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`IPR Page 1/32
`
`Santen/Asahi Glass Exhibit 2010
`Micro Labs v. Santen Pharm. and Asahi Glass
`IPR2017-01434
`
`
`
` 2
` 2
` 2
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`
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`IPR Page 1/32
`
`Santen/Asahi Glass Exhibit 2010
`Micro Labs v. Santen Pharm. and Asahi Glass
`IPR2017-01434
`
`
`
`Oolli'teenleu'ic
` !%&
`
` 5
`
`(:37
`;H9H99I
`Anchidonic Acid
`JH"H#;
`" ! " !
`in...”
`TmO
`Pmua\cyclin Synrhase
`\[vm
`Cum/v
`
`POE,
`
`PG],
`
`Figure l. Bioeynthesis of prcetnglsndina and proatacyclin.
`< 0 !!
`Proolaglandin Nomenclature
`
` !4
`)
`
`
`coco.
`gs
`C K5
`K5
`-
`’94
`fineKI
`E
` F
`H0 m
`W3 Fa
` -6
`<
`PG, (derived from dihomo-y-llnolenic acid)
`
`Ito. - (CHAfiOOH
` 7
`,!! !
!/
`
`, >./ 66>
`WWilm- .0H
`
`
`on
`
`. :
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`
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`on
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`6>
`
`P61 (derived from arechidonic acid)
` 7.,!! ! !/
`“1- Wm,
`Mm-
`
`r0'
`
`
`
`
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`
`
`6>
`
`PG, (derived from eImstentaenmr and)
` 7L,!! !/
`- Wm
`WRm-
`;;H;M;F
`:OH
`
`
`
`
`
`Figure 2. Prostaglandin nomenclature.
`< . !
`priate, recent synthetic improvements as well as the
`
` ?
`initially reported synthesis will be described. Due to
` ! ? 1! 1!%
`the large number of such compounds, discussion for
` 1 !
`!
`the most part will be limited to those which have reached
` ? 1 ! ? !
`some stage of clinical evaluation. The prostaglandin
` !
`analogs are listed in Table 1 along with their primary
` !1 ?
`therapeutic indication and, where possible, their clinical
` ! !
`? 1
`
`or market status. Similar information for proatacyclin
` '
`analogs is given in Table 2.
` 1 .
`u. Prosiaglendln Analogs
`(( !"
`A. Background
`"0 ' !
`Although PGs have been examined for a variety of
`" 7 15 !
`clinical indications, the predominant use of E type PGs
` !
` ! 3 7
`has been for peptic ulcer and cardiovascular diseases
` 1 ! ! !
`and F type PGs for gynecological or fertility control
`!< 7
`applications. To date, the only widely marketed PGE
` !
` ?! '! 73
`analog is miaoprostol (for prevention of gastroduodenal
` , !!
`ulcers caused by nonsteroidal antiinflammatory drugs);
` !1! ! /E
`but several others are approved in some countries and
`1 ! !
`others are in late phase clinical study (Table l). PGF
` !,1 / 7<
`compounds have found limited utility in human re-
` ! ! !
`
`153‘ Chemical Reviews. 1993. Vol. 93. No. 4
` ?
`
`9
`4
`
`
`
`Paul W. Collins received a 5.8. in Pharmacy from the University
`oi South Carolina in 1962 and a PhD. In Medicinal Chemistry from
` # ! 0
`the Medical College at Virginia in 1968. After postdoctoral study
` .! %-!
`with Professor Alfred Burger at the University of Vi'dnla, he Joined
` -! 9 ( "! !
`GD. Searte In 1967 where he ls presently Senior Research Fellow
`? " !0 9
` &!
`In the Department of Chemistry. Dr. Collins's career at Searle has
`7% *? < ?
`been largely devoted to the modification of naturally occurring
`( % % F
`prostanolds for antiuicer and other therapeutic applications. He
`1 !! !
`is the oo-invenlor of misoprostoi. enlsoprost. and rembrostol. Dr.
`! ! >
`Collins has published and lectured extensively on proetaglandins.
`
`
`! %
`holds 30 us. Patents. and is a torrner member of the editorial
` 1 !! !5 !
`
`advisory board oithe Jounalormddnaichemistry. He was a
` ! )
`! ( 1 !
`ecu-recipient of the 1990 Monsanto Edgar M. Queeny Award given
`!1! + -! >?
`for the discovery of miseprostol.
`
)-3! -G"?!
` !
`
`
`
`Steven W. Diurlc was born In Leicester. U.K.. in 1954. He obtained
`a B.Sc. doves (ist class honors) in Chemistry from the University
`#%+ ? 1(:
` =
` >1!
`of Leeds in 1976 and completed his doctoral studies at the same
`0 ! , /
`Institution in 1979. After a postdoctoral fellowship at The Ohio
`:!* ! ! ! !
`( * " ! ? 6
`State University In the laboratories of Protessor Philip D. Magnus.
`heiohed Searle In 1981 where he is presently Research Felow
` 1 %-
`
`In the Department of Chemistry. His research interests are in the
` &! ( 2 ? < ?
` % >
`design and development of novel therapeutic agents for the
`treatment of Inflammatory diseases and. In particular. agents that
`! ! !
`Inhibit or antagonize the actions of Ilpoxygenase derived products
` ( !!
`
`
`of arachldonic acid such as leukotriene B4.
` 1 @ 5 !!!
` ! ! ' 0$
`one or more of these problems. Success in finding
` 1 !
`acceptable drug candidates has been diffith and has
` 1 ! !! 1! !
`also been compounded by poor clinical efficacy in many
` 1 !!1
`therapeutic areas.
`
`Prostacyclin was discovered in the mid-19708 and,
`
` ? ! ! !
` !
`
`
`
`Steven W. Diurlc was born In Leicester. U.K.. in 1954. He obtained
`a B.Sc. doves (ist class honors) in Chemistry from the University
`#%+ ? 1(:
` =
` >1!
`of Leeds in 1976 and completed his doctoral studies at the same
`0 ! , /
`Institution in 1979. After a postdoctoral fellowship at The Ohio
`:!* ! ! ! !
`( * " ! ? 6
`State University In the laboratories of Protessor Philip D. Magnus.
`heiohed Searle In 1981 where he is presently Research Felow
` 1 %-
`
`In the Department of Chemistry. His research interests are in the
` &! ( 2 ? < ?
` % >
`design and development of novel therapeutic agents for the
`treatment of Inflammatory diseases and. In particular. agents that
`! ! !
`Inhibit or antagonize the actions of Ilpoxygenase derived products
` ( !!
`
`
`of arachldonic acid such as leukotriene B4.
` 1 @ 5 !!!
` ! ! ' 0$
`one or more of these problems. Success in finding
` 1 !
`acceptable drug candidates has been diffith and has
` 1 ! !! 1! !
`also been compounded by poor clinical efficacy in many
` 1 !!1
`therapeutic areas.
`
`Prostacyclin was discovered in the mid-19708 and,
`
` ? ! ! !
*)!
`
`like the PCs, was originally thought to be a revolutionary
` ' 7
`? 1
`find for therapeutics, especially in the cardiovascular
`!
` !
`arena. But, due to similar problems of instability (the
` 0
`! 1 1 ,
`tug for PGIg at pH 7.4 and 37 °C is 3 min), metabolism
`;. 7(.>*! *N /
` 1
`and lack of selectivity, PG12 and its analogs have also
`! '
` 7(.!
`experienced a difficult path to therapeutic success.
`5 !!
`This review5 will focus on the synthesis of therapeu-
` ? ?
`
`like the PCs, was originally thought to be a revolutionary
` ' 7
`? 1
`find for therapeutics, especially in the cardiovascular
`!
` !
`arena. But, due to similar problems of instability (the
` 0
`! 1 1 ,
`tug for PGIg at pH 7.4 and 37 °C is 3 min), metabolism
`;. 7(.>*! *N /
` 1
`and lack of selectivity, PG12 and its analogs have also
`! '
` 7(.!
`experienced a difficult path to therapeutic success.
`5 !!
`This review5 will focus on the synthesis of therapeu-
` ? ?
`tically useful analogs of PGa and PGIz. Where appro-
` 7! 7(.#
`
`IPR Page 2/32
`
`IPR Page 2/32
`
`
`
`Prostaglandln and Prostacyclln Analogs
` !! "
`
`productive indications and are more extensively used
`! ! ! 5 !
`for farm animal estrus synchronization.
` @
`The synthesis of prostaglandins has occurred over a
` ! !
`period of about 25 years beginning in the 1960s with
`!1. 1 )?
`the natural compounds and extending into this decade.
` !!5! ! !
`The evolution of synthetic methodology will be apparent
` ! ? 1
`as the newer analogs and improved routes to older
` ? ! ! !
`compounds are described.
` ! ! 1!
`B. Synthesls
`0
`1. Arbaprostil
`"1
`In the late 1960s and early 1970s, researchers at
`( )! *)
`
`Upjohn reported‘iv7 two clever approaches to the problem
` & !
*? 1
`of rapid metabolism of the 15-hydroxy group of natural
`! 1
`of rapid metabolism of the 15-hydroxy group of natural
`! 1
!5
`PGs. By placing a methyl group at 0-15 or two methyl
` 70
`PGs. By placing a methyl group at 0-15 or two methyl
` 70
?
`groups at 0-16 of PGE2, oxidative metabolism of the
`
`
`groups at 0-16 of PGE2, oxidative metabolism of the
`
`
73.
`5! 1
`hydroxy group was prevented, and the resulting com-
` !5 ? !
`!
`5! 1
`hydroxy group was prevented, and the resulting com-
` !5 ? !
`!
`pounds, 15-methyl-PGE2 and 16,16-dimethyl-PGE2,
`!
`
73.!
`
`
!
73.
`
`were orally active and pharmacologically more potent
`? !
`and longer lasting than PGE2 itself. Unfortunately,
`! 73.
`
`the side effects of these two compounds have severely
` ! ? !
`restricted their clinical utility. 16,16-Dimethyl-PGE2
` !
`
`
`were orally active and pharmacologically more potent
`? !
`and longer lasting than PGE2 itself. Unfortunately,
`! 73.
`
`the side effects of these two compounds have severely
` ! ? !
`restricted their clinical utility. 16,16-Dimethyl-PGE2
` !
`
%
73.
`has become widely used as a pharmacological tool and
` 1 ?! ! !
`standard while 15-methyl-PGE2 has been pursued as
`!!?
`has become widely used as a pharmacological tool and
` 1 ?! ! !
`standard while 15-methyl-PGE2 has been pursued as
`!!?
73. 1!
`a clinical candidate for ulcer disease in its (15R)-epimer
` !! !, /
`a clinical candidate for ulcer disease in its (15R)-epimer
` !! !, /
`form. Arbaprostil, (15R)-15-methyl-PGE2, is the un-
` "1
`, ./
73.
`
`
`naturally configured and biologically inert diastereomer.
` !!1 !
`It is active by oral administration, however, because
`( 1 !
` ?
`1
`the tertiary allylic alcohol at 0-15 readily epimerizes
`under the acidic conditions of the stomach to a mixture
`
! @
`! ! ! 5
`of isomers. This strategy was utilized because the side
` ? @!1 !
`effects observed with arbaprostil were less than those
` 1!? 1 ?
`experienced with the (15S)-isomer.
`5 !? , /
`! ! ! 5
`of isomers. This strategy was utilized because the side
` ? @!1 !
`effects observed with arbaprostil were less than those
` 1!? 1 ?
`experienced with the (15S)-isomer.
`5 !? , /
`The total synthesis of 15-methyl-PGE2 was reported
`
73.?!
`in 1974.5 This original synthesis (Scheme 1) was
` *2 , /?
`analogous to the popular Corey route.9 Oxidation of
` 65!
`the benzoate 1 (rather than the p-phenyl benzoate
` 1@ ,
`in 1974.5 This original synthesis (Scheme 1) was
` *2 , /?
`analogous to the popular Corey route.9 Oxidation of
` 65!
`the benzoate 1 (rather than the p-phenyl benzoate
` 1@ ,
1@
`commonly known as Corey’s lactone) with Collins
` '? B /?
`reagent (Grog—pyridine) gave the unstable aldehyde
` , )
`commonly known as Corey’s lactone) with Collins
` '? B /?
`reagent (Grog—pyridine) gave the unstable aldehyde
` , )
!/ 1 ! !
`which was reacted in unpurified form with dimethyl
`? ? !! ? !
`(2-6xoheptyl)phosphonate to give 2. The tertiary
`,.
`which was reacted in unpurified form with dimethyl
`? ? !! ? !
`(2-6xoheptyl)phosphonate to give 2. The tertiary
`,.
!5 / .
`methyl group was introduced by treatment with either
` ? ! !1 ?
`methyl magnesium bromide at —78 °C or trimethyl-
` 1 !
`methyl group was introduced by treatment with either
` ? ! !1 ?
`methyl magnesium bromide at —78 °C or trimethyl-
` 1 !
*2N
`aluminum in benzene at room temperature. Attack
` 1@ " '
`Scheme 1'
` $
`
`o
`«9
`g
`
`If
`HO
`
`5
`
`‘NWGOOGHI
`cH
`OH
`
`5
`
`_—————
`hlad
`
`4
`
`o
`
`E
`HO
`
`.
`a“ WCOOCH,
`CH?
`0“
`arbaprostll
`(methyl ester)
`
`)
`
`" (a) CrOg/pyridine. (b)(MeO)2HHC(O)Cgl-Iu. (c) MeMgBr.
`(d) CH30Na. (e) DIBAL. (f) Ph3P==CH(CH2)sCOOH. (8)CH2N2.
`,/ 6;!,1/,-)/. H > ,)/ >, /-- 0
`(h) MessiN(Et)g.
`(i) H3+0.
`,!/ >&64,/%(0":,/ H >, >./ 66>, / >.4.
`, /- 4,3/.,/>O)
`
`IPR Page 3/32
`
`Chemlcal Revlews, 1993. Vol. 93. No. 4
`1535
` ?
`
`9
`4
`
`s:
`
`+
`
`a—__.
`
`Scheme 2‘
`0THP
` .P
`CH-o
`
`Q >G
`
`flmfiluCOOCH:
`OM—. M
`
`1
`
`!
`
`o
`
`forthcoocn,
`
`( >&+& 66 >&
`
`G
`
`W H5
`
`
`
`“NM/cocoa
`
`CH,
`
`OH
`
`“ (a) Ylide reaction.
`(b) H3+0.
`(c) [0].
`(d) I(CH2)°COOCH3/
`base.
`(a) 0504.
`(f) MsCl/pyridine.
`(g) PhD/acetone solvolysis.
`I,/R !
` ,1/> O) , /S)T,!/(, >./ 66 >;
`1
` ,/66$,/- ;!, />6;
`Scheme 3‘
`I)
` $
`
`Q
`
`ngx“
`GM6K
`0
`
`OQX>< ’L (gm
`!
` $
`
`D
`
`9
`
`f
`
`I
`
`£35;
`
`6.3 W0 CN
`
`$
`0
`W ”6
`“(a) CIZC=C=O.
`(b) Zn, NI-LCL (c) Resolution with (—)-
`ephedrine. (d) m-ClCJLCOaH. (e)HCOOH.
`(f) CsHuC(Bl'2)CN,
`,/ . H6H) ,1/U
`4> ( , / ? ,
/
`PlN(Me)z]s~ (E) H2304.
` !,!/
> 6>,/> 66>,/ > ,0./ 4
`
`
` S4,-/.T, />.)
`at the lactone or benzoate was avoided by control of
` 1@? !!1
`reaction conditions. The resulting mixture of epimeric
`alcohols 3 was treated with sodium methoxide in
` ! 5
` ? ! ? ! 5!
`methanol to cleave the benzoate ester and provide the
` 1@!!
`diol 4 again as an inseparable mixture of C-15 epimers.
`! 1 5
`
`
` S4,-/.T, />.)
`at the lactone or benzoate was avoided by control of
` 1@? !!1
`reaction conditions. The resulting mixture of epimeric
`alcohols 3 was treated with sodium methoxide in
` ! 5
` ? ! ? ! 5!
`methanol to cleave the benzoate ester and provide the
` 1@!!
`diol 4 again as an inseparable mixture of C-15 epimers.
`! 1 5
`Reduction of the lactone with diisobutylaluminum
`! ? !1
`hydride (DIBAL) at -78 °C and treatment of the
` !! ,%(0":/
*2 N !
`resulting lactol with the ylide of (4-carboxybutyl)-
` ? ! ,
`resulting lactol with the ylide of (4-carboxybutyl)-
` ? ! ,
151 /
`triphenylphosphonium bromide followed by esterifi-
` 1 ! ?!1
`cation with diazomethane gave the PGF analogs 5 as
` ? !@ 7<
`a separable mixture of 15-epimers. The assignment of
`1 5
`configuration at 0-15 was originally based on biological
`
? 1!1
`activities but was confirmed by X-ray crystallography
` 1? !18
`activities but was confirmed by X-ray crystallography
` 1? !18
`of the p-bromophenacyl ester of (158)-5. Selective
`
1 , /
`monosilylation of (15R)-5 at C-11 followed by oxidation
` , /
?!15!
`with Collin’s reagent and subsequent removal of the
`? B !1A
`silyl protecting group gave the methyl ester of arbap-
` 1
`with Collin’s reagent and subsequent removal of the
`? B !1A
`silyl protecting group gave the methyl ester of arbap-
` 1
`rostil. Interestingly, the conditions used to remove the
` (
` !!
`trimethylsilyl group (methanol, water, trace of acetic
` ,
`?
`
`acid, room temperature) did not cause epimerization
` !
` /!! @
`at 0-15 while conditions traditionally used to remove
`
? !! !
`tetrahydropyranyl (THP) groups (acetic acid, water,
` ! ,> / , !
`?
`
`THF, 40 °C) caused complete epimerization within 3
`><
`)N / ! @?
`h. Arbaprostil has also been synthesized by the early
` "1 1 @!1
`Upjohn bicyclohexane mesylate approach6 (Scheme 2)
` & 1 5 , ./
`and by a commercial-scale process10 (Scheme 3) de-
`!1
`tetrahydropyranyl (THP) groups (acetic acid, water,
` ! ,> / , !
`?
`
`THF, 40 °C) caused complete epimerization within 3
`><
`)N / ! @?
`h. Arbaprostil has also been synthesized by the early
` "1 1 @!1
`Upjohn bicyclohexane mesylate approach6 (Scheme 2)
` & 1 5 , ./
`and by a commercial-scale process10 (Scheme 3) de-
`!1
) , /!
`veloped at Upjohn which uses a modification of the
` ! & ? !
`bicyclohexane chemistry to produce the intermediate
`1 5 ! !
`to compound 2 in Scheme 1.
` !.
`The synthesis of Corey’s lactone was one of the first
` B ?
`reported routes to classical PGs. The original process
`! 7
`was modified and improved by Corey and others9 and
`? !!! !1 ! !
`is the basis for the large-scale preparation of several
` 1
`PGs. Further improvements in this process have
` 7 <
`recently been reported.11 Coreyn‘ described a catalytic
` 1! P! 1!
`
`IPR Page 3/32
`
`
`
`company
`
`Upjohn
` &
`
`code no.
` !
`
`therapeutic
`indication
`
`!
`antiulcer
`
`
`1536 Chemlcel Revlswe. 1993. Vo|. 93. No. 4
` ?
`
`9!
`4
`Table 1
`1
`
`compound
` !
`arbaprostil
`1
`
`misoproetol
`
`
`enisoprost
`
`
`enprostil
`
`
`trimoprostil
`
`
`rioprostol
`
`
`structure
`
`
`o0oI
`
`I’9 0 o
`
`”CH3
`
`
`\\\\/\/\’ COOCHS
`
`I
`
`2éo
`
`oooOIu
`
`OH
`
`\\\\ _,=/\,CODCH3
`
`= o@
`5H
`
`0
`
`)
`
`H5
`>6
`0
`
`H5
`0
`
`5
`HO
`O
`
`H0
`0
`
`OooOE
`
`OI
`
`Om I
`
`OH
`
`’4
`
`OmIu
`IO ’6
`
`=
`HO
`C]
`
`\“W COOH
`
`Searle
`
`
`Seal-1e
`
`
`Syntax
`5
`
`Roche
`
`
`Collins and mum
` ! !%+
`
`clinical/
`market
`
` ;
`statue
` '
`
`phase III:
`Arbacet
` (((C
`"1
`
`marketed:
`Cytotec
` '!C
`
`
`80-29333
`
.
`
`SC-34301
`
`
`SC-34301
`
)
`
`antiulcer
`
`
`antiulcer
`
`
`dropped
`!!
`
`RS-84,135
`
`
`antiulcer
`
`
`antiulcer
`
`
`dropped
`!!
`
`RS-84,135
`
2
`
`
`antiulcer
`
`
`R0-21,6937
`6
`
`
`antiulcer
`
`
`R0-21,6937
`6
.
` *
`
`antiulcer
`
`
`marketed:
`Gardrin
` '!C
`7!
`
`phase III/
`dropped
` (((;
`!!
`
`TR-4698
`Miles/Ortho and
`Bayer AG
`- ;6 !
` *
`
`antiulcer
`
`
`marketed:
`Gardrin
` '!C
`7!
`
`phase III/
`dropped
` (((;
`!!
`
`TR-4698
`Miles/Ortho and
`Bayer AG
`- ;6 !
2
`0"7
`
`antiulcer
`
`
`marketed
` '!
`
`ZK-94726
`U=
`0"7
`
`antiulcer
`
`
`marketed
` '!
`
`ZK-94726
`U=
*.
`
`Schering AG
` "7
`
`Lepetit
`:
`
`ONO
`646
`
`antiulcer
`
`
`phase HI
` (((
`
`MDL-646
`-%:
`
`Schering AG
` "7
`
`Lepetit
`:
`
`ONO
`646
`
`antiulcer
`
`
`phase HI
` (((
`
`MDL-646
`-%:
`
`antiulcer
`
`
`phase II
` ((
`
`ONO-1308
`646
)2
`
`antiulcer
`
`
`marketed:
`Ronak
` '!C
`'
`
`phase II/III
` ((;(>
`
`Hoechst—Rouaeel
`HR-260
`>
`
`antiulcer
`
`
`marketed:
`Ronak
` '!C
`'
`
`phase II/III
` ((;(>
`
`Hoechst—Rouaeel
`HR-260
`>
>
.
)
`
`antiulcer
`
`
`Merck AG
`- '"7
`
`EMD-33290
`3-%
`
`antiulcer
`
`
`Merck AG
`- '"7
`
`EMD-33290
`3-%
.)
`
`antiulcer
`antihypertensive
`
`
`
`phase II
` ((
`
`IBI
`(0(
`
`SeaJ-le
`
`
`Glaxo
`7 5
`
`antiulcer
`
`
`antiulcer
`SC-46275/SC-48334
`
`
`antiulcer
`antihypertensive
`
`
`
`phase II
` ((
`
`IBI
`(0(
`
`SeaJ-le
`
`
`Glaxo
`7 5
`
`antiulcer
`
`
`antiulcer
`SC-46275/SC-48334
`
.* ;
2
`
`GR-63779X
`7
`
`GR-63779X
`7
**8
`
`antiulcer
`
`
`marketed:
`Rosal
` '!C
`
`
`dropped
`!!
`
`phase I/II
` (;((
`
`nocloprost
`
`
`mexiprostil
` 5
`
`ornoprostol
`
`
`dimoxaprost
`! 5
`
`tiprostanide
`!
`
`HO
`0
`
`H5
`
`0
`
`HO
`0
`
`IOm
`
`5H
`
`\\‘\/\/\/ COOCHQ
`“\OCHS
`
`5H
`
`o
`\\\\‘y\/\, COOCHS
`
`5H H
`
`2
`
`ooI
`0E(‘0
`OmI
`
`QM 664
`
` 66 >
`
`rosaprostol
`
`
`6>
`
`N(:
`
`
`
`remiprostol
`
`
` MM
`6>
`
`>6
`
`4> 6
`
`
`antiulcer
`
`
`marketed:
`Rosal
` '!C
`
`
`dropped
`!!
`
`phase I/II
` (;((
`
`nocloprost
`
`
`mexiprostil
` 5
`
`ornoprostol
`
`
`dimoxaprost
`! 5
`
`tiprostanide
`!
`
`HO
`0
`
`H5
`
`0
`
`HO
`0
`
`IOm
`
`5H
`
`\\‘\/\/\/ COOCHQ
`“\OCHS
`
`5H
`
`o
`\\\\‘y\/\, COOCHS
`
`5H H
`
`2
`
`ooI
`0E(‘0
`OmI
`
`QM 664
`
` 66 >
`
`rosaprostol
`
`
`6>
`
`N(:
`
`
`
`remiprostol
`
`
` MM
`6>
`
`>6
`
`4> 6
`
K.V
`
`
`
`
K /
`
`IPR Page 4/32
`
`IPR Page 4/32
`
`
`
`IPR Page 4/32
`
`IPR Page 4/32
`
`
`
`Proataglandln and Prostacyclln Analogs
` !! "
`
`Table 1
`(Continued)
`1 , !/
`
`structure
`
`
`\\\E/>/‘COOCH3
` 66 >
`
`OH
`
`company
`
`Lederle
`:!
`
`Chemlcel Revlews, 1993. Vol. 93. No. 4
`1537
` ?
`
`9
`4 *
`
`clinical/
`therapeutic
`market
` ;
`code no.
`indication
`status
` '
`
` !
`!
`
`CL-115,347
`antihypertensive
`phase II/
` :
` * ((;
`dropped
`!!
`
`ONO
`646
`
`ONO-1206
`antihypertensive marketed:
`646
.)
'!C
`6
`
`Pfizer Schering AG CP-34089
`fertility control
`marketed:
`Nalador
`@ "7
`6
`
`Pfizer Schering AG CP-34089
`fertility control
`marketed:
`Nalador
`@ "7
)2 '!C
`
`4 !
`
`ONO
`646
`
`Upjohn
` &
`
`101
`( (
`
`ICI
`( (
`
`ONO-802
`fertth control
`marketed:
`646
`
`4 !
`
`ONO
`646
`
`Upjohn
` &
`
`101
`( (
`
`ICI
`( (
`
`ONO-802
`fertth control
`marketed:
`646
2). '!C
`
`
`fertility control
`phase III/
` (((;
`!!
`
`[01 80,996
`veterinary use
`( (2)
`
`
`marketed
` '!
`
`ICI 80,008
`veterinary use
`( (2)
`))2
`
`marketed
` '!
`
`Syntax
`5
`
`RS-84043
`veterinary use
`
`
`
`fertility control
`phase III/
` (((;
`!!
`
`[01 80,996
`veterinary use
`( (2)
`
`
`marketed
` '!
`
`ICI 80,008
`veterinary use
`( (2)
`))2
`
`marketed
` '!
`
`Syntax
`5
`
`RS-84043
`veterinary use
`
2)
`
`marketed
` '!
`
`Syntex
`5
`
`RS-9390
`
`
`marketed
` '!
`
`Syntex
`5
`
`RS-9390
`
)
`
`veterinary use
`
`
`marketed:
` '!C
`
`
`Kabi Phanmacia
`PhXA41
`=1 8"
`
`antiglaucoma
`
`
`phase II
` ((
`
`compound
` !
`viprostol
`
`
`limaprost
`
`
`sulprostone
`
`
`eme rest
`
`
`meteneprost
`
`
`cloprostenol
`
`
`
`fluprostenol
`
`
`fenprostalene
`
`
`prostalene
`
`
`latanoprost
`
`
`O
`
`5
`HO
`
`O
`
`HS
`
`(EJH é
`
`0
`G‘“WCONHSOZCH
`=
`=
`O '<: :>
`H5
`5H
`
` 64>6& >
`
`0
`
`H8
`
`CH2
`
`H8
`>N
`2”
`6>
`
`(5).-1
`
`(23H
`
`
` 66>
`
` 66>
`
`meow-l
`E
`:
`O@
`6H
`01
`H0
`>6
` M
`2H
`6>
`a:“\WCOOH
`E
`=
`O
`HO
`5H
`cs3
`9FM
`>6
`
` I
`3H
`6>
`= “‘2 a =/\,COOCH3
`;VY‘0 —<: 3}
`HMM
`
`5H
`959
`
`veterinary use
`
`
`marketed:
` '!C
`
`
`Kabi Phanmacia
`PhXA41
`=1 8"
`
`antiglaucoma
`
`
`phase II
` ((
`
`compound
` !
`viprostol
`
`
`limaprost
`
`
`sulprostone
`
`
`eme rest
`
`
`meteneprost
`
`
`cloprostenol
`
`
`
`fluprostenol
`
`
`fenprostalene
`
`
`prostalene
`
`
`latanoprost
`
`
`O
`
`5
`HO
`
`O
`
`HS
`
`(EJH é
`
`0
`G‘“WCONHSOZCH
`=
`=
`O '<: :>
`H5
`5H
`
` 64>6& >
`
`0
`
`H8
`
`CH2
`
`H8
`>N
`2”
`6>
`
`(5).-1
`
`(23H
`
`
` 66>
`
` 66>
`
`meow-l
`E
`:
`O@
`6H
`01
`H0
`>6
` M
`2H
`6>
`a:“\WCOOH
`E
`=
`O
`HO
`5H
`cs3
`9FM
`>6
`
` I
`3H
`6>
`= “‘2 a =/\,COOCH3
`;VY‘0 —<: 3}
`HMM
`
`5H
`959
M
`6>
`
`H5
`>6
`9H
`6>
`
`HMM 66 >
`0H
`6>
`
`H5
`I
`>6
`
`>6
`
`""0 Z
`nO
`i
`W$F4HMM 66Q;
`IOn:
`OmI
`
`>6
`
`6>
`
`enantioselective Dials—Alder reaction between 6 and 7
` %
`6>
`
`H5
`>6
`9H
`6>
`
`HMM 66 >
`0H
`6>
`
`H5
`I
`>6
`
`>6
`
`""0 Z
`nO
`i
`W$F4HMM 66Q;
`IOn:
`OmI
`
`>6
`
`6>
`
`enantioselective Dials—Alder reaction between 6 and 7
` %
" ! 1?
!*
`in the presence of 10 mol % of the (8,8) catalyst 8
` ) X ,
`/ 2
`which gave the adduct 9 in greater than 95 % ee (Scheme
`? !! X ,
`4). The adduct 9 was then converted to enantiopure
`/ !! ? !
`iodolactone 13 by a sequence of high yield steps.
`! 1 A !
`Treatment of 9 with aqueous lithium hydroxide-
` ? A !5!
`in the presence of 10 mol % of the (8,8) catalyst 8
` ) X ,
`/ 2
`which gave the adduct 9 in greater than 95 % ee (Scheme
`? !! X ,
`4). The adduct 9 was then converted to enantiopure
`/ !! ? !
`iodolactone 13 by a sequence of high yield steps.
`! 1 A !
`Treatment of 9 with aqueous lithium hydroxide-
` ? A !5!
`hydrogen peroxide followed by esterification with
` ! 5! ?! 1 ?
`ethanol gave 10 which was transformed to the methyl
` )? ? !
`thio derivative 11 by deprotonation with LDA (lithium
` !1!? :%",
`diisopropylamide) and quenching with dimethyl dis-
`! !/!A ? ! !
`ulfide. Base cleavage of the ester and oxidative
` ! 0 ! 5!
`decarboxylation provided 12. Baeyer—Villiger oxidation
`! 15 !!.0
9 5!
`of 12, hydrolysis of the resulting lactone, and iodolac-
`.
` !
`!!
`of 12, hydrolysis of the resulting lactone, and iodolac-
`.
` !
`!!
`tonization produced, after recrystallization, the iodo-
`@! !
` @
` !
`
`lactone 13 in 100% ee. Deiodination with tributyltin
` ))X %!? 1
`hydride and protecting group manipulation provided
` !!! !!
`the traditional Corey lactone alcohol.9 Stork11b applied
` ! ' 1 !
`a radical cyclization trapping methodology to the
` ! @ !
`preparation in a single step of the lactol intermediates
` !
`17 and 18 (Scheme 5). The mixed iodoacetal 15 was
`*!2, / 5!! ?
`obtained by treatment of 14 with ethyl vinyl ether and
`1!1 ? !
`N-iodosuccinimide. Reaction of 15 with tributyltin
`4
! ! ? 1
`chloride, sodium cyanoborohydride, a catalytic amount
` !
`! 1 !!
`
`of AIBN and tert-butyl isocyanide as the radical trap
`"(04 !
`chloride, sodium cyanoborohydride, a catalytic amount
` !
`! 1 !!
`
`of AIBN and tert-butyl isocyanide as the radical trap
`"(04 !
1 ! !
`produced the lactol 16. The nitrile could be readily
`! ! !1!
`converted to the aldehyde 17 by reduction with DIBAL.
` ! ! !*1! ? %(0":
`Alternatively, use of 2-(trimethylsilyl)-1-octen-3-one as
`"
`.
`produced the lactol 16. The nitrile could be readily
`! ! !1!
`converted to the aldehyde 17 by reduction with DIBAL.
` ! ! !*1! ? %(0":
`Alternatively, use of 2-(trimethylsilyl)-1-octen-3-one as
`"
`.
, /
`the radical trap provided the vinyl ketone 18 directly.
` ! !! '2!
`
`IPR Page 5/32
`
`IPR Page 5/32
`
`
`
`1538 Chemlcal Reviews, 1993, Vol. 93. No. 4
`2 2 ?
`
`9
`4
`Scheme 4'
`0%an
`
`
`(El/—
`
`*
`
`kriiP
`
`4.
`
`PhCH,O
`
`Ph
`
`Ph
`
`CF,SOIN\
`
`AIM.
`8
`
`,Nsozcs,
`
`3—._b'_.
`o
`N
`D
`i
`
`H
`CDOEI
`
`morale
`
`..__>
`
`60051
`
`11
`
`OCHJD
`
`Colllne and Diurlc
` !%+
`of exo and endo lactol isomers. Inversion of 0-12 of 19
`5!! (
.
`was cleanly achieved by heating with a mixture of acetic
`? !1 ? 5
`acid and morpholine (3: 1)
`in dimeth-
` ! ! , C/ !
`was cleanly achieved by heating with a mixture of acetic
`? !1 ? 5
`acid and morpholine (3: 1)
`in dimeth-
` ! ! , C/ !
`oxyethane-water at 70—75 °C for 72 h to give 18.13 (S)-
`5
?*)
* N *. 2 ,/
`BINAL-H was used to stereoselectively reduce the
`0(4":
> ? ! !
`w-chain (lower side chain) ketone of 18 to the (S)-alcohol.
`?
`w-chain (lower side chain) ketone of 18 to the (S)-alcohol.
`?
, ?! /'2 ,/
`2. Misoprostol
`.-
`Misoprostol is a 15-deoxy-16-methyl-16-hydroxy an-
`-
!5
!5
`alog of PGE1. It is currently marketed worldwide as
` 73( '!? !?!
`Cytotec for the prevention of gastroduodenal ulcers
` !!
`induced by nonsteroidal antiinflammatory drugs
`! ! 1 ! !
`(NSAIDs) and was the first PG analog approved for
`,4"(%/!? 7 !
`antiulcer therapy. Misoprostol’s discovery was prompt-
` - B! ?
`ed by the observation that translocation of the pivotal
`!1 1
`15-hydroxy group of PGE1 to C- 16 did not affect gastric
`
!5 73&
!!
`antisecretory activity but did significantly reduce side
` 1!! ! !
`effects. 1‘ Addition of a methyl group to C- 16 to block
` "!!
`antisecretory activity but did significantly reduce side
` 1!! ! !
`effects. 1‘ Addition of a methyl group to C- 16 to block
` "!!
1 '
`oxidative metabolism produced misoprostol.
`5! 1 ! !
`Misoprostol is synthesized via a conjugate addition
`- @! & !!
`route“,15 This approach, which has been widely
`B
`? 1 ?!
`researched, involves the conjugate addition of orga-
` !
` & !!
`oxidative metabolism produced misoprostol.
`5! 1 ! !
`Misoprostol is synthesized via a conjugate addition
`- @! & !!
`route“,15 This approach, which has been widely
`B
`? 1 ?!
`researched, involves the conjugate addition of orga-
` !
` & !!
`nometallic derivatives ofthe 01--chain to cyclopentenones
` !
`which generally already contain the appropriate a-chain.
`? !
`An alternative three-component coupling procedure,
`"
!
`
`in which the a-chain is incorporated by reaction with
`?
`
`in which the a-chain is incorporated by reaction with
`?
!1 ?
`the enolate arising from the initial conjugate addition
` & !!
`reaction, has been elegantly researched and refined by
`
` 1 !!!1
`Noyori et al.16 These general approaches are illustrated
`4 !
`in Scheme 7. The advantages of this strategy is the
` * !
`versatility in preparing analogs and the stereoselectivity
`obtained in the addition reaction. Other variations of
` !
`1! !! 6
`this route have been reported.”-21
` 1!*
`the enolate arising from the initial conjugate addition
` & !!
`reaction, has been elegantly researched and refined by
`
` 1 !!!1
`Noyori et al.16 These general approaches are illustrated
`4 !
`in Scheme 7. The advantages of this strategy is the
` * !
`versatility in preparing analogs and the stereoselectivity
`obtained in the addition reaction. Other variations of
` !
`1! !! 6
`this route have been reported.”-21
` 1!*
.
`Seheme 7
`O
`
`H
`
`“
`
`+
`
`_
`“w“, _»
`
`'
`M
`+ w”
`
`
`2. or chain
`derivative
`
`0
`
`s
`X
`
`o
`
`.
`X
`
`.m-
`‘
`7 m
`
`“JO
`1‘
`'/ a,
`
`X 0
`
`x
`
`[
`
`[
`
`X - H or OR; R - protecting group
`> 6E
`8
`
`With misoprostol, which was first prepared in the
`#
`? ? !
`early 1970s, the initial organometallic reagent was
` *)
` ?
`resourced from a vinyl iodide obtained by derivatization
` ! !!1!1!@
`of the protected racemic homopropargylic alcohol 20
` ! .)
`with either DIBAL or catechol borane followed by
`? %(0": 1 ?!1
`treatment with iodine (Scheme 8). The vinyl iodide 21
` ? !, 2/ !!.
`was then converted to a vinyl copper species 223 or a
`? ! ..
`cuprate reagent 22b by treatment with n-butyllithium
` ..11 ?
`Seheme 7
`O
`
`H
`
`“
`
`+
`
`_
`“w“, _»
`
`'
`M
`+ w”
`
`
`2. or chain
`derivative
`
`0
`
`s
`X
`
`o
`
`.
`X
`
`.m-
`‘
`7 m
`
`“JO
`1‘
`'/ a,
`
`X 0
`
`x
`
`[
`
`[
`
`X - H or OR; R - protecting group
`> 6E
`8
`
`With misoprostol, which was first prepared in the
`#
`? ? !
`early 1970s, the initial organometallic reagent was
` *)
` ?
`resourced from a vinyl iodide obtained by derivatization
` ! !!1!1!@
`of the protected racemic homopropargylic alcohol 20
` ! .)
`with either DIBAL or catechol borane followed by
`? %(0": 1 ?!1
`treatment with iodine (Scheme 8). The vinyl iodide 21
` ? !, 2/ !!.
`was then converted to a vinyl copper species 223 or a
`? ! ..
`cuprate reagent 22b by treatment with n-butyllithium
` ..11 ?
1
`(n—BuLi) followed by cuprous iodide or copper pentyne,
`,
`(n—BuLi) followed by cuprous iodide or copper pentyne,
`,
0:/ ?!1 !!
`
`respectively?” Conjugate addition of either of these
` ..$ & !!
`reagents to the protected racemic hydroxycyclopen-
` ! !5
`
`respectively?” Conjugate addition of either of these
` ..$ & !!
`reagents to the protected racemic hydroxycyclopen-
` ! !5
`tenone 23 provided misoprostol in good yield after
`. !! ! !
`protecting group removal.
`
`A superior cuprate precursor is the vinylstannane
`"
`24. A simple 2-4-h sunlamp irradiation of a mixture
`." .
! 5
`of 20 and tributyltin hydride in ordinary pyrex glassware
`.)!1 !!!5 ?
`gave the (E)-vinylstannane 24 plus about 15% of the
` ,3/
`of 20 and tributyltin hydride in ordinary pyrex glassware
`.)!1 !!!5 ?
`gave the (E)-vinylstannane 24 plus about 15% of the
` ,3/
. 1 X
`corresponding (Z)-isomer. Conversion of 24 to a
` ! ,U/
`corresponding (Z)-isomer. Conversion of 24 to a
` ! ,U/
.
`vinyllithium species with n-BuLi at —60 °C and addition
` ?
`vinyllithium species with n-BuLi at —60 °C and addition
` ?
0:
)N !!!
`
`as:
`sf.
`0
`
`CN
`
`75+ 16
`
`DEL
`
`ic
`
`Z
`
`13$
`
`0
`
`79+
`17
`
`)
`
`*
`' (a) Ethyl vinyl ether, N18, —20 °C.
`(b) Bu38nCl, NaCNBHa,
`t-BuNC,AIBN.
`(c) DIBAL. (d) Bu3SnC1,NaCNBHs,hv (254nm),
`,/3
`4(
`
`
`as:
`sf.
`0
`
`CN
`
`75+ 16
`
`DEL
`
`ic
`
`Z
`
`13$
`
`0
`
`79+
`17
`
`)
`
`*
`' (a) Ethyl vinyl ether, N18, —20 °C.
`(b) Bu38nCl, NaCNBHa,
`t-BuNC,AIBN.
`(c) DIBAL. (d) Bu3SnC1,NaCNBHs,hv (254nm),
`,/3
`4(
`
.)N ,1/0
`4 40>
`
`2-(trimethylsilyl)-1-octen-3-one.
`
`4 40>
`
`2-(trimethylsilyl)-1-octen-3-one.
`
04
`"(04, /%(0":,!/0
`4 40>
` ,. /
`
`.
`"(04, /%(0":,!/0
`4 40>
` ,. /
`
`.
, /
`Keck12 has also reported a variation of this latter
`= '. !
`reaction using a vinyl stannyl enone (Scheme 5) radical
` , /!
`trap.
`
`Larock11c employed an ingenious one-step palladium-
`: ' !
!
`promoted intermolecular coupling of three different
` !
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