l||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
`
`US(}(l62654_"-1B1
`
`(12; United States Patent
`Miiller et al.
`
`(HI) Patent No.:
`(45) Date of Patent:
`
`US 6,265,431 B1
`Jul. 24., 2001
`
`(54) CYCI.()Al,KANU-[N[)Ul.l£ AND -
`AZAlNl]'()I.IC IJERIV/\'l"lV'ES
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`(75)
`
`Inventors: Ulrich Miiller, Wuppertal (DE);
`Richard CoI1neI],'[‘rL1mbull, CT (US);
`Siegfried Goldman n, Wuppe rial; Rudi
`Griitzmiann, Solingen, both of (DE);
`Martin Beuck, Nilford, Cl‘ (US);
`Hilmar liisehofi; Dirk I);-nzer, bolh 0|‘
`Wuppcrtal (DI.-'); Anke Domdey-Bette,
`Hiickeswageli (DE); Stefan Wulllfeil,
`llildcn (DE)
`
`('33) Assignee: Bayer Aktiengesellschaft, lieverku:-zen
`(DE)
`
`*
`
`Notice:
`
`_
`Y
`Subiect to an disclaimer, the term of this
`patent is extended or arljilslcd under 35
`U.S.C.‘..
`l54(b) by U days.
`
`(21) App]. No.2 09/313,035
`
`(22
`
`Filed:
`
`May 17, 1999
`
`Related U.S. Application Data
`
`(62) Division ofapplication No. U3g’B87,78'l, filed on Jul. 3, I997,
`which is a division of application No. U8x'535.698. filed on
`Scp. 28,
`l‘.J‘.J5, now Pat. No. 5,684,014.
`
`.
`
`1,-‘L972 Maurer cl. ul.
`3,632,807
`10.-‘L988 Gillaid ct al. .
`4375.680
`5.-“I996 Mullcrel ul.
`. ....................... 5I4;'4m
`5,521,206 *
`1l3'l‘J‘)7 Muller el Ell.
`5,.é84,lJl4
`H1998 Muller cl :11.
`S,?'T6_,964
`.
`9.51999
`l.L' nlicrs at al.
`5,952,498
`F{)Rl:'.IGl\l PF{l‘l:'N'l" DOCUMl:lN'l‘S
`
`.
`.
`
`0234708 *
`0 234 ms A1
`u 30:) we A2
`0310129 *
`n 310 129 A2
`n 406 237 A2
`0 5:39 359
`n can 035 Al
`
`(EP).
`9.-‘L987
`(I-LP) .
`W198?
`(1-_'P)
`.
`1.!1~'J8iJ
`4,-1939 (1-:9) .
`4;"1989
`(RP) .
`7Il‘)*)2 (I-LP) .
`10,-‘L992
`(EP) .
`M994 (RP) .
`(}'l'I-[ER PUB[_l(.‘Al'I()NS
`
`Ilelcrocyclcs, vol. 22, No. '10, 1984 (pp. 23?7—22?9).
`
`* cited by examiner
`
`Priiiiaijir EJi'c1iiiine1‘—/'\lan L. Rotman
`;1.SZ§f.§l(lfII Ex(mi.I'ner—Rila Desai
`(74) Arrorriey, Agent, or F."rm—l‘~lorris McLaughlin &
`Marcus
`
`(30)
`
`Foreign Application Priority Data
`
`(57)
`
`ABSTRACT
`
`Om‘ 4’ [Q94
`(SI)
`Int. Cl._'
`
`44 35 4-”
`(DE)
`.................... .. A6'lK 3I,n"403; (TIEIYI) 2{I9,r'82;
`(‘U7D 209/2'.’
`........................ .. 514x408; 5145411; 543x439;
`543,499
`(58) Field of Search ................................... .. 548E439, 449;
`514E408, 411
`
`(52) U.s. C].
`
`C'yc]0al.kano-ir1d0le and -azaindole derivatives are prepared
`by ruaulitiri 0|‘ appropriately sulnstiluled carbuxylic acids
`wilh amines. The cycle-alkano-indole and -azaindole deriva-
`lives are suitable as active compounds for nwdicamcnis,
`preferably arilialherosclerotic medicarnenls.
`
`7 Cla:ims, No Drawings
`
`1 of 72
`
`PENN EX. 2223
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`US 6,265,431 B1
`
`1
`CYCI.()Al.-KAN()-[l\I)()l.E ANI)
`-AZAINDOLE DILRIVATIVES
`
`This is a division of application Ser. No. tt8r887,78t,
`filed on Jul. 3, 1997, now allowed, which is a division of
`application Ser. No. 08r’535,698, filed on Sep.28,1995, now
`U.S. Pat. No. 5,684,014.
`The present invention relates to cycloalkano-indole and
`-azaindole derivatives, processes for their preparation and
`their use as medicament-3, in particular as antiatherosclerotic
`medicaments.
`
`It is known that increased blood levels of triglycerides
`(hypertriglyceridaemia)
`and
`cholesterol
`(hypercholestcrolaernia) are associated with the genesis of
`atherosclerotic vessel wall changes and coronary heart dis-
`eases.
`
`S
`
`10
`
`15
`
`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—ltlU. There is
`therefore, as bellore, a great need to make available elleetive
`medieaments for the control of atherosclerosis and coronary
`heart diseases.
`
`The present invention relates to cycloalkano-indole and _
`-azaindole derivatives of the general formula (I)
`
`K]
`
`(U
`
`30
`
`R3
`
`R‘
`
`I
`
`I
`
`_\'
`
`
`t”1,_<’:/\(n_._
`
`R3
`
`: I)
`
`in which
`
`R1 and R3, including the double bond oonneeting them,
`together form a phcnyl or
`
`pyridyl ring or a ring ofthc 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 phcnyl
`ring or a 4-
`to 8-mcmbcred
`cycloalkene or oxocycloalkcnc radical,
`all ring systems mentioned under R '/12.2 and RBKR" option-
`ally being substituted up to 3 times by identical or
`difierc-nt halogen, tritluoromcthyl, carboxyl or hydroxyl
`substituenls, by straight-chain or branched alkoxy or
`alkoxycarbonyl each having up to 6 carbon 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,
`T) represents hydrogen, cycloalkyl having 4 to 12 carbon
`atoms or straight—chain or branched alkyl having up to 12
`carbon atoms,
`
`40
`
`4-5
`
`50
`
`SS
`
`ti?!
`
`2
`
`group,
`CS
`or
`CO
`E represents the
`I. represents an oxygen or sulphur atom or a group of the
`formula —Nl~’.i’,
`wherein
`
`R" denotes hydrogen or straight-chain or branched alkyl
`having up to 6 carbon atoms, which is optionally
`substituted hy hydroxyl or phenyl,
`R5 represents phenyl or a 5- to 7—membered saturated or
`unsaturated heterocycle having up to 3 heteroatoms from
`the series consisting of S, N andfor (), the cycles option-
`ally being substituted up to 3 times by identical or
`different nitro, carhoxyl, halogen or cyano substituents or
`by straight-chain or branched alkenyl or alkoxyearbonyl
`each having up to 6 carbon atoms or by straight-chain or
`branched alkyl having up to 6 carbon atoms, which is
`optionally substituted by hydroxyl, carboxyl or by
`straight-chain or branched alkoxy or alkoxycarbonyl each
`having up to 6 carbon atoms, andfor the cycles optionally
`being substituted by a group of the formula —OR'" or
`—Nn“it”,
`wherein
`
`R 1" denotes hydrogen or straight—chain or branched alkyl
`or alkenyl each having up to 6 carbon atoms,
`R” and R1: are identical or different and denote phenyl,
`hydrogen or straight-chain or branched alkyl having up
`to 6 carbon atoms
`
`or straight—cliain or branched aeyl having up to 8
`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 8 carbon atoms,
`represents hydrogen, carboxyl or straight-chain or
`branched al.koxycarbonyl having up to 5 carbon atoms,
`or represents straight-chain or branched all-Lyl having up to
`6 carbon atoms, which is optionally substituted by
`hydroxyl or by a group of the formula —O—CO—Rl5,
`wherein
`
`R‘;
`
`R15 denotes phenyl which is optionally substituted up to
`3 times by identical or different halogen or hydroxyl
`substituents or by straight-chain or branched alkyl
`having up to 5 carbon atoms,
`or straight—ehain or branched alkyl or alkenyl each
`having up to 22 carbon atoms, each oi" which is
`optionally substituted by a group of the formula
`—t}l{“’,
`wherein
`
`R” is hydrogen, ben7._vl, triphenylmethyl or straight-
`chain or branched aeyl having up to 6 carbon atoms,
`R7 represents hydrogen or
`R6 and R7 together represent the group of the formula =0,
`if appropriate in an isomeric form, and their salts.
`The cyeloalkano-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. Physiologically acceptable
`salts of the compounds according to the invention can be
`salts of the substances according to the invention with
`mineral acids, carboxylic acids or sul phonic acids. Particu-
`larly preferred salts are, for example, those with hydrochlo-
`ric acid, hydrobromie acid, sulphuric acid, phosphoric acid,
`methanesiilphonic acid, et.hanesnlphonic acid,
`toltJcncs1Il—
`
`20f72
`
`PENN EX. 2223
`CFAD V. UPENN
`lPR2015-01836
`
`

`
`US 6,265,431 B1
`
`3
`phonic acid, benzenesulphonic acid, naphthalenedisul—
`phonic acid, acetic acid, propionic acid, lactic acid, tartaric
`acid, citric acid, furn aric acid, malcic acid or benzoic 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 10
`cihyldmmd’ db. or tilclhyldimric’ db or mclhlmuldminc’
`dicvclohexylamine, dimethylaminoethanol, arginine, lysine,
`'
`,
`.
`.
`ethvlenediaminc or 2—phenylethylamine.
`‘
`.
`the
`Including the double bond of parent structure,
`,
`,
`_
`,
`3
`,,
`,
`,
`,
`,
`cycloallcene iadical (R R ) in the context oithe iiiveiittoii in l—
`.
`general represents a 4 to 8—membcred hydrocarbon radical,
`_
`_
`_
`preferably a 5- to 8—membered hydrocarbon radical,
`tor
`
`20
`
`example a cyclobiitene, cyclopentcnc, cyclohexcnc, cyclo—
`heptene or cyeloocteiie radical. The cyclopcntcne,
`,
`cvclohcxene, cyclooctene or eycloheptene radicals are pre-
`is
`d
`,
`,
`_
`,
`5
`arm
`lleterocycle (R ) in the context of the invention in general
`_
`represents a saturated or unsaturated 3-
`to 7-membered
`as
`1
`1
`_
`1
`,1
`hcterocycle, prctcralaly a 5- to 6-mcmbered hcterocycle, —.
`which can contain up to 3 heteroatoms lrom the series
`consisting of S, N andfor
`(1. Examples which may be
`.
`.
`.
`.
`mentioned are: pyridyl, thienyl, fury], pyrrolyl,
`thiazolyl,
`oxazolyl, inmdazolyl, morpholinyl or pipeiidyl. Pyridyl and m
`thienyl are preferred.
`_
`in
`The compounds according to the invention can exist
`stereoisomeric forms which either behave as image and
`
`mimlr image (flfiaflllflmfir-‘*3. 0T d0 which (10 00' h‘‘-l1ii\'‘’- 515
`image and mirror
`image (diastereoiiiers). The invention 35
`relates both to the enaniiomers and diastereomers and their
`respective mixtures. Tliese mixtures of the cnanliomers and
`diastereomers can be separated in a known manner into the
`
`5l°’°°15‘3m°"1‘33l1Y umfmm Cflnsml-1'3m-"L
`Prclicrred coiiipoitiids of the general forinula (I) are those 40
`in which
`IR:
`'
`'ld'
`'th'd bl'b I
`*‘t'Ulh‘
`R1
`an‘
`’ ml‘ " ml:
`"
`U”
`L Um °°”““' mu
`°m=
`logmhcr form 3‘ phony] or
`
`pyridyl ring or a ring of the formula
`
`NR8 _
`
`0
`
`46
`
`50
`
`55
`
`_
`I
`_
`,
`wmrcm
`R3 denotes hydrogen or straight-chain or branched alkyl
`having up to 3 carbon atoms,
`R3 and R4
`including the double bond connecting them
`J
`5
`,_
`together
`form a phenyl
`ring or
`a cyclopcntcnc,
`cyclohexene, cycloheptene, cyclooctenc,
`oxocyclopenteoe, oxocyclohcxenc, oxocyclohepicnr: or
`mmcycloocrmc radical‘
`all ring systems mentioned under R‘/R‘ and RBKR4 option-
`any being Subsrirurcd up re 3 rimes by idcnrical or
`different lliiorine, chlorine, bromine, trilliioromethyl, car-
`boxyl or hydroxyl substituents, by straight—chain or
`branched alkoxy or alkoxycarbonyl each having up to 4 bf‘!
`carbon atoms or by straight—chain or branched alkyl
`having tip to 4 carbon atoms, which,
`in turn, can be
`
`60
`
`4
`substituted by hydroxyl or by straight—chain or branched
`alkoxy having up to 3 carbon atoms.
`D represents hydrogen, cyclobutyl, cyclopentyl, cyclohexyl,
`cycloheptyl. cyclooctyl 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 represeiits a
`group of the formula —NR”,
`whgmvn
`R9 denotes hydrogen or straight-chain or branched alkvl
`.
`.
`.
`_
`.
`'
`having up to 5 carbon atoms, which is optionally
`.
`_
`substituted by hydroxyl or phenyl,
`.
`.
`.
`.
`.
`represents phenyl, pyridyl, turyl, thienyl or imidazolyl, each
`.
`.
`.
`.
`.
`.
`_
`01 which is optionally substituted up to 2 times by
`.
`.
`.
`.
`.
`.
`identical or dilTerent nitro, carboxyl, fluorine, chlorine,
`.
`.
`_
`_
`.
`.
`bromine or cyano substituents, by straight—chain or
`branched amen [Or alkoxv carbon leach havm U to 4
`y
`’.
`g
`p
`carbon atoms or by straight—chain or branched alkyl
`.
`.
`.
`.
`.
`liavitig up to 5 carbon atoms, which is optionally substi-
`tuted by hydroxyl, carboxyl or by straight-chain or
`.
`branched alkoxy or alkoxycarbonyl each having up to 5
`‘
`,
`y
`.
`y
`y
`.
`carbon atoms, anti,-or the cycles are optionally stihstittiteil
`by a group of um formula
`CR“, or _NRnR,»;,
`_
`whfircm
`‘
`.,
`‘
`10
`R dC“01°5 h}"d"089“ 0’ Smllghh‘-haln 0" branchcd alkyl
`"T “ll‘°">'l Wich l“1V1"t’. “P l" 4 ‘—‘*'''l”“ *l“‘"''-‘*»
`R“ and R” are identical or different and denote phenyl,
`hydrogen or siraight—chain or branched alkyl having up
`to 5 carbon atoms
`
`or denote straight-cliain or branched aeyl having tip to
`6 Car-hrm arr,m_.;_ which is oprirrnally Subsrirurcd by a
`group of me formula _NR13R1",
`wherein
`R‘-3 and R” arr,
`
`r]i[]‘r,rr,m and r1r,m,rr,
`
`jdwrjca] Ur
`
`hydrogen or s1raight—chain or branched acyl having
`up [0 (3 carbon atoms,
`R6 represents hvdrogen, earboxyl or straight—chain or
`'
`-
`branched alkoxycarbonyl liaving up to 4 carbon atoms,
`or represents straight—chain or branched alkyl having up to
`5 carbon atoms, which is optionally substituted by
`hydroxyl or by a group of the formula —()—(T()—R15,
`
`I
`I
`I
`_
`wherein
`R” denotes phony] which is optionally substituted up to
`3 times bv identical or different
`fluorine
`chlorine
`_,
`3
`9
`bromine or hydroxyl substituents or by straight-chain
`or braiiclicd alkyl having up to 4 carbon E1l(llTlts',
`or straiglit—cliaiii or braiiched alkyl or alkeiivl each
`having up '0 30 Carbon atoms
`each or which is
`’
`.
`_
`r
`7.
`r
`_
`Opllonfi,-lly bubmwlei by a group of the formula
`h R.
`’
`,
`,
`w,fr_em
`15, hyllrogw’ benzyl’ ‘“l’,l“"“Y1““"‘l‘3" or Sl””ghl'
`R
`chain or branched aeyl having up to 5 carbon atoms,
`7
`R6 rcpresfnu’ hydrogen °r
`aiidR ‘together tepreseiit the group of the fotiuula =0,
`1[ il|3_'PT0P1'li*-W 113 3-D 1-‘=‘01T16T1C 10TlT1s and their 531115-
`l]3“'C"lm'l}'P1'°f°"’°d ‘30mP0l"1d5 Oflhc 8309731 fmml-113 (ll
`affi lh0-‘-C iii Which
`R1 and R‘,
`including the double bond connecting them
`together form a phenyl or
`
`3 of 72
`
`PENN EX. 2223
`CFAD V. UPENN
`IPR2015-01836
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`

`
`US 6,265,431 B1
`
`pyridyl ring or a ring of the Eormula
`
`NR5 _
`
`wherein
`
`R” denotes hydrogen or methyl,
`and R4,
`including the double bond connecting them,
`together
`form a phenyl
`ring or
`a cyclopentene,
`eyclohexene, eycloheptene, cyclooctene,
`oxocyclopentene, oxocyelohexene, oxocycloheplene or
`oxocyclooclene radical,
`
`all ring systems mentioned under RVR3 and RSKRJ
`optionally being substituted up to 2 times by identica]
`or different fluorine, chlorine, bromine, trifluoromethyl,
`carboxyl or hydroxyl substituents, by straight—ehain or
`branched alkoxy or alkoxycarbonyl 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 by hydroxyl, methoxy or ethoxy,
`D represents hydrogen, cyclopenty], cyelohexyl,
`cycloheptyl, cyclooctyl or straight-chain or branched
`alkyl having up to 6 carbon atoms,
`group,
`E represents the —C0— or —CS
`I. represents an oxygen or sulphur atom or represents a
`group of the formula —NR°,
`wherein
`
`30
`
`RC’
`
`6
`represents hydrogen, carboxyl or straight—chain or
`branched alkoxycarboinyl having up to 3 carbon atoms,
`or represents straight-chain or branched alkyl having up to
`4 carbon atoms, which is optionally substituted by
`hydroxyl or by a group of the formula —O—CO—R15,
`wherein
`
`10
`
`15
`
`R15 denotes phenyl which is optionally substituted up to
`3 times by identical or different straight-chain or
`branched atkyl having up to 3 carbon atoms,
`or denotes straight-chain or branched alkyl or alkenyl
`each having up to 19 carbon atoms, each of which is
`optionally substituted by a group of the formula
`—()R“’,
`wherein
`
`triphenylmethyl or
`R16 denotes hydrogen, benzyl,
`straight—chain or branched acyl having up to 4 carbon
`atoms,
`
`R7 represents hydrogen or
`R“ and R7 together represent the group of the formula =0,
`
`if appropriate in an isomeric form, and their salts.
`
`A process for the preparation of the compounds of the
`general formula (I) according to the invention has addition-
`ally bcen found, characterized in that
`
`earboxylie acids of the general formula (II)
`
`(II:
`
`R3
`
`R"
`
`R‘
`
`R3
`
`N
`l
`
`rxigll _
`
`:
`
`I)
`
`40
`
`in which
`
`R9 denotes hydrogen or straight-chain or branched alkyl
`having up to 4 carbon atoms, which is optionally
`substituted by hydroxyl or phenyl,
`R5 represents phenyl. pyridyl or thienyl, each of which is
`optionally substituted up to 2 times by identical or dif-
`ferent nitro, earboxyl,
`fluorine, chlorine, bromine or
`cyano substituents, by straight—chain or branched alkenyl
`or alkoxy-carbonyl each having up to 3 carbon atoms or by
`straight-chain or branched alkyl having up to 4 carbon
`atoms, which is optionally substituted by hydroxyl, car-
`boxyl or by straight—chain or branched alkoxy or alkoxy—
`carbonyl each having up to 4 carbon atoms,
`
`andfor 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 alkeny] each having up to 3 carbon atoms,
`
`R“ and R” are ident.ical or dilIerenl and denote phenyl,
`hydrogen or straight—chain 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 —N[-t”R“,
`wherein
`R13 and R” are identical or different and denote
`hydrogen or straight—chain or branched acyl having
`up to 5 carbon atoms,
`
`4-5
`
`R1, R2, R”, R4 and D have the meaning indicated,
`are amidated using compounds of the general formula (Ill)
`
`(III)
`
`50
`
`in which
`
`R5 has the meaning indicated
`and
`
`R17 has the indicated meaning of R6, but does not represent
`carboxyl,
`
`in an inert solvent and in the presence of bases andfor
`auxiliaries,
`
`functional groups are varied by
`if appropriate,
`and,
`hydrolysis, esterilicalion or reduction.
`
`E1?!
`
`The process according to the invention can be illustrated
`by the following reaction scheme:
`
`4of72
`
`PENN EX. 2223
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`US 6,265,431 B1
`
`
`
`C03H
`
`OH
`
`II2N/\\/
`
` cu,
`
`I )i:hlm'o1nethane,.'trierhylmn ine .
`1-hydrox_\'—l E l—henzon'iazo1e and
`S-[F-diincthylaitii I1t)propy'.)-
`X-elth 5.'leaJ'ho:liimidr.' h_\'dJ".1hloJ'id4:
`
`
`
`Separation of
`dl{iSl(:1't.201'l'I(:1'5
`
`
`
`
`
`so
`
`line earth metal hydroxides, such as, for example, barium
`Suitable solvents for the amirlation are in this case inert
`hydroxide, alkali metal carbonates such as sodium carbonate
`organic solvents which do not change under the reaction
`orpotassium carbonate, alkaline earth mctalearbonates such
`conditions. These include cthers, such as diethyl ether or
`as calcium earbonale, or alkali metal] alkoxides such as
`telraliyrlrofuran,
`l1E1l0g|.:l'tUl'l}'(]l'0Cal'lJUl']5 such as ,
`dichloromethane,
`lriehlorornelhane,
`telraehloromelhane,
`35 sodium or potassium methoxide, sodium or potztssiurn
`lrielilurrselliane,
`letraellioroelliarie,
`l,2—diehloruel.l|aI1e or
`ellloxirle or potassium 1erl—l)u1oxi(lL;, or organic amines
`triehioroethylene, hydrocarbons such as benzene, xylene,
`(11'ialkyl(C]—C5)amines) such as lriethylamine, or hetero-
`toluene, hexane, eyelohexane or petroleum fractions,
`eyeles such as l,4-diazabieyelo[2.2.2]oelane (DABCO),
`nitromethane, rlimethylformamide, acetone, acetonilrile or 50 1,8-diaza|)icyclo[5.4.0]undec-7-ene (DBU), pyridine,
`hexamelhylphosphorarnide.
`ll
`is also possible to employ
`diaminopyrirline, melhylpiperidine or morpholine. [1 is also
`mixtures nfthe solvents. Dichloromcthane, tctrahyrlrofilran,
`possible to employ alkali metals such as sodium and their
`acetone and dimelbflformamide are particularly preferred.
`hydrides such as sodium hydride as bases. Sodium and
`Bases Which can be employed for the process according
`potassium carbonate and triethylamine are preferred.
`to the invention are in general inorganic or organic bases.
`The base is employed in an amount from 1 11101 to 5 mol,
`These preferably include alkali mctalhydroxidessuch as,for
`preferably from "I mol to 3 mo], relative to l mo] of the
`example, sodium hydroxide or potassium hydroxide, alka—
`compound of the general formula (II).
`
`bf‘!
`
`5 of 72
`
`PENN EX. 2223
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`US 6,265,431 B1
`
`in which
`
`10
`
`(W)
`
`T—H?C
`
`\\
`
`|
`
`/
`Y
`D
`
`-
`2
`CO Rm
`
`»
`
`9
`in a temperature
`The reaction is in general carried out
`R1, R2, R3 and R4 have the ineaiiiiig indicated,
`range from 0° C.
`to 150° C., preferably from +20° C. to
`+']']0" C.
`in inert solvents, if appropriate in the presence of a base.
`Suitable solvents for
`the process are the customary
`The reaction can be carried out at normal, increased or
`5 organic solvents which do change under the reaction con-
`\
`x
`-
`.
`.
`,
`.
`.
`reduced pressure (u...g. (1.3 to 5 bar). In general, the reaction
`ditions. These preferably include ethers such as diethyl
`is carried out at normal pressure
`-th‘
`-thl=th-
`d" ‘-t‘1‘hdl'
`l'ld'
`'
`‘
`il_;y;r:’)Ca1r?J:::L;u:hma: ;:n:1:n:'
`linylflznfl ”:;]6Ee Lhc:;1n:r
`The ainidatioii can optionally proceed via the activated
`eyclohexane or petroleum fractions, or lialogenoiiydrocar-i
`Stage of ‘hi: acid halides’ which can hf; limpamdllrom the
`corrcspondmg acldsby macho“ “nth lhl0nylchlO“d°’ph°S' 10 bons such as dichloromethane
`lrichloromethane
`'
`'
`.
`.
`.
`'
`.
`.
`i
`i
`‘
`5
`,
`Plwms _mChl°mle' Ph°5pl_m“"’ p°m""hl°”de* Ph°*‘Ph°"'*'
`tetrachloromelliane, dichloroetliyleiie,
`lricliloroelhylene or
`ll‘-l’“"l"l‘l“ “l‘l’“‘l3’l “lll"“‘l"-
`ehlorobenzene or ethyl acetate
`triethylamine pvridine
`The abovcmcntioned bases can optionally also be
`dime I h 3”
`5" lph ox ids , dj mu 1 h 3, Ifornl aimid ,: ’
`elTlPl9Y5ll [OT ll“: 3l'l3l‘lall0” 3-5 iiCl(l'blU(lll'lg Wxllliirlesv
`hexamethylphosphoramidc, acclonitrile, acetone or
`Suitable auxiliaries are also dehydrating reagents. These l5 1-.[1romc1]3ane,
`11
`jg, also possible to use mixtures, of the
`include,
`for example, carbodiimides such as
`solvents mentioned.
`l)imethyll:>rm2Imitle and tetral'iydroft.t—
`diisopropylcarhodiimide, dicyelohexylearbodiimide and
`ran are preferred.
`N -(3 -dimelhylaminopropyl}-N'-ethylcatbodiimide hydro-
`The bases employed for the process according to the
`chloride or carbonyl compounds such as carbonyldiimida— ,0 invention can in general be inorgaiiie or organic bases. Tliese
`zole or 1,2-oxazolium compounds such as 2-etliyl-5-phenyl-
`P"°l°l'3l3l}'
`lncllldc alkall mclal
`l1Ydl'0Xl5l95r
`ll" Cxamplca
`1_3_0xaZo]ium_3_5ulphonam or pl-Opancphosphonic
`sodium hydro-xitle or potassium hydroxide, alkaline eartli
`anhydride or isobutyl chloroformate or benz.otriazoIylo_xy-
`mclal hydloxlclcss ll” °l“lmPl_°- llarlllm llY‘3ll'0xlCl‘3s alllall
`Iris-[climethylanino)phosphoni1itn hexalliiorophosphate or
`metal Carbonate? Such 5“ mdlllm carbomlc or pmasslum
`diphcflyl phosphoramidatc or methancsulphonyl Chloride’ if 35
`l..dl':)(]|']dlc, dllxdllllléltflllddflll
`|'i'Icl.c1l]l{ catcliitaiialeshsueli asdealciuin
`appropriate in the presence ofbasessuch as triethylamine or
`car xm_mc or a
`a_l meta ,a 0X1 “5 Sm",
`as 50 [Elm or
`.
`.
`.
`.
`.
`_
`_
`potassium methoxide, sodium or potassium ethoxide or
`N-ethylmorpholine or N-methyl pi peridine or dicyt..lohexyl-
`_
`,
`_
`,
`_
`potassium tert-butoxide, or organic amines (tr1alkvl(C,—C,.)
`..
`.
`_
`.
`.
`.
`Carbodnmldc and N-hydmxymcclnlmidt
`amines) such as triethylamine
`or heteroeycles such as
`Hm “1°'d'b‘“‘}‘“,’=’ agcmfi and ,dchydr:1ung Icagcms are In 30 l,4—dia2ahicyc1o[2_2_2]octane (DABCTU), 1,8—dia7ahicyclo
`generalemployed in an amount from 0.3) to3 moI,preferalily
`[5'4'0]undcc_7_Gm UJBU)’ PW]-dim’ diaminopwidinc’
`from l to 1'5 mol‘ relative to 1 mol of ml: corresponding
`melliylpiperidirie or morpholirie
`ll
`is also possible to
`carbmlyllc a_Cl(l5l‘
`_
`employ alkali metals such as sodium or their hydrides such
`for example
`The variation of functional groups,
`as Sodium hydride
`ba5%S_ Sodium hydride polassium
`hydrolysis, esterification and reduction, and also separalion 35 carbonalc, Uifilhylamim, pyridine and pmassium mm
`of isomers and salt formation is carried out by customary
`|,m0x;dc_ mm or ])A];(;[) are P1-efm-I-cd_
`ntfllhfillti
`In general, the base is employed in an amount from 0.05
`ilihll CtiTl'3(3X)tliC Eicid-S Of lhil general ftifmlllfl (ll) art? DOW
`niol to It) Inol, preleralily lirom 1 mol to 2 mol, relative to
`and can be prepared by reacting
`40 1 mo] of the compound of the formula (IV).
`compounds of the general formula (IV)
`'l'he process according to the invention is in general
`carried out in a temperature range from —30° (T, to +100” (1,
`preferably from —l0° C. to +60° C.
`'l'he process according to the invention is in general
`45 carried out at normal pressure. However, it is also possible
`to carry out llie 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 of the general formula (IV) are known or
`can be prepared in analogy to known methods.
`The compounds of the general formula (V) are known or
`can be Prepared in analogy to known melh0ds_
`.
`‘
`_
`_
`_
`_
`‘
`‘
`.
`I'he ct)Iript)urit_l.s of the :general formula (I) d|..(.U[Lll[]g to
`the invention have an uuioreseeable spectrum of pharma-
`cological action
`They can be used as active compounds in medicaments
`m for the reduction of changes to vessel walls and -for the
`'
`treatment 01 coronary heart disorders, cardiac insu fticieney,
`brain power disorders, ischaemie brain disorders, apoplexy,
`circulatory disorders, disorders of the microcirculation and
`thromboses.
`the proliferation of smooth muscle cells
`Furthermore,
`plays a decisive part
`in the occlusion of vessels. The
`compounds according to the invention are suitable for
`
`in which
`D has Ihli meaning ifldicalfld,
`ill l"3l"l"'*‘jl7'll-"_ 3 l.VPlCal
`ll‘ Wlllg glmlllv for l7x_3'“Pl"r Clllmlllfia
`‘tiaromine, iodine, tosylate or mesylate,prelerahly bromine,
`an
`Rm reprcqcnlg [C _(_‘ )a1kvl
`i
`‘_
`'1. "l
`“
`’_
`.
`.
`witli compounds of the geneial formula (V)
`
`50
`
`_
`35
`
`R,
`
`R,.
`
`R,
`
`R»;
`
`’
`
`|
`
`|
`
`V
`|
`ll
`
`(W
`
`[,5
`
`6 of 72
`
`PENN EX. 2223
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`US 6,265,431 B1
`
`12
`IC_,,, value indicates at which substance concentration the
`light absorption is inhibited by 50% in comparison with the
`control (solvent control without substance).
`
`11
`inhibiting this proliferation and thus preventing atheroscle-
`rotic processes.
`The compounds according to the itivention are distin-
`guished by a lowering of the ApoB-100-associatetl lipopro-
`teins (V[.lJl. and its degradation products, e.g. I.|)I.), of
`ApoBl[)0, of triglycerides and of cholesterol. They thus
`-
`P
`l
`5
`P P
`have useful
`su erior
`iliarmaeolotical
`ro erties in eoIn-
`parison with the prior art.
`Surprisingly, the action of the compounds according to the 10
`invention consists first in a decrease or complete inhibition
`of the formation and/or the release ofApuB—l00-associated
`lipoproteins from liver cells, which results in a lowering of
`2. Detemiination of the VLDL Secretion in vivo in
`the VLDL plasma level. This lowering of VLDL must be
`1170 H3mS1¢l'
`accompanied by a lowering of the plasma level of /\po]3l0'0,
`The en-ca or me 1651 Subslanocs on VLDL Secmlion in
`LDL, triglycerides and cholesterol; a number of the above—
`vivo is investigated in the hamster. To do this, golden
`mcnliomd risk factors whlch are involved in Vessel wall
`hamsters are anaesthetized with Ketaset (83 mgikg so) and
`“hang” “"3 thus 5lmull‘l‘“f“’”Sl3' dc‘fr"“S°‘l
`ill“ °°mP°”"‘l5 "“3°°"d1"3'° Yb‘? "“'°“““" ca" thcrcfmc :0 Nemhulal (50 rug/kg Lp.) after premetlieatinn with atropine
`be employed for
`the prevention and treatment of
`(83 mg/kg 5‘C')_ when the animals have become mflcx_fl_cc’
`atherosclerosis, obesity, pancreatitis and constipation.
`the jugular vein is exposed and cannulatcd‘ U25 mhekg of a
`l. Iiiliibitioti of the Release of ApoB100-associated
`20% Slwnglh Solution of Trim“ wR'l339 in Physlolgi-lnlcal
`Ijpoprotcins
`25 saline solution
`then adrninistered. This detergent inl1ibiLs
`The test for detecting Llie inhibition of the release of
`:h:d:llll:l::;t::lall‘::::hal:: ajfi ‘t::l:b:?:3l:
`A ollltltl-associated li o roteins from liver cells was ear-
`,
`'
`,
`_
`_
`_
`ritI:)d out in vitro using iiuiiured liver cells, preferably using
`VLDL par,tlClcl;' Tllls lrlglyfmrldc use can be used as a
`cells of the human line HepG2. These cells are cultured
`mcllsulc Ul ll” Vl‘Dl‘ mcmlmll mm‘
`under standard conditions in medium for the culture of ‘lo
`Blmd ill‘ take“ fm_m_Ih° fmlmals bcfom and also one and
`cukaryolic C0115, preferably in RIJMI 1640 with 10% [Dela]
`two hours after administration of the detergent by puncture
`Calf Scmm_ Hcpuz Cells synthesize and Sccmm mm the
`ofthc retroorbilal venous plexus. The blood is incubated for
`culture supernatant ApoB—ttl0—associated lipoprotcin par—
`“V0 hm-‘rs "1 T00”-' l°mP'3”‘l”T"3- and me“ Uwmiglu 31 4° Cw
`ticles which in principle are built up in a similar manner to 35 l" ‘‘'d‘” “l end C_l"m"g C‘'’ml’l‘3'“ 13''
`I11 is [hm ‘5‘l‘“"‘l['”E'_>‘'”l 9”
`the VLDL and LDL particles which are to be found in the
`10'UU0§v1°rE D-f'n”]“l’5'1'lh° n_'_gl3'E'i°°r_1‘]i: ‘}"1°n":""1"l;almn lrffhg
`lasml
`serumt uso tainet istetermine wit
`t e &t1( 0 21 mm t ie
`P These particles can be detected using an immunoassay for
`c0_l-lll-l-lclclally avllllable ellllyme lesl (MelCk0lllSl® lllglyc"
`human LDL This immunoassay is carricd out using ami_
`ende No. 14354). 1D0_t«‘l oi serum are treated with l.00,ltl ot
`bodies which have been induced against human I.|)I. in 40 lwl mag.“-ll In 96__l-mlc plat” aml lncuballid in mom lum-
`rabbits under standard conditions. The aiiti—LDL antibodies
`pellllurl: [of lo mlllulela lhe Upilcal. dens“? ls the? dell"-
`(rabbit ami_LDL Ab) were purified by aflinjty chmmalog
`mined at a wavelength of 492 nM in an automatic -plate-
`on an
`I
`I
`P
`_
`.
`'
`.
`.
`C
`.
`I
`.
`1
`.1
`iurilied rabbit auti—l_.l)l.Ab are adsorbed on the surface of as
`physiological saline solution. The triglyceride concentration
`Llasu-C’ uxpcdicntly, [his adsorption is cam-Cd Om on ‘he
`colllllmcd "l lllc Samples ll; dclcrmlllcd wlll_l the ald of a
`plastic surface of mierotitre plates having 96 wells, prefer—
`standard curve measuretl
`in ‘parallel.
`in this model,
`test
`ably on Maxismp plaws‘ H. Ap0B_m0_aSS0Cialed parades
`subsllluclls are lllllrlllllsllllcll lllllavcnoulsly clllllll ll-l-lll-lull-
`are present in the supernatant of IIep(}2 cells, they can be
`bound to the insolubilized rabbit anti-IDI. Ab, and an 50 alily lllclom lllclglplsll-lllllilltlll
`lllllj clclcllghclll, or orally fir
`immune complex results which is bound to the plastic
`3" Cu ancousy C we ml lawn 0 macs 65”‘
`surface. Unbound proteins are removed by washing. The
`immune complex located on the plastic surface is detected
`using monoclonal antibodies which have been induced 55
`
`_
`_
`Ex" M‘
`E
`3;
`51]
`
`_,,
`‘
`Icsnlm moml
`33
`1-J..{lJ'l
`2‘:
`
`S
`
`l5
`
`int.
`
`.‘\lo.
`
`t-2135,, [nigfkgj p_u_
`
`against human LDL and purified according to standard
`conditions. These antibodies were conjugated with the
`enzyme peroxidase. Peroxidase converts the colourless sub-
`strate TMB into a coloured product in the presence of H202.
`After acidification of the reaction mixture with 112804, the 50
`specific light absorption at 450 t'tt"t'I is determined, which is
`a measure of the amount of /\p(il3¥l00-a:-;soL'iated particles
`which have been secreted into the culture supernatant by the
`HOPGZ £30115.
`Surprisingly, the compounds according to the invention
`inhibit the release of the Apol-Ht}tl—associated particles. The
`
`(,3,
`
`2
`5
`7
`
`m 15
`34,
`7“ 30
`
`3' Inhibition 0fIl'll'°5T1iT_13-1 TTit—’,l}’0¢1'id"5 AbS0FPli011
`ln VW” (TMS)
`'11-“; 5u|;.51am;¢5 which an to 13¢ i]_'1\I'g5[ig;[|_cd [or [hair
`triglyceride absorptiominhibiting action in vivo are admin-
`istered orally to male Wistar rats having a body weight of
`between 170 and 230 g. For this purpose, the animals are
`
`7 of 72
`
`PENN EX. 2223
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`13
`divided into groups of 6 animals '18 hours before substance
`administration anti
`food is then withdrawn [rorn them.
`
`Driiikiiig water is available to the animals ad Iibituni. The
`
`US 6,265,431 B1
`
`14
`
`-continued
`
`l_ N ‘M
`L”
`Ex. No. 5
`h"'N°' 30
`
`1-3ernmtrig|3.'oeride rise in
`¢.-, (3 imp}
`:4
`'1“,
`-16
`3’
`
`animals of the control groups receive an aqueous tragacanth e
`suspension or a tragacanth suspension which contains olive '
`oil. The tragacanth-olive oil suspension is prepared using an
`Ultra-Tnrrax. The snbstaiices to be investigated are sus-
`pended in an appropriate tragacanth-olive oil suspension
`likewise using the Ultra—'l'urrax, directly before substance 10
`Statistical evaluation is carried out using Studcnt’s t test
`adIT1iDiS1Iflli0D-
`aflef Preliminary Checking Oflhe Variflncfls for h0m083'1eilY-
`To determine the basal serum triglyceride content, blood
`Substances which at one point
`in time statistically sig-
`is taken from each rat by puncture of the retroorbital venous
`plexus before stomach tithe application. The Iragacanth H nificantly (p<(J.tJ5) decrease the postprandial serum triglyc-
`snspetision,
`the tragaeantli-olive oil suspensions without
`'
`eride rise by at
`least 30% compared with the untreated
`substance (contr