United States Patent
`
`[19]
`
`[11] Patent Number:
`
`5,712,396
`
`
`
`[45] Date of Patent: Jan. 27, 1998
`Magnin et al.
`
`USD057l 2396A
`
`FOREIGN PATENT DOCUMENTS
`
`European Pa. 011’.
`Eumpean Pat. Oil’,
`
`.
`
`.................
`
`171198?
`89[B4-1980
`0344979 121989
`3'}‘3969lAl
`"#1985
`0284986 10Fl9'l'0
`0535172
`123197 3‘
`0756099
`81' 1956
`WIPO.
`W088-(1)061
`1! 1988
`WIPO.
`WO900?5J3
`‘[1990
`WO907513
`711990 WIPO
`W09324495 1231993 WIPO
`
`
`
`..
`
`OTHER PUBLICATIONS
`
`Burton. DJ.. J. Am. Chem. Soc. 1989. 111. 1773-1776.
`Su. D. et :11. Can. J. Chem. 1989. 67. 1795-1799.
`Fauington. G.K.. et al. J. Med. Chem. 1985. 28. 1668-1673.
`Musicki. B.
`et
`31. T.S. Tetrahedron Lett. 1991.
`3'2.
`126?-1270.
`Carretero. LC. et al. Tetrahedron 1987. 43. 5125-5134.
`Callahan. L. et ai. Analytical biochemistry 1989. 177.
`67-71.
`Amin. Dilip et al. “Bisphosphonates used for me treatment
`of bone disorders inhibit squalene synthase and cholesterol
`biosynthesis". Journal of Lipid Research. vol. 33. 1993. pp.
`1657-1663.
`
`Primary Exarm'ne:hFloyd. D. I-[igel
`Attorney Agent. or _F‘:'rm—Burton Rodney
`
`[571
`
`ABSTRACT
`
`u—Phospl1onosulfonate compounds are provided which
`inhibit the enzyme squalene synthetase and thereby inhibit
`cholesterol biosynthesis. These compounds have the for-
`mula
`
`o z o
`II
`I
`II
`R'—P|'--$—?=0
`R’0 R‘ 0R‘
`
`,
`_
`,
`wherein R’ 15 on’ or R“; R’ and R;a_:c independently H.
`allovl. arylalkyl a13'10rc1'C10aJk)'1:R 15 H.a1kyl.aryla1k5'l
`or aryl; R4 is H. alkyl. aryl. arylalkyl. or cycloalkylz. Z is H.
`halogen. lower allcyl or lower alkenyl‘. and R‘ is a lipophflic
`group which contains at least 7 carbons and is alkyl. alkcnyl.
`alkynyl. mixed a11u:ny1—a1kynyL aryl. arylalkyl. cycloalkyl.
`
`d
`. Nky‘
`‘ "7 °
`.
`6°.
`“:30
`accepts-ble salts an or
`a
`ve, including
`pr°flrI=3_wr-I5 of the phosphomc (phosphmw) and-‘or sul-
`fomc acids-
`
`26 Claims, No Drawings
`
`[54]
`
`[76]
`
`at-PHOSPHONOSULFONATE SQUALENE
`SYNTHETASE INHIBITORS
`
`Inventors: David R. Maglin. 40 Cottage CL.
`Hamilton. NJ. 08690; Scott A. Biller.
`136 Nancy La.. Ewing. NJ. 08638;
`John K. Dickson, Jr.. 105 Dawn D11.
`Mount Holly. NJ. 08060; R. Michael
`Lawrence. 48 W. Crown Terrace,
`Yardley. Pa. 19067; Richard B. Sulsky.
`71 Gregory 1.3.. Franklin Park. NJ.
`03823
`
`[21] App]. No.: 266,888
`
`[22] Filed:
`
`Jul. 5, 1994
`
`Related U.S. Application Data
`
`[63]
`
`CDI1ti.nuat.iu1 of Ser. No. 109,762, Aug. 20, 1993, aban-
`doned. which is acontinuation-in-pan of Ser. No. 967,901,
`Oct. 28, 1992. abmdoned.
`
`[51]
`
`Int. C16
`
`CUTF W38; C07? 9553;
`0071-7 9115506‘, C071‘ 916512; A6IK 3lf66
`[52] U.S. Cl. ............................... 546fl2'. 514394; 5141114;
`5141127; 514479; 514180; 514131; 514486;
`514239‘. 514492; 544232; 544043; 5444244;
`546/23‘, 5413450; 540!-471; 54{}’474: 540542;
`5481112; 5490113: 558u'4S', 56317; 562121;
`56%: 56285
`[58] Field of Search ......................... S58l45:562)'17,
`562:"21. 23. 35; 54622. 23; 5483112. 113;
`5443232. 243. 244: 5401450. 471. 474.
`542; 514427. 80. 81. 86. 89. 92. 94. 11:1.
`127
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`.
`
`....- 553345):
`6 266,461
`.. zsoms
`3:53:45 :1:
`553!-I5
`
`.
`
`
`
`2,336,230 1271943 Di
`dal.
`2,966,665 12,1966 G,:f,’,6, 6, ,6
`3,595,330
`171911 Firestone ................
`35557232
`441912 Ch.I:i.sta1sen et al.
`............
`3,819,676
`621974 Chistensen et al.
`------«--«---»
`2.3533-151%:
`¢¢a131-
`-
`s
`W 5*
`-
`42.5-1,215
`3:1-331 Knmp et al. .............-....-... 553145 x
`------—-
`..... 553345 :1:
`4,781,865 1171933
`mm" 548,112
`4J95‘m5 H1989
`553145
`4.937.367
`s.+199o
`5432359
`s,ou,933
`471991 Bamettet al.
`5,272,123 12.31993 Roscn et :1. ........-................... 553145
`5,391,743
`2r1995 Ebtino et al. _._..._........._........ 546m
`
`.
`
`.
`
`.
`
`.
`
`.
`
`1 of 93
`
`PENN EX. 2205
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`1
`
`ct-PHOSPHONOSULFONATE SQUALENE
`SYNTHETASE INHIBITORS
`
`5,712,396
`
`2
`-continued
`
`0 Z
`II/
`It X
`Y I’
`>| K \Z
`R
`
`R
`
`El'il)£0l08t.IlB
`
`I0
`
`wherein R can be SO,H. and X and Y are hydroxy or
`functional equivalent precursor to epoxide: eg. 0]-l. halo.
`azide. RCO,—. RS0,0—. R,S+—. R,N*—. Ar0—.
`R2PO2—. RSO,NR‘--. One of X and Ymust be an oxygen
`radical.
`El’89:’O-3-14-980 (Smith Kline) discloses tit-antagonists of
`the structure
`
`wherein Y or 2 may be —SO,R. —P(R)0(OR). -—~PR,0.
`-+PO(0R)2. and amides.
`W0 83l0O06l
`(Atnersharn) discloses Technelzium-99
`complexes for bone scanning having the structure
`
`35
`
`1120:?
`
`R1
`
`31
`
`‘F
`([|'3)u—P0:H2
`R‘.
`
`wherein R‘ and R3=H. S0,H or alkyl substituted with S0,}!
`and optionally one or more heteroatoms; R‘ can also be
`SO,H or OH. NH, Ni-IMe. N'Me,. lower allcyl substituted
`with a polar group;
`R’=sa.tne as R‘ except not S03}! and n=0. 1.
`U.S. Pat. No. 4.032.521 (Merck) discloses intermediates.
`in aephalospcrin synthesis. of the structures
`
`This is a continuation of application Ser. No. 109.762.
`filed Aug. 20. 1993. now abandoned. which is a
`continuation-in-part of application Ser. No. 967.904. filed
`Oct. 28. 1992. now abandoned.
`
`FIELD OF THE INVENTION
`
`new
`to
`invention relates
`The pro sent
`:1-phosphonosulfonate compounds which are useful
`in
`inhibiting cholesterol biosynthesis by inhibiting de novo
`squalene production. to hypocholcsterolemic and ant:iathero-
`sclerotic compositions containing such compounds and to a
`method of using-such compounds for inhibiting cholesterol
`biosynthesis and atherosclerosis.
`
`BACKGROUND OF THE INVENTION
`
`Squalene synthetnse is a mlcrosornal enzyme which cata-
`lyzes the reductive dimcaization of two molecules of fame-
`syl pyrophosphate (FPP) in the presence of nicotinamidc
`adenine dinucleotide phosphate (reduced form) (NADPH) to
`fonzn squalenc (Poulter. C. D.; Rilling. H. C.. in “Biocsyn-
`thesis of Isoprenoid Compounds". Vol. L Chapter 8. pp.
`413-441. I. Wiley and Sons. 1981. and references therein).
`This enzyme is the first committed step of the de novo
`cholestttrol biosynthetic pathway. 'I'he selective inhibition of
`this step should allow the essential pathways to isopentenyl
`tRNA. ubiquinone. and dolichol to proceed unimpeded.
`Squalene synthetase along with HMG-CoA reductase have
`been shown to be down-regulated by receptor mediated LDL
`uptake (Faust. J. R.; Goldstein. J. L.: Brown. M. S. Proc.
`Nat. Acad. Sci. U.S.;-L 1979. 76. 5018-5022). lending cre-
`dence to the proposal that i.n.lI.ihit:ing squalene synthetase will
`lead to an up-regulation of LDL receptor levels. as has been
`demonstrated for HMG-CoA reductase. and thus ultimately
`should be useful for the treatment and prevention of hyper-
`cholesterolernia and atherosclerosis.
`
`U.S. Pat. No. 3.657.232 (Merck) [Division U.S. Pat. No.
`3.822.296) discloses antibiotics of the structure
`
`OH
`
`0 I
`
`I/
`
`R
`
`U
`P
`H \OH
`R
`R
`
`"ix? N < P0351:
`
`SCI:
`H2“ —< P03Et1
`
`N02
`
`W0 9Ctt‘075l3 (Gas Research Instime) discloses electro-
`lytes for fuel cells ofthc strucuine
`
`01
`
`|
`
`i 0120):?i ,-R-(sew).
`
`wherein R=organic radicals with l or more F atoms‘.
`R‘=H. alkali metaL Zn. Cd:
`R‘=H, lower nlkyl;
`
`wherein R=S0,H. S0211‘, H. hydrocarbyl other than alltyl
`(eg. alkenyl. alkynyl. phenyl and naphthyl). substituted
`hydrocarbyl. C0-_.H. C0212“. SO3N'R,. hete-recycle‘.
`amino‘. OH. OR. SH. SR. CHO. halogen. N02. CN. PO,H2.
`AS03112. acyl. —CHR‘R3 where R‘=H. Me; R’=R as above.
`preferably at least one R not :H. R preferably contains 1-10
`carbons. ‘Tally substituted.
`Starting mataials employed to prepare the above antibi-
`otics include
`
`02
`II/
`R
`P
`>—< ‘z
`R
`
`R
`
`60
`
`65
`
`2of93
`
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`
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`lPR20l5-01836
`
`

`
`3
`
`5 ,7 12,396
`
`4
`
`1-=2. 3; and x, y=l. 2. 3.
`US. Pat. No. 4.254.215 (Ciba Gcigy AG) discloses a
`process for photographic developers wherein one compo-
`nent of a developer solution is:
`
`5
`
`HO2C
`
`O
`
`O
`
`D
`
`O
`
`[*1 2
`
`1-1
`
`N1r’E\’
`10
`
`0
`
`11....
`
`P110“ -C —P—
`II
`I
`0
`OPI1
`
`..
`
`" ..
`
`2
`
`2,4.
`
`HS——D——(W)..
`
`wherein 11:1 to 4.
`
`D=op1:ional1y substituted. satin-ated or unsaturated ali-
`phatic radical (<40 carbons]. can be intu-rupted by
`heteroatoms such as 0. S0,. NH. NR.
`
`W=PO,R,. S0,R. S0311. —NY—SO,R. —S0-_.NRg.
`—SSO,R. CO-AR. OH. NR3‘. NR3, CONR,.
`DE 898739691-A (I-Ioechst) {Dawent #89-173507f24)
`discloses herbicides and plant growth regulators of the
`structure
`
`R5
`
`0
`0
`N ’
`0
`II
`R‘\I|
`s A
`9
`B2’ "ir"||‘N14JL|
`o
`R-1
`
`N
`
`R3
`
`z
`J\
`
`R‘
`
`wherein Y=Cl-l. N; X.-——o. S; 2.-—=Cl-I. N; R‘. R1'=C1—c6
`alkyl or allcoxyz R’=}-I. C1-C6 alkyl or alkoxy. C2-C6
`alkenyl. alkynyl. alkcnyloxy. alkynyloxy; all optionally sub»
`stituted with one or more halogens; and R‘=I-I. C1-C4 alkyl
`or physiologically acceptable cation.
`New intei-mediates are disclosed of the structures
`
`0
`I 0
`[.1
`“ \{l
`32/ ‘~91’ | ‘-
`I NH;
`:3 0
`
`0
`1 0
`Q
`" ~J'
`g:
`‘C II‘
`R
`I3 0
`
`N11;
`
`10
`
`Musicki. Bx, Wid].ansk'L T. S. Te1:rahed.1-on Lett. 1991. 32.
`1267-1270 discloses compound 4 as a synthetic intermedi-
`ate.
`
`0
`
`0
`
`..“Z>(
`
`Cl
`
`0
`
`0
`
`0 X:
`
`\f02
`CH;-P0(0Et);_
`
`Carretero. J. C.; Demillequand. M.; Ghosez. L.. Tetrahe-
`dron 1937. 43. 5125-5134 discloses
`
`3
`(E?0l:l’-'CH2S0sX
`1ax=m
`lbx=i-Pr
`2.aX=Li
`2bX=n-BIL.N
`
`35
`
`for use in the synthesis of vinyl phosphonates via a Home-
`Ennnons reaction.
`Callahan. 1...; Ng. Ks. Geller. D. H.: Agarwal. K.:
`Schwartz. N. B..Analytical Biochemistry 1939. 17167.71
`discloses an analog of ADP [aclenosine diphosphatc) of the
`‘O struaure
`
`NH:
`
`Burton. D. 1.. I. Am. Chem. Soc. 1989. 111. 1773-1776
`discloses electrolyrtes and chelators of the structures
`
`45
`
`0
`_0JS/\ll/O
`L
`
`Q
`
`N
`
`N
`
`I
`
`N
`A
`
`N
`
`°
`
`(H0)-iP(0)‘:F29C'aN‘ (1f0)zP(0‘JCF230:H
`
`HO
`
`OH
`
`Su. D3. Cen. W9. Kirchmcler. R. L.; Shrceve. I- M.. Can. 50
`J. Chem. 1989. 67. 1795-1799. disclose electrolytes and
`daemon of an smlmlm
`
`(c,H,o),1>(o)c1=nrso,Na (c,H,o),s-:o)ca=uso,N.
`(HO)-,P(O)CFl-IsD,Na (uo),p(o,u:ngo,y
`
`((%}I50)2P[DX:F(sO3N°xSozN‘)
`
`(cqH.o>.Pco)c:=(so.Na).
`
`DESCRIPTION OF THE ]NVEN'I'ION
`is pro-
`‘ In accordance with the present invtion.
`55 vrded cs-phosphonosulfonate compounds which uanrtnt cho-
`lesterol biosynthesis. and thus are usd’ul as l1ypocho1ester-
`0:::'|;lCan:antratha-osclezonc agents and have thefollowmg
`s
`ure
`
`5“
`
`U Z O
`II
`I
`ll
`""‘;“f"f=°
`:30 at out
`
`1
`
`whflein R: is OR: In Rio‘ R3 and R5 are the Same or
`Farrington. G. K; Kumar. _A.', Wcdler. F. C.. J. Med.
`1985. 23. 1668-1673 discloses compound 10
`an 65 difiel-cut andan H‘ alkyl. aryhlkyl‘ 51.3.1‘ cyclmlkyl’ a metal
`Inhibitor of aspartatc tmnscavrbamslasa Compound 24 Is a
`ion or other pharmaoeutically acceptable rations as defined
`synthetic intamediaxc.
`below. or a prodrug ester:
`
`3 of 93
`
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`
`

`
`5
`
`5,712,396
`
`6
`
`D Z 0
`ll
`I
`ll
`R50--lI3—(1L‘-?=D
`R30 R’ UK‘
`
`T 0
`
`IA
`
`IS
`
`The term "prodrug esters” as employed herein includes
`prodrug esters which are known in the art for both phos-
`15 photos and carboxylic acids. Examples include the follow-
`ing groups: (1-a1|:anoyloxy)aIkyl such as.
`
`‘I? an
`C
`-..C/
`line’ ‘*0’ “‘
`
`R
`
`3}
`
`R
`W 19
`C xcx
`or an’ ‘*0’ “"
`
`R10
`
`wherein R“. R” and R” are H. alkyl. aryl or atyl-alkyl;
`however R130 cannot be 1-10. Examples of such pmdrug
`esters include
`
`CI-I:CO:CHe—. CH;C0:(|3H—.
`CH
`
`duo.
`
`in’
`or C2Hs0C0C-‘I2-.
`
`i—C4HsC0:C1-12-.
`
`(F=5°I'I¢d)
`
`Other examples of suitable prodrug esters include
`o
`o
`o
`
`O
`
`‘
`
`0
`
`i
`
`0-
`
`0
`0 /[L 0
`
`0
`
`0-—
`
`('R3I.}'I
`
`U
`
`c—
`
`0 +-
`
`R'
`
`CH,_-
`
`R5“ is H. alkyl. arylalkyl or any];
`R‘ is H. allay]. cycloallryl. aryl. aryl-allay]. metal ion Cl’
`other pharmaoeutically acceptable cations as defined
`below. or a prodrug ester;
`Z is H. halogen. lower alkyl or lower alkenyl;
`R1 a lipophilic group containing at least 7 carbons and is
`alkyl containing 7 to 25 carbons in the chain; allcenyl
`containing from 7 to 25 carbon atoms in the chain and
`from 1 to 6 double bonds; alkynyl containing 1 to 6
`triple bonds; mixed alkenyl—al.l:ynyl containing 1 to 5
`double bonds and ] to 5 triple bonds; and where in the
`above groups alkenyl andior allrynyl may be substi-
`tuted or unsubstituted; cycloalkyl; cycloheteroallryl
`linked through a carbon on the ring or a heteroatom:
`aryl; heteroaryl; heteroarylalkyl; cycloallrylallryl;
`cyclcheteroalkylallqrl: or a group of the structure
`R6
`
`\
`R‘-Ar—(cts),~
`a|/ \n'-
`
`wherein Ar is aryl (such as phenyl or naphthyl). heteroaryl
`(S or 6 membered) and may include one to three additional
`rings fused to AI (such as aryl. cycloallryl. heteroaryl or
`cycloheteroalkyl) and wherein (CH2)? contains from 1 to 15
`carbons. preferably 2 to 12 carbons. in the chain and may
`include 0. l. 2 or 3 double bonds andlcr 0. ]. 2 or 3 triple
`bondsinthenormalchain.andmayco.ntainane1l1eaor
`amino func‘I:ioninthechain.a.nd1ormay include 0. 1.2 mi}
`substitnents as defined below for R‘; and R‘. R’. R‘ and R“
`aretl1esarneordiil’erentandareH.al.l:ylcontaining1to4-0
`an-bons. preferably from 3 to 25 carbons. alkoxy containing
`1 to 40 carbons. preferably from 3 to 25 carbons, alkenyl
`containing 2 to 40 carbons. preferably from 3 to 25 carbons.
`allrenylcary containing 2 to 40 carbons. preferably from 3 to
`25 carbons. alkynyl containing 2 to 40 carbons. preferably
`from 3 to 25 carbons. alkynyloxy containing 2 to 40 carbons,
`preferably from 3 to 25 carbons. cycloheteroalkyl.
`cycloheteroalkylallryl. heteroaryl. cycloallryl.
`cycloalky]allcyL Ar-allcyl. (such as arylalkyl). A10 (such as
`aryloxy). Ar-amino (such as arylamino). hydroxy. halogen.
`nitro. Ar (such as aryl). amino. substituted amino wherein
`the amino includes 1 or 2 substituents (which are allay].
`alkenyl. aryl or any of the Ar groups mentioned above).
`thiol. alkylflnio. Ar-thio (such as arylthio). alkylsulfinyl.
`Ar-sulfinyl (such as arylsulfinyl). alkylsulfonyl. Ar-sulfonyl
`(such as arylsulfonyl). carboxy. cyano. allroxycarbonyl.
`aminocarbonyl. alkylcarbonyloxy. Ar-carbonyloxy (such as
`arylcarbonyloxy). Ar-carbonylamino {such as
`arylcarbonylamino) or alkylcarbonylamino. as well as any
`of the Ar groups as defined above. and 1:referably wherein
`the total number of carbons in the substituted Ar—(CH2),,—
`group exceeds 10 carbons:
`including pbarmacentically
`acceptable salts thereof such as alkali metal salts such as
`1itl1.iu.u1. sodium or potassium. alkaline earth metal salts such
`as calcium or magnesium. as well as zinc or aluminum and
`other FDA approved cations such as ammonium. choline.
`diethanolarnine. ethylenediamine. and salts of naturally
`occtning amino acids such as argininc, lysine. alanine and
`the like.
`
`The (Cl-12),, group may contain 1. 2. 3 or more allryl.
`alkoxy. alkenyl. alkynyl. hydroxy andlor halogen substitu-
`ents as well as any of the substitnents defined for R5.
`Thus. the compounds of the invention include thefollow-
`ing sub-genuses:
`
`wherein R“ can be H. nlkyl (such as methyl or t—hntyl).
`arylalkyl (such as benzyl) or aryl (such as phenyl); R“ is H.
`as allryl, halogen or alkoxy. R” is alkyl. aryl. arylallryl or
`R
`alkoxyl. and n, is 0. 1 (I 2; or R’ and
`can be linked
`together as in
`
`4 of 93
`
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`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`5,712,396
`
`refers to straigrt or branched chain radicals of 2 to 40
`carbons. preferably 3 to 30 carbons in the normal chain.
`which include one to six double bonds in the normal chain.
`such as \rinyL 2
`nyl. 3-butenyl. 2~b1.lteny1. 4-pentenyL
`3—pentenyl. 2-heatenyl. 3-hexenyl. 2—heptenyl. 3-heptenyl.
`4-heptenyl. 3-octenyl, 3-nonenyl. 4-clecenyl. 3-uudeI:enyL
`4-dodeoenyL 4.8.l2—tetradecatrieny1. and the like. and which
`may be optionally substituted with l
`to 4 substituents.
`namely. halogen. alkyl, alkoxy. alkenyl. alkynyl. aryl.
`arylalltyl. cycloalltyl. amino. bydroxy. alkanoylarnino.
`alkylamido. arylcarbonylamino. nitro. cyano. ttliol andlor
`alkyiltgtio, as well as any of the other substiments as defined
`for
`.
`Unless otherwise indicated. the term “lower alkynyl” or
`“alkynyl” as used herein by itself or as part of another group
`refers to straight or branched chain radicals of 2 to 40
`carbons. preferably 2 to 20 carbons in the normal chain.
`which include one triple bond in the normal chain. such as
`2-propynyl. 3-butynyl. 2-butynyl. 4-pentynyL 3-pentynyl.
`2-heatynyl. 3«l1exynyl. 2-heptynyl. 3-hc1'|lY|1}'l. 4—heptynyl.
`3-octynyl. 3-nonynyl. 4—decynyl.34.rndecynyl. 4-dodecynyl
`and the like. and which may be optionally substiuned with
`1 to 4 substituents. namely. halogen. alkyl. alkoxy. allrenyl.
`alkynyl. aryl. arylallcyl. cycloalkyl. amino. hydroxy.
`alkanoylarnino. alkylamido. arylcarbonylarnino. nitro.
`cyano. thiol. andlor alkylthio. as well as any of the other
`substiments as defined for 11‘.
`Examples of suitable (CI-I,J_, groups include
`
`—CH=C!-I—CHz—, —Cl{:CH =CH —. —C E C—CI-I2 —.
`
`CH3
`—cH:C_=eCCHz—, —i:.—_c:.II-—CHz—.
`-tCKz)z—.
`-(Cllah-.
`-(C1194-.
`
`$113
`—(C!h)1—{iJ—CH:CH2—. —CH,-;(|2l-I—. —Cl-I-2fi?l'ICl-12-.
`CH;
`CH.
`Cat,
`
`—C|.‘HCf&-.
`on,
`
`-*i!HCH2CHz-. —CHI|3HCfl:—.
`can,
`on,
`CH5
`
`5”"
`—CHz—t]'.'—CHa—. —(C'H.-:)s—-
`cu,
`
`‘I
`-(CHz)n—ff—CH;—.
`F
`
`«I211;
`(121
`-CH:—CH-CH2-. -(CHz):—f|2H-. -CH-z-*.i.‘—Cl-h—.
`CH:
`CH;
`
`--C!{z—li'1H—i'i‘l-l-—CH;--. —Cl-l¢—i.i.‘I-I—CI-l;—(lCSH—.
`CH3 CH,
`CH;
`CH;
`
`1“
`‘i’“
`—Cl{—Cl-hcl-13-, —CH—CH:CHa. —CH:0CHz—.
`
`-0CH2C1‘1:-- - -2 -NH‘~‘HzCli:-.
`
`‘f"’°
`—CH;—N—CH;—,
`
`or —ll\I—CH;CH;—.
`CH:
`
`The term “halogen” or “halo” as used herein refers to
`chlorine. bromine. fluorine. and iodine as well as CF, with
`chlorine or fluorine being preferred.
`
`10
`
`15
`
`35
`
`45
`
`55
`
`65
`
`7
`
`oI
`
`I
`o—c—a1*
`
`0 o —(
`llz’
`or —P\
`(firth):
`0
`
`o—fi—nI9
`0
`
`(names)
`
`o o
`II!
`—P\
`o
`
`if
`o—c—It"
`
`Unless otherwise indicated. the term “lower alltyl” or
`“allryl” as employed herein alone or as part of another group
`includes both straight and branched chain hydrocarbons.
`containing 1 to 40 carbons. preferably 1 to 20 carbons. in the
`normal chain. more preferably 1 to 12 carbons. such as
`methyl. etliyl. propyl. isopropyl. butyL t-butyl. isnbutyl.
`pentyl. hexyl. isobexyl. heptyL 4.4-dimethylpcntyl. octyl.
`2.2.4-nirnethylpentyl. nonyl. decyL undecyl. dodecyl. the
`various branched chain isomers thereof. and the like as well
`as such groups including 1 to 4 substituents such as F. Br. C1
`or I or CF3. allroxy. aryl. atylalkyl. alkenyl. cycloalltyl.
`amino. hydroxy. alkylarnido. allranoylarnino.
`arylcarbonylamino. nitro. cyano. thiol andlor alkylthio. as
`well as any of the other substitnents as defined for R‘.
`Unless otherwise indiaued.
`the term “cycloalltyl” as
`employed herein alone or as part of another group includes
`saturated or partially unsaturated cyclic hydrocarbon groups
`containing 3 to 12 carbons. preferably 3 to 8 carbons, which
`include cyclopropyl. cydoblltyl. Cyclopentyl. cydohexyl.
`cycloheptyl. cyclooctyl. cyclodecyl and cyclododecyl.
`cyclohexenyl. any of which groups may be substituted with
`l to 4 substituents sud: as halogen. alkyl. alkoxy. hyclroxy.
`aryl. arylalkyl. cycloalkryl. allrylamido. alkanoylamino.
`arylcarbonylamino. amino. nitro. cyano.
`tniol andlor
`alkyltétio. as well as any of the other substituents as defined
`for R .
`Unless otherwise indicated. the term “and” as employed
`herein refers to monocyclic or bicyclic aromatic groups
`containing from 6 to 10 carbons in the ring portion. such as
`phenyL napbthyl. ca phenyl or naphthyl substituted with 1 to
`4 substituents such as alltyl. halogen {CL Br or F). alkoxy.
`hydroxy. amino. allcanoylarnino. arylcarbonylarnino. arjrl.
`arylalkyl. qrcloalkyl. alkylamido. nilro. cyano. thiol andlor
`Elli.)-'lI£ll0. as well as any of the other substituents as defined
`for R .
`The term “aralkyl”. “aryl-alkyl" or “ary1—1ower allryl” as
`used herein alone or as part of another group refers to allryl
`groups as discussed above having an aryl substinient. such
`as benzyl or phenethyl. or naphthylpropy].
`The term “lower alkoxy”. “al.lroxy". "aryloxy" or
`“aralkoxy" as employed herein alone or as part of anotha
`group includes any of the above nllwl, aralkyl or aryl groups
`linked to an oxygen atom.
`The term "lower alkyltltio”. alkylthio". “arylthio” or
`"aral.lryl1.hio“ as employed herein alone or as part of another
`group includes any of the above alkyl. alkyl, aralkyl or aryl
`groups linked to a sulfur atom.
`The term “lower alkylatnino”. "a1ky1amino”.
`“a.rylamino". or “ary'lalkyla.mino” as employed herein alone
`ca‘ as part of another group includes any of the above allryl.
`aryl or arylallryl groups linked to a nitrogen atom.
`The term “al.lranoyl" as used herein alone or as part of
`another group refers to alkyl linked to a carbonyl group.
`Unless otherwise indicated. the term “lower allrenyl” or
`“a1I:enyl“ as used herein by itself or as part of another group
`
`5of93
`
`PENN EX. 2205
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`5,712,396
`
`10
`-continued
`
`NL
`
`/£'N\:flo.
`
`and the like. The above gl'IJ|?)S may include 1 to 3 substitu-
`enls such as any of the R groups as defined above. In
`addition. any of the above rings can be fused to a cycloalkyl.
`aryl. hetaoaryl ca‘ cycloheteroalkyl ring.
`The term cycloheteroallylalkyl” as defined by R‘ refers to
`cycloheteroalltyl groups as defined above linked through a C
`atom or heteroalom to the “C” of
`
`9
`The term "amino" as used herein refers to unsubstituted
`amino as well as monosubatitllted amino or disubstiuited
`amino wherein the substituents may be alkyl antllor a:yL
`The term “metal ion” refers to alkali metal ions such as
`
`sodium. potassium or lithium and alkaline earth metal ions
`such as magnesium and calcium. as well as zinc and
`aluminum.
`
`The term “cyclohaeroalkyl" as used herein as an R‘
`substiuient refers to a 5-. 6- or 7-mernbered saturated ring
`which includes 1 to 2 hetero atoms such as nitrogen. oxygen
`andlor sulfur. linked to the carbon “C" of
`
`5
`
`10
`
`through a carbon atom or a heteroatom. where possible.
`optionally via the linker (CH2)? (which is defined above).
`such as
`
`group through a (CHQP chain wherein p is preferably 1 to 8.
`The term “hueroa:rylalky1” as defined by R’ refers to a
`heteroaryl go-up as defined above linked llarough a C atom
`or hderoatom to the “C” of
`
`C?‘ CKO KS5
`N D
`C) <0}
`
`andthelike.The above groups rnayinclude 1 to3aubstitu-
`ents such as any of the R“ groups as defined above. In
`addition. any of the above rings can be fused to a cycloalkyl.
`aryl. heteroaryl II cylcloheteroalk)-'1 ring.
`
`The term “heteroaryl" as an R‘ substituent refers to a 5-
`0: 6-membered aromatic ring which includes 1. 2. 3 or 4
`hetero atoms such as nitrogen. oxygen or sulfur. which is
`linked to the carbon “C” of
`
`45
`
`35
`
`through a —(CH,)p— chain as defined above. where p is
`preferably 1 to 8.
`Preferred are compounds of formula land IA wherein R’
`is OR’andR’isameta1ionsuchasNaorK. or Hora
`pharmaoeulically acceptable salt or more preferably a pro-
`drug ester;
`R3 is H. a metalion such as Na or K;
`R‘isametalionsuchasNaorK:
`R‘ is alkenyl such as
`H
`
`1-1
`
`cm‘?&c\CH1/cm‘?¢c\Cm_(cK:L_
`cu,
`CH3
`
`wherein (CH2), is defined as (CH2)p above and x is prefu'-
`ably 2 to 8.
`
`H
`
`H
`
`H
`
`50 Cm\4i"'C‘cu{CB1‘rI:’C‘cu{Cm‘?“’C‘CH.+cm:
`
`CH:
`
`CH:
`
`CH:
`
`I
`
`‘’‘‘f‘5'
`
`N
`
`/
`
`“N.
`
`N ¥' N,
`.
`,
`
`,
`
`—
`
`through a carbon atom or a heteroatom. Where possible,
`optionally via the linker (CH1)? (which is defined above). 55
`sud] as
`
`Inis 1 to 5;
`
`N
`
`S
`
`D
`
`I
`
`‘
`
`I
`
`m
`
`Rllb
`
`Rlle
`
`(CH3):-
`
`all:
`
`n=l to 15;
`as R". Rm’. R‘”’. and R” are independemly selected from
`H. alkyl such as propyl. alisoxy. such as methoxy or
`pmpyloxy. alkenyl such as
`
`6 0f 93
`
`PENN Ex. 2205
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`5,712,396
`
`12
`Schemes L IA and II
`
`5
`
`1°
`
`15
`
`General Schemes for the Preparation of u-
`
`Phosphoncsulfonates
`
`Scheme 1
`
`if
`if
`_
`z
`= T 5
`N0 'f\_l/T 0
`|v—x(n1)
`11130
`‘f no
`x=L11:;m
`H
`11
`
`11
`
`C"°xC¢C"\CH:/CH’x_
`H:
`
`IC
`
`Cm"u'I:#CH"cm’CH1‘$”cH";
`
`CH:
`
`CH:
`
`cm
`
`CH,
`m
`
`5*
`
`R
`
`‘Ii
`>c=c-.
`
`i-I2C=CH—CHn-:
`
`{u’I3}!—|
`
`R.I.:i
`
`wherein R12. R13‘ and Rm’ are independently sclectedfrom 1°
`H. aryl [such as phenyl or naphthyl). alkylphenyl (such as
`p-pl'opy],pl1enyl. p-pentylphenyl). alkyl containing 1 to 20
`carbons (such as p-heptyl). hale. alkoxy(sud1 as methcxy or
`ptopyloxy). alkenyl (such as
`
`25
`
`ii‘
`ff
`Z
`__
`tim
`R‘5O—I|'\\| /?_02i9
`R90
`$ R60
`R’
`IE
`
`(RE. RE‘. Rx’ we indnnendenfly -Ikyl, IIIL -rylnlkyl or cycle-flit?!)
`
`CH3\C=C.‘H—, CH]‘*c¢'cH“cH;’CH1“c“"CH”"):
`éu,
`(I211.
`clan;
`
`arylalkyloxy (such as phenethyloxy). alkenyloxy (such as
`cm-cl:=CK(CH2}.10—).
`CH:
`
`arylosxy (such as phenoxy). phenylalkyl (such as benzyl.
`phenylpropyl). alkylphenoxy (such as orthobutylphenoxy).
`allcenylphenyl (sud: as
`
`cu,—c|:=cH
`CH8
`
`)-.
`
`R"—(C.'.['Ia),v--(f=CH—(C.H1);‘—:
`em
`H
`R“_(aw_‘l:_C}h_{CHfi’__
`
`at
`
`CH’
`
`30
`
`35
`
`40
`
`45
`
`ii’
`ii’ 2
`E.’ 2 E
`|?,,5()—|i|\(|:/?=0 or M0--P|'\g:/'.i3=0 or
`11130
`L on
`no | on
`n:
`at
`1”
`"3
`o
`o
`o
`:1
`1;! f II 0
`or 110-
`M()—
`S=
`/
`M!)
`Mg? gm
`3:
`‘G
`
`o
`II 0
`?.
`S:
`\ /
`‘'3 LR’,
`gt
`F
`
`
`
`if
`Z—CHg—S=0 l
`“(L
`2}E:IP(0)(DR1’)(0R:’]
`
`50
`
`EA
`
`nn
`
`wherein R1‘ is my]. hetczroaryl. aqrloxy. hcxeroarylony.
`qgcloalkyl. heterocycloalkyl. and (CI-IQ‘, and (CH2)_,,. are as 55
`defined above for —(Cl-I,)P—. Preferred p’ and p“ are
`independently 1 to 4;
`
`Au-’~—o—.u'—{cH,},_
`
`wherein Ar‘ andhrz are independently selected from any of
`mom groups defined hereinbefore. and (CH,)p is as defined
`"”°i'"b°f°r°'
`The compounds of the invention may be prepared accord-
`ing to the following reaction sequences.
`
`50
`
`65
`
`0
`
`0
`
`II
`I
`II
`R‘3°—l|’\| A’:
`R150
`'|3 11.40
`H
`
`"
`
`Procedure employed is similar to that described by
`Carretrero . LC .; Demillequand. M .; Ghosez. L. .
`Tetrahedmll. Vb]. 43. 1987. pp 5125-5134.
`
`7 0‘ 93
`
`PENN Ex. 2205
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`13
`
`Scheme 11
`.uuemu&very,zunheaddedanuR‘
`(where Z = lower E1 or hazing}.
`
`l)l:I|5e
`
`0
`2) tlkyhtiou
`0
`2:0 1%.;
`H
`R15O—I7I
`|\-. I /I
`3°";"“°"
`11.30
`C Rm
`3‘
`L
`alml)
`
`5,712,396
`
`5
`
`10
`
`Pm D-
`
`1C‘
`
`D
`0
`I. 0 ‘5
`2
`:90 II
`|\\(I://‘I
`R150
`I R1 0
`R1
`
`IC
`
`33
`
`14
`-continued
`Schurc In - A.l1'.y||tion Reaction of Electrophiks
`mwid. IgnYaJ.d'I1-ieatesn‘:
`
`(allylin acetate — Typo 2)
`
`if
`E f
`_
`H
`'
`1c _ ]1l5o_§|a_(|;:?_o
`R1-‘O $11:
`09-1‘
`(EH;
`Ian:
`R‘
`K?
`(whm R‘isR‘—cH=cH—c:H,—)
`
`Scheme IV-Pxcpnulion of(I)inJkaxyphosphi:1yl)::ettnn.esu1k:nic
`licmacidsaits
`schennm-Altymianancamormecuopmles
`mfim flhmmHmY2MfihmmE
`o z
`0
`II
`I
`II
`15 ¢a5o—-1>—-c——s=o +
`‘
`I
`1:
`I
`ago we
`
`R‘!
`
`-55593”
`
`11
`
`um
`
`W % W
`n,5n—p—c—s=o
`I
`I
`I
`R130
`R1 on
`[D
`
`{R.1=6fl1y1ornI.’o:rl°aIkyI) M=K.Na
`
`/
`11 ” R°'C’{
`
`C]-[=CH;
`
`PtI“ba.nc
`"l'HF"'> ‘C
`
`(D)
`
`as
`
`3 of 93
`
`PENN Ex. 2205
`CFAD V. UPENN
`lPR20l5-01836
`
`0
`0 Z
`ll
`II
`I
`n,=U—P—c—s=0 +
`I H
`I
`W0 M0
`
`31-241 %
`(X3isXcu-an
`anetarc)
`
`II:
`
`["3
`
`0 2 0
`II
`I
`II
`R:-"0-II*—€|?—?=0
`R|’O R‘ DIM"
`
`K:
`
`P*fiA-
`
`ms.
`
`II
`
`+ Rlx
`
`""3
`
`I-C
`
`0
`mum
`"
`+ R°*CH=CH —-W
`3
`
`II
`
`fl’
`‘ii’ ?
`RISo_T_(l:_?=0
`R130 ca,
`011,4
`[
`CH
`CH
`I
`R‘
`Ic
`
`30
`
`as
`
`40
`
`45
`
`so
`
`55
`
`0 2 0-
`II
`I
`II
`3-9-|’°“|""]3‘?=°
`RPO R‘ 02.4
`
`IC
`P|r1B(1)R.'=a.lkyl,
`-zschllryl.
`‘flak?’
`
`ac‘)
`
`0 z 0
`It —P—c—s=o
`[50
`II
`I
`II
`I
`I
`I
`1:130 R1 on
`ID
`
`Part
`
`2
`
`60 R‘4=”‘u;l
`
`MDH
`
`R.T.m80°C.
`
`rate.
`
`(ill-IYI-'I'=Ii==!Il1?=-'l5'P=1)
`
`or
`
`ii’
`occa,
`
`ED
`
`.
`'°"°°“°“
`‘
`W
`b))v[HC03c-t
`pyridi-.ne.o1MON:
`inCHg0Hot
`01'
`CFSC-H20“-DP‘-H10
`¢)M1.DMFot
`d)M1.18-c:uwn45,'11IF
`2)‘MCIH(upl.inrnl).
`
`O z
`
`D
`
`Rl,0_I|I_(::_I?I=0
`1.30 at on
`
`ID
`
`

`
`15
`SchemcV-Hepantionof
`(liydloxyalknxyplnsphhnyijnnclinnesulfizutic
`
` maciisamrfi.
`gm
`Monnuciclaall m9 Diacidnit
`hm
`m
`[E
`
`5,712,396
`
`5
`
`16
`-continued
`_5°**.£.V_IL
`0
`D
`g=o or
`3
`xi--9
`|\‘I/I
`M0
`‘'3
`on
`R1
`
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`
`0
`0
`lsI=0
`Z
`R5-*—1}!
`|\(|:/I
`M0
`._
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`R1
`
`IN
`
`of
`_
`Schmevlwi
`mmymxyppmphmylmnmmumam
` _ 31%
`
`=‘ 4:
`R. R1
`
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`81331 Itrla an'l=lk¥L€I'°1m3k}’
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`51753’)
`op(xx:alpImDnnca\'uJ,pr
`2)MD-Hutxninmp.
`11.’. Ic.’= alksLcycbtllwl.=nr|nlkr1
`
`Mamunermcidorsuli
`IF
`
`
`
`10
`
`ram-..1c
`R‘:tnI1r1
`
`1)Tr'nnc:h§I1si1ylind.idu:('IMSI)or
`Tldsluudapzolmacavonguz
`2 "0"
`1)Gunvetsion no11) asderribed in
`Pm-IB(1)orB(1)Schen:aIV
`2)'I'MSBror'1'HSBrmda
`pmomnmwngn
`pm-;3_n: Eli-—:—:% IG
`
`R3
`
`1)'I'MS'korTMSBran:l.:
`pzomnswmngw
`2)1a_1a.mwn.5.1HF
`3 “OH
`
`10
`
`Pa:-tC.IC
`R1‘*W1
`
`Schemes VIII. IX, IXA and )(—-General Schemes
`for :11: Preparation of I1-{Alkyl-or AryI-
`hydmx)'phosph.i.nyl)sulf0|1at.es
`
`5chu:oeVT|1
`
`0
`0
`g_0flL5'*m%
`z
`1,!
`15¢
`|\_‘(|:/I
`nI—x
`’“’°
`1: “*‘°
`V
`
`0
`0
`0
`II
`.
`II
`II
`Z
`s=o k~—P f
`n=-—1=
`|\_I/|
`|
`31:0
`II: 3,40
`ago
`‘I?
`E R‘
`‘L R‘
`
`0
`II
`S=0or
`1
`on
`
`15
`
`0
`s___0
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`Uh“
`we
`2>c:r<on_-=3:
`_
`20 z_?}[ .
`RI
`
`VI
`
`25
`
`30
`
`35
`
`40
`
`0
`
`o
`
`H_l||1\\TX%=D
`“,0
`mi “D
`R‘
`
`D
`
`arylahsan
`
`if
`Z
`if
`3=Q.
`R5-u_P
`I
`'
`R1;(|;\-21.0
`I‘
`R
`[K
`
`an
`
`]]_‘
`D»!
`or
`IN
`
`
`
`L==_wi..
`
`0
`
`IELO
`
`nbase
`
`2)cn=(om’)a
`
`Z-'?HRg"0
`3’
`50 mm“
`
`55
`
`an
`
`Alkyhflm
`if
`if
`s=c- mm”
`Z
`1:-—1=
`|‘\‘_!:/I
`R130
`l R140
`,
`R
`IO
`
`I
`_
`Alky1ntumR:a:-honmednbbgy
`A.l)i1eq.ofbmcR"¢Al5-I
`2) ll!‘-I{a1('l{I.l= I at Dr)
`
`65 a.
`
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`s=o
`Z
`It-'--—P
`I
`I
`I
`1:.-'o\\f/It/no
`1
`1‘
`[K
`produclfll
`
`9 “f 93
`
`PENN Ex. 2205
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`17
`-continued
`
`
`
`0
`ll
`l)l:use
`2;cn=(oR.3),
`i=0 T
`/
`z—ui:Hn.4o
`R}.
`
`5,712,396
`
`13
`-oonfinued
`
`
`5
`
`m
`
`H
`IN H
`ILo1-IN 4}“K0
`
`{'3
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`Chemica Sczipta 25. 5-11.
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