HUE024161T2 - Kinazolindion-származékok terápiás alkalmazása kardiovaszkuláris területen - Google Patents

Description

THERAPEUTIC APPLICATIONS m 11 1 P CAB.Ö(OV'AS€:EL.AE FIELD OF QGINAZOLINEOEOLIE

ÜFRIVAl -VFS A ssfoeci-matter .of the invention is the «se of tgumwolfocdioaederivatives: as medicaments or for rwrafoksurmg a medicament -founded for the feafemf and/or prevention of at least one cardiovascular disease.

The: iovetfooo relates snore panrenkfoy -° fov esc of gmmmetmedlone derivatives capable of actingas Inhibitors of phosphodiesterase 7 tPOETj. indeed eves, for sosie of these derivatives, .capable of also acting ax inhibitors of phosphodiesterase 8 (PiTfof it being known that it is not ruled oui: for these same fofoisAdmediese dedvanves also to be capable of acting via other hfologleâlfoiediemmal rowes on the cardiovascular .system, oath foe aim of treating one or room cardiovascular eoodhion(x) ottdfor pxeventing dm appearance of such eondltiotgs).

Phosphodiesterases (PSDEs) are hbtaoeikuat' en cynics responsible tor the hydrolysis of c AMP (cyclic adenosine dy S'-sronophosphate) add cGMP (cyclic gttsnostne s hS^sroratphosphal«} secondary messengers to give Inactive S’-monophosphate nucleotides. cAME and cGMP play an essential role in cell signalling paihways and are involved tn nninerona physiological psoeesse;:.

The ishlbitioii of phosphodiesterases is reiecied by an increase in intracellular concentraties» of eAM:P and cGMP, resulting: in die specific activation of phosphorylation palhways : evolved in varied fonchonul responses. The incfcase m the intracellular concentrations of cAMP or of cGMP using selective inhibitors of phosphodiesterases appears to bo a. promising approach in the treatment of various diseases (Bender and Beavo, Pharmacol. Key,., /2006) SS, 488-520}. Tile inhibitors of phosphodiesterases are thus of Interest as foempemu: agentsand as pharntaeological tools.

To date, eleven families of phosphodiesterases have been Identified. They are: distinguished: by their printsry structure,, their subsume specificity and their sensitivity with regard to various effectors ,efo inhibitors specific tor PDEs, Each fonfoy is composed el one or mote genes which are expressed in venons tissues in foe fotto of splicing variants (Bender and Beavo, Pharmacol. Rev.. «3006) 58 488-520; Engster, Pharmacol, ïlafofoetfo , (2006) 109. foe-358 y

PDE-I, POE? and POLE specifically hydrolyse «AMP arid PDE5, PDE6 and PDB9 spec focal:y hydrolyse cGMP

The family ΡΌΒ7 B represented fry -he isoiornrs POE7A and PDB7B orlginabng lion; two distinct genes.

Unman POITA (Vlichmfo w ah, J. Blot. Chew.. (1963) 268, I2fo;5-129/2; flan et ai:., J. Biol, Chets,, (Pfo?) 272:, 16152-1615/:: Wang et ah, Blocltem. Biophys, lies, Cotntwm., (20001 220, 1271-1277} and human POP7B ; Sasalb et a I. Bioebeoc Biopbys. Kcs. Eimromw, (20150), 271, 575-508: Gardner et ah, Btoeherrn Binphys. Res, Commun.. (2000} 272, ):80- :0:2) scleehveiy Lvdndyse eAMF with V!ioh;n.fos constants (Elm) of 0.1 fo 0,2 uM and 0.13 to (1,2 phi respectively. The catalytic part of PDE7B exhibits approximately 075¾ homology with that of PBE7A,

Three splicing variants are knows- lia PDK7A. EÖB7A1 mà FDE7A3 are expressed ntainly in she cells of the Immcue system and of foe lungs, while EDB7A2 Is above all expressed in the muscles of the skeleton, ihe heart and the ktdoeys, For PDE7B, three variants: have also recently been ideatibcii (Gtembyca and Smith, Drugs Future, (2006) 31, 207-229)

115602-14007 MBsJG

Tfee ft* mà BBE7B sto voty Ässp, suggesting that these feeo tefarmr te distinct inactions: Mm èe pàyn&fegtei· yteprfat.: I»À dis expressed m tateoptefe cûh, &e.ta#k, §k placenta, ttespto*,· ti»e rmsscksofdre ùému, drefep Lep% eeSs, the collecting Îitec-Âs kidneys, ami tte adrenal glands. Strong exporte of PBE7B: % detected, sir te pshcreas, tp heap Bis: ihymid asd m #?%ssBkkâyÇôss^yçx te* %i& ψΜ) St, m4m

Wang st al,, Bkfeheta, Bisphyu. Bes:. {»«· QfK$» 1% î4Wi2?% eoppmMba of the messenger &amp;*$** (teêMm of PDOAand PDE?8 k observed in sotne tissues. ÎIssB tbeesse in dmosteoblasts (AMsgomel P Cel! Mol. Bsol. Lett., MOOS) 10. .Î05M19) and in some regions of the brain: several areas of tire cortex, the dentaie gyros, the msjmi? of the cotnponenss of the M&amp;iory sysktu, the striatusa, numerous nus&amp;i of the tttalsrnus sad xb« pyrrmisM seife: of the hippocampus tMmvcrsL Synapse, (2081):40, 20] -214; Beyesdrisarri el. al, Meruosckuse, (2§05) Ώ% l 17M I SS). In. csmtrsst,; is some areas .of 4# hrsis, miy one oftetwo feotern fe expressed,. 'Idas, only the xMMM of mmA are present m mm y :»iet .of Me brain »ten, Bliendao, Ä* uiBNASidf PDB7B »m posant at high eea«oni*atkm in itov nucleus aecombeus mâ die dorsal motor nucleus: of Me vagus nerve, white the tnÉNAs ofBDB7A am: rsoi detected diem φ®&amp; et al, Bytrapxe, pBÖ!) 4Ö,2ölMä4: BeyesArisatxi ei at.,. B:eexoSereîïce,: (280:5} 172, Π73-Ι IBM. A stidkedsisttsr of the p^t invention is is particular iprsputfc x$ßim3<m of ptlàaoHa^i»» dem turves, whisk eas pspve to he poxmrM inbihitom df POP, dr of PIPE? and of PB||, aeeonMpg ht âte detivsikss, or ptkheap act by other biploglcal motes, A ::;rdj}ec.i.-.oi.«:U:r Of she PkeOtipu is compounds of ploxcHtg general io> nuna. ftp.

re. which «« Ks pgpMseots;: s a hydrops atepp m ..Cföii. là wlbeh ,R Is a hytfeoguu moor, a. fP**C$)· Acoy gswup, sa aryl grosp, a {(....-t B cpkaikyl group of ^ PrGy alkyl poop, the said alkyl opSiossdy Pehtg subsiihded ψ ;; . one or oros-e Isydrosyl groap;«}. . a benxyloxy grdup, - a (Cj'Cs) alkoxy group, opbtausMy sssbsbtxstyd by an as'yb «r . s (CyC*,) «ypfcsaüty} grosg;, x ss cfitonaSy Substituted iCrCs) alkyl group;.

Ilj tepresseras: * s bydrogets «dont, SS 8 kalogiîï: SiOSg « a cyas« group, ss iS aims :gm«p:» * a (CrQ> sikyj: gsxaxp opsioualiy sxsbabsuitd by ;hs -NBj or els« by es -NB€{ö)Rb gross, with Hb as dußsed below, sss an -ORa group in wblek Ra repress«*«: ,. s hydsogen atony . a (C :-0,,} alkyl group optkoally sibstumed by oue or more baksgus islmxslyg by « or sj-sore bydrosyl groopdk by ao aryl grorsp asïd/or by ease or more cyan« group(s), . a (Oj-Cd srlkynyi ·ψχ®φ, . ao aryl group. ««··· Rs représente: ss a liydroget· atosg s a fealoge;* atom,. « a hytbxntyl gsxswp, a a cyarso group, a au -SCF;! group, ss a nitre gre-rp, a ass -SlOlfrra&amp;yl group, as '•SfO}a.;i~boterOvyeloaifcyl group, an -O-S0:rsryl group opoonasly aubsliuiiud by os« or aw badges sssssgy}: a as “aikylssbuosilkyi or mycksälkyksohmulkyl group, e&amp;ek opiiomsHy snbxbiaied oti the esd alkyl, x as opisosuaiy substituted soipbosaurssie gamp, an« arvi group or a b«i«rosryl group, the saisi gsxasp bdsg sxososydk; or polyoyolio sud is: addition optionally feemg subasksned by a (€:-€,.} alkyl group, by tare to- rsstae hsfogen attss(sb or by a sCrG I aikoxy group, a a beserocyeksaikyl group optionally substituted by a C'r Cs) slkyi gsxnip, p a (€: -€,) alkyl gsxsrsp optionally substituted by: - see or mors: bsrlogen Storni sj, - an aryl group wlxicb ears be substituted by one ta· more badges stom{s) or by orse s>t mors bydsxmyi gToupsts), - a heserossryi group, - s>ne tsr more kydrexyl gros;p(s} winch «as; bo suhstitatodi by an isryl gnxup itedf optionally substituted by osxe tsr more halogen aiousls}, or v v.'·'»' oRK " ** U' ' s\N <·' v r >' It s U i A«ky.< «rouf*» aoov«, « * -C(ô»Nfôb8c group. with Rb and He being as defied bdow. g. :¾ -Cp'kOHc stc-ap or aft -0-Ci.O)ORc group. wnh He Sunup as ck-luted below-, s 3 iCs-Cj.3 aikosv group, optionally subs;in.ued by - an stoincslkt I group, , an aasinocycbolky! g=c?up, :::u . a cycioakyl group. - K keieroe ye loatkyi proop, - 0 ruonooydle or peùyoydie höioroaryl group. ......., <...;- or more livdroxyi groups *}, ., ouc of iHOro halogen atornsgs}, :::::: ..: a yCi-CG ssskosy group, :. a ..<;:(030Rc group. with Re- bsing as detk«dfcek>Yk ...... .......................... .. ;r-C(OsNRbKe group,. wits Rb mdHe besag.as dsiined below, aM or - a&amp; an-S or otore It&amp;logen atotn{s}. a cyan«- group, a . o-v V* a<Ww group, -aa 0 huk-nlh s i gt"up nod t* s ârW\ÙSp i group, .,m ..pi.cycloiilkyl group, a« -G-aryl group or an -O-beterocyeioalkys group, each opoorubly .,*$0®^^·' y y :: ........ , . :UJ aryx iiroup, iRdf optionally substituted by one or more aaiogos stomps) or by 3 0„.rC*} -glkyigroiJpv:: -::oue or nso:r«%äiof33SOtporrsi, assdRrr :::::: v v 0 s „v , S X ' OsJUs Vi's «\\ b '!!>«''' : * ?ut -N:R"CO"NH'~heteroary] group or as "bsH-CO-NH-li's-i.';;} alkyl ..g optk'oaHv hcow· rubsiilurob lv „ ?v more hakuest atonxs; iv a esauo gteup, ns 0 suno ok up bÿ group- <··*'· ' *.....- -,,· >ηϋ«' hydroxyl g.roup(s) or by a (C;~C,) aikoxy group. ore *- ·’ ' yv .. ::;yy:· :: ::y .ye ο::::·: :,, g m --N-sC: -C<.: alkyl group, « being possible for the iCrC*» alkyi .group κ» 00 subsume« oy i.,ne or mors? arvl groop(s) opiioually substituted by oft« or r»ore halogeo aknrpss and/or csy an Sob ...gkixspyyyyy;::' 8 an NibC.O-.uyl «roup or an -NH-CG-Ixicioaxyi group, euch opbcruoly »ebag νηνοίηη-χ: by one or HsyrehalogenatosRx|:: y; v~ <«|se R'. ibtms, wiib Λ. a poJyoydic hetonraryl gn>up op;is>naMy subsa-auied r>y » (<-<<«») sbkoxy group or a Ci-kki alkyl group optional)y subsbaued by an aryl group which ears Useli 0« sabstauK*} by 00« or rsK-re ; ;bulogS35 atorsR#l ;.y :;^^Ryireprssesrs aliydrogds ^0!n-orakCdii^):-jal%1J^pj; .««< Rb reprosunss: , a bydrogeo. as.ona. . a iCpO s sskvl tnoup opbenaltv »ü&amp;t&amp;*g# or more Stalogert atom·«}, by orte or mors divuroxyh cyaso, memo, Ucteroeyüoaikyi m (C,O *&amp;oxy groups) or Oy ats aryl group opnoua# substituted bw öiiö or sötrre feajofeii» . a · C.-CïJ cycloaikyt group-., a (€r€y: alkyayl gÄ- d; d h . a iC'rCO nikoxy proof?, . an axyUio^ opUDîssHy ^üirued by oî?s or more biibgea atomCs);

-~Ra represents a hydrogen atom or a (0:-Cs) alkyl group optionally substituted by one or more vä îhon Rh amt Re knm seemher "Oh the tnsrogvss ,nmn m ohnh thcv «r jftjehed λ p<'he>eUn Vw'SM on v4'0'ct Vï kvl yîvno ;o and » repsvaenn asîfependeotly of or*? another, me value 0, 1 or 2, if being uadcrMWi ffeb mtngd; . «*&amp;#*, indepeadeiUly of os» another, the value i, 2 or 3, it besag uo<ferstoo<| that when ,0 h s,siter ^ 0f oossi to Ä then the R; groups are en separate carbon atoms and can bo different Ross esse isoÉRr end teheo o% grater than os- equal to 2, mots the R s gW are on separate carbon atoms sod can be different fcosn one another; _ q represents the value 0 or 2, it bang msdersfeod thus. when -.¾ - 0, then sise niirogetsmss heterocyclic ^^.mKbe/rottvmtomn-tmnd n 'te I J ' 4 <* '*b.o-oqmna ohn - np systetn is no lostger bndgeo asto ss os the type. :-:sÿi^i its i ï^s:; iifc ëiî4: îâ

«*<» r represents the value 0 or I, IW the treatment of at least one cardiovascular disease sndfer to prevent the appearance of at least one card to vase til ttr o Isease,

The compounds of geticmi ibrnufe (i) ear, comprise otto or more äsymsrsetrk carbons. They eats àms enfef of dsaateteoisonrers. IhesO; ebm#:nbom # dtasteremsomers. and their ; asistiaev. sncisi^mg race-use· suixtares, corse wishsa the javenP^*·

Pae to gëaeral.toma^'ïl) can ai» exist is the §sm.nt of rosaosci or nsropwoviset type.

ïlso -ô&amp;i&amp;^usâii 'êiptimh # cs®s ; m&amp;t m or Â*Nfc sails :¾¾¾ îâslâs. S#M sss;Iîs|: ccî^ïîÎ vvi^iisï tbii

These salts, as« advantageously prepared ^ÄpiÄceiftjc&amp;liy acceptable adds to the $&amp;% ôfNÂfer adds, for esa-npls of swe in she purification ·'* ^-psrauon of -he ootnpssBds ot g«wsl formula (?) also cospo wishsr; the srsvespsosx.

The oosspomiife of gestern! Ibmala (Il eap ssldo oc$#dsf lp fö^dalliSii? «ïs: oilÿ f0r»:PS«3ttag::»%&amp;ÎP lhe-.psypptoa;.;; 11« sôïnpoandi: of general somsohs (1) «an In addition ocrer in the foras of hyosates or of solvases. m. âm foris of cspehissdkms «Äe®äÄs mik eins sïî ssssd OKileiiiite «I wafer es: wish îc aoiydsi· bydxaiesi jlssfc g^em^hlaifee Investi«···: Âsscordlng ¢0 ibe prsdesst isxventio·). she N-oxidss of she oor«pos.srs<K oossyprisssg di adnoe sähe- «oses with«» Sb« snvenoost. : i’hss eesnposesdi: of ïûmxM-W In adÄtoceldlh: the :üM$$pfi Öso espsifsrlse ibose m iv6Ä ##·sf 8*30 bysSregdb ßgrboso m halopxt. $« particular cfciorine or fiuorioc, «kovs« have bcess --epbeed by their vadioacsive sso tores, for eoessplc tritisnsu so order to svpbscc hydsospox. or carhess·· i 4, in ordet so replsco ciobi·«· ; 2. hsxäx bbclscd c-xssxposu-rb axe s>f nss in research. nsesabebsox ;>t phsis'snocokiäieiie oodsess or in Ä!ogid&amp;?¥$^ in tfe« oosstexs of the snvesbsosx, the following do Irais sons apply: ; ; - in (Ch .Ci.), slid otsssetihssi is>dsdss : ilol«:m5ls5e she poSbifele sihibet bf ensfeso atom's ^»ssri ip a chain .or « s'Sr·« τ-uss, by wav of example, C;.C, represents a carbon chain which can have frossr 1 to 6 carbon ssIosps,: t fe»1 jr hf -Wy of exsssplsb (Cp-Cs) sepresebib ^feasboiolai« wlbdlx estil have Sk>sïs I id 5or also {£%€<>};cap refîtes«;« IMssBtÄasfea tbsg which «six ^ s- idÎ&amp;Xÿf à« 4D«a8ö$ gfep essmprisisxg a .-utiatated, linear or branched, attph&amp;nc chain; V'OS^' 5 V" \ ' SV«'X 'Xs, 003.0 ,! oar OT f" '' V „ „hpf s' f . P ^ P" ' \ W Sr pi! s , 0'oo:

Swss :sct;ykB;.c ssnpsbsradosp. For esanxpk, s; thkytsyl:#«ί§ϊ Φ* represen· ;Ss-5 «shynyl, pxopysryP iani she ;fei . ; I :

^ j ^ , , \ " 'Λ O s< nviî\ y '1' ' ai '< 5 ^ s i >N \i' r θ'-ess. O N j. >s. Sv-asn-bcsl c&amp;s;bsns. cbsiss s>f f s<> 6 cssrNsn: sssosxsij, ss- pssrsscdar a pxeSbyl, otby];. ppxpys, spsp.-opy 1. duyi . ^vsn-sallv oss-Mbr Cj dkrijUo Ν^Γ. i ^'ü-; îvvI· «ässtiädieö a«tnhi|!||e i$ Mjih^bcïfi pr : .5:,v,sw.s'fi>iy boss* > so lb rdctbbors per tisxy. Mcsxîion sspiylbe soossooydb ssryl giosjps,: of V.S· Osi-nrvi ososrü 'tvV.sO s xv's ' s s N v 1 » *v. i <\ s

Kt's .ses ,'ivîso jLCv-mn ssws>. « îrfîKiOT'NtneîtoKhio eîvSJp, .s sw« n',sis,*; go'sjp, an dhos\ esosxy xts ^ , xM ^ Ws>i^vl-sa!nh<axs >t w... a» s ' χ „.s.-Λ κ.....' ' x u*\ ' \ **<. s *£ «^lô&amp;lkyîâînkoëkôxÿ: :§t»«p- or a pmp* för · «sample: - posycydfe axyt. an optkmaliy sutwörowd polycyd« atomattc system comprising kess § to i4 messbar«·· per ring. pmfersfeto frosts S to ï 0 members ':ftof s'srsg, mé feimsgrisfsig &amp;«?m. 2: to ! b täsga, st tossstssm ei the rsegs of whsds to mw£^ld:'#otioa bay- U·· '»54«%. ^.mratpfe of poiyeydte j»yi gsspps, of feeaatkytee, «Iraeet«, skä«; conmsae, ,πφκφ»# o^Mïafeî«;..te ;po%oyÄ sryl grt% osa »« substituted fey a group which can fee ox« or oxers hatogea atoms», a hydrosvä group, a cya*» group, a tdfiuorooxeffeyMpo grosp, s oste group,.«» afcl group, am alfemy; group,: m aikylüi group, s ssmiisytssPghpsxyi gssegp, an alkyteÄoÄyf or afliylmoi-msvslosikyf group which ly opiloomfy sbbstksited^au spky&amp;srsmoafexy or oycfpsllyiaifetaoafkexy grppp or <s sulphorsssrsbde group;. for:.e5çsgpplpt - s bridged nssg: is blbyclè sfefecdrfe coPspsisjag, acebrdsgg kr the kimïihk», a agimgess: atom,: m whfefe at %äS::E tm emboss: sbpM ssiesmsmepsM viss» sspgls feogd or a eaSfepss: bkato »sfehiOsb eossprisfe 2 cefbosr mootis, äymeo o;V. ample, the itvy.enamsi.mod oug îs ot tsn-ixpe

% b h P ·'" s os' 2 and wish Öse other grossps and iodseee as «le fined ub®ve; ' eyefepdryk a kifesrssted cyisHe ssspfiasse grsasjp scossspsisbisg: item a to % emboss atosns. Menders ssssy fee ' , 0\ v> o' 'S, ' s.o ' ^\s vp' ό» '< 'tsssk vetop »'\? ivV iS'ife, , ",'S o-m, , xs-xvi arosjp; - halogeji. a llsiorlne, a obionsie, a hxoîïiixs: or au kdiue; • haioaUcyt: (CVCe,) aikyi sufestitnted by one so three halogen a<osö|% ' isetos'oaryl: a suococycKc atooxatic system eotnpmtng town 5 to sdsissg samites,. prefsssfeiy frorst 5 0> 10 rtog members. aud comprising one so several hetenoatom*.. «such as rafsvsgess, cssygsrs or ssslghsrr atoms. ids·: ssfexsges* atoms· bars fee m sise fèm. of N-sxxksos. For ekiisxspls, a saorssxjyclks Iseserstoycls eaa fee a pyrrsrs, a pyssj2tste:s :si: styspmife, ;s pyridserfexs, a s^aidips, a: pyrstsxidsrsg:, a pyrrole, ap: ssosfeipKose, ast saousaoîe, a msssit, sso umdeseoto. a morpholhse, ;s thiophene, a plpes'cseme, a usazeUdme. a dmydropysxohdusr. a pipermme, as: axc-pme, atsd the like·, a bieycht heierocyele· can be cm ssoqemoiine. a ptcridsne. a duv-roan curd the hike; a tripypli« -hererocyde ecsn fee a photsanShrolssse. ;s tsmtbssse, arsd she bks; eoivrcho 'reus, rs%: .5r opoor'dy 'UbstituU'd pvAcyclts' avn'it»e: avxsesrs cispspsissog fesxs b to 14 sspegsfesm per stag; psv&amp;mfely Fiopr k so f O sgeissfees?» per bssg, obd esxssspmpig Fpsp 2 to I if sdsrgSj: sdsibossally sxisrsptkistg one.to ?evmi betssrosut-srsa, such ms sutsv-gest. avy^ex» or soiphux iStosssss· iss sst festst oxse of Site nsigu, ssstd at lessst oste of the rings of which ss ssrossi&amp;tfe. Mention .stay bo made, ass examples of polycyef so hetorearyl grossps, ilf issPoie, bersesksl'ssss, fcesrisss&amp;ole, beôÂb:so|4sosto, l>esx®slrteo&amp; bsmgoifesasofe, bop^okssxole, ^pÉsoB^I %o%eife!Ö:fitSäii,; nufetzole, spHsakdlsfsof phibalsebsèv pössxoxssftäxe, feuph§iyri#ie> 2Josisyim>~iH-:ssKki|&amp;, 0 Jbsùyb'bsersroboni, 2J -drhvds o ssuk :x<p k:is;dsyds:nqs.oris>hr:0, äxsi;abydst>s\o<ps.rs'xOibxe or tsorahysdro· boqbo&amp;rohne: a hr-ro'ocydo;sÎK:vs; ao optionally 5>üfe?dïUK-d satssrsted rsîsg coHipri.*?$g bons 8 ;o 8 anusu; and corupnsuso one k· «ererb hvssensasosss«, such as oürogin, osya-a or rubb.sr atsMsra. in a; least one of the rings. or several > v',\ v V' ""as sre v ' h si v \ J' »cros > r< ' \ x vw xT v\ v x, x x'-OsVxlx s '-Λ < ! N a ^V'ibi S IV ;8 \ i; X 5« X xXi„\UOl<\\ xi O'o'-b'X^ i\'»U', ·. OUX nd.r K, a pipxCSV'tOx x*s -ss&amp;epasca asr s.oho:s:is.:hhi>ie. 3 (hsosoorphoibre, a ieirahydropyrajx, a ierooxhybrodi.sopys'an, a prpxsroiusr', a osascpar;.., and s.bo like: ~ hydroxyl: os A)H group; ·· ribro: ass -·ΝΟ> group; •vi>soi..a.-C©^:giö5ip; 8. - .-xîd-'iîiOni'Oxb oros.ο γίΓΟ'xpoodnïa ο die κ”'0.000 8θ b V-rbr : ο: 4'xX--N i'\xix\dkxl. jlkvs asar •oploaUtyl being as defined abov«; • nrdaîoronK'ihylddxï ss PeilneO i>y she ibsosuls -Sd.l ;·.. ....... i us dcrmotx, a Ss yrdcrou-'XJ tbo, us the pseseat xk'senpis*>sx. obo an atom or a group ss subsisted or opÿbaally sufebltubd fey oso ot more defined groupé) or atormsp she xobsbiuen-s can bo idesbcai to or , 'V X V '<vVl ΛΚ 1'iM.ov \ xx <s'd ''8' v X x 'x'ox'x . \ x' a». 5 \.··ρ»ν«ηι o' * Χχ x ' ' ' \ xO r 'sxx χχ'χ" ' xl x ' ' k xi <'x' nompounda of Ibimula si) in which A represents as aryl group. in particular a phenyl or heteroaryl group* su pfirdiîuisîi Sä p. Tid'd .'îx'xip, .O'd 3.11 '.ItÇ x-'ltÇt S!.iî"?i>'e,î<'SSiix x'.St.î 'îîbix.;' 0r0 0' xi;.dfSOxi RtC 00000:1 ΪΟΠΟΛΟίϊ -.1.- defined above;

Μ«**' 'Xx \ ' x' r"t xx x »P Vs χΟχ x x r XX 'x χ' v *-<.λ < i a erou.' > x ' \v*'Os A Ärmste i 0 tt xt Use a ^ su and a Xxtch ix'prosenss ;. .roci fil R..' other Surnom ^ xndkcs .uu ax ^ lured in the general Ibnnuk *1) deîisred esbove. W«tkM vux posnrde uv gshox^'o \uro x ' ax 0'J'tu c ' 0' lo sxxxrsï.x^ -J u oUorn? W*s p ef sbs'sraris si tsx xxh.cî» i’> r"'x'îx'x"xisx s x( , tb axKxî xj 's.p s r^OxOb« u srsetbyl sodstod by m-'--' •MilCiOlRh gtoap x« whkh Rb and the oshar substitïixsnti; ;rr:ii::bdk*s> are îsx ddinod for ibe compomà of ger-rrai ibrrssxikx (B defbed sdxnnî. it-lrotioiä may be made, aawng she cossrpoursda ns accmdance svids she drvoxssioss. of a group of compound^ pf prssx.ox! hnnxU .0 us "bch 1''; :*w^ au ' SR.s 8'b ^ Rs rvog «<t aSi thx« osSxs vlw.l.u”S, xä'sd

s.'Sxhxx' "S prosy x;x dpfs'Sed sss siso -s'sVS'xSS txXs sx-ssl til'· d-'istsoo xdV'xX may be made> among the compound, t« actordcmce svxsp she iuventiotu of a group of compounds s>f posresus Vso,ou KUm M R· **> a hbro-s, w« os -J Vx' » txxdixVx^ 0 '> h'dsovxi os a (C. OJ xsibi opro'tsbk xbvsssx.sed bx an -NU or pise 0' cox Nth>v^ o-'ç R'" trd thx os-e. ssp.ntxrm, mh! ssxdrecx beissg as dufmed so dre pèserai fôfsxsuia {! s deisned abow.

Mention may hx. '·ϊ*χ " κ χ î ' χ \ v u i , -, ' ' ' *' ' v ' 1 v‘u ' ' *- '* vs fR ' ,* genera? formula (it La which A w a pfceayl. R ä i? &amp; -C<0)R group *8 *bieh R κΐ**'**** a hydaxam atom, g tqusi to 0, a and m each have the value L and R; represents -OR», Ka sad the outer substituents &amp;no mdsex-s 'debts: a* defined is the geaersi fo^saän {U deimed above.

Montn'n suv K x'xaxb, «asm,' tbx cc!,';x>u'vK u cu'Cx- d^\o 'X»sh tnx xmentxexx. at a gi0yp^cs.'ss;v>unas of cenend Ibnnula ti) xs wheh A o a plumy I. R: m a A Ubh camp xn 'ohu'h R A'paxvxim « manxes .sans, a rt in 0, a and m each have she \'&amp;lue I, p is equal to 2. one of the Rr. RryyPs 55 ^vRa and the otner ot the Rc «roups i» a halogen ttfobb lia and the other svÉRRoeata: and : Rafises being as qpttaso m the .gâterai: totnruJ« ..;;;;::: defined above. yumU-'n :uo tv ,xv.dx' asvng the , eaxpexus a xn ace ox,ins. e vxxth the' xnvxmmm. ei a govip of eotnpoanos ofgwral Ibmtula ,r ex «bah \vi pumvl R,u x «V»R mxxxxp ns ''hah R tepto-uaR atimb^gx-r,umm, q ts oqPtti to 0, a and ut **x h hax e tbo value t, p * I and R, is a methyl sufcstltated by an -Mi-CO-Rh group, Rfe and the other substb seam and indicé being as debited in the geaerai tbrmufe φ deüoed above,

Ataäaguouely, in Ute cmnposmds of .formula (I), Ute R; group is «* *h<' 6 P0®“» °r ihi ^A-ùmo-; .:h:;.'f -se;mh>dnxininasxdina ring system, The compounds of ftrauit il} cm abo have *e )h group m Utef ^waonet lhe:,d-dK«\o l : .1 a.\aah\xl:oqtmuvt»»o «**»* "'*»· ?Uo R gamm· m the a ,md 7 ixspixmaeast h$ sdesflcll # i&amp;fiaent"...... aAdvttntngctmsiy, xn tise voatpottitda oi ionratht U), P b eqvat; ïO ï ns

Th« compounds of natterai formula φ cars be in Ute base, hydrate or <0*™* *°mï'n ihe ,onn oS' *°R?<5fs <:<s: in the form c?f dxdr tttRîntcs. lw .x -xpvx'sth tbrax. 'vtxxm n \ th»'R Uk- two R« gtvxtnx a, in dx- d atus « îvs>smm. v« the nao λ xxtxd can be ddiersnt tVxxx'» oxts atxatdtcx'. .· . a,· >.„ ^·ΐ·χ-^ν «Xîh Rts dtventma ateadoaed ab<>\c aKo. T'ae combisattons xH tne groups ot· ·ΐ,ο»·»»ρθν»»»ΐν ·«»* ,κ-w.u^vv . - .... · copte wiflttp;Up IpYpmidba :::: i .« r „ ,, N,,-.Xc t-s «,'orxlaace with the saventjon, oj the

Mcxvxon xtxx, ne xxxads' ,:, evvxnptx'S vx mx v x,o .po„ ,.,s - . ,νχ .foikmiag c«>®|>ounds: V' t : ;3bd.M, ':vhtrMRd ;.<:vSxtr!Sx<.,-rn ''RR4 ,et;,hxdtvmmxx.-ma·: iS-y;]oxy ; pmpanetsitnie V ' 5 X ' „W ' dt - 'x^ d ä'V-, VCR X V ' v ,u ' 01 " 'Λ* h Λλ1'

No. 1' ;n..ii-.tx^tytpiperidm-.4.yt)b.(i!4..;limetktxyiteanytp2.4-dl· . y1|os:;y|at;ehm%tfe : _ y Kïî, 4:;;E^n-Ci^ !!' yijosy tpmpanenii.riie V *“ * -κ ν\χ·«ι < '»> ' C b·* \h pc*'* 5 <- ^ » v vV , ' ' Mefraimfroq^r uo' ni

No. 51:4-1 ?'{3^4<raeiho*ytasusy1fH2'8uok*- i -^luotosne^yl^diOxyH^ -dk»S!C?"3,4-<Hfedtö^ä?äxo.b«*I<2H>-yljpj|>er{-dfK^-i*c&amp;rfe^d.«hyde ïftk ί 2: K< }-3C«iylpipendi«-4 -yl>-3 <3,4-dœK^x>fc«»y$H>*i2- ßuoro- I *

Cifee^jî^byOethOxy }quûî&amp;»>h8«'2,4( î H,3B}-dk>nv.

No. i ? 4.p.'G,4-dio:44N>xYhmxv0-2,4.<Ho:\O-64 2,2,2-0-- (kioiociboxy î- 3 ,4 -dihydrou/oioiiXoHo - i i 2B)-yl|;>i?>t'rküru>· $ -«obadifchysfc

No. i_4i; 3 2,4(1 H.3H)-<bo;:s>; ;No. 16; 4'·^··(2ΐ2··4ί8»ί5ΐο^^οχν)4ΐ··(Ι>4··4ΐΚί®^ΐθχν%ϊΚ^!}'·2Ν^:^5Χ0“3Ν'·4;ΐί^&amp;ίρ0®^οΐΗ^:!ί2!·!|·' :

Ne. 20: N'vi[343N<bs5sifcos}450s;zyl}'!4 bfönsyipipönöia'-dryiNdN-diöxe-lN.d'd· : îet;Xshy4ïx>qti«;;i<:oii«'0 -yHmedry; î aecuurddc N0.22214K, eo ' v«v «-* 'f» i w'x\ «u*\ ' '-(' "*.«**Nowtvi*·\lk*a«u «V«» ‘AUUB) dibsîfc^Xll’ôeMâ^fc.

Ko. 23 )4-2(3-(3.4 -d:meîhoxyK'Î5ïyij--i (S for«syipi{K-i'!din-4-yi)-2>-i-<boxo· i ,2.3.4-t«ïr;diydroqxùnas:ob>!;-4· y\)$ocïl:)4 i Îbrmamkse.....

No. 24: NMjB(l-3<ti$y1p:-pen<}»iM-yr)-J'{3,4-<lÎm«$àoKyb«»Ây0'2»4«d}<ïs.o-L2.3>4'UntâhydroqujmÂo!Bv 4-ÿi|sïi«Sby!:| fonsaîïdsie N. 3< N--Π N .icuNo^'endoï 4-Nï 3 vU-doouNKxb^K^NN-Odv'.o L'N '--YO.iGdn-·,.;, u,-.,vUn· 6->y I j 5ô<?ihÿ| ί aeoGsddo

No. 32: 4-'f{H2^-dtHuoîoethoxy)-2.4“d?oxô-3.-Mihy{ircsqax8^XÎ>{H5"^^^.5"yM?{lws^58fc''‘i-CÂt'^ôç8'at:

No.33:443H'M»d5chIomfemy!HK2,2~difl«ot<^hoxy}4.4-4ioKO“ï.4^ife>'dro<îui8âXPim4i>H> K^ok&amp;hyde N'' * * . ,3 ' v. v xî\ ) o w - ai . *o ^Iw' % * * ,o\' ' * N 0 0 5 lyppendme* i -Csirbaldehyde \' ' wiG » t-, 4'. Oi\0-nx3 V'i' > x -*- * x ' * ' 4 t>i uiv i«v - '* IC^p^'-ylj^ôÎbÿdlls^î^Âô 2: N-\ ';-. 4 ;!» iv2.2-dUh.'''toeihv'x'V \ -(i-Gnrnk'Gernh-H'KK- 1 4;\\iU0V!ioUi5-.N2H>- y!:|ssçshyi|bosiæoiv;;:oià.:::

No. 37:4- {fô.-(22(-d[iNH>fooÎb<>sy}'4r-(I--famn'1pipondôa--4'y;.i--2i4-«KiSO'-Î,4'<iLi'iydri>qm;iiâ:ioÎÎO-..4.2MV yy»U5yi}--N42-x5ioO«>xyeÖ5yNb8ä5cs:axfbdö: :;

No. 38; 4-p4X4rdsmÄxybso3:y^ M esrbiddohydq 2

Ko, 3ÎP:;4#-i2:,3--:diS§oo3s:d!0^ N ;; ; U g N p: H2H .--y ijp^pçndiftc.' 1 <arbal<k:hyâc N-' P) 4 |o P2-dPx'n\ds.'P-'p î2 b'-d-.o'· ·<Ov\(! -·! οηΝοχΡ-ο'ΡΟ.-Κϊκ-ο 2 4-Äydroquissaofe- ! (2l-i}-y!]pipoxjdk«:o(-x4xbNd4liyde 3 : ! (IIIVvl jpïpsïy î4sîî®:' fctf âfàâûtâfyÿ* îiiî'»y<tro<âUi.Îî'ï&amp;Jî<5i'iiî·· ï ( 3ΐ·Χ^-yî iP’sjscî'ïîîîxîïî··- ï -< fci

No 43: 4.{6-i2.2-diÔu«MX*tbox\0'3-(3.44œwha4#oxiy|>2>4'<âiox^3?4*<ÎÎÎi>'â^J^î3^a*^^ - - viJâKèpâ-ô' l-oiärfeaMshyde :No. 47'. cas-bsideKydo

Mb, 49v :#- |B-|i3 ^cj-Çii;îpôîsïÿl<;iK:y)- 4 -3ÎlteÎhxixyÎÎ^ïiKy!j 4%φ^ϊη»2θΗ»- U2H}*y* i piperidine-1 -carbaWehyde K0 50; 2-(5-(i 64:L2--4|SHoroeihosy|-1 -( ! ”5ΐΓβ;νΙρφθΓΚθο-·4''ν1}-·214-άΐο.ΐίο- (J>-â:ÉÿifdfdlssKoss^

Mo. 5i: 3«»^^y!p^^âi^4:«-5àW4é^e 8--SKöbjcYofo:!p.2.1j^ (

Jfcyx!feqykuæo&amp;> l.(2(i)--;yi(|yp8riils®'-:I -oa?bal4efeyd« !.(2:H)--yfJppSïbi^

Ko. 58:4-p-(4-€MoKdx:oxylH--[2--îl-fôrob-<0uorom«kyj}eîb>xy]~2.4b!Oxo-3.4bihydi;>quli:!a:i<i!i!v ! (2H}-vHpiperklb:s- î -carbâktebyés

No. 5®·: 4-|3?[3^fe^yio*yM-»ns^^ Äybx)qab^ol>s--1 f 2 NNy! (ps|>«dsMos-· I-0srb<dtbl?^ib

No: 22; 443..pyNéi:®NksxyteN?;N<N2~fe^^ ? -œrfeakMpîe 2?2N:)-pjpipsnds^--I'-Sistisldobyib dibydfo^ibw.olls--l('Hs>! fttpedÄe-ï:-eaîbald«ây4s

No. ?f:: 4-p--p--8lib~o4.rSDoÉoxybemyi^^pN&amp;oï»-1 dbyôï^bbis^lb-· ! (2:Îl^l|^end:im-î:'Csrbd.^hÿde : . Mö.79:'4-P43>4Äefcs^^W2Aö^fex^t^ox^3^8^^Ä8*^m"1'2^''' ^npî^kfe®--i--i.«»%^dehyé3: däbydiöqsÄgob)4pP)Np84?dN!N2--Siö^ 4.;6.|·24ΐαοηνI aaoroR5«Uvyl}«tfaoxy>3-<3-hy(feoi{H*«5«^x>ber:2y})··?^ 4ΐοχο··3,4- ^y^oqu^otm-U^HKvUp^dia^l^bayehyd« Ç' : - .p.rp.< > 4-'di.:r;Sîh<i>: ylxwylVS-fcthox v--3.4"dksxo··.^ .4 ·*!θνοΓύφΚΓ.82θ4:ΐ' HIMVyl jpspiiKlssKv 1 -carbiddehv<k x 9-j. 4.{ cj.<|5cbioiK>>343.4-djmetboxytoyn- iptpendmo- I -carbakîeîiydô .....::: ir,i-4.(7.*:hlo«^.i344iTs«hi^b<my{KÎ.4-diwx^3.4-dihjx}wq«jaa?*Hn4i2H>YÎipâpeïïd«»-i· carbakkbyik

No ^i^aPba^^^itkoi-nyÄhYhcihoxyl^y^b^Mv 1 oiobvxvNov^ : 4.d».Xv'*34- dil«xÎJ^H!»wi!aOt2HK4}p^id«»4-carba1dchy{k πp 446.id!t1uvtoaBÄlmy}-343.4-din3eitojtoy5>2-4*dioxy'3-4”{iihydwq«ißS^5«i'uiH>" νΙΙρφοχκοΒ«· : "v«n>&amp;K:c&amp;jU£ \x : ; λ : b» - - , n\:b.b '-''N· '-.v'vN x K ---- ' *x- yljpspondssco- l-pssMMpbyd«

Np, 1:14; 4:-16-i2>4li®re~:14lpp:Ps®ö|)y%^^ :b44il&amp;y«!-6d«ibiäa<!b-5-l *21·}-yljplperkibie··!-carbsldphydij M&amp; Î I6i 4- bV;>Ouorv-*-(tîuorwatffeyl»«boxy l-3-<.3-»^tKoxyi>s«ayl>-2alHlioxi^lbd-rdhydroqaiisaan.nl· l(2Hkvl|p3p«îiiHn«' 1 arN.kkbvk' dth>Pivpraya.Häis' 1«2H> \i;p;|\'fukäK'4-xarba\kdmfe

No. U 8.443··(3>δ^>·ό«ηζ>'ΙΗ43-Π^«ν14H«o?omiHb>lRdx>xy|··2.4-όκ>χο4,4^νάν>>?αΐ«»2θ^' 1(2Ηρν1)ρφοπ4ί:χ:' i -«srbakttyd*

No. 124:4-1343-chlom-4-<2- c^hoxyeUK>xy)be!»yiH-|2-fiaon>-1 · 1 «yotomethyl mhoxy 1-2,4-dioxo-3,4”«îtbN»it^»qa}S:j* oUn-1 (3Rl-\ t ipjpcmhtte- 1 -^jrbækkbyds

No. 130: 4··[3-ί314~dl«lte>hen^γl)-^5·f2·a«ä>f<>-l··{Γf»omtnt‘^iyi)βίh«xy^2Λô'Λ'CO-3.4' dâbydrssîuissKobîs.- ii;2H}<y!jp!perk!k;e-l -CMb&amp;ldehydi

No ..-:. 4 . - »4 „"Οογ. 3 ο:ο4ν\\ίνη^ρ.ο.;:-;Ν.χ.. ivk..ooov'.a5k 4 .--1 .4 l«'v' V dlbwProqdoa/oba- is 2B by : jplpondioo-i -c&amp;d*aidk-by&amp;; N-- !- ' : -- γ :U'--o : * du.'rooxod·.' ΒοϊΝ,νλ | - O o ,Vo..v.b\:N --;V\o. Ju \ - '4 dlbydre^ai :ss«olk:-· 1 |IHkyl||ss|3gddifi;e- s -carbsidsibyde

Ko. i id : 4-{6-(2-Öoom- s mhaxy M,4 -dio.xo-3-[4 .{arin»x>«'«R;:hyD^xi2yl |-3.4 ^bydr^ais}a2ol}a-U2fi'}-yl|p>%^Mi^-i-c«tbaIdebyde V V- 1 p^.'Nw .Uv.'f.n.'tinlKxhvax' '' ο-..iVw'X' -da". - 1 - ySife>^;"0^iJxn:itK>>:5:i5-1: (2li)-5^1 j p ip« rfelissö“ !

No. Ï43. 443-f4-(benzyl*xy}-3-mo:iioxybcnzj ίρό-μ-Πίχοο.1 : na^mwibyiWtht^x )-3.4-dio.xo-3.a â^ydr«^wa»^bïy2.(3M^ylï:^p:py5:m-i -Karb&amp;yefepte: i :

Kiï; ; il 4 S ; 4- Î:6--[;a--fluoï^5-:i: : d:b;. d?V4Uo\!.'vhr.-U. UNyl ; pipondmo-t ".wsba.dohoPc ! (2 H}· vljpliedéise- Pàa*%;ÂOÿife λ·> 5Ρ di<.">o 3,4 „ 3 \ ' ^ > < ' > ο- ··. ; ! α * μ \ 5«. \λ :-Ρ . . ' nt\ \χ (i \ΐπ'ί ' /ίί \ \ \ ' χ" \\ \ ·< 4 ν'Ροι Ν' ' λ ν. οή > ' ] ΐ.2^ί>>·5 >pipcfïdme~ I ~c aibakleiiyde

No, 10S: 44.J-(b^to^M~yljss«{hyi}.6-[2“n5Kîn>· ? ··(öoorortR^hy Iteskny] -2 A ΟχοχοΝΜ -djkydroqsoiaxaH»·· i {2H}-yiii>ipeod8«>· i .«arbakÈehyàe

No. Ν'" 4 v'U' . -i t? u·' ï ^>"U V' N vo :V\j s - ' - p .smhUï»ttsp üo, Ph on,] 'jJn'V' ' 3 âshvidsoqimïSKoiiîl·-1 (2 li:N>1;|p^ô^dî80'-l^cs:d:ssidoNÿâ<X:: >\. N'' 4~VA'ΝΝ^Ο'ΟρΚχΟΐοοιοΦΝίοίΝv. ]--.'.'·-4:on 3 p-ρρ V4. 3 N-hnoxO· \4. S&amp;fâm9UR‘.Vx>htt 03H' uH’^^ix-î . ΑΆΚ'ϊ uk

Xo sp' 4,!{. p tki-'ίν x ^nmwmx'Os'î'tiîîv'ivj 3 i.3 Oeihx'x^-4-îmnîs> .bx'*v> J -carb^sklsfeydc

ÿlôi V?$i <&amp;*·μοϊο*:Η>tVskovxl·N< > \V '^nivniov* N* 2P 4foxo- i .4-djhy<jiro<pbwoUn*3{2HVvn a5«^yî>phôn<js.yiscmmsde Nô, ! 78: N37aofoaîStàv!)«É^v];':N{3''mstâK>s;v--4 -pa;poxyOeozyh-2t4 -dioxo-4.4- dihyd»x)qä«n*Kolio·· I ŒH)-yI pipeHdme^aHœldebycte

No. 133: 2 -{ ;;..{cyçiopcoîyk>s:y}-3-i (6-(2-fiuoro- ï •{OooïOiïiApONhoxyj-·3-( 1 -0>rn;y!pipev!<iœN-yO-2N·· diox«-lN-<iihydfx;qmo&amp;«i>{j«"3{2HVyil-{mrÖ}Y!}}>be»<>xyi-N-methyliM,'e5ai«^«; V A-S ' ; ...v x\ "X ovi',' ikotv- U^voviAoX'ikon ' U- k'ovdoovs Pso I A 5 4 'X' 'νΛΚΜΧ.' ' 20\ U MOI 'V* \ V ,Ü \

No. 13:5. 'p-K.'CÏopotp.'. !o\\ f-5-ί !6-j24h.[Oîî'- 3 ;3v-cοηΟρΟοοοη> ; "0 -iovniylpipondiit- 4-yi?-.k-x·- ilkjXiNä ;No. IM: 4- \' 4y , . v N s i x ."M 'v M\nk i '\\ V4‘ ' " '* ' ' * ' ^ΝΆοΡχ·’^·-.. ^- 4κ;χο-3A-dÉÿdrôqPssxoki!:- 3(2H>-yl| |Ao5:kPA4 -osakddekyïii?; :: J N 3ihvxks'x^0'.u.x\ ο-Ιχ'Η' \S ρρ.Ά.χ 3 . PA.k'hvk \' »V » ' p,\v\'.r'.v\NV'.R\vVir\iiî! 'î'y'»' 'n\il· .\o\iv &amp;4kkhydtoou?sa?oim- 3 {2 H )-> 1 ? pjpmdxoo 3 -cartaJddsydc V' X S Λ x0ol'V>3'NO!x'',!'Ν\Λ ' Οχ, 4'Ά\χν\, V P'ï>:.'-'Vîv.NîxPxm"-uw S^^dshyàro^y äKaxoiia- H2d>yl jppexkk«»- \ «carbaieefayâe \o 4.;.y î o N "Ν-^κ ·:·'''χ' ' 3.4-dihyorxK:uioaxo304 -1 -2 H)-y}: ρρχίηό:;"- î -csrhald^hyde N;:>. 2.00: 4dé~r2-d)xs>^M?few>{3ïethy3)ôtteyj-2<i4-4tô.so-'3r(4.H3^^^'^">‘^OÂ^^·'^* OihyOr'NOxOvUoHn- 3 (Oü)- y îïpspendîne-K οπχΟόΝχ. Oo ^^^^ôim26Îià'H2HV-yUp»p^K&amp;»-l-caïi>«!<iebyUe - ; ·

No .'03:4- (Η 2··0ΐίθο> Ni nuoroaxphyDethoxy'!-M< ? '-oxphyk1Η -itîdol'6-yDmethyîj--.kWwx^>·->· dihv'droquimizoHn-i (2yNyNpspmdi8£-l vcarbakkOxyde

No 00.·\· 4-:^l^Kuk.rKip'thiioUiox^)^-ovn-oN>V!v>!!^' [.' Oü,"·'' 5 Nl^xxox-iM'xd.ocxV-.·*. ^%c»”?.4--dih>-<tr<H}uin&amp;«olmr-M2P)-y! ] pjperiôia^î-c^aîd«byde

No. 20N 2040 ;&amp;.4.Nilooro-04r:uoo^ou?;.by?)ethoxy]N.-N obÎoiy4opiin-:'^;ïo-y)o.:.o-dK>i.v--i.-;·-Âydîxfqx»qa.?oxm- 3(2H xy iNocdiylk Noxïtbo>: yphaxo: y j^nKâhytaocMmete Ni>. >12: ds%dxxpàiXiaoîsx1 (2H)-yl ; piporxhne- Ncorhakohyde NO). 213:4-(6-12-?luv!''N'l {iU.v«*v*n«U K ,4 \hxKP ' »4 ορν-Οχ 2 Nvo"·" ' 4 Äyd^mnsääEoU»* 1 i 2) D-yi : plpcoidhxe-O -carbabidxyde \o ' N ο Λ ' 1 .,k»'^!'Ui'o.\ ' v N v v '* ^tT /xU ' " dsxydroq^baaolx« · \ ONTi-yi \ piporidbx:· Ncasbabkbydo

No. 2'ïé: 4~ (6- (2· flooro- ! -{fiuntvWthd xrihow j 2N--.oovs Oqq.xîK'bO''''·' avîioli >,*-Âydtoqoissàob«·- 5 ON \ ;-->= \ pbx-ndbxo l-catba&amp;M&amp;yâv

No. 21B:4-|4-[2-4lxi«ï«.x 3 .(ÜxoNsdäsdxyxkdxsxyj'-o'l.^ö'Sietht^ysxÄiSäyUlsileii-'^^iy^-oo4· ΟίΚΟΐχ-ρχοΐ^οοΟχϊ- \ 0H s y ΟοφοΟχΝο' ' -x arNAkNtx.0

No. 223:: 4-044-(1 M--bpd»abdaaok Nyi0οκίνΙΝ|-00ka>N0N(b^ 0 ; y ; : : 0

,||bydr<^|i|a^im-;l(|^;4} pylpsàl^l^^akiehyile' N

Mo. 2.24: 4-:b-j2-4koxo- j-Ohxom!5xeÜsy!)odx>xy|0--0oosd5oay043-«)SÜxyii)ix.>poxy)boä)ayi]0.4.<noxo. 34Nlbys^pqxî4WoOo· ^2H)-yi îpq?etù05*-l-o:xxb;âk)ehyik:

N-\ .'VJ :o ..' door- i * 0x«vox<U!\ Hoibou p » : - 'οοΟκ-\> .0χ:οθΛχΟο:Ιο.ον AN\y Ovo.'y 0-. N 20.0.0.:.

No * '- ' yX . oo -.’;, \n\>'xo i-' s vo χ ï-s-Ow. v-î. \ . 0 0 x-xoxo 1 (ä^-Äe&amp;ylkÜiö.xv}»2,4-dioxi>»3..4^ib><}jr<fqu>mi;ol5H- i (2. H bylj pxp<oibbxe-· l ·-esxrNddobyda

No 3-O- 4 -j ? y ; Ox-o:.'OthsOp;u:!V Όy OoeîhO Ή ΝΡ^οϊοΟ ρΙοοΐ-οο-Όρ. ΠοΟί-..'· χ j ...4 ko«'- M-dn5ydaîq0oaaohs:--P'2}îyyi]pipoî]diî:iO-Î -xiobabkbyde V- ")' J ,!' ' Puoso ! iîNiO'.."OÎh\lxO\ï\'x' ' X^H'ih'w 4 N-rv« kohox.Ov«.’N . Ax««' Οχ- 3'' 4 0 k\X koxoüv''χ \"x.\0- ' Oaoi.-' 0 s ' 'kuo-·- * *d.v ox.vîbx l\;b'χ'Ν ' 1 χ'*ον' 5 4 dxbyxboqoxsaaob a- U2B}'Vljpiperkbne·-1 -carbaidohyde

Nb. 234:4.-p-(44(3'aosîyïpyio:)lidm'-3--yI)osy]:'2kï)oda):sybdo4yi}-4)I2-|NiPN)-d -p:poô>ifeo^ÿ:04^Nxf JO 0 2,4-dssx:o-3x4-dihydîx)qîiio&amp;2o}în-l i2H)-y] ipipendssa·- Ncaxbaldehyde

Nx'..:'0 -4-0- ρΐ-ΡΝ'ΐΗί-χχ'Ν'χ. \Po\\''4-'.oodio\\KS!'x'k ."-| Mu >χν· ï ΐ,ΐΡίχ'ϊΡΛΟΐίτ Ox'tPO'.vjON· dibyo-3,4-<l(byxîrixpôîs;â;:oba. 1 (2Uky|)p^«ndbs<:- J -caibakk-hyd*

No. 240:4^?-(4-|·(4<?χΙθ{Χί1>δ»ί'^Ι>οχχ|·'3'χη«ΐ^θΛ:ν|>«οζνΐ^·6·[2·.Πχ!θΚ}“1'·(&amp;οτβ5ϊ«ΐώνΙ}ο^οχ>ί]'2χ4- 1 'Xx ' > x ' x!q ' . ' » y !iN v o<i\î d» a x.< bv \"xx ' V 4 -, 4 s ' \ ' -N ' ' \Κ' ' ,0v Oîicns K'tVvvî '-î eU'N\v"-i-sihv'Su -isj'jwc-kr - U 7HVx'toipers Joc-· ! -64ίΝ·2·5θ3χοο

V i O N\ '· «*V o*r«tVK Vx\ ' *' t'vi'K", ' î>J <iihydrc^tto&amp;a>las-î (2BVyi) piperidine-! -carixbskbyde

No. 24§:4.(3^4-e?.b<>xy“3~n^{hoxytss2y^6-{2.-hy^msyeiboxy)-'^4^ioxo-3,4-dihydtx>q«m2;oim«· b(2Mj-yi;pbpeiidine-l<;^bakidiy<fc

Na. 24b; 443-1442^2J-dâîydiô- !U π£4 I d> s * mesKowben^ o \ ' l-eariisidesyae M&amp;. 250: ^l'J-Jd-^j^-diöhiorObiä^p^yl'S-msihoxybeä^yij-^^-äuojxvi -(iko^ss^ysiesbö^yi-^^; ifax^jWihytoqaimîSoJî^iXHi'yîJp^â^jdjae'-.l'^aj^yehÿicle.....

No 7 s ï, 4- >-[7 fUiv-î-o-l-i OuofOîiK'îhxïKîhow]- VNwnon-oxv· -J · 7 o-\- Nipipcîviîsv '-\Γ8'!θθχΝ'Κ'Χ'\5 ' ; 0\N0 bi-'li: \Jî'\}U>ÎW\ , X 5¾. "Hi — 1^000 7'SX' ? v> î\ï’vi 'U\\î '

Ho. 254:- 'v'v w Nv'‘"i ^ - woN«' ' ' - ' b ^ \ c ï ^Urx' ÂX0'3,4-d jbydîoq«jjmoU>v 1 {2 H $-yl ? pjperidiee· I -<afbaîd«byck &amp;<>. 258; 4'P-i3,4'd}tnsi&amp;oxybcnj:y{}-6-!2-nuoro« Ιοh>xboxymed:y]}ethoxyj-2î4-'d;;>xv>- M·· Äy^^plaaMin-1 (2H î- vijpjpmdme· î -eafb«Jâèhv(k;

Nb.263; C3R}-2-[2 icyds^îk6:y!osy>-5d ; 6-f2··ΐ)«ο·κν· 1 •^aoiomestiyljethoxyl*- HI.-forBsylpipendia^-y!>-3>4-3i6xë4s4-#ky<iïxx^iHi»Kd&amp;-3i2HN>6ViXiebxybpii«îy:sxy i:S>Ksp5ï5Ks;.c sdd

No, 264: #li§“i2-flucTO*^e«t>m*sh>l>eUK->xyj· ?-|ii-methyi-3•{shK.'phvrKNyi*-11i-pyrascol'?>· yl)a>xxby]}“3oNdk>>: 0-2x4'dih>xhxxxÙ5Xo;i:okn'U2il)-yâ}pipendi:se-!<:arbakùïhyde

No 270: 4-;6-i2·-flnoro' 1 « iîaororneïhyi ί0ΐΗοχ>·}·344-!$-nu*thyMTM-ox&amp;diasttlTNy;iber;;':ylj--2,4.-;.Ui>x;>- 3,4-d»hyds-<xîx»i3'.420kft-H2ii)-yUpipeodïîe8-!-c-arbal<khyüe

Nv ' s :jv o- î diviosm v.S\vk'k\ s 2 * d o\' ' > * .pxvn a a N \7-6« '<·!> Ns

No. 27ο. 4- ;6·!.Ν0;Κ'Γθ-! 3ikioa;xi<it!syh<4ho\yl-M(i-nsoähyb>-phoriyi-Ui-pynäxoNi-yäimeihyl)^^- diox;>3,4-äifaydroq usna «j i in·· ? ( 2 KM < p^ntfo«» 1 -oaxfcskiehyds ‘N'oi-$78; 4·IMi'fluorcM -{iixu>fomslfeyl)ethoxyj-2;^oxo<3-U&amp;4 iH-pyrnoi-l-yOpyridiö-J·· ;;: y!|oîsibyi|--3ÿ4;'dâ4yîfoqsâxîa4o3îis~H2H|'-yiipâp^kis5«-'i~câd5&amp;idsfe54ds

No. 27b: 4- ; 6-f2-8uwo-I-Cfiuoro«K4h>4)edsosy |·2,4·<!«>χο·3--{(2- (thinphsn-2·yt)pyn»«j<ljTs-5-yl)meihyi|- • dOx-.K οοχη, ' -, UNS - N pr\o>inc I 0x60,30-3

No. 280·. 4- o-y[:.;..ΟχχοΓ<:··-3-{5ΐχ«>ΐθοχού!ν!}νίΟχϊχν 1-73-14-(i-«Kohybni-pynx;;<>!-'5'>··;.bx4xxyij-2.4--dio:\0-3,4-v ' \d- \y - o*x ' '·’! \ ,-, yx-ndi x' I ; xN-kU vk<

No. 282' 4-b5--f2-tlooKx-b(rau>o.v6x;käyl.kXhoxyj-7v-|'4--{3'OXXhy!'i.:s7,-\Xo\adi;^x0-S-yl)b<a5>:x-fj-2.4'dx:-xo·· !x4-dihydf-oqi50?as> an-! i 2 H I .-y Ü piperidine·- ï -osibaiikhyde \' '4' . v,\ v>x Ό, .'-x^'i N ' N Ouvre vtK xor 'd'o'X'Ox'\N ' v, ! xx \ ,. ,:r ^ «''' dko;o-· iyb-dshydroqsxsxa:ioiio-3i.iOi)'VÎi x63byiiph.o:X<:-x,y jaoi:!«'acxi \v 0' o ^ V Λ \\ VtîS' V W'i'OW , V V ' -i , : s c.2 xäs '> dihydroqujaaaoiin-iCSH^yljpips-ätne-l-catbaJdehyde

No. UM» Hooi-'-bmu^r.xovdoOodx^vj-ÔN-bx'v'-M^x'b.Xi'.rsndioô ^oxcth>5j 3.4· J;h> üroqymvîAîün· ? (.: H ï-vï îpjperùfo«:· ) -oaiboidkiYik

No.:s?:4-{6424kot^^(Huomm¢%l)ethoxyJ'3HïM«^φbolm4-vi)pyr:dm-3-y{}tncMhy!j^2Λdbxo· 3.4- dihy<koq«}a8^alia-^H>;yl.ïî>ÿ5«d^«er:'ï-c»fb8^«^e

No „-μ>ρνοώη ' ’•fovbrN · :M^Hyäro<(utai^]i&amp;· ( C2tt)v^|>ip^5^ja»-'j^rhsWehy^

No. 392: 4* f0x2-;öüopp-1 *{^*>ra«hyi}eth0*y>3 " l<* -«H-{Kyl-f-pk'»Yl·· i H -ρρηζοί- tytortliyi]-* .4 V' 244 4 v ;> !2 fooio '> . : ..•όλοΙλΛ'”'·.' '··* t Ό ''kp'';>. j ^ \ s 4 ii'N'o 1" dîîsyïîaxj«inaz<iHîî -3( 2H}· y; ; «jeihy i'îbîphvrny \· 2-cxth ooxrib

No. 299. K^iî--3-i2-{cyc(i^c«iyîttxyi--5-( lO-pdKiofo^ L (r!uyr-:>n>ÆÙ->!}etho>.y;S· = -i ; --fo-'nîyîpiperîdiîï-^- 'b.'N.W' 1.4 2foOoH.xî\i vb* b J b N;ruNhO!Hv'x V' \ οχΟοίοορχ. mîmoo

No, 297: 4- fv-Aoro-N·! Mluoro-1-i aiKi«HS*by[}eihosy]-2,4--dK)so-:>ô4-ùhio(3>c:\-2--yi}beÎîs:y5>-3,<i - §.^urhNdobyde

No. 2^:4H6.(2'r«iorc>i'(0ao«v»nethyi)ftihoxy>3*i3--ßxsüioxy~4»(iy««pk-.iHv4--yij«thy0lx^^yl|-2,4..

No. 299; dpN-p-iPoro-Kikoroo^ylM^F^Äo^ d:iiko--3.4'5li!^oqKisssoHs~ 1 (2H)--yi yppondm«- 1 -essridsiefeyde

No. 300; 443 - (' 4 - fp-s4^ÄoÄea^^yl»^Äx#^ixy11 1- : : : y p(«oj3o:a^hy!}eÎ!3ô^yy'2.4'ôio>:<.:--3,4-dih>dnxfiiiai4ïc.4:ia' !(2H}--yl)pi()ex'idiäK:' l.-«ari>aMeaydc

No. 30i; :242:'{Gycbpoaiyloxyy5~C{6''[2"lkO]fO'i--{ß4on>nx4.hpJotl!OsyNN4i--P«^l>b«i'km-4--y(3-o.4-- v v\ 1 * \0 \ V '' oUK >* \j' \ N\' v-v axAutv

No. 392:(i-p-ia^'NilMOfosasibylK*c«y !-i·(Mo»niyîpip«Tâ*»-*-_ ;y!H^bxo-K4-(«hydrx>quba2oh8--3{2HVy|jmetby^h«s{oxyipfo^8R<H6 scié -feÂÎ-^S^-^om-iH^tooasad^&amp;^c^j-î^î-mfiliîOî^fpR^^xc-t^beaylpyrrolNlb^ p|oxy(^oxyP2.4-diöxo-3N~kliy^qk»saöIsM(2H|-p}pi|x?nääoa--i-o&amp;^jdehyki

No. 300; 4-; 3.[4χί vcbho:vhr.o9aosy)-.Nn\ct(K>>;>1x>-x:\[i-o-|2-'Huoov s.'üuoro'.ooihykiiu'··;)·! \4-dsoxo'.x4.-d3iydso4«o$SLi:obs-:î QHVyi ; piponciisxx l-carbakiohyde

No. 307; 4-y^;4^ίbeiu·:.ylosy}--3·'G!··¢îhoxybeo:ίy(|·'?'îkJoro-'0'p'i^ooΓO··^-(ΓhiO!oί!x:!2iyi}i:0;i>xy |4..ί-dxxo>-3.4-dd$yifeoqoin&amp;xolxl·- U 2Η}·>4 lopoddioo-O-c&amp;rOoîdohyiii;

No. 3o.3:4N7-nuorO'9-i2.-4l'4or';vN-a]uoros3eihy9iôyN>XYy.o!4-hydo>xy'-3-'3^kG4;>tierG:y;h2i4'ôioxo-- 3.4- 4kyd:-oqoîîXSÂo(Îio s (2H)-yU psperkbos-1 -tarbokiohyde

No. 300: 4- {3v !4--(c.yc.b.>Dxx>|N';03Gkosy}-::v ioothoxyheni:yi!-7-·Π5.ϊΟ!·ο-6' : 2-buon> i - |doorc>vO<4hyi}odîoxyj'2,4'<HoxO'3.4'0>.hydîoq4iïââ?.o!.50-''.i2H ί-yi ίρχχχχίοχ;'· ! 'CixofixiCiode Ν' Nd 4 *' d.'\v f' ;li." v <f .x '\K\d ' ' .\dv\' + (2-!sx4Kvipâ.-f>poxyïbo;5.x\ ΐΐ'2.4ηίΐοχθ'3.4χ^3ινθΧ'^θ'.:)χ?.·>Ιΐί·“Ν'2Ι·Π'ν]':ρΐ{Χ'ΓίΟίϊΧ'··ί·-ί'&amp;ί'Ν34ΐν(ΐν2ο ( 1 'Oioibylskox ypeOzyl b2pNkNP-'3 .4 '<bl5ydo>tpisS4o>0X 1( 2.H |yy! | pipdnd ixo-1 'Oaibslpebydb X \ vt X Π Ή SX O Î* » ίΜ.χίίν

No. 315· 4' i?~iNiotO"6’i2'iRioro~^l'ItluoroineÜiyOoîhoxy 1-3·· : 16-î >-ou'thq>:;ypk:öyi||>yri<lxB--3· :Yl|î3SSthvl V2,4*450X0-3,4 »dl hydroqussaxol sa· J (2H}-yl | pipendx}« · s -caxassksahyde

No, 3 Ιό: 4- ^?-Π«0Γ0'δ-12-?Ux>ro-H ßaori>n^üiyi)etfeoxy]'3-x(<5H2« ûuosxxpbosïyôpNÂ 2 J-dkiSO'i^'difcjfds'ocjuisasolio-1 i2il)-y!) psptxxbsxx.1 .-earbakift&amp;yd« V ' ' * " 'lu O '' 2 '‘»y.' îSl.OSxOOÏ'Vseikx'y' 1 v N t\ 'ΧίρΡΟΟ',^Χ' ât ' V OÎOn'·· (2H>yl}ptpeddi«e- i <srb*d<lehy<!e

Ni». ïw. 4·.1?-ίΪ80ΐ·0»·^-ΐ2-ΐ1«ΟΚ?>Ί-(ίΐΛ.>» N«" \"U |K\S ' 0-1 ' O'M' Ο 5\>1Γ''Κ«' \ 'wh.N 1 Xy-.o'-x 1' \\ 'H' '5 p»îx v v NN \Jo \0 *1' 4 1,1^' 0TO J,\ v Vh<'\ 1 Ό ^ ''y* x\\' ' ' '

No j;p cl o ^';i.yVi jiohî-î-'-\'.v! '<.>VyO.' yS'-'-sIs- . ό 1 Ρ.--ο 1 iflaor»>a5.e5hyl}eîhoxyj'2.4-dio)t<v>.4~d{hy<{rcsq^a^oUfi * U SHVyH piperidine-1 -carbakfchysk «iibÄ0-3$*$te-$sx3^«Ä V i' \<.riOô-o.-!.U!«re<-:â-i . ' <.r ο. ο !<Ό y\ v y\ y y 'y' > i " N n! \ λ ; ! ο T ' ' 1' ' . fy '\ ' < ·» b’iO\ ϊΆ 'y'y λ* ' tfu>'ro->ÎH:2*:£]«ôîX» 1 {N^netKiVtivox N N xœtb}3'x-1th'yOî. Vn-2 yVi N^y^ol-o-' ylpseiM}-2y4-Âxo'3y4y-di|yilr«pspii3:oisa'· 1 :::^ vl:l#KîXÿ^?i3H>fl!o2»4y<fcsô-3<44d^fsfc^!ft«}*solte-'Î.Ci2ï>î^>^sP^>«»i4fe®”J'^'asi)â^h5ijl8· lN;$uopame%|)sàox-$-MNfeô·^^ .Â.;|!^4>|Mttan^6-CMayOï^4y#a«5aï^%l}^xy^34'4~CS-;mei|^4,2^xÀ^k3^î^xÿ1|-·.. l^b^3,^iàydîX5^ii«sG^lk-lt20)-yî}p^Â8®-t^sfeâM«Éfdé :|:

No. 32": 4.-B"i4.-|{3<hlor<H)en:iyi}oxy]-y3ymo^oxybeo2y|*..7..BL:?yR:.-;!-42-ilxH>i«··!··

No. 321:4-!3~<:6-(3.5-dlchlox»ptes>%FÄr3->;tM^ ;; ilsoxo%4-'dibydjoipiH>a^oyo-lQH}'y]jp:i::xo-:dino->lycio-bs:iilohyyfc

No, 324:4-N'?'iltiôr<)-'îNi2'Bi!ôrO'l <&amp;oroaiethyl.k'tbyOxy NI-( | - ibrrnylpiperid«}···*· yt > -3,4•dioxo··!.4-dihyifc\^um&amp;xoifc3-3s 2H>yl, methyl &amp;ipb?ßy?-2-esa$x5aitrik. ν< 1 ' 1 1 - y1 y ο y 3 1 y -X ît'-OX Xi y)\'0\ ' y y y V 1 \ ' f y Ί X î 1' di!iyiSPNNis2b:ilS!·' 1 pilNyi ) piporiilsXi^lNMsiMdp^'Pe:::

No. 331,4- i ?·.0οοϊο··6·42 öooso·· 1 -{iRioxo.wiby1)sd50xyi--3 |(6-<3<-fiwoîOphôay0p^^3«ylj?ndiiy5! -3.-3 -yhoxo-ON 'dîhyiirixsuîssiol-n-l (3H.ryi ipipoddxsx- s -caxbaldchydc.

No. 332:3-(¾ >7röu.<>ro-a42· (luonx- M.fi«:>roï«e3h;yUc5hoK> )- H. ! - κ>πην{ρφ«Ηαάι·4-νΟ'~-4-^οχο« 1 A~ 4Γΐίν5ΐχ'<ί£ΐθ!.θίϊΐ:ο:όχ>3:2H 1-y! N>xcN:yl}p.V3'Klso-2~>4 pxisÎxeîîôi'ik' N?>. 33.3·: ! •(iluoKsmetbvI-^^xyj-'^^-dioxo-:^,^^ îs^ôiî^ïiiii- ? (3il) Ipîjï^ss^lâs«-

No. 334:4*{'3*Ûtok:-!" ^8iëiQ:Mtàfl)«ôio^ÿ|if»4-^^^3<4-<MhÿiÉ%^Âm4“î|2î^)~ÿ]l|Mpn4fei&amp;-|~é«s1)»tâ8^'âè:::'..

No, SM: N{/4iuörO'i>-i2“älij.<m>- Nfius>«>Hie{hy}>ciho\y)~.)-i4.ia?<>^)î>oü«'4“yiï««{hyÎ5benx>1i.2.4-f5l^)-'^i|pi|>erKSïâë-l''Carb3id<;.hyd<ï

No.; 33;6: 4'· {'?' äi)et!ios;y j>'2ÿ4-'d.iÎïÂô-'3-> > ; ; ÿ!|ïoe#i>^} o.4-düsyikos^âm0«OiN''i4âM}-'Vl}p^ôriiMo«-1 •'C^a^khvde \ '' ^ ^ ό ' L\ ' > Vslnw ' s '\ 'Ki *' Nn\>' ' ·* dlhydroquis-üiÄolis- ; (2H jppspondsoo- ä 'CorbaiôdxyUo...........

No. 3Mr 4N?-'8ooro;~882'-8ooro48':ü:oöt®!äKÄiy!}eip^^ J-^^ïlï^éro^Taîitt^o.imrl.iSlî^ÿÎÏ | 'Ho.. $ff': \Ί v t\ \>. » ' Λ 'κ 1 v κ "Ns<i' 'vn' * dsoxo-3N-dihvdfoqoh^£oL4> Ν^?.Ηκ>4: pj^nüôK^l-catbakk^Vik ....... ···· ..... ;<:

No. 348; 3ν(Ν&amp;3Οϊ£>·ο#4&amp;Ν?χΡ4!Νκ:>ϊοϊ:π0%1^^ N diNfe>p8^o!N^ < fe 34b3^M*$meies*^ ilioxod .2.3.4 ·ΐο^»Ιΐν4ϊί>οχο.οο:ί·θ11πο··7·«δΓ8θΒ5θ:! le N*. 342:: 4v[34445rö:8p>oopp?NNiöiö-H^^^

No. 343: 483· M4'i3.4--du;hi<:«;b:;n£y8oxy]N42- meihosyeîhosy}NoxyU--'?'iN<>:Ki-682-8xiOïo-'J·'

No. 344: 'Vnvh'OoUi'KKoko ju'KV'.'ipqvïiO.ne : \&amp;ri-.8N3Oo Νλ%· MS: ·44Ιχ«χ#«*8*>1:} 4:dl'5i)rî>*S-:|f ÂwsBéàÿlJdli^ * {2Epli%snd:N<;~ 1 OisrNdoeky# ; ; ;

Ns. 348; 443s {4~ipN''dNI8ô?oteîKyliSKyj:'-3-k2''8sisroe8îSKy|beîiKyN:-7^xieK>'H2-'5:N(5ïô-'N· :; Äo«5m«%i;«ÜJoxy)-2,4^iöXC^4^h>^^^ia'P«^Äpmd}a®»l^rbaWehydii

No. 358' 44.VN-k2'Ch!or(>4-'8a(,m8e!i£ylïoxyN3'OK;üâ<>xyix;!î£yU..?-Oo<>K;--443-8xiOK·· i ί3Νοη:οκ4>ν·ϊί4κ)χν|·2.4·4Κΐκο-3.4-<ο4νο~ο^4κοζοΙ!οΝ(2Η}'ν|;ρίρ«505ΐ·θ'θ<:;ιΓ8*]3εΐ>ν<1ο

No. 35Î: 4·[3-<4·s(2.4 •dkhîorobetuyJK'Xy!· 3-nä«tlK>syb»n«yij '7..ö;joro-0'i2'8uoro-i- ÄOKKO«diy8tiho£y]-2>dK?Ko3.4dd=yi}mquKB£oüo-H;:H}-y!jpipondii5o-ä<.ä8xd8ehyde

No. 353: .'î.;3.o4.:(3-chkïro-ôN]iKm>boo>:yho>:yjN'-:ne8Ko:yhen;':yU '?'8ï;oi'o-ô-Î.;';looa>-l·

Uov'Kooc4'o4v4v\xpN 8v\o \4 Jd:\vk-'qu'suvokn-U-88 >; P'^'.KhîK ä'0 NvooN Jo

No.353v44'3H44H2.6-dlchlorob«nayi>ox5'i-3“meU50syb<iiii:yiN7-ajciiX?-442-i3uore-i~ ^lte^meth>4}<:thoxv|«2s4'dbxo-3N^iHyd«>quxna20»o·» I ( 2n}*yî|i>jper!dm^t -c&amp;ifcBlitebyde

NoP84:44P:4.|fö<:tetObo!:s:yl}o:K:y!P-KMl^ ;; avOCOi'e:vvl\U.'xx;0.4-dw'Ndüi^ot'Vuavo'ΐί·\3Η) x.p'^vdw '* Ν' ί"' ' ' Λ 'Ν' * ' λ ί >λΟ 0' ΐ'ν ('Ν' 1' V\'tN' ' ' \ '' ' t!luom{a!?{byl)elfeox>J-2,4^bxo>3,4-d<KydK>qm8&amp;2o{«5* I (2KVy}]ptperid8M>> I -oarhaMehyde

Ni». 3^7: -5-{?^-ΐΊ«ί>ϊ<.'-ΐ'-[ -tsUOt<>-l I--ίΙ·- -y ?)v-2v4-4fe s«-· ϊ '1%. 35$. 4-15- {4-((3,4-d}cbbtophenoxy}tneAv1I-3-metbox.vb^2y^ *?»8ικκο>6>12~&amp;>ι>κ>' I « Ötevxaeihyl}<f{hoxv]-2,4'Ujo\0'3,4'dibydsoqumw>{in-ί(2H î-yipipeddioe- î <art»ajkkhyik $3&amp; 360.4· {?-0u«tx:-“Ö*i2'ÖyöK>“ I '{rt«iKomeâs>^}«th<5xyj-’A4*<üox«-3»f4“(2'ph««yl«lhÿO^<ïKy^^ lilf#!q«|^oîin”l{2H j-yS >ρφοη<Κ»ο· I -<58îb«!ikhyés Νο;.|$2/443Ν!4*{ί^3·(#;Μρ«Ν^||^^ ::

Na 3#:4"|3"|4»f(4<hil!ifopkx8&amp;^>md^ / ^ ί :Ιΐ:ίΐ;ϊ3Γΐ>ΐ53ί? iiît v l)ei: hiOS y J ' O ^:<} S ,.4 - -îli b v dîXïai îsîïâkô ? i;î î -1 ί 21Ï ) yl ::

No. 3?!: 4-i 3d-<h^:'ry'^224-cd;orobctay!Kixy}· N.ôîhoxyhe!XKy[| ·7··Π·Ν(Π>Νί2· fluoro-t- ::./1:- 1%. 3:23/4-p“{3';chioxo^4(2,4“dklkir<feïxy|«>xvj'5-^tafb«8zy!|~/-fluom-ëi2-'Biiô:ÎXï-i·' v '^.ΐΜ/^^'δ^^^Η^Ι^ΐΙ^οίοΙίδίϊ^ΗϊχχΙ-Ϊ-^&amp;οχ^ίΐΐε»!}···^^»^!«®^-!·« p^^s®^^lîe^x>|-%4^joxo-î,44^^^»t^«Ss“ïCfH)“^^^dâj«*1<at^ygî|yâ« ” 'Mo-$70! 4~ß'i^({X>äisMQmbm^i)<>x^}~^~m^xyhm£yi'i -l-âmm-^MÏmFOr·^';

No. 3??: 4-i/'(4- ([d^hkifô'ivCtrinuorooKïkïykbcnsyi'jcsy) 4--metk*ybe^yk-'?-'^^>n>6-{2--kiK>n>· 1 ·· Να 37§: 4:-'P-M:4-'[(3-'N:d:ôaphâi3ôxv|sâPîPÿ1|-'3-sâ^PsoKÿbe:s;Kj;ÎN”'ifei>SÎS''â:î-'P;dhiaô>:i:·' ί^Ϊ0' 3SÔ: 4 Î3~f4-fiis55--iiißsioridbesi^^i><xs 3--îït^Îb<ïx:^Î3iiï5Syl) :; (ftuoronKïihyDethoxy^'S^-üioxovk^dibydrwîu^aatsolia-t^Hhyljpipediibe-l-CÂtbaiàehyd«

No» 341:4'k3i^kfe®aïfkix.p'lNs^i30Nyfe^kâ|v7-iï«os:d'ë'-p4?doiÎi'I-4;ôaïr!3ô3«Éki}î4iaxÿ]'2,4' 's ' xWo'/> ' 3. ' '.ν' '· v c\ ' u’ orbN s m!

No. >82 4.p^4-Î(?-'3W^«'>-5'ntt<>roboti2y])oxy!-3-melboxybcÂiÂyU-7-ilaor)Î>~$v^%oiXîv|ï''.. (fiuon>ajeüiyUeiλ'xy]'2^iOxO'3v4vUjhyâtoq«ia8ZoIm“l<2Hî-yljpxporidj«e-i-«atb3{aohyde " ' No;'3$3'? 4>|.?-âüoro^'P.4feo^vl^ioroïô^hfi)ettoçyj-3*{3-t8«iisox>-4->[4' :kHIx»ïot5Ây^b8^yljoxy|be^l)/2A^^-^”^H>^^samUî^i'(2H}~yi;;pip«^ae-i-câîfesiâo1n!de;:·

Mov 3g4î ·4τβ* (44t2^iihbmbgt^l)oxÿ|-î^BÂ^teizyl ) ~7-i\mr^S^2^ovù~l-ÎSwmmÂy0etexÿi-2>4^t>xe'34^&amp;5îà^8mm»te-ÎC2E)->fjp$|$ed^er.l<4À!8âiefcyde-:

Mo. 3k5:: 4v4Î4“t{?”Sô<»^xP'^i}^:H^ÂÂ%#^teyi“'k<î'S%xÿ)|!ij^®^i3“4»y|ir^4^5!ôiS^~ll·«^ K^t^yî^-2^e#^t>îife«i3^bî3fe^'j*ÈSe^yl ) i-i·; V κ·> ' *< \ ' v t''n>- > LvîO'NvYlVb» \\ \ Ό 0' ~ 1 U v > i2noNï>..'tM ν.ΐαοΜΓίαΐ .'i'ae!ho\\pHcnoxyka<-ihU'NO.'N3'.-oOo V' k” ί * Ά ' ïlu»" v w"*.i «'.Jtsi'X'.K'wii ’ ikk'.\ itkîo ". TÜbvi#i 443r.:t44K3i4r$pÄorp|i^ ..· ^0- : 4^ 17 >iî^qri>v6^|‘2·'^? VM5S0'-'^flm>rvst^ethyl|^hos.y s-3 -' ·· Ne,. 39Ö:,^4^“-8w>KM"|^{(3Äo»>to^k*s-y|"3«»^is0x^%w^I)'^-t2“i«0Tö-'I·» |â^omd^>yl)ethosy;j/\4--aioxo~3,4"d%db<;i8.«iMig.oHR-H''H}-y]jpiperidîS3<î-î-caïb8i<îehydê;· :

No:, 491; 4-ρ-·!4ί-|0^dMtuorobsaxy^Â^-S-meéiOXÿij^yîi-^im^eH^p^Iïfâîïÿ«·?--:

No. .392:o4*l3-fl4$j6K&amp;^ö»Hirfe«im&amp;kml-i*y!>3-meite^enzy!|>?*{l\äor0^*|2*fiöoro>i“:. paof«si>iÜjy!)«:Éasyf-£ÿ4-45C!se-3,4^âmlto{|MmâK0Îfe-l:pSï'-yI|pâp«ridiik;N~csib«klsj5ÿàe

Kfô.»^4<];T-¾orß^l-fi«ofOr¾i|ίlwrö^%i>Ä^x^r^(^&amp;ί«y^P5P«r^^»^*'^¾,·2¾^dt0χo..tf4« dife3^oq«sa»KoHs-3(2M;)»yi}'mie:&amp;y^hôa>i3ÿ4^ch]ôrol^ô2mesiîlpl>0Sât<î

Na. 394'y44ff-imo^i2^aôf^ï^S{^»e%â)ste^H^^mylpipÉ^^ïi-4~y{>2%4.-dti>x<>4#*··

No. 403: SN-dfehkoo^ ïddaorosaNfeylleslkNyj^^^ :i-4-si.ostk.ï.»4-5î!iÎ\ J’ \|î!snoiOïÎii y.!!!' tSpe'wV.Π - e oîÎî">N!'â'fîs\IÎN'ni<iïînO<.

Thé eoaspoersdx m acv-ciâaoce wish ifee iaveaùots c«u t>e preparers by the methods dismasted m she .¾%¾¾½ $cl?S5i^' 1Ί8.4<..... :ίό tksa whleli: hnlewS; £he sems 'lesryissg grpopT sa sKsdersaobd Io saesse a gs$l»p -«-teà. ca» fcg -family: eubsdiyiod, with depisrsps'e <sf. «tu elechosr pair, 'by ekayage et ai hetetply&amp;P basil Ilos groap ysu thus oo sssstsy rëpî&amp;eed by.setter grosip.,..for exasxgle dards# *ä bufesrshstsbsr reswhsxs. Sport iesyissg g:sm*pa a«,, tor axssaole, hsds>|«as or sa isibyatesihybsoxyi ..groups sssbls sss s rssesyhsssy lohyNso. sssisiste, sähst sise sites. axsihlfskss et ieàvsrsg gtoaps sai^le^aoosJbr thesr pfgpsï^s^:arogjvou m''AdvanSéts ilïgasâc o sseaassry . .>. Ni^ao. ,>îo oeitws!

Wiley iakrscseace. pp. 310-316.

The terra "prosecsive groap Pi?' Is sradesalossd so rsressst s gwup '"' ^îï:;^ -s ** P^îbse to preveis? Sise ;, ov <. i x .·.« vS\ o % s\ ' >\ s\octon 3j>v o vh..s" e . v k.\ a " '' 1 ^ '5< 'v u ' ' v° Çs rsiolçehlé aller cleavage sceosteiagta aasdstxb kaewa tsr a pats» ûlMs4: &amp; üR' ars ;;

The tea Nsssrptss'ssry pj'Oîsseîiv-e group for ammsssior a&amp;e&amp;ha&amp;r ^ te^tatôod so w^aa the: ppascbys groups; assois as iwsse described irr iPsotecitee Grsstsp mlOtgShfc Sysrthesss, tareeee id&amp;..:à&amp;*y%t»r*. P.G..*«.,. psiblisteai by Wiley laséséciéoees. 1994, ssstd tePsotecthsg Otroaps. Koeser»«^ è~t., sNsî-x, G<e*».g i >**«*»«Λ «%,

Meatiôsr sassy fee s«s-fer esrssaplw of ksaporssry psoWehve gs^ps lar ansnsev (Sucb as ^tepÂayl. de^abk xsî kts seid lÄdlassw ot beoeyteyc^oyL cleavabfe by:: :: i:: ;:: feyérogeooîym), tenspeataiy prosecsive gâxx:p>> ibr aatboxybo «e>o.s:· 4^·^. ^Sv*VAl ewshyi or eûsy] or sors-baSy! esters which esta be hydrolysed m a <’r ;îcid ;ncddiîn) ^ mtmm- P«>tecave groups kr alcohols or glseaols. such as kirdsydrswswsyh o ^:î*«âaasÿl hwo 'N v\\K kohiK such as runopk, Λ ovuv* e > ' ^ v v ' άι*^ ^ 'Λϊ' made to the veU known general methods described m Protective Οκ»φκ,.α$β above. \p i\ S*3tk 1 i \It ' <, i h >N «0 \ 'V 'V 'ÇjJfvPfJvsiV p.v.wt.'.v .te-v'v-PS Λνλ>—g

5>> ihc oisetrntstssAces. The compounds of fbstmiis: si) ran eonsprsse precursor groups us- o-A»,r here n ovo y.swpN u4k,h ass generated subsequently in one or mote other stage«. M &amp;e general sytAelic schemes *vl»ç!fe -ths: staitnsg cosropount» ;md soe pAndurns, vuoe.n met? nsetod of preparation is τ··μ described. are ctntunerct&amp;Uy available or are oescribcd iß dit »nvtamre Os oisc c<*&amp;. he prepared according; to srwthods which ère deSprthed thereto or whiets; are iqspwts to a pe;:q>srskn;C<i amas Si h ihe pure cn&amp;ntionaera of the compounds in accordant weh she tnveniw can be obtained irota •u8®«d<wwB8tiy:;pm>p$ew^i>n'<w:'igte'bgçbSnâipiwe:nhmmaip^8pàx<*r«ÎS8»:'wbmW'Wr$|!ioum8 6<>mpn86:: seid or ankae hatciiouai groups. by »elective erystalfeutiosiS of diastereossosnenc sato· ootaitseo ay reaction os the pompostpd» .φ with .«tod andhes or chiral acids. respectively ; : : : :

The compounds: of general ibitnulh (¾ cm be obtained sseeontspg to ihs: following. Schemes 1: so 4. vist; of oosee®: for darky, tho R* group: has: been chosen m teeksg: H hydrogen, g aod py reprcee^: i. add 2 respectively aod the R> and R> groups have been set; as isKhcaksi its the se hemes. However, si u> so sse tiSkserateOd Oust tw esht ho as defined fo the general fxmm}&amp; (ip thaï 1¾ aral %. m.imc M posimm fodiesied he the. general lomosk (H apd font p stsd p’ can be as defined is the gerraral forspsdn (1).

The synthetic routes describedbelow sesye solely as illustration and are weder so satctntsstissces lisssitag, 4 pesyon shilled fo the sat easy apply s4Pa>ui: 4sioc«lty ike teaeisasg beksw to tb«: etusposstst» et torstmta (.11 :ior wiueh Is I*.,.K-.t, Ra,li, Jp·,: ?#,. tf p? p' -mé$ are as ikbswd is ibs gestersi ihmtits H).

AceoMiog to Sehessw i, site costspissttlofikosuls (IV) is optsdsed by a mlapivo atubssdos rAs by seaotiîta a iîotsptsHïd olibtatrak ill}:, hr which I;s represettls a aikyi: grorsp md·. Rj is as skitoesl: ior sho essssspoustd of tenu!» |l) with a etsopsusdiof tortstuls (!0|) hr ats acid tstedtsosi a-sd io the preseoee of a sesfueasg aaetst. sueh: ;sa sodtsstsv tstsseetoxybssjohydrsde. The Rt.s grotsp of fc oosppoood of Rir-tspist (HI) is a proteOtive aststsi for i&amp;e mtim· thssetsost&amp;t gtosqs which rosy ad%«»tageously he ierf4kttosye;tr|K0tyi: (hoeT: The eotspbsrcsd: rsf Mmdä (W$ ihsrs &amp;mmê·. h ssdweqsossfy aeyiai;edS: acsxstdissg so roeshods weh ktsos-ts: iw a pethOh SMiiod ist die ars, with as.alkyf or aryl ehkwfoiraate to gfye she: eohtpisdtid: of fostsA: :<V> tst which if5 ropreseota s :i€v-€fd a-I^ gtosp or Sts aryl gsosp which: is substituted. Ä hydrolysis resshoH: in a hasse tsieshum makes it possible its obisls the cossipsrsHtds of ibrtsuJa (¥1) whieh^by a esrupilKg ttisehoa wÄa:pö«^öUs*d oflbonA;..... = V3IK hr which hi is as defisted fe the eostpscuad of fotnreia (i).; s'esults is the cossposrads of fonstsda (VfH). As;s sstratssofeetdar epi:i«iuiow :teasiios; in the hasto medsuos ssake? if possihie so oblsisr dss spthraxidirsedboe derivahves of fornsulatiX}. The protecswe grossp PCt for she serene ihssctsosssl gnrap is sahseq-icsstsy ö:feaeed,: ibr essatssfe to: aehf rö^dÄ whep..RG is a hoc, to givedhe eosttpotsstds of ibratulss fia) wbleh give, by ass sseykiiost reaction, rise cesupoceeis of torsrsuhi sib}. the'compound's offet&amp;uîà (Ta) as« cotnposrad« of iontstiia si) änd esth act as sPiemsedsssie Rsr odtef ÿ cotsrpouhds of Tèrmüis φ esn h ssa the costsptwstdaof fastuia tsbh

Sehern« î

The compounds of formais- (!) for «Äh R;;· represents -ÜRa, Ra being: as defined for the compound of formula (i), correspond to the Immola (RI), Thsy can be obtained to?» the compounds of formula (X) according to the fallowing Sehern« 2:, The -compounds of formula fie), obtained i>y a hydrogenolysls reaetxm on the smspounda of fennels (X), are sabieeled, for example, to m alhyisbot; resents; with art alkylating agent of type Rs~X, in winch .¾ its as dsfofod lor the compound of formula (I) and X represents a leaving group (such as a 'halogen atom, tor example), in ihn presence of a base, such as caesium carbonate (CsjCO;), or also to a Mibfo&amp;ofeu reaction (Synthesis, I9fl, with an alcohol of type RaT):H.: St; being as defined: for the compound of Ibrnmia (f)> to give compounds of formais (Id), lbs .«mnpouiKte of fortottk (X) and fits compounds pf formula (let are contpotunh, of fomuna (1) and cart hot as intermediate tor other eompouuds of formulai?'), »seit as the contpounds- of formais (M).

Sehern« 2

Alternatively» the eompoumls <>:f tbrsnsbss (Id) cm be obitensdi by Ibtowssg tbe pmeedurs: dbsenbed m Schemed...............

The cotntxsnnds of Îbemnls (Xk) are obtained by a ns.sâcophibe aromatic sobstsPstsoo reaction involving a compound of formula (Xï%. in which W is ns dofmsd above, am! an alcohol cftyirc fla-Off, in which ils k an defined for she cosnpogad -of Commis (I), in the presence efa base,. The sednetioo of the eitro group of the compounds s>f fbrmsba (XII) sesults in the eosaespoixtlng aolkoo derivatives (XIII), A reductive amirntiien reaction with: a cosopomsd of formula (IM), in which PCI iss a protective group for amibe functional grosses, sssoh ns. for example, bec, resnits in the eourposmds of fossntda (XIV), The compounds of ibsamsia (XV) are obtained hy rcaerioo of a emnpouob of fentnia (XIV) whit polassiem Isocyanaic (KVCO) io an seid medium, An hstsmsmiecular cycilvalion reaction In a basic medium snakes it possible to obtain the compounds of formula (XVI), The psxsteetive grostp 1X5 Is cleaved by methods· web knows* to a getsost skilled in she art to give the compounds of Ibsssmla tXVilr An: acylation reaction· results In the compounds of fennsik (XVII ip Finally, the cosspouods of Ibsen ala (Id) seat obtamed either by sst alkyhsthm reach on will; a derivative of Type (XIX), so svbicb X repseserss a leaving group, such as a halogen alom, in she presesce of a base, such as, tor example, caesium carbonate, nr also by a Milstmobts reaction wsth a benvyl stlcohol of type (XX), 1st the cosnpoonds XIX) smd (XX), R;: is as defined above.

Scheme 3

The c«8poönds so ähron-la (¾) surd (if), m which R>. mom pardetdarly represents a group of type-CIR-NBC(0}Rh, Rb Oeing defined a;; in she sro-npo-nsd of fonrruia (I), esss bo prepared; according to the fhlowhsg Reisen·« 4. I): is understood that. in Schemas 3,. the Re group illustrated is of -Q-Bh type ansi is is the 6 positisss of she quisoaroh-teslios'e sSnscsare (see, tor exasopk. eotnpnstnd. (XVifi)} but that it is also possible to have a second R:j grosso, as statlned in the general Rsrtoela (In hr the 7 position of She sasoe qaisssrolkcdissae grosjp. rh« tedueho« of Ïhs? sskre φ*®ρ coispoasds <sf type iXX?}, io which &amp;' sad PG' ate as defined aixae, (he i\V aro\:p ad\&amp;otagco»*ly be?ag hoe. seauhs m the eonrsspooding axidino derhudwa ( XXH) *«κ&amp; hy s reduce aaknsnoa reacsion is which ibey rescî in 8» acid asedixoss and advaasageowdy in the presence of a rsihîCîSf agshfe. sods tiiacfeiesyho^phyifiifc, Wish à mmpomâ of fonaÀ (¾¾¾ which F8 repsésesieà tewylöxycarfäoayl pnhschvs ^oup ihr assises, -pm zmip&amp;mik »F femada :(X.X.ffl$, » scytaös rsachen wish sa aJkyi hr sryt ddmofôîmaîs, i&amp; which F.” xogs-esostiSs a (Qf-Cg) aikyl gfofcf of sa ssyi podp wisich is sabsdnshsd, sesoha in she oosopmaids oFibmidis (XKPÜ). Ile ^dsssxoiisssxboae IWlogxies of feel», DfXVj can fee-ohiaMed by s hydà>iysfe siswiios is a basic sseilhah assd iisss hy a cbephssg cföscisbSi w'ihs a coaspsatad of fonfcofe (Viig is which Rs &amp; M deÜaed ihr Che cassspaasd of ibmoia iff Mloiw-csi hy satin isPasiWfecdaf cysaksSioa ceaasioa .¾ a basal sped hi Pi. ?1xe 'f® * gshsih l|s; feshiy a hoc) iis s ahccgpyaSiy claavyd y iss as acht bsööhdw Φ «i m the cpn^oishls of fern#. (Xl'Vl) which, hy aeyhhna, give «psgsosssds of ;;;; tesfe (XXVlIh ih: hdhch: Rb if a* dsiacd $m she: costpouad: of tbrasak fl). The F8 proseotivs g!‘e«i>.of ...,: (XXVH; is ctested by a hydrogenolysjs .seastips to give :i|tç Oftoiföwfe H«% Ä« ·>Γ knock 00 ·*** okenseo hy an avykkoo reaction oa me c<ysnpoa:s«is of ionrud« (kl

Seheose 4

h is obvioxs Chat s perso» skilled1st - he an will he tx a positiets: » efeoose, is the light «f his·.kaotsktdg®. and she literature« other appropriate protective groups which sxeke possible the introdnchoa of ail the vitro« described la the general fonsuJs (I),

When the cotopoossd of ibrtnxia (!) eoosprises a bridged: ring, it cas be obtained wlthoot distinction: by tine of fne synthetic ernstes described: above.

The ioiiowhsg procedures xed examples bsserthe the preparation of sotrte eonspouods is aceotxkne« with site hsYesrtiott, Tlsese procedures and etatntples are stet hxbtiag s»d verve ortly to iiksxirats the presets: hsvexbox.

Is the ptooedtirex and e\aotpN>: below: - îké ssass j*pecim are produmjl oo a $*aâr*t$ot* sj&amp;x:àr»meter of Platform LC'Z t>ps (Waters) ou of ZQ 4000 sîw (WatesM ia positive eiactrosgsev soiàsâttoa oeode; - the NMR (Stieles»' rssgaetis sesosaacs) spectra ass produced ott. a Footer transform spect-oateser (feite) si a esopesauae of ieöCdC (exotwtsgsahio protosts stet seeoeded); - s fi Anglet - d~ diXiblstv - as ~ etudiigld, - hebroad sdgsai t::: triples, - q ---- tastete· - l>MSÖ'iiv: destessted dhrtethyl StdpihOxide., ·> CÖCI;? - deofcratad citloiolibta·. l'lte ittixhtsas of soilvesss see qasatifêed is volaseteifio sattes.

Ilse NMR. spectra sssd muss- spectra cosdsna the structates of the œïïspùiœâa obtained aocordissg to the exatap tes be lost··. let the exatapies, whticfe feftotv, the .fotloodsta abosaviatsosts are tssed: ACM: aeetoaxtnte AcOBt: ethyl acetate AcOFk acetic acid DEO: lJMtasiâl>tevclo(5,4.0]tii5deç-?-eîse DCM; diddosatxtethase DCE: f,2~didskstoedtaae BI.AD: slitsopesepxl aetidîcasEoxyïate DIEA; dikopiXîpÿiaîïiHte DMF: NM-dlïseilïsdferiïKâtaîide:

EtOH; vtaaool IISTF;; Ö-(tesxoitiaxol- Ε νΙχΜ.Ν.ΝΑΝ' ΟοΙκϊΐοοΐΕνΙοΐο-Εοίο bessfhxtroghosphaie IBCf. oobstyt ehtoatf esesate MeOH; axethsxte!

NaBflfOAc);: sodiata tdacettixÿDOtsshvtlesde AT: asshiost teatpesasose seta: chaise fits?; Setrtthydro&amp;tast

Nls-e ttedevlstrtbse: TFA: tsiiitioroaeetse acid

The foHowiog examples describe the préparas»»· of soxsse compotmds P? accordance with the sovenhori. These shasspies are not Isrssiiissg and serve only to illustrate the pmsent ksvemion. 11s; »«mherrof the compounds m the exasstples refcrto those gives la the tshl&amp;helow,. itt wniel· the eiiextsieai stnsetom apt! she physical properties of a lew emspomtife la nceordassc« with the isreenfou ere illustrated, h ' ®'XAMPLE:'!tC«mp»«»iM-0^ ::

Ptasparasfes of tp--(S<4-tltsiHhh<ssyhe55t:>r5'hti-rto'to,v^p^^h5hlh“4'yfh24-'dfos:o·-! >2,3,4»· •teÂhyôroqeiaazoIlR-é-yllasy^aeetotiitriie

1S1 -tôissefhyfelhyi :

A mixture of 2 g of ssrefeyt 2-omfeo--S-<besrt:;yli>s>^^ösfef : 3. î. T of U-dnnethyieiby! 4-ό^η|Χ·η<ΐ«^1··ο^ν<>hae «ad 3.29 g of NnBSföAes, en 10 mi os AcOH * «wdxaed ander a microwave «d (Biotsge Initistot Sisty) at 1 i^CAA' 20 .mho The mm reaction ss repeassts «tits* lots of 2 g ot 3sefhyt

The shme rcmÈmmM^m iotSn^ The zom®mä.pmäm te taken up 1« AeOa The organic phase ls ^feed *ôfe HH,Cl soiofem end with a saturéMaHCO> eofeüott, dried over H&amp;jSO, asc filtered, sxtd the solved As evaporated ooder redticeo ;>masore. the restitue ;s ehrotnnmgtitpkid on silica ^ ArOBmeptane sdxmm, (3/95, wv) es far as ;; (ddrT&amp;vAôÀo give I(lslghf'0se:;«spdc^i?BÄ^ :

Kl ~l>isueth> ktk> I 4“U fox> V i-y&amp;sethunearforoybpkesyi Ü<2'-roesh> i- prepoxÿO^&amp;ôftyUstBhiôlpîperMïHihd-earbwxviâSe

A mixture ef 2 g of L\-4l»tsedîyfeshyÈ 4- U4^bes^}oxy)«2Hmethc^yc8iteiyî> p?kawl];mrbss^ obUHsed tîs stage ΙΛ.> 0.87 mi oi DiEA, 1.78 «si of 1BCF sad I § o?

NsOH io 10 Μ of ΪΧΈ Is irfadi&amp;O wOarstmkr^wsive Seid at S0*C for 30 sa, The same roactfoss as mpeaied wîîîï 4 obset lots of 2-4 «f ί . { 1 msrbtayfose. Π-e S retarde« -midis tiro «ssîsbmed. lie comsisad product is kies up is AcOEi sod driered, tuid sise Etiras? is evaportssed ussder seduced pressure. lie residue ss ehretÄogrspheäo« isi&amp;akf^ «tsÄö .Wat issued osai with au AcOËt/hcptane mixture, i S 0/90, v/v) as for as (50/50, v/y). so give 9.3 g of the expected product ::: ................ ............ .......... dygiM-

Sedksm sek of S-dbeuxpksxyfo2.-{{l4(1 J -dltsethy tether sea rinse* IHripmdi«*4~>i}|(2·· tsusibsdpropoxyiemiossvljumimObeuxtbe add

A mixsus-c of 9.3 g os" icl-dikkhyktisji :4¾^^ ma^vferopoxy)«3rfH?nyl]«mjno?pjpendme-i-caii>oxy{ato obtained iu ssige l » an<* ·α·4 oä NaUit tss 4O'j$s| <»f MeOH is heated at lOO'C for 3h Ο » κ v. *t u ό s >· ^ ' » \ »* v ^ sv<v s ^ N* addrxi. Dsys.tsg is earned out over NtrfoO,. Ehnkfou is carried out aad the solveat is evaporated saidcr reduced pressure so give 0. /g os rue wspecipo prodsu.:. SMe* j .-4-. fte^«kîxyçsrNi.8yî>amîfKsiplpmA^I‘-csrbs>syls«ie

 tnixinre; <4' 6g of sxsarts ssii ci 5dhertKy3oxv}4f-({i d{I JxkïOôk^ykÙ!Osy}c;xoosyi]|Âoddi8-'4·' y] < [{:^:üχ;ihj^lpjo'x&amp;yKoàdK>îïy] |;5ϊΒ ΐ·ϊ.<ΐ>?χαΐ;<-:ΐ«ΐ: &amp;i:kl obtained b stage 3.3 atsd 4.42 g of DIE A in 250 «ή of DMF is stirred at AI for 15 stsirt. 6.4$ g of ICETüsr« added and fe nïtsttne is k:fi stirring A«· 30 snits. 2.4B g of Yersiryitsttiae are added attd the reaettet? tnkMe is stirred 1er 4¾ 00, it is öxpomkd under tedvated pressure, the residue is Msn as 5« AcOEt, washed with a saturated NHd'.d «olstic-n sud wii a satumed NaMG% ssiutkss:, dried suer 2¾¾¾ sad Ottered. stud iîte solventes evapïsuteü under reduced .pressure. The residue ta ehronmto^èedm-s&amp;s'iei, sMiutr being: carried nut with at? AeOB/ktptssse snlxiura, tikkfh dy) as (a? as (60.40, v/vj, to gke 2J:go? expested product. 14^Ι^Μ*>&amp;Ιβ>4 44|^(Ni^llö#)^f|(vlHiiin«tiioxyi»e«3syl^2,4~iUoxo^4-Äy4r^ötoÄÄ" î42HK#l'^p!Ât!Nî^boxyiat«

A mixttae of 2,5g of Eixiitoethyletityi d^^^benzvioxy^^-IO.A-^rnxtihox^KiaxyiVarfia^yM·· psspy]itisohutasye&amp;rboî?yi;sÎî?i>x?]p!per:dïrïe··! -carboxylase obtained it? stage 3.4 and A4 g of N&amp;OH in J8.5 m3 of £)C£ is ttradtated under a ntiorowave Odd at. Ü0sC for 30 ttstt?. The same reaction is repeated with 2 oi8<5f Ms of 2.5 g of Ekdintethykthy; 4.(;4-(b«;oxyioxy^2di j^-dtmet'soxybsmzylX'astbarnoyllph1·'^^' &amp;-réà;tim Übdia &amp;f«s'fco-isdbtââïïâi·3%e çimbim&amp;^aé^ot is i&amp;ta s:|ï:;u5 DCMj: dried over jk&amp;)0Ù£m4 dfeed, aâddlrd solvsbt W. j^|tâ&amp;ted kÉJet:. tpäpföbdptSSdidtü giydéJ g df«:Kpôpf pxPsei 1 f SâSSJLâ: ^Iksxyloxyy^a^âaeth^besxyl)-! nipi^Hdifi^yl^siuaxoUae'S^C iH,3H>di<Hie

A tsix&amp;iï of 3.5 g of äJ-diinoihylethyi 4-[ö-(bcä5syimy)~3-i3v4'di:erethoxysOs-5Äffis}~2,4“iäKSSiK3oi' iîÎh^ïoq^fiiïa^olè^'dCSl^Hÿ^pspeifâdinsî- l^castaxyMe o&amp;tassed m Steg« :! .5 s«d 25 sd orTF A rs ôd ïM ®f .OCM is sboed ;R AT for 2¾ dû. Tisse obScbu'e is oeotr&amp;liissi with K>COv h is dl-ercd asaf the bSïniSe -s evaposanx· oMér rbdsssd ptessdsoi fh« residse is iatai dp sd D€M asd vmsissd Ä â saSiïd HâlKXA soiabos asd ita; widi iiïî t% bisCH soiii-kïS. The sdhttea is dried osér PbS€% add Eiterest ssd tde soteeRi rs evsposybest Rsder wà&amp;$é :^ssüîp ta 'givo:"2L§? g of ihi§s e&amp;pmeà posted

SigsâUï ^'HBsa^lexy^^^'dimeih^syfeon/Nn M Alum»'M'dtf»?*(2*ΙΗ%*Ρ«*·Β*“*~ cwMtàztwi*

\ οονο- ο» dog λ,' ^(«ΛΚΛί' ^iÄed id 1.7 mM.I13 g oi attOBOiuum fotrnes« is S nüofACN is irradiated trader a tntsrowsv« tkld at i 4QX ïm Ih 00. The mlxiura is fil»««* and the Stete k evaporated «Mer reste# $mm-iö gis® 5):.52 :g of feaxpected predasf :: f :. Straft-lS: Compatît! rNe< 5: «*Ι«ιΙγ*»\\*2,·^»ϊΙ«χ·^Ϊ«4-<ϋ6·3?·#<κ}»Ι»4!*·©Ιϊ»4.(2·Ην5)|μ^ρΜ·ίά«\«> î~ earbsddebyde

A «nature of 0.618 g of ^4^>roenxyk>xy)0^5,4^meth<>xv!>cia;yl)»2^-<liox(>-3.4-dö{y(}rä^Äs^lia^:: U2H)-Yl|^n<ih\e>i-c&amp;rt>âWcbytie Stated m sbgs 1.7. 0.44 g of atimstskitït. fertsase sed 0J24 g of Fd?€: (U?%) ra U; ml of HOH purged betssrsfiasd «dit tùirogee is irradiated eader a œââxswave psii aï WO. te ;>i; 00. Tfta «ùsUure is tlfesb and sis? fi strate is evajxsraksi under reduced pressure so give ¢.5:13 g of Sis? espec-ed pnxluet.

Stage 1,9; Comtmmd 5½. 6

Yi|axy}-aiß»töaitHle · ·

0.|7 g <ii4-'{;y-43vf''?iis»sii0osÿo0?i4>3:^;6--fwdîvsÿ--2ei<06s^ï--8^4::liihyôî?i?guÎssKo|jS'4(2ïii-'Yi'|sip4âSîdàs;-' l^stbaJdehyds obtained iß stage ι 8 and 0 i:5 g of Os*CO< xn i sal ot DKH are stirred for )5 min at A T 0.0$6 s of bros5S5aceSsSkn|e la added atsd 8¾¾ reaction axktute is sxtbvstp«s»U> irradiated varier a xmcrvwave f»dd at lOO^Cibs Î5mm, Ids Mteteb ami evaporated under reduced pressure the residue is cbrosnategtaplicd-oa .sliica get, elutkes befeg caaied oat with m kleOH DCM mtaturts i }#o, c-’v) as Sat «s «4/96. r v>, to give 0.112 r of the expected product, i CXAMKTlg &amp; Cousppntsd No. 8

FfeimsÄs 0 f P#«aeetyi|tipnditä^-yi}^”(3^-dä5stetbesyljessyTk2: j.di0so~i .23,4k ϊ#ΪΤ8&amp;ν0ί«φΐΙ«83®8Ϊ01>Φ3#ΟΧγ*ί«<Ϊ^'»ΜΪΓΐί»

$j-Aeeislpspeddj«~4~yiMMjbesiyUmKt-(.M -«Hmpthexybe»?v0*|sthuaoU?re~2d?i&amp;A/f)~dhto«

ο. 14 j£ of aceiys chloride is added to 3 mixture et 0,6 g of §-fbenxytoxyM*t3öMmiethox>^»f ?>·*- oîMaiued; scsîOîdmg » spjge !-# § #f MEk in lü ml vt DC M axïDd to tr€. The mixture is sumtd »? AT overnight. U is washed twit® «-ids « saturated NH*€i solution »ad tfluaed, aod tte the δ Urne is evaporaei ttsd«? tedöced pressure to give 0.64 g of the expected product,

Stage 22*. Corapottud No. l I .< l-Aeetyipiper&amp;ß»“4*yI)-5“{3N4‘dii»eth«>xyh«a*yl}-6«hydrexytj1i*{»sxoUne~2»4<3t.i>dH^iva®

troxture of 0,64 g of ;·? i-aeetylpiixsidin-T-ylTd-^ru^loxyVM^Khmethoxyix^xytxpunsaotiue-'-»Ή . ' t tjt di\.>Av îv4 ϊα \t χχ l ·.> -M g v'' » 'W'l ? '" 'ut, to » \ ‘v « h » v r s ' iä' 008 purged helbrehaad %j?iyfditog:eh is irtoditoed Ptotot; à ttoerewave iisM at dtf'C tor eh oix Ihe oaxo-xy i»i: ttoeted. tux? the filtrate- is evaporated utiderreduced-psreswe to give 0.4S g oi toe expecteo prouucf.

Stags jL3; 3 ylloxviacsioastrSils

ÛA2 g; öf elstaiued i» surge 2:.3 and (h ! 73! g of Cs^OÖ&amp; bi 3'îôl of BStf ats Stirnjil ior !Si?j|a at .&amp;f>...ô<03t ig of 'fert&amp;äg^MlMle is added and die reaction nuxtore is subsequently smdtated under a «acroxvave field ai löO*C far IS .«si». it is filtered aod ähr: filtra-e is evaporated »oder reduced pressure. The residue is dutuxaitographeg sas. Silk:® gel, ekuxori being named ont with aa MeOii/iXÀI tnixtur«. (\t,(*% v/vs as far as !4/<kk v/vg to give dvûg4 g::of the expected product. E JCAMFiiE 3-, Campewad M». 34

Synthesis of 4*{3'<4-chlor«be»*ylHK242-'difta«r«*tis»>xy.l“2>4*di0Kd»3>4~dihydrequiaaxoS«*1..(iiS^ fd|pâf>sr.idbïe-l-earbayeisyde

Stage 3.1;

Metbÿï 5A2s2'<Sillnardet}K>x5;T^v»dr«Se!Eia«ïï:fe

S.53 g cf il.e-diftnoroelfanoi are added to a soiutiou of 17.31 § of ïxvsA&amp;y* ..···*.u^ck..ai~ «h· wv·, T.S4 g of N£t} and 32.71 g of '2,8%9-tr«s«^}ntYl"2.5.8(9-{S5raa'ia-l-phosphabsoyciop. >.3j«»«»vv.ar.e Û. N a^..? îîÎvsi^f iyiiïfi'îi.'d ^r\v^SijXts anhydrous THF. The liste A stirred at AT for 30 miu, The soleesd at evapor;»'--'- - · : ' · · - Wüsif is added sud extradioa ts carried oat with AcQEt 'The extract is washed with a INaqaeous HCI sohmot·, wit)) waist and the« with a xmmsted N«€! soTuHok. it is dried over MgSO.; and filtered, aod the soivetd : ts: evaporated under reduced pressure to give ? î g of die expected product. SSä&amp;tM;

Methyl 2>smiBi^5'<3«2>dif1u«m>thoxy>be»zoate

e ' o v χ ' \ 't y -, 'tioxO ' i\K' \v ' tOx ' md 1 \i mixture of300 ml of AcOEu 50 ml of'EtOH aad 5 -re of AcOTT are stiired at AT coder a hydrogen aduospitore: for24h00.

The sosn.c^ îs fit-a \. sod c\ spaced ooJxt ' educed presse re tö give 1406 g; of the expec ted prodsci· &amp;m2â* I,i~i>i««*fh?teth?i 4-{(4~{2>2*dxna0!roetfeoxj?}->2~(8aeth«>xyearb»tiyi)phe«yJ|*«diK>)pipeddiee'l-: etmhtmyiste . .....

.A ttsim-pre of 4 g of methyl Z-ww«··?·-^-diduotoetbex>}bens&amp;wue atid o.$8 g of ]?]-dlmcihy1ethyl 4'-o.id!pipdrsdiae~\-éüÉrhjfeyiaid'ÄÄedΜ'stage %ϊ m l5imliof AeOH is itemed at 9fA£ :i*r lO tmo, It is allowed to «tool to ÀÎ ttsd 7.3' $ of ^ÉIi(OAc)a ore added!' Tim xshsprse is led staAag si AT for Oh tfe it is extracted ^ ;tsx AeOEt arid me extract is a.:»hed o im e, xamrased K :CO; soktiioo and then wtth water, it is dried sreer Msßi.h. fdtered ami evaporated under reduced: pressoreLip give d,|3 g of the e x pec ted prod ac t, SäM: i,14>is«ethyky5hyi 4v^esrhatR0yif4'(:2?2'«Mlt8orm.dhosy^24os.ethoyyesrhos>yi)- pfeiyilamlsolpipesidsrse^lrearhttxyitrie

1 JS g of potassium isocysoate is Ädos: of 4 œ{ of water are added to a solum« of 6.63 g of i.t ditaetttylethy) *· i H *{2.2*djßuo«^tey^H[s»S!t]\oxycärf)<my%k®v1} «mino ) piperidüsM-carboxylate <à:suncd in stare \3 sn 40 tal of AcOH. The mixtiwe h sdnedatAT for !2h 00 OJsextracted with ΛοΟΕι.sad. tS« dadact: js washed with: amnsated· soiudöst a&amp;d ides with, waierf it ss #ted «*β! ^S#P*<· blteres aod wàpoftiied-w^' &amp;àitkdpï&amp;&amp;fe tô gÄ&amp;$S g #thé expected pré&amp;scï.::::·· I,f-ffia4kbyle&amp;j4 4-ΉΗ*-2 JfSlä«ri®thosy)'2s4-'diox«--3,4-ds!iydroqo«WO^»“l|2f?)-yl|päferi<lpe'· ;Î-<«sr&amp;«x!!ïlat8i

2: j g of :!ΐ:6#8ΐο0!)?ί®ΐ6ν1 sSäiso Ipiperidiae-' lisesjfesÿis^ obôtiïied m stage 3,4 so sglstioSs ssi: a àdsbxte of ft? mû «t dteaite &amp;«d 5 sd of s IM aqueous NaOH aoiidton am irradiated uttder a microwave field st i3ü’'C fox 30 tsuxs. Mmmüon « carried oat wéh AcOEt: aad da- sxt.xaa ia oeuîndbcd a-dh a IM aqueous HCl soktdoxt, abshed wsds wa;ar, dried o:«*ï MgSO*.· iîtered and evaporated tradenredi&amp;ed pmsssd;. The tesidsife obuixtedds, irôvrated is mx AcOi-f peatane mixture ta give Ose expected psôdust The sàs&amp;ë imsedod is repoAktped odlk 2 obier ids «h 23 g wf ; fdxT. dktwthyi ethyl 4-Ma?Jaî3^yH4a'2J. diOuoroeOsoâyî-;Mfmeîkv\;vcarhor.yr?p]s<;îsyOj&amp;iosooM>iîxaidioc-d · carboxykte obsaixted m stage 3,4 to give, in totst. 5 63 g. of expected product. iK2'Jvt>tO5torvKdhox>0*Ttgsperklk'-4''yi)qtxmaKods5e'-1i!4(ii!fJ2TS"diotss?

A xelshios of S.63g of Ivloiihtethyleioyl 4'ii6'f2i2'^ifE00:iX!edKixy)-2;4-dsoxo-3,4-dilsydxoi^i®a^olio-Κ4^)Α?!^φθΓίό4ίθ·' Αί«:·^οχν^&amp;ϊ ebiaked o: >asge 3..5 :sa 70 öd of iomdc seid is fiisred at AT for 2h0i), The soiveot is evaporated a.ader cedsced press«re (o give 6.13 g of the expected product is the form of the fotmio seid ssii

Stege 3,7; 4-16-(2,2-.0^0^^150^^)-2,4-0.10^0-3,4-01^1^0^8201^-1(2^)-5--11^^0^1¾^ t-csrbaMehyiie

A .mixture of 6.13 g of 6':{2;2'diikio;xiedtesg)-d gpipeodss-4- ylgisissxoliaeA,4i i7?i33/}-'d:iose obteised is slsgs 3.6 sod 3.12 g of ateteoshm sbooaie is 28tel of ACN mé 28 M of dkateae is irtediateti boote s irbetowave Heid af l-lCfC for id 80. i he reaches tetxtore is rua isio water. The stixters is ftisared aod the précipitas« is wasixxi with roter ttes! Sites with ether to give 4.4? g of the expected grodaco

Stege 3,8: Compteod No, 34 4“i3-{4"€hior&amp;hessyi)Ai-'{2,2-ditlts«rtfet)5osyi-'2,4'ditteo-3A~dii5yds'tsgoissioi55id(2Al·' y 1 Spipers.d.ioe-· .1 ~e arts a idehy d e

A nasturo of 0 ?< 4 ->i Ή'*'-*2 J^duomdhovs )-- Jus\o- 1 \~Hh } Ur-n^&amp;ae« :.,. v ,.ioV,, o^r 0,- *' - -hc '' ' '* «** «.* ^ 5 ! '' 'il ' nr' - ‘ ' Hv A'x 5'"‘ ' ' 'V*^' l'' ^ ^ ., rsyg Î si-o^ .u vr IrP'O VuU «< oshk'd sad '^vsg o 'w«'> ou *\h «a:^ ukï ^ - grated MaC.1 etofan. The ospdc .phase is dded. «^ Ä ®**ά'άά'νφ**»* noter xcàrxsd pœssM* The mid«« is de«mtoV&amp;*A o« silica φ* ^ carrW ^»AcOEt, to give 0.U6 g *rt the expdeted product, v EXAMPLE 4: Coïsipesah A». 49

Synthesis of 4-|3‘l>hÎ<î'(f5ofîi'5iiyi«xÿ)-i“ïfteîfî«xÿ&amp;«'»«y'ij-6-(2j2”iUflH<îrô«îaoxy}-2,4*dîex<K>><i·' d%dr^as8^dikv5ß/.0^n|#eesd]säeu^arhayehyih;

0 \72 g of F.MAÏ) :is added to :a sßohöö of O.lS g: of 4^6-{2!^KixSiKsix»{hox^^d'i#â^:^#rt dikydm^io&amp;eohsl·-1 ; 2/fhyi Ipspendsoe-l-eafhshiehyde: ohtaised M sPïgs 3.7, 0,142 g of ;4-{cydopen:äy?oxy}-3·· ssotlpïgyphepyilsÎSpihsshd add 0.2:22 g of 1¾¾ id $ m oi M^mmm THF. The nôxfôtte is ^paTst Aî âf |'2| (g) ssd Ijesä öl #s€ Sor 1 h ö(L M is edaposssed oader oidsced Is pphied m sdfea gels oleMoü bdog ^nieo oas wih -\cOEt, io give 0.083 g of she expected prodac*. EXAMPLE 5: Ο»αψο«ικ1 N«. 20

Syaihesis of :V-{J3>(3,4-diiaethoxy&amp;«a*yl)*I“(Mefœyipip«ri<lla*4-yI)*2>4~<Hoxo“L23sd'' ietrais ydroi| «in a soli a*S-yl ! ssedby 3 ] ««eta solde

iSS&amp;Sul#

Methyl 2-sisis9-5”{ ||<I»f-dss»ethyieihosy}earho8ylis?Äo]mei:hy])l?e«2«sfe:

^iÜ A ô,2?3'g iojf me*M :i§~;Ö.!i.irsg--:^:_:-id>6' ': äsäsjosiiiäi i&amp;rnxds and 0.094 g e£ PdfCÎ P:W$-:js ÎO ss! öfTdüff piig«a fesiètëpïpÿd P’dh HÄ$?.g*9*Äs a*a<ha;ed ;: «ndér &amp; mierovv&amp;ve field; m l2d*C far 5 am 1¾ imfàm stilted md the f##S B eeitpferhsed 8^teé r«éae^.;; prsssei«. die mate .1* ë%ma^aphed on «die« gel. elution being earned ont with ms AeOid/hept«nn rnmmm, {$/95, v/v) as far as (50--70, v/v), ic- give 0-2 g of the expetded product B^à^-^l^ÿiljl^âaaef^iiÂxyKar^ôj-llaailaoimaîfeÿlH^metfeexy«

.4 soknkm of Lfefe g of benzyl 4~oxop>perKitn\-i-oarooxyhte ann ; g tn nasht« ..NUainio-.V^ ;p s.s-d!jneihÿl®dp3s;ÿiciul?çùtvl;]aniiftô|:.ineti;ÿ!|beaiîoa?p; tîidtpîtéd re nhgd5d ;tn Pr äg! id Dvlt-I et ad%i| tgopgase ai Àfi'to e suspension of 2.04 g of bîaBHiOAc);. »« a nïutore of20 mi ofOCM «tsd 0.4i ad ol AeOH. The nnxture is «uxed at: .4? for 131; 00 m&amp;$m.s Imêm lM g offeiaBBiOAe};; dt« added. Aider stirring for 6h 00. Lofe g -Of m added end the mixmre * mt^à u AT for 4Sh 00, A «««« MÆÇOi «Laden 4 added and exmu-bxi is earned tan wnh PÄ 7-¾ ^»te phase n- washed Mth * Nat, a i.d \.dfe\4 -.M.'vr ,vtou Vdh t ^ dor Pod M L* ' .-voo'n H "- Tax oe \. an lot s '-> «,v (he; fdtraie. is.map&amp;méà nt; der seduced pmmte. The residue is chromatographed ο» sdica gel. station mm$. earfed ont Mdt a^&amp;söß^ i.hgouire expected product ..........

Stone 5.3;

ASSmMAW.SSVtW ®^ÿl4Pf4--{ii;(fii~d.ÎmeUî>ieihystdesrbnn.vI|esdno}.tsxdbvl}--2d.Îindiï«ayeisriKïïi>1}plîeâsy.iL· <e?feosyesrfeenvl}«nd(tnH5d>ö?Msne-'I''«nd>n;syinie

' ν. ν \ tn«a· i.?*> m et s.il > ixlmdot a >. >0.,,^ ν' «..v ' ot 16.θϊ Besson *«-I [44 :||i >1 1 >-2 -·[: îxs öth< ? x ?syl )|? jsmissis U' ösä?oxysMs ostaioed in stage 13 lit? 1¾ ml of DCMc It^mmare i» Ä*®d aï AT 0>r T days, Il ss ®y^rsted· ïiôîfeï seduced pressas« * îh.«: résiiSae k ta&amp;üf m. Wssi oifpyridte l lû M} &amp;8<f 0.7 '§id e%l ix Sâ-Msâ. the fe steed M "ÀT for 4!s00. I is eslapomted· ander ïsâvsmê;:^»m&amp;· Ί&amp;« :iÄbe. is £|iiss:î?à4>§isp5«ïi os silica gel, «tMm het«g csnMoat with ah. A«OEt/heptane mxim* 00/90« v;v) as ik as [30770. v/v}: to pye 0,875 « of the expected product.

Bea^i 4-P-43,4-ïimeihss:jrhes^)'-64 IMI^'-âissatfe^leïfeosvicarlôisyilsïssteïH^O^^S^^ImO'

À mixture of o.lô5 g : ol feeute 4AH-3 liï 07-'0iïhstii53«Û3Ox;a catenyfjnndniik [ffiadiiOayosiboayOphösyäj(etjaox>«3rboayl)am»xi \piperidine- I -carboxylaie obtained sa usage 5.3 and 0,028 g of LK0T is 5 sa ' U U ' \ ' ' v» v h«y \ <. >s hv ί'\μ\μ> vb>v^ etd\ i tndu'Xd î k< ' ; mmMt'à'Wî field ay iOOX' foî sis 00. H is fUieted and Ose fdaats is ev&amp;porated under reduced pressure. The residue is teen up in 3 ini of OMF. 0.1 OS g ot Di£A ss added susd ;he mixture à. steed as AT for IQ ύ 0.159 g ofHBTU is added and the sn.istnse is steed at AT for M.wè&amp;QMi.f, o? veiatrylarnitse issubsequently added send the mixture is stirred at AT for id 00, 0.5 mi of DBÖ is added arid she taixiyre is steed at AT for 4Sh 00. It is evaporated msdsr redaced nsessam mà the residue is taken up its AcOEs The sofotbn t* cashed 3 times with a saturated NH^C! solution and twice with water. It. is dried over Na2.$0* sad tillered, tred ta«·;· .... .filtrat« is evaporated under reduced prepare. The tesidue k chromatographed oa stUca gel eu-uon beiag ;;;s«-:ed out with sat At Obi- DCM mixture: (ΙΟΛΚκ vAt) as fer as (20-^0, w'v}, to give Ö 104 g of the expected prttdao. S&amp;S&amp;M:

Bettxyi 4>|â^gplaataethyô',M3<4~<lim,tbaxybenxyt>2x4-diox<H3»4-d$b>'droq«iB8zalia*î(2^>* >4ip{p«r^!a®»£HKsr%®xyb»te

Λ solution of 0. i02 g of bensyi 4-{:>s:>A'-.dinuO:h*syix-:na\4}oS-.k:iXxJ--dimgtitykid:iOt:y.i·· öxrboi5yä)<oniK>:doxiäy0'-2.d..dsox«--3.4..dd)yd:tx|OHiasoIlx- !:f;k/i-yf!p^erxlae·. Itarboxyhik obttridgd m Mag® 5.4 andfhS sol of'll A in 9.5 usl of DCM k stirred at AT for 2 it 09, A saturated ktsBCCh solution. is addsd.lne •digitale phase is dried over j9a..:SO..: aad fbtered, and the kltraie is evaporated ander reduced pressure to gsw 0,1)9 g ofihe expected: prsxioct I»Mt B«»«yt 4-|é-|(a«:tylaaMH»>.}m«thiyï} •3-(3>4“«MH«tthox5îfec»^yJÎ>*2,4-tl.t»so-3«4-dôtydr»q«iaa*oS[5H“ l(2îl^yi}pip«ritHa«-l-c.arh«xylate

0.Ö49 g of acetic anhydride is added tit a solation of 0.-09 g of benxyi 4-(SHaiïtatotnefitylcT c!ie:ekisOsyitcojiyi)CD-.diitx<3~C4Mdvydroi:pttos!iOistr· i i ef/Cylpipenouse·- i warbos vhde obtained in stage 5.5 and 0.09 i# oi NEt; bcï on of DCM &amp;sd ibe pdkp?" is stirred at AT tôt Ut «0. DCM w added and dtc solution 1¾. washed wdh a saturated NHpft sMuhoo. tfien vuüt a IN He t soktireri then neb a ,!N ΐν,ν)H soiatren and. then sä .waser. The· crgaoie phase Is dried over iShoSCd and filleted, arid sae futrate is evaporaxeti ugder m<»icec pressure to .give ödö4 g of the expected product.

Siissjsl·' . .^J#etf*>J}&amp;€etamSd<f

A îtîïsxîîjxsï: :ef 0,1 g »f heuiKvi 4·j':6--{Xiiee{ylaïSiROiî55Sthÿi!"^'U^dîâîî«.ihox:ÿfceii25il)''2;4';£Üôx.&amp;';3^4-^ydi^màmli»-$Wf)->4|pipmdm6rii:«c8iï0xyM«· ohtaiued: ht slag® PA d,d.l tg o.r mrn&amp;xmm tbttmte sad mm gMVèC (IW4) is 2 mi of ECp psrpd b«lbrakand'ÄÄW * imshaied usdsra nkeavtmBM iât WG ftr m mm. TM mmurs is Steed m* the mmto is evaporated xmä&amp;t mtesd pressure te gi ve 0.077 g ofttte expected predoid-

Staga 5J: Compound N«, 2d h~ySj.tu«i:hyi) acetamide

A mixture of 02)70 g of ^f|:^OÀ-4iî5iedîoxybeoeyI}~2A'dKîxoriOpiperKîia^-yl)-si:A:Ad-· ka«i)iy0oaq!0naxoloiO^yf|aäetfey· kreet&amp;snldc: obiaiued I« stage S ? and 0,1)28 -g oi ammonrena Icntme m --7-^ ACM Is sn'adlased trader a microwave field at i40®€ ibr shOO, The mixture Is .filtered aud the » creapomAri sadef reduced pressée. The residue is chretea-ogtspfeed ou silica gel, elution beâig carried Wï^ m MeOH TCM nOxrere, i0.5 4Q.5, γ.\ ) as far as (7/83, v/v), » give 83)2$ g of she expected product.

The chemical structures and the physical properties of eonspounds corresposxhmg to the general tprpiv^ 'Λ· according to the invention, and also of some of their intermediate {in particular cooiponuds 32, 55, -IP &amp;βώ 25 ?), are illustrated In the following table.

! \ < ν .<> ί < Is t Ά Μ V . ' > X ' V V "Λ Ο ph:«US8.<.oiogr«SS rvi’s xtb.îJ' hwc Ί\«'" 5 Ï Ut .îdxnouue ,«. « Ctî'P'UU'.i'xiK u'ïOV sUs'sS «ï.Vs j·).: Measnremexrt «f the inhibitory activity «( the compeuads .ta accordance with the iaventios 'with regard to PMI7

The afetKry of the compounds of ibrnmla i{) to inhibit PDE? is measuted using an «s-'sniUtiC «.*:«, tsuud -v -he «.'pstsoox -b xxdvvuu c <s«V;.no ot P1H b fo'm tho :. !Ä&amp;gdve/;S^ÄM^: {pmdact of ifs^sssf^lfe reaoiioif? 'by sMls layer nfepÄngi-npby on pölycihyfcsumhisxe tPLU cellulose. after halhssg die etizyroatie «-action. The S’-AMP is extracted ouanmanveiy ftrnn the tin oeihlvse .uni it* tadnutofn =f> s* «xcasused n.oap a honni .-cuitiSUtion count«·, T he inhibitory activity of the con-potssxds otlbrt&amp;ate <l) with sogatd to PDF? is represented 0\ thi u «b-h w .v wen« K\ . ik'innh «> hn w nut» o >" dv « η «u. xd v.unèu ·, M,>ui id the pasty which tunke« it possible to reduce the c«symusic P#xmy # TM?}>¥ The lower Use 1¾ vslueSi the gretskir the inhibitory p&amp;vmot 4® G««posmtfS. ;;· Mäissäfe' , ,,.. , «ν.,.ν ΛΧ·' · .bt| t "N ' tO 1 1 t * Vt'^ λϊ\ !’ s >00 *' ' 'V*.' 1 ' «tu (V \ The Science*. Boston. United Stase«):, the rolips«m -was ptsmimsed Srm Bigtna (St Louts, Mo, Litsfteé Siatess and the sheet* of poiymhylenmnine oellntpse F nsstie >>f plastic tor thin layer chromatography sects pnmhnsed from Merck (Darnsstadt. Germany). All the other prodsxcts used are of eontxnercinl origin.

Ihtsyste

Ensttan PDF? was pum&amp;liy purified font 4« HUT~?b cell In* by folio·* ing a method tsÄ|8«fcte.Äy hy Bloom«sd Betävo (Proc. Nul. Need. Sei USA. (!») V3. MUG-; g i oys The eTtivtne'ptettuntton ohtaioetl is stereo st -sus.· to a hunts u eoxpnsxsg ,.0 utM ol > t xs* :Βα#Η T.0), S PtM ofMgCin A mM ef BOTA* IÄ of dhhiothMhöl and 20%iof giycesoL As lbs partially porified PDF? is eox-tanainsted by PDIsh it is secossary h> add lu μΜ ot xohpvam t*e?et:hvc iaitiurtor of PDF4) in 5he enzymatic assay in order 50 costpietety inhibit the PDE4 activity The Michadis constant i Km} of PD£7 Mr cAMP, measuted catog the radiochemical assay deserÜMid below, is 2 s n.M &amp;Édia??d:ofTt«?l|;iotï^j«.âCCSgdniîS^

The eotopousd* of formula (I) to be tested ns PDS? inhibitors dissolved «t DMSO at a concentration of 10 tnM These solutions are sidiseqncntiy diluicti in eas;.-.ade in DMbO «t order to obtain solution* with the desired concentrations. The lauer are snbeeqnentiy diluted to one-ttvennui in 1\ ws,x Notu t> uxc BMSt *o,utnus . c Lau 'ts Ltulu 'tie ftbn in she enrvunaho assoy. ihv svb.mmx ο;' w-Hpsasrx (adsksi k she aasay is? order to completely bxhxbi; -he eomaminattog PDbd acuvuy) is prepared io an identical way a«d contributes 1% of D-MSO to the oxsaymatk assay, ο

PlodLPdiydkdcjKeay 1 -fee assay is c&amp;aied out in l.Stsxi Eppendorf tubes comprisnag 40 inM of Ixis-lKii (pH n\ vs -s Vv v s ' x'V '* s i. \ N w r -. x \ * ' x v " o. . χ Ή] ^ x N \ ΧΛ V ο *ίΚ ' V xx s ^ s M ^ 5 <· ' t !' !' j»DE7 in a Sn&amp;l voixnne of 100 μΐ The asKav k carried out in the absence (control satnpie} or ut the presence-(teased Ateple) of Ä çsteposKids m%â sgt- FDE7 mkibshtrs. The fi.pl cpbcetsh'kiik «I . DMSiä in the asset' is 2%· rteacftoo is- kdiiitosi % s$$#qk pf easytod pod- te sasixples ;»» msàiÏsined .ai: -mMmi Sk Ihmmm.-IL·· exsaymatic diMioa is a#satsd so mp. obkk &amp; degrest of conversion of 10 ίο i 5%. The st;a:yxtsm;c rcactios? is halted by ksxxserssos of the ssopx-cxed Eppeo<brf mix* sa a water bais at I0CPC tot T mltsuses. Bleaks (reaction halted kpsxmdismly after addition' of -dt« -Smyrna} are: ksdlstded hx each; exgetkstest. The kssrtpibs are : so&amp;seqxiasklv etmtrilhged at 10 ÖMlxg far 1 mkstei am! ad ssicpct pMtoajbf 1Ö μΐ of srigesa-ksmt is ; ; dspsislteb 2 esb (tobt the bssttobt bilge of a sheet of PIS·· -cdidkise : %&amp; -«êMi 10 pg of eAbfB itdd 10 pg of 5!-Aft kswj beesJ sioposhed beforehand; in order to tebtste the rsagratton 4gd to make is easser so cast ou? the strips of FBI eebkore comprising she S'- AMP, which take place subsequently. ; 8 rnksaxtiot; lasses with a width of I cPt as·? dehttsited pet plats by soraptsxg the edkslose te;h a spatsxis ovcs a width ot ! mm. lise pkxles see developed over their erstisv lex-ash with a 0J0 M seiet loss of UO in water by ascessdsxsg ci?xox?xatogmpl:y. The ô'-AMP (M 0.20} sissi she cAMP s.Rf 0.47; are vk-xahs-xi trader l/V sight at 254 ssxm The ssrrps of PEI cellulose comprising the S’-AMP arc eus out astd the ittsstboikie is q-taaiitatively extracted its couasieg ilssks will; 2 mi of a sHusktrs which ia IBM ia tbmtic add aad 2M ia asmsosheet tontsa-e sa water (rixtary xoex \ s ' s -ο-.; x \s\. ek xv x -ο ;k ot s<. u ' ..sxsoe box d x. ' NoPb we ttxy.xk ' s .mx Pox o' blxe«h%dlac). the radioactkhy ia di>e;xmd ®ms; a Hgssid semMMatiost csxsmsot ümsdd 1414, Pcrkhx-ElrectfWaiiaci. Each assay is eaxricsi exit ks daphease. Tise radkaskx-hy speei&amp;ally associated with he 5'»AMP terxx-ed in sk eervxnasxe soact;oe is obtained by sabtmekxg she ntcaa value of biasxks hoixs the mc&amp;x; valase of she edtittols· (or treated- samples). ; ϊ.·ο oeïc. ss.-po v" mb bs s-'; et p: H'"1 .e &amp; po.x e . oox;«;eno;s m' she coxoponnu tested x '' - λ \ c x\( .. oxs o B\ s t m s'' \ ' x" ' ' moe '.V' " .so :: teattod-mnpkdj x If :^^1' op Ή-e fCS;. xs tbx o xxocxx’xatKx;x tiso conssvxxcd x.sx.sxdxsm; sesè-'d χχχ ko oxsx\ xxte.ix makes is possible to reduce the e;xryr;;;pk: activity of FDE? by >0%. f 'feitldf his dhikhodve atalspclhshsistg otabstpisis, tlso Sobowlssy î^ii^iÎÎ;s x&amp;hrlstt 7 ICjo valxies -tssiscaled ;>eiow : <.\>nip<:und

No- 16: .446^22-dinaun>clk>xy)-3"0»4-djmeih<'xybeazy^· .:.4·« to v>· .v*·· u·'**' <«h-wi{t>qm8ia^ol?s40EH^^#ife^ ^aKfe&amp;wefeyo* :

No .:-1OA'dnnemewvni^-o .:: doonvbukc-nnnukiVk^ jO^eyo-M- 0 Oibvdf0ûii5îî3i:olîï:-Î<.ÏH ï-yijpipscr!d*xtv>-i -earbddehytse ^ 7?>~ ·. v ά c v\ be O' <' ÿw8>" *' '* fv;X:^ dkyikodu-na-aoShv5 (2H j-ynpiperid«»·1 -curbaidehydo ;Ni>. 7'?: N~\ίΛ·*0,4·ϋΐ?η«ϋΐΛχγϊχ:»2>·Ι)·)4 ί4onaylp«^0dja-3->s K 4'öi.>xo«U,3<4« Ο..Ό tefeahy<feïH|wi«a2:olin'6"ytjme%·! ; acetamide

No.9?:44k7.didHoro-M3bktotk>xybe^ US*] U ?.H) yijnipendke-·! -earhaibehyde

Mo Π:: 4-Γ6-(d:n»ior;>;?>eüK>sy)- MMHUoKtiKftybeiByih2.4-dsoxo-3,4~ 0-006?

dîhydKiOumaxolm-1:2ΗρνΠρφοπαη;ο··I•raatkdehyde; ;J 2} Mvjwtfsw*«« ot Ose inhibitor} avihit} of contpoatHh is «crordaa«? with tit« iev898:ti»a;wltit: regard to . vS -i v-.<- p*\ . -- vl .'iV. S 3' 1*3 3.-.4 ' ' k\ ÎOv'ftr** !l\ i.40->.tU ί'-. Vy

vélues-« oh^-tei kM

CiHäp^adJii· ,:j :1¾ p«7 ίμΜ>?: IC«PDE8 <uM| »&amp;Jr:|P!;:: ........... ........9'ϋΛ*ΐ.................. ^,3Si;;i: ": ΐξ ojs;;:;;.

M-:x294 0.037 0.0 ί S 3} £v»laaî«>o *f the c«p*îuh?s «3 &amp;j»«r<î»»c* with the mvmioa la a *»««»« atotkd of ^yo«aai!W: tmWm m ischemi«.re|»«rre^n «tofe.::

Mate C57B6 «5Me ; 25-2e g: an. aruextknkod -keorkoe ) g Me \0«·>ϋο- o-.O e. Eg ü'O iiSï-i pissed ïJxîsfei respsanory assixtiîace kîkîO doing ; n&amp;cgecied te a ^ùtSpOip^if·: : targeted : :$ tssposiag tbs .bean:' £aAs kdssmk i? léwr Mmaâ % the ;^aiÄni HgàidÉf :«-<#«; M wroapry ; ; - ' aiiesÿ: ÀÉer 45 iknuks «f eomoary oeoltssiosg die |igpsre-M removed id order ;o make poxx'.ble Μ sepéildski-s: of she region mtdered sehende. Ader clodng the itocax end restoring the pleural cavity, the animals .¾¾ placed ist a revive? cage leet compounds Nos U, 5h; 233 »ad 309 ere administered 5 inmates betöre repextuxlor: ; intravenously a; a dn>.e of 3 nnp'kg and ·φ^βΜ·Μ^::¾ vddke r".5rg Cresiophor ÜH40 e :: : ' :22.1;^lyüipiairi3l; ïs s pliv'sfesia^iestl ........

After 24 fours of cardiac ntperfusion. the srhtnaN are sgrun stmvuthetized ttcetatmoe > Ikk» uko-ue '-- 7 „-Vp -! ' '' t-est so ru ' u \ .< . dr \ ,0¾. λ ! i<> '»'tat rtur.-r: for 4 rth nates) in order to dilate the corooary '••ascoisdere. 1 he {«It coronary artery la reli pt-ared <»·« a soiafiep of fivstm blue (3%. 200 to 500 pd) is injected by carotid tvtropetfasion tn otder to .deiemkoe the regies; -at ventricular risk. The heart is then mttoved and hruoersed in a saturatea &amp;£> soltdios;: la order to stop à in diastole. Transverse section* oi i roro are prodocen. ;.ocr:b<ded 0» tdofertyltetiasolistst ckksride (1¾¾ ist I’lTSTstt :3f%! βψ 2 sbautes ssto thon pieced sh tmmM&amp;hy*'», (42(-) twmäghx, -The.MraäÄim tuait wakes -t possible to vj*uahr.e the viable tet-ior; wstnm «»e regional risk. The surface area of the iafarctki·* wsta respect to we rcgsosi. at res. :S ίίν:οη.ίηηα, >*>. mug» analysis.

None of the compounds tested inod-Ocs the region at nsk, expressed «silt rc;-pcvt to c-1· igirtace area of the led ventricle.· Cotupounth Nos 11, Ms< - 33 and ·'·-·' MSttafk&amp;otty reont.e she iO-of the tnltkh-,, '-a-;,---0-1 '.-.hi; ' .."g--..; ,- fn, »sy'-oo ,0 --'-Τ. Τ'- -"», '' e "'· 'ίΐν* respectively.

Aecordidg to die invention, the compounds of lontmla tit deleted aeove. in accordance with &amp;© mvoubon. can be used m stédisaunstïts ibtersdad to tpstt at «tast one «»»dm^&amp;twu doc-k? and·;or to prevent the appearance of ai: kasi orte cardiovascular otsease.

Mes a uu « «'«- K t,v' -s oard--N\ neeniar d’v asc^, t-u ov«Odpk -4 iltss&amp;ses eftbe. eardjse »>aseies (i%Äsas«&amp; of ihe-tost valves* ?k* * diseases of d;e heart thythm and diaeat<e:; of e&amp;rdisa; çendocUP»,a?!« y*:’ ’t* ‘Vx f^v *

According to the mvenuun» the eotnpoutids of turmu» (tt trs acwtdasKc t»tth the iii.v,!*t.-v..- eas ha-sued ss tRedicatsents intended to treat at kststosre cararotystcw--? vps:a->t· asid e , -c pfv * the appsarasce of at least ose ciirdsovasenlar dtsease choses wyw^Piy au,.sc^~-.: ^ pardculst' contractile cardiac dystoieikio seasdritig freut s sRyocutstiàl *Otàtvbs»*y cheese,\ „s»>:>t,>.«.s •«sfh ftper&amp;sioà h|jtÂu of the cmitac .attdtor· skeletal .muscs«»· p»v*».Ov.a*/ .i>pe. .v..swti, ibreaiSj pesbaAgioptaaiy arterial scsiepesikiAcdh Or uiütoat »tdPg d Nv1·^ ^«-rosvkpsts cofïï'pHcaiSorsa. auch- at., for tanotpie, piapue rupmrch ancisnsns «»*» !"'i:''*ia!-! disvU^cs, va.-d-3s oucsTciCncN, odatao ctadu'uao'v sud us>\\ard.ot M teed '»nd or 0,^^......'nh"> bo to-. 0; -..-. '-.,\l tosî'auh if' n ,--y-otU-yuc u n> '*' 1 !iS ' a ^! ^0 t) ! ' - s- "> O.UIV« vO \ 4 u v 1 ' K ' '' O'id st putkiiuii fx xOt tp-u sub "f fotioulvt iO cti'Nsen trottt eonsOv«*''"· k. go, ;;,: to 23. 32 to 43, 42 so 31:. >3 κ· 72, "4, 7b. 7«, 7«. ,M> to .-. Id., ‘US. \ ί I i~, 1 *·*-1 !6 jo I IS. 13.4.. 130, 131, 133 to B5, .143, 143, 153, I3S, t60. m M ihK I /0, 5 », I 'M M « lOhMdk.iu- Oke W3. |·ϊ4,2ρο, 7ot.3m, fop, 20', .'B.-'B.-'K' Μθ.„».2-θ ...:4,...0...,3, 23ο, 2'2 to 2-4. 23T 740, 242, 243 743, 24ο, 250 75k 2>k 2\4, 2-·'- -- 0. 2 .. f\ - " ;|·2g5 ibm 2« 292,294,¾¾ 297 ίο 302, 305 to 3:12, 355 to 34 >, 349 to 355,::33¾. 353,360, 34?.. 359, 373, 373, 375 to 3??, 379 to 394 aad433, .\nother <a}hs«es*ntats*f of fo* invetthott -s s compound corrcspondmg to the general tOraaOs {i) ,ό defused above in particular ^ conspouads of fomsul* «0 vigors fwm <.ot-xpmmds x>, I ! t v 57 5 ·', y 33 K' 3\ <' *o 4\ 43 te 53, 5< te 57 “5, '4, W 5, "7 5- to * \ Kj.>, 0)8, U i. Π2, 114. HOto U3. 124, LM), Bi, 133 to 155, M3, 145,155, 153, 160, 165 to 102, {r,x -5 m w 186, 188, 1*7 i90, 193, 194, 200, 201, 203, 200. 20?. 212, ?.B, 215, 216, 2 !8, 223. 224, 226. 225, 2,30. 232 to 234, 239, 240, 242, 343. 345. 246, .250, .251, 254, 253, 263, 264. :>?Ü, 375. 276. 225 ίο 760. 232, 28), 385 to 287, 289. 292. 294. 295, 297 to 302, 305 w 313. 96 o 5*9 u- v <55 55'· 9¾. ><'· ^ 5" 9 M'M to 5-7 r« to and 40.1. intended ta neat at leant one cardiovascular disease andrer to prevent the appearance ofal le,«s< one cerd'O'-asetf,« Jtaeise, ,v,hntt«iCi.ouaL -isdetirtc«^'''^. ) : Btanssseutfeii eemptssitJOns : eeuipBnsg, as active: pmcijde, at least one eompeund in ssdÄhcei ^ invention .sale described these ph^natcenOeal eornpositiobs eptsxprhse m effective doc ' -. > -, ' n « >, * t tn n >,r x ' x s «, '•««do« and also at leais otieplidriStttoealioallv asoepisble sseipienp ::::: ο1: The saidi dxeipiettls are ehosei;, aeeerditsg to lise pOsœtseeplieaïlornx and the method «1' ; p: administration desired, front the weal exclpietPs which are hunva to a perrott skilled In the art.

In the nhaxrnseeetkxtl compositions described hexe for oral, sublingual. subetaarusom-. ,.:: e«',eves, nt.«, xthtnxxtn-'W t-yncal. local. intratracheal. intranasal, nttXiSdcttnut. oi xî-cx*x iulxninistrstton, the active principle of itxxntnia (1) above or its cpbottal salt, solvate or hydrate can be administered in «ni; .adntitttshatksn form, ns s mixture with eon vest; iot;ai pharmaceutical excipients. to animals and human beings for the prophylaxis or ireatnteth: of the diseases defined .above.

The appro;>r!ate unit adxninintxatloo Loans cotnpti.se forms by the oral roots, sect; as tablets, soft or hard gelatin capsules, powders, grasmies «tut mal saiuttot» or suspensunts, sublingual, buccal, mtratmehe-äi. Jttftaooul&amp;r or tmranas&amp;i admlRsstr&amp;txou forms, .tons;s lor ^dbtxrnSfratiiph 6y i;7aiaiiou, -opteal, frasjSd^imaJ.,) tetranutsentar ox «.«avonoux adnntnstr.n. n; to-ms, 'ν,'ν.1 .to.run oe. nett \·η> nod urtpktnts Is·,' eve, ':se ox.»de. t,-t ton«.« apphcnrlon, of the constjonnds according to the invention in creasns, gels., ointments or Ionovs.

d- -m, ,.v .'vex o'e s ,'.r < an," n enrn.on touv -4 ,·. voonwnd ,.,'so'd&amp;rce w-th :V inveo.lioo in the lorsnofa tablet e&amp;ncotnprise the following composers ;

Contpoxtnd ilo. ; 4^iracthos.yberszylhl4l'fofmylpjpetidirr 4-yi)-2,4«diox<> 1,2,3,4«tetfah>-tltvHjuxnaiaolm"b -y] foxy tpropanenitrth') 5t).0 ntg ivbmnito! 223.75 mg

CfoseaeateOose sodés® 6.0 sog

Mstiae starch I5.Ö œg

Hy0roxyjnxfsylms0gifee!kloǤ 2.25 mg

Mugstesirsss »rt» 3.0 mg.

The seid tsrfo forsrts «tssspme dasm ja erster io make possible d&amp;üy .sdraiaisirattea of 0.5 mg to höh mg of active prhreipte per hforvidrad, toore partkadarly of. 0.5 mg ro 200 osg. asoöfcifig to the pharsttaoeisdcal dosage ibrss.

There may be eases where higher or lower stosages are appropriate ; auch dosages do oot depart Bam the scope of the iavesiiori Accordiog ip the usual prselice, rite dosage sgsproptiare to each pshesh: is Ossessoloeil by the pkysieias according ro the method of acimmistrnifeR arsd toe weight arsd sespeuse of lise said patieot A method for tire treatsnesx sefofor preswolioo of foe eartiiovasofoar diseases iodicsttod above cosoprises the gdositsfolratlou, to a patlerfo of aa eifoet-ve dose of a oosopoarsd So aeeonfostee wrth ilre hsveotiors or of oee rtf he hydrates or solvates.

Claims (11)

1. Saabadakm igénypontok i , :(!) íútiŰÁ:X::\ kÓbkla VegvUie;

   v akb a képletben '· Λ jeknksO ankkopar: vagy ον-ηκΗοηονοροη: - R; jaksttáse: »ybrogés&amp;töm. * ·( ui:lk ahk R jökméae bákogbaakan, CrQ::ís^s;xlc^poxt, adksegörk (CrCiboikioaskbcsopon vagy i(kkk Kkkksopoo. ahol az aikiksopnri adok o aeiben helyePesttett a kbvetkes'ökke): * cg) vagy több hku«:eibsnp»rt, * ben.;k:kv\ba;>p<irg * i(k-i';.}íukc3;t:n>piiru arnek adón evetben aíoc\op;ntud beReueioseu. vagy * (C > · CRcikkad ki kxop>ít, * adok evetben heivettexkeii (CiRkypykxopork • R;; jelentése: * kdrogévsatoov * festogénstoxft·; K cianocsopöit, * nkiocxopoít. s (Ck'CsIsikkcaopoit, amoR adok evetben -Ni R cxopokía; vagy továbbá bklKROíRb esopontsl is ledyenesluxt ahol Rb jelentése a/ alábbiakban n-eghaRrooetb » - ORa c:v>pon okol Ra jeiemew a kOvctke/b: * nkkoyénsnno. * (€rCk}aikikxopork anxeR· adott esetben beReléexketi egy vág) söbb hakgknaK-nnosk agy vagy több k:kroAkosop<;nkk. ;:a besöpörted éx/vagy egy vagy több eiantKsepottía:!, * (CrC4.jaikio!kaopork * ariiexogort: - Rj jelentése: * hidnyknao'nn. ·· baiogérsatoíO:. kKtroxUesopott, ' cianoosopon, s -'SCF i csoport, x mímcsopört «ba(0g,:;o«kdeso:porb d»<Og,;í0eieröerklosSkKesöpörk -0-SO?.-sriív.sopí>nv adott esetben egy vagy több kakígéríatonntad helyettesítve; * -alkbai'-iaoídk;; vagy -v;kíöaikbannnoalkbesopo?'l:, amelyek mindegyike a tennótáns aikbcseporíoo adok: esetben hsíyeíieshett, * adob: esetben helyettesített srttttvnan'hdeseporí, » arilcsoporí vagy heíetxrarbcsoport, amely nsotíodídnsos vagy palkhkhms év továbbá adott esethess helyettesíted (Cb-CVhdkiksrmobtai. egy vagy több bakgénaíotttmal vagy (C :»C;daÍböxksogob:, » heterocikioaikbesöpert, amely adott esetheti helyettesíted íCrQd&amp;^Ucsoptnltaí, " tC rkk. satbikssspvn. anseiy adott esetben helyettesített a követkeaökkeh - egy vagy tdbb halogértatotn, ·- anícsopest, amely adott eseibets helyettesített egy vagy több hatogenaK-mnnb vagy egy vagy több bekötik söpört-ak - ísetetoardcsopotl:, -egy vagy több Máma besöpört, .amely vagy amelyek belyeítesítve ict-etnek olyan ariktsoperdak amely ntaga is sakkt escíberi helyettesített egy vagy több hidogénatoíírmsk vagy - heterodkle&amp;ikíRsoptnt; omeiy adod esetben helyettesíted Cö(0)Ra esoponísn vagy ((Ví ryhkbcsopordat nátnéíísd Rs jelentése a lentiekben ntegbakiimred:, * -ClOthlRbRc csapon, ahol kb as Re jelentése aa: aíahbiakbait meglíaiamaoít, " -CvösORe csoport vagy -(MyO)öRc csoport, ahol Re jd vetése ax alábbiakba:!· amaentérorots. * (CvRFtalkostesopert. amely adott esetben hdyedasHod a Mlv-dmrokkes: - aíoiooalksksnptnd - sSsssnsiseikloatkítesópívt, · dktoalki lesöpört, - h<-;ers>ciklodkbesopnrt - snornvnkkm»:; vagy polioíktwaos ketcvnarbssopsn'i, - egy vagy több bidroxilesopork - egy vagy több haíogenatom, - (C s -Cdsikox lesöpört, - -C(0>üRo csoport, ahol Re jeíemése aa alábbiakban maghatároáetk - vt(0;NkbR·: csoport, ahol Kb és Ke jelentése ax alábbiakban meghaíároaod, és/vagy - arbcsopen amely maga adott cserben helyettesített egy vagy több hnbgrnetommal eiaoo-esöponiaí, {CrCjgatkoxieseportíat dddralogéoatklbsoportta; és 'vagy RalogdtalkilesoporttaJ, *'O-eikloalkikvopon, -€í-atbvSopori: vagy ks-heteroetkivalkdcsopoít, amelyek mindegyike adott esetben helyeUesiteb a kevdkcxdkkd, -· as iksöpört, amely maga adott esetben helyettesített egy vagy több balogénaíemossal vagy (C í •kkknksicsoporoai, - egy vágy jobb hatogénatom éstvsgy · (CrRb) slkillcsoporí, :η·κ·Ιν maga adob.esőiben helyettesített adk/soporttal * -3kH-Cö--NB-ankvo;pöít, 'Ni^CCv-NH'hvívrö;KÍksq>on: vagy ·ΝΗ ·ίΛ>·ΝΗ·:(Λ·Γ;:; alkllcsogört ame-· ívek mindegyike atkái esetben aelyirttestíeir egy vagy több hakigénatororoak ciaítoesopontak oltto-· csoportsai, egy vagy több hkiroxlksopixéta! vagy (Cr-CBiilkoxicsotxtrhai, * 'NgCy^^yvkikísöpoíl ahol a fCkCksakiksapoit hslyettexitetí leltet egy vagy több olyan arilesoportktl amely vagy amelyek adtát esetben helyetiesltve vasknakí egy vagy több halogéaatoníiösl és/vagy Sö:. csoporttal, * -NH~€G~sriksöpö*t vagy 'MH-€Í>heleroamesoporS, aavJyek mindég yske atkái esetben kclyeoesiteii egy vagy uá/b halogénstonsesai; vagy R:í A-val egyék olyas; poiieiidnso:; hetssoarílesoporiot alkok amely adok esetben iselyetleslteii iCváhpalkoxIcsoportial vagy arhesoporual (amely maga is egy vagy röbb h;rtogénomnsmai helye-ía/IOá; lekes) vagy adott esetben helyettesített (CaCmalkílcsoportiak • R.j jelentése hidrogénatom: \agy tibálijnlkllcsopmí: - Rb jelentése: * hldrogénatorn, * (C;-Cd aíknesopoo. amely adok eveiben helyettesítek egy vagy több hakígéna:omn;si, egy vagy -óbb bhiíosll-, eiano·, amit»·, hetefoeikloaiídö vagy {Crkk)alkísvksí>ps)1taf vagy olyan srilesopontak amely maga egy vagy több ísaiogéxatommat kelyeltesksh lehel; " (Cj-C í.ye Ikloslkücsopoék * (CrC^dalkinikvopeR;. * (C: --Qlalkosicsopori, * srilcsonort amely adok eve· bee helyettesített egy vagy több Ixdogenaionoos!; ~ Re jelentése nkbogénslom vagy egy vagy több bölogénammnsas adott esetben belyekesáek {€ r-€í.)alki lesöpört: vagy Rb év Re polkikksov heieroariiesotxnlrá vagy beteroeikloaikílesoponöt alkot avval a niírogenaionxna!, mixlyhe/: kapcsolódnak; · m es n ékéke egymástól lugyetlennl ö, 1 vagy 2: avval a megkötess·:.'!. hogy raers<3; - p és p értéke egymásaié! ks ege kanéi k 2 vagy 3. avval a megkötéssel, begy na p ériéke 2 vagy erikái nagyobb, akkor av R:: csoportok kűlönbovd svériatossmken vannak és egymásról eltérőek lehetnek, és ha p' értéke 2 v;rgy ennél nagyobb, akkor a/ R csoportok klrlönbövo svémnomokos vatatak és egynsőstiM eltérőek lőhetnek; - q értéke 0 vagy 2, avval a nsegkötesseb hogy ha q :: (I, akkor av a ahrogémartolmó beíeroeikin-sós csoport, amely a 2;4oliexo·· 1:2.3,dnairnbldixikirsavoins gytblirendaver i-helyveieben lévő nib rögénatomreal van össvekapesoiva, nlties továbbá áihkhdya. és av alábbi típusú:

   ahol Rs, R; m is sí Ideitsése a ioátiekbea ixseghatátoaoR; és - r értéke 0 vagy 1 - báals vagy savadofciös só kassájába;! legalább egy kaortovasakdöds betegség keaeléséberi édvagy legalább egy kanálé vas akoláris betegség kiaiái: olásanak trtegelöaésértsa vde dkalmaaásra.
2. 2. Vegyiket ag igéstyped sxgnmt aJkataxáaáertt, ί»χ«3·| hogy a k&amp;rdjomsxkuíMs beteg ség a kovvtkeaok kosai vast megváí&amp;satva: (1) kosboráé;: betegségek, (ii) a: saivíamek betegségé·, (bité salvbíh leatyák betegségei, (tv) a sdvbarok betegségek (v> sál sotrntAza varok és sdvtagerveaetés; betegségek, és tv;} vere-k»>ck megbetegedései,
3. 3- Vegylhet a* k vagy 2. igénypont saerimi áifcdnraaásra, sassaí jidkíssseave, hogy a kardiovásakdátis betegség a kovetkeabk kőéül vas raegvákasttvs; odokardiárts kdárktos. különösen miokardiárts Marktós követ-ksarnényekéni rtdlépo saivössssehúabdási anyag a vad·· és vagy eádamok mperíüaiös sérüléseivel össaeínggö onc bele védések. · adóba; i trragas vérnyomás, ntlRbbroats, érpteabka dán! áriét lés sadmlet saram bdllesaiésé-vei vagy aaélkük mberosékleroais és aa eaad járó komplikációk. seivelégtdenség, I.iieíjeu: saivbaj és viralis és/vagy bakteriális eredeté saívlaomgynlládás, 4, 'Vegyűfét aa déaö igéaypósaxsk bármelyike sgerirsti .alkalmazásra, ssxk&amp;I jeliemeave, hogy A jelentése teái lesöpört vagy pírtól lesöpört.
4. 5. Vegyiket a» eloao igéttyporUok báromlyibe sámánét arkaiírsazásra, oaaal j«.lteis«xye, hogy q ~ 0, továbbá m és ti éfteke egyatéíd i,
5. 6, Yegytikrt &amp;a doaö Igéstypohrttk bármely ike saendr álkalmaaásra, aaaal jebessteave? Rogy R:, jelentése (Cj-Cddkilesoport, különösen -Ms-CO-Rb csoporttal - ahol Re jelentése aa I. vagy 2, Igény pasiban rnegkatá-roaet; - belydtesííeí! nméilesopört.
6. 7. Vegyidet aa 1-5, igénypontok bármelyike sémiért alkakoaaásra, saaal jeReoseave, hagy R;; jelentése -ORa esepert, ahol Re jelentése a a I. vagy 2. Igénypontban megrtataroeeR. R. Vagyidet ea 1-5. igénypontok bártodytke saerioéi slkaRnánásüs, axáal jéiietReave- hogy R? jdéntése bsiogétsatom vagy aiötmgénátom vagy ciano- vagy aidrsvib vagy olyan tC;-Cdalkiksopork amely ártott esetben helyettesítve van -14% csoporttal v&amp;gy továbbá -RHC(0)Rb Csoporttal is: akta Re jelentése aa t, vagy 2, le és-poriban osegrtaiámeert.........
7. 9, Vegyidet aa l-t. Igénypontok báretelyike szennái AAsásáisni, aaassl jolknasezve, Sogy: -- A jelentése a 4. igénypontban nmghmárosodr -- n. m és a értéke oa 5, igénypontban enegbádro/ost • R> jeleatese a b,, 2. vagy S. igenyptiadssn meghaiáioaott. H), Vegyöiet av 1-3, igénypontok bánnelyike saedeti atotoxásta,. .axxal .jellentesvo,. :&amp;«gy A jeieatése ienörsopor·. R; joleittese -C{R)R esopoit, a;;o; R jeienirtv titdrogénatofit, e értéke 0, o és ot értéke egyaránt i és R: je;en;ése --ORa, aha! Ra jeierbése aa s. vagy 2. tgétiypoBtfeaa ioegadoti. i i. Vegyhiet aa t-3. tgenypoittstk bárieeiyikp saeíjpti aikatmaaásni, astaai jehetoeave, hogy Aqdeatése feoövsoport, R; jdadése -CéO}E esopórt, atioi R jelemése btdrogéoatoí». t} értéke ö te és;« értéke egyaráoí í, g értéke i és R- ·νΑ;9ό?·ί -NI i -RO -Hb ésoporttat aboi Rb jdentése aa R vagy 2, igénypo?iR;ai:t tbégbrtároabtt ··" adyeüesitett mettlesbpssri,
8. 12. VegyoÍei aa b-3. igéoypordok bármelyike saermt! alkaksaaásra, aaaal jdtéoievve, hogy A leissstése iee; lesöpört, R. jeleatése -C(b}R csoport, ártól R jeletttése hkirogénaumt, í; értéke ö, a és trs értéke egs:aráat kp értáke 2 ás az R> csoportok közöl az egyik jeledese -Oka - ahol Ra jdeístése az ;. vagy 2, ;g:knpoo;ba·· meghatározott és a/ R:í csoportok köeö; a másik jelentése haiogésiatom,
9. 13. Vegyisiet az 1-3. igénypontok bármelyike szerinti afelmasásm, assza! jellemezve, Rogy az ÍR csoport: a 2.o-d!íís:o-- L23,4-íoPahiílrok:ííKírt:slói gyticürsndxzer S-bdyxetébers van és egy további R >: csoport sebet -ansely azonos vagy dobd a lent eortbett R;: csoporttól - a 2,4~#oxo-i,23xddeírah-idrPkinazrtS:in gyürürondsser 7~ helyréiében, tn.isryRistt ssz eotlReílii) általános képied vegyület bázis, bábát vag\ szzslváe fóríMjábarg ixosnetek formájában vagy· ezek keverékéi formájában váz,
10. 14. Vegyitiet az i-3. igéssypeatok bármelyike szerinti aiRabzssrzássxs, tsz alábbiak kozd kiválasztva: 1.2'-|p-f3<4-dias4tox)benzi]:)vl.'-{!4ömrtipípendb5'4-t{)~2d-dks>;0“l,23jíl-'toi:r;5h-íbrt>k!.ní5iZoiín-i6-5tjos<sj·· ptopansritíis 2. Ι··(1··;5ςοίΐ1ρίρ3Γκ11ίν-441)·'34οί4-ίΗχηζ·οχ11>οηζίΙ}·'ό4νί4νοχί4ίχ'δ.ζο11η^,4(ΙΗ3Η:!·'ί1ΐϊ>$? 3. (Π 41 •aee1ilp;pcr!Űi-S''rti:r.3-?;P4d!íoe:Osibenzir}-2.4d!0\o· i 33.44eSo:ácdrekieazoioob-is jeri}aecíoak:ii 4. 2-(1.1 -(I-accsbpipvs;bin'4--ilS-.b{ k4.-dbsscíOAÍbcnzrt j-2,4-<boK,v 1 (33,4- tetraÍsidieskirsazolbt-b-iljöxii -psopánnSh'b 5. ; ; 14k4.-doneU>xibeozb}-4 -(i ΡοΓοοηορν^οΡ·!··!·ίΪ5··2.4·4;ον·,·0 23,4.-;víraiburok;uazobs:'i>-iikrtlUa:eiooi;ril 6. (i:ks3!4'-diosetoxiböítZ5Í)'O'-(Í-ibrtS;ilpipefidb:S'-4'b}'2,4-áioxv>' í:J3c^4etfisb:ib!'okitiaz<4in-6-ii]ími)ai:et0fíbrii Π. 4-|3-(3.4-dhucU>\ibíci!s·il)-d'i2'íí-ío·'' 5 -{Híso- íssí:·sí s-eto-d 1 -2-di<íNi?-3.-5-uü-ííirok:;>;vz:>i;f·-·i?2H;-5i ipiperidin-1-karbabfebid 12. i -<i -'íScc;ii.s:piper5d3f!--4--5Í>-i3--:(3db-ifiísis-tovdb«s5e::il>"23'[2'fl3,sor'! '(f4t5í5;rnseí:ií>í?toxílksn;s.^oii3Z''3,;4(Í lis3fId-díösv 13. d-p-íl^-ílisnsítoxíbenzálb-di^'vikíXO-b-Cz/i^-tfiSnorotosiKijd-dMárokmazO'Hsr"](2H)-!i]pipefidió·· 1 -ksrbakishki 14. k;(rtaceídpipetídm:'4-d}'b-í23-ÍÍitbioreto:\í;v3-(3d'dbs5etovibeisziiÍkírí;szobr!--2d(bH.3H)'diOf; 10. 4'{θ';(2:3'θ10οοΓθίοχϊ)'3·'(3ζ!-41ίϊνν:ϊθχ1ό«ί5ΖΪΟ·'24Ρ41οζο·33ϊ··41όΐΡζο1νηίΖΖοΙΐ53' i(2M>U|pipe.ddm~Í~ kinbaldebid
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