PCT
`
`WORLD INTELLECl1JAL PROPERTY ORGANIZATION
`ln1emational Bureau
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) International Patent Classification 4 :
`C07C 69/738, 69/732, 59/90
`C07C 59/56, 59/34
`C07D 309/30, A61K 31/365
`A61K 31122. 31/19
`
`Al
`
`(11) Ioternatlonal Publication Number: · W086f03488
`
`(43) International Publication Date:
`
`· 19June"1986 (19.06.86)
`
`(21) Intenaatlonal Application Number:
`
`PCT/EP85/00653
`
`(22) International Filing Date: 29 November 1985 (29.11.85)
`
`(31) Priority Application Number:
`
`677,917
`
`(32) Priority Date:
`
`(33) Priority Country:
`
`4 December 1984 (04.12.84)
`us
`
`(71) Applicant: SANDOZ AG [CH/CH]; Lichtstrasse 35,
`CH-4002 Basel (CH) ..
`
`(72) Inventors: KATHA WALA. Faizulla, G. ~ 39 Woodland
`Avenue, Mountain Lakes, NJ 07946 (US). WA IT AN(cid:173)
`ASIN, Sompong ; 39 3A Eagle Rock Village, Budd
`Lake, NJ 07828 (US).
`
`(81) Designated States: AT (European patent), AU, BE (Eu(cid:173)
`ropean patent), CH (European patent), DE (Euro(cid:173)
`pean patent), DK. Fl; FR (European patent); GB
`(European patent), HU, IT (European ·patent), JP,
`KR. LU (European patent), NL (European patent),
`SE (European patent).
`·
`
`Published
`:
`With international sea~h report.
`Before the expiration of the .time"limit for amending tire
`claims and to be republished in the event of the receipt
`of amendments.
`
`(54)Title: INDENE ANALOGS OF MEVALONOLACTONE AND DERIVATIVES THEREOF
`
`RP.?t~z
`
`2
`
`1
`
`(I)
`
`R
`
`~R5 (II)
`
`-c-
`- c -
`~ ' ,{ .....
`I p
`R7 R7
`
`or ·CH•
`. ' <ivJ
`·OH
`
`R
`~ 3• 10
`- -CHz·C-CHzCOOH
`bH
`'
`
`(III)
`
`-~H-
`OH
`
`(V)
`
`~
`
`(57) Abstract
`
`Compounds of formula (I). wherein R is hydrogen or primary or secondary C 1-6alkyl, R 1 is primary or secondary
`C 1-6alkyl or Rand R1 together are (CHi)m or (Z)-CH:rCH=CH-CHi- wherein mis 2, 3, 4, 5 or 6, Ro is C 1-6alkyl, C3•7cyc(cid:173)
`loalkyl or ring A (ll) each or R2 and R.i is independently hydrogen, C 14alkyl, C 14alkoxy (except t-butoxy), trifluorome- .
`thyl, fluoro, chloro, phenoxy or benzyloxy, each of RJ and Rs is independently hydrogen, C1.3alkyl, C1.3alkoxy, trifluor(cid:173)
`omethyl, fluoro, chloro, phenoxy or benzyloxy, ~is hydrogen, C1•2alkyl, C 1•2alkoxy, fluoro or chloro, with the· proviso
`that there may only be one each of trifluoromethyl, phenoxy or benzyloxy on each of the phenyl and indene ·rings X is -
`(CH2)~ - or - (CHi) CH c:: CH(CHi)q· wherein n. is I, 2 or 3 and both q's are 0 or one is 0 and the other is I, ai;id Z is (III J
`wherein Q is (JV) wfterein each R7 is the same primary or secondary C 1-6alkyl or together they represent -(CHui-. -(CHi)3-
`• Rio.is hydrogen orC 1.3alkyl, with the proviso that Q may be other than (V) only when X is-CH=CH-or-CHrCH=CH(cid:173)
`and/or R 1o is C 1.3alkyl, in free acid form, or in the form of an ester or -lactone thereof or in salt form as appropriate, which
`are indicated for use as hypolipoproteinemic and anti-atherosclerotic agents.
`
`1 of 56
`
`PENN EX. 2254
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international appli(cid:173)
`cations under the PCT.
`
`AT Austria
`AU Australia
`BB Barbados
`BE Belgium
`BG Bulgaria
`BR Brazil
`CF Central African Republic
`CG Congo
`CH Switzerland
`CM Cameroon
`DE Gennany, Federal Republic or
`DK Denmark
`fl
`Finland
`FR
`France
`
`GA Gabon
`GB Un\icd l{jogdom
`HU Hungary
`IT
`Italy
`JP
`Japan
`KP Demoaalic People's Republic
`of Korea
`KR RepubllcofKorca
`LI
`Liechlcnstcin
`LK
`Sri Lanka
`LU Luxembourg
`MC Monaco
`MG Madagascar
`ML Mali
`
`MR Mauritania
`MW Malawi
`NL Nelherlands
`NO Norway
`RO Romania
`SD Sudan
`SE Sweden
`SN Senegal
`SU Soviet Union
`TD Chad
`TG Togo
`US United States of America
`
`2 of 56
`
`PENN EX. 2254
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`W086/03488
`
`PCT/EP8S/006S3
`
`INDENE ANALOGS OF ~VALOHOLACTONE AND DERIVATIVES THEREOF
`The invention concerns indene analogs of mevalonolactone and derivatives
`..
`thereof, processes for their production, pharmaceutical compositions
`containing them and their use as pharmaceuticals in particular as hypoii(cid:173)
`poproteinemjc and anti-atherosclerotic agents.
`The invention is especially concerned with compounds of formula I.
`
`~.
`
`I
`
`R3~1 o
`-z
`2
`1
`wherein R is hYdrogen or primary or secondary c1_6alkyl,
`R1 is primary or secondary t
`6alkyl or
`_
`1
`R and R1 together are (CH2)m or (Z)-CH2-CH=CH-CH2-
`wherein m is 2, 3, 4, 5 or 6,
`Ro is c1_6alky1, c3~:~1 or ring A
`
`4 is independently hydrogen, c1
`4alkyl, c1_4alkqxy (except
`each of R2 and R
`
`_
`t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benz¥1oxy,
`
`each of R3 and R5 is independently hydrogen, c1
`3alkyl, c1
`3alkoxy, trifluoro(cid:173)
`
`_
`_
`methyl, fluoro, chloro, phenoxy or benzyloxy,
`is hydrogen, c1
`alkyl, c1
`alkoxy, fluoro or chloro,
`_
`R
`_
`2
`6
`2
`with the proviso that there may only be one each of trifluorom~thyl, phenoxy
`or benzyloxy on each of the phenyl and indene rings
`X is -(CH2>n- or -(CHZ)qCH=CH(CHZ)q-
`wherein n is 1, Z or 3 and both q 1 s are 0 or one is O and the other
`is 1,
`
`R
`5..
`3110
`and Z is -1'-CH -C-CH COOH
`2 AH 2
`
`II
`
`wherein Q is -H1
`
`-,
`0
`
`·or -CH(cid:173)
`' OH
`
`- C -
`c( 0
`I
`I
`R7 R7
`
`3 of 56
`
`PENN EX. 2254
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`W086/03488
`
`PCT/EPSS/00653 ·
`
`-2-
`wherei n each R7 is the same primary or secondary c1_6alky1 or.together
`they represent -(CH2l 2-, -(CH2l 3-,
`alkyl,
`R10 is hydrogen or c1
`_
`3
`with the proviso that Q·may be other than -CH- only when X is -CH=CH- or
`I
`-cH
`alkyl,
`OH
`-cH=CH- and/or R10 is c1
`_
`3
`2
`in free acid form, or in the form of an ester or
`salt form as appropriate.
`Suitable esters include physio.logically acceptable esters e.-.9· ·ph~siolo­
`gically hydrolysable and -acceptable esters.
`By the term 11physiologically-hydrolysable and -acceptable ester 11 is
`meant an ester of a compound in accordance with the invention in which.the.
`carboxyl moiety if present is esterified, and which is hydrolysable:under
`physiological conditions to yield an alcohol which is itself p;hysiolog~fally
`acceptable, e.g. non-toxic ~t desired dosage levels. For the avoidance: of
`doubt, throughout this application it is the right hand side of the x radical
`that is attached to the Z group. Preferred such esters as Z can be ;epresented
`together with the free acid by formula Ila
`
`-lactone thereof :or:in.
`
`or formula Ile
`
`Q •
`
`II a
`
`Ile
`
`~10
`-CH-CH -C-CH -COOR
`2 I
`I
`2
`11
`OH
`OH
`~10
`-Q'-CH2-f-CH2-cooR11
`OH
`wherein R11 is hydrogen, c1_4alkyl or benzyl preferably hydrogen,
`C1_3alkyl, n-butyl, i-butyl, t-butyl or benzyl,
`is -c- or f 'o and
`8.
`A R
`7 7
`R7 and R10 are as defined above with the further proviso· that R
`11
`(fc'o
`is other than hydrogen when Q' is
`I
`I
`R7 R7
`When lia i.s in salt form R11 represents a cation.
`When Z is in lactone form it forms a &-lactone of formula lib
`
`4 of 56
`
`PENN EX. 2254
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`W086/03488
`
`PCT/EPSS/00653
`
`-3-
`
`lib
`
`, .
`
`and references to 11 l actone 11 hereinafter ref er to o-1 actones~.
`Salts of the compounds of the invention, e.g. of the compounds of
`formula I, include in particular their pharmaceutically acceptable salts.
`.
`.
`Such pharmaceutically acceptable salts include e.g. alkali metal :salts such
`as the sodium and potassium salts and salts with anrnonium.
`References to compounds of formula I, II, Ila, IIb and Ile and sub(cid:173)
`species thereof are intended to cover all forms unless otherwise stated.
`Depending on the nature of R1 and R the compounds of formula I may be
`divided into two main groups, namely, those wherein R is hydrogen or primary
`or secondary c1_6alkyl (Group IA) and those wherein ~l and R together represent
`-(CH2)m- or (Z)-CH2-CH=CH-CH2- (Group IB). These groups may be further divided
`depending on the nature of Z, namely when Q is -9H- and the Z is in other·
`OH
`than lactone form (sub-group "a"); when Z is a group of formula Ilb {sub-group
`"b"); and when Q is -c- or -~c, and Z is in other than lactone form {sub-
`0
`11
`group "c 11
`0
`~
`7 7
`The resulting six groups are designated as IAa, !Ab, IAc, IBa, IBb, IBc.
`As is self-evident to those in the art, each compound of' Groups IAa,
`!Ab, IBa and IBb (and every subscope and species thereof) has two centres
`of asynmetry (the two carbon atoms bearing the hydroxy groups in the group
`of formula Ila and the carbon atom bearing the hydroxy group and the carbon
`atom having the free valence in the group of formula lib and, therefore,
`there are four stereoisomerk forms (enantiOmers) of each compound (two race(cid:173)
`mates or pairs of diastereoisomers), provided that" R and R1 are identical
`or taken together are -(CH2Jm- or (Z)-CH2-CH=CH-CH2- and_that·Rll does not
`contain any centre of asymmetry. The four stereoisomers may be designated
`.
`.
`as the R,R, R,S, S,R and S,S enantiomers, all four stereoisomers being within
`the scope of this invention. When R and R1 are different and/or R11 contains
`one or more centres of asynmetry, there are eight or more stereoisomers. ·
`
`) .
`
`5 of 56
`
`PENN EX. 2254
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`W086/03488
`
`PCT/EPSS/00653.
`
`-4-
`Si nce it is preferred that Rand R1 be identical or taken together ~{CH2 lm-;
`or { Z )-CH
`-CH=CH-CH
`does not contain a centre of asymmetr.y
`- and that R
`2
`11
`2
`and for reasons of simplicity any additional stereoisomers resulting from
`the presence of a centre of asyirmetry in.the 1-position of the;indetie ring
`and/or one or more centres of asynmetry in R11 wi 11 usually be: fgnored, it ...
`being assumed that R and R1 are identical or take.n together are ~(cH2 l~: or
`{ Z )-CH
`-CH=CH-cH2
`- and that R11 is free of centres of asymmetry. As.· 1 s · a 1 so.
`2
`self-evident each compound of Groups IAc and IBc (and every subscope and ·
`species thereof) has one centre of asynmetry (the carbon atom.bearing the
`hydroxy group in formula Ile and therefore there are two enan~iomers· of' each
`compound, provided that R and R1 are identical or taken together are -(CH2 ~m
`or (Z)-CH2-CH=CH-CH2
`- and that R11 does not contain any centre of as~try.
`The two stereoisomers may be designated as. the 3R and 3S. is~m~rs, both. ,being
`w.ithin the scope of this invention. When R and R1 are different and/or R11
`contains one or more centres of asy11111etry, there are four or more stereo-
`i somers. For the reasons set forth above, any additional stereof somers ·
`resulting from the presence of a centre of asynnetry in the ·1~posi~i.on .of
`the indene ring and/or one or more centres of asyt1111etry in R11 will usually
`be ignored.
`Ro preferably does not contain an asynmetric carbon atom and i.s prefer.(cid:173)
`ably Ro' where Ro' is c1_4alkyl not containing an asymmetric ~arbo~ atom
`is R~',
`or Ring A, more preferably Ro 11
`, wherein Ro" is ring A wherei.n.R
`4
`RS is Rs'. and R6 1s R6
`1 even more preferably Ro" 1 where Ro'"'. i.s ring .A
`wherein R4 is R4
`, Rs is Rs" and R6 is R6
`11 and most preferably ·R:o'"' wherein
`Ro"" is ring A wherein R4 is R4
`, Rs is Rs"' and R6 is R6
`, . in, Ro"" R4
`is preferably R4" 11
`When R is hydrogen or primary or secondary c1_
`alkyl it is. prefe~ably.
`6
`hydrogen or primary or secondary c1_6alkyl not containi:ng an as~etric carbon
`, where R1 is hydrogen or prim.ary or. secondary ch4-
`atom and is preferably R1
`alkyl not containing an asynmetric carbon atom, more preferably R" wh~re ·
`R" is hydrogen or c1_2alkyl and most preferably c1_
`alkyl and:Rl is preferably
`2
`primary or secondary c1_6alky1 not containing any asynmetric carbon atom
`and is preferably R1 ', where R1 ' is primary or secondary c1_4a1.kyl not.
`, where R1" is c1.;.
`containing an asymmetric carbon atom, more preferably R1
`a.lkyl, and most preferably c1
`alkyl.
`_
`2
`
`11
`
`-
`3
`
`11
`
`•
`
`111
`
`111
`
`11
`
`•
`
`•
`
`6 of 56
`
`PENN EX. 2254
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`W086/03488
`
`PCT/EP8Sf00653
`
`11
`
`1
`
`1
`
`1
`
`11
`
`-5-
`Prferably, when R, R1
`, etc., as
`, etc. is other than hydrogen, R, R1
`the case may be, is identical to Rl' R1 •, etc., as the case may be. ·
`When R and R1 taken together are -(cH2)m- or (Z)-CH2-CH:;CH-CH2 ~. they
`are preferably -(CH2)m-' more preferably -(CH2)m,-· even more preferably
`-(CHz)m11 - and most preferably -(CHZ)m111 - 1 especially -(CH2)4-, wherein m is
`as defined above, and m1
`1 m11 and m111 are as defined below.
`R2 is preferably hydrogen, c1_3alkyl, n-butyl, i-butyl, t:-butyl, ~1 _3 -·
`a 1 koxy t n-butoxy t
`i-butoxy, tri fl UOromethyl t fl uoro t ch 1 OrQ t phenox~ Or
`benzyloxy and is preferably R2', where R2
`1 is hydrogen, c1 ~3alkyl, methoxy,
`fluoro, chloro or benzyloxy, more preferably R2
`, where R211 is hydrogen or
`
`c1_3alkyl, and most preferably hydrogen.
`1 is hydrogen.or c1_3alkyl, and inore
`R3 is preferably R3
`, where R3
`preferably hydrogen.
`Preferably, not more than one of R2 and R3 is a member ~f the group
`consisting of !-butyl, trifluoromethyl, phenoxy and benzyloxy. More prefer(cid:173)
`ably, R2 and R3 are not ortho to each other unless at leas·t one .of them ts
`a member of the group consisting of hydrogen, c1_2alkyl, c1_2a,lkoxy', fluoro
`and chloro.
`R4 is preferably hydrogen, c1_3alkyl, n-butyl, i-butyl, t-butyl, c.1_3-
`alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, P,henoxy or
`1 is hydrogen, c1_3alkyl, trifluoro(cid:173)
`·benzyloxy and is preferably R4
`, where R4
`, where R4" is hydroge.n or c1 _2-
`methyl, fluoro or chloro, more preferably R4
`alkyl, and most preferably R4
`" , where R4111 is hydrogen or met,hyl, especially
`
`R4
`1111 is hydrogen or 3-methyl.
`, where R4
`R5 is preferably Rs'• where Rs' is hydrogen, c1_2alkyl, fluoro or. chloro,
`more preferably Rs 11
`, where Rs" is hydrogen or fluoro, and most preferably
`Rs", where R5 11 is hydrogen or 4-fl uoro.
`1 is hydrogen or c1_2alkyl, more preferably
`R6 is preferably R6', where R6
`R6
`
`, whe~e R611 is hydrogen or methyl, and most preferably,R6" 1 ,.where R6
`is hydrogen or 5-methyl.
`Preferably, not more than one of R4 and R5 is a member of the gro,up
`consisting of !-butyl, trifluoromethyl, phenoxy and benzyloxy. More preferably
`, etc.)
`, R4", etc.), Rs ·cRs'• Rs 11
`no two of R4 lR4
`, R6
`• etc .• ) and R6 (R6
`are ortho to each other unless at least one member of eac~ pair. of sub.sti(cid:173)
`tuents that are ortho to each other is a member of the group consisting of
`- -
`.
`hydrogen, C1_2alkyl, c1_2alkoxy, fluoro and chloro.
`
`1111
`
`11
`
`1
`
`111
`
`1
`
`11
`
`:
`
`7 of 56
`
`PENN EX. 2254
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`W086/03488
`
`PCT/EPSS/00653
`
`1
`
`11
`
`-6-
`The preferred R4-bearing phenyl groups are phenyl, 4-flUOf;'Ophenyl •. 3,4-
`and 3,5-dimethylphenyl, 4-fluoro-3-methylphenyl and 3,5-dimethyl:-4-fluoro(cid:173)
`.phenyl, with 4-fluorophenyl and 3,5-dimethylphenyl being mo~e preferred;
`Preferably each R7 is c1_3alkyl or both R7
`1 s taken togethe/.are:(CH2.>2·
`or (CH2 >3; more preferably each R7 is c1_2alkyl or both R7
`1 s taken together.
`)3 and most preferably each R7 is c1_2alkyl.:
`are {CH2}2 ·or {CH
`2
`R10 is preferably R10 •, where R10 • is hydrogen or methyl,:and more
`preferably hydrogen.
`1 is hydrogen, c1 _3alkyl~ n-brityl,
`, where R11
`R11 is preferably R11
`11 is hydroge.n or c1_3-
`i-butyl, t-butyl or benzyl especially R11
`11 where R11
`• which is hydrogen or c1_2alkyl.
`alkyl, more preferably R11
`Compounds of formula I wherein Z is of formula II, Ila.or. Ile are most
`preferably in salt form. Preferred salt•forming cations are those tree'from
`centres of asymmetry especially e.g. sodium, potassium or ammonium, most
`.
`.
`preferably sodium. Such cations may also be di- or tri-valent and are balanced
`by 2 or 3 carboxyl ate containing anions. Any -CH=CH- containing bridge as ..
`X is preferably trans i.e. {E).
`X is preferably X' which is CH2CH2 or -(E}-CH=CH-, more preferably -{E)(cid:173)
`CH=CH-.
`Z is preferably a group o~ formula iia, IIb or Ile whereip ,R10: fs~R10 •
`(especially hydrogen) more preferably a group of formula na, !lb or Ile,
`1 or a cation even more preferably
`wherein R10 is hydrogen and R11 is R11
`a group of formula Ila or !lb whereinR10 is hydrogen, and R11 is R11
`11 or·
`a cation;and most preferably a group of formula Ila wherein R10 is hydrogen,
`.
`and R11 is a cation, especially sodium.
`mis preferably m', where m' is 2, 3, 4 or 5, more preferably m",.where
`m11 is 2, 3 or 4, and most preferably m'", where m'" is 2 or 4, espe~ialJy-4.
`n is preferably 2.
`As between otherwise identical compounds of formula I, those wherein
`Z is other than lactone form are generally prefer~ed over thos~ wherein.Z
`is a group of formula IIb, with those wherein Q is CH being gene,rally
`preferred over those wherein Q has.another meaning.OH
`·
`.
`
`8 of 56
`
`PENN EX. 2254
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`WO 86/03488
`
`PCTfEP8Sj006S3.
`
`-7-
`Insofar as the compounds of Groups IAa and !Ba and each of t.he subgroups
`thereof are concerned, the erythro isomers are preferred over the threo
`isomers, erythro and threo referring.to the relative positions.of the hydroxy
`groups in the 3- and 5-positions of the group of formula Ila.
`Insofar as the compounds of Groups !Ab and IBb and each of the subgroups
`thereof are concerned, the trans lactones are generafly preferred over the
`cis lactones, cis and trans referring to the relative positions of R10.and
`· ·
`the hydrogen atom in the 6-position of the group of formula Ilb. :
`The preferred stereoisomers of the compounds of formula I tiavi!"g only
`two centres of asymnetry wherein X is -CH=CH~ or -cH2-cH=CH- and:z is a gr~up
`of formula Ila are the 3R,5S and 3R,5R isomers· and the racemate of which
`each is a constituent, i.e. the 3R,SS-3S,SR (erythro) and 3R,SR-3S,SS (~)
`racemates, with the 3R,SS isomer and the racemate of which it is a constituent
`being more preferred and the JR,55 isomer being most preferred.
`The preferred stereoisomers of the compounds of formula I having only
`two centres of asyrrmetry wherein X is -( CH2) n - or -CH=CH-CH2- ~and z .. is .a
`group of formula Ila are the 3R,5R and 3R,5S isomers and the racemate of
`which each is a constituent, i.e. the 3R,SR-3S,SS (erythro) ~nd 3R,SS-3S,SR
`(three) racemates, with the 3R,5R isomer and the racemate of which it is
`a constituent being more preferred and the 3R,SR isomer b~ing :most pre,ferre.d.
`The preferred stereoisomers of the compounds of formula l having only
`two centres of asymnetry wherein X is -CH.=CH- or -cH2CH=CH- and Z f s a group
`of formula Ilb are the 4R,6S and 4R,6R isomers and the racemate of which
`·
`each is a constituent, i.e. the 4R,65-4S,6R <!!::!!!! lactone) and l\R,6R-.4S,6S
`(cis lactone) racemates, with the 4R,6S isomer and the racemate of whi,ch
`it is a constituent being more preferred and the4R,6S isomer bein~ most
`preferred.
`The preferred stereoisomers of the compounds.of formula I having onJy.
`two centres of asynmetry wherein Xis -(CH2)n- or -CH=CH-cH2,:and Z is a
`group of formula Ilb are the 4R,6R and 4R,6S isomers and the racemate of
`which each is a constituent, i.e. the 4R,6R-4S,6S (trans lactone) and 4R,6S-
`4S,6R leis lactone) racemates, with the 4R,6R isomer and the racemate of
`which it is a constituent being more preferred and the 4R,6R ~somer being
`most pref erred.
`
`9 of 56
`
`PENN EX. 2254
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`W086/03488
`
`PCT/EPSS/00653
`
`-8-
`The preferences set forth in the preceding four paragraphs also apply
`to the compounds of Groups IAa, IAb, IBa, IBb having more than .two cent~es
`of asymnetry and represent the preferred configurations of the 'indic.ated
`positions.
`The preferred stereoisorners of the compounds of formula I ·having just
`.
`-CH-
`.
`. ·
`one centre of asynmetry wherein Q is other than
`'
`are the 3R isomers and ·
`OH
`,
`.
`the racemate. of which they are constituents i.e. the 3R-3S racemate·with
`the 3R isomer being more pref erred. These preferences a 1 so apply to : the ·
`compounds of Groups IAc and IBc having more than one centre of:asyrrmetry
`and represent the preferred configuratfon of the indicated. posit.ion.
`Each of the preferences set forth above applies, not only to the
`compounds of formula I, but also to the compounds of Groups IAa, IAb, IAc,
`IBa, IBb and IBc as well as to every subgroup thereof set :forth in ~he speci(cid:173)
`fication, e.g. Groups (i) et seq., unless otherwise indicated.· When any_
`preference contains a variable, the preferred significances of that variable
`apply to the preference in question, unless otherwise indicated •.
`Preferred groups of compounds of formula I include the compounds
`(i) of Group IAa wherein Ro 1s Ro', R is R', R1 is R1', R2 _is R2', R3
`is R3
`, R10 is R10 •, R11 is R11 • and Xis X',
`(ii) of {i) wherein Ro is Ro", R10 is hydrogen, R11 .i_s R11 ••, and Xis
`(E)-CH=CH-,
`(iii) of {ii) wherein Ro is Ro'", R is R", R1 is R1
`, or especially a cation,
`is hydrogen, and R11 is R11
`
`{iv) of (iii) wherein Ro is Ro"' wherein R4111 is R4
`R1 is c1_2alkyl and R2 is hydrogen
`{v) of (iv) wherein R11 is a cation. especially sodium, _potassi_um or
`anmonium, especially sodium,
`(vi) of Group IAb wherein Ro is Ro' , R is R' , R1 is R1 ' , : R2_ is R2' ,
`R3 is R3
`, R10 is R10 •, and xis X',
`(vii) and (vi) wherei_n Ro is Ro", R10 is hydrogen, and X 1.5 (E~-CH=CH-,
`, R2 is R211 and
`
`(viii) .of (vii) wherein Ro is Ro"', R is R", R1 is R1
`·
`R3 is hydrogen,
`
`{ix) of (viii) wherein .Ro is Ro"" wherein R4111 is R4
`R1 is c1_2alkyl and R2 is hydrogen,
`
`1
`
`1
`
`111
`
`11
`
`, R2 _is R2"_, R3
`
`11
`
`" , R is c1_2a.l_kyl,
`
`11
`
`1111
`
`, R i,s c1 _2alky1,
`
`10 of 56
`
`PENN EX. 2254
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`W086/03488
`
`PCT/EPSS/00653 ·
`
`R
`2
`
`1
`
`1
`
`111
`
`R11
`
`11
`
`, and X'is
`
`11
`
`, R
`3
`
`is hydrog.en, R.11 is
`
`111 is R4
`
`1111
`
`, R2. ishydrogen,
`
`-9-
`taken togeth,er.are -'.(CH2)in-'
`(x) of Group IBa wherein Ro is Ro', Rand R
`1
`is R2
`, R10 is R10 •, R11 is R11 •, and xis x•,'
`, R3 is R3
`·
`(xi) of (x) wherein Ro is Ro", R10 is hydrogen, R11 is R11
`(E)-~H=CH-,
`is R
`(xii) of (xi) wherein Ro is Ro"• , R
`2
`2
`, particularly a cation, and m is m',
`(xiii) of (xii) wherein Ro is Ro 1111 wherein R4
`and mis m",
`(xiv) of (xiii) wherein R11 is a cation in particular sodi~m, :potassium
`or anmonium, especially sodium,
`(xv) of Group IBb wherein Ro is Ro', R and R1 taken together are :-(CH2)m(cid:173)
`R2 is R
`, R
`is R
`, R10 is R10 •, and xis X1
`2
`3
`3
`is hydrogen, and X is (E)-CH=CH-,
`(xvi) of (xv) wherein Ro is Ro", R
`10
`, R3 is hydrogen, and m
`(xvii) of (xvi) wherein Ro is Ro'", R2 is R2
`is m',
`(xviii) of (xvii) wherein Ro is Ro'"' wherein R4
`and mis m",
`(xix)-(xxviii) of (i)-(v) and (x)-(xiv) wherein the hydroxy groups in .
`the 3- and 5-positions of the group of formula Ila have the erythro configura(cid:173)
`tion,
`(xxix)-(xxxvi) of (vi)-(ix) and (xv)-(xviii) wherein R10 and the hydrogen
`atom in the 6-position of the group of formula IIb are trans to.each other,,
`i.e. the trans lactones,
`(xxxvii) of Group IAc wherein Ro is Ro', R is R', R1 is ~1 ·, R2 i~ R2 ' .•
`is c1_
`1 s taken together are (CH2>2
`alkyl or the two R7
`R
`is R
`1 each R
`3
`7
`3
`3
`or (CH2
`, R10 is R10 •, R11 is R11 • and X is X' with the provi:s9 that X may
`>
`3
`be -cH2cH2
`- only when R10 is methyl,
`is c1_2
`Cxxxviii) of (xxxvii) wherein Ro is Ro" each R
`alkyl or the
`7
`, R10 is hydrogen •. R11 is R11 "
`2 or ( CH
`)
`)
`two R
`'s taken together are ( CH
`3
`7
`and X is (E)-CH=CH-,
`.
`(xxxtx) of (xxxviii) wherein Ro is Ro", R is R", R
`" •.
`is R1", R2 is R
`1
`2
`is c1
`is hydrogen or c1_2alkyl, most
`_
`is hydrogen, each R
`alkyl and R
`11
`2
`7
`
`1
`
`1
`
`,
`
`11
`
`111 is ,R4"",,R
`
`2
`
`,is hydr~gen
`
`2
`
`2
`
`R
`3
`preferably a cation,
`
`11 of 56
`
`PENN EX. 2254
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`W086/03488
`
`PCT/E~Sf006S3
`
`1
`
`1
`
`1
`
`1
`
`-10-
`111 is R4"", R is c1_2alkyl_,
`(xl) of (xxxix) wherein Ro is Ro'"' wherein R4
`R1 is c1_2alkyl, and R2 is hydrogen,
`.
`.
`(x11) of (xl) wherein R11 is a cation, especially sodium, potassium·
`·
`or anmonium, particularly sodium,
`(xli1) of Group I.Be wherein Ro is Ro', Rand R1 taken together are -.{CH2>
`, each R7 is c1_3alkyl or the two R7
`1 s. ~ake~ tQgether
`m-, R
`, R3 is R3
`is R2
`2
`are -(CH2>.2 or 3-, R10 is R10
`, and Xis X', with: the.provisos
`, R11 is R11
`that R11 may be hydrogen only 'llhen Q is -co-, and X may be -CHzCH2- only
`.
`when R10 is methyl,
`(xli1i) of (xlii) 'llherein Ro is Ro", each R7 is c1_2alkyl or bothR7
`, and X 1s
`taken together are -CCH2>2 or 3-, R10 is hydrogen, R11 . is R11
`(E)-CH=CH-
`, R3 is hJ,drogen, each
`(xliv) of (x111i) wherein Ro is Ro"', R2 is R2
`R7 is c1_2alkyl, R11 is R11
`111 (especially a cation), and mis m',
`
`(xlv) of (xliv) wherein Ro is Ro 1111 wherein R4111 is R4
`, R2 .is hydrogen,
`and m is m",
`(xlv1) of (xlv) wherein R11 is a cation, particularly sodium, potassium
`or anmonium especially sodium and
`(xlvii)-(lvi) of (xxxvii)-(xlvi) wherein Q is -co-.
`Groups (i)-(xviii) and (xxxvii)-(lvi) embrace each of the.possibl~
`stereoi somers, racemates and mixtures of di astereoi somers. Groups (xix.>.~
`Cxxviii) embrace the 3R,5S and 3S,5R ·;somers and the 3R,5S-3S,5R racemate
`. :
`..
`.
`of the compounds wherein Xis (£)-CH=CH- havi.ng just two centres: of- asynmetry
`and the corresponding compounds having more than two centres of asY11111etry,
`and Groups (xix) and(xxiv) also embrace the JR,SR and JS,SS isomers. and the
`3R,5R-3S,SS racemate of the compounds wherein X is -CH2cH2- having just two
`centres of asY11111etry and the corresponding compounds having more than two
`centres of asY11111etry. Groups (xxix)-(~xxvi) embrace the 4R,6S and 4S,6~
`isomers and the 4R,6S-4S,6R racemate of the c~mpounds wherein X is (E)-CH=CH(cid:173)
`having just two centres of asY11111etry and.the corresponding compounds ~aving
`more than two centres of asymmetry and Groups Cxxix) and Cxxxiiil also embrace
`the 4R,6R and 4S,6S isomers and tne 4R,6R-4S,6S racemate Qf the compounds
`wherein X is -CH2CH2- having just two centres of asymmetry and the corres(cid:173)
`ponding compounds having more than two centres of asymmetry.
`
`1 s
`
`11
`
`11
`
`1111
`
`...
`
`"
`
`12 of 56
`
`PENN EX. 2254
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`W086/03488
`
`PCT/E~5/006SJ
`
`-11-
`A particular compound group covers those compounds of formula I wherein
`
`Ro represents ring A 1.15
`
`6
`.
`R is hydrogen or primary or secondary c1_6alkyl not containing an ~sy11111etric
`carbon atom, and
`R1 is primary or secondary c1_6alkyl not containing an asYnmetric carbon
`atom or
`R and R1 taken together are -(CH2)m- or (Z)-CH2-CH=CH-CH2-.
`wherein m is 2, 3, 4, 5 or 6,
`R2 is hydrogen, c1_3alkyl, !!_-butyl, .!_-butyl, !-butyl, c1_3alkoxy, .!!_-but~xy,
`..!_-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or ~enzyloxy,
`R3 is hydrogen, cl _Jal kyl. C1_3alkoxy, trifluoromethyl I fluorci,. chloro·,
`phenoxy or benzyloxy,
`with the proviso that not more than one of R2 an~ R3 is trifluoromethyl~
`not more than one of R2 and R3 is phenoxy,
`and not more than one of R2 and R3 is benzyloxy,
`R4 is hydrogen, c1_3alkyl, !!_-butyl, .!_-butyl, !-butyl, c1_3alkoxy, .!!_-butoxy,
`.:!._-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
`. Rs is hydrogen, c1 _3a l kyl, c1_3a1 koxy, trif 1uoromethy1, fl uoro., ch 1 ~ro,
`phenoxy or benzyloxy,
`R6 is hydrogen, c1_2alkyl, c1_2alkoxy, fluoro or chloro,
`with the provisos that not more than one of R4 and Rs is trifluoromethyl,
`not more than one of R4 and Rs is phenoxy,·and not mer~ than one of R4
`and R5 is benzyloxy,
`X is -(CH2) - or (E)-CH=CH-,
`n
`.
`wherein n is 1, 2 or 3, and
`,10
`Z is -CH-CH2-C-CH2-COOR11
`rlH
`JH
`
`(a)
`
`or
`
`13 of 56
`
`PENN EX. 2254
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`W086/03488
`
`}>CT/E~S/00653
`
`-12-
`
`5
`J)H
`-~C!!(~R
`·13
`I
`io
`l. ~~H2
`
`:(b), ..
`
`wherein R10 is hydrogen or c1_3alkyl, and
`R11 is hydrogen, R12 or M,
`. .
`:
`wherein R12 is a physiologically acceptable and hydrolyzable ···
`ester group, and
`M is a pharmaceutically acceptable cation.
`
`.
`
`where::e1::m::~;:: ;:rfor:P.;fula
`
`0
`
`I
`
`I
`
`I may_b:
`
`prepared by the following reactions
`
`l
`2
`and substituents are as defined above.
`a) when X is (CH2)n or (E)-CH=CH- and R10 is hydrogen redu_cing a compound
`of formula IV
`
`IV
`
`XII
`
`Ind-X -CH-CH -C-CH -COOR
`l bH
`2 B 2
`13
`wherein R13 is a radical forming an ester, and x1 is (CH2 >n or {E)-CH=CH-,
`b) when Xis (CHz)n or (E)-CH=CH- and R10 is c1_3alky1 hydrolysing·a compound
`of formula XII
`~lOa
`Ind-X -CH-CH -C-CH -COOR
`1 O 2 bH 2
`13
`C=O
`R14
`wherein RlOa is c1_3alkyl, R14 is part of an ester forming group
`and x1
`and R13 are as defined above,
`c) when X is -CH=CH- or -c~2 -CH=CH- and IIb is in 4R,6S configuration . or
`X is -CH2cH2 or CH2cH2cH2 and lib is in 4R,6R configuration deprotecting
`a compound of formula XXXIX
`. J5H OP.ro
`. :
`.
`.
`:
`XXXIX
`.
`H
`.
`
`I
`
`I
`
`Ind-X"
`
`0
`
`0
`
`14 of 56
`
`PENN EX. 2254
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`W086/03488
`
`PCT/E~S/00653
`
`-13-
`wherein X11 represents -CH2CH2, -CH2cH2CH2, -CH=CH- or -cH2CH=CH-: an.d Pro
`is a protecting group,
`d) when Xis -(CH2>2-, -(CH2)3-, -(CH2)qCH=CH(CH2)q- deprotecting a: compound
`of formula XXX II
`
`RlO
`.
`I
`Ind-x" • -rH-cH2-cb-cH2cooR13
`OPro
`Pro
`wherein X" 1 is -(CH2>2-, -(CH2)3- or -(CH2) -CH=CH-(CH
`) -,
`q.
`q
`·
`and q, R10 , R13 and Pro are as defined above,
`e) when Q is -c- oxidising the corresponding. compound of formula I ,wherein·
`0
`· •
`.
`Q is -CH-
`6H
`f) when Q is f!C'o and II is in ester form ketalising the corresponding
`
`xxx11
`
`2
`
`I
`
`I
`
`R7 R1
`compound of formula I wherein Q is -~-
`g) hydrolysing a compound of formula I in the forni of an ester or a lactone or
`h) esterifying or lactonising a compound of formula I in free.acid.form,
`and when a free carboxyl group is present, recovering the compound obtained
`in free acid form or in the form of a salt.
`R13 is preferably c1_3alkyl, n-butyl, i-butyl, t-butyl or benzyl, more
`
`preferably c1_3alkyl and especially c1
`2alkyl and R14 is preferably c1_3alkyl
`_
`more preferably n-c1
`3alkyl, especially c1
`2alkyl.
`_
`_
`Process a) is particularly suited for compounds wherein X is -(CH2>n-
`6r (E)-CH=CH and in ester form.
`Process b) is particularly suited for compounds wherein X is -(CHz)n(cid:173)
`or (E)-CH=CH in salt form.
`Process c) is particularly suited for compounds wherein X is -(E)-CH=CH(cid:173)
`and the lactone is in 4R,6S configuration and those wherein X is -CH2cH
`-.
`2
`and the lactone is in 4R,6R configuration.
`Process d) is particularly suited for compounds in ester form.
`It will readily be appreciated that the various forms of the 'compounds
`of formula I may be interconverted. as indicated in g) and h) above, whereby
`lactonisation may only take place.when Q is -CH- and ketals cannot be isolated
`OH
`in free acid form or esterified.
`
`..
`
`15 of 56
`
`PENN EX. 2254
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`W086/03488
`
`PCJ/E~S/00653
`
`-14-
`In the same way compounds obtained according to a) to f) may.be as :appro(cid:173)
`priate hydrolysed to free acid forms and free acid forms may be.esterified
`or lactonised to produce a desired end-product. The invention thus also·
`provides a process for preparing a compound of formula I which comprises ,
`hydrolysing a compound of formula I in ester or lactone form or:estedfyfog
`or lactonising .a compound of formula I in free acid form and wh~n:a free
`carboxyl group is present recovering the compound obtained in free acid form
`or in the form of a salt.
`-.
`Unless otherwise stated reactions are performed in a manner.conventional
`for the type of reaction involved. Molar ratios and reacticm tiines are as
`a rule conventional and non-critical and are chosen according t:o principles
`well established in the art on the basis of reactions and conditions employed.
`Solvents, alone or as mixtures, are generally chosen which remain _inert
`and liquid during the reaction in question.
`nitrogen or a nobel gas,
`Examples of inert atmospheres are usually
`nitrogen being preferred. Most reactions, includin~ those wher~in use of
`an inert atmosphere is not mentioned, are carried out under such.for
`convenience.
`EP 114027 and 117228 including the examples thereof disclose analogous
`processes and further suitable reaction conditions.
`Reduction according to a) is preferably carried out using a mild ~educing
`agent such as sodium borohydride or, a complex of t-butylamine and borane
`in an inert organi°c solvent such as a lower alkanol, preferably ethanol,
`conveniently at a temperature of -10° to 30°C, under an i.nert atmospher;e.
`Use of an optically pure starting material will lead to oolr t\tf<> optical
`isomers (diastereoisomers) of the resulting end product. However, if.stereo~
`speeificity is desired it is preferred to utilize a stereo-selective reduction
`in order to m