`
`Unlvercliy of
`Hou¡ton
`
`Depanrnent ol Chomistry
`Houston, lsxaE 77204.564f
`713^749.?612
`
`February 1ö, 1ggû
`
`Dr. J. Ðavid Leander
`Senior Flesearch Scientisl
`M607
`Ully Research Labs
`Lilly Gorporate Center
`lndianapolis, lN 46285
`
`Dear Dave;
`
`I would like to requ€.s
`that continuod support be provided by the E. l. ully
`9gnp"ly lor o.ur investþatìons on the devet-ürñdìì or ftï';hãmåtiäiiosii,c
`agenls lor lreatment of central neryous systems disorders. Our ralionale is clear
`and iE saleiy based on our recent aehiedements.
`
`o
`
`rf\q
`PhcH2-NH"fi-1
`oH
`0 _ L 274959
`. Wiih thê discovqr{.ol t¡¡q59, r¡ have intensifird our eftorts to fu¡v discern
`the structure activity raldtionrHp of ttnn unnåturåtãnrilããöd;.-ivÊil-oüäí izs
`analogues hqye_ þ,e9n prepared and wah¡ateo.Eg orisrânitir.,b låãi,liJöuiained
`in the Fall of t9f9 support our continued investi!ffiñ1.--
`
`rrl NH-C-0Hs
`o
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2066 - 1/5
`
`
`
`Page 2
`February 16, 1gg0
`ll¡¡-
`ñi,.^.
`lJttclt l..1vtt.
`
`*1f
`
`rol
`
`7602 will
`
`R I
`
`Itiloo
`
`c Hs-c- NH-CH-C-NH-CH2 Ph
`
`(racemate) L 2476A2 ËÐso 8.S mg/ kg
`
`(racemate) L Z0A8S1 ËDso 10"6 mg/ kg
`
`R.
`
`Fl-
`
`ÇÌ
`,N\NJ
`R. - NH(OCH3) (rmmate) L A46906 ED¡o < 10 mø kg
`
`$&Iffi .ï"1ü#i|il,_#[ffi l*å,ï-'f ,;#9,î:f ff P.î,iïîffi åîSlStinll].
`. The .synthetic ðhallenses Tor tÏe präñ;i¡o; oi i are-nàiñéi ì,ìu¡al nor
`M ES activity.
`insurmountable. {pti,ll"rv focus {oi rhe propoôeð iuñà¡ng pdrioã Ëlfö' "',
`preparation and cvaiuation of analogues þos'sessing a sníail Cá¿onlti¡stituted
`heteroaromatic rino. subsrituenr at th-eï:põð¡riú:- äiË finãrmacolãg¡õãlrrilürts
`obtained in this sei¡es tJãäiþð¿räd thäñ, ;l;óri ,;iiü ãårdtðñalñs enã;ilomeric
`forms of rhe drug cand¡dare wïil ue prépár'eããnoiväruãieo.
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2066 - 2/5
`
`
`
`R I
`
`cH3-C-NH-CH-C-NH-CHzPh
`iltf
`CIO
`
`I
`
`Page 3
`February 16, 1990
`Dear Dave:
`
`R- thiarol¡, isothhrole, oxâzols, ieoxazola,
`imid¡¿ol¡,pynrch, S-pyridyl, ?-pyrimldyl
`srco¡xl, reconüy I fiat d *ngorûrr pfrafitÞlogtc¡r propoTly hes ceen
`discovered br our clasË ol unnaturd aniino rxi Ce*vativesl a-ÄzáöuOótituìeO
`adducts displayed potent activity in a writhino assay cond¡¡cted at l-¡i¡v. -
`Signilicantly, several candidateö exhibited oielererítial activity in the ívrithing
`screen vsrsus the corresponding MËS assát.Th¡s-d¡ft€rent¡átion
`in activitie-s
`sugggstq that the.a-eza adduús do not reaOily penetrate the btood-bráin nãrlier
`and, furthermore indicates that th€se compouhris may provê beneficiai toittre
`control of perípheral pain disease states. initial tests håve coni¡rmàðinai ftré
`unigg.e.ch.iral"specificity observed for this class of compounds in the ÈrES iest ¡s
`paralleled in the writhing screen.
`
`H I
`
`0H!-C-NH-CH-C-NH-C H2Ph
`
`lfiloo
`
`EDso {writhing} 12.7 mgl kg;
`EDso {MES) > 30 < 100 mg/ h{
`
`EDso (writhing) <10 mg/ kg;
`EDso i[¡lES) >100 mg/ kg
`
`{racernate't L 2472A1
`
`{racemate) L 202S75
`
`NI N
`
`R-
`
`R*
`
`R--
`
`{racematr} L 202851 EDso {writhing) 27.6 mgl kg;
`ËD¡o ûlES) 10.6 mg/ kg
`Tþeîg prefmiqry gudies harc proviñtl us with ¡ cto¡r obþctive. We otan rc
`elucidate the SAR for this subcláss of compourÉ. verLüoh of the a-srj¡stturnt
`þoth in size and ths heteroatom substitution pattom shoun permii us t0 iãplãt '
`
`,N\
`-N\tt
`,N\NI\4
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2066 - 3/5
`
`
`
`Page 4
`February 16, 1990
`uêaf uave:
`ñ-,-
`A:_
`
`-
`
`discern the extent of activity^within this class ol compounds, and advance a
`candidate to Proj€ci Team Status. The synthetic prðtócols i^rtr¡crr nermit irrã
`preparation of these derivatives have been already developed in'õui tãOorãtory.
`
`R I
`
`c Hû_c_¡ff.{-ct{,c- NH-CH2 P h
`
`il[oo
`
`I
`H= -NHB', -NR'r, where R'* alkyl
`
`B* -N<
`
`/T\
`-TI
`NX\-J
`-Nì\l
`.
`'{n encþssd.*dget þr tlt proposed study is provided. The lunds arç
`p¡ Ta1ily^earmarked for ãn crprridncü postdoc{órat ieilow ano suboiieã. ór.
`l-11?T uawhney has bÊen instrumentat in nearty every phase of th'e current
`proisst' r-le.has made. o]any outstand¡ng contribúlions bôth in the oevãloplìent ot
`-ño
`1.9yv-9v-nt!etie protocols to þrepare..key ðompounds àñ¿trôiicñirairïJélritiön.
`:Hlqfn ç.Pquqsi.êd for my ow-n efforts or any publication costs. These wi¡ be
`3?!9q?9 oy existing glants. .lf any additionaf Ínformatíon is needed ploasé ðó not
`nesllate 10 r8quest it. As is alwavs lhg case, we in Houston, vêry muóh appreciate
`your input, heip, and support.
`with best wishas.
`
`Sincerely,
`
`"¿*vt qJ *
`
`Harold Kohn
`Professor of Chemistry
`cc: Dr. David Robertson
`Dr. Dennis Zimmerman
`
`HK:psl
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2066 - 4/5
`
`
`
`prûposÊq Budgêt lor Nôyêmbår 1 . '! ggo'Ogtober 3t ' l ggl
`
`Dr. Kailash SawhneY
`
`Ëxpandable SuPPlies
`
`$21,983.00
`
`8,017.00
`
`$go,ooo,oo
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2066 - 5/5
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