B2
`
`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`I lllll llllllll II llllll lllll lllll lllll llll I II Ill lllll lllll lllll 111111111111111111111111111111111
`
`( 43) International Publication Date
`14 April 2005 (14.04.2005)
`
`PCT
`
`(10) International Publication Number
`WO 2005/033100 Al
`
`(51) International Patent Classification7 :
`C07H 15/00, C07D 205/08
`
`C07D 405/04,
`
`(74) Agent: CARRIERA, Andrea; Isler & Pedrazzini AG,
`Gotthardstrasse 53, Postfach 6940, CH-8023 Zurich (CH).
`
`(21) International Application Number:
`PCT /CH2004/000584
`
`(22) International Filing Date:
`15 September 2004 (15.09.2004)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`03405719.0
`
`7 October 2003 (07 .10.2003) EP
`
`(71) Applicant (for all designated States except US): LIPI(cid:173)
`DEON BIOTECHNOLOGY AG
`[CH/CH]; Her(cid:173)
`mann-Hiltbrunner-Weg 25, CH-8713 Uerikon (CH).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): CARREIRA, Erick
`[US/CH]; Chapfstrasse 73, CH-8126 Zumikon (CH).
`HAUSER, Helmut
`[AT/CH]; Hermann-Hiltbrunner(cid:173)
`weg 25, CH-8713 Uerikon (CH). KVAERNO, Lisbet
`[DK/CH]; Kronenstrasse 37, App. 16, CH-8006 Zlirich
`(CH). RITTER, Tobias [DE/CH]; Neugasse 52, CH-8005
`Zurich (CH). \VERDER, Moritz [CH/CH]; Marktgasse
`16, CH-5620 Bremgarten (CH).
`
`(81) Designated States (unless otheiwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI,
`GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE,
`KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD,
`MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG,
`PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM,
`TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM,
`zw.
`
`(84) Designated States (unless otheiwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
`FR, GB, GR, HU, IE, IT, LU, MC, NL, PL, PT, RO, SE, SI,
`SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`with international search report
`
`For two-letter codes and other abbreviations, refer to the "Guid(cid:173)
`ance Notes on Codes and Abbreviations" appearing at the begin(cid:173)
`ning of each regular issue of the PCT Gazette.
`
`--
`------
`iiiiiiiiiiiiiii ----iiiiiiiiiiiiiii
`iiiiiiiiiiiiiii ----
`
`'l"""""i
`~ -(5_4_)_T-it-l-e:~N-O_V_E_L~H-YP~O-C~H-O_L_E_S_T_E_~_O_L_E_MI~-C-C-O~MP~O-UND~~s~~~~~~~~~~~~~~~~~~~~~~
`
`0
`0
`'l"""""i
`('f")
`('f")
`
`0 --"" 0
`
`0
`M
`0
`~
`
`invention
`The present
`(57) Abstract:
`relates
`to
`novel
`hypocholesterolemic
`compounds of formula (I) useful in the
`treatment and prevention of atherosclerosis
`and for the reduction of cholesterol levels
`as well as to pharmaceutical compositions
`comprising said compounds alone or in
`combination with other active agents.
`
`(I)
`
`1 of 96
`
`PENN EX. 2259
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`WO 2005/033100
`
`PCT/CH2004/000584
`
`1
`
`Novel hypocholesterolemic compounds
`
`The present invention relates to novel hypocholesterolemic com(cid:173)
`pounds useful in the treatment and prevention of atherosclerosis
`and for the reduction of cholesterol levels as well as to phar(cid:173)
`maceutical compositions comprising said compounds alone or in
`combination with other active agents.
`
`Atherosclerotic coronary heart disease represents the major
`cause for death and cardiovascular morbidity in the western
`world. Risk factors for atherosclerotic coronary heart disease
`include hypertension, diabetes mellitus, family history, male
`gender, cigarette smoke as well as serum cholesterol. Elevated
`concentrations of serum cholesterol have been demonstrated by a
`number of clinical studies to be a major contributing factor in
`the development and progression of atherosclerosis, which is
`characterized by the formation of cholesterol-containing plaques
`in the aorta and lesser arteries.
`
`In mammals, 1/3 of the serum cholesterol is derived from exoge(cid:173)
`nous dietary sources which enters the body through absorption in
`the intestine and 2/3 of the serum cholesterol are derived
`through endogenous de novo synthesis in the liver involving a
`complex set of enzyme-catalyzed reactions and regulatory mecha(cid:173)
`nisms.
`
`Recently it has been shown that intestinal cholesterol absorp(cid:173)
`tion is an energy-independent, protein-mediated process {Hauser,
`H. et al, Biochemistry 1998, 37, 17843-17850; Schulthess, G. et
`al, Biochemiscry 2000, 39, 12623-12631; Werder, M. et al, Bio(cid:173)
`chemistry 2001, 40, 11643-11650) rather than a passive diffusion
`
`process. The proteins facilitating intestinal cholesterol ab(cid:173)
`sorption were identified as two brush border membrane-resident
`scavenger receptors (Hauser, H. et al, Biochemistry 1998, 37,
`
`2 of 96
`
`PENN EX. 2259
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`WO 2005/033100
`
`PCT/CH2004/000584
`
`2
`
`17843-17850; Werder, M. et al, Biochemistry 2001, 40, 11643-
`11650) . Both in vitro and in vivo animal experiments confirmed
`the presence of these two scavenger receptors in the intestinal
`BBM and proved that they are responsible for the protein(cid:173)
`mediated cholesterol uptake.
`
`Various 2-azetidinone compounds have been reported as being use(cid:173)
`ful in lowering cholesterol and/or in inhibiting the formation
`of cholesterol-containing lesions in mammalian arterial walls:
`For example WO 93/02048, WO 94/17038, WO 95/08532,
`PCT/US95/03196, U.S. Pat. No.5,633,246 describe 2-azetidinone
`compounds with different substituents at the 3-position, and
`U.S. Pat. No. 5,756,470 discloses 2-azetidinones having varying
`substituents at the 4 position. Other azetidinone derivatives
`include for example elastase inhibitory substituted azetidinones
`disclosed in European Patent 199,630B1 and European Patent Ap(cid:173)
`plication 337,549A1. The most prominent representative of these
`
`2-azetidinones, Ezetimibe (also known under trade names Zetia™
`
`and Ezetrol®), has been in use as a cholesterol-lowering drug in
`
`monotherapy and in dual therapy combined with a statin. It is
`the first representative of the new class of cholesterol(cid:173)
`lowering drugs that inhibit intestinal cholesterol absorption by
`targeting the two scavenger receptors in the intestinal brush
`border membrane described above.
`
`However, it has been shown that the 2-azetidinones upon admini(cid:173)
`stration are readily absorbed and extensively metabolized into
`the pharmalogically active glucuronide of which over 95% re(cid:173)
`mained in the intestinal wall upon direct administration as the
`glucuronide (van Heek, M. et al. Br. J. Pharmacol. 2000, 129,
`1748-1754).
`In addition side effects such as allergic reactions
`including rash and angiodema have been reported.
`
`Applicants have now discovered that the compounds of the present
`invention with the structural characteristics as depicted in
`
`3 of 96
`
`PENN EX. 2259
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`WO 2005/033100
`
`PCT/CH2004/000584
`
`3
`
`formula I and in particular formulas II and III are able to in(cid:173)
`hibit the protein-mediated process mentioned above by which cho(cid:173)
`lesterol absorption is mediated, while overcoming the above de(cid:173)
`scribed disadvantages of compounds known in the art. Thus the
`compounds of the present invention are particularly useful in
`the treatment and prevention of atherosclerosis and for the re(cid:173)
`duction of cholesterol levels.
`
`In a first aspect, the present invention thus relates to novel
`hypocholesterolemic compounds of formula I, and in particular to
`compounds of formulas II and III having a four- or five-membered
`ring, respectively.
`
`In one embodiment, the present invention is directed to a com(cid:173)
`pound of formula I, or a pharmaceutically acceptable salt or
`solvate thereof,
`
`I
`
`wherein
`
`p
`
`x
`
`n
`
`Ra
`
`represents -N< or -C=,
`
`(sp 2 -
`represents independently of each other -CH2 - , CR1
`-co- or -cs-, wherein R1
`hybridised), 0,
`-NH-, =N-,
`represents H or NR2 , wherein R2 represents H or lower al(cid:173)
`kyl, which optionally is linked to z such that a bicyclic
`structure is formed;
`
`represents 1 or 2,
`
`represents H,
`
`lower alkyl,
`
`-OR3 ,
`
`-0(CO)R3 ,
`
`-0(CO)OR3 ,
`
`-COOR3,
`
`4 of 96
`
`PENN EX. 2259
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`WO 2005/033100
`
`PCT/CH2004/000584
`
`4
`
`P03H or halogen,
`CH=CHCOOR3 I
`wherein R3 and R4 represent H or lower alkyl,
`
`-CN,
`
`Rb
`
`represents H, OH,
`
`-0802W wherein W represents
`
`optionally
`
`aryl
`
`or
`
`heteroaryl,
`
`-0802Me,
`substituted
`OCO(CHOH) 2 COOR5 wherein R5 represents H or lower alkyl; or
`represents the formula -8p3-R6,
`
`wherein 8p3 represents a covalent bond, -0-,
`0802CHr, -0802 - , -0802- (p) C6H40- and R6 represents one of
`carbohydrate structures A-D:
`
`-OCH2-,
`
`A
`
`c
`
`wherein
`
`B
`
`D
`
`R7, Ra, Rg, Rn, Ri2, R13 and Ri4 represent independently of
`each other H,
`lower alkyl, aryl(lower alkyl), -CO-lower
`alkyl, -CO-aryl, -803 - or -P03 - ,
`
`Rm represents -CH20R16 or -COOR17 , and
`
`Ris represents
`
`-CH2 NH2 ,
`-CH20P03 - or
`-COOR17 ,
`-CH20R16 ,
`CH20803 - , wherein R16 and R17 independently of each other
`represent H,
`lower alkyl, aryl (lower alkyl) ,
`-CO-lower
`alkyl, -CO-aryl, -803 - or -P03 - ,
`
`5 of 96
`
`PENN EX. 2259
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`WO 2005/033100
`
`PCT/CH2004/000584
`
`Z
`
`Sp1
`
`Sp2
`
`5
`
`represents optionally substituted aryl or heteroaryl,
`
`represents a spacer unit, such as a straight-chain or
`branched lower alkyl group -(CH2)p-, wherein p is from 2-
`6, which is unsubstituted, mono or poly-substituted by
`OH,
`-OR1a, halogen or cyano group, wherein one or more -
`
`CH2- groups may independently be replaced by -0-, -CO-,
`co-o- I
`-o-co- I
`-NR19- I
`-and wherein R18 and
`lower alkyl;
`
`-O:=C(cid:173)
`-CH=CH- I
`-CO-NR19- I
`-NR19-CO- I
`R19 represent a hydrogen atom or
`
`represents an optional spacer unit, such as a covalent
`bond or a straight-chain or branched lower alkyl group -
`(CH2) q-, wherein q is from 1-6, which is unsubstituted,
`mono or poly-substituted by -OH,
`-0R20 , halogen or cyano
`group, wherein one or more -CH2- groups may independently
`be replaced by -0-, -co-, -C0-0-, -0-CO-,
`
`-NR21 - , -NR21 -
`-and wherein R20 and R21
`-C=C-
`-CH=CH-,
`-CO-NR21-,
`CO-,
`represents a hydrogen ~torn or lower alkyl;
`
`y
`
`represents optionally substituted aryl or heteroaryl,
`
`with the proviso, that if P = -N<, n=l, X = -co- and Sp2 repre(cid:173)
`sents a covalent bond, R6 may not represent carbohydrate struc(cid:173)
`tures A or D for Sp3 = -0- and R6 may not represent carbohydrate
`B for Sp3 = -OCH2-.
`
`Preferably, if P = -N<, n=l, X = -co- and Sp2 represents a cova(cid:173)
`lent bond, Rb may not represent H or OH and Sp3 may not represent
`a covalent bond, -0- or -OCH2-.
`
`In a preferred embodiment, the present invention is directed to(cid:173)
`wards compounds of formula I wherein P = -N<, n = 1 and X = -co(cid:173)
`' -CS-, -CH2- or -NH-.
`
`Thus, the present invention is preferably directed towards com(cid:173)
`pounds of formula IIa-d
`
`6 of 96
`
`PENN EX. 2259
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`WO 2005/033100
`
`PCT/CH2004/000584
`
`6
`
`Ila
`
`lie
`
`llb
`
`lld
`
`or a pharmaceutically acceptable salt or solvate thereof,
`
`wherein the groups Ra, Rb, Sp1 , Sp2 , Y and Z are as defined above.
`
`In another preferred embodiment, the present invention is di(cid:173)
`rected towards compounds of formula I wherein for P = -N<, -(X)n(cid:173)
`represents -OOC-, -COO-, -CONH-, -CH=N-, and for P = -C=, -(X)n(cid:173)
`represents -NH-N= or -0-N=.
`
`the present invention is directed towards compounds of
`Thus,
`formula IIIa-f:
`
`7 of 96
`
`PENN EX. 2259
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`WO 2005/033100
`
`PCT/CH2004/000584
`
`7
`
`lllb
`
`llld
`
`Ille
`
`or a pharmaceutically acceptable salt or solvate thereof,
`
`wherein the groups Ra, Rb, Sp1 , Sp 2 , Y and Z are as defined above.
`
`In a further preferred embodiment, the present invention is di(cid:173)
`rected towards compounds of formula I with P = -N< where -(X)n(cid:173)
`represents -CH-C=NR- or -CH-NH-CR- or wherein ring z is coupled
`to -(X)n- to form bicylic compounds.
`
`the present invention is further directed towards com-
`Thus,
`pounds of formula IIIg-h:
`
`/SP
`y
`
`N
`H
`
`lllh
`
`lllg
`
`8 of 96
`
`PENN EX. 2259
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`WO 2005/033100
`
`PCT/CH2004/000584
`
`8
`
`Ra preferably represents H,
`-COOR3,
`-NR3R4,
`-OR3,
`lower alkyl,
`- CN,
`- N02, S03H, P03H or halogen, more
`-CH=CHCOOR3,
`CONR3R4,
`-CF3,
`preferably H,
`lower alkyl,
`-CONR3R4 or halo-
`-COOR3,
`-NR3R4,
`-OR3,
`gen, most preferably H, lower alkyl, -OR19 or halogen, wherein R3
`and R4 represent independently of each other H or lower alkyl.
`
`-OS02W wherein W repre(cid:173)
`-OS02Me,
`Rb preferably represents H, OH,
`sents Phenyl
`(Ph} or isomers of salicylic acid (all combinations
`of disubstituted phenyl with OH and COOH substituents} i or the
`formula
`-Sp3 - R6,
`wherein Sp3 pref er ably represents a covalent
`bond, -0-, -OCH2-
`or -0S02CH2- and R6 represents one of carbohy-
`drate structures A-D, preferably carbohydrate structures A, B or
`D. More preferably Rb represents H, OH, -0S02Me, -0S02Ph; or the
`formula
`-Sp3-R6 , wherein Sp3 preferably represents a covalent
`bond, -0-, -OCH2- or -0S02CH2- and R6 represents one of carbohy(cid:173)
`drate structures A-D, preferably carbohydrate structures A, B or
`D.
`
`Sp1 preferably represents a straight-chain or branched - (CH2) m(cid:173)
`group, which is unsubstituted, mono or poly-substituted by -OH,
`-OR18, halogen or cyano group, wherein R18 represents hydrogen or
`-
`lower alkyl and mis 1 to 3. More preferably Sp1 represents a
`(CH2}3-, which is unsubstituted or substituted by -OH or halogen.
`
`Sp2 preferably represents a straight-chain or branched - (CH2}p(cid:173)
`group, which is unsubstituted, mono or poly-substituted by -OH,
`-OR20, halogen or cyano group, wherein R20 represents hydrogen or
`lower alkyl and p is 1 to 3. More preferably Sp1 represents an
`to 3, most preferably a
`unsubstituted - (CH2)p-, wherein p is 1
`covalent bond.
`
`-COOR17 or -CH2NH2, wherein RiG
`Ris preferably represents -CH20R16 ,
`and R17 independently of each other represent H,
`lower alkyl,
`-803- or -P03-,
`aryl {lower alkyl),
`-CO-lower alkyl,
`-CO-aryl,
`preferably H, acetyl or benzyl.
`
`9 of 96
`
`PENN EX. 2259
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`WO 2005/033100
`
`PCT/CH2004/000584
`
`9
`
`R 7 , Rs, R9, R 11 , R 12 , R 13 , and Ri4 preferably represent independ(cid:173)
`ently of each other H,
`lower alkyl, aryl-lower alkyl, -co-lower
`alkyl, -CO-aryl, more preferably, H, acetyl or benzyl.
`
`The term "optionally substituted aryl group" should be under(cid:173)
`stood to include an aromatic ring system having 4 to 10, pref(cid:173)
`erably 5, 6 or 10 ring atoms. The aryl group can be substituted
`with one or more substituents, which may be the same or differ(cid:173)
`ent, and are selected from a group as defined hereinafter. Non(cid:173)
`limiting examples of suitable aryl groups include phenyl, naph(cid:173)
`thalene or tetraline groups, most preferably phenyl groups sub(cid:173)
`stituted by halogeno, preferably fluoro.
`
`The term "optionally substituted heteroaryl" should be under(cid:173)
`stood to include an aromatic ring system of 5 to 14, preferably
`5 to 10, more preferably 5 to 6 or 10 ring atoms, in which one
`or more of the atoms in the ring system is/are atoms other than
`carbon, for example nitrogen, oxygen or sulfur. The heteroaryl
`can be optionally substituted by one or more substituents, which
`may be the same or different, and are selected from a group as
`defined hereinafter. Examples of suitable 6-membered heteroaryl
`groups include pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and
`the like. Examples of useful 5-mernbered heteroaryl rings include
`furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl,
`pyrazolyl, oxazolyl and isoxazolyl. Useful bicyclic groups are
`benzo-fused ring systems derived from the heteroaryl groups
`named above, e.g., quinolyl, phthalazinyl, quinazolinyl, benzo(cid:173)
`furanyl, benzothienyl and indolyl.
`
`The term "lower alkyl" should be understood to include straight
`chain and branched hydrocarbon groups having from 1 to 8, pref(cid:173)
`erably 1 to 6, more preferably from 1 to 3 carbon atoms, which
`may be optionally substituted. Non-limiting examples of suitable
`lower alkyl groups include methyl, ethyl, n-propyl, isopropyl,
`n-butyl, t-butyl, n-pentyl, fluoromethyl and trifluoromethyl.
`
`10 of 96
`
`PENN EX. 2259
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`WO 2005/033100
`
`PCT/CH2004/000584
`
`10
`
`The term "branched" should be understood to represent a linear
`straight chain hydrocarbon group having one or more lower alkyl
`groups such as methyl, ethyl or propyl, attached to it.
`
`The term "lower alkoxy" should be understood to include "lower
`alkyl-0-"-groups, wherein the lower alkyl groups are as de(cid:173)
`scribed above and have from 1 to 8, preferably 1 to 6, more
`preferably from 1 to 3 carbon atoms. Methoxy, ethoxy and isopro(cid:173)
`poxy groups are especially preferred.
`
`The term "aryl(lower alkyl)" should be understood to include an
`aryl(lower alkyl)group in which the aryl and lower alkyl are as
`previously described. Non-limiting examples of suitable
`aryl{lower alkyl) groups include benzyl, phenethyl and naphth(cid:173)
`lenylmethyl.
`
`term "optionally substituted"
`the
`If not otherwise indicated,
`should be understood to represent substituents independently se(cid:173)
`lected from the group consisting of aryl, heteroaryl, aryl(lower
`alkyl) ,
`(lower alkyl) aryl, aralkenyl , heteroaralkyl, alkylhet(cid:173)
`eroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy, ary(cid:173)
`loxy, aralkoxy, acyl, aroyl, halogen, ni tro, cyano, car boxy,
`alkoxycarbonyl, aryloxycarbonyl,
`aralkoxycarbonyl, aminoalkyl,
`alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkyl(cid:173)
`thio, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl,
`preferably lower alkyl, hydroxy, lower alkoxy, cyano, alkylthio,
`amino,
`-NH (lower alkyl), -N(lower alkyl) 2
`(which alkyls can be
`the same or different), carboxy, -C(O)O-(lower alkyl) and halo-
`gen. Those skilled in the art will recognize that the size and
`nature of the substituent(s) will affect the number of substitu(cid:173)
`ents which can be present.
`
`term "halogen"
`The
`chloro, bromo.
`iodo,
`erably, fluoro.
`
`include fluoro,
`to
`should be understood
`preferably, fluoro and chloro, most pref-
`
`It is understood that all isomers, including enantiomers,
`
`11 of 96
`
`PENN EX. 2259
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`WO 2005/033100
`
`PCT/CH2004/000584
`
`11
`
`stereoisomers, rotamers, tautomers and racemates of the com(cid:173)
`pounds of formula I and in particular the compounds of formulas
`II and III are contemplated as being part of this invention. The
`invention includes stereoisomers in optically pure form and in
`admixture, including racemic mixtures. Isomers can be prepared
`using conventional techniques, either by reacting optically pure
`or optically enriched starting materials or by separating iso(cid:173)
`mers of a compound of formula I and in particular the compounds
`of formulas II and III.
`In a pref erred embodiment the stereo-
`chemistry in the central ring is such that the substituents at
`the 3- and 4-position are in trans configuration to each other.
`
`In yet a further embodiment, preferred combinations of groups Ra
`and Rb include combinations wherein Rb is as defined hereinabove
`and is in para-position (in relation to the linker Sp2 ) and Ra is
`as defined hereinabove, most preferably H, and is in meta(cid:173)
`position.
`
`Thus in a further pref erred embodiment the present invention is
`directed towards a compound of formula IVa,
`
`IVa
`
`wherein Ra, Rb, Sp1 , Sp2 , P, X, Y, Z and n are as defined herein(cid:173)
`above.
`
`Such preferred combinations are thus compounds of formulas IIa-f
`and IIIa-h wherein Rb is as defined hereinabove and is in para(cid:173)
`position (in relation to the linker Sp 2 ) and Ra is as defined
`
`12 of 96
`
`PENN EX. 2259
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`WO 2005/033100
`
`PCT/CH2004/000584
`
`12
`
`hereinabove, most preferably H, and is in meta-position.
`
`Further preferred embodiments include combinations, wherein Sp 2
`is a covalent bond and Y and z represent optionally substituted
`phenyl rings.
`
`Thus in a further pref erred embodiment the present invention is
`directed towards a compound of formula IVb,
`
`IVb
`
`wherein Ra, Rb, Sp1 , P and X are as defined hereinabove and
`wherein R 21 and R22 pref er ably represent H, lower alkyl, lower
`alkoxy or halogen, most preferably in para-position.
`
`Such combinations are thus compounds of formulas IIa-f and IIIa(cid:173)
`h wherein Sp2 is a covalent bond and Y and z represent optionally
`substituted phenyl rings.
`
`Compounds of formula I and in particular compounds of formulas
`II and III may be prepared using methods of preparation kwnon in
`the art and are described in the following paragraphs:
`
`The 2-azetidinone portions of the compounds of formula II can be
`prepared by known methods, such as are disclosed in U.S. Pat.
`Nos. 5,631,365, 5,756,470, 5,767,115, 5,846,966, 6,207,822, U.S.
`Provisional Patent Application No. 60/279,288 filed Mar. 28,
`2001, and PCT Patent Application WO 93/02048, each of which is
`incorporated herein by reference. Compounds of formula IIa ac(cid:173)
`
`cording to the invention may then be obtained by further linkage
`
`13 of 96
`
`PENN EX. 2259
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`WO 2005/033100
`
`PCT/CH2004/000584
`
`13
`
`to appropriate carbohydrate structures using literature proce(cid:173)
`dures as illustrated by the Examples.
`
`Compounds of formula IIb may be obtained through conversion of
`~-lactams to thiolactams 1 most commonly performed with Lawes(cid:173)
`son' s reagent (Verkoyen, c. and Rademacher, P. Chem. Ber. 1985,
`118, 653-660; Yde, B. et al. Tetrahedron 1984, 40, 2047-2052;
`Steliou, K.; Mrani, M. J. Am. Chem. Soc. 1982, 104, 3104-3106;
`Clader, J. W. et al. J. Med. Chem. 1996, 39, 3684-3693}.
`
`Compounds of formula IIc may be obtained through conversion of
`~-lactams to azetidines, which may be achieved by a number of
`wellknown methods in the art, such as (1) direct one-step reduc(cid:173)
`
`tion with reducing agents of the composition AlHxC13-x1 such as
`chlorodihydroalane or alane {Jackson, M. B. et al. Aust. J.
`Chem. 1983 1 36, 779} 1 or diborane (Jackson, M. B. et al.; Aust.
`(Yamashita, M.
`J. Chem. 1983, 36, 779-788}, AlHC1 2 and DIBAL-H
`and Ojima 1 I. J. Am. Chem. Soc. 1983, 105, 6339-6342; Ojima, I.
`et al. J. Org. Chem. 1991, 56 1 5263-5277}; and (2) cyclodehydra(cid:173)
`tion of 1,3-amino alcohols using various methods (Sohar, P. et
`al. Chem. Soc. Perkin Trans. 2 2000, 287-293; Suga 1 H. et al. S.
`J. Am. Chem. Soc. 1994, 116, 11197-11198; Barluenga, J. et al.
`Tetrahedron 1996, 52, 3095-3106; Obika, S. et al. Tetrahedron
`Lett. 2003, 44, 5267-5270} as also outlined in the Examples.
`
`The preparation of compounds of formula IIIa is effected as out(cid:173)
`lined in Scheme I through initial Sharpless asymmetric amino hy(cid:173)
`droxylation reaction of the desired trans-1, 2-disubsti tuted al(cid:173)
`(Demko, z. P. et al. org. Lett. 2000, 2, 2221-2223; 0 1 B(cid:173)
`kenes
`rien1 P. Angew. Chem. Int. Edit. Eng1. 1999, 38, 326-329; Bod(cid:173)
`kin, J. A.; McLeod, M. D. J. Chem. Soc. Perkin Trans. 1 2002 1
`2733-2746}, followed by chromatographic separation to obtain the
`desired regioisomeric product. Subsequent cleavage of the para(cid:173)
`toluene sulfonamide group furnishes a primary amine which upon
`Buchwald-Hartwig arylation reaction (Hartwig 1 J. F. Ace. Chem.
`Res. 1998, 31, 852-860; Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.;
`
`14 of 96
`
`PENN EX. 2259
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`WO 2005/033100
`
`PCT/CH2004/000584
`
`14
`
`Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805-818) and subse(cid:173)
`
`quent exposure to triphosgene eventually leads to the formation
`of the desired oxazolidinones of formula IIIa. Alternatively,
`they can be accessed as outlined in the Examples.
`
`Sharpless Asymmetric
`Am inohydroxylation
`Ar3~Ar4 --------,i~
`=
`OH
`Ar3- \_
`OTBS
`Ar4 K
`~,
`
`OnN.._Ar1
`
`0
`
`§
`OTBS HN,A
`r1
`
`OH
`Ar3~Ar4
`OTBS
`NHTs
`
`a) Triphosgene ~OH
`Ar3
`Ar3
`
`b) TBAF
`
`OH
`Ar3~Ar4
`OTBS
`NH2
`
`I Buchwald-Hartwig
`~ arylation reaction
`
`Scheme 1
`
`Compounds of formula IIIe may be obtained e.g. as illustrated in
`Scheme II using known methods in the art (Mish, M. R. et al. J.
`Am. Chem. Soc. 1997, 119, 8379-8380; Guerra, F. M. et al. Org.
`Lett. 2000, 2, 4265-4267). Alternatively, compounds in which sp2
`is not a covalent bond can be synthesized as demonstrated in the
`Examples.
`
`R~Xc
`0
`
`a) KOH
`b) (COClh
`
`TBAF
`
`J
`R
`Buchwald-Hartwig
`Ar2,,,'I
`arylation
`Ar2,,,,!!,,,,C02Bn
`
`'('C02Bn
`
`In analogy with
`ref. mentioned
`above
`
`Ar 1
`
`N~N
`'so2CH2CH2SiMe3
`
`HN~N
`'so2CH2CH2SiMe3
`
`Scheme II
`
`15 of 96
`
`PENN EX. 2259
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`WO 2005/033100
`
`PCT/CH2004/000584
`
`15
`
`The preparation of pyrazolidinones of formula IIIc proceeds in
`an analogous strategy to that reported in the literature as il(cid:173)
`lustrated in Scheme III (Lou, B. S. et al. J. Org. Chem. 1995,
`
`60, 5509-5514; Tomkinson, N. C. 0. Rodd's Chemistry of Carbon
`Compounds (2nd Edition), Asymmetric Catalysis, Ed. M. Sainsbury
`2001, 5, 199-258).
`
`Scheme III
`
`It has been found that the use of sulfonate linkages in e.g. the
`Rb or Sp3 group,
`i . e. 1 inking carbohydrates to the phenylene
`ring is particularly beneficial in that the S=O double bonds in
`the linkages may function as hydrogen bond acceptors compared to
`the more non-polar nature of a C-glycoside linkage. Such link(cid:173)
`ages have not yet been reported to link carbohydrates to other
`kinds
`of molecules.
`Furthermore
`the
`linkages
`are
`hydrolyzable, i.e. the carbohydrates are not hydrolyzed off.
`
`non-
`
`It has further been shown that the compounds of the invention
`display superior pharmacological activities and are able to
`overcome the drawbacks of known cholesterol-lowering agents us(cid:173)
`ing well-established methods in the art, e.g. evaluation of
`their ICso value for cholesterol uptake in rabbit brush border
`membrane vesicles (BBMV) as well as in Caco-2 cells (Hauser, H.
`et al, Biochemistry 1998, 37, 17843-17850; Schulthess, G. et al,
`Biochemistry 2000, 39, 12623-12631; Werder, M. et al, Biochemis(cid:173)
`try 2001, 40, 11643-11650; Boffelli, D. et al. FEBS Lett. 1997,
`
`16 of 96
`
`PENN EX. 2259
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`WO 2005/033100
`
`PCT/CH2004/000584
`
`411, 7-11) (see also Table I) .
`
`16
`
`Thus, the compounds of the invention, e.g. compounds of formula
`I and their pharmaceutically acceptable acid addition salts, ex(cid:173)
`hibit pharmacological activity and are, therefore, useful as
`pharmaceuticals. The compounds of the invention have been shown
`to effectively inhibit cholesterol absorption and are therefore
`useful in the treatment and/or prevention of atherosclerosis and
`of the reduction of cholesterol levels.
`
`Thus in yet a further aspect, the present invention is directed
`to a method of treatment and/or prevention of atherosclerosis,
`of the reduction of cholesterol levels and of treating or pre(cid:173)
`venting a vascular condition, comprising administering to a mam(cid:173)
`mal in need of such treatment an effective amount of a compound
`of formula I and in particular a compound of formulas II and
`III.
`
`The novel compounds of formula I can be used, for example, in
`the form of pharmaceutical compositions containing a therapeuti(cid:173)
`cally effective amount of the active ingredient, if appropriate
`together with inorganic or organic, solid or liquid, pharmaceu(cid:173)
`tically acceptable carriers suitable for enteral, e.g. oral, or
`parenteral administration. Accordingly, tablets or gelatin cap(cid:173)
`sules are used that contain the active ingredient together with
`diluents, typically lactose, dextrose, saccharose, mannitol,
`sorbitol, cellulose and/or lubricants, e.g. diatomaceous earth,
`talcum, stearic acid or salts thereof, such as magnesium
`stearate or calcium stearate, and/or polyethylene glycol. Tab(cid:173)
`lets may also contain binders, typically magnesium aluminium
`silicate, starches, typically corn starch, wheat starch, rice
`starch or arrow root starch, gelatin, tragacanth, methylcellu(cid:173)
`lose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone,
`and, if desired, disintegrators, typically starches, agar,
`alginic acid or a salt thereof, e.g. sodium alginate, and/or ef(cid:173)
`fervescent mixtures, or absorbents, colourants, flavourings and
`
`17 of 96
`
`PENN EX. 2259
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`WO 2005/033100
`
`PCT/CH2004/000584
`
`sweeteners.
`
`17
`
`Thus in another aspect, the invention relates to a pharmaceuti(cid:173)
`cal composition comprising a compound of formula I, and in par(cid:173)
`ticular a compound of formulas II and III (and optionally other
`therapeutically effective agents), and a pharmaceutically ac(cid:173)
`ceptable carrier for the treatment or prevention of artherio(cid:173)
`sclerosis or for the reduction of cholesterol levels.
`
`The terms "effective amount" and "therapeutically effective
`amount" mean that amount of a compound of formula I and in par(cid:173)
`ticular compounds of formulas II and III (and optionally other
`therapeutically effective agents) , that will elicit a biological
`or medical response of a tissue, system, animal or mammal, which
`includes alleviation of the symptoms of the condition or disease
`being treated and the prevention, slowing or halting of progres(cid:173)
`sion of one or more conditions, for example atherosclerosis, hy(cid:173)
`percholesterolemia.
`
`The pharmaceutical compositions so obtained which, if desired,
`contain further pharmacologically active substances, are pre(cid:173)
`pared in a manner known per se by conventional mixing, granulat(cid:173)
`ing, sugar-coating, solution or lyophilising methods and contain
`from about 0.1% to 100%, preferably from about 1% to about 50%,
`lyophilisate to about 100%, of active ingredient.
`
`The compounds, compositions and treatments of the present inven(cid:173)
`tion can be administered by any suitable means which produce
`contact of these compounds with the site of action in the body,
`for example in the plasma, liver or small intestine of a mammal
`or human. Thus the novel compounds of formula I may also be
`used in the form of compositions for parenteral, oral, transder(cid:173)
`mal administration or infusion solutions. Such solutions are
`preferably isotonic aqueous solutions or suspension which, e.g.
`in the case of lyophilised compositions that contain the active
`ingredient by itself or together with a carrier, such as manni-
`
`18 of 96
`
`PENN EX. 2259
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`WO 2005/033100
`
`PCT/CH2004/000584
`
`18
`
`tol, can be prepared before use. The pharmaceutical compositions
`can be sterilised and/or can contain excipients, typically pre(cid:173)
`servatives, stabilisers, wetting agents and/or emulsifiers,
`solubilisers, salts for regulating the osmotic pressure and/or
`buffers.
`
`In yet a further aspect, the invention relates to a kit compris(cid:173)
`ing an effective amount of a compound of formula I and in par(cid:173)
`ticular a compound of formulas II and III in a pharmaceutically
`acceptable carrier (and optionally an effective amount of an(cid:173)
`other therapeutically effective agent), optionally in separate
`compartments.
`
`The following non-limiting Examples illustrate the above(cid:173)
`described invention in more detail.
`
`EXAMPLES
`
`Materia1s and Methods: Reactions in anhydrous solvents were all
`performed using oven dried glassware under an atmosphere of ar(cid:173)
`gon.
`Reagent grade sol vents were all purchased from chemical
`companies and used without prior purification. For chromatic pu(cid:173)
`technical grade sol vents were distillated prior to
`rification /
`use. TLC was performed using Machery-Nagel Alugram Sil G/UV2 s4
`TLC plates and visualized with ultraviolet light at 254 nm and
`12 g phosphor molybdic acid in 250 mL EtOH or 10% H2S04 in MeOH
`(v/v) . Chromatographic purification of products was accomplished
`using dry column vacuum chromatography on Merck Silica Gel 60
`(15 - 40 µm) according to literature procedures (Pedersen, D. S.
`and Rosenbohm, C. Synthesis 2001, 2431-24