`
`WORLD Jl'ITELLECTUAL PROPERTY ORGANIZATION
`International Bu~au
`
`PCT
`
`...
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PC1)
`
`(St) International Patent Classification 4 :
`C07D 233/64, 405/06
`C07F 7/18, A61K 31/415
`C07F 9/65, C07D 233/00
`C07D 405/00, C07F 7 /00
`A61K 31/00. C07F 9/00
`
`Al
`
`(11) Iutemational Publication Number:;
`
`W086/07054
`
`(43) International Publication Date: 4 December 1986 (04.12.86)
`
`(21) International Application Number:
`
`PCTfEP86/00297
`
`(22) International Fiiing Date:
`
`16 May 1986 (16.05.86)
`
`(72) Inventor: WAREING. James,. Richard ; 402 Millbrook
`Avenue, Randolph. NJ 07801 (US).
`
`(31) Priority Application Number:
`
`736,679
`
`(32) Priority Date:
`
`(33) Priority Country:
`
`22 May 1985 (22.05.85)
`us
`
`(81) Designated States: AT (Europ.ean' patent)~ AU, B.E (Eu(cid:173)
`ropean patent), CH (European patent).. DE (Euro(cid:173)
`pean patent), DK, Fl, FR (European patent), GB
`(European patent), HU, :rr (European :patent), JP,
`KR, LU (European patent), NL (European patent),
`SE (European patent)!
`·
`·
`
`(71) Applicant (for AT only): SANDOZ-ERFINDUNGEN
`VERWALTUNGSGESELLSCHAFf M.B.H.
`[AT/
`AT); Brunner Strasse 59, A-1235 Vienna (A1).
`
`(71) Applicant (for DE. only): SANDOZ-PATENT-GMBH
`[DE/DE]; Humboldtstrasse 3, D-7850 LOrrach (DE).
`
`(71) Applicant (for all designated States except AT DE):
`SANDOZ AG [CH/CH]; Lichtstrasse 35, CH-4002
`Basel (CH).
`
`Published
`With international search report.
`Before the expiration of the time limit for amending the
`claims and to be republished in the event of the receipt
`:
`:
`of amendments.
`
`.
`
`.
`
`(54)Title: IMIDAZOLEANALOGSOFMEVALONOLACTONE AND DERIVATIVES THEREOF.
`
`(I) }=<-z
`
`N~N -R2
`
`(II)
`
`(III)
`
`H
`
`-ere 'i..,..D"
`
`i-itu
`c,i;;Hz
`b
`
`(IV)
`
`(V)
`
`-e-
`ll
`0
`
`(57) Abstract
`
`Compounds of formula (I) and the pharmaceutically acceptable acid addition salts thereof, wherein l,l1 and R2 are
`alkyl not containing an asymmetric carbon atom, cycloalkyl, adamantyl-1 or possibly substituted phenyl, R3 is hydrogen,
`alkyl not containing an asymmetric carbon atom, cycloalkyl, adamantyl-1, styryl or possibly substituted phenyl, X is -
`(CH~m·· -CH =CH-, -CH=CH-CHr or -CH.rCH=CH-, wherein mis 0, I, 2, or 3, and Z is formula (II) or formula (III)
`or with Ra is hydrogen and Rb is hydroxy, or CRaRb is formula (IV) or formula (V) wherein each R 1s is.primary or secon(cid:173)
`dary alkyl not containing an asymmetric carbon atom, the two R 1s's being the same, or the two R 15's taken together are -
`(CH~q-. wherein q is 2 or 3, R 13 is hydrogen or alkyl, and R 14 is hydrogen, a physiologically acceptable ester group, or a
`pharmaceutically acceptable cation, with certain provisos and the use thereof for inhibiting cholesterol biosynthe~is and
`lowering the blood cholesterol level and, therefore, in the treatment of hyperlipoproteinemia and atherosclerosis, pharma(cid:173)
`ceutical compositions comprising such compounds and processes for and intermediates in the synthesis of such com(cid:173)
`pounds.
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`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the fjont pages of pamphlets publishing international appli-
`cations under the PCT.
`-
`
`AT Austria
`AU Australia
`BB Barbados
`BE Belgium
`BG Bulgaria
`BR Brazil
`CF Central African Republic
`CC. Congo
`CH Switzerland
`CM Cameroon
`DE Gonnany. Federal Republic of
`DK Denmark
`Fl
`Finland
`FR
`France
`
`GA Oabon
`GB Uniled Kinadom
`HU Hunpl)I
`IT
`l1a1Y
`JP
`Japan
`KP Dcmocralic People's Republic
`of Korea
`KR Republic of Korea
`LI
`Liecb1ens1ein
`LK Sri Lanka
`LU Luxembourg
`MC Monaco
`MG Madagascar
`ML Mali
`
`MR Mauri!Bnia
`MW Malawi
`NL Netherlands
`NO NOJWBy
`RO Romania
`SD Sudan
`SE Sweden
`SN Seneaal
`SU Soviet Union
`TD Chad·
`TG Togo
`·United S1aiu of America
`US
`
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`IMIDAZOLE ANALOGS OF MEVALONOLACTONE AND DERIVATIVES THEREOF
`
`This invention relates to compounds of the formula·
`
`(I ) I
`
`and the pharmaceutically acceptable acid addition salts
`thereof,
`wherein Ri
`
`is C1-6alkyl not containing an asymmetric carbon
`atom, C3-7cycloalkyl, adamantyl-1 or
`
`-+•s
`
`R6
`wherein R4, Rs and R5 are as defined below,
`is C1-6 alkyl not containing an asymmetric carbon
`atom, C3-7cycloalkyl, adamantyl-1 or
`
`R2
`
`_,_
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`R3
`
`wherein R1, Re and Rg are as defined below,
`is hydrogen, C1-6alkyl not containing an
`asymmetric carbon atom, C3_7cycloalkyl,
`adamantyl-1, styryl or
`
`~11
`
`Rl2
`
`wherein RlO• R11 and Rt2 are as. defined below,
`is -(CR2>m-, -CH=CH-, ~CHmCH-CB2- or -CH2-CH=CB-,
`wherein mis 0, 1, 2 or 3, and
`
`..
`
`X
`
`z
`
`RlJ
`31
`5
`is -CH-CH2-C-CH2-COOR14
`I
`
`..
`
`OH
`
`I
`
`OH
`
`(a) I
`
`(b)
`
`or
`
`Rl 3
`31
`4
`-O-CB2-C-CH2-COOR14
`1
`OH
`
`wherein O is -c- or -c-
`6'-o
`~
`I
`r
`Rls Rls
`
`( C) I
`
`(Cb) I
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`wherein each Ris is primary or. secondary
`C1-5alkyl not containing
`an asymmetric ca~bon atom, ·
`the two Rts's being the
`same, or
`the two Rts's taken together·
`are -(CH2>q~·
`wherein q is 2 or 3,
`RtJ is hydrogen or C1-3alkyl, and
`R14 is hydrogen, R16 or M,
`wherein R16 is a physiologically
`acceptable ester
`group; and
`M is a pharmaceutically
`acceptable cation,
`with the proviso that z may be a group of Formula.
`c only when (i) Xis -caaca- or -CH2-CH=CH-, (ii)
`RlJ is C1-3alkyl or (iii) both (i) and (ii),
`wherein each of R4, R1 and Rl o is independently hydrogen, .
`C1-3alkyl, n-butyl, .!,-butyl, S-butyl, C1-3alkoxy,
`n-butoxy, i-butoxy, trifluoromethyl, fluoro,
`chloro, bromo, phenyl, phenoxy or benzyloxy,
`each of Rs, Rs and R11 is independently hydrogen,
`C1-3alkyl, C1-3alkoxy, trifluoromethyl, fluoro,
`chloro, bromo, -COOR17, -N(R19) 2 , phenoxy or
`benzyloxy,
`wherein R17 is hydrogen, Rte or M,
`wherein Rt8 is C1-3alkyl, n-butyl,
`!-butyl, ~-butyl or
`benzyl, and
`is as defined above, and
`M
`each Ri 9. is independently C1-5alkyl not
`containing an asymmetric carbon atom,
`and
`each of R5, Rg and R12 is independently hydrogen,
`C1-2alkyl, C1-2alkoxy, fluoro or chloro,
`with the provisos that not more than one substi(cid:173)
`tuent on each of Rings A, B and C independently is
`
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`trifluoromethyl, not more than one substituent on
`each of Rings A, B and c independently is phenoxy~
`and not more than one substituent on each of .. Rings ;
`_A, B and C independently is benzyloxy,
`with the provisos that (1) when Z is a group of Formula· c
`wherein Q is a group of Formula cb1 the compound is in free
`base form and either (i) R14 is R16 and each R17 is.
`independently Rl a or (ii) R14 is M and _each R17 is
`independently RlB or Mand (2) when (i) R14 or at -least:~ne
`R17 is M·or (ii) R14 and at least one R17 are M, the compound
`is in free base form,
`processes for and intermediates in. the synthesis thereof,·
`pharmaceutical compositions comprising a compound of Formula·r
`and the use of the compounds of Formula I for inhibiting
`cholesterol biosynthesis and lowering the blood cholesterol
`level and, therefore, in the treatment of hyperlipoproteinemia
`and atherosclerosis.
`By the term "physiologically acceptable ester group"
`is meant a group· which, together with the -coo- radical to
`which it is attached, forms an.ester group which is
`physiologically acceptable. The preferred such groups are the
`physiologically acceptable and hydrolyzable ester groups. By
`the term "physiolegically acceptable and hydrolyzable ester
`group" is meant a group which, together with the -coo- radical
`to which it is attached, forms an ester group which is
`physiologically acceptable and hydrolyzable under
`physiological conditio~s to yield a compound of Formula I
`wherein R14 is hydrogen and an alcohol which itself is
`physiolo~ically acceptable, ~, non-toxic, at the desired
`dosage level, and which, preferably, is free of ~enters pf
`asymmetry. Examples of such groups are C1-3alkyl, n-butyl,
`J:.-butyl, ~-butyl and benzyl, collecti"vely referred to as: R'16·
`The compounds of Formula I except those wherein R14
`and/or one or more R17's are M may be converted into pharma(cid:173)
`ceutically acceptable acid addition salt form. By the term
`"pharmaceutically acceptable acid additiori salts" is meant
`those acid addition salts that are physiologically acceptable,
`i.e., that do not significantly increase the toxicity of the
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`basic compound or otherwise adversely affect its pharmaco(cid:173)
`l~gical activity.
`such pharmaceutically acceptable acid
`addition salts are included within the scope of this: inv,en(cid:173)
`tion.
`Included are salts with strong organic acids, ~· the
`methanesulfonate, ethanesulfonate, benzenesulfonate and
`,,E-toluenesulfonate salts, and salts with strong inorganic
`.
`,
`acids, ~' the hydrochloride, hydrobromide and sulfate,
`salts. The pref erred strong acids are those having a pK: ( the
`pK of at least the initial dissociation step if the acid has
`more than one) in water at 2s•c. below about 3, more· prefer(cid:173)
`ably below about 2 and.most preferably below about 1.
`For the avoidance of doubt, throughout this applic.a(cid:173)
`tion it is the right-hand side of the X radical that is
`attached to the z group.
`As is self-evident to those in the art, each compound
`of Formula I wherein Z is a group of Formula a orb (and every
`subscope and species thereof) has two centers of asymmetry
`(the two carbon atoms bearing the hydroxy groups in the group
`of Formula a and the carbon atom bearing the hydroxy group and
`the carbori atom having the free valence in the group of
`Formula b) and, therefore, there are four stereoisomeric forms
`(enantiomers) of each compound (two racemates or pairs of
`diastereoisomers), provided that Rt4 does not contain any
`center of asymmetry. The four stereoisomers may be d·esignated
`as the R,R, R,S, S,R and s,s enantiomers, all four
`stereoisomers being within the scope of the invention·. When
`Rt 4 contains one or more centers of asymmetry, there ·are eight
`or more stereoisomers. On the other hand, each compound of
`Formula I wherein z is a group of Formula c (and every
`subscope and species thereof) has a single center of asymmetry
`(the carbon atom bearing the hydroxy group in the group of
`Formula c) and, therefore, there are two enantiomers of each
`compound, prov.ided that R14 does not contain any center of
`asymmetry. The two stereoisomers may be d~signated as the 31\
`and 3S enantiomers, both being within the scope of this
`invention. Since it is preferred that R14 not contain a
`center of asymmetry and for reasons of simplicity, in both
`cases any additional stereoisomers resulting from the presence
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`of one or more centers of asymmetry in R14 will usually be
`ignored, it being assumed that Ri 4 is free of centers of=
`asymmetry. Each pharmaceutically accept.able acid addition
`salt contains the same number of centers of asymmetry as.the
`corresponding free base provided that the acid does not
`contain any center asymmetry.
`The compounds of .Formula I and the pharmaceutically
`·acceptable acid addition salts thereof· may be divided into ·
`four subgroups, Groups IA, IB, IC and ID, based upon the
`.significances of Rl and R2.
`
`Group
`
`IA
`IB
`IC
`ID
`
`!l
`Other Than Ring A
`Ring A
`Ring A
`Other Than Ring A
`
`!§.
`Ring B
`Other Than Ring B
`Ring B
`0th.er Than Ring B.
`
`The compounds and pharmaceutically acceptable acid
`addition salts of each of Groups IA, IB, IC and ID may be
`divided into three subgroups based upon the significance of z
`~, Groups IA~, IAb and IAc (those of Group IA wherein .z is
`a group of Formula a, b or c, respectively), Groups IBa_, IBb
`~nd Ibc (those of Group IB wherein z is a group of Formula a,
`b or c, respectively), Groups ICa, ICb and ICc (those of Group
`IC wherein Z is a group of Formula a, b or c, respect.ivel.Y)
`and· Groups IDa, IDb an<l IDc (those of Group ID wherein Z . is a
`group of Formula a, b or c, respectively).
`Preferably, one of R1 and R2 is C1-6alkyl not
`containing an asymmetric carbon atom and the other is Ring A
`(if R1) or Ring B (if R2>· RJ is preferably Ring c. More
`preferably, the preferences set forth in the preceding two
`sentences occur si~ultaneously.
`Also preferably, at least one of R2 and R3 is other
`than tertiary alkyl.
`O is preferably -co-.
`R1 is preferably R\x, where Rtx is C1-6alkyl not
`containing an asymmetric carbon atom, more pr·e"ferably a'; x•
`where Rlx is C1-3alkyl, .!!-butyl or £-butyl, even more
`preferably R'l'x, where R'fx is C1-3alkyl, and most preferably
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`1
`
`'
`
`I
`
`,.
`
`ti
`
`'
`
`~
`
`llf
`
`t
`
`IU
`
`•
`
`.!-propyl; or
`Rl is preferably Rly, where Rly is Ring A, more
`
`preferably R1; y, where R'1 y is Ring A wherein R4 is R~, Rs is:
`bl
`h
`i.
`Rs, and R6 is R6, even more prefera y Rly• w ere Rly is R ng
`A wherein R4 is R4, Rs is Rs, and ff6 is R6, and most
`00
`•
`..
`.
`preferably Rly• where Rly is Ring A wherein R4 is R4, Rs ls
`Rs, and R6 is hydrogen, especially phenyl, 3,5-dimethylphenyl
`-0r 4-fluorophenyl and more especially 4-fluorophenyl.
`R2 is preferably R2x where Rix is Ring e, more
`preferably R2x1 where R2x is Ring B wherein R7 is R17, Re is
`.
`·
`m
`R9, and R9 is Rg, even more preferably R2xi where R2x is ~ing
`•
`B where n R7 is R7, Re is R9, and Rg is Rg, and most
`i
`preferably Ri"x, where R2~ is Ring B wherein R1 is R7, Ra is
`Ra, and Rg is hydrogen, especially phenyl, 3 ,S-dimethylphenyl
`or 4-fluorophenyl and more especially 4-fluorophenyl; or
`R2 is preferably Ray• where Ray is C1-6alkyl not_
`containing an asymmetric carbon atom, more preferably Riy•
`where R2y is C1-3alkyl, !!-butyl or 1-butyl, even more
`preferably Riy, where R2y is C1-3alkyl, and most preferably
`1-propyl •
`. RJ is preferably R), where R13 is C1-6alkyl not
`containing an asymmetric carbon atom, cyclohexyl or Ring C,
`.
`more preferably R3, where Rj is.Ring c, even more preferably
`R1j, where R'j is Ring c wherein R10 is R110, Rl 1 is Rn, and R12
`is R112, and most preferably li'j, where :R)' is Ring C wherein R10
`is R11 o, Rll is R'h, and Rl 2 is R112, especially phenyl.
`Each of R4 and R1 is preferably R4 and R1,
`respectively, where each of R4 and RJ is independently
`hydrogen, C1-3alkyl, fluoro, chloro or-bromo, more preferably
`R4 and R7, respectively, where each of R4 and Rj is
`independently hydrogen, methyl. or fluoro, and most preferably
`hydrogen or fluoro, especially 4-fluoro.
`Each of Rs and Re is preferably Rs and Ra,
`respectively, where each of Rs and R's is independently
`hydrogen, C1-2alkyl, fluoro or chloro, more preferably Rs and
`Ra, respectively, where each of Rs and Ra is independently
`hydrogen or methyl, and most preferably hydrogen.
`
`I
`
`,
`
`I
`
`~
`
`If
`
`I
`
`• ..
`i
`~·
`
`-
`
`7 -
`
`-·------·····--·· . .
`
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`Eacn of R6 and Rg is preferably «6 and Rg,
`respectively, where each of R6 and ~9 is independently
`hydrogen or methyl, and most.preferably hydrogen.
`R10 is preferably R1o, where R110 is hydrogen,
`C1-3alkyl, C1-2alkoxy, trifluoromethyl, fluoro, chloro, bromo
`or phenyl, more preferably R11101 where R11o is hydrogen, methyl
`. or fluoro, and. most preferably hydrogen.
`Rl 1 is preferably R111, where R'11 is hydrogen,
`C1-2alkyl, fluoro, chloro, bromo, -COOR117 or -N(R119.>2/ more
`preferably if11, where :Ri 1 is hydrogen or methyl, and most·
`preferably hydrogen.
`Rt 2 is preferably R112, where R112 is hydrogen or
`methyl,. and most preferably hydrogen.
`Preferably, each of Rings A, B and C independently
`bears a maximum of one substitu ent selected from the group
`consisting of !_-butyl, trifluoromethyl, phenyl, phenoxy and
`benzyloxy. More preferably, when any two or all three of .the
`substitu ents on Ring A [R4 CR4, etc.), Rs (Rs, etc.) and 'Rs
`(R16, etc.)), Ring B [R7 CR?, etc.), Rs (R's, etc.) and Rg CR19,
`etc.)] and. Ring C [Rto (R\o, etc.), R11
`(R111• etc.) and R12
`(R112, etc.) J independently are ortho to each other, at least
`one member of each pair that are ortho to each other is a
`member of the group consisting of hydrogen, methyl, methoxy,
`·fluoro and chloro. Also more preferably, at least one of th·e
`~ positions of each of Rings A, B and C independently has
`a member of the group consisting of hydrogen, fluoro and
`methyl.
`
`Rt 3 is preferably R13, where R113 is hydrogen or
`methyl, and most preferably hydrogen.
`R14 is preferably R14, where Rt4 is hydrogen, Rl6 or·
`b.
`II
`M, more prefera ly R1.i, where R14
`l·S hydrogen, C1-3alkyl or· M,
`even more preferably R14, where Rl4 is hydrogen, C1-2alkyl or
`M, and most preferably M, especially sodium.
`·
`Preferably, each RlS is ·Ct-Jalky~ or both R15's takel"!
`together are -(CH2)q-; more preferably·, each R15 is C1-2alkyl
`or both Rls's taken together are -(CB2>q-; and most
`preferably, each Rls is C1-2alkyl.
`
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`R16 is preferably a physiologically acceptable and
`hydrolyzable ester group, more preferably R1f6, where ·Ri6 is·
`C1-3alkyl, n-butyl, 1-butyl, £-butyl or benzyl, even more
`preferably C1-3alkyl, and most preferably C1-2alkyl,
`especially ethyl.
`·
`I
`I
`Preferably, each R11 is independently R11, wheFe :R17
`I
`.
`is hydrogen, Rle or M; more preferably, each R17 is
`independently R'11, where R1i 7 is C1 -2alkyl or M.
`Also preferably, when a compound contains two or more
`R17's, each R17 is independently R18 CRis or C1-2alkyl) ~r the·
`Ri7's (R 117's or Ri7 1 s) are identical, each of them being
`hydrogen or the same M.
`More preferably, either (i) Ri3 is hydrogen, R~4. (if
`present) is R116, and each Ri 7 is indep~ndently R19 or tn) R 14
`(if present) and each R17 are identical, each of them being
`hy~rogen or the same M.
`Preferably, each Ri e is independently R18, where R118
`is C1-3alkyl1 more preferably, each R1s is independently
`C1-2alkyl.
`Each R19 is preferably. R19, where each R19.is
`independently C1-2alkyl.
`Any -CH=CH-, -CH=CH-CH2-.or -CH2-CH=CH- as xis
`preferably trans, i.e., (E).
`Xis preferably X', where x• is -CH2CH2- or ~CH=CH-,
`more preferably -cH~cH-, and most preferably H;c=c~8 ,
`i.e., (E)-CH=CH-.
`z is preferably a group of Formula a wherein RlJ is
`RlJr and R14 is R114, a group of Formula b wherein R1J is R11J
`I
`'
`.
`.
`or a group of Formula c wherein O is -co-, RlJ is RlJ• and R14
`is R14, more preferably a group of Formula a wherein Ri3 is
`hydrogen, and Ri4 is i14, a group of Formula b whereinR13 is
`hydrogen or a group of Formula c wherein O is -co-, RiJ is
`hydrogen, and Ri4 is Ri4, and most preferably a group of·
`Formula a wherein RiJ is hydrogen, and Ri4 is R14, preferably,
`C1-2alkyl or M, more preferably ethyl or M, most preferably M
`and especially M'.
`mis preferably m', where m' is 2 or 3, and most
`preferably 2.
`
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`Each Mis preferably free from centers of asymmetry·
`and is more preferably M1
`, i.e., sodium, potassium or·
`ammonium, and most preferably sodium. For simplicity; :each
`formula in which an M appears.has been written as if M were·
`monovalent and, preferably, it is. However, M may also' be
`divalent or triv.alent and, when it is, it balances the charge
`of two or three carboxy groups, respectively. Thus; Fo~ul~ I
`and every other formula containing an M embraces compounds
`wherein M is divalent or trivalent, .!!.:..9..:.1 compounds containing
`two or ~hree monocarboxylate-containing anions per catiori M.:
`Preferably, when a compound contains two or more M's, they are
`the same.
`As between otherwise identical compounds of Form~la I
`and pharmaceutically acceptable acid addition salts thereof,
`those wherein ·z is a group of Formula a are generally pre(cid:173)
`ferred over those wherein z is a group of Formula b or c.
`Insofar as the compounds of GrQups lAa, IBa, ICa and.
`IDa and the pharmaceutically acceptable acid addition salts
`thereof and each of the subgroups thereof are concerned~ the
`ervthro isomers are preferred over the !h!:!2 isomers, erythro
`and ~ referring to the relative positions of the hydroxy
`g~oups in the 3- and 5-positions of the group of Formula a.
`Insofar as the compounds of Groups IAb, IBb, ICb ·and
`!Ob and the pharmaceutically acceptable acid addition salts
`thereof and each of the subgroups· thereof are concerned~ the
`~ lactones are generally preferred over the cis lactones,
`cis and~ referring to the relative positions of Ri3 and
`the hydrogen atom in the 6-position of the group of For~uia b.
`The preferred ste·reoisomers of the compounds of: .
`Formula I and the pharmaceutically acceptable acid addition
`salts thereof having only two centers of asymmetry wherein X
`is a direct bond, -CH=C~- or -CH2-CH .. CH-, and z is a group of
`Formula a are the 3R,5S isomer and the racemate of which ft is
`a constituent, i.e., the 3R,5S-3S,5R (erythro) racemate~
`The preferred stereoisomers of the compounds of
`Formula I and the pharmaceutically acceptable acid add1tion
`salts thereof having only two centers of asym~~~ry ~her~in x
`is -CH2-, -CH2CH2-, -CB2CH2CH2- or -CHaC!f..,.c·tf2-, and Z is a
`
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`group of Formula a are the 3R,5R isomer and the racemate of
`which it is a constituent, ~' the 3R,5R-3S,5S {erythro)
`racemate.
`The preferences set forth in the preceding two para(cid:173)
`graphs also apply to the compounds of Formula I and the
`pharmaceutically acceptable acid addition salts thereof
`wherein Z is a group of Formula a having more than two.centers
`of asymmetry and represent the preferred configurations of· the
`indicated positions.
`The preferred stereoisomers of the compounds of
`Formula I and the pharmaceutically acceptable acid addition
`salts thereof wherein X is a direct bond, -CH=CH- or
`-CH2-CH=CH-, and Z is a group of Formula.bare the 4R,6S and
`4R,6R isomers and the racemate of which each is a constituent,
`.l:.!.:.1 the 4R,6S-4S,6R (~ lactone) and 4R,6R-4S,6S {cis
`lactone) racemates, with the 4R,6S isomer and the racemate ~f
`which it is a constituent being more preferred and the 4R,6S
`isomer being most preferred.
`The preferred stereoisomers of the compounds of
`Formula I and the pharmaceutically acceptable acid addition
`salts thereof wherein X is -CH2-, -CH2CB2-, -CH2CH2CH2- or
`-ceacH-CH2-, and z is a group of Formula b are the 4R,6R and
`4R,6S isomers and the racemate of which each is a constituent,
`i.e., the 4R,6R-4S,6S (~ lactone) and 4R,6S-4S,6R (cis
`lactone) racemates, with the 4R,6R isomer and the racemate of
`which it is a constituent being more preferred and the 4R,6R
`isomer being most preferred.
`The preferred stereoisomers of the compounds of
`Formula I and the pharmaceutically acceptable acid addition
`salts thereof having just one center of asymmetry wherein z is
`a group of Formula c are the 3R isomer and the racemate of
`which it is a constituent, i.e., the 3R-3S racemate, with the
`JR isomer being more preferred. These preferences also apply
`to the compounds of Formula I and the pharmaceutically
`acceptable acid addition salts thereof wherein·Z is a group of
`Formula c having more than one center of asymmetry and
`represent the preferred configuration of the indicated
`position.
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`Generally, the compounds of Formula I are-·preferred
`over the pharmaceutically acceptable acid addition salts of
`the corresponding compounds.
`Each of the preferences set fo~th above applies, not
`only to the compounds of Formula I, bµt also to the compounds
`of Groups IA, IB, IC and ID and the pharmaceutically.
`acceptable acid addition salts thereof and those of Groups
`.iAa, IAb, IAc, IBa, IBb, IBc, ICa, ICb, ICc,. IDa, IDb and IDc.
`as well as to every other subgroup ~hereof set forth in the
`specification, ~, Groups ( i) et se9., unless otherwise ..
`indicated. When any· preference or group contains a variable,
`the preferred significances of that variable apply ~o the .·
`preference or group in question, unless otherwise indicated.
`Preferred subgroups of Groups IAa, IAb, IAc, IBa, IBb
`and IBc include the. compounds a·nd the pharmaceutically
`acceptable acid addition salts
`(i) of Group IAa wherein R1 is Rixr R2 is R2x, ,R3 is
`R13, R13 is R113, R14 is Ri4, and X_isX',
`(ii) of (i) wherein R1 is R'hc, RJ. is R1j, R1J is·
`hydrogen, R14 is R14, and X is (E)-CH=Ce-,.
`{iii) of {ii) wherein RJ is It], and R14·is R11'4,
`(iv) of (iii) wherein R1 is R'i'x (especially J:-propyl),
`Ri is R2x• and RJ is RJ,
`(v)-{viii} of (i)-{iv} wherein R14 is M, preferably M'
`and especially sodium,
`(ix)-(xvi) of (i)-(viii) wherein the hydroxy gro~ps in
`the 3- and 5-positions of the group of Formula a have th.e
`erythro configuration,
`(xvii)-(xxiv) the 3R,5S enantiomers of (ix)-(xvi) when
`x is -ca=cH- and the 3R,5R enantiomers of (ix) when X is
`-CH2CH2- 1
`(xxv) of Group IAb wherein R1 is R'1 X' R2 is
`' RJ.• R13 is _R113 1 and X is x',
`,.
`( xxvi) of (xxv) wherein R1 is
`Rtx• RJ is
`...
`hydrogen, and X is (E)~CH~CH-,
`(xxvii~ of (xxvi) wherein RJ is R),
`(xxviii) of {xxvii) wherein Rl is ~'.bt. Lespecially
`_!-propyl), R2 is R2'x• and RJ is R)':
`
`II .
`R2x•
`
`R) is
`
`•• RJ, R1J
`
`is
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`(xxix)-(xxxii) of (xxv)-(xxviii) wherein R13 and the
`hydrogen atom in the 6-position of the group of Formula b. are
`~to each other, i.e., the~ lactones,
`(xxxiii)-(xxxvi) the 4R,6S enantiomers of
`(xxix)-(xxxii) when X is -CH•CH- and the 4R,6R enantioniers of
`(xxix) when X is -CB2CH2- 1
`(xxxvii) of Group IAc wherein R1 is R1x, R2 is Rzx• RJ
`·iS RJ, Rl 3 is R113, Rl 4 is R114, each R1 5 is C1 -3alkyl or both
`Rls's taken together are -(CH2)q-, and Xis X',
`(xxxviii) of (xxxvii) wherein Rl is Rlxr RJ is ,R3, R1J
`is hydrogen, R14 is R14, each Rls is C1-2alkyl or both Rls's
`taken together are -(CH2)q-, and X is (E}-CH=CH-,
`(xxxix) of (xxxviii) wherein R3 is R)', R14 .is R1t14, and·
`each Rls is C1-2alkyl,
`(xl) of (xxxix) wherein Rl is K1x (especially
`tu
`u•t
`i
`J,-propyl), R2
`s R2xr and RJ is RJ,
`(xli)-(xliv) of (xxxvii)-(xl) wherein O is -co-,
`(xlv)-(lii) of (xxxvii)-(xliv) wherein R14 is M,
`.
`preferably M' and especially sodium,
`.
`(liii)-(lxviii) the 3R enantiom~rs of (xxxvii)-{liif,
`(lxix) of Group IBa wherein Rl is Rtyr R2 is Ri~, RJ
`is R13, R1J is RlJ, R14 is R14, and X is X' ,
`(lxx) of (!xix) wherein R2 is R2y• RJ is RJ, R1J is
`hydrogen, R14 is R1i4, and X is (E)-CH=CH-,
`( lxxi) of ( lxx) wherein RJ is RJ, and R14 is R1'4,
`(lxxii) of (lxxi) wherein Rl is R1~, R2 is R2y
`(especially J,-propyl), and RJ is ilJ',
`(lxxiii)-(lxxvi) of (lxix)-(lxxii) wherein Ri4 is M,
`preferably M', and especially sodium,
`(lxxvii)-(lxxxiv) of (lxix)-(lxxvi) wherein the
`hydroxy groups in the 3- and 5-positions of the group of
`Formula a have the erythro configuration,
`(lxxxv)-(xcii) the 3R,5S enantiomers of
`(lxxvii)-(lxxxiv) when X is -CH=CH- and the JR,SR enantiomers
`of (lxxvii) when X is -CH2CH2-,
`(xciii) of Group IBb wherein Rl is R'ty• R2 is R2yr RJ
`is R), R1J is Ri3, and Xis x•,
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`(xciv) of (xciii) wherein R2 is Rly• RJ is R'), R13 is
`hydrogen, and X is (E)-CH=CH-,
`(xcv) of (xciv) wherein RJ. is R1j',
`( xcvi) of ( xcv) wherein Ri is R'1'y• R2 is R1iy
`(especially j-propyl),. and R.3 is R'j',
`(xcvii)-(c) of (xciU)-(xcvi) wherein Rt3 and_ the
`hydrogen atom in the 6-position of the group of Formula b. are
`-trans to each other,
`(ci)-(civ) the 4R,6S enantiomers of (xcvii),-(.c): wheriX
`is -CH=CH- and the 4R, 6R enantiomers of ( xcvii} when X is.
`-CH2CH2.:.,
`'
`,,
`.
`(cv) of Group IBc wherein Ri is Riy• R2 is R2y•·. RJ is
`RJ, Ri3 is RlJ• R14 is R114• each Rts is Ct-3alkyl or both
`Rts's taken together are -(cH2 >q-, and Xis X',
`(cvi) of (cv) wherein R2 is R2y• RJ is RJ, RtJ is
`hydrogen, Rt 4 is R114, each Rt 5 is Ct-2alk~l .or both Rt 5 's .
`taken together are -(CH2>q-, and X is (E)-CH=CH-,
`(cvii) of (cvi) whl;!rein RJ is it3, Rt4 .is R11'4, and each
`Rts is c 1_2 alkyl,
`( cviii) of ( cvii) wherein R1 is R'1'y• R2 is R2y
`(especially j-propyl), and R3 is ij',
`(cix)-(cxii) of (cv)-(cviii) wherein Q is -co-,
`(cxiii)-(cxx) of (cv)-(cxii) wherein Rt4 is M,
`preferably M' and especially sodium, and
`(cxxi)-(cxxxvi) the 3R enantiomers of (cv)-(cxx).
`Groups (ix)-( xvi) and ( lxxvii) and ( lxxxiv) embrace
`the 3R,SS-35 ,SR racemate and the JR ,SS and JS ,SR enantiomers
`when X is -CH=CH-, the 35,SR enantiomer being least preferred
`and the 3R,5R-3S,5S racemate and the 3R,5R and 3S,SS
`enantiomers when X is -ce2ce2-, the 3S,SS enantiomer being.
`least preferred.
`Groups (xxix)-(xxxii) and (xcvii)-(c) embrace the
`4R,6S-4S,6R racemate and .the. 4R,65 and 4S,6R enantiomers when
`x is -ce=cH-, the 4S,6R enantiomer being least preferred, and
`the 4R,6R-4S,6S racemate and the 4R,6R and 4S,6S enant_iomers
`when X is -CH2CH2-, the 4S,6S enantiomer being least
`preferred.
`
`, ---·
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`.
`
`~
`
`.
`.
`
`-.
`
`Insofar as Groups ICa, ICb and ICc are concerned, the
`preferred subgroups are those that correspond to Groups
`(i)-(lxviii) wherein R11x in Groups (i), (xxv) and (:xxxvii") is
`replaced by R'lyr
`nRl is R'1x" is deleted from Groups (ii).,
`:
`(xxvi) and (xxxviii) and "Rtx (especially .!-propyl)" .in Groups
`(iv), (xxviii) and (xl) is replaced by R';'y, i.e., Groups.
`.
`(cxxxvii)-(cciv).
`Insofar as Groups IDa, IDb and roe are concerned~ the
`preferred subgroups are those that correspond to Groups ( i )- ·
`(!xviii) wherein R'2x in Groups ( i), (xxv) and (xxxvii) i~
`replaced by R2y1 "R2 is R2y" is added to Groups (ii), (xxvi)
`and ( xxxv iii), and .R2 x in Groups (iv) , ( xxvii i) and ( xl) . is
`replaced by •Riy (especially .!-propyl)", i.e., Groups .. (ccv)- ·
`( cclxxii) •
`. It goes without saying th.at all of the provisos. set
`forth above in connection with Formula I apply to Groups (i)(cid:173)
`(cclxxii) and any other group set forth in this application.·
`A representative group of the compounds of Formula I
`and the pharmaceutically acceptable acid addition salts
`thereof are those wherein one·of R1 and R2 is Rlx and the
`other is Ring A wherein R4 is other than bromo and Rs is oth~r
`than bromo, -COOR17 and -N(R19) 2 (R6 being as defined above)·,
`RJ is Ring C wherein Rlo is other than bromo and R1t is other
`than bromo, -COOR17 and -N(R19)2 (R12 being as. defined above),
`Xis X', and Z is a group of Formula a wherein.R13 is
`hydrogen, and R14 is hydrogen, a physiologically acceptable
`and hydrolyzable ester group or M or a group of Formula b
`wherein R13 is hydrogen, each of the variables not defined
`here being as defined above, with the provisos that not .more
`than one substituent on each of Rings A and c independently is
`trifluoromethyl, not more than one substituent on each of
`Rings A and C independently is phenoxy, not more than one
`substituent on each of Rings A and C independently is
`benzyloxy, and the compounds must be in free base form when ~
`contains an M.
`
`I
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`The free bases of each group that embraces both free
`bases and pharmaceut1cally acceptable acid addition salts·are
`preferred.
`
`The compounds of Formula I and the pharmaceuticaliy
`acceptable acid addition salts thereof may be synthesized a's
`follows:
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`Reaction Scheme I
`
`The compounds of Formula I wherein any R11 is. Rte: and
`either X is -ce~ca- or -ce2-ca=ce-, and z is a group of
`Formula b having the 4R,6S configuration or X is -CH2