l||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
`
`US(}(l6245775Bl
`
`(12; United States Patent
`Miiller et al.
`
`(HI) Patent No.:
`(45) Date of Patent:
`
`US 6,245,775 B1
`*.]un. 12, 2001
`
`(54) CY(.'l.()Al,KANU-[N[)()l.l*LAND
`-AZ/\ll'N'I)()l.E I)l‘lRlV/\'["[Vl‘lS
`
`(75)
`
`Inventors: Ulrich Miiller. Wuppertal (DE);
`Richard Connell, Trumbull, CT (US);
`Siegfried Goldman n, Wuppe rtal; Rudi
`Griitzmtann, Solingen, both of (DE);
`Martin Beuck, Nilford, Cl‘ (US);
`Hilmar liisehotf; Dirk I);-nzer, both 0|‘
`Wuppertal (DI.-'); Anke Domdey-Bette,
`Hiickeswageit (DE); Stefan Wolllfi.-II,
`[Iildcn (DE)
`
`('33) Assignee: Bayer Aktiengesellsehaft, lieverku:-zen
`(DE)
`
`( *) Notice:
`
`issued on a continued pros-
`This patent
`ecution application filed under 37 CFR
`l.53{d), and is subject to the twenty year
`patent
`term provisions of 35 U_S_C'_
`154(a](3).
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.(.‘..
`l54{b) by U days.
`
`(21) App]. No.: 08/887,781
`
`(22)
`
`Filed:
`
`Jul. 3, 1997
`
`(52) U.S. LII.
`
`.......................... .. 514E292; 514E411; 546,-'86;
`546387; 548,’444
`(58) Field of Search ...................... .. 546,’86, 87; 5147292,
`514541 1; 5483444
`
`(55)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`514t’4|1
`lx'lf)T2 Mature-r et al.
`?t_.(:32,8i'J'i'
`546,84-5
`l[.|,"l988 (iillard et al.
`-1-,T»'5,(18[i
`514g'40iJ
`5,r'l996 Muller el :11.
`5,521,206
`514E292
`5.684.014 * 11,-‘L907 Muller cl (:1.
`514,394
`5_.Ta' _.964
`7fl‘)‘)8 Muller el :11.
`....................... 544E252
`5,952,498
`W199?!
`[_¢-nfers. at al.
`EORl:'.IGN PAl‘l:'N'l' DOCUMl:LN'I‘S
`
`
`
`..
`
`0 234 K18 A1
`0 300 676 A2
`o 310 17:: A2
`0 513 533 A2
`0 496 237 A2
`0 509 359
`0 0'1? 035 At
`
`(I-LP) .
`W198?
`H1989 (EP) .
`4..-'iosc:
`(EP) .
`#1992 (EP)
`7.-‘L902
`(E-1") .
`l0x'l 992 (EP) .
`9_»'t9C;'4
`(EP) .
`0'l‘IIlLR PUBLlCA'.[‘IONS
`
`................................... .. 51471100
`
`Heteroeycles, vol. 22, No. "Ill, 1984 (pp. 2277—22'/'9).
`
`"‘ ciletl by examiner
`1’rr'm(n'_v Exm:iiner—Alan L. Rotman
`(74) Aftr)rm3 , Agent, or
`I-'irm—Norris McI_au_ghlin 8:
`Marcus
`
`Related U.S. Application Data
`
`(5?)
`
`ABS'l'RAC'l'
`
`(52) Division of application No. L|2$;’535_.f)$}8_. filed on Sep. 28,
`1995, new Pat. No. 5,68-1__tJ14.
`
`Foreign Application Priority Data
`(30)
`Oct. 4, 1994
`(D1-;)
`.............................................. .. 44 35 477
`
`(51)
`
`Int. Cl." .................... ,. A61K 311437; A61K 3171103;
`(I171) 4717114; (I17!) ’2(J9;‘82
`
`(.‘yeJoakano—indole and —azttind0le derivatives are prepared
`by re-m:tiun of appropriately :-sultrstituted carbonylic acids
`with amines. 'l'he tzyelualkanwindole and —azainLlole deriva-
`lives are .-zuituhle as active compounds for metlieanmentss,
`preferably antialheroselerotie medieamenls.
`
`8 Claims, No Drawings
`
`1of71
`
`PENN EX. 2222
`
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`US 6,245 ,775 B1
`
`1
`CYCLOAI.-KAN()-[l\I)()l.E ANI)
`-AZAINDOLE DERIVATIVES
`
`S
`
`10
`
`15
`
`This is a division of application Ser. No. [l8t'535,698_,
`filed on Sep. 28, 1995, now U.S. Pat. No. 5,t'184,(]l4.
`The present invention relates to cyeloalkano—indole and
`—azaindole derivatives, processes for their preparation and
`their use as medicamcnts, in particular as antiatherosclerotie
`medicaments.
`
`It is known that increased blood levels of triglycerides
`(hypertriglyceridaemia)
`and
`cholesterol
`(hype-rcholesterolaemia) are associated with the genesis of
`atheroselerotic vessel wall changes and coronary heart dis-
`eases.
`
`A distinctly increased risk of the development of coro-
`nary heart disease is moreover present
`if these two risk
`factors occur in combination, which is accompanied, in turn,
`with an overproduction of apolipoprotein B—lU0. There is
`therefore, as before, a great need to make available effective
`medicaments for the control of atherosclerosis and coronary
`heart diseases.
`The present invention relates to cyeloal.kano—indole and
`-azaindole derivatives of the general formula (I):
`
`R1
`
`(1)
`
`5
`
`R3
`
`R‘
`
`CH1
`
`2
`I. represents an oxygen or sulphur atom or a group of the
`formula —NR°,
`wherein
`
`R9 denotes hydrogen or straighl—chain or branched
`alkyl having up to 6 carbon atoms, which is option-
`ally substituted by hydroxyl or phenyl,
`R5 represents phenyl or a 5- to 7—membered saturated or
`unsaturated heteroeycle having up to 3 heteroatoms
`from the series consisting of S, N andfor U, the cycles
`optionally being substituted up to 3 times by identical
`or different nitro, carboxy], halogen or cyano substitu-
`enls or by sIraig|1t—eltain or branched alkenyl or a|koxy—
`carbonyl each having up to 6 carbon atoms or by
`straight—chain or branched alkyl having up to (1 carbon
`atoms, which is optionally substituted by hydroxyl,
`carboxyl or by straight—chain or braiiclred alkoxy or
`alkoxycarbonyl each having up to 6 carbon atoms,
`andfor the cycles optionally being substituted by a
`group of the formula —URm or —NR“R”,
`wherein
`
`R10 denotes hydrogen or straight—chain or branched
`alkyl or al.keny] each having up to 6 carbon atoms,
`R“ and R12 are identical or different and denote
`phenyl, hydrogen or straight—ehain or branched
`alkyl having up to 6 carbon atoms or straight-
`chain or hranelied aeyl having up to 8 carbon
`atoms, which is optionally substituted by a group
`of the formula —NR13RJ‘l,
`wherein
`R” and R” are identical or different and denote
`hydrogen or straight-chain or branched acyl
`having up to 8 carbon atoms,
`represents hydrogen, carboxy] or straight—chain or
`branched alkoxycarbonyl having up to 5 carbon atoms,
`or representsstraightchain or branched alkyl having up
`to 6 carbon atoms, which is optionally substituted by
`hydroxyl or by a group of the formula —O—CO—R15,
`wherein
`
`R” denotes phenyl which is optionally substituted up
`to 3 times by identical or different halogen or
`llydroxyl subslituettts or by s1raiglIt—chain or
`branched alkyl having up to 5 carbon atoms, or
`slraigh1—eliain or branched alkyl or alkenyl each
`having up to 32 carbon atoms, each of which is
`optionally substituted by a group of the formula
`—oR“',
`wherein
`
`R1“ is hydrogen, benzyl, triphenylmelhyl or straight-
`chairi or branched aeyl having up to 6 carbon
`atoms,
`
`R
`:18
`
`
`
`|,_lA\R6{ -2' - R?
`
`
`
`I)
`
`i
`
`R“
`
`in which
`
`R1 and R2, including the double bond connecting them,
`together lorm a phenyl or pyridyl ring or a ring of the
`Formula
`
`wherein
`
`R” denotes hydrogen or straight-chain or branched
`alkyl having up to 4 carbon atoms,
`R3 and R4, including the double bond connecting them,
`together form a phenyl ring or a 4- to 3-memlrered
`cyeloalkene or oxocycloalkene radical,
`all ring systems mentioned under RIIR3 and Rail?‘
`optionally being substituted up to 3 times by iden-
`tical or dilferent halogen, trifluoromethyl, earboxyl
`or hydroxyl substituents, by straight-chain or
`branched alkoxy or alkoxycarbonyl each having up
`to 6 earbon atoms or by straight—chain or branched
`alkyl having up to 6 carbon atoms, which, for its part,
`can be substituted by hydroxyl or by straight-chain
`or branched alkoxy having up to 4 carbon atoms,
`D represents hydrogen, cyeloalkyl having 4 to 12 carbon
`atoms or str:tigl:tl—chain or branched alkyl having up to
`12 carbon atoms,
`13 represents the —CO— or —CS— group,
`
`40
`
`4-5
`
`50
`
`bf‘!
`
`R7 represents hydrogen or
`R5 and R7 together represent the group of the formula
`=0,
`if appropriate in an isomeric form, and their salts.
`The cycloalkano—indole and —azaindole derivatives
`according to the invention can also be present in the form of
`their salts. In general, salts with organic or inorganic bases
`or acids may be mentioned here.
`In the context of the present invention, physiologically
`acceptable salts are preferred. Physiologieally acceptable
`salts of the compounds according to the invention can be
`salts of the substances according to the invent.ion with
`mineral acids, earboxylie acids or sulphonic acids. Particu-
`larly preferred salts are, for example, those with hydrochlo-
`ric acid, hydrobromic acid, sulphuric acid, phosphoric acid,
`methanesulphonic acid, ethanesulphonie acid,
`to1tJenes1Il—
`
`20f71
`
`PENN EX. 2222
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`US 6,245 ,775 B1
`
`3
`phonic acid, benzenesulphonic acid, naphthalenedisu|—
`phonie acid, acetic acid, propionic acid, lactic acid, tartaric
`acid, citric acid, fumaric acid, malcic acid or henzoie acid.
`Physiologieally acceptable salts can also be metal or
`ammonium salts of the compounds according, to the inven-
`tion which have a free carboxyl group. Particularly preferred
`salts are, for example, sodium, potassium, magnesium or
`calcium salts, and also ammonium salts which are derived
`from ammonia, or organic amines, such as, for example
`cthylamine, di- or
`triethylamine, di- or
`trichanolamine,
`dicyclohexylamine, dimethylaminoethanol, arginine, lysine,
`ethylenediamine or 2—phenylethylamine.
`the
`luelutliug,
`the double bond of patient structure,
`cycloaikene radical (R3;‘R‘l) in the context ofthe invention in
`general represents a 4- to 8—membered hydrocarbon radical,
`preferably a 5- to 8-membered hydrocarbon radical, for
`example a eyclobutene, cyclopentene, cyclohexene, cyclo-
`heptene or cyclooctene radical. The cyelopentene,
`cyclolrexene, cyclooctene or cycloheplene radicals are pre-
`Ierred.
`
`lleterocyele (R5) in tlte context of the invention in general
`represents a saturated or unsaturated 5-
`to 7—mcmbcred
`heterocycle, preferably a 5- to O—mct11bere(l hcteroeyele,
`which can contain up to 3 hcteroatoms from the series
`consisting of S, N andfor 0. Examples which may be
`mentioned are: pyridyl, thienyl, fury], pyrrolyl, thiamlyl,
`oxazolyl, imidazolyl, morpholinyl or piperidyl. Pyridyl and
`thienyl are preferred.
`The compounds according to the invention can exist in
`stereoisomeric forms which either behave as image and
`mirror image (e nantiomers], or do which do not behave as
`image and mirror
`image (diastereome rs). The invention
`relates both to the enantiomers and diastereomers and their
`respective mixtures. These mixtures of the enantiomers and
`diastereomers can be separated in a known manner into the
`stereoisomerically uniform constituents.
`Preferred compounds of the general formula (I) are those
`in which
`
`10
`
`15
`
`‘
`
`30
`
`R1 and R2, including the double bond connecting lltem,
`together Form a phenyl or pyridyl ring or a ring of the
`formula
`
`40
`
`NR9,
`
`wherein
`
`R“ denotes hydrogen or straight-chain or branched
`alkyl having up to 3 carbon atoms,
`R3 and R4, including the double bond connecting them,
`together
`form a phcnyl
`ring or a eyclopentcne,
`eyclohexene, cyeloheptene, cyelooetene,
`oxocyclopcntene, oxocyclohexene, oxoeycloheptene or
`oxoeyclooetene radical,
`all ring systems mentioned under RWR2 and I13/"R"
`optionally being substituted up t.o 2 times by iden-
`tical or different
`fluorine, chlorine, bromine,
`trilluoromethyl, carboxyl or hydroxyl substituents,
`by straight—ehain or branched alkoxy or alkoxycar—
`bonyl each having 11p
`to 4 carbon atoms or by
`straight—chain or branched alkyl having up to 4
`carbon atoms, which, in turn, can be substituted by
`hydroxyl or by straight—chain or branched alkoxy
`having up to 3 carbon atoms.
`
`4-5
`
`50
`
`55
`
`E1?!
`
`4
`D represents hydrogen, cyclobutyl, cyclopentyl,
`eyelohexyl, eycloheptyl, eyclooetyl or straight—chain or
`branched alkyl having up to 10 carbon atoms,
`E represents the —CO— or —CS— group,
`I. represents an oxygen or sulphur atom or represenLs a
`group of the formula —NR'°,
`wherein
`
`R” denotes hydrogen or straight-chain or branched
`alkyl having up to 5 carbon atoms, which is option-
`ally substituted by hydroxyl or phenyl,
`R5 represents phenyl, pyridyl, furyl, thienyl or imidazolyl,
`each oliwhich is optionally substituted up to 2 times by
`identical or dillerent nitro, carboxyl, iluorine, chlorine,
`bromine or cyano substituents, by straight-chain or
`branched aikenyl or alkoxy carbonyl each having up to
`4 carbon atoms or by straight-chain or branched alkyl
`having up to 5 carbon atoms, which is optionally
`su bstitutcd by hydroxyl, carboxyl or by straight—chain
`or branched alkoxy or alkoxycarbonyl each having up
`to 5 carbon atoms, andfor the cycles are optionally
`substituted by a group of the formula —OR‘" or
`:NRl1R13’
`wherein
`
`R” denotes hydrogen or straight—chain or branched
`alkyl or alkenyl each having up to 4 carbon atoms,
`R” and R13 are identical or diflerent and denote
`phenyl, hydrogen or straight-chain or branched alkyl
`having up to 5 carbon atoms
`or denote straight-chain or branched acyl having up
`to 6 carbon atoms, which is optionally substituted
`by a group of the formula —NR‘3R”,
`wherein
`R” and R” are identical or different and denote
`hydrogen or straight-chain or branched acyl
`having up to 6 carbon atoms,
`R° represents hydrogen, carboxyl or straight—chain or
`branched alkoxycarbonyl having up to 4 carbon atoms,
`or represents straight—chain or branched alkyl having up
`to 5 carbon atoms, which is optionally substituted by
`hytslroxyl or by a group of the formula —O—(.‘ —
`R .
`wherein
`
`R15 denotes phenyl which is optionally substituted
`up to 3 times by identical or different fluorine,
`chlorine, bromine or hydroxyl suhstituents or by
`straight-chain or branched alkyl having up to 4
`carbon atoms, or straight-chain or branched alkyl
`or allienyl each having up to 20 carbon atoms,
`each ofwhich is optionally substituted by a group
`of the formula —OR1°,
`wherein
`
`R” is hydrogen, benzyl, triphenylmethyl or
`straight—ehain or branched acyl having up to 5
`carbon atoms,
`R7 represents hydrogen or
`R5 and R7 together represent the group of the formula
`=o,
`
`if appropriate in an isomeric form, and their salts.
`Particularly preferred compounds of the general formula
`(I) are those
`in which
`
`I{‘ and R2, including the double bond connecting them,
`together form a phenyl or pyridyl ring or a ring of the
`formula
`
`30f71
`
`PENN EX. 2222
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`US 6,245 ,775 B1
`
`5
`
`xi<9
`
`i
`
`U
`
`w L'I(.'-ll'I
`h
`_
`R3 denotes hydrogen or methyl,
`R" and R4, including the double bond connecting them,
`mgclhcr
`fmm 3 l"h‘3“)'1 ring 0‘ 3 CYC]0P'3"‘C“°a
`cyclohexene, cycloheptene, cyclooctene,
`oxoeyclopentene, oxoeyclohexenc, oxocycloheptene or
`UXWY‘5100‘v'“511° ”‘dl‘—'?11»
`311 ring 5Y5l'-‘m5 mcntmncd “Rd” Rims and Rzmq
`optionally being substituted up to 2 times by iden-
`
`6
`or represents straight—chain or branched alkyl having up
`to 4carbon atoms, which is optionally substituted, by
`Iiydroxyl or by a group of the formula —O—CO—
`R”,
`wherein
`R15 denotes phenyl which is optionally substituted
`up to 3 times by identical or different straight-
`
`chain or branched alkyl having up to 3 carbon
`a([:n::nm,
`v
`v
`es straight-chain or branched alkyl or
`alkeny] each having up [Q 19 carbon atoms,
`each of which is optionally substituted by a
`g[[}upDfLhc, [Urmu1a_()R”’,
`wherein
`R” denotes hydrogen, benzyl, triphcnylmethyl or
`straight-chain or branched acyl having up to 4
`carbon atoms,
`
`5
`
`10
`
`q
`‘-
`
`In
`
`30
`
`35
`
`R7 rwrcsunls hydmgcn m.
`R5 and R7 mmlhcr rcpmqcm the group of the formula
`=0
`3’
`‘
`
`’
`if appmprialc in 3“ lmmcfic fmmo and lhclr “[151
`A process for the preparation of the compounds of the
`general formula (I) according to the invention has addition-
`ally been found, characterized in that carboxylic acids ofthe
`gcncml rm'T"-"3 (")1
`
`R3
`i
`
`Rt
`
`_{1
`'
`
`l
`
`l
`
`N
`
`33 j
`
`ml
`
`fluorine, chlorine, bromine,
`tical or different
`trifiuoromethyl, carboxyl or hydroxyl substituents,
`by straight—ehain or branched alkoxy or alkoxycar—
`bonyl each having up to 3 carbon atoms or by
`straight-chain or branched alkyl having up to 3
`Carbon atoms, Which, for its part, can be Substituted 35
`by hydroxyl, methoxy or ethoxy,
`D mp,-csnms hydrogen, cyclopnmyl’ cyclohcxyl’
`eyclolieptyl, cyclooctyl or straight-chain or branched
`allay] having up to 6 carbon atoms,
`]_i represents the —C0— or —CS— group,
`L represents an oxygen or sulphur atom or represents a
`group of the formula —NR",
`wherein
`R9 denotes hydrogen or straight—chain or branched
`alkyl having up to 4 carbon atoms, which is option-
`ally substituted by hydroxyl or phenyl,
`R5 represents phenyl, pyridyl or thienyl, each of which is
`optionally substituted up to 2 times by identical or 40
`,
`,
`dilferenl nitro, carboxyl, Iluorine, chlorine, bromine or
`"1 WI-"ch
`cyano substituents, by straight-chain or branched alk-
`R1’ R3’ R3’ R4 and D have the meaning indicated,
`enyl or alkoxycarbonyl each having up to 3 carbon
`alums or by Stralghbchiun (ir bmlmhcd alkyl llavmg up 45 are armidated using compounds of the general formula (III):
`to 4 carbon atoms. which is optionally substituted by
`
`( “J
`
`F02”.
`
`\ I
`Y
`I)
`
`50
`
`hydroxyl, carboxyl or by straight—chain or branched
`alkoxy or alkoxycarbonyl each having up to 4 carbon
`atoms, aiidfor the cycles are optionally substituted by a
`group of the formula —OR‘° or —NR“R”,
`wherein
`Rm denotes hydrogen or straight-chain or branched
`alkyl or afkenyl each having up to 3 carbon atoms,
`R“ and R‘: are identical or different and denote 55
`phenyl, hydrogen or straight-cliain or branched alkyl
`having up to 4 carbon atoms
`or denote straight-chain or branched acyl having up
`to 5 carbon atoms, which is optionally substituted
`by a group of the formula —NR13R“',
`wherein
`R13 and RV‘ are identical or differelit and denote
`hydrogen or snnigt-n_(_-nnin nr brnnchnd any]
`having up to 5 carbon atoms,
`R5 represents hydrogen, carboxyl or straight—chain or
`braiiclied alkoxycarboiiyl having, up to 3 carbon atoms,
`
`(HI)
`
`R5
`
`17
`R '
`
`H»
`
`in which
`_
`,
`_
`‘
`R" has the mcanmg lndlcalcd
`€il'I(l
`R” has thc jndicatcd meaning of R“, but docs nm
`rt;-,p1'es,e[1|_ carboxyl,
`.
`_
`.
`.
`60 .
`in an inert solvent and in the presence ot bases andfor
`auxlhancb’
`functional groups are varied by
`and,
`if appropriate,
`M hydrolysis, esterilication or reduction.
`The process according to the invention can be illustrated
`by the following reaction scheme:
`
`4 of 71
`
`PENN EX. 2222
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`US 6,245 ,775 B1
`
`
`
`l )ich|ororn(:L|1an::,."tricLh 3-'|an1inc ,
`1-l1_\.':J roxy-1H-hen;-uLriazo|e and
`N '—(3 —;J i m elh ylani inop rr3py'l)-
`NQH N-clhylearhridiimidc ||_\'(i1'[)Cl'IIOI'iU{J
`
`I-I2N
`
`00321
`
`
`
`Scparlion of
`dirnslcreomcrri
`
`
`
`
`
`
`
`i
`tI:~—t\'rr/\\/
`
`on
`
`5
`c?o—.\n1/\\/
`
`OH
`
`Snitahle solvents for the amidation are in this case inert 50 or potassiumcarbonat.e,alkaline earth metal carbonates such
`organic 501V3fllS Which (10 I101 change Ufldfif U16 l’€iiCli0l'l
`as calcium earhunalc, or alkali metal all-(oxides such as
`C0Y1djli0I1S- Th¢S¢ incl‘-ldf Cthfiffi. 511911 35 dieihl-"1 311137 01'
`sodium or pola.-;s-;ium rnethoxide, sodiunr or prilassiurn
`”_’”“-"d“’f"“" ha,l“g"’“°h5’dr°““bL‘“5 '‘5'"‘‘h
`"5
`elhoxide or potassium tert-butoxide, or organic arnities
`diehloromethane,
`tnchloromethanc,
`tetrachloromelhanc,
`(1fia]k),l(C1_cfi)1_lmiDeS) Such as 1rieIh),11_lmine1 or hc1em_
`rricioroerane,
`rerrachloroerhane, 1,2-dichloroethane or
`55 cycles Such as 114_diazabjcyC10[2_2_2]0clam (DABCOL
`triehlorocthylene, hydrocarbons such as licnzene, xylene,
`] 8_di117ahic C10“ 4 0]undcC_7_cm=1 (DBU)
`ridine
`’
`tolnene, hexane, cyclohexane or petroleum fractions,
`?
`.
`'
`.3
`" '
`.
`.
`.
`.‘ py .
`.
`1h
`_
`1].
`1h 11.
`.
`_
`_1
`_
`__
`.
`.
`1
`rlramrnopynrrrie,rnelhylpiperrdrne or morpho11ne.II1s also
`l'1]l.]'0I‘l'1(.l.
`21I'](.,
`rmel y ormamrde,
`:1:.r,tonr., ar.r.1onilnlr. or
`11,“
`_]k_].
`1111 1
`1 d m .
`l
`I
`1h 1
`_
`_ d.
`hexamelhylphosphoramide.
`is also possible lo employ
`pm“. a 0 cmpoy d .dl ms dl’5uL ‘is’ so m.m ln
`6”
`II
`.
`.
`.
`hydrides such as 50Cil‘|.lI'1’1 hvdrtde as bases. Sodium and
`mixtures of the solvents. Drchloromcthane, tclraydrollrran 60
`.
`.
`‘
`.
`1
`.
`1
`1
`.
`_
`1
`.
`_
`p(.llil.‘§.‘~i]LlI'l'I carbonate and lriethylamrne are preferred.
`aeelone and cl1n1elh}l.forrnarn1de are parlrullarly preferred.
`_
`_
`1
`Bases which can be employed for thc process according
`lthe base is erripluyed 11] an amount from 1 [1101 to 5 Irrul,
`to the invenlion are in general inorganic or organic bases.
`Preierably [mm 1 T1791 10 3 “Wis T"'l~‘-l1""=" W 1 mo] of "73
`These preferably include alkali metal hydroxides such as, for
`'~"J”1l-l‘-Wild Ur lb“ ‘=’.‘511'-W1] {UT1111113‘ (I1).
`example, Soclillm hydroxide or potassilrm hydroxide, alka— III‘!
`The reacliori
`is in general carried mil in a lerriperature
`]ine earlh rnelal hydroxides, such as, for example, barium
`range from 0° C.
`to 150° (2., preferably from +2U° C. to
`hydroxide, alkali metal earhonatesr-‘.11ch as Rn(‘li‘|]I"l'I earhonate
`+11(J° C.
`
`5 of 71
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`PENN EX. 2222
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`US 6,245 ,775 B1
`
`S
`
`10
`
`own or
`
`10
`9
`The reaction can be carried out at normal, increased or
`ditions. These preferably include ethers such as dicthyl
`ether, dioxane, tetrahydrofuran, glycol dinietliyl ether, or
`reduced pressure (e.g. 0.5 to 5 bar). In general, the reaction
`hydrocarbons such as lieniene,
`toluene, xylene, hexane,
`is carried out at normal pressure.
`cyclohexanc or petroleum fractions, or halogenohydrocan
`The amidation can optionally proceed via the activated
`l‘J('I[‘I5 such as rlieliloromethane,
`triehloromethane,
`_
`‘
`stage of the acid halides, which can be prepared from the
`l"l”Ch"’”"melh3“*3s d1Ch]"T0C1hyl5“‘7_-
`lr1Ch1¢'{“‘31hYl"r{“=_ Ur
`crirresponding acids by reaction with Ihionyl chloride, phos—
`Clllorobcnzencv or ethyl, accl'al'°-_l'r1°l'h3"lamm°v pY“‘_7lmc’
`phorus trichloridc, phosphorus pentachloridc, phosphorus
`dime t h yl
`su l ph o X ide , di m e [h 1 form a rn id e ,
`mbmmidc or Uxalyl Chlmidu
`hcxamethylphosphoramide, acetonitrile,‘ acetone or
`Th‘: above memioned bases can Oplionauy also bc
`nitromethane.
`It is also possible to use mixtures of the
`,
`.
`,
`.
`_
`_
`‘
`_.
`.
`.
`_
`.
`_
`.
`.
`.
`.
`employed for the dmlddllutl as d(.lCl-l)t.t1Clll'lg auxiliaries.
`solvents mentioned Dimethylformamide and tetrahydrol'u—
`,
`.
`.
`.
`.
`.
`..
`,
`_
`-
`ésuitahle al1XlilE1t'1CS are also dehydrating reagents.
`lhcse
`ran are prelerred.
`.
`..
`.
`_
`_
`_
`The bases employed for the process aceordinn to the
`m°lud°’
`rm uxampl“ “”lmd”m'd°” “ch M‘
`-
`-
`..
`v
`-
`.
`-.
`~.
`.
`.3.
`.
`diiso )l'0
`lcarbodiimide die clohex lcarbodiimide and
`mwinuon “in m general morgmm or oigamt bdwbi Thflw
`N—['%ELliiiiLft.hyl'1Iiiiiiopr0l:iyl)—l\il—etliylciirbodiimide
`livdro—
`prclerably include alkali metal hydroxides,
`for example,
`*
`_
`‘
`._~ I
`l5 sodium hydroxide or potassium hydroxide, alkaline earth
`Chlorldc 01' °3Tl‘0{‘}’l ‘30mP0‘-md5 such 35 C3"b0"l'ld'"“'d3'
`meta] hydwxi(1¢_.,-’ for example’ barium hydroxide’ alkali
`zole or 1,2—oxazol1uni compounds such as 2—ctliyl—5—plienyl—
`metal carbonates such as sodium carbonate or potassium
`173"’X37"lium'3'5“ll’h““a1"’ 0’ P”’Pa“5PhU5Ph""l‘-'
`carbonate, alkaline earth metal carbonates, such as calcium
`aiiliydride or iso-butyl cliloroformate or beii2otria2oIyloxy-
`carbonate, or alkali metal alkoxides such as sodium or
`tris-(dimethylamino)phosphonjum hexafluorophosphate or
`diplieiiylpliosplioraiiiidate or methaiiesulplionylcliloride,if 20 potassium metlioxide, sodium or potassiuni etlioxide or
`appropriate in the presence of bases such as triethylamine or
`potassium tert-butoxide, or organic amines (trialkyl(C,—C6)
`N—etliy1niorplioline or N—metliylpiperidine or (JlC}'Cl0l'lCX)r’l—
`aiiiiiics) such as trietliylaininc, or heierocycles such as
`carbodiimide and N-hydroxysuccinimide.
`1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo
`The acid-binding agents and dehydrating reagents are in
`[5.4.0]undec-7-ene (DBU), pyridine, diaminopyridine,
`generalcmployed in an amount from (1.5 to3moI,prefera|ily '15 methylpipcridine or morpholine.
`It
`is also possible to
`from '1
`to 1.5 mol, relative to 1 mol of the corresponding
`employ alkali metals such as sodium or their hydrides sueli
`carboxylic acids.
`as sodium hydride as bases. Sodium hydride, potassium
`for example
`The variation of functional groups,
`carbonate,
`triethylamine, pyridine and potassium tert-
`hydrolysis, esteritication and reduction, and also separation
`butoxitle, DBU or DABCO are preferred.
`of isomers and salt formation is carried out by customary 30
`In general, the base is employed in an amount from 0.05
`methods.
`mol to 10 mo], preferably from 1 mol to 2 mol, relative to
`The earboxylic acids of the general formula (II) are new
`1 mo] of the compound of the formula (IV).
`and can be prepared by reacting compounds of the general
`The process according to the invention is in general
`formula (IV):
`carried out in a temperature range from -30° (T. to +lU(l° C,
`35 preferably from —lU° C. to +t'JU° C.
`The process according to the invention is in general
`carried out at normal pressure. However, it is also possible
`to carry out the process at elevated pressure or at reduced
`pressure (e.g. in a range from 0.5 to 5 bar).
`The compounds of the general formula (III) are known
`per se.
`The compounds ofthe general formula (IV) are known or
`L‘2t]ZI1l]Jt‘: prepared in afna]-llogy to kppwn |'lilC|.(l‘l0;lS.
`km
`'1 e £:0Il'.I“(Jl.l]2I(S o 1 e genera
`ormu a V are
`45 can be prepared in analogy to known methods.
`The compounds of the general formula (I) according to
`the invention have an unforeseeahle spectrum of pharma-
`cological action.
`They can be used as active compounds in medicaments
`so for the reduction of changes to vessel walls and for the
`treatment of coronary heart disorders, cardiac insu ilicieney,
`brain power disorders, ischaernic brain disorders, apoplexy,
`circulatory disorders, disorders of the microcirculation and
`thromboses.
`the proliferation of smooth muscle cells
`1-‘urthermore,
`plays a decisive part
`in the occlusion of vessels. The
`compounds according to the invention are suitable for
`inhibiting this proliferation and thus preventing atheroscle-
`rot ic processes.
`The compounds according to the invention are distin-
`gitishcd by a lowering ofthe Apol-l—1tl(J—associated lipnpro—
`reins (VLDL and its degradation products, e.g. LDL], of
`Apol-3-100, of triglycerides and of cholesterol.
`'|‘hcy thtis
`have useful, superior pharmacological properties in com-
`(:5 parison with the prior art.
`Surprisingly, the action of the compounds according to the
`invention consists first in a decrease or complete inhibition
`
`'i‘—i-13:‘
`
`l
`
`\\
`I
`/N/CO2R1”_.
`
`D
`
`(re;
`
`40
`
`in which
`D has 1116 meaning illdifi-1lt‘»d,
`for example
`'1‘ represents a typical
`leaving group,
`chlorine, bromine, iodine, tosylatc or mesylate, prefer-
`ably bromine,
`am]
`R13 rcpwscm,-, ((j1_[jA)a_[ky]‘
`will] Compounds of the gcncral [On-nula (V)
`
`Q,
`‘
`
`Ql
`
`R,
`‘
`
`1
`‘"
`
`|
`
`|
`
`H
`
`_
`(W 55
`
`so
`
`in which
`R1, R2, R3 and R" have the meaning indicated,
`in inert solvents, if appropriate in the presence of a base.
`Suitable solvents for
`the process are the customary
`organic solvents which do change under the reaction oon-
`
`6 of 71
`
`PENN EX. 2222
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`US 6,245 ,775 B1
`
`5
`
`55
`
`‘J
`F
`X" ' 0'
`2
`g
`'
`
`fin
`FD
`' ”"[m"' “]p'0'
`10-15
`5-5
`10-20
`
`12
`11
`Nembutal (50 rngfkg i.p.) after premeditation with atropine
`of the formation and/or the release of ApoB— l00—associatcd
`(83 nigkg s.c.). When the animals have become rellex—frce,
`lipoproteins-. from liver cells, which results in a town: ring, of
`the jugular vein is exposed and cannulated. (1.25 mlftcg of a
`the Vl.lJ[_ plasma level. This lowering of \J'I.Dl. must be
`2(}"}FJ strength solution of Triton WR-1339 in physiological
`accompanied by a lowering of the plasma level of ApoFt—
`saline solution is then administered. This detergent inhibits
`‘l[l(),
`l.l)[_., triglycerides and cholesterol; a number of the
`“"5 lllml-‘ml*71"'1 “P355 and "1115 ]"33d5 l“ 3 H53 in ll“: "it-'.lY‘-"
`above mentioned risk factors which are involved in vessel
`eride level as a result of a lack of catabolism of secreted
`Wat] Chzmgcs an, [hug _.,jmu]l,mcnu_.,1Y dnnrnasctt‘
`VI-DL l-"““i"'l°5- This ”i.’:'l}"-“id” “*5” 93” be “ed “-5 3
`The eompoutids aeeorditig to the invention can therefore
`"leisure of the VTDL Sccmtlon rate‘
`be employed for
`the prevention and treatment of
`10 mm“ is lam“ fmm ill“ animals l’°l°'° and 3'5“ 0"“ and
`atherosclerosis, obesity, pancreatitis and constipation.
`two hours after administration of the detergent by puncture
`1_ [nhininnn nf Inn Release nf AnnH_-[U0_An_,;nnin1cd [Jnn_
`ofthe retroorbilal venous plexus. The blood is incubated for
`nmlnins
`two hours at room temperature, and then overnight at 4° C.,
`Tnn “:51 for nntnnnng the Inhibninn nf Inn rnlnnnc nf
`in °"l"’r “J end ‘5_]0mhi3 ‘3°mPl°"3lyv ll l5 [hen ‘-‘‘=''“lT‘l[Ut§_‘'5d 3-‘
`ApoB—lO0—associated lipoprotcins from liver cells was car—
`ried out in vitro using cultured liver cells, preferably using 15 H1000 E. ["7 5 T"‘“”l‘5-"-Tl1°l”glYC°T1d° C““‘5“v“1T3-T10“ "1 ll“?
`95115 of 1]“; human tinn Hung; '1'[n_.nn nulls an; cnllurnd
`serum tliusobtained is determined with the aid ofa modified
`under standard conditions in medium for the culture of
`C‘“T'm‘7“-3l3ll}'
`'*“"3ll5lbl‘7 CHZYWC 1951 (M‘5l'Cl\'0l‘35l® lrigll"-3'
`eukaryotic cells. preferably in RPMI "[640 with 10% foetal
`‘ride N0’ 14:f’5‘i)- l00xr101‘S<=rUm ale "cited wllh loofll Ur
`calf gel-um_ Hang; cells synthesize and secrete J'_n[n the
`test reagent ]l't ‘)fi—_holc plates and incubated at room tem-
`culture supernatant ApoB—lU0—associated lipoprotein par— :0 pcmturc for '0 mmulcs‘ Thc optical dc“-‘ml’ if‘ then d‘3[°"'
`ticles which in principle are built up in a similar manner to
`milled 3‘ 3 Wavclcnglh of 493 "M in 3'1 automatic Flam‘
`the VLDL and LDL particles which are to be found in the
`reading “PP““““" {SIT ST’‘’‘’‘”‘)- S‘“'”"'' *"a"ll’l"-‘"’ haVl“S 3“
`nlanmn
`excessively high triglyceride concentration are diluted with
`These particles can be detected using an immunoassay for
`Physlfllfigkfal Salim 50l“1i0_n- The 1l'l$1Y‘3'3"i‘_l'3 C°nC°"_tr3ll0'1
`human I.|Jl_. This immunoassay is carried out using anti— “:5 comalncd '" the 53mP1'-"5 1:9 ‘3l'~'lCl'mm'3d ‘Vllh thc 31d 0f 3
`bodies which have been induced against human LDL in
`standard cl-“V9 mcasurcd 1" P31'3ll'31‘ 1“ ‘hi-5 model» 935‘
`rabbits under standard conditions. The anti-l_l')l_ antibodies
`5"b5“’'3'‘3‘i5 3” a‘lmim5l°'“3d i“”3"°"9“51Y cllh‘-‘I imm‘-‘d1"
`(rabbit anti-l_l')I. Ab) were purified by aflinity chromalog-
`alcly bcforc admlnlslrallon of ll“? dclcrgenl 0" many or
`raphy on an innnunnnnrbnnt using human LDL -1-nnnn
`subcutaneously before initiation of anaesthesia.
`purified rabbit anti-I.l)I. Ab are adsorbed on the surface of 30
`plastic. Expedientl_v,
`this adsorption is carried out on the
`plastic surface of rnicrotitre plates having 96 wells, prefer-
`ably on Maxisorp plates. If ApoB-100-associated particles
`are present in the supernatant of IIep(i2 cells, they can be
`bound to the insolubilized rabbit anti-LDL Ab, and an 35
`immune complex results which is bound to the plastic
`surface. Unbound proteins are removed by washing. The
`3. Inhibition of Intestinal Triglyceride Absorption in vivo
`immune complex located on the plastic surface is detected
`(rats)
`using monoclonal antibodies which have been induced
`The substances which are to be investigated for their
`against human LDL and purified according to standard 40
`triglyceride absorption-inhibiting action in vivo are admin-
`conditions. These antibodies were conjugated with the
`istered orally to male Wistar rats having a body weight of
`enzymc peroxidase. Peroxidase converts the colourless sub-
`between 170 and 230 g. For this purpose, the animals are
`strate TMB into a coloured product in the presence oflI302.
`divided into groups of 6 animals '18 hours before substance
`After acidification of the reaction mixture with IIQSOJ, the
`specific light absorption at 450 tun is determined, which is «is administration and food is then withdrawn from them.
`a measure of the amount of ApoB—1[lU—a:~sociated particles
`Drinking water is available to the animals ad libitum. The
`which have been secreted into the culture supernatant by the
`animals of the control groups receive an aqueous tragacanth
`lIepG2 cells.
`suspension or a tragacanth suspension which contains olive
`Surprisinyy, the compounds according to the invention
`oil.'t'he tragacan1h—olive oil suspension is prepared using an
`inhibit the release ofthc Apol-3-I00-associated particles.'lhe so Ultra—'l‘urrax. The substances to be investigated are sus-
`IC_,n value indicates at which substance concentration the
`pended in an appropriate l.l'd_‘._!,'cICaI'1lll-()li\«"t.’. oil sttspension
`light absorption is inhibited by 50"’/E in comparison with the
`likewise using the Ultra—'I"urrax, directly before substance
`control (solvent control without stlbstance).
`administration.
`To determine the basal serum triglyceride content, blood
`is taken from each rat by puncture of the retroorhital venous
`plexus before stomach tube application. The tragacanth
`suspension,
`the tragaeanth—olive oi] suspensions without
`substance (control animals) or the substances suspended in
`an appropriate 1rag,acanllJ—olive oil suspension are then
`an administered to the fasting animals using a stomach tube.
`Further taking of blood to determine the postprandial serum
`triglyceride rise is carried out, as a rule, 1, 2 and 3 hours after
`stuntacli tube application.
`The blood samples are centrifuged and, after recovering
`the scrutn. the triglycerides are determined photometrically
`using an EPOS analyzer 5060 (Eppcndorf G