`
`. ~ Europilsches Patentamt
`
`,, European Patent Office
`Office europ6en des brevets
`
`j
`
`®
`
`®
`
`EUROPEAN PATENT APPLICATION
`
`@ Publication number:
`
`0 221 025
`A1
`
`@) Application number: 86810470.4
`
`@ Dateofflling: 21.10.86
`
`® Int.ct•: C 07 D 207/337
`C 07 D 307/54,
`C 07 D 333/24, A 61 '.K 31 /34,
`A 61 K 31/38, A 61 K 31/40 .
`
`@ Priority: 25.10.85 US 791198 07.01.86 US 816664
`
`@ Date of publication of application:
`06.05.67 Bulletin 87/19
`8 Designated Contracting States:
`AT BE CH DE ES FA QB GR rr u LU NL se
`
`@ Applicant: SANDOZ AG
`Uclltstraeu 35
`CH4002 Baael (CH)
`8 Designated Contracting States:
`BE CH ES FR GB GA rr U LU NL BE
`
`@ Applicant: SAHDOZ.PATENT-GMBH
`Humboldbtraue 3
`D-'J'.850 L6rrech (DE)
`@ Designated Contracting States: DE
`
`@ Applicant: SANDOZ-ERFINDUNQEN
`v-.itungageaellac:haft m.b.H.
`BrunnerStraae59
`A-1235Wlen (Al)
`@ Designated Contracting States: AT
`
`@ Inventor: WaNlrig, James Richard
`402 Miiibrook Avenue
`Randolph, N..I. 07801 (US)
`
`Damon, Robert Edaon
`23158 Weal Vlaw
`Wharton, N..I. 07885 (US)
`
`® H.terocycllc analog• ot mevalonolactone and derlvlltlvee thereof, proceaHa for their production and their un ••
`phanMCeutlcale.
`@ . Compounds of formula
`
`R}-(Rb
`d\ y/'Ra
`
`I
`
`wherein
`Ra is a group -X-Z. Rb is Rz, Ac is R3. Rd Is R• and Y is a group
`-H- or
`I
`Ai
`Ra is R,, Rb is a group -X-Z. Re is Rz. Rd Is R3 and Y Is O. Sor a
`group -H-;
`l4
`Rt. R2. R3, and R, independently are C1-ealkyl not containing
`an asymmetric carbon atom. C3.7cycloalkyl or a ring
`
`.....
`-c
`
`II)
`N
`0
`
`0
`
`a.. w
`
`or in the case of R3 and R, additionally hydrogen. or for A3
`whenYisOorS
`
`'c = c:l\a
`'1_f
`'Rl9
`whereby R11 Is hydrogen or C1.3alkyl and R11 and Rte are
`independently hydrogen C;.3alkyl or phenyl; each A5 is
`independently hydrogen. C1 .3alkyl. n-butyl, I-butyl. !·butyl,
`C1.3alkoxy. _!!-butoxy. !·butoxy. trifluoromethyl: fluoro. chloro.
`bromo, phenyl. phenoxy or benzytoxy: each Re ls independently
`hydrogen. C1.3alkyl. C1.3alkoxy. trifluoromethyl. ftuoro. chloro.
`bromo. phenoxy or benzyloxy, and each R1 is independently
`hydrogen. C1.2alkyl. C1.2alkoxy, fluoro or chloro.
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`with the proviso that there may only be one each of
`trlfluoromethyl. phenoxy or benzyloxy in each ring A present. X
`is (CH2)m or (CH2)qCH-CH-(CH2)q. mis O. 1. 2 or 3 and both
`q's are O or one is O and the other is 1.
`
`~
`z is -CH-CH -C-CH -COOH
`2
`2
`J
`I
`OH
`OH
`
`II
`
`wherein Re is hydrogen or C1.3alkyl.
`rn tree acid form. or in the form of an ester or 6-laclone thereof
`or In salt form as appropriate. which compounds are indicated
`for use as pharmaceuticals in particular as hypolipoproteinemic
`and anti-alheroscleroUc agents.
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`Description
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`0221025
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`HETEROCYCLIC ANALOGS OF MEVALONOLACTONE AND DERIVATIVES THEREOF. PROCESSES FOR
`THEIR PRODUCTION AND THEIR USE AS PHARMACEUTICALS
`
`The present invention concerns heterocyclic analogs of mevalonolactone and derivatives thereof,
`processes for their preparation. pharmaceutical compositions containing
`them and
`their use as
`pharmaceuticals especially as agents for treating hypar-llpoproteinemia and atherosclerosis.
`More partlcularty the invention concerns compounds of formula I
`
`I
`
`wherein
`Ra ls.a group -X-Z, Rb is R2. Re Is R3, Rd is R, and Y Is a group -H- or
`I
`Ri
`Ra Is R,, Rb Is a group -X-Z, Re is R2, Rd Is R3 and Y is 0, S or a group -N-:
`.
`l4
`R,, R2, A3 and R4 independently are C1-ealkyl not containing an asymmetric carbon atom. C3.7cycloalkyl or a
`·
`ring
`
`or In the case of R3 and R.. additionally hydrogen, or for A3 when Y Is 0 or S
`
`whereby R11 is hydrogen or C1.3alkyl and R1a and R19 are Independently hydrogen C1.3alkyl or phenyl; each
`Ra Is independently hydrogen, C1.3alkyl, n-butyl, I-butyl, t-butyl, C1.3alkoxy, n-butoxy, i-butoxy, trlfluoro(cid:173)
`methyl, fluoro, chloro, bromo, phenyl, phenoxy or benzyloxy: each Rs Is independently hydrogen. C1-3alkyl,
`C1.3alkoxy, trifluoromethyl, fluoro, chloro, bromo, phenoxy or benzyloxy, and each R1 is independently
`hydrogen, C1-2alkyl, C1-2alkoxy, fluoro or chloro, with the proviso that there may only be one each of
`trlfluoromethyl, phenoxy or benzyloxy In each ring A present. X Is (CH2)m or (CH2)qCH-CH-(CH2)q. mis O.
`_1,_2_or_3_and both.q's are_O_or_one_is_O.and.the.other is 1, -
`
`'9
`Z is -CH-CH -C-CH -COOR
`2
`I
`2
`J
`.
`OH
`OH
`
`II
`
`wherein A9 Is hydrogen or C1 .3alkyl,
`in free acid form, or in the form of an ester or 8-lactone thereof or in salt form as appropriate.
`Suitable esters include physiologlcally acceptable esters e.g. physiologically hydrolysable and -acceptable
`esters.
`By the term •physiologically-hydrolysable and -acceptable ester is meant an ester of a compound In
`accordance with the invention in which the carboxyl moiety if present Is esterlfied. and which is hydrolysable
`under physiological conditions to yield an alcohol which is itseH physiologlcaUy acceptable, e.g. non-toxic at
`desired dosage levels. For the avoidance of doubt, throughout this specification it Is the right hand side of the
`X radical that Is attached10-the Z group. Preferred such acids, esters and salt forms as z can be represented
`together with the free acid by formula a
`
`2
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`¥9
`-CH-CH -C-CH -COOR
`2
`2
`10
`I
`b
`H
`OH
`wherein
`Rs is hydrogen or C1.3alkyl and
`Rio Is hydrogen, a physiologically acceptable ester forming group (R11) or a pharmaceutiCally acceptable
`·
`cation (M).
`When Z Is in iactone form It forms a &-lactone of formula b
`
`a
`
`b
`
`and reference to "lactone· hereinafter refer to 0-lactones.
`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 ammonium.
`References to compounds of formulae I and IA-ID and subscopes thereof are intended to cover all forms
`unless otherWise stated.
`Depending on the nature of the various substituents the compounds of formula I may be divided into four
`main groups, namely
`
`R~2 'I
`~-
`-z '
`R4 ~
`1 IB
`
`,
`
`These four groups may be further divided into two sub-groups each depending on the ·significance _of Z as
`either a group of formula II in other than lactone form (sub-group "a") or a group of formula b (sub-group •b").
`The resulting eight sub-groups are designated as formulae IAa, IAb, 18a, 18b, ICa, ICb, IDa, IDb respectively.
`As Is self-evident to those skilled In the art, each compound of formula I (and every sub-group and species
`thereof) has at least two centres of asymmetry (e.g. the two carbon atoms bearing the hydroxy groups in the
`group of formula a and the carbon atom bearing the hydroxy group and the carbon atom having the free
`valence In the group of formula b) and these lead (e.g. with two centres) to four stereolsomlc. forms
`(enantlomers) of each compound (two racemates .or pairs of diasteroisomers). In preferred compounds .
`having only two such centres of asymmetry these four stereolsomers 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: Depending on the nature
`of substltuents further asymmetric carbon atoms may be present and the resulting isomers and mixtures
`thereof also form part of the invention. Compounds containing only two centres of asymmetry (four
`menmentloned stereolsomers) are preferred.
`·
`·
`·
`Preferably in compounds IA-ID one of R1 and R2 Is C1-ealkyl not containing an asymmetric carbon atom and
`the other is a Ring A. Also preferably in compounds 18 and IC, one of R3 and A4 Is a Ring A and the other is
`hydrogen or C1-ealkyl not containing an asymmetric carbon atom, preferably hydrogen or C1-2alkyl and most
`preferably hydrogen except that R4 in compounds IC is preferably other than hydrogen. More preferably, the
`preferences of both preceding sentences occur simultaneously. Thus, the preferred compounds 18 and IC and
`each of the sub-scopes thereof are those having attached to the pyrrole ring two Rings A end two alkyl groups
`· or in compounds 18 especially one alkyl group and one hydrogen. Even more preferably the two Rings A are
`ortho to each other. Also preferably the pyrrole ring does not bear two ortho tertiary alkyl·groups.
`
`In Formula 18:
`R1 is preferably R1Bx. where RJBx is Ring A. more preferably R\ Bx. where R\ Bx is Ring A wherein Ai; Is
`a; . Rs is Rg . and R1 is R7 . even more preferably Rj Bx. where Rt Bx is Ring A wherein A5 is a'5 . Rs Is
`R6 • and A1 is hydrogen, and most preferably phenyl, 4-fluorophenyl or 3,5-dimethylphenyl, especially
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`4-fluorophenyl; or
`R1 is preferably R1ay. where R1By is C1-ealkyl not containing an asymmetric carbon atom, more.preferably
`Rj ay. where a; By is C1.4alkyl not containing an asymmetric carbon atom. and most preferably.!-J>ropyl.
`R2 Is preferably R2ax. where R2ax is C1-ealkyl not containing an asymmetric carbon atom, more preferably
`•i ax. where Rj ax is C1.4alkyl not containing an asymmetric carbon atom. and most preferably l-propyl; or
`R2 is preferably R2&y. where R28y is Ring A, more preferably R2 By, where Rj By Is Ring A wherein R& is
`Rs . Re Is R'e, and R1 is R'1, even more preferably •2 By. where R'i By Is Ring A wherein Rs is R·s. Re is R·e
`and R1
`Is hydrogen, and most preferably phenyl. 4-fluorophenyt or 3.5-dlmethylphenyt, : especially
`.
`4-fluorophenyl.
`,
`R3 Is preferably R3Bx. where R3Bx Is hydrogen or C1 .ealkyl not containing an asymmetric carbon atom, more
`I
`•
`..
`I
`•
`preferably •1 ax. where Jl3 ax s hydrogen or C1-2alkyl. even more preferably R3 ex. ·where ~3 Bx is
`hydrogen or methyl, and most preferably hydrogen; or
`.
`R3 is preferably R3ay, where R39y is Ring A, more preferablv R] By. where Rj By .is Ring A _where.In R Is R'5,
`Rs is R'e. and R1 is R'1, even more preferably Jlj ey, whereRj ay is Ring A wherein Ra is R".s, Re is R"e. and
`R1 is hydrogen, and most preferably phenyl.
`.
`.
`R• is preferably R4Bx, where R4&x Is Ring A, more preferably Rt Bx where Rt Bx is Ring A wherein Rs ls ~·a ·
`• Re ls R's, and R1 ls R'1, even more preferably 84 Bx. where R'4 Bx is Ring A wherein Rs ls R"s. Rs:is R"e, and
`R1 ls hydrogen. and most preferably phenyl: or R4 IS preferably R4By. where R4By is hydrogen or Ci-ealkyl not .
`containing an asymmetric carbon atom, more preferably a4 By; where •• By is hydrogen or C1.2alkyl. even :
`more preferably •4 ay. where •c By Is hydrogen or methyl. and most preferably hydrogen.
`·
`
`In Formulae IA. IC and ID:
`R1 Is preferably R1cx. where R1Cx Is C1-ealkyl not containinq an asymmetric carbon atom, more preferably
`a\ ex. where aj ex is C1.4alkyl not containing an asymmetric c~on atom, an~ most preferably !-propyl. or
`R1 Is preferably R1ey, where R1ey Is Ring A, more preferably R1 ey, where R1 Cy Is Ring A wherein Rs ls
`a'5 • Re ls •i and R1 is a1
`7 • even more preferably a'j ey, where a.1' eyls Ring A wherein Rs is Rs • Rs ls. Rfi •
`and R1
`Is hydrogen, and most preferably phenyl, 4-fluorophenyl or 3,5-dimethylphenyi, especially
`4-fluorophenyt.
`.
`R2 Is preferably R2cx. where R2cx is Ring A, more preferably R1 ex. where R2 ex Is Ring A wherein Rs Is .
`Rs • Re is R'e and R1 is R'1, even more preferably al ex. where R2 ex Is Ring A wherein Rs ls R"s, Re lsk" •
`and R1
`is hydrogen, and most preferably phenyl. 4-fluorophenyl or 3,5-dimethylphenyl, especiifily
`4-fluorophenyt; or
`· .
`.
`R2 is preferably R2cy. where R2ey is C1 .ealkyl not containing an asymmetric carbon atom, more prefer~bly .
`a2 ey. where Rz Cy is C1.4alkyl not containing an asymmetric ~arbon atom, ~nd most preferably !~propyl.
`R3 Is preferably R3cx. where R3cx is Ring A, more preferably R3 ex. where R3 ex is Ring A wherein Rs Is
`R's. Re ls R'e. and R1 is R'1, even more preferably Jlj ex. where R"3 ex Is Ring A wherein Rs is R"s. Re ls R"e.
`_
`,
`.
`and R1 Is hydrogen, and most preferably phenyl; or
`R3 is preferablY, R3ey, where R3ey is hydrogen or C1-ealkyl not containing an asymmetric carbon atom,
`more preferably ll) ey, where a] ey Is hydrogen.or C1.2alkyl, and even more preferably aj ey, where Rj ey
`is hydrogen or methyl, especially ·hydrogen.
`.
`In the compounds of formulae IA and ID, especially the former, R3cy. R3cy' and R3cy" Include
`-CH- C(CH3)2.
`.
`
`In formula IC:
`R• is preferably R4cx. where R4cx is hydrogen or C1-ealkyl not containing an asy_mmetrlc carbon atom,
`more pref~rably R4 ex. where a4 ex C1-zalkyl, even more preferably methY!. or
`· ·
`R;t IS preferably R4Cy. where R4Cy is Ring A, more preferably Rt cy. where a4 cy Is Ring A wherein R Is R'5
`• Re is R's, and R1 is R'1, even more preferably~ cy. where R'4 cy Is Ring A wherein Ra is R"s. Re is R"e. and
`R1 is hydrogen, and most preferably phenyl.
`In addition, In the compounds IA and ID R2 Is preferably C1-ealkyl not containing an asymmetric carbon
`atom. especially isopropyl or t-butyl, or phenyl or p-substituted phenyl, especially p-fluorophenyl and A1 Is
`preferably phenyl or p-substituted phenyl especially p-fluorophenyl.
`'
`Of IA and ID the former are preferred.
`In each of IA. 18, IC and ID the following preferences apply.
`Each Rs independently is preferably R11' where R&' is hydrogen, C1 .3alkyl, C1 .2alkoxy, trifluoromethfl, fluoro
`or chloro, more preferably Rs· where Rs" ls hydrogen methyl orfluoro. In the case of R1 and R2 being a.Ring A
`each a; is preferably fluoro, especially 4-fluoro. In the case of R:i and R• being a Ring~ R6" Is prefef"Qbly
`hydrogen.
`·
`Each Re independently is preferably Re' where Rs' is hydrogen. C1.zalkyl, fluoro or chloro more preferably
`Re· where Rs" is hydrogen or methyl, most preferably hydrogen.
`Each R1 independently is preferably Ri where R1' is hydrogen or methyl, most preferably hydrogen~ ·
`Preferably, each Ring A. independently bears a maximum of one substituent selected from:the group
`consisting of t-butyl, trifluoromethyl, phenyl, phenoxy and benzytoxy. More preferably, when any two or all
`three of the substituenls on each Ring A independently are ortho to each other, at least one member of each
`pair that are~ to each other is a member of the group consisting of hydrogen. methyl, methoxy; fluoro and
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`chloro. Also more preferably. at least one of the ortho positions of each Ring A, independently has a member
`of the group consisting of hydrogen, fluoro and methyl.
`·
`·
`·
`When R1 andfor R2 Is a Ring A these are independently preferably phenyl. 4-fluorophenyl or
`3.5-dimethylphenyl, more preferably the latter two and most preferably 4-fluorophenyl.
`·
`When A3 and/or A4 is a Ring A these are independently preferably phenyl.
`Re Is preferably Ag', where Re' is hydrogen or methyl. and most preferably hydrogen and R10 Is preferably
`R10'. where R10' is hydrogen, R11' or M, more preferably R,o·. where R1o· Is hydrogen, C1.3alkyl or M;even
`more preferably R10"'. where R,o·· is hydrogen. C1-2alkyl or M. and most preferably M, particularly M' and
`·
`especially sodium.
`R,, is preferably R,,·. where R11' Is C1-3alkyl. n-butyl, i-butyl, t-butyl or benzyl. more pr:eferably.R11·; where
`R11" Is C1.3alkyl, and most preferably R11"', where A;,·· is C1-2alkyl, especially ethyl.
`·
`·
`· ·
`Any -CHcaCH-. -CH-CH-CH2" or -CHz-CH=CH- as Xis preferably trans, I.e., (E).
`X is preferably X', where x· Is -CH2CH2- or -CH ... CH-, and most pr8i&r8bly
`
`H........._
`c =
`
`/
`(I.e •• (E)-CH-CH-).
`Z Is preferably a group of formula a wherein Re is Re' (especially hydrogen), and Rio. Rio' or a group ·Of
`formula b wherein Re Is Re' (especially hydrogen). more preferably a group of formula a wherein Re Is
`hydrogen. and Rio is R10· or a group of formula b wherein Rs Is hydrogen, even more preferably a group of
`formula a wherein Re is hydrogen, and R10 Is R1o"' or a group of formula b wherein Rs is hydrogen, and most
`preferably a group of formula a wherein Re Is hydrogen, and Rio Is M. preferably M' and espl[!clally sodium.
`m is preferably m', where m' Is 2 or 3, most preferably 2.
`M is preferably free from centers of asymmetry and is more preferably M'. I.e., sodium, potassium or
`ammonium, and most preferably sodium. For simplicity, each formula In which M appears has been written as ff
`M were monovalent and, preferably, it Is. However, It may also be divalent or trivalent and, when It ls, It balances
`the charge of two or three carboxy groups, respectively. Thus, formula I and every other formula containing an
`M embraces compounds wherein M is divalent or trivalent. i.e.. compounds containing ' twO or three
`carboxylate-contalnlng anions per cation M.
`-
`As between otherwise identical compounds of formula I, those where Z is In other than lactone form are
`generally preferred over those wherein Z is a group of formula b.
`·
`·
`·
`·
`Insofar as the compounds of Groups IAa, IBa, ICa. and IDa and each of the su~roups thereof are
`concerned. the erythro Isomers are preferred over the threo Isomers, erythro and threo referring to.the reiatiVe
`positions of the hydroxy groups In the 3- and 5-positions of the group of formula II.
`.
`Insofar as the compounds of Groups IAb, IBb. ICb, and IDb and each of the sub-groups thereof are
`concerned, the trans lactones are generally preferred over the els lactones, cis and trans referring to the
`relative positions of Re and the hydrogen atom in the 6-positlonof the groupof formula b.
`The preferred stereolsomers of the compounds of formula I having only two centres of asymmetry wherein X
`is a direct bond, -CH- CH- or -CH2CH - CH-, and Z is a group of formula a, are the 3R.SS Isomer and the
`racemate of which It is a constituent, I.e., the 3R.SS-3S,SR (erythro) racemate.
`The preferred stereoisomers of the compounds of formula I having only two centers of asymmetry wherein X
`is -CH2-. CH2CH2-. -CH2CH2CH2-or-CH-CH-CH2-. and Z is a group of formula a. are the 3R,5R isomer and
`the racemate of which it is a constituent, I.e .. the 3R,5R-3S,5S (erythro) racemate.
`The preferences set forth In the preceding two paragraphs also apply to the compounds of formula I hav.ing
`more than two centers of asymmetry and represent the preferred configurations of the indicated. positions.
`The preferred stereoisomers of the compounds of formula I wherein X is a direct .bond, -CH ... CH- or
`-CH2-CH- CH-. and Z Is a group of formula b are the 4R,65 and 4R,6R Isomers and the rai;:emate of which
`each is a constituent, i.e., the 4R.6S-4S,6R (trans lactone) and 4R,6R-4S,6S (els lactone) racem11tes with the
`4R,65 isomer and theracemate of which it is a constituent being more preferred.
`·
`·
`,
`:
`The preferred stereoisomers of the compounds of formula I wherein X Is -CH2-. -CH2CH2-. -CH2CH2CH2- or
`-CH-= CH-CH2. and Z is a group of formula bare the 4R,6R and 4R.6S isomers and the racemate of which eai;:h
`Is a constituent, i.e .. the 4R,6R-4S.65 (trans lactone) and 4R,6S-4S,6R (cis lactone) racemates, with. the.4R,6R
`Isomer and the racemate of which It IS'iiConstituent being more preferred and the 4R,6R Isom.er being most
`.
`•
`•
`• .
`preferred.
`Each of the preferences set forth above applies unless otherwise stated, not only to the compounds of
`formula I, but also to the compounds of groups IA. 18, IC and ID and those of Groups IAa, IAb, IBa, IBb, ICa,
`ICb. IDa and IDb as well as to every other sub-group thereof set forth in the specification, !11:• Groups (i)
`et.seq.. unless otherwise Indicated. When any preference or group contains a variable, the preferred
`significances of that variable apply to the preference in question, unless otherwise Indicated. Preferred groups
`·
`of compounds include compounds:
`(I) of Group IBa wherein A1 is R1ax ! A2 is R2Bx. R3 is R3Bx. R4. R4ax. Re is R's. R10 is R'~o. and Xis X',
`
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`(ii) of (i) wherein R1 is R'tax. R2 is R'211x. R3 is R'3Bx. R4 is R'411x, R9 ls hydrogen. Rto is R"to, and X·is
`(E)-CH-CH-,
`,
`(iii) of (ii) wherein Rt is R"1ax. R3 is R•3a11, R4 is R"49x. and R1 is R•'to. preferably M, .
`(Iv) of Group IBa wherein Rt Is R1ay. R2 is R29y, Ra ls 83ay. R4 IS R4ay. R9 ls R'9, Rto is R':10~ and X Is
`x·
`(V) of (Iv) wherein Rt is R'tay. R2 ls R'211y. R3 is R'3ay. R4 is R'4ay. Rs is hydrogen. R10 is R".10: and X'is
`(E)-CH .. CH-,
`(vi) of (v) wherein R2 is R"2ay, R3 ls R"3ay. R4 IS R"4By. and R1ois R .. 10. preferably M.
`(vii) of GrouplBawherein R1 lsR1ay. R2, R2ay. R3 is Raa11. R,. is R4a11. R9 is R'11, Rto ls·R'to. an~X isX',
`(viii) of (vii) wherein Rt is R'tay, R2 ls R'2ay. R3 ls R'38x. R,. is R'4a11. Rg is hydrogen, Rto is R" 10. arid X
`is (E)-CH - CH-.
`.
`(Ix) of (viii) wherein R2 is R'29y, Ra ls R"3a11. R,. is R'49x. and R10 Is R"' 10. preferably M;
`(x) • (xviii) of (i) - (Ix) wherein the hydroxy groups in 3- and 5-posltions of the group of formula a have
`the erythro configuration,
`.
`(xix) of Group IBb wherein Rt is A1B11. R2 is Rzax. R3 ls R311x, R4, R48x, R9 is R'9, Rto is R'to. and Xis
`.
`x·.
`- - -
`(xx) of (xix) wherein R1 is R'1a11. R2 is R'29x, R3 Is R'3ax. R,. is R'4a11. R11 is hydrogen, and X Is • ·
`(E)-CH-CH-,
`(xxl) of (xx) wherein Rt Is R" 1ax. Ra ls R•3ax. and A4 ls R"4ax.
`(xxll) of Group IBb wherein Rt Is R1ay, R2 ls A28y. R3 ls R3ay. R4 ls R4ay. Rs ls R'11. and Xis X',
`(xxlll) of (xxll) wherein Rt is R'1ay, R2 Is R'29y, R3 Is R'3ay, R4 Is R'49y, Rs Is hydrogen, and X is
`(E)-CH ... CH-,
`.(xxiv) of (xxiii) wherein R2 ls R"29y. R3 isR'3ay. and A .. ls R"4ay.
`(xxv) of Group IBb wherein Rt Is Rtay. R2 is R2ay. Ra is R3ax. R4, R4ax. R11 is R'11, Rto is R'to, and Xis
`
`..
`
`·
`
`.
`
`x· .
`
`r
`
`(xxvi) of (xxv) wherein R1 is R'1ay, Rz is R'2ay. R3 is R'3ax. R4 is R'ux. R9 is hydrogen. and X is
`(E)-CH- CH-.
`.
`.
`(xxvii) of xxvi) wherein R2 is R"2ay, Ra isR"3ax and R4 is R"4ax.
`(xxviii) - (xxxvi) of (xix) - (xxvii) wherein R9 and the hydrogen atom in the 6-position or the group of
`Formula bare trans to each other, I.e., the trans lactones.
`(xxxvii) of Group ICa wherein RtliR1ex. R2 ls R2cx. R3 is R3cx. R,. is A4cx. Rs is R's Rto is R'10. and X
`isX',
`(xxxviii) of (xxxvil) wherein R1 is R'tcx. Rz is R'2cx. R3 is R'3cx. R4 ls R'4cx. Rs ls hydrogen. Rto Is R·to.
`and X Is (E)-CH - CH-,
`.
`.
`(xxxlx) of (xxxviii) wherein R2 lsR·2c... Ra is R"3ex, R4 is methyl and Rto is R"'to. preferablyM,
`(xi) of Group ICa wherein R, is R1ey. R2 ls R2ey. R3 is R3cy, R,. Is R4ey, Rs is R's, Rio Is R' 10. and Xis
`.
`. ,
`'(xii) or (xi) wherein R1 is R'1cy. R2 is R'2ey. R3 is R'3cy. R4 is R'4ey, R9 is hydrogen, R10 is R·10. and x
`is (E)-CH =-CH-.
`(xiii) of xii) wherein Rt is R"tcy. Ra is R"aey, R4 is R"4cy. and Ro is R"'o, preferably M.
`(xllll) - (xlvill) of (xxxvli) - (xiii) wherein the hydroxy groups in the 3- and 5-posltlons of the group of
`Formula a have the erythro configuration,
`(xlix) of Group ICb wherein R, is R1cx. R2 is R2cx. R3 is R3cx. R4 is R4cx. Rs is R'e, and Xis X',
`(I) of (xlix) wherein R, is R'1cx. R2 is R'2cx. Ra is R'3cx. R4 is R'4c11. R9 is hyqrogen, and X is
`..
`(E)-CH ... CH-,
`(Ii) of (I) wherein R2 ls R"2cx.-R3·ls R"3cx. and R4 is methyl,
`(Iii) of Group ICb wherein A1 is R1ey, A2 ls R2ey, Ra is R3cy. A4 ls A4Cy. Re ls R'11 and Xis X', .
`iliii) of (Ill) wherein R, is R"1ey, A2, Is R'2cv. R3 is R'3cy. R4 Is R'4cy. Rs is hyqrogen'. and X is
`(E)-CH-CH-,
`.
`.
`.
`(liv) of (liii) wherein Rt is R'1ey,Ra isA"3ey,and R4 is A" 4Cy. and
`(Iv) - (Ix) of (xlix) - (llv) wherein A11 and the hydrogen atom in the 6-position of the gr~up of Forrnula·b
`are trans to each other, i.e. the trans lactones.
`·
`·
`Groups (x) - (xviii) and (xlili) - (xlvlll) embrace the 3R.55-35.SR racemate and the 3R.55. and . 3S.5R
`enantiomers of the compounds wherein Xis -CH ... CH-. tha 3S,5R enantlomer being least preferred, and the
`3R,5R-3S,5S racemate and the 3R.5R and 35,55 enantiomers of the compounds wherein X is -CH2CH2·. the
`35,55 enantiomer being least preferred.
`Groups (xxviii) - (xxxvl) and (Iv) • (Ix) embrace the 4R,65-4S,6R racemate and the 4R.65 and 45.SR
`enantlomers of the compounds wherein X is -CH ... CH-. the 45.6R enantlomer being least preferred. and. the
`4R,6R-45,6S racemate and the 4R,6R and 45,65 enantiomers of the compounds wher&ln X Is -CH2CH2-. the
`45,65 enantlomer being least preferred.
`Preferred groups of Formulae IA and ID include those that correspond to groups (xxxvil) - (Ix) and the
`groups corresponing to groups (xxxvii)-(xxxix). (xlill)-(xlv). (xlixHlil and (lv)-(lvli) wherein any Ran Is A3c¥
`(including 2-methyl-prop-1-en-1-yl), any R ex is R'3cv (including 2-methyl-prop-1-en-1-yl), and an)' A"3Cllf is
`R"3cy (including 2-methyl-prop-1-en-1-yl) I.e. groups (lxi)-(xcvl) (for group IA compounds) and (xcVil)-(cxxxil)
`(for.group ID compounds). It goes without saying that none of these groups contain an A4 substitute~!.
`
`6
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`5
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`2S
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`4()
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`PENN EX. 2256
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`Two groups of compounds of formula I are those wherein Ra Is R,, Rb Is -X-Z, Re is R2. Rd Is Ra and Y Is 0
`or S, R,, R2 and Ra are Independently C1 -ealkyl not containing an asymmetric carbon atom, C3. 7cycloalkyl or a
`Ring 8
`
`-OR6
`
`R7
`or In the case of Ra additionally hydrogen, each Rs is independently hydrogen. C1-3alkyl, ii-butyl, .!~butyl,
`t-butyl. C1.3alkoxy. n-butoxy. i-butoxy. tritluoromethyl, fluoro, chloro, phenyl, phenoxyor benzyloxy. each Rs ls
`independently hydrogen, C1 .3alkyl. C1-aalkoxy. trifluoromethyl, fluoro. chloro, phenoxy or benz}ttoxy. and each
`R1 ls Independently hydrogen, C1-2alkyl, C1-2alkoxy, fluoro or chloro with the proviso that there may only be
`one each oftrltluoromethyl, phenoxy, orbenzyloxy In each Ring B present, Xis (E) CH-CH or-CH2-CH2- and
`z is
`
`..
`0
`whereby R,o is hydrogen. a physiologically acceptable ester group or a phannaceutically acceptable'catlon.
`Two other particular groups of compounds of formula I are those wherein Ra Is -X-Z, Rb is R2; Re Is Rs: Rd Is
`R• andYls -N- and those wherein Rais R1. Rb ls-X-Z, Reis R2. Rd isRaandYls -N- whereby R1, R2, Ra
`•
`•
`~
`~
`and R4 independently are C1-salkyl not containing an asymmetric carbon atom, Ca.7cycloalkyl or a Ring C
`
`or In the case of Ra and R4 additionally hydrogen, each R11 is independently hydrogen. C1~aalkyl, !!-butyl,
`I-butyl, t-butyl, C1-aalkoxy, n-butoxy, 1-butoxy. trifluoromethyl. fluoro, chloro, bromo. •phenyl, phenoxy 'or
`henzyloXy. each Re.ls indepeOdently hydrogen, C1-aalkyl, C1-aalkoxy, trifluoromethyl, fluoro, chloro, phenoxy
`· ·or benzyloxy, and each R1 Is independently hydrogen, C1-2alkyl. C1.2alkoxy, fluoro or chloro,
`with the proviso that there may only be one each of tritluorornethyl, phenoxy or benzytoxy in each Ring C
`present, X Is (CH2)m. -CH-CH·. CH-CH-CH2 or CH2CH-CH and Z Is
`
`or
`
`f 9
`-CH-CH -C-CH -COOR
`2 I
`2
`10
`1
`OH
`OH
`- -(cid:173)
`. - . --
`- CH
`~/OH
`/
`-CH
`C
`l'R
`I
`.0
`/CH2 9
`"-c
`II
`0
`
`5
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`10
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`15
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`20
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`25
`
`30
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`35
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`40
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`45
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`50
`
`55
`
`60
`
`wherein Rs is hydrogen or C1.3alkyl and R10 is hydrogen. a physiologically acceptable ester group or a
`pharmaceutically acceptable cation.
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`PENN EX. 2256
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`IPR2015-01835
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`The compounds of formula I can be prepared by the following reactions where a stands for
`
`0221025
`
`wherein Ra, Ab, Re. Rd and Y are as defined above including provisos
`a) when R9 is hydrogen reducing a COJ!lpound of formula VIII
`0-X-CH-CH -C-CH -COOR
`VIII
`2 n
`2
`12
`OH
`0
`wherein A 12 is a radical forming an ester substantially inert to the reaction conditions
`and Xis as defined above,
`b) when R9 is C 1.3alkyl hydrolysing a compound of formula XVI
`
`I
`
`0-X-CH-CH
`2
`I
`0
`I
`C=O
`A13
`wherein R9 is C1.3alkyl. R13 is part of an ester forming group and X and Ru are as defined above,
`c) when X Is -(CH2)2-. -(CH2)3-, -CH -CH- or -CH2CH- CH-
`deprotecting a compound of formula XXVll
`
`. XVI
`
`RHX'°pro
`
`o-x")l o.,Lo
`
`XXVII
`
`wherein x· represents -(CH2)2-. -ICH2)s-. -CH-CH- or -CH2CH-CH(cid:173)
`and Pro is a protecting group,
`d) when X Is -(CH2)2·. -(CH2)s-. or-(CH2)qCH-CH(CH2)q(cid:173)
`deprotectlng a compound of formula XI
`
`XXII
`
`wherein x·· is -(CH2)2-. -(CH2)3- or -(CH2)q-CH .. CH-(CH2Jq-, and q, Re. R12 and Pro are as defined
`above,
`e) hydrolysing a compound offormula I In the form of an ester or a lactone,
`f) esterifying or lactonising a compound of formula I in free acid form, or
`g) esterifying a compound of formula I In lactone form, and when a free carboxyl group is present,
`recovering the compound obtained In free acid form or In the form of a salt. In processes a),bJ and d) R12
`Is preferably C1 .3alkyl, n-butyl, I-butyl, t-butyl or benzyl, more preferably C 1-38lkyl and especlally C1-2alkyl
`and R13 ls preferably Ct-3aikyl more preferably n-C1.3alkyl, especially C1-2alkyl.
`.
`Reduction according to a) is preferably carried out using a mild reducing agent such as sodium borohydride
`or, a complex of t-butylamine and borane in an inert organic solvent such as a lower alkanol, preferably
`- ethanol, conveniently at a temperature of -10° to 30"C, under an Inert atmosptiere.
`Use of an optically pure starting material will lead to only two optical Isomers (dlastereolsomers) of the
`resulting end. product. However, If stereospeclflcity is desired it is preferred to utilize a stereo-selectiV9
`reduction in order to maximize production of a mixture of the erythro stereolsomers (racemate) of which the
`preferred stereoisomer (as set forth above) is a constituent. Stereoselectlve reduction Is preferably carried
`out In three steps. For example In the first step, the ketoester of formula VIII is treated with a tri(primary or
`secondary C2-•alkyl)borane. preferably triethylborane or tri-n-butylborane, and optionally air to form a
`compkHc. The reaction temperature is suitably 0° to 50° C, preferably 0° to 25° C. The first step Is carried out in
`an anhydrous inert organic solvent. preferably an ether solvent such as tetrahydrofuran or a mixture of
`tetrahydrofuran with methanol (preferably 3-4:1). In the second step, the complex Is reduced with sodium
`borohydride, preferably In the same solvent as utilized for the first step, at -100° to -10°C, preferably-90 .. to
`
`8
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`
`-70°C and then quenched e.g. with 100/o HCI. In the third step. the product of the second step Is, for example,
`treated with, preferably, anhydrous methanol at 20° to 60°C. The amount of methanol is not critical.
`However. a large excess,!.:&:· 50-100 moles per mole of ketoester of formula VIII, Is typically utlilzed;
`Hydrolysis according to b) ore) is carried out In a manner conventional for such reactions e.g. employing an
`inorganic hydroxide such as NaOH or KOH with, if desired subsequent acidification to give the free acid form.
`Suitable solvents are mixtures of water and water miscible solvents such as lower alkanols e.g. methanol or
`ethanol and reaction conveniently takes place at temperatures from 0° C to 75° C e.g. 20 fo 70° C. If It Is desired
`to recover the compound In a salt form corresponding to the cation of the hydroxide employed· then· slightly
`less than equivalent amounts of the latter may be employed. In b) R 13 will conveniently be the same as R 12 e.g.
`C1.3alkyl more preferably n-C1.3alkyl. especially C1-2.
`.
`· ·
`•
`:
`In process b) when Q is a pyrrole ring bearing a hydrogen atom on the nitrogen atom thls·will.also bear a
`protecting group for example a further-s-a13group. Preferably however in this case a protecting group of
`0
`formula -Si(R34) (R3&) (R3e) is used Instead of -~-R13for both NH in the ring and OH In: ttie side chain
`0
`.
`
`(R34,R35 independently .. C1-ealkyl especially methyl, R3s ... C1-ealkyl especially methyl or t~butyl the latter
`being preferred). Such protection groups may be introduced and removed In conventional. manner.
`Lactonlsatlon according to f) is carried out In conventional manner e.g. by heating the corresponding acid in
`an anhydrous Inert organic solvent e.g. a hydrocarbon such as benzene, tolu