C,,]alkylaminosulfonyl, ((f,—(f,,)
`perlluoroacylarnino,
`((.,—(.m)acyloxy, and ((_,—(.m)
`pcrfluoroalkylaminosuIfonyl’
`(C1_C4)
`aCyl°xy(C1_C10)alkyli and I
`perlluoroalkylarninosulfonyl, di((T,—C,,]alkylsulfonyl, and
`(I) —((III:),,(T()R“, where R4 1S selected from hydroxy,
`(C1_C'I)pcI-flu0r0a]_ky1Su1fony1’
`Phfinyls —NRlR2s
`(C1‘C4)a1li}’1-
`(C1‘C-4)
`orwhereR1 and Rfgtaken togetherwith the nitrogenatom
`P“““UW3lk}'l» ((:1‘C4l3lk0XYa (5-‘1’(74l
`to which they are attached, form a saturated, partially—
`PCTllU‘“U3ll“”‘}'s {(33—(7x)CYC1“3ll\'Yl» and (c3—cr>:)
`saturated or aromatic heteroeyelic ring, wherein said het—
`9}"-'l"’3ll“3"Yl_s
`_
`erocyclic ring contains a total of from 3 to 14 ring atoms and
`incorporates optionally an additional 1 to 4 ring heteroatoms 35 Whflc " 15 3“ lmfigcf lmm 1 10 4-
`selected independently from oxygen, nitrogen and sulfur,
`Al3Wf°T_Wd5Ub8TUUP0l‘lh°‘3?mP0U1'1'1l’5Offormula-(1)*“'1(l
`wherein said heteroeyelic ring may have optionally from 1
`lb“ -‘51*"c"1-‘*0"1C_““-3 Phflrmaceuucalll’ 39061313513 -‘$3111-‘5 anfi
`10 4 Subsmucnts Sclcctcd indepcndemly from halogen,
`hydrates -thereol, includes those cornpounds wherein (3 1s
`hydroxy, cyano, nitro, oxo. thioxo, aminosulfonyl, phenyl,
`-‘*“’l'3‘-"ml lmmi
`phcngxy’ phcnyhhjo, bcnzyl‘ bcnzoyl’ bcnzylgxy’ (CFCJO) 40
`(a) a phenyl or heterocyclic ring wherein said heterocyclic
`alkyl,
`(C!—C_:)p31'[1]_[(3['0alkyl,
`(C1—C1U)a_[kgxy,
`((“_l_C,l)
`ring contains a total offrom 3 to 7 ring atoms, wherein
`pcffluorgalkgxy,
`(Cl_Cl0J;[]koxyc;[rbony1’ ((j1_C10)
`said heterocyclic ring incorporates a total of from 1
`to
`ajkyhhjo,
`(C1_C10)a1k}/lamina, di(C1_C10}a[ky]amjn0,
`4 ring heteroatoms selected independently from
`(C1_Cm)a]ky]a mi;-10 c al-be Hy],
`C1 f( C I _C I 0)
`oxygen, nitrogen, and sulfur, wherein said heterocyclic
`alkylamjngcarbonyl’ di(C1_C1CD31kylaminQ(C1_C10)alk0xy’ 45
`ring may be saturated, partially saturated or aromatic,
`(C1431 0);.cy1,
`[C,_(Tmpc4-fluoroacyl
`((_‘,_(_‘m)acy]amino,
`and wherein each of said phcnyl or heteroeyelie rings
`(C1_ClO)acylQxy’ am] (C1_C10);[cylQxy‘ and (C1_C10)a]_ky],
`may each have optionally from 1
`to 4 substituents
`whm-3 R3 [5 Sclcc[c(] from
`NR1R3, phcnyl’ ((j1_C10)
`selected independently from halogen, hydroxy, phenyl,
`alkyl, ((I1—C,,)perIluoroalkyl, (C,—(T,,]alkoxy and ((f,—(f,.,)
`bcnzyls bcnzoyls bcnzylgxys [Ci—Cio)3-lkyls (C1-C4)
`pgffiugroaflgoxy,
`perfluoroalkyl,
`(C,—C,D)alkoxy,
`(C1-C4)
`(2) ((I3—C,3)cycloalkyl or ((I3—(I3)cycl(ualkenyl wherein
`P0l'flU0l'0al-k0XY- (C.-Cufialkoxycarbonyl, lcrcm)
`each of said (C3—CH)cycloalkyl and ((f3—(f,,]cycloalkenyl
`alkylthio. (C1_C10)alkylami0v di(C1—Cm)a1ky1amin0,
`may have optionally from 1
`to 4 substituents selected
`(C1—C1[;}ii1li}'l31'1'1iTlUCiifl'30Dy1, di(C1—C-ml
`independently from halogen, hydroxy, cyano, nitro, oxo,
`alk)'13fl1U10C3i'b0fl)'1. Cli(C1—C1o)a1kYl«'lmlU0(Crcio)
`thioxo, arninosulfonyl, phenyl, phenoxy, phenylthio, benzyl, 55
`alkoxy, (C.—Cm}-'iC)'l, (C,—Cm)pcrfluor0acy1, (C1_Cfi)
`benzoyl, benzyloxy, ((T,—Cm)alkyl, ((7,—(f,,)periluoroalkyl,
`aC)'l3mlfl0.
`(C.—C¢=.)IJ01'flU01'03CY1amlU0-
`(C1_C1[J)
`((I1—Cm)alkoxy,
`[C1—(7,,]perlluoroalkoxy,
`(C,—C,[,)
`a‘3)'10XYs and (C1—C1o)a‘3Yl0xY(C1—C1o)3llk)/12
`alkoxycarbonyl,
`[C1—(T1D)alkylthio,
`(C1—(fm)alkylamino,
`(h) (C:—C,2)alkyl wherein said [(T2—(T,2)alkyl is substi-
`di((I1—(Iu,)alkylamino,((71—C10]alkylaminocarbonyl,
`tuted optionally with from 1-3 substituents selected
`di(C1—C10)alkylaminoearbonyl, di(C1—C10)alkylamino 60
`from:
`((T1—(fm)alkoxy,
`((T1—Cm]acyl,
`(C,—Cm]periluoroacyl,
`(1) phenyl, halogen, cyano, hydroxy, —NRlR2,
`((I1—(I,,_,)acylarnino, (CI1—(710)perfluoroacylamino, (C,—(fm)
`—OCOR3, (C,—C4)alk0xy, or (C1—C_,)perfluor0al.kOxy,
`acyloxy, and [(T1—(T10)acyloxy(Cl—(T10]alkyl, and
`where R?’ is selected from —NRlR2, (C1—C,,)£tlkyl and
`(3) a saturated, partially-saturated or aromatic heterocy-
`(C,—C_,)perfluoroalkyl,
`clic ring containing a total of from 3 to "[4 ring atoms, 65
`(2) (C3—Cfi)eycloalkyl or (C3—C,.,)eycloalkenyl wherein
`wherein said heterocyclic ring incorporates a total of from 1
`each of said (C3—C5)cycl0alkyl a1'1d [C3-C0-)CyclOalkenyl
`to 4 ring heteroatoms selected independently from oxygen,
`may optionally have from 1
`to 4 substituents selected
`
`3 of 37
`
`PENN EX. 2219
`CFAD V. UPENN
`
`lPR2015-01836
`
`

`
`6,121,283
`
`6
`
`10
`
`35
`
`so
`
`60
`
`l_,,_
`
`b
`
`1.1
`
`5
`independently from hydroxy, (C1—C,,]alkyl, ((f,—C,,)alkoxy,
`—(CII3):()CII3,
`and (C,—C4)al_koxycarbonyl, and
`4'-'l'riIluoromelhylbiphenyl-2-carboxylic acid-[2-(2-
`(3) a saturated, partially-saturated or aromatic heterocy-
`melhoxyethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-
`clic ring containing a total of from 3 to 6 ring atoms, wherein
`amide;
`said heterocyclic ring incorporates a total of from 1
`to 4 ring
`—(CH2)3OCH2CH3,
`hcteroatoms selected independently from oxygen, nitrogen
`4'—Trifluoromethylbiphenyl—2—earboxylic acid—[2—(2—
`and sulfur. wherein said heterocyclic ring may have option-
`ally from 1 to 4 substituents selected independently from
`cthoxycthyl)—1,2,3,4—tetrahydroisoquin0lin—6—yl]—amide;
`halogen, hydroxy, phenyl, benzyl, bcnzoyl, bcnzyloxy,
`—(CH2):CN,
`(C,—Cm)alkyl,
`(C,—C,,)perfluoroalkyl,
`(C,_—Cm)alkoxy,
`4'-'|'riI]uoromelhylbiphenyl-2-carhoxylic acid-[2-(2-
`(C,—C,0)a_lkoxyca_rb0nyl,
`(Cl—C,0)alkylth1o,
`(C,—C,0)
`cyanoelhyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide;
`alkylamlno, d1[(T1—(.'10)alkylam1no,
`((f1—Cm)
`—(CH2)3OCOCH3,
`alkylaminocarbonyl, di(C,—C,0)alkylarninocarbonyl,
`di(Cl—(I10)alkylamino((71—Cl0)alkoxy,
`(C1-C4)
`Acetic acid 2-{6-[(4‘-trilluoromethylbiphenyl-2-carl')onyl]-
`perlluoroalkoxy,
`(C1—C10)acyl,
`(C1—Cm)acylamino,
`amino]—3,4{|ihydro—1H—isoquinolin—2—yl} —ethyl ester;
`(E‘:1_—((;l0?[?C1rflllL)E':ZliE1yla‘I'i'l1El']1L?,
`((T1—Cm)acyloxy, and 15 _(CH2)3OCON(CH3)3!
`1
`h H. h‘
`.fl
`4,
`.
`(
`-1
`-Io)=“-Y Ox“ -1
`-1o)4 3':
`D.
`h 1
`I
`.
`.d 3
`‘tn uororllcl V1319 :“ny'
`provided that (C3—C1:)alkyl does not include unsubsti-
`‘mm yca”am'C _ac‘
`“'{{"[_(
`mica any],
`2-carbonyl)-am1r1o]-3,4-d1hydro-1II-1soqu1nol1n-2-
`(c) [C3—C6)cyeloalkyl or (C3—C5)cycloalkcnyl wherein
`yl}cthyl 05-‘Cf;
`each of said ((T3—(.'6]cycloall\'yl and (C3—(-36) 20 —((j1|2):N|1:,
`cycloalkcnyl may have optionally tmm 1 to 4 5"b5mu'
`4'-Trilluoromelhylbiphenyl-2-carhoxylic acid-[2-(L
`ems Selected Independently tmm hydroxy’ (C1-C4)
`aminoeth l)-1 7 34-tetrahydroiso uinolin-6- l]-amide‘
`alkyl,
`[C1—C_,)alkoxy,
`(Cl—Cl0)acylamino,
`((T1—C10)
`Y
`’”"‘
`‘
`" q
`y
`’
`perfluoroacylamino and (C,—C4)a1koXycarbonyl; and
`—'f(?I:'2)2NHCOCH3»_
`_
`1
`((1) _{CH3)"C0R-4’ whgrc R4 is Selccmd from hydl-oxy’ 25 4 -Ir1I]uoromelhylblphenyl-2-carhoxyltc ac1d-[2-(2-
`phenyl, —NR‘R*,
`(C1—C_,)alkyl,
`(C1—C_,)
`acetylaminoelhyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-
`perfluoroalkyl,
`(C,—C4)alkoXy,
`(C1-C4)
`amidc;
`periluc]il:c)alll\'t)xy,
`[C_,—C,,)cycloalkyl, and (f_.,—Cfi)
`_((:IL)q(:()N((:|I3)”
`cyc on cny,
`,
`.“ “
`“.
`_
`.
`.
`Wham n is an imcgcr [mm 1
`to 4‘
`30 4 —"frrfluoromcthylbrphenyl—?2—earboxyl1c ac1d—f2—(;-
`More particularly preferred of the compounds of fonrtula
`(I1mcthylf3arbam0ylmhyl)'1"'3‘4'l°trahydrO15Oqum0hn'
`(I) including the stereoisomers, pharmaceutically acceptable
`6'}’]]'3""'1dc3
`salts and hydrates thereof, are those compounds of the —(:|I;C0N((:|I3)2,
`subgroup wherein G is selected from:
`4‘-Tri[luoromelhylbiphenyl-2-carboxylic acid-(2-
`(a) [(T:—C,2)alkyl, wherein said ((T2—(f,2]alkyl is substi-
`dimethylcarbamoylethyl-l,2,3,4-tetrahydroisoquinolin-6-
`Iuted optionally with a group selected from phenyl,
`y1)_a1-njdc;
`halogen, cyarto, hydroxy,
`((T1—(f4)all\'oxy, or a
`_CHqCON(CHqCH_)q
`saturated, partially-satu-rated or aromatic heterocyclic
`4._Trfflu0r0mé‘lhy“;ipheny1_2_Carb0xy1iC aCid_(2_
`ring selected lrom thtenyl, pyramlyl, pyrroltdmyl,
`I. h I
`b
`1 h 11934
`h I
`.
`.
`1.
`6
`pyrrolyl,
`furanyl,
`thiazolyl,
`isoxamlyl,
`imidariolyl, 40
`(Ila yflalj amoy cl y_ ""’ ‘tetra yc rolsoqumo m‘
`_
`triamlyl,
`tetrahydropyranyl, pyridyl, and pyrimidyl,
`y)’am‘ C’
`wherein each of said heterocyclic rings may have —(C“2):N”S(0)2(:”3s
`optionally from 1
`to 3 substitutents selected indepen-
`4'-'|'rilluoromelhylbiphenyl-2-carhoxylic acid-[2-(2-
`derttly from halogen,
`(C1—(T4]acyl,
`(C1-C4)
`methanesulfonylaminoethyl)-1,2,3,4-
`Perfluflmacyla (c1‘c4)‘i1k)‘1:
`(C1—(:4)P”fl“'5’ma]kYl 45
`letrahydroisoquinolirr-6-yl]-amide;
`{(:C1—C4))all(loxy,
`[C1—C_,)alkylaminocarhonyl, and
`_(CHq)qN-HCOC1;-3’
`(T,—(I,, acy amino;
`4,_T .fl" "
`[h lb. h
`pgovlildeld that ((T2—(T,2)alkyl does not include unsubsti-
`flu::?rI:caCyc1l;)1::_¥lin(f;Ee(:):1yy1;']:1:l ,){ ,%[4_(
`.
`.
`.
`.
`tuic ay;
`(b) —{CH2),,NR1R:, where n is an integer from 2 to 4;
`lclmhydmlmqulmhndyl}'dm1de’
`‘
`'
`and
`—(Cl:I2)3NHCOCH3C-H3,
`(C) _(cH2)”c0R'=, where n is 1 or 3_
`4'—Trrlluoromothylbrphenyl—2—earboxyl1c acrd—[;—(2—
`The following compounds of formula (I), including the
`Proplonylamlnoclhyl)‘1-2-3=4‘l°lrahydr°150‘-1“m011n'5'
`stcreoisomers and the pharmaceutically acceptable salts and
`yl]—amide;
`hydrates thereof,
`listed hereinbelow together with their 55 _(CH2):Nl—IC00CH_,,
`C0"1'°5P0ndin5‘3 IUl_3AC Chcmlcal Ham‘-35: arc mpccially Pm‘
`(2-{6-[4'-'l'ri[1uoromethylbiphertyl-2-carbonyl)-amino]-3,4-
`fared wherein G is Sclcclcd from:
`dihydro-1Il-isoquinolin-2-yl}e1hyl)carbamic acid methyl
`—ClI2(:[)()II,
`c§lm__
`{6—[(4'—Trii‘luoromethylbiphenyl—2—earbonyl)—amino]—3,4—
`_(&.I| ’) N”(.”0
`,
`,
`_
`’
`dihydro-1H-isoquinolin-2-yl}-acetic acid;
`_
`'
`_ 3 3
`'
`_(CHfl)4CH3,
`4 —Trrfluoro_mcthylbrphenyl—2—earboxyl1c ‘acrd—[2—(2—
`4»_-I-nvfl]*_1OmheIhylbiphcnyl_2_carbOxy1ic acid_(n_pcmyl_1’2’
`formylamlnoethyl)-1,2,3,4-tetrahydrolsoqulnolln-6-yl]-
`3,4—tetrahydroisoquinolin—6—yl)—amidc;
`am‘d°3
`‘
`‘
`—(cH,),oCH,,
`—(C_H:)3NHC0NHCfH3.
`4’-Trilluoromethylhiphenyl-2-carboxylic acid-[2-(3- as 4'-'l'r1Iluurumclhylblphcnyl-2-carboxyllc ac1d-{2-[2-(3-
`methoxypropyl)—1,2,3,4—tetrahydroisoquinolin—(j—yl]—
`methylurcid0)—cthyl]—1,2,3,4—tetrahydroisoquinolin—6—
`amide;
`yl}—amide;
`
`.d_ .J_ .J_ 9 9 .J_
`
`’“"’
`
`’
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`7
`
`jl(7H2J2 N
`cling,
`
`4'—Trifluoromethylbiphenyl—2—carboxylic acid—{2— [2—(1—
`methyl-'1H-pyrrol-2-yl)ethyl]-"l,2,3,4-
`tetrahydroisoquinolin—6—yl}—amide;
`
`‘I0
`
`:(c7H3;,—E—/\\N_.
`
`4"-'I'rilluoromethylbiphenyl-2-carboxylic acid-{2-[2-(2II-[1,
`2,4]triazol—3—yl—ethyl]—‘I,2,3,4—tetrahydroisoquinolin—6—
`yl}-amide;
`
`20
`
`—cH3ctH
`
`8
`The following selected functional group definitions and
`examples thereof are employed throughout the instant speci-
`fication and the appendant claims and are offered by way of
`illustration, and not by limitation.
`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 atoms. Representa-
`tive of such radicals are methyl, ethyl, propyl, propylene,
`propynyl,
`isopropyl,
`isopropylerie, 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 methoxy, ethoxy, 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 sub-
`stituent wherein the individual hydrogen atoms thereof may
`be substituted therefor with one or more and preferably from
`1
`to 9 fluorine atoms. Exemplary of such radicals are
`trilluoromethyl, pentalluoroethyl, heptailuoropropyl and the
`like.
`
`4‘ -Trifluoromethylbiphenyl-2-carbo xylic acid-[2-(2,2-
`dipher1ylethyl)- I ,2,3,4-tetrahyd roisoq uinolin-6-yl]-
`amide;
`
`T (C1 I232
`
`\X
`
`/ .-
`
`4"-'I'rilluoromethylbiphenyl-2-carboxylic acid-[2-(2-pyridim
`2-yl-ethyl- 1 ,2,3,4-tetrahyd roisoquinolin-6- yl]- amide;
`
`4‘—Triflu orom ethylb iphenyl—2—carboXylic acid —(2—
`phenylethyl—1 ,2,3,4—tetrahydroisoqu inolin—6—yl)—amide;
`
` H
`
`4'—Trifluoromethylbiphenyl—2—carboxylic acid—(2—piperidin—
`4—yl—1,2,3,4—tetrahydroisoquinolin—6—yl)—amide; and
`
`O
`
`4’-Trilluoromethylbiphenyl-2-carboxylic acid-[2-{l-
`triflu0romethylacetyl—piperidin—4—yl)—1,2,3,4—
`tetrahydroisoquinolin—6—yl]—amide.
`
`30
`
`Illustrative values for the term “(C1-C1D)alkoxycarbonyl”
`include methoxycarbonyl, ethoxycarbonyl,
`propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, and
`the like.
`
`Illustrative values for the term "(C,—C,0)alkylthio”
`include the corresponding sulfur-containing congeners of
`the term “alkoxy" as defined hereinabove,
`including
`methylthio, ethylthio, propylthio, isopropylthio, butylthio,
`isobutylthio, pentylthio, hexylthio, heptylthio, and the like.
`Illustrative values for
`the term “[C,—C,D)alkylamino”
`include methylamirio, ethylamino, propylamino,
`isopropylamino, butylamino, isobutylamino, and so forth.
`Illustrative values for the term "di[C1—(T1D)alkylamino”
`include dimethylamino, diethylamino, dipropylamino,
`di-isopropylamino, and the like as well as N-methyl-N5
`ethylamino, N-ethyl-N'-propylamino, N-propyl-N'-
`isopropylamino, and the like.
`Illustrative values for the term “((T,—(Tm)acyloxy" include
`aoetyloxy, propionyloxy, butyryloxy, and the like and also
`include such radicals which incorporate a cyclic substituent
`such as benmyloxy.
`Illustrative values for the term “(C_,—C,,)cycloalkyl”
`include cyclopropyl, cyclohutyl, cyclopentyl, cyclohexyl,
`and the like.
`
`Illustrative values for the term “[C3—C3)cycloalkenyl”
`include cyclopropenyl, cyclobuteriyl, cyclopentenyl,
`cyclohexenyl, cycloheptenyl, and the like.
`It is to be understood that the term "heterocyclic ring” as
`employed throughout the instant specification and appen-
`dant claims embraces heterocyclic radicals which may be
`either monocyclic and polycyclic in nature. Exemplary of
`monocyclic heterocyclic ring systems are radicals such as
`furanyl, thienyl, pyrazolyl, pyrrolidinyl, pyrrolyl, thiazolyl,
`isoxazolyl, imidazolyl, triazolyl, tetrahydropyranyl, pyridyl,
`pyrimidyl, and so forth. Exemplary of polycyclic heterocy-
`clic ring systems are radicals such as indolyl, benzofuranyl,
`benzimidazolyl, quinolinyl, acridinyl, phthalazinyl, and the
`like.
`
`if a carbocyclic or
`It is to be understood further that
`heterocyclic ring may be bonded or otherwise attached to a
`
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`9
`designated substrate, including compound (I), through dif-
`fering ring atoms without denoting a specific point of
`attachment, then all possible points are intended, whether
`through a carbon atom or a trivalent nitrogen atom.
`lior
`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 “treatment” as employed herein
`are meant
`to embrace prophylactic as well as disease-
`remitive treatment.
`
`invention further provides pharmaceutical
`The instant
`compositions suitable for the treatment of conditions includ-
`ing 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, pharmaoeutically
`acceptable salts and hydrates thereof, in combinat ion with a
`pharmaceutically acceptable carrier or diluent.
`The compounds of the instant
`invention inhibit or
`decrease Apo B secretion, likely by the inhibition of lVI'I'l-’,
`although it may be possible that additional mechanisms are
`involved. The compounds are useful in treating any of the
`disease states or conditions in which Apo B, serum
`cholesterol, andfor
`triglyceride levels are elevated.
`Accordingly, the instant
`invention provides a method for
`inhibiting or decreasing Ape B secretion in a mammal in
`need thereof which comprises the administration of an Apo
`B secretion inhibiting or decreasing amount of a compound
`of formula (I) or a stereoisomer, pharmaceutically accept-
`able salt or hydrate thereof. The invention further provides
`a method of
`treating a condition selected from
`atherosclerosis, pancreatitis, obesity, hypercholesterolemia,
`hypertriglyceridemia, hyperlipidemia, and diabetes which
`comprises administering to a mammal, especially a human,
`in need of such treatment a therapeutically effective amount
`of compound (I) or a stereoisomcr, pharmaceutically accept-
`able salt or hydrate thereof. A preferred subgroup of the
`conditions described hereinabove is atherosclerosis, obesity,
`hypercholesterolemia, hypertriglyceridemia,
`hyperlipidemia, and diabetes.
`The compounds of this invention may be used in con-
`junction with other pharmaceutical agents, including other
`lipid lowering agents. Such agents include, for example,
`cholesterol biosynthesis inhibitors and cholesterol absorp-
`tion inhibitors, especially IIMG-(To/\ reductase inhibitors
`and HMG—CoA synthase inhibitors; HMG—CoA reductase
`gene expression inhibitors; Cl.-"l'P inhibitors; bile acid
`sequestrants;
`librates; cholesterol absorption inhibitors;
`ACAT inhibitors, squalene synthetase 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 mam-
`mals {e.g. humans) by conventional methods.
`Specific cholesterol absorption inhibitors and cholesterol
`biosynthesis inhibitors are described in detail hereinbelow.
`Additional cholesterol absorption inhibitors are known to
`those skilled in the art and are described, for example, in
`I-’(I'l' W0 94,r'[l0480.
`Any HMG—CoA reductase inhibitor may be employed as
`the second compound in the combination therapy aspect of
`the instant invention. The term HMG—CoA reductase inhibi-
`
`tor refers to a compound which inhibits the biotransforma—
`tion of hydroxymethylglutaryl—eoenzyme 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
`
`10
`therein). A variety of these compounds are described and
`referenced hereinbelow. U.S. Pat. No. 4,231,938 (the dis-
`closure of which is hereby incorporated by reference) dis-
`closes certain compounds isolated after cultivation of a
`microorganism belonging to the genus Aspergillus, such as
`lovastatin. Also, U.S. Pat. No. 4,444,784 (the disclosure of
`which is hereby incorporated by reference) discloses syn-
`thetic derivatives of the aforementioned compounds, such as
`simvastatin. Additionally, U.S. Pat. No. 4,739,073 (the dis-
`closure of which is hereby incorporated by reference) dis-
`closes certain substituted indoles, such as Iluvastatin.
`Further, US. Pat. No. 4,346,227 (the disclosure of which is
`hereby incorporated by reference) discloses MI.-23613
`derivatives, such as pravastatin. In addition, EP 491,226
`teaches certain pyridyldihydroxyheptenoic acids, such as
`rivastatin. Also, US. Pat. No. 4,647,576 (the disclosure of
`which is hereby incorporated by reference) discloses certain
`6-[2-(substituted-pyrrol-1-yl)alkyl]-pyran-2ones 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 compound in the combination therapy aspect of this
`invention. The term IIMG-(Io/\ synthase inhibitor refers to
`a compound which inhibits the biosynthesis of
`hydroxymethylglutaryl—coenzyme A from acetyl—coenzyme
`A and acetoacetyl-coenzyme A, catalyzed by the enzyme
`HMG—CoA synthase. Such inhibition may be determined
`readily by one of skill in the art according to standard assays
`(e.g., Methods of Enzymology, 1975; 35: 155-160 and
`Methods of I_in7.yrnology, 1985; 110: 19-26 and the refer-
`ences cited therein). A variety of these compounds are
`described and referenced hereinbelow. US. Pat. No. 5,120,
`729 (the disclosure of which is hereby incorporated by
`reference) discloses certain beta—lactam derivatives. US.
`Pat. No. 5,064,856 (the disclosure of which is hereby
`incorporated by reference) discloses certain spiro—lactone
`derivatives perpared by culturing the microorganism
`MF5253. U.S. Pat. No. 4,847,271 (the disclosure of which
`is hereby incorporated by reference) discloses certain oXet—
`ane compounds such as
`ll-(Shydroxymethyl-4-oxo-2-
`oxetayl)—3,5,7—trimethyl—2,4—undeeadienoic acid derivatives.
`Other IIMG-(Io/\ synthase 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 IIM(i-(IoA reductase transcription inhibitors that
`block the transcription of DNA or translation inhibitors that
`prevent translation of mRNA coding for HMG—CoA reduc-
`tase into protein. Such inhibitors may either affect transcrip-
`tion or translation directly, or may be biotransformed into
`compounds that have the aforementioned attributes by one
`or more enzymes in the cholesterol biosynthetic cascade or
`may lead to the accumulation of an isoprcne metabolite that
`has the aforementioned activities. Such regulation is readily
`determined by those skilled in the art according to standard
`assays (Methods of Enzyrnology, 1985; 110: 9-19). Several
`such compounds are described and referenced below how-
`ever other inhibitors of HMG—CoA reductase gene expres-
`sion will be known to those skilled in the art US. Pat. No.
`
`5,041,432 (the disclosure of which is incorporated herein by
`reference) discloses certain 15—substituted lanosterol deriva-
`tives. Other oxygenated sterois that suppress the biosynthe-
`sis of HMG—CoA reductase are discussed by El. Mercer
`(Prog. Up. Res., 1993; 32: 357-416).
`Any compound having activity as a CETP inhibitor can
`serve as the second compound in the combination therapy
`
`6 of 37
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`11
`aspect of the instant invention. The term (fI_‘"l'l-’ inhibitor
`refers to compounds which inhibit
`the cholesteryl ester
`transfer protein (CI.-'TP) mediated transport of various cho-
`lesteryl esters and triglycerides from high density lipopro-
`tein (I[[)l.) to low density lipoprotein ([.l)[.) and very low
`density li protein (VI .[)I.). A variety of these compounds are
`described and referenced hereinbelow however other CETP
`inhibitors will be known to those skilled in the art U.S. Pat.
`
`No. 5,512,548 (the disclosure of which is incorporated
`herein by reference) discloses certain polypeptide deriva-
`tives having activity as Cl_i'I"l’
`inhibitors, while certain
`CETP-inhibitory rosenonolactone derivatives and
`phosphate-containing analogs of cholesteryl ester are dis-
`closed in J. Antibiot., 1996; 49(8): 815-816, and Bioorg.
`Med. Chem. I.ett; 1996; 6: 1951-1954, respectively.
`Any ACAT inhibitor can serve as the second compound in
`the combination therapy aspect of this invention. The term
`AC/\'I'
`inhibitor refers to compounds which inhibit
`the
`intracellular esterification of dietary cholesterol by the
`enzyme acyl (To/\:cholesterol acyltransferase. Such inhibi-
`tion may be determined readily by one of skill in the art
`according to standard assays, such as the method of Heider
`et al. described in Journal of Lipid Research., 1983; 24:
`1127. A variety of these compounds are described and
`referenced hereinbelow however other ACAT inhibitors will
`be known to those skilled in the art. U.S. Pat. No. 5,510,379
`(the disclosure of which is incorporated by