HRP20020782A2 - Carbamate caspase inhibitors and uses thereof - Google Patents
Carbamate caspase inhibitors and uses thereof Download PDFInfo
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- HRP20020782A2 HRP20020782A2 HRP20020782A HRP20020782A2 HR P20020782 A2 HRP20020782 A2 HR P20020782A2 HR P20020782 A HRP20020782 A HR P20020782A HR P20020782 A2 HRP20020782 A2 HR P20020782A2
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- compound
- ring
- indole
- triazafluorene
- oxygen
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Description
Srodne aplikacije
Ovom aplikacijom zahtjeva se prioritet u US Provisional Patent Application 60/192,826 koja je podnesena 29.ožujak 2000.
Područje izuma
Ovaj izum je iz područja medicinske kemije i odnosi se na nove spojeve, i na njihove farmaceutske kompozicije, koji inhibiraju kaspazu tako da posreduje staničnoj apoptozi i upali. Izum se odnosi i na metode upotrebe spojeva i farmaceutskih kompozicija ovog izuma u tretiranju bolesti gdje je uključeno djelovanje kaspaze.
Pozadina izuma
Apoptoza, ili programirano umiranje stanica, je vodeći mehanizam kojim organizam eliminira neželjene stanice. Deregulacija apoptoze, jednako pekomjerne apoptoze ili izostanak do nestanak, uključen je kod brojnih bolesti kao što je karcinom, akutne upalne i autoimune smetnje, ishemične bolesti i određene neurodegenerativne smetnje (vidi općenito Science, 1998, 281, 1283-1312; Ellis et al., Ann.Rev.Cell.Biol., 1991, 7, 663).
Kaspaze su srodne enzimima cistein proteaze i ključni su medijator važnog puta za apoptozu i staničnu razgradnju (Thornberry, Chem. Biol.r 1998, 5, R97-R103). Taj važni put različito ovisi o tipu stanica i sredstvu za podražavanje ali ovi putovi apoptoze koja se javlja kod međusobnog približavanja u zajednički učinak puta koji dovodi do proteolize ključnih proteina. Kaspaze su uključene u obje faze učinka važnih putova i dalje u suprotnom smjeru pri njegovom uvođenju. Kaspaze suprotnog smjera uključene u pokretanje događaja počinju aktivirati i dolazi do aktiviranja drugih kaspaza pa su tako uključene u kasnije faze apoptoze.
Kaspaza-1, prva identificirana kaspaza, je isto poznata kao enzim za pretvaranje interleukina ili "ICE".
Kaspaza-1 pretvara prekursore interleukina-1β "pIL-1β" u pro-inflamatorni aktivni oblik specifičnim cjepanjem pIL-1β između Asp-116 i Ala-117. Osim toga kaspaza-1 kao i jedanaest drugih poznatih humanih kaspaza, sve koje cijepaju specifično na aspartil ostatke. To isto je uočeno kod direktnog zahtjeva za najmanje četiri ostatne amino kiseline na N-terminalnoj strani mjesta cjepanja.
Kaspaze su kalsificirane u tri skupine ovisno o sekvencijama amino kiseline koja se preferira ili primarno prepoznaje. Skupina kaspaze koja uključuje kaspaze 1, 4 i 5, pokazala je da se preferira hidrofobne aromatske amino kiseline na poziciji 4 na N-terminalnoj strani mjesta cjepanja. Druga skupina koja uključuje kaspaze 2, 3 i 7, prepoznaje ostatke aspartila na objim pozicijama 1 i 4 na N-terminalnoj strani mjesta cjepanja, a preferira se sekvencije Asp-Glu-X-Asp. Treća skupina, koja uključuje kaspazu 6, 8, 9 i 10, tolerira brojne amino kiseline u primarnoj sekvenciji prepoznavanja, ali čini se za preferirane ostatke s razgranatom, alifatskom stranom lanca kao što je valin i leucin na poziciji 4.
Te kaspaze isto mogu biti grupirane u skladu s njihovom razumljivom funkcijom. Prva subfamilija sadržava kaspaze-1 (ICE), 4, i 5. Te kaspaze može se pokazati da su uključene u razvoj pro-inflamatornih citokina i zbog toga igraju značajnu ulogu upalnom u procesu. Kaspaza-1, je najviše proučavani enzim ove klase, aktivatora IL-1β prekurzora proteočlitičkog cjepanja. Taj enzim zbog toga igra ključnu ulogu u inflamatornom odgovoru. Kaspaza-1 je isto uključena u razvoj faktora indukcije gama interferona (IGIF ili IL-18) koji stimulira produkciju gama interferona, ključ prisutnosti imunoregulatora tog moduliranog antigena, aktivaciju T-stanica i adhezije stanica.
Spomenuta kaspaza upotpunjuje drugu i treću subfamiliju. Ti enzimi su od središnjeg značenja u intracelularnom važnom putu koji dovodi do apoptoze. Jedna subfamilija sadržava enzime uključene u početni događaj u putu apoptoze, uključujući transdukciju signala od membrane plazme. Članovi ove subfamilije uključuju kaspaze-2, 8, 9 i 10. Druga subfamilija, sadržava efektore kaspaza 3, 6 i 7, a uključeni su u događaj finalno nizvodno cjepanje koje da rezultira sistematskim lomom i smrti stanica apoptozom. Kaspaze uključene u nizvodne signale aktivacije transdukcije kaspaze, koji potom unište mehanizme oporavka DNA, fragmente DNA, ogole stanične citoskelete i na kraju fragmente stanice.
Četiri sekvencije amino kiseline primarno prepoznate kaspazom detrminirane su za enzimske substrate. Talanian et al., J. Biol. Chem., 272, 9677-9682, (1997); Thornberry et al., J. Biol. Chem. 272, 17907-17911, (1997). Poznavanje četiri amino kiselinske sekvencije primarno prepoznate s kaspazama koristi se u dizajniranju inhibitora kaspaze. Reverzibilni inhibitori tetrapeptida proizvedeni imaju strukturu CH3CO-[P4]-[P3]-[P2]-CH(R)CH2CO2H gdje su P2 do P4 predstavnici optimalnog prepozvanja sekvencija amino kiselina i R je aldehid, nitril ili keton sposobni za vezivanje na kaspaze cistein sulfhidril. Rano i Thornberry, Chem. Bol. 4, 149-155 (1997); Mjalli, et al., Bioorg. Med. Chem. Lett. 3, 2689-2692 (1993); Nicholson et al., Nature 376, 37-43 (1995). Ireverzibilni inhibitori bazirani na analognim tetrapeptidima prepoznaju sekvencije koje su pripravljene kada R je acikloksimetilketon - COCH2OCOR . R je dokazan po izboru supstitucijom fenil a kao što je 2f 6-diklorbenzoiloksi i gdje R je COCH2X kada X je ostatna skupina kao što je F ili Cl. Thornberry et al., Biochemistry 33, 3934 (1994); Dolle et al., J Med. Chem. 37, 563-564 (1994).
Korisnost inhibitora kaspaze za tretiranje različitioh stanja bolesti sisavaca povezanih s porastom stanične apoptoze pokazano je upotrebom inhibitora peptidične kaspaze. Naprimjer, na modelu rodenata, inhibitori kaspaze su pokazali redukciju veličine infarkta i inhibiciju kardiomonocitne apoptoze nakon infarkta miokarda, za redukciju volumena lezija i neuroloških deficita koji potječu od kapi, za redukciju post-traumatskih apoptoza i neuroloških deficita kod traumatskih oštećenja mozga, učinkoviti su u tretiranju fulminantnih destrukcije jetre, i za poboljšanje preživljavanja nakon endotoksičnih šokova. Yaoita et al., Circulation, 97, 276 (1998); Enders et al., J Cerebral Blood Flovr and Metabolism, 18, 238 (1998); Cheng et al., J. Cl i n. Invest., 101, 1992 (1998); Takovlel et al., J Neuroscience, 17, 7415 (1997); Rodriguez et al., J. Exp. Med., 184, 2067 (1996); Grobmver et al., Mol.Med., 5 585 (1999).
Općenito peptidični inhibitori gore opisani su veoma potentni protiv nekih kaspaza enzima. Međutim, ta potencija uvijek se ne reflektira na celularne modele apoptoze. Osim toga inhibitori peptida su pravilno označeni nepoželjnim farmakološkim svojstvima kao što su slaba oralna absorpcija, slaba stabilnost i brzi metabolizam. Plattner and Norbeck, in Drug Discovery Technologies, Clark and Moos, Eds. (Ellis Horwood, Chichester, England, 1990).
Ovo je izvještaj o modificiranim inhibitorima peptida. WO 91/15577 i W093/05071 prikazuju inhibitore ICE peptida formule:
[image]
Gdje Z je N-terminalna zaštićena skupina, Q2 je 0 do 4 amino kiseline; Q1 je elektro negativna ostatna skupina.
WO 99/18781 prikazuje dipeptid inhibitore kaspaza formule :
[image]
gdje R1 je N-terminalna zaštićena skupina; AA je ostatak prirodne α-amino kiseline ili β-amino kiseline; R2 je vodik ili CH2R4 gdje R4 je elektronegativna ostatna skupina; R3 ili alkil ili vodik.
WO 99/47154 prikazuje dipeptid kaspaze inhibitore formule:
[image]
gdje R1 je N-terminalna zaštićena skupina; AA je ostatak neprirodne α-amino kiseline ili β-amino kiseline; a R2 je po želji substituiran alkil ili vodik.
WO 00/023421 prikazuje (supstituirani) alkil dipeptid inhibitore apoptoze koji ima formulu:
[image]
gdje n je 0, 1 ili 2; q je 1 ili 2; A je ostatak određene prirodne ili ne-prirodne amino kiseline; B je atom vodika, atom deuterija; C1-l0 ravan lanac ili razgranati alkil, cikloalkil, fenil, substituirani fentil, naftil, substituirani naftil, 2-benzoksazolil, substituirani 2-oksazolil, (CH2)mcikloalkil, (CH2)mfenil, (CH2)m (substituirani fenil), (CH2)m(1- ili 2-naftil), (CH2)mheteroaril, halometil, CO2R13, CONR14R15, CH2ZR16,CH2OCOaril, CH2OCO(substituirani aril), CH2OCO(heteroaril), CH2OCO(substituirani heteroaril), ili CH2OPO(R17)R18, gdje R13, R14, R15, R16, R17 i R18 su definirani u aplikaciji; R2 je odabran iz skupine koja sadržava vodik, alkil, cikloalkil, fenil, substituirani fenil, (CH2)mNH2; R3 je vodik, alkil, cikloalkil, (cikloalkil)alkil; fenilalkil, ili substituirani fenilalkil; X je CH2, O=O, O, S, NH, C=ONH ili CH2OCONH; a Z je kisik ili atom sumpora.
WO 97/24339 prikazuje inhibitore pretvaranja enzima interleukin-1β formule:
[image]
gdje R1 predstavlja H, alkil, alkoksi, karbocikl, heterocikl, i različite druge skupine; AA1 i AA2 su jednostruke veze ili amino kiseline, a Y predstavlja skupinu formule:
[image]
Gdje Tet prsten predstavlja tetrazol prsten; a Z predstavlja, inter alia, alkilen, elkenilen, O, S, SO, i SO2.
Ep 618223 prikazuje ICE inhibitore formule :
R-A1-A2-X-A3
gdje R je H, zaštićena skupina, ili po izboru prster supstituirani PhCH2O; A1 je ostatak α-hidroksi- ili α-amino kiseline; A2 je ostatak α-hidroksi kiseline ili α-amino ili A1 i A2 oblik zajedno s pseudodipeptidom ili dipeptidom ostatak mimetičkog dipeptida; X je ostatak deriviran iz Asp gdje A3 je CH2X1COY1, CH2OY2, CH2SY3 ili CH2(CO)mY6, gdje Xl je O ili S, M je 0 ili 1, a Y1, Y2, Y3 i Y6 su po želji supstituiram ciklične alifatske ili aril skupine.
WO 98/16502 prikazuje, inter alia, ICE inhibitore formule:
[image]
R1 i R2 su opisani u aplikaciji a pirolidin prsten je supstituiran različitim skupinama.
Dok je izvješteno o brojnim inhibitorima kaspaze, nije jasno koji od njih posjeduje određena farmakološka svojstva da bi bio terapijski upotrebljiv. Zbog toga, prisutna je stalna potreba za malim molekulama inhibitora kaspaze koje su potentne, stabilne i penetriraju kroz membrane tako da osiguraju učinkovitu inhibiciju apoptoze in vivo. Takve supstancije će biti izuzetno korisne u tretiranju gore spomenutih bolesti gdje enzim kaspaza igra ulogu.
Sažetak izuma
Utvrđeno je da ti spojevi ovog izuma i njihove farmaceutske kompozicije su učinkoviti inhibitori kaspaze i stanične apoptoze. Te supstancije imaju opću formulu I:
[image]
gdje:
Z je kisik ili sumpor;
R1 je vodik, -CHN2, -R, -CH2OR, -CH2SR, ili -CH2Y;
R je alifatski C1-12, aril, aralkil, heterociklični, ili heterociklilalkil;
Y je elektronegativna ostana skupina;
R2 je CO2H; CH2CO2H; ili ester, njihovih amida ili izostera;
R3 je skupina sposobna za pristanje u S2 sub-mjesto kaspaze;
R4 i R5 uzimaju zajedno s interventnim dušikom oblik mono-, bi- ili sustava tricikličnog hetero prstena a imaju 1-6 heteroatoma odabranih od dušika, kisika ili sumpora.
Supstancije ovog izuma imaju inhibitorna svojstva preko ciljanog reda kaspaze s dobrom učinkovitosti u staničnom modelu apoptoze. Osim toga, te supstancije imaju dobru penetraciju i farmakokinetička svojstva i, kao posljedicu njihove aktivnosti, imaju dobru učinkovitost protiv bolesti gdje je uključena kaspaza.
Detaljan opis izuma
Ovaj izum osigurava nove spojeve, i njihove farmaceutski prihvatljive derivate, tako da su upotrebljivi kao inhibitori kaspaze. Izum isto osigurava metode za upotrebu spojeva za inhibiciju aktivnosti kaspaze i za tretiranje kaspazom-posredovanih bolesnih stanja. Ti spojevi imaju opću formulu I:
[image]
gdje
Z je kisik ili sumpor;
R1 je vodik, -CHN2, -R, -CH2OR, -CH2SR, ili -CH2Y;
R je C1-12 alifatski, aril, aralkil, heterociklični, ili heterociklilalkil;
Y je elektronegativna ostana skupina;
R2 je CO2H; CH2CO2H; ili esteri njihovih amida ili izostera;
R3 je skupina sposobna za pristajanje u S2 sub-mjestu kaspaze;
R4 i R5 uzimaju zajedno s interventnim dušikom oblik mono-, bi- ili sustav tricikličnog hetero prstena a imaju 1-6 heteroatoma odabranih od dušika, kisika ili sumpora.
Kao što se koristi ovdje, sljedeće definicije će se primjenjivati osim ako je drugačije indicirano. Pojam "alifatski" ovdje se koristi u značenju ravnog ili razgranatog lanca C1-C12 ugljikovodika koji je kompletno zasićen ili koji sadržava jednu ili više nezasićenih jedinica. Naprimjer, prikladna alifatska skupina uključuje substituiranu ili nesubstituiranu ravnu, razgranatu ili cikličnu alkil, alkenil ili alkinil skupinu i njihove hibride kao što je (cikloalkil)alkil, (cikloalkenil)alkil ili(cikloalkil)alkenil. Pojam "alkil" koristi se sam ili kao dio veće polovice koja se odnosi na ravni i razgranati lanac koji sadržava jedan do dvanaest atoma ugljika. Kada se koristi pojam alkil kao dio veće polovice, kao u aralkil ili heteroaralkil, alkil dio će preferirano sadržavati jedan do šest ugljika. Pojam "halogen" znači F, Cl, Br ili I. Pojam "aril" odnosi se na monociklične ili policiklične aromatske skupine prstena koje imaju pet do četrnaest atoma, kao što je fenil, naftil i antril. Pojam "heterociklična skupina" Odnosi se na zasićeni i nezasićeni monociklični ili policiklični sustav prstena koji sadržava jedan ili više heteroatoma i prsten veličine od tri do devet kao što je furanil, tienil, pirolil, pirolinil, pirolidinil, dioxolanil, oksazolil, tiazolil, imidazolil, imidazolinil, imidazolidinil, pirazolil, pirazolinil, pirazolidinil, izoksazolil, izotiazolil, oksadiazolil, triazolil, tiadiazolil, piranil, piridinil, piperidinil, dioksanil, morfolinil, ditianil, tiomorfolinil, piridazinil, pirimidinil, pirazinil, piperazinil, triazinil, tritianil, indozinil, indolil, izoindolil, indolinil, benzofuranil, benzotiofenil, indazolil, benzimidazolil, benztiazolil, purinil, kvinolizinil, kvinolinil, izokvinolinil, cinolinil, ftalazinil, kvinazolinil, kvinoksalinil, l,8-naftiridinil, fteridinil, kvinuklidinil, karbazolil, acridinil, fenazinil, fenotiazinil, ili fenoksazinil. "Heteroaril" odnosi se na heterociklični prsten koji je aromatični. Smatra se da su spojevi ovog izuma ograničeni na one koji mogu postojati u prirodi kao stabilni kemijski spojevi.
Pojam "karbociklična skupina" odnosi se na zasićeni monociklični ili policiklični sustav prstena ugljika od tri do četrnaest ugljika koji mogu biti spojeni na aril ili heterocikličnu skupinu. Primjeri uključuju cikloheksil, ciklopentil, ciklobutil, ciklopropil, indanil, tetrahidro-naftil i slično.
Alifatski, alkil, aril, heteroaril, heterociklil, ili karbociklil, koriste se sami ili kao dio veće polovice, odnose se na substituirane ili nesupstituirane skupine. Kada se substituira, te skupine mogu sadržavati jedan ili više substituenata. Primjeri prikladnih substituenata uključuju halogen, -R, -OR, -OH, -SH, -SR, zaštićeni OH (kao što je acikloksi); fenil (Ph), substituirani Ph, -OPh, substituirani -OPh, -NO2, -CN, -NH2, -NHR, -N(R)2, -NHCOR, -NHCONHR, -NHCON(R)2, -NRCOR, -NHCO2R, -CO2R, -CO2H, -COR, -CONHR, -CON(R)2, -S(O)2R, -SONH2, -S(O)R, -SO2NHR, -NHS(O)2R, =O, =S, =NNHR; =NNR2, =N-OR; =NNHCOR, =NNHCO2R, =NNHSO2R, ili =NR gdje R je alifatska skupina ili substituirana alifatska skupina.
Dušik koji se može supstituirati na heterocikličnom prstenu može se po izboru substituirati. Prikladni substituent dušika uključuje R, COR, S(O)2R, i CO2R, gdje R je alifatska skupina ili substituirana alifatska skupina.
Dušik i sumpor mogu biti u njihovom oksidiranom obliku, a dušik može biti u kvaterniziranom obliku.
Pojam "elektronegativna ostatna skupina" ima definiciju koja je poznata stručnjacima (vidi March, Advanced Organic Chemistry, 4th Edition, John Wiley & Sons, 1992). Primjeri elektronegativne ostatne skupine uključuju halogene kao što su F, Cl, Br, I, aril, i alkilsulfoniloksi skupine, trifluormetansulfoniloksi, OR, SR, -OC=O(R), -OPO(R6) (R7); gdje je R alifatska skupina, aril skupina, aralkil skupina, karbociklična skupina, alkil karbociklična skupina, heterociklična skupina, ili alkil heterociklična skupina; a R6 i R7 nezavisno odabrana od R ili OR.
Kada je R2 skupina u obliku estera ili amida, prezentirane supstancije podvrgnute su metaboličkom cjepanju u odgovarajuću karboksilnu kiselinu, koja je djelatni inhibitor kaspaze. Zbog podvrgavanja tom metaboličkom cjepanju, točna priroda ester ili amidne skupine nije kritična za djelovanje ovog izuma. Struktura R2 skupine može biti u granicama od relativno jednostavnog dietil amida do stereoidnih estera. Primjeri estra R2 karboksilne kiseline uključuju, ali nisu njima limitirani, alifatski C1-12, kao što je C1-6 alkil ili C3-10 cikloalkil, aril, kao što je fenil, aralkil, kao što je benzil ili fenetil, heterociklil ili heterociklilalkil.
Primjeri prikladnog R2 heterocikličnog prstena uključuju, ali ne limitiraju ga, su 5-6 člani heterociklični prsten koji ima jedan do dva heteroatoma kao što je piperidinil, piperazinil, ili morfolinil.
Amidi R2 karboksilne kiseline mogu biti primarni, sekundarni ili tercijalni. Prikladni substiutuent dušik amida uključuje, ali ne limitra, je jedna ili više skupina nezavisno odabranih skupina od alifatske, aril, aralkil, heterociklil ili heterociklilalkil skupina gore opisanih za R2 ester alkohola. Slično, drugi pro-lijekovi su uključeni unutar cilja ovog izuma. Vidi Bradly D. Anderson, "Prodrugs for Improved CNS Delivery" in Advanced Drug Delivery Reviews (1996), 19, 171-202.
Izostere ili bioizostere R2 karboksilne kiseline, estera i amida rezultat su izmjene atoma ili skupine atoma za kreiranje novog spoja s jednakim biološkim svojstvima kao izvorna karboksilna kiselina ili ester. Bioizosterična zamjena može biti fizikalnokemijskoj ili topološkoj osnovi. Primjeri izosteričnog zamjenjivanja karboksilne kiseline je CONHSO2(alkil) kao što je CONHSO2Me.
R3 može biti skupina sposobna za pristajanje u S2 sub-mjestu kaspaze. Takve skupine poznate su iz brojnih inhibitora kaspaze o kojima je izvješćeno (vidi WO 91/15577, WO 93/05071, WO 99/18781, WO 99/47154, WO 00/023421, WO 9724339, EP 618223, WO 9816502, svi koji su gore opisani). Međutim, struktura pojedinih enzima kaspaza uključuju S-2 submjesta koja su isto poznata. Referencije za strukturu kaspaza uključuju sljedeće: Blanchard H, et al., J.Mol.Blol. 302(1), 9-16 (2000); Wei Y, et al., Chem.BioI. 7(6):423-32 (2000); Lee D, et al., J.Biol.Chem. 275(21): 16007-14 (2000); Blanchard H, et al., Strukture Fold Des.7(9): 1125-33 (1999); Okamoto Y; et al, Chem. Pharm. Buli. (Tokyo) 47(1): 11-21 (1999); Margolin N, et al, J.Biol.Chem. 272 (11) :7223-8 (1997); Walker NP, et al., Cell 78(2):343-52 (1994); i Wilson KP, et al., Nature 370(6487): 270-5 (1994).
Da li je skupina koja će pristajati na S-2 submjesto ovisiti će o određenoj kaspazi koja će se razmatrati. Veličina subsite će biti u granicama od malog S-2 submjesta kaspaze-3 koje su grupirane na veliku C4 alifatsku skupinu na relativno velikom submjestu koje postoji na skupini koja ima molekularnu masu od oko 140 Daltona, kao što je naftil skupina. Veličina, istovremeno elektronske prirode, R3 skupina utječe na selektivnost inhibitora kaspaze. Iz gore navedenih referencije osigurano je, bez stručnjaka može se gotovo utvrditi da li je skupina pristaje na S-2 sub mjesto kaspaze, naprimjer, upotrebom standardnog programa modeliranja kao što je Quanta Macromodel.
R3 skupine uključuju to da su odabrane od vodika, postranog lanca prirodne α-amino kiseline, ili substituirana ili nesubstituirana skupina molekulske mase sve do oko 140 Daltona odabrana od alifatske, aril, aralkil, heterociklil, i heterociklilalkil skupine. Primjer R3 alifatskih skupina uključuje metil, etil, propil, izopropil, ciklopropil, butil, izobutil, sec-butil, tert-butil, ciklobutil, pentil, ciklopentil, heksil, i cikloheksil. Primjeri R3 aril skupina uključuju fenil, indenil i naftil. Primjeri R3 heterocikličnih skupina uključuju pirolidinil, pirolinil, imidazolidinil, imidazolinil, pirazolinil, pirazolidinil, piperidinil, morfolinil, tiomorfolinil, piperazinil, homopiperidinil, i kvinuklidinil. Primjeri R3 heteroaril skupina uključuju furanil, tienil, pirolil, oksazol, tiazolil, imidazolil, pirazolil, izoksazolil, izotiazolil, oksadiazolil, furazanil, triazolil, tiadiazolil, piridinil, piradazinil, pirimidinil, pirazinil, triazinil, indolil, izoindolil, indolinil, benzofuranil, benzotiofen, indazolil, benzimidazolil, benz-tiazolil, purinil, kvinolinil, izokvinolinil, kvinolizinil, cinolinil, ftalazinil, kvinazolinil, kvinoksalinil, naftiri-dinil, pteridinil, kromanil, i izokromanil. Kao što je gore opisano svaka skupina može sadržavati jedan ili više substituenata.
R4 i R5 zajedno uzimaju s interventnim dušikom oblik mono-, bi- ili tricikličnog sustava hetero prstena koji ima 1-6 heteroatoma, preferira se 1-4 heteroatoma. Takvi prstenovi uključuju substituirani i nesubstituirani indol, izoindol, indolin, indazol, purin, dihidropiridin, benzimidazol, imidazol, imidazolin, pirol, pirolidin, pirolin, pirazol, pirazolin, pirazolidin, triazol, piperidin, morfolin, tiomorfolin, piperazin, karbazol, fenotiazin, fenoksazin, dihidrofenazin, dihidrocinolin, dihidrokvinoksalin, tetra-hidrokvinolin, tetrahidroizokvinolin, dihidronafthiridin, tetrahidronafthidrin, dihidroakridin, 5H-dibenzo[b,f]azepin, 10,11-dihidro-5H-dibenzo[b,f]azepin, β-karbolin, pirido[4,3-b]indol, 2,3,9-triazafluoren, 9-tia-2,10-diazaantracen, 3,6,9-triazafluoren, tieno[3,2-b]pirol, ili dihidrofenantridin. Prikladni substituenti na R3 ili R5 uključuju jednu ili više skupina nezavisno odabranih od halogena, -R, -OR, -OH, -SH, -SR, zaštićenu OH (kao aciloksi), fenil (Ph), substituirani Ph, -OPh, substituirani -OPh, -NO2, -CH, -NH2, -NHR, -N(R)2, -NHCOR, -NHCONHR, -NHCON(R)2, -NRCOR, -NHCO2R, -CO2R, -CO2H, -COR, -CONHR, -CON(R)2, -S(O)2R, -SONH2, -S(O)R, -SO2NHR, ili -NHS(O)2R, gdje R je nezavisno odabran od alifatske skupine ili substituirane alifatske skupine.
Spojevi ovog izuma gdje R2 je COOH su gama-ketoacidi, koji mogu biti u otopini kao i otvoreni oblik 1 ili ciklizirani hemiketalni oblik 2. Predstavljanje ovdje oba izomerična oblika znači da uključuje drugi. Isto tako, kristalizacija može isto javiti gdje R2 je CH2COOH, i tako kristalizirani izomeri smatraju se uključenima kada ih predstavlja prsten otvorenog oblika.
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Isto tako stručnjacima će biti jasno da određeni spojevi ovog izuma mogu biti u tautomernom obliku ili hidratiziranim oblicima, svi takvi oblici spojeva su cilj izuma. Ukoliko nije na drugi način određeno, znači da ovdje opisane strukture uključuju sve stereokemijske oblike strukture; tj., R i S konfiguracije za svaki asimetrični centar. Radi toga, pojedine stereokemijske izomere kao što su enantiomerične i diastereomerične smjese prezentiranih spojeva su unutar cilja izuma. Ukoliko nije na drugi način određeno, ovdje prikazane strukture isto znače da uključuju spojeve koji se razlikuju samo u prisutnosti jednog ili više izotopički obogaćenog atoma. Naprimjer, spojevi imaju prezentiranu strukturu osim za zamjenjenu vodika s deuterijem ili tritijem, ili zamjenjenu ugljika s 13C- ili 14C-obogaćenim ugljikom unutar su cilja ovog izuma. Jedno ostvarenje ovog izuma odnosi se na spojeve koji imaju jednu ili više, preferira se sve, od sljedećih osobina:
(i) Z je kisik.
(ii) R1 je vodik, -R, -CH2OR, -CH2SR, ili -CH2Y.
Više se preferira, da je R1, -CH2OR, -CH2SR, ili -CH2Y. Također se preferira da R1 je -CH2Y. Još više se preferira, da je R1 -CH2F.
(iii) R2 je CO2H ili ester, njihovih amida ili izoestera.
(iv) R3 je skupina koja ima molekulsku masu sve do oko 140 daltona, kao što su alifatske ili aralkil skupine. Više se preferira, da R3 je C1-C4 alkil skupina koja pristaje u S2 sub mjesto reda kaspaza.
(v) R4 i R5 zauzimaju zajedno s interventnim oblikom dušika monociklični, biciklični ili triciklični heterociklični ili heteroaril sustav prstena gdje svaki prsten sustava ima 5-7 atoma prstena.
Ključ osobina prezentiranih spojeva je hetero sustav prstena formiran uzimanjem R4 i R5 zajedno s interventnim dušikom. Biciklični ili triciklični heterocikl ili heteroaril prstenovi su preferirani preko monocikličnih prstenova. U skladu s preferiranim ostvarenjem koje se odnosi na spojeve koji imaju jedan ili više, a preferiraju se sve, od sljedećih osobina:
(i) Z je kisik;
(ii) R1 je vodik, -R, -CH2OR, -CH2SR, ili -CH2Y, više se preferira, da je R1 -CH2Y, a najviše se preferira da je R1 je -CH2F;
(iii) R2 je CO2H ili njihovi esteri, amidi ili izostere;
(iv) R3 je skupina čija je molekulska masa sve do oko 140 daltona, sve alifatske ili aralkil grupe, više se preferira, C1-C4 alkil skupina; i/ili
(v) R4 i R5 zauzimaju zajedno s interventnim oblikom dušika monociklični, biciklični ili triciklični heterociklični ili heteroaril sustav prstena gdje svaki prsten sustava ima 5-7 atoma prstena.
Primjeri preferiranih monocikličnih prstenova uključuju triazol, piperidin, morfolin, tiomorfolin, imidazol, pirolidin, pirazol, i piperazin. Primjeri preferiranih bicikličnih prstenova uključuju indol, izoindol, indolin, indazol, benzimidazol, tieno[3,2-b]pirol, dihidrokvinoksalin, dihidrocinolin, dihidronafthiridin, tetrahidronafthiridin, tetrahidrokvinolin, i tetrahidroizokvinolin, više se preferira indol ili indolin. Primjeri preferiranih tricikličkih prstenova uključuju karbazol, fernotijazin, β-karbolin, pirido[4,3-b]indol, 2,3,9-triazafluron, 9-tia-2,10-diazaantracen, 3,6,9-triazafluren, fenoksazin, dibenzoazepin, dihidro-dibenzoazepin, dihidrofenazin, dihidroakridin ili dihidrofenantridin, više se preferira karbazol, fenotiazin ili dihidrofenantridin.
Specifični primjeri spojeva I su u Tablici 1.
Tablica 1 Primjeri spojeva formule I (Z je kisik)
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Nakon procjene brojnih R4-N-R5 heterocikličnih prstenova, utvrdili smo da triciklični spojevi gdje je kraj prstena stvarno co-planarni pokazuje iznenađujuće široko djelovanje kaspaze u usporedbi s acikličkim analozima ili drugim tricikličkim sustavima prstena koji nisu stvarno co-planarni. Ta stvarna co-planarnost može biti ostvarena kada je sredina prstena tricikličnog sustava prstena 5- ili 6-člani prsten, kao što je u prstenu karbazola ili fenotiazina.
Osim toga, stvarani co-planarni triciklički sustav prstena, kao što je biciklični sustav prstena kao indol i indolin, daju bolju širinu djelovanja kaspaze od odgovarajućih spojeva gdje R4-N-R5 heterociklični prsten je monociklični kao što je piperidin, piperazin ili morfolin.
Zato, preferirana ostvarenja ovog izuma odnose se na spojeve formule I gdje R4-N-R5 je triciklični sustav prstena koji ima 1-6 heteroatoma, preferira se 1-4 heteroatoma, odabranih od dušika, kisika ili sumpora gdje kraj prstena sustava prstena ima 5-7 atoma prstena, a sredina ima 5 ili 6 atoma prstena.
Jedan aspekt ovog ostvarenja odnosi se na spojeve formule II:
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gdje je X veza, -S-; -O-; -CH2-, ili -NH-, Z, R1, R2 i R3 kao što je gore opisano. Kada X je -CH2- svaki od metilen vodika može se po izboru zamjeniti s -OR, -OH, -SR; zaštićenim OH (kao što je aciloksi) , -CH, -NH2-, -NHR, -N(R)2-, -NHCOR, -NHCONHR, -NHCON(R)2, -NRCOR, -NHC02R, -C02R, -CO2H, -COR, -CONHR, -CON(R)2, -S(O)2R, -SONH2, -S(O)R, -SO2NHR, -NHS(O)2R, =O, =S, =NNHR, =NNR2, =N-OR, =NNHCOR, =NNCO2R, =NNHSO2R, ili =NR gdje R je C1-4 alifatska skupina. Kada je X -NH- vodik može biti zamjenjen s alkil, CO(alkil), CO2(alkil) ili SO2{alkil). Preferirane skupine za R1, R2 i R3 su kao što je gore opisano.
Spojevi ovog izuma mogu se proizvesti općom metodom poznatom stručnjacima za analogne spojeve, ilustriranom općom shemom dolje prikazanom i pripremljenim primjerima kao što slijedi.
Shema I
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Reagensi: (a) R5-N=C=Z (2); (b) NaOH/THF/H2O; (c) EDC/DMAP/HOBt; (d) i. Dess-Martin periodinan, (ii) TFA/DCM
Gornja shema I pokazuje put sinteze za dobivene spojeve gdje R4 je vodik. Reakcija izocianata ili tioizocijanata 2 s derivatom mlječne kiseline 1 daje karbamat 3. Ester skupina 3 se hidrolizira upotrebom baze ili, kada je ester t-butil skupina, upotrebom trifluoroctene kisleine da se dobije kiselina 4, koja je potom spojena s amino alkoholom 5. Ovisno o prirodi R1 i R2 može se koristiti amino keton, na pravom položaju amino alkohola, koji ukida kasniji korak oksidacije. U tom slučaju fluormetil ketoni gdje R1 je CH2F, amino alkohol 5 može se dobiti metodom Revesz et al., Tetrahedron Lett., 1994, 35, 9693. Konačno hidroksil skupina u spoju 6 je oksidirana a nastali spoj tretiran prikladno u skladu s prirodom R2. Naprimjer, ako se u produktu zahtjeva da je I R2 karboksilna kiselina, potom R2 u 6 je preferirano ester, a finalni korak u shemi je hidroliza.
Polazni komercijalno dostupni izocijanati i tioizocijanati 1 ili mogu biti pripravljeni reakcijom amina s fosgenom ili ekvivalentom fosgena (ili tiofosgena za proizvodnju tioizocijanata) u prisutnosti baze kao što je trietilamin. Derivati laktata komercijalno su dostupni ili se mogu pripraviti reakcijom amino kiseline s diazotizacije reagensom kao što je NaNO2.
Shema II
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Reagensi: (a) CDI/THF; (b) MeOTf/CH2Cl2; (c) R4R5NH (b) /THF.
Shema II gore pokazuje put sinteze za dobivanje spoja I ovog izuma gdje R4 je alkil skupina ili kada R4 i R5 zajedno čine prsten. Reakcija derivata laktata 2 s 1,1'-karbonildiimidazola (CDI) daje imidazolate 7. Metilacija 7 s metil triflatom, slijedi reakciju s aminom 8 (vidi J.Med,Chem,f (1996), 39, 982) daje intermedijer 3. Shema I gore pokazuje kako 3 može biti pretvoreno u I.
Shema III
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Reagensi: (a) COCl2/CH2Cl2; (b) 1/THF.
Alternativni put sinteze za dobiveni spoj I ovog izuma gdje R4 je alkil skupina ili kada R4 i R5 zajedno formiraju prsten što je pokazano u gornjoj Shemi III. Tretiranje amina 8 s fosgenom daje intermedijer 9 karbamoil klorid. Reakcija 9 s derivatima laktata 1 daje intermedijer 3.
Shema IV
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Reagensi: (a) Cl3COC (O) Cl/THF; (b) R4R5NH (8); NaOH, Bu4NBr.
Gornja Shema IV pokazuje put sinteze za dobiveni spoj ovog izuma gdje R4 je vodik ili alkil skupina ili kada R4 i R5 zajedno formiraju prsten. Reakcija hidroksi estera l s fosgenom ekvivalentom fosgenu kao što su difosgen ili trifosgen vode do intermedijera kloroformata 10. Reakcija 10 s aminom 8 daje intermedijer 3.
Spojevi ovog izuma su dizajnirani za inhibiciju kaspaze. Radi toga, spojevi ovog izuma mogu se analizirati na sposobnost njihove inhibicije apoptoze, otpuštanje IL-1β ili direktno djelovanje kaspaze. Ispitivanje za svako djelovanje je dolje opisano u Djelu ispitivanje, a također je poznato u struci.
Jedno ostvarenje ovog izuma odnosi se kompoziciju koja sadržava spoj formule I ili njihovu farmaceutski prihvatljivu sol, i farmaceutski prihvatljivi nosač.
Da bi farmaceutski prihvatljive soli spojeva ovog izuma bile korisne u tim kompozicijama, te soli su preferirano dobivene iz anorganskih i organskih kiselina i baza. Uključujući te soli kiselina kao što slijedi: acetate, adipate, alginate, aspartate, benzoate, benzen sulfate, bisulfate, butirate, citrate, kamforate, kamfor sulfonate, ciklopentanpropionate, diglukonate, dodecilsulfate, etansulfonate, fumarate, glukoheptanoate, glicerofosfate, hemislufate, heptanoate, heksanoate, hidrokloride, hidrobromide, hidrojodide, 2-hidroksietansulfonate, laktate, meleate, metansulfonate, 2-naftalensulfonate, nikotinate, oksalate, pamoate, pectinate, persulfate, 3-fenil-propionate, pikrate, pivalate, propionate, sukcinate, tartarate, tiocianate, tosilate i undekanoate. Soli baza uključuju amonijeve soli, soli alkali metala, kao što su soli natrija i kalija, alkalne soli zemljanih metala, kao što su soli kalcija i magnezija, soli s organskim bazama, kao što je soli dicikloheksilamina, N-metil-D-glukamina, i soli s amino kiselinama kao što su arginin, lizin, i tako dalje.
Isto tako, bazične skupine koje sadržavaju dušik mogu se kvaternizirati sa takvim sredstvima kao smanjeni alkil halidi, kao što su metil, etil, propil, i butil klorid, bromidi i jodidi; dialkil sulfati, kao dimetil, dietil, dibutil i diamil sulfati, halidi dugog lanca kao decil, lauril, miristil i stearil kloridi, bromidi i jodidi, aralkil halidi, kao benzil i fenetil bromidi i drugi. Pri tom se dobiju produkti disperzibilni u vodi ili u ulju.
Spojevi korisni u kompozicijama i metodama ovog izuma mogu se isto modificirati dodavanjem određenih funkcionalnosti za pojačavanje bioloških selektivnih svojstava. Takve modifikacije su poznate u struci i uključuju one koje povisuju biološku penetraciju u dati biološki sustav (npr. krv, limfni sustav, centralni nervni sustav), povećavaju oralnu bioraspoloživost, povećavaju topljivost da bi se omogućila aplikacija injekcijom, izmjenu metabolizma i put ekskrecije.
Farmaceutski prihvatljivi nosači koji se mogu koristiti u tim kompozicijama uključuju, ali ne ograničavaju, izmjenjivače iona, aluminij, aluminijev stearat, lecitin, serumske proteine, kao humani serumski albumin, bufer supstancije kao što su fosfati, glicin, sorbična kiselina, kalijev sorbat, djelomična gliceridna smjesa zasićenih biljnih masnih kiselina, vode, soli ili elektrolita, kao protamin sulfata, dinatrij hidrogen fosfata, kalij hidrogen fosfata, natrij klorida, soli cinka, koloidalnog silicija, magnezij trisilicilata, polivinil pirolidona, tvari na bazi celuloze, polietilen glikola, natrij karboksimetilceluloze, poli-akrilata, voskova, polietilen-polioksipropilen-blok polimeri, polietilen glikol i lanolin.
U skladu s preferiranim ostvarenjem, kompozicije ovog izuma su formulirane za farmaceutsku administraciju sisavcima, preferirano ljudima.
Takve farmaceutske kompozicije prezentiranog izuma mogu se administrirati oralno, parenteralno, inhalacijom spreja, topički, rektalno, nazalno, bukalno, vaginalno ili putem implantacije spremnika. Pojam "parenteralno" ovdje uključuje subkutano, intravenozno, intramuskularno, intra-artikularno, intra-sinovialno, intrasternalno, intratarhealno, intra-hepatično, intralezionalno i intrakranijalno injekcijonom ili infuzijskom tehnikom. Preferira se kompoziciju aplicirati oralno ili intravenozno.
Sterilni injekcioni oblici kompozicija ovog izuma mogu biti vodene ili uljne suspenzije. Te suspenzije mogu biti formulirane u skladu s poznatim tehnikama u struci upotrebom prikladnih tvari za dispergiranje i vlaženje i tvari za suspendiranje. Sterilni injekcioni preparat može biti sterilna otopina za injekcije ili suspenzija u ne-toksičnom razrjeđivaču prihvatljivom za parenteralnu upotrebu ili otapalu, naprimjer kao otopina u 1,3-butandiolu. Između prihvatljivih veziva i otapala može se upotrijebiti voda, Ringer-ova otopina i izotonična otopina natrij klorida. Osim toga, sterilna, čvrsta ulja uobičajeno se koriste kao otapala ili medij za suspendiranje. U tu svrhu, svako blago ulje može se upotrijebiti uključujući sintetičke mono- ili di-gliceride. Masne kiseline, kao oleinska kiselina i njezini gliceridni derivati se koriste u pripravi injekcija, kao prirodna farmaceutski prihvatljiva ulja, kao što je maslinovo ulje ili ricinusovo ulje, osobito u njegovoj polioksietiliranoj verziji. Te uljne otopine ili suspenzije isto mogu sadržavati razrjeđivače alkohole dugog lanca ili sredstva za dispergiranje, kao karboksimetil celulozu ili slična sredstva za dispergiranje koja se uobičajeno koriste u formulacijama farmaceutski prihvatljivih oblika doziranja uključujući emulzije i suspenzije. Drugi uobičajeno korišteni surfaktanti, kao Tveen-ovi, Span-ovi i druga sredstva za emulgiranje ili pojačivači bioraspoloživosti koji se uobičajeno koriste u proizvodnji farmaceutski prihvatljivih čvrstih, tekućih, ili drugih oblika doziranja mogu se isto koristiti u svrhu formulacije.
Farmaceutske kompozicije ovog izuma mogu se oralno aplicirati u svakom oralno prihvatljivom obliku uključujući, ali ne limitirajući, kapsule, tablete, vodne suspenzije ili otopine. U slučaju tableta za oralnu upotrebu, nosači koji se uobičajeno koriste uključuju laktozu i kukuruzni škrob. Uobičajeno se dodaju sredstva za podmazivanje, kao magnezij stearat. Za oralnu administraciju u obliku kapsula, upotrebljivi su razrjeđivači uključujući laktozu i suhi kukuruzni škrob. Kada se zahtjeva vodena suspenzija za oralnu upotrebu, aktivna tvar se kombinira sa sredstvima za emulgiranje i suspendiranje. Ako se zahtjeva može se isto dodati sredstvo za zaslađivanje, okus i boju.
Alternativno, farmaceutske kompozicije ovog izuma mogu se administrirati u obliku supozitorija za rektalnu administraciju. Oni se mogu pripremiti mješanjem sredstva s ne-iritirajućim pomoćnim sredstvima koja su čvrsta na sobnoj temperaturi ali tekuća na rektalnoj temperaturi i radi toga će se rastopiti u rektumu i otpustiti ljekovitu tvar. Takvi materijali uključuju kakao putar, pčelinji vosak i polietilen glikole.
Farmaceutske kompozicije ovog izuma mogu se davati topički, osobito kada cilj tretmana uključuje područje i organe lako dostupne za topičku aplikaciju, uključujući bolesti, oka, kože, ili nižih dijelova probavnog sustava. Prikladna topička formulacija se lako pripravi za svako od tih područja i organa.
Topička aplikacija za niže dijelove probavnog sustava može biti učinkovita u formulaciji supozitorija za rektalnu aplikaciju (vidi gore) ili u odgovarajućoj formulaciji za klistir. Topički-transdermalni falsteri mogu se isto koristiti.
Za topičku aplikaciju, farmaceutske kompozicije mogu biti formulirane u odgovarajućoj masti koja sadržava aktivnu komponentu suspendiranu ili rastopljenu u jednom ili više nosača. Nosači za topičku aplikaciju spojeva ovog izuma uključuju, ali ne limitiraju, mineralna ulja, vazelinsko ulje, bijeli vazelin, propilen glikol, polioksietilen, polioksipropilen spojevi, vosak za emulgiranje i vodu. Alternativno, farmaceutske kompozicije mogu se formulirati u prikladni losion ili kremu koja sadržava aktivne komponente suspendirane ili rastopljene u jednom ili više farmaceutski prihvatljivih nosača. Odgovarajući nosači uključuju; ali ne limitraju, mineralna ulja, sorbitan monostearat, polisorbat 60, cetil ester vosak, cetaril alkohol, 2-oktildodekanol, benzil alkohol i vodu.
Za oftalmičku upotrebu, mogu se formulirati farmaceutske kompozicije kao mikronizirane suspenzije u izotoničnoj, pH podešenoj sterilnoj fiziološkoj otopini, ili preferirano, kao otopina u izotoničnoj, pH podešenoj sterilnoj fiziološkoj otopini, jednako sa ili bez konzervansa kao što je benzalkonijev klorid. Alternativno, za oftalmičku upotrebu, farmaceutske kompozicije mogu se formulirati kao masti kao što je vazelin.
Farmaceutske kompozicije ovog izuma isto se mogu dozirati nazalnim aerosolom ili inhalacijom. Takve kompozicije su pripravljene u skladu s poznatim tehnikama u struci farmaceutske formulacije i mogu se pripraviti kao otopine u fiziološkoj otopini, koristeći benzilni alkohol ili druge prihvatljive konzervanse, promotore absorpcije za povećanje bioraspoloživosti, fluorokarbonate, i/ili druga uobičajena sredstva za rastvorljivost ili dispergiranje.
Gore opisane kompozicije su osobito .korisne u terapijskim aplikacijama koje se odnose na bolesti posredovane s IL-1, bolesti posredovane apoptozom, upalne bolesti, autoimune bolesti, poremećaje destrukcije kosti, proliferativne poremećaje, infekcijske bolesti, degeneartivne bolesti, bolesti povezane sa smrti stanica, bolesti povezane prekomjernim dnevnim unošenje alkohola, bolesti uzrokovane virusima, uveitis, infalmatorni peritonitis, osteoartritis, pankreatitis, astma, iscrpljenost odraslih respiratornim sindromom, glomerulonefritis, reumatoidni artritis, sistemski lupus erittematosus, skleroderma, kronični tiroiditis, Grav-ova bolest, autoimuni gastritis, diabetes, autoimuna hemolitička anemija, autoimuna neuropatija, trombocitopenija, kronični aktivni hepatitis, miastenija gravis, upalna bolest crijeva, Crohn-ova bolest, psorijaza, atopički dermatitis, scarring, graft vs host bolest, odbacivanje organa nakon transplantacije, osteoporoza, leukemija i s njom povezani poremećaji, mijelodisplastični sindrom, poremećaji povezani s multiplim mielomom, akutna mijelogena leukemija, kronična mijelogena leukemija, metastatički melanom, Kaposi-jev sarkom, multipli mijelom, hemoragični šok, sepsa, septički šok, opekline, šigeloza, Alzheimer-ova bolest, Parkinson-ova bolest, Huntington-ova bolest, Kennedy-eva bolest, prionska bolest, cerebralna ishemija, epilepsija, ishemija miokarda, akutne i kronične bolesti srca, infarkt miokarda, kongestivno zatajivanje srca, ateroskleroza, transplantiranje premosnice koronarne arterije, atrofija spinalne muskulature, amiotrofična lateralna skleroza, multipla skleroza, encefalitis povezan s HIV-om, aging, alopecija, neurološka oštećenja radi udara, ulcerativni kolitis, traumatske oštećenje mozga, oštećenje leđne moždine, hepatitis-B, hepatitis-C, hepatitis-G, žuta groznica, denga groznica, ili japanski encefalitis, različiti oblici bolesti jetre, bolest bubrega, poliaptična bolest bubrega, bolest gastričnog i duodenalnog ulcera povezana s H.pylori, HIV-infekcije, tuberkuloza, i meningitis. Spojevi i kompozicije su isto upotrebljive u tretiranju komplikacija povezanih s transplantiranjem premosnice koronarne arterije i kao komponenta imunoterapije za tretiranje različitih oblika karcinoma.
Količina spoja prisutnog u gore opisanim kompozicijama treba biti dostatna da uzrokuje mjerljivi pad brojnih bolesti ili u aktiviteta kaspaze i/ili apoptoze stanica, mjeren s jednim od ispitivanja opisanih u primjerima.
Spojevi ovog izuma isto su upotrebljivi u metodama za očuvanje stanica, što može biti potrebno za transplantirane organe ili za očuvanje krvnih produkata. O jednakoj upotrebi inhibitora kaspaze izvješćeno je (Schierle et al., Nature Medicine, 1999, 5, 97). Otopina koja sadržava inhibitor kaspaze uključena je u metode tretiranje za čuvanje stanica ili tkiva. Potrebna količina inhibitora kaspaze ovisiti će o djelotvornosti inhibitora za dati tip stanica i dužinu zahtjevanog vremena za štićenje stanica od apoptotičke smrti stanica.
U skladu s drugim ostvarenjem, kompozicije ovog izuma mogu dalje obuhvaćati druga terapeutska sredstva. Takva sredstva uključuju, ali ne limitiraju, trombolitička sredstva kao što su aktivator plazminogena tkiva i streptokinazu. Kada se upotrebljava drugo sredstvo, drugo sredstvo može se administrirati kao odvojeni oblik doziranja ili kao dio oblika doziranja spojeva ili kompozicija ovog izuma.
Treba shvatiti da specifični režim doziranja i tretiranja za svakog pacijenta ovisiti će o različitim faktorima, uključujući aktivnost specifičnog spoja koji se koristi, dobi, tjelesnoj masi, općenito zdravlju, spolu, dijeti, vremenu aplikacije, putu ekskrecije, kombinaciji lijekova, i prosudbi liječnika i težini određene bolesti koja se tretira. Količina aktivnih tvari ovisiti će o određenom spoju i drugim terapijskim sredstvima, ako su prisutna u kompoziciji.
U preferiranom ostvarenju, izum osigurava metode za tretiranje sisavaca, koje imaju jednu od gore navedenih bolesti, obuhvaća korak administracije navedenim sisavcima gore opisanih farmaceutski prihvatljivih kompozicija. U tom ostvarenju isto su administrirana druga terapijska sredstva ili inhibitor kaspaze, i može se dostaviti zajedno sa spojem ovog izuma u jednom obliku doziranja, ili kao posebni oblik doziranja. Kada se aplicira u posebnom obliku doziranja, drugi inhibitor kaspaze ili sredstvo mogu se administrirati kao što je poznato od prije, u isto vrijeme, ili slijedi administraciju farmaceutski prihvatljive kompozicije koja sadržava spoj ovog izuma.
Zato će ovaj izum biti detaljnije objašnjen, sljedećim pripravljanjem i testiranjem primjera. Ti primjeri su samo u svrhu ilustracije a nisu konstruirani da bi na bilo koji način limitirali cilj ovog izuma.
Primjeri sinteze
Sljedeći Primjeri osiguravaju postupak sinteze za odabrane spojeve ovog izuma
Primjer 1
[3S/R]-5-fluor-4-okso-3-[(S)-3 metil-2-(karbazol-karbamoiloksi-butirilamino]pentanoična kiselina
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Metoda A
(S)-2-(klorkarbamoiloksi)-3-metilmaslačna kiselina, tert-butil ester
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U otopinu difosgena (4.55 g) u THF (34 ml) na 0°C doda se otopina (S)-2-hidroksi-3-metil maslačne kiseline tert-butil ester (za metodu priprave vidi Tetrahedron. Lett., (1993), 7409) (4.0 g) i piridin (1.82 g) u THF (34 ml) kap po kap tijekom 25 minuta.
Nastalu smjesu se ostavi na toplom na sobnoj temperaturi kroz 4 sata. Smjesa se zatim filtrira preko celita a filtrat koncentrira pod reduciranim tlakom. Ostaci se ponovo-rastope u dietil eteru (200 ml) i ponovo filtriraju preko celita. Filtrat se koncentrira pod reduciranim tlakom da bi se dobio imenovani spoj kao žuto ulje (5.27 g) : 1H NMR (400 MHz, CDCl3) δ 0.98-1.10 (6H, m), 1.55 (9H, s), 2.30 (1H, m), 4.83 (1H, m).
Metoda B:
(S)-3-metil-2-(karbazol-karbamoiloksi)-maslačna kiselina, tert-butil ester
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U otopinu karbazola (15.15 g) u diklormetanu (180 ml) i THF (142 ml) na 0°C doda se granulirani natrij hidroksid (5.45 g) čemu slijedi tetrabutilamonij bromid (2.93 g). Nastala smjesa se miješa kroz 30 minuta potom se doda kap po kap otopina klorformata (21.41 g) u THF (81 ml) preko 55 min. Smjesa se potom ostavi na toplom na sobnoj temperaturi preko noći. Diklormetan (1 L) i voda (350 ml) se dodaju a organska faza se odstrani. Vodena faza se potom ekstrahira s diklormetanom (2 x 250 ml) a spojena organska ispere vodom (200 ml), zatim slanom vodom, osuši (magnezij sulfat), filtrira i koncentrira. Ostaci se purificiraju flash kromatografijom (0-5% etil acetat/heksan) da se dobije navedeni spoj kao bezbojno ulje (29.3 g): 1H NMR(400 MHz, CDCl3) δ 1.15-1.23 (6H, m), 1.55 (9H, s), 2.52 (1H, m), 5.27 (1H, d), 7.36-7.57 (4H, m), 8.03 (2H, d), 8.47 (2H, d).
Metoda C:
(S)-3-metil-2-(karbazol-karbamoiloksi)-maslačna kiselina
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Trifluoroctenoj kiselini (84 ml) doda se kap po kap uz miješanje ledeno hladna otopina (S)-3-metil-2-(karbazol-karbamoiloksi)-maslačna kiselina, tert-butil ester (4.11 g) u bezvodnom DCM (300 ml). Smjesa se miješa na 0°C kroz 2 sata potom na sobnoj temperaturi kroz l sat. Smjesa se koncentrira pod reduciranim tlakom a potom ostaci rastope u suhom DCM a otapalo se ponovo odstrani pod reduciranim tlakom. Postupak se ponovi nekoliko puta da se odstrani višak trifluoroctene kiseline. Ta dobivena kiselina je kao svjetlo zelena guma (3.30 g): 1H NMR(400 MHz, CDCl3) δ 1.12-1.37 (6H, m), 2.70 (1H, m), 5.47 (1H, m), 7.32-7.56 (4H, m), 8.00 (2H, d), 8.37 (2H, d).
Metoda D
[3S/R,4S/R]-5-fluor-4-hidroksi-3-((S)-3-metil-2-(karbazol)-karbamoiloksi-butirilamido)-pentanoična kiselina, tert-butil ester
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Izmješanu smjesu od (S)-3-metil-2(karbazol)-karbamoiloksi-mlječna kiselina (3.03 g), 3-amino-5-fluor-4-hidroksi-pentanoična kiselina tert-butil ester (2.42 g), HOBt (1.58 g), DMAP (1.49 g) i THF (80 ml) se ohlade na 0°C potom se doda EDC (2.24 g). Smjesa se ostavi kroz 16 sati na toplom na sobnoj temperaturi zatim koncentrira pod reduciranim tlakom. Ostaci se purificiraju flash kromatografijom (15-45 % etilacetat/heksan) da se dobije navedeni spoj kao bijela pjena (4.60 g): 1H NMR(400 MHz, CDCl3) δ 1.09-1.50 (15H, m), 2.49-2.80 (3H, m), 3.20-3.62 (1H, m), 3.92-4.58 (4H, m), 5.32-5.42 (1H, d), 6.86 (1H, brm), 7.40-7.55 (4H, m), 8.02 (2H, d), 8.35 (2H, m); 19F NMR (376 MHz, CDCl3) -229.6, -229.7, -230.8, -231.4.
Metoda E
[3S/R]-5-fluor-4-okso-3-[(S)-3-metil-2-(karbazol-karbamoiloksi-butirilamino]-pentanoična kiselina, tert-butil ester
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Izmješana smjesa od [3S/R,4S/R]-5-fluor-4-hidroksi-3-((S)-3-metil-2-(karbazol)-karbamoiloksi-butirilamido)-pentanoična kiselina, tert-butil ester (4.60 g), u bezvodnom DCM (100 ml) tretira se s 1,1,1-triacetoksi-1,1-dihidro-1,2-benziodoksol-3(1H)-on (4.68 g) na 0°C. Nastalu smjesu se čuva na 0°C kroz 2 sata, razrijedi s etil acetatom, potom izlije u 1:1 smjesu zasićenog vodenog natrij hidrogen karbonata i vodenog natrij tiosulfata. Organski sloj se odstrani, a vodeni sloj se ponovo-ekstrahira s etilen acetatom. Spojeni organski ekstrakt se osuši (magnezij sulfat) i koncentrira. Ostaci se purificiraju flash kromatografijom (10-40 % etil acetat/heksan) da se dobije imenovani spoj kao bijela krutina (3.96 g): 1H NMR(400 MHz, CDCl3) δ 1.85 (4.5H, s), 1.94-1.31 (6H, m), 1.36 (4.5H, s), 2.59 (1H, m), 2.70-3.11 (2H, m), 4.91-5.31 (3H, m), 5.40-5.49 (1H, m), 7.25 (1H, brs), 7.42 (2H, m), 7.53 (2H, m), 8.04 (2H, m), 8.35 (2H, m); 19F NMR (376 MHz, CDCl3) -232.0, -232.1.
Primjer 1A
[3S/R]-5-fluor-4-okso-3-[(S)-3-metil-2-(karbazol)-karbamoiloksi-butirilamino]-pentanoična kiselina
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Pripremi se korištenjem sličnog postupka kao što je opisano gore u Metodi C. Produkt je izoliran kao bijela krutina (88 % zadnji korak): IR (krutina) 1721.2, 1695.6, 1664.9, 1449.8, 1378.1, 1198.9, 1040.1, 758.5 cm-1; 1H NMR(400 MHz, d6-DMSO) δ 1.01 (6H, brm), 2.41 (1H, m), 2.54-3.04 (2H, m), 4.31-4.82 (1H, m, CH2F), 5.10-5.41 (2.4H, m), 7.45 (2H, m), 7.57 (2H, m), 8.22 (2H, m), 8.30 (2H, m), 8.51-8.99 (1H, brm), 12.60 (1H, brs); 13C NMR (100 MHz, d6-DMSO) δ 19.0, 19.1, 19.3, 30.4, 30.5, 30.6, 32.9, 34.5, 34.7, 47.3, 47.4, 52.0, 52.3, 80.4, 80.8, 83.2, 83.4, 83.4, 85.1 85.2, 116.2, 116.3, 124.1, 125.7, 125.9, 137.9, 151.7, 151.9, 152.0, 168.8, 169.0, 169.2, 172.0, 172.1, 173.1, 173.2, 202.2, 202.4, 202.5, 202.6; 19F NMR (376 MHz, d6-DMSO) -226.6 (t), -226.8 (t), -230.5 (t), -230.9 (t), 232.9 (t), -233.0 (t); MS (ESI+ve) 443 (M+H).
Primjer 2
[3S/R]-5-fluor-4-okso-3-[(S)-3-metil-2-(3-klorkarbazol)-karbamoiloksi-butirilamino]-pentanoična kiselina
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Pripremi se korištenjem sličnog postupka kao što je opisano gore u Metodama A-E. Produkt je izoliran kao bijela krutina (99 % zadnji korak): IR (krutina) 1721.2, 1690.5, 1664.9, 1444.7, 1367.9, 1209.1, 1040.1 cm-1; 1H NMR(400 MHz, d6-DMSO) 5 1.02-1.13 (6H, m), 2.40 (1H, m), 2.50-2.99 (2H, m), 4.30-4.85 (1.6H, m), 5.09-5.48 (2.4H, m), 7.48 (1H, m), 7.56-7.66 (2H, m), 8.20-8.32 (3H, m), 8.39 (1H, m), 8.55-8.99 (1H, brm) , 12.5 (1H, br); 13C NMR (100 MHz, d6-DMSO) δ 18.1, 18.9, 19.1, 30.4, 30.5, 33.0, 34.5, 34.7, 47.4, 52.0, 52.3, 80.6, 80.9, 81.1, 83.4, 83.43, 85.1 85.2, 103.8, 104.0, 117.0, 119.3, 121.3, 122.3, 124.3, 124.7, 127.2, 127.4, 127.9, 128.5, 136.6 138.4, 151.5, 151.6, 151.7, 168.7, 168.9, 169.0, 169.1, 172.0, 172.1, 173.1, 173.2, 202.2, 202*4, 202.44, 202.8 (C); 19F NMR (376 MHz, d6-DMSO) -226.6 (t), -226.8 (t), -230.4 (t), -230.9 (t), 231.0 (t), -232.8 (t), -232.84 (t), -232.9 (t) / MS (ESI+ve) 477 (M+H).
Primjer 3
[3S/R]-5-fluor-4-okso-3-[(S)-3-metil-2-(3,6-diklorkarbazol)-karbamoiloksi-butirilaminoj-pentanoična kiselina
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Pripremi se korištenjem sličnog postupka kao što je opisano gore u Metodama A-E. Produkt je izoliran kao bijela krutina (99 % zadnji korak): IR (krutina) 1721.2, 1659.7, 1470.3, 1434.4, 1367.9, 1209.1, 1075.9, 1045.2 cm-1; 1H NMR(400 MHz, de-DMSO) δ 0.98-1.14 (6H, m), 2.30-2.50 (1H, m), 2.50-3.01 (2H, m), 4.29-4.84 (1.5H, m), 5.09-5.41 (2.5H, m), 7.66 (2H, m), 8.19-8.29 (2H, m), 8.45 (2H, m), 8.57-8.99 (1H, brm), 12.60 (1H, br, OH) ; 13C NMR (100 MHz, d6-DMSO) δ 15.5, 19.1, 19.2, 30.4, 30.45, 30.6, 33.0, 34.5, 34.7, 47.3, 47.5, 52.0, 52.3, 80.8, 81.1, 81.2, 83.4, 84.43, 85.1, 85.2, 117.8, 121.1, 126.3, 128.4, 128.7, 136.9, 151.2, 151.4, 168.6, 168.8, 168.9, 168.95, 172.0, 172.04, 173.1, 173.14, 202.2, 202.3, 202.4, 202.6; 19F NMR (376 MHz, d6-DMSO) -226.6 (t), -226.8 (t), -230.4 (t), -230.8 (t), -232.8 (t), -232.9 (t) ; MS (ESI+ve) 511/513 (M+H).
Primjer 4
[3S/R]-5-fluor-4-okso-3-[(S)-3-metil-2-(2-klorkarbazol)-karbamoiloksi-butirilaminoj-pentanoična kiselina
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Metoda F:
4'-klor-2-nitrobifenil
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U otopinu 2-bromnitrobenzena (646 mg) i THF (17 ml) pod dušikom doda se tetrakis(trifenilfosfin) paladij (0) (900 mg). Nastala smjesa se miješa na sobnoj temperaturi kroz 20 min, potom se doda otopina 4-klorfenil borna kiselina (1.0 g) i etanolu (17 ml), a nastala smjesa se miješa na sobnoj temperaturi kroz 1 sat. Zatim se doda 2M natrij karbonat (17 ml), a reakcijska smjesa se zagrije do refluksa kroz 2 sata. Smjesa se zatim ostavi na hladnom i koncentrira pod reduciranim tlakom. Ostaci se rastope u etil acetatu (100 ml) a vodeni sloj se odstrani. Organska faza se ispere slanom vodom (20 ml), osuši (magnezij sulfat), filtrira i koncentrira. Ostaci se purificiraju flash kromatografijom (0-10 % etil acetat/heksan) da se dobije imenovani spoj kao žuta krutina (646 mg): 1H NMR(400 MHz, CDCl3) 8 7.24-7.31 (2H, m), 7.41-7.47 (3H, m), 7.52 (1H, m), 7.65 (1H, m), 7.90 (1H, d).
Metoda G:
2-klorkarbazol
[image]
Smjesa 4'-klor-2-nitrobifenil (640 mg) i trietil fosfita (1.9) zagrije se na 150 °C kroz 3 sata. Smjesa se potom ostavi na hladnom i purificira flash kromatografijom (5-10 % etil acetat/heksan) da se dobije imenovani spoj kao bijela krutina (382 mg): 1E NMR(400 MHz, d6-DMSO) δ 7.12-7.23 (2H, m), 2.40 (1H, m), 7.46-7.54 (2H, m), 8.12 (2H, d).
Primjer 4
[3S/R]-5-fluor-4-okso-3-[(S)-3-metil-2-(2-klorkarbazol)-karbamoiloksi-butirilamino]-pentanoična kiselina
[image]
Pripremi se upotrebom postupka sličnog kao što je gore opisano u Metodama A-E. Produkt se izolira kao bijela krutina (99 % zadnji korak): IR (krutina) 1731.4, 1695.6, 1664.9, 1424.2, 1367.9, 1326.9, 1193.7, 1045.2 cm-1; 1H NMR(600 MHz, d6-DMSO) δ 1.58-1.70 (6H, m), 2.85-3.10 (1H, m), 3.10-3.54 (2H, m), 4.85-5.39 (1.4H, m), 5.56-5.98 (2.6H, m), 7.94-8.20 (3H, m), 8.73-8.90 (4H, m), 9.10-9.56 (1H, brm) , 13.2 (1H, br); 13C NMR (100 MHz, d6-DMSO) δ 17.7, 17.9, 19.0, 19.1, 19.2, 30.4, 30.5, 33.0, 34.5, 34.7, 52.0, 52.3, 80.6, 80.9, 81.1, 83.4, 84.43, 85.1, 85.2, 104.0, 117.1, 121.1, 122.1, 124.2, 124.4, 124.6, 124.8, 129.0, 132.0, 138.2, 138.4, 151.6, 151.61, 168.7, 168.9, 169.0, 172.0, 172.05, 202.4, 202.42, 202.6; 19F NMR (376 MHz, d6-DMSO) -225.93, -226.2 (t), -229.8 (t), -230.3 (t), -232.3 (t), -232.4 (t) ; MS (ESI+ve) 477 (M+H).
Primjer 5
[3S/R]-5-fluor-4-okso-3-[(S)-3-metil-2-(2,3-diklorkarbazol)-karbamoiloksi-butirilamino]-pentanoična kiselina
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Pripremi se upotrebom sličnog postupka kao što je gore opisano u metodama A-E. 2,3-diklorkarbazol se proizvede koristeći postupak sličan opisanom u Metodama F i G. Produkt se izolira kao bijela krutina (98 % zadnji korak): IR (krutina) 1721.2, 1695.7, 1434.4, 1367.9, 1204.0, 1188.6, 1045.2 cm-1; 1H NMR(400 MHz, d6-DMSO) δ 1.04-1.14 (6H, m), 2.29-2.48 (1H, m), 2.53-3.00 (2H, m), 4.30-4.84 (1.7H, m), 5.09-5.41 (2.3H, m), 7.49 (1H, m), 7.63 (1H, m), 8.20-8.33 (2H, m), 8.42-8.49 (1H, m), 8.62 (1H, m), 8.80-9.00 (1H, brm), 12.5 (1H, br) ; 13C NMR (100 MHz, d6-DMSO) δ 17.7, 17.9, 19.0, 19.1, 30.5, 33.0, 34.5, 34.7, 47.5, 52.0, 52.3, 80.8, 81.0, 81.2, 83.4, 85.1, 85.2, 116.3, 117.9, 121.5, 122.4, 124.1, 124.6, 126.1, 126.6, 129.0, 129.7, 136.8, 138.5, 151.4, 151.45, 168.6, 168.9, 172.0, 172.03, 173.1, 202.2, 202.3, 202.4, 202.5; 19FNMR (376 MHz, d6-DMSO) -226.6 (t), -226.8, (t), -230.3 (t), -230.8 (t), -232.8 (t), -232.9 (t) ; MS (ESI+ve) 513. (M+H) .
Primjer 6
[3S/R]-5-fluor-4-okso-3-[(S)'3-metil-2-(2-trifluormetil)-karbazol-karbamoiloksi-butirilaminoj-pentanoična kiselina
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Pripremi se upotrebom sličnog postupka kao što je gore opisano u metodama A-E. 2-trifluormetilkarbazol se proizvede koristeći postupak sličan opisanom u Metodama F i G. Produkt se izolira kao bijela krutina (85 % zadnji korak): IR (krutina) 1731.4, 1695.7, 1434.4, 1321.8, 1198.9, 1122.1, 1065.7 cm-1; 1H NMR(400 MHz, d6-DMSO) δ 1.06-1.15 (6H, m), 2.42 (1H, m), 2.50-3.01 (2H, m), 4.29-4,83 (1.6H, m), 5.08-5.42 (2.4H, m), 7.53 (1H, m), 7.68 (1H, m), 7.83 (1H, m), 8.29-8.40 (2H, m), 8.48 (1H, m), 8.64 (1H, m), 8.80-9.01 (1H, brs); 13C NMR (100 MHz, d6-DMSO) δ 17.4, 17.6, 19.0, 19.1, 30.4, 31,0, 32.9, 34.5, 34.7, 52.0, 52.3, 80.7, 80.9, 81.1, 83.4, 85.1, 113.3, 116.3, 120.9, 123.6, 124.4, 126.2, 127.2, 127.5, 127.8, 128.1, 128.9, 137.2, 138.9, 151.6, 168.6, 169.0, 172.0, 202.2, 202.3, 202.4, 202.6; 19F NMR (376 MHz, d6-DMSO) -60.4 (s), -226.6, (t), -226.8 (t), -229.9 (t), 230.4 (t), -231.0 (t), -232.9 (t), -233.0 (t) / MS (ESI+ve) 511. (M+H).
Primjer 7
[3S/R]-5-fluor-4-okso-3-[(S)-3-metil-2-(2-metilkarbazol)-karbamoiloksi-butirilamino]-pentanoična kiselina
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Pripremi se upotrebom sličnog postupka kao što je gore opisano u Metodama A-E. Produkt se izolira kao bijela krutina (90 % zadnji korak): IR (krutina) 1726.3, 1700.7, 1664.9, 1552.2, 1460.0, 1552.2, 1460.0, 1367,9, 1332.0, 1209.1, 1193.7, 1040.1 cm-1; 1H NMR(400 MHz, d6-DMSO) δ 1.01-1.19 (6H, m), 2.30-3.00 (6H, m), 4.29-4.85 (1.5H, m), 5.11-5.52 (2.5H, m), 7.29 (1H, m), 7.45 (1H, m), 7.55 (1H, m), 8.05-8.18 (3H, m), 8,27 (1H, m), 8.50-9.10 (1H, brm), 12.50 (1H, brs); 13C NMR (100 MHz, d6-DMSO) δ 17.7, 18.0, 19.0, 19.1, 19.2, 22.2, 30.4, 30.5, 30.6, 30.6, 33.0, 34.5, 34.7, 47.4, 52.0, 52.3, 52.7, 80.3, 80.6, 80.7, 80.8, 83.2, 83.4, 83.5, 85,2, 85.2, 103.8, 104.0, 116.2, 116.3, 116.6, 120.3, 120.4, 123.4, 124.0, 125.2, 125.8, 127.3, 137.5, 137.9, 138.2, 151.7, 151.9,151.9, 168.8, 169.2, 169.2, 172.0, 172.1, 173.1, 173.2, 202.3, 202.4, 202.5, 202.6; 19F NMR (376 MHz, d6-DMSO) -226.55 (t), -226.76 (t), -230.43 (t), -230.89 (t), -232.84 (t), -232.97 (t).
Primjer 8
[3S/R]-5-fluor-4-okso-3-[(S)-2-(karbazol-karbamoiloksi)-butirilamino]-pentanoična kiselina
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Pripremi se upotrebom sličnog postupka kao što je gore opisano u Metodama A-E. Kloroformat se proizvede iz tert butil estera (S)-2-hidroksibutanoične kiseline koristeći postupak kao što je opisan u Metodi A. Produkt se izolira kao bijela krutina (90 % zadnji korak): IR (krutina) 1716.1, 1654.6, 1449.8, 1372.9, 1326.9, 1204.0, 1050.4 , 1029.9 cm-1; 1H NMR(400 MHz, d6-DMSO) δ 1.03-1.12 (3H, m), 1.96-2.15 (2H, m), 2.50-3.01 (2H, m), 4,31-4.82 (1.8H, m), 5.11-5.43 (2.2H, m), 7.45 (2H, m), 7.59 (2H, m), 8.18-8.32 (4H, m), 8.58-9.05 (1H, brm), 12.60 (1H, brs); 13C NMR (100 MHz, d6-DMSO) δ 9.8, 9.9, 9.94, 24.9, 25.1, 25.2, 33.0, 34.6, 34.7, 47.4, 52.0, 52.3, 77.1, 77.3, 77.4, 77.45, 83.4, 83.5, 85.2, 85.22, 116.3, 120.6, 124.0, 125.7, 127.9, 137.9, 151.5, 151.7, 169.5, 169.8, 172.0, 172.1, 173.1, 202.3, 202.4, 202.5, 202.6; 19F NMR (376 MHz, d6-DMSO) -226.6, (t), -226.8 (t), -231.4 (t), -230.0 (t), -232.9 (t), -233.0 (t).
Primjer 9
[3S/R]-5-fluor-4-okso-3-[(S)-3,3-dimetil-2-(karbazol-karbamoiloksi)-butirilamino]-pentanoična kiselina
[image]
Pripremi se upotrebom sličnog postupka kao što je gore opisano u Metodama A-E. Kloroformat se proizvede iz tert butil estera (S)-2-hidroksi-3,3-dibutanoične kiseline (za postupak proizvodnje vidi Tetrahedron. Lett., (1993), 7409) kao što je opisano u Metodi A. Produkt se izolira kao bijela krutina (94 % zadnji korak): IR (krutina) 1782.7, 1721.2, 1526.6, 1444.7, 1373.0, 1332.0, 1301.3, 1198.9, 1117.0, 1040.1, 753.3 cm-1; 1H NMR(400 MHz, d6-DMSO) δ 1.15 (9H, s), 2.50-2.98 (2H, m), 4,29-4.88 (1.5H, m), 4.97-5.45 (2.5H, m), 7.45 (2H, m), 7.59 (2H, m), 8.23 (2H, m), 8.33 (2H, m), 8.50-8.97 (1H, brm), 12.50 (1H, brs); 13C NMR (100 MHz, d6-DMSO) δ 27.3, 33.4, 34.5, 34.6, 34.7, 34.8, 35.1, 52.5, 52.9, 83.5, 83.9, 84.0, 84.1, 84.3, 85.7, 85.73, 116.7, 116.8, 121.2, 124.6, 124.64, 126.2, 128.4, 138.4, 152.2, 152.4, 152.5, 168.4, 168.7, 168.8, 168.9, 172.6, 172.65, 173.6, 202.6, 202.8, 202.9, 203.0; 19F NMR (376 MHz, d6-DMSO) -226.5 (t), -226.6, (t), -230,9 (t), -231.5 (t), -232.9 (t), -233.0 (t). MS (ESI+ve) 457 (M+H).
Primjer 10
[3S/R]-5-fluor-4-okso-3-[(S)-2-(2-klorkarbazol-karbamoiloksi)-butirilamino]-pentanoična kiselina
[image]
Pripremi se upotrebom sličnog postupka kao što je gore opisano u Metodama A-E. Kloroformat se proizvede iz tert butil estera (S)-2-hidroksibutanoične kiseline kao što je opisano u Metodi A. 2-klorkarbazol se proizvede kao što je opisano u Metodama F-G. Produkt se izolira kao bijela krutina (77 % zadnji korak): IR (krutina) 1733.03, 1699.89, 1662.97, 1448.18, 1423.38, 1369.84, 1332.48, 1215.16, 1199.62, 1052.26, 1033.17, 764.57, 747.53, 720.08, 651.85 cm-1; 1H NMR(400 MHz, d6-DMSO) δ 1.06-1.10 (3H, m), 2.01-2.09 (2H, m), 2.53-298 (2H, m), 4,34-4.78 (1.6H, m), 5.14-5-39 (2.4H, m), 7.45-7.61 (3H, m), 8.24-8.31 (4H, m), 8.63-8.99 (1H, brm) , 12.50 (1H, brs); 13C NMR (100 MHz, d6-DMSO) δ 9.7, 23.7, 25.0, 31.3, 34.6, 34.8, 52.0, 52.3, 77.4, 77.6, 83.4, 85.2, 110.9, 111.6, 116.2, 116.3, 119.0, 119.4, 120.7, 120.9, 121.9, 122.1, 124.2, 124.3, 124.6, 124.8, 126.3, 128.3, 130.2, 132.0, 138.1, 138.4, 151.3, 169.6, 172.1; 19F NMR (376 MHz, d6-DMSO) -226.60 (t), -226.83, (t), -230.34 (t), -231.88 (t), -232.84 (t), -232.99 (t).
Primjer 11
[3S/R]-5-fluor-4-okso-3-[(S)-3-metil-2-(indol)-karbamoiloksi-butirilamino]-pentanoična kiselina
[image]
Pripremi se upotrebom sličnog postupka kao što je gore opisano u Metodama A-E Produkt se izolira kao bijela krutina (92 % zadnji korak): IR (krutina) 1731.4, 1664.9, 1536.8, 1454.9, 1393.5, 1326.9, 1239.8, 1035.0 cm-1; 1H NMR(400 MHz, d6-DMSO) δ 1.30-1.62 (6H, m), 2.79 (1H, m), 3.00-3.48 (2H, m), 4,77-5.04 (1.6H, m), 5.42-5.88 (2.4H, m), 7.29 (1H, m), 7.70-7.90 (2H, m), 8.10-8.31 (2H, m), 8.51-8.63 (1H, m), 8.91-9.45 (1H, m), 13.0 (1H, brs); 13C NMR (100 MHz, d6-DMSO) δ 15.5, 17.3, 17.6, 18.9, 19.2, 30.6, 32.9, 34.5, 34.7, 47.4, 52.0, 52.3, 65.3, 80.0, 80.3, 80.5, 83.4, 83.41, 85.1, 85.2, 104.02, 108.7, 108.71, 108.8, 114.9, 122.0, 123.5, 125.0, 126.3, 130.5, 135.0, 150.4, 168.8, 169.0, 169.1, 169.14, 172.0, 172.1, 173.1, 202.2, 202.4, 202.5, 202.6; 19F NMR (376 MHz, d6-DMSO) -226. 3, (t), -230.0 (t), -230.5 (t), -232.3 (t), -232.4 (t), -232.5 (t), -232.6 (t); MS (ESI+ve) 393 (M+H).
Primjer 12
[3S/R]-5-fluor-4-okso-3-[(S)-3-metil-2-(fonotiazin)-karbamoiloksi-butirilamino]-pentanoična kiselina
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Metoda H
(S)-3-metil-2-(fonotiazin)-karbamoiloksi-maslačna kiselina
[image]
Uz mješanje otopini tert-butil estera (S)-2-hidroksi-3-metilmaslačne kiseline (za postupak pripreme pogledaj Tetrahedron. Lett., (1993), 7409) (300 mg) u THF (5 ml) na 0°C doda se natrij hidrid (60% suspenzija u mineralnom ulju, 72 mg). Nastalu smjesu se miješa 30 minuta potom se doda fenotiazin-10-karbonilklorid (450 mg) i smjesa se ostavi na toplom prostoru kroz 12 sati. Reakcijska smjesa se razrijedi s etil acetatom (15 ml) i vodom (3 ml). Organska faza se odvoji a vodena faza se ekstrahira s 2 x 5 ml etil acetata. Spojena organska se ispere slanom vodom (5 ml), osuši (magnezij sulfat), filtrira i koncentrira. Ostaci se purificiraju flash kromatografijom (0-10% etil acetat/heksan) da se dobije imenova supstancija kao bezbojno ulje (528 mg) : 1H NMR(400 MHz, CDCl3) δ 0.75-0.96 (6H, m), 15.8 (9H, s), 2.20 (1H, m), 4.86 (1H, d), 7.12-7.45 (6H, m), 7.70 (2H, m).
(S)-3-metil-(fonotiazin)-karbamoiloksi-maslačna kiselina
[image]
Deprotekcija tert-butil estera (S)-3-metil-2-(fonotoazina)-karbamoiloksi-maslačne kiseline (528 mg) izvodi se trifluoroctenom kiselinom kao što je opisano u Metodi C da se dobije kiselina kao bjela krutina (440 mg): 1H NMR(400 MHz, CDCl3) δ 0.77-1.00 (6H, m), 2.29 (1H, m), 5.02 (1H, d), 7.15-7.48 (6H, m), 7.70 (2H, m).
Primjer 12
[3S/R]-5-fluor-4-okso-3-[(S)-3-metil-2-(fonotiazin)-karbamoiloksi-butirilamino]-pentanoična kiselina
[image]
Pripremi se upotrebom sličnog postupka kao što je gore opisano u Metodama C-E. Produkt se izolira kao bijela krutina (98 % zadnji korak): IR (krutina) 1782.7, 1710.9, 1521.5, 1465.2, 1260.3, 1219.4, 1168.1, 1045.2, 758.5 cm-1; 1H NMR(400 MHz, d6-DMSO) δ 0.64-0.87 (6H, m), 1.96-2.16 (1H, m), 2.40-2.98 (2H, m), 4.50-5.42 (4H, m), 7.28 (2H, m), 7.39 (2H, m), 7.49 (2H, m), 7.68 (2H, brm) , 7.88-8.91 (1H, brm), 12.61 (1H, brs); 13C NMR (100 MHz, d6-DMSO) δ 16.8, 17.1, 19.0, 19.2, 30.3, 30.5, 33.0, 33.2, 34.5, 34.8, 47.3, 52.0, 52.4, 79.3, 79.6, 79.7, 83.4, 83.5, 85.1, 85.2, 103.8, 127.1, 127.2, 127.3, 127.4, 131.4, 138.0, 138.1, 152.6, 152.8, 158.82, 169.3, 169.5, 169.7, 172.0, 172.1, 172.13, 202.3, 202.4, 202.6, 202.8; 19F NMR (376 MHz, d6-DMSO) -226.6 (t), -226.8, (t), -230.3 (t), -231.3 (t), -232.9 (t), -233.0 (t). MS (ESI+ve) 475 (M+H).
Primjer 13
[3S/R]-5-fluor-4-okso-3-[(S)-3-metil-2-(2-klorfonotiazin)-karbamoiloksi-butirilamino]-pentanoična kiselina
[image]
Metoda I:
2-klorfenotiazin karbamil klorid
[image]
U suspenziju 2-klorfenotiazina (2 g) i ksilena (20 ml) doda se difosgen (3.4 g). Smjesa se zagrije na 140°C kroz 18 sati. Smjesa se ohladi a ksilen se odstrani pod reduciranim tlakom. Ostatak se purificira flash kromatografijom (2-5% etil acetat/heksan) da se dobije imenovani spoj kao smeđa krutina (2.04): 1H NMR(400 MHz, d6-DMSO) δ 7.26-7.43 (4H, m), 7.45-7.51 (1H, m), 7.59-7.68 (2H, m).
Primjer 13
[3S/R]-5-fluor-4-okso-3-[(S)-3-metil-2-(2-klorfonotiazin)-karbamoiloksi-butirilamino]-pentanoična kiselina
[image]
Pripremi se upotrebom sličnog postupka kao što je gore opisano u Metodama C-E. Produkt se izolira kao bijela krutina reverznom fazom HPLC (61 % zadnji korak) : IR (krutina) 1732, 1460, 1365, 1207 cm-1; 1H NMR(400 MHz, d6-DMSO) δ 0.70-0.87 (6H, m), 2.02-2.10 (1H, m), 2.58-2.90 (2H, m), 4.34-5.37 (4H, m), 7.27-7.88 (7H, m), 8.31-8.81 (1H, m); 13C NMR (100 MHz, d6-DMSO) δ 16.7/16.9, 18.9/19.1, 30.3/30.3, 34.5/34.8, 52.0/52.4, 79.6/80.0, 84.2/84.3, 127.0, 127.3, 127.3, 127.6, 128.0, 129.0, 130.5, 130.9, 131.7, 137.5/137.5, 139.1/139.1, 152.3/152.5, 169.6/169.7, 172.0/172.1, 202.3/202.7 (2d, J) 14.1/14.0; 19F NMR (376 MHz, d6-DMSO) -226.6 (t), -226.8, (t), -233.0 (t), -233.1 (t).
Primjer 14
[3S/R]-5-fluor-4-okso-3-[(S)-3-metil-2-(3-klorfenotiazin)-karbamoiloksi-butirilamino]-pentanoična kiselina
[image]
Pripremi se upotrebom sličnog postupka kao što je gore opisano u Metodama H, I i C-E. Fenotiazin se pripremi u skladu s postupkom opisanim u J. Chem. Soc. (1970), 2437-2441, Produkt se izolira kao bijela krutina (89 % zadnji korak): IR (krutina) 1717, 1527, 1469, 1350, 1322, 1217, 1042 cm-1; 1H NMR(400 MHz, d6-DMSO) δ 0.67-0.85 (6H, m), 2.00-2.06 (1H, m), 2.58-2.87 (2H, m), 4.33-4.86 (2.6H, m), 5.12-5.36 (1.4H, m), 7.27-7.30 (1H, m), 7.38-7.51 (3H, m), 7.36-7.68 (3H, m), (8.24-8,82 (1H, m); 13C NMR (100 MHz, d6-DMSO) δ 17.3/17.6, (CH3), 19.4/19.5 (CH3), 30.8/30.8, 35.0/35.3, 52.5/52.9, 80.0/80,1, 84.7/84.8, 127.2, 127.3, 127.6, 127.9, 128.6, 130.7, 131.2, 133.7, 136.9/137.0, 137.8/137.8, 153.0/153.2, 170.1/170.2, 172.5/172.6, 202.9/203.2; 19F NMR (376 MHz, d6-DMSO) -226.7 (br) , -226.9, (br) , -233.0 (t). MS (ESI+ve) 509/511 (M+H).
Primjer 15
[3S/R]-5-fluor-4-okso-3-[(S)-3-metil-2-(3,7-diklorfonotiazin)-karbamoiloksi-butirilamino]-pentanoična kiselina
[image]
Pripremi se upotrebom sličnog postupka kao što je gore opisano u Metodama H, I i C-E. Fenotiazin se pripremi u skladu s postupkom opisanim u J. Chem. Soc. (1970), 2437-2441. Produkt se izolira kao bijela krutina reverznom fazom HPLC (76 % zadnji korak) : IR (krutina) 1793, 1721, 1521, 1465, 1317, 1214, 1086, l'44 cm-1; 1H NMR(400 MHz, d6-DMSO) δ 0.71-0.76 (3H, m), 0.84-0.88 (3H, m), 2.05-2.12 (1H, m), 2.58-2.92 (2H, m), 4.31-4.87 (2.5H, m), 5.09-5.36 (1.5H, m), 7.47-7.56 (2H, m), 7.67-7.71 (2H, m), 7.72-7.81 (1H, m), 8.39-8.87 (1H, m); 13C NMR (100 MHz, d6-DMSO) δ 16.7/16.7/17.0, 19.0/19.1/19.2/19.3, 30.3/30.3/30.4, 34.5/34.8, 52.0/52.4, 79.8/80.1, 84.2/84.3, 127.3, 127.4, 127.7, 128.5, 129.2, 129.7, 131.4/131.4, 132.0, 133.1/133.2, 136.4/136.5, 138.8/138.9, 152.2/152.3, 169.5/169.6, 172.0/172.1, 202.4/202.5; 19F NMR (376 MHz, d6-DMSO) -226.5 (br), -226.8 (t) , -232.9 (t), -233.0 (br).
Primjer 16
[3S/R]-5-fluor-4-okso-3-[(S)-3-metil-2-(3,4-diklorfonotiazin)-karbamoiloksi-butirilamino]-pentanoična kiselina
[image]
Pripremi se upotrebom sličnog postupka kao što je gore opisano u Metodama H, I i C-E. Fenotiazin se pripremi u skladu s postupkom opisanim u J. Chem. Soc. (1970) , 2437-2441. Produkt se izolira kao bijela krutina reverznom fazom HPLC (58 % zadnji korak): IR (krutina) 1736, 1436, 1365, 1222, 1050 cm-1; 1H NMR(400 MHz, d6-DMSO) δ 0.66-0.85 (6H, m), 2.00-2.08 (1H, m), 2.57-2.93 (2H, m), 4.30-5.35 (4H, m), 7.31-7.71 (6H, m), 8.27-8.83 (1H, m); 13C NMR (100 MHz, d6-DMSO) δ 16.8/17.1, 19.0/19.1, 30.3, 34.5/34.8, 52.0/52.4, 79.8/80.0, 84.2/84.3, 179.2/178.6, 127.1, 127.3, 127.5, 128.2, 128.5, 128.5, 129.6, 130.0, 133.7, 137.3/137.3, 137.6/137.6, 152.5, 169.5/169.5, 172.0/172.1, 202.3; 19F NMR (376 MHz, d6-DMSO) -226.6 (t), -226.8 (t), -232.9 (t).
Primjer 17
[3S/R]-5-fluor-4-okso-3-[(S)-3-metil-2-(9,10-dihidrofenantridin)-karbamoiloksi-butirilamino]-pentanoična kiselina
[image]
Pripremi se upotrebom sličnog postupka kao što je gore opisano u Metodama H, I i C-E. 9,10-dihidrofenantridin se pripremi u skladu s postupkom opisanim u J, Chem. Soc. (1951), 3207-3211. Produkt se izolira kao bijela krutina reverznom fazom HPLC (56 % zadnji korak) : IR (krutina) 1732, 1365, 1226, 1212, 1203 cm-1; 1H NMR(400 MHz, d6-DMSO) δ 0.84 (6H, m), 2.05 (1H, m), 2.55-2.90 (2H, m), 4.28-5.36 (6H, m), 7.26-7.43 (5H, m), 7.75-7.77 (1H, m), 7.89-7.91 (2H, m), 8.24-8.81 (1H, m); 13C NMR (100 MHz, d6-DMSO) δ 17.1/17.4, 18.9/19.0, 30.3/30.4, 34.4/34.8, 46.9, 51.9/52.4, 79.0/79.4, 84.2/84.3, 123.8, 124.3, 125.1, 125.7, 126.2, 128.0, 128.2, 129.3, 128.5, 131.5, 134.1, 136.9, 153.1, 170.0/170.1, 172.0/172.1, 202.4/202.8 ; 19F NMR (376 MHz, d6-DMSO) -226.7 (br), -226.9 (br), -233.1 (t). MS (ESI-ve) 455 (M-H).
Primjer 18
Dibenzo[b,f]azepin-5-karboksilna kiselina-1-(1-karboksimetil-3-fluor-2-okso-propil-karbamoil)-2-metil-propil ester
[image]
Pripremi se upotrebom sličnog postupka kao što je gore opisano u Metodama H, I i c-E. Produkt se izolira kao bijela krutina (100 % zadnji korak): IR (krutina) 1791.2, 1714.9, 1683.4, 1525.6, 1492.6, 1370.1, 1325.6, 1229.3, 1212.5, 1053.4, 1032.7, 798.4 cm-1; :H NMR(400 MHz, d6-DMSO) δ 0.50+0.68 (6H, 2 x m), 1.90 (1H, m), 2.54-2.93 (2H, m), 4.20-5.44 (4H, m), 7.02 (2H, s), 7.30-7.80 (8H, m); 13C NMR (100 MHz, d6-DMSO) δ 18.73, 19.17, 30.34, 34.56, 52.18, 84.37, 127.92, 128.61, 128.69, 129.63, 130.83, 134.40, 153.90, 169.64, 172.23, 202.29, 202.43, 202.63, 202.76; 19F NMR (376 MHz, d6-DMSO) -226.83 (t), -226.87 (t), -232.93 (t) ., -233.07 (t), -233.10 (t), -233.32 (t); MS (ESI +ve) 469 (M+H).
Primjer 19
10,11-dihidro-dibenzo[b,f]azepin-5-karboksilna kiselina-1-(1-karboksimetil-3-fluor-2-okso-propilkarbamoil)-2-metil-propil ester
[image]
Pripremi se upotrebom sličnog postupka kao što je gore opisano u Metodama H, I i C-E. Produkt se izolira kao bijela krutina (100 % zadnji korak): IR (krutina) 1796.9, 1683.9, 1521.8, 1491.5, 1368.3, 1324.8, 1278.6, 1213.4, 1201.9, 1108.0, 1056.4, 931.1, 776.5, 746.7 cm-1; 1H NMR(400 MHz, d6-DMSO) δ 0.50-0.95 (6H, m), 1.90 (1H, m), 2.55-3.00 (2H, m), 4.20-5.30 (8H, m), 7.10-7.50 (8H, m); 13C NMR (100 MHz, d6-DMSO) δ 15.24, 16.79, 39.44, 52.43, 78.36, 84.34, 126.80, 127.89, 128.43, 130.29, 136.29, 154.09, 169.58, 170.03, 172.19, 173.12, 202.28, 202.42; 19F NMR (376 MHz, d6-DMSO) -226.76 (t), -233.01 (t), -233.11 (t), -233.38 (t); MS (ESI +ve) 469 (M+H).
Primjer 20
[3S/R]-5-fluor-4-okso-3-((S)-2,3-dihidroindol-1-karbamoiloksi-3-metil-butirilamino]-pentanoična kiselina
[image]
Metoda J:
(S)-2-(imidazolkarbamoiloksi)-3-betil maslačna kiselina, benzil ester
[image]
Uz mješanje otopini benzil estera (S)-2-hidroksi-3-metilmaslačne kiseline (za pripravu vidi J. Med. Chem., (1996), 39, 982, 1.5 g) i THF (20 ml) doda se karbonilimidazol (1.17 g) i nastala smjesa se miješa na sobnoj temperaturi kroz 12 sati. Reakcijska smjesa se koncentrira pod reduciranim tlakom a ostatak se ponovo-rastopi u etil acetatu (30 ml). Otopina se ispere s 1% fosfornom kiselinom (2x 10 ml), potom slanom vodom (10 ml), osuši (magnezij sulfat) filtrira i koncentrira da se dobije imanobana spoj kao bezbojno ulje (1.89 g): 1H NMR(400 MHz, CDCl3) δ 1.02 (3H, d), 1.11 (3H, d), 2.47 (1H, m), 5.15 (1H, d), 5.18-5.32 (2H, m), 7.11 (1H, s), 7.18-7.60 (6H, m), 8.20 (1H, m).
Metoda K:
(S)-(2,3-dihidroindol-1-karbamoiloksi)-3-metil maslačna kiselina, benzil ester
[image]
Uz miješanje otopini (S)-2-(imidazolkarbamoiloksi)-3-metil maslačne kiseline, benzil estera (355 mg) u THF (7 ml) na 0 °C doda se metil trifluormetansulfonat (0.13 ml). Nastalu smjesu miješa se 30 min. Indolin (280 mg) se potom doda i smjesu se ostavi na toplom na sobnoj temperaturi kroz 12 sati. Reakcijska smjesa se koncentrira pod reduciranim tlakom a ostatak se ponovo otopi u etil acetatu (30 ml). Otopina se ispere zasićenom otopinom natrij bikarbonata (5 ml) potom 1M klorovodičnom kiselinom (2 x 5 ml), zatim slanom vodom (5 ml), osuši (magnezij sulfat), filtrira i koncentrira. Ostatak se purificira flash kromatografijom (5-78% etil acetat/heksan) da se dobije imenovani spoj kao bezbojno ulje (342 mg): 1H NMR(400 MHz, CDCl3) δ 0.86-1.18 (6H, m), 2.35 (1H, m), 3.08-3.25 (2H, m), 4.05-4.25 (2H, m), 4.95-5.23 (3H, m) , 6.95-7.91 (9H, m).
Metoda L:
(S)-(2, 3-dihidroindol-1-karbamoiloksi)-3-metilmaslačna kiselina
[image]
Uz mješanje otopini (S)-(2,3-dihidroindol-1-karbamoiloksi)-3-metilmaslačne kiseline, benzil ester (342 mg) u metanolu (25 ml) doda se 10% paladija na ugljiku (80 mg). Smjesu se hidrogenizira na sobnoj temperaturi kroz 2 sata. Potom se smjesa filtrira preko celita, a filtrat koncentrira da se dobije imenovani spoj kao bezbojno ulje (255 mg): 1H NMR(400 MHz, CDCl3) δ 0.95-1.21 (6H, m), 2.40 (1H, m), 3.20 (2H, m), 4.01-4.25 (2H, m), 4.95-5.15 (1H, m), 6.97-7.99 (4H, m).
Primjer 20
[3S/R]-5-fluor-4-okso-3-((S)-2,3-dihidroindol-1-karbamoiloksi-3-metil-butirilamino)-pebtanoična kiselina
[image]
Pripremi se upotrebom sličnog postupka kao što je gore opisano u Metodama C-E. Produkt se izolira kao bijela krutina (94 % zadnji korak): IR (krutina) 1680.2, 1485.6, 1413.9, 1137.4, 1050.4, 758.5 cm-1; 1H NMR(400 MHz, d6-DMSO) δ 0.95 (6H, brm) , 2.17 (1H, brm) , 2.50-2.94 (2H, m), 3.12 (2H, brm), 3.84-4.23 (2H, brm), 4.27-5.39 (4H, m), 6.98 (1H, m), 7.22 (2H, m), 7.67 (1H, brm), 7.78-8.30 (1H; brm), 12.50 (1H, brs); 13C NMR (100 MHz, d6-DMSO) δ 17.2, 19.0, 19.2, 27.3, 30.4, 30.6, 32.9, 34.5, 34.6, 47.3, 47.35, 52.0, 52.2, 78.3, 83.4, 85.1, 104.0, 114.2, 123.0, 125.4, 127.5, 131.7, 170.0, 172.07, 172.1, 173.2, 173.25, 202.3, 202.5, 202.6; 19F NMR (376 MHz, d6-DMSO) -226.7 (t), -226.8 (t), -233.1 (t), -233.3 (t); MS (ESI +ve) 395 (M+H).
Primjer 21
[3S/R]-5-fluor-4-okso-3-[(S)-3-metil-2-(karbazol)-karbamoiloksi-butirilamino]-pentanoična kiselina, dietilamid
[image]
Metoda M:
Uz miješanje otopini kiseline (Primjer 1; pripremljenoj kao što je opisano u Metodama A-E) (100 mg) i THF (2 ml) na 0°C doda se dietilamin (16 mg) i THF (0.5 ml) čemu slijedi 1-(3-dimetilaminopropil)-3-(etilkarbodiimid hidroklorid, EDC) (48) . Smjesa se potom zagrije na sobnu temperaturu preko 12 sati. Otapalo se odstrani pod reduciranim tlakom a ostatak se purificira flash kromatografijom (50-60 % etil acetat/heksan) da se dobije amid kao bjela krutina (54 mg); 1H NMR(400 MHz, CDCl3) δ 0.69-1.38 (12H, m), 2.42-3.37 (7H, m), 4.85-4.92 (1H, m), 5.01-5.55 (3H, m), 7.31-7.70 (5H, m), 7.90-8.05 (2H, m), 8.25-8.42 (2H; m); 19F NMR (376 MHz, d6-DMSO) -232.6 (t), -232.8 (t); MS (ESI +ve) 498 (M+H).
Primjer 22
[3S/R]-5-fluor-4-okso-3-[(S)-3-metil-2-(karbazol)-karbamoiloksi-butirilamino]-pentanoična kiselina, etil amid
[image]
Pripremi se upotrebom sličnog postupka kao što je gore opisano u Metodi M. Produkt se izolira kao bijela krutina (62 %) : 1H NMR (400 MHz, CDCl3) δ 0.96-1.31 (9H, m), 2.21-2.45 (1H, m), 2.48-2.80 (2H, m), 3.15-3.84 (2H, m), 4.23-4.76 (3H, m), 5.05-5.42 (1H, m), 6.42-6.48 (1H; m), 7.38-7.60 (4H, m), 7.95-8.09 (2H, m), 8.20-8.41 (2H, m); 19F NMR (376 MHz, CDCl3) -223.8 (t), -224.5 (t), -226.5 (t), -227.1 (t), -231.9 (t), -232 (t); MS (ESI +ve) 452 (M+H2O).
Primjer 23
[3S/R]-5-fluor-4-okso-3-[(S)-3-metil-2-(karbazol)-karbamoiloksi-butirilamino]-pentanoična kiselina, piperazin amid
[image]
Pripremi se upotrebom sličnog postupka kao što je gore opisano u Metodi M. Produkt se izolira kao bijela krutina (78 %): :H NMR(400 MHz, CDCl3) δ 1.10-1.35 (6H, m), 1.80-3.55 (14H, m), 4.28-4.98 (1H, m), 5.0-5.45 (3H, m), 7.38-7.60 (5H, m), 7.95-8.08 (2H, m), 8.27-8.45 (2H, m); 19F NMR (376 MHz, CDCl3) -232.5 (t), -232.7 (t); MS (ESI +ve) 525 (M+H).
Primjer 24
[3S/R]-5-fluor-4-okso-3-[(S)-3-metil-2-(karbazol)-karbamoiloksi -butirilaminoj-pentanoična kiselina,
N,N-dimetilaminoetil amid
[image]
Pripremi se upotrebom sličnog postupka kao što je gore opisano u Metodi M. Produkt se izolira kao bijela krutina (49 %) : 1H NMR(400 MHz, CDCl3) 8 1.14-1.31 (6H, m), 1.88-3.04 (13H, m), 3.88-4.41 (3H, m), 4.57-4.74 (1H, m), 5.33-5.61 (1H, m), 6.86-7.12 (1H, m), 7.33-7.56 (4H, m), 8.01-8.05 (2H, m), 8.27-8.41 (2H, m); 19F NMR (376 MHz, CDCl3) -222.4 (t), -222.5 (t); MS (ESI +ve) 513 (M+H).
Primjer 25
[3S/R]-5-fluor-4-okso-3-[(S)-3-metil-2-(karbazol) -karbamoiloksi-butirilamino]-pentanoamid
[image]
Metoda N:
Uz mješanje otopini [3S/R]-5-fluor-4-okso-3-[(S)-3-metil-2-(karbazol-karbamoiloksi-butirilamino]-pentanoične kiseline iz Primjera 1 (150 mg) i dikormetana (1.5 ml) i dimetilformamida (0.075 ml) doda se karbonildiimidazol (66 mg). Smjesa se miješa kroz 2 sata ohladi na 0 °C za vrijeme uvođenja mjehurića amonijaka. Smjesa se razrijedi etil acetatom/10 % otopinom kalij vodik sulfata. Organska faza se odstrani, a vodena ekstrahira s etil acetatom. Spojena organska se osuši iznad megnezij sulfata, filtrira i koncentrira. Ostatak se purificira flash kromatografijom (5% metanol/diklormetan) da se dobije amid kao bijela krutina (80 mg); 1H NMR(400 MHz, CDCl3) δ 1.10-1.28 (6H, m), 2.12-2.75 (3H, m), 4.10-4.85 (4H, m), 5.29 (1H, m), 6.36, 6.55, 6.78,6.98 (1H, 4 x s), 7.17 (1H, m), 7.42 (2H, m), 7.50 (2H, m), 7.99 (2H, m), 8.29 (2H, m); 19F NMR (376 MHz, CDCl3) -225.47 (t), -226.00 (t), -227.33 (t), -227.50 (t), -228.43 (t); MS (ESI +ve) 424 (M-H20+H) .
Primjer 26
[3S/R]-5-fluor-4-okso-3-[(S)-3-metil-2-(karbazol)-karbamoiloksi-butirilamino]-pentanoična kiselina, cikloheksi ester
[image]
Pripremi se upotrebom sličnog postupka kao što je gore opisano u Metodi M. Produkt se izolira kao bijela krutina (37 %): 1H NMR(400 MHz, CDCl3) δ 0.90-1.80 (16H, m), 2.59 (1H, m), 2.75-3.15 (2H, m), 4.40 (0.5H, m), 4.64 (0.5H, m),4.95-5.45 (4H, m), 7.25 (1H, m), 7.42 (2H, m), 7.52 (2H, m), 8.05 (2H, m), 8.36 (2H, m); 19F NMR (376 MHz, CDCl3) -231.95 (t), -232.08 (t) .
Primjer 27
[3S/R]-5-fluor-4-okso-3-[(S)-3-metil-2-(karbazol)-karbamoiloksi-butirilamino]-pentanoična kiselina, n-propil ester
[image]
Pripremi se upotrebom sličnog postupka kao što je gore opisano u Metodi M. Produkt se izolira kao bijela krutina (82 %) : 1H NMR(400 MHz, CDCl3) δ 0.80 (3H, m), 1.13-1.36 (6H, m), 1.42 (1H, m), 1.58 (1H, m), 2.60 (1H, m), 2.80-3.08 (2H, m), 3.70 (1H, m), 3.98 (1H, m), 4.92-5.50 (4H, m), 7.21 (1H, m), 7.40 (2H, m), 7.50 (2H, m), 8.0 (2H, m), 8.32 (2H, m); 19F NMR (376 MHz, CDCl3) -232.00 (t), -232.01 (t); MS (ESI +ve) 485 (M+H).
Primjer 28
[3S/R]-5-fluor-4-okso-3-[(S)-3-metil-2-(karbazol)-karbamoiloksi-butirilamino]-pentanoična kiselina, izopropil ester
[image]
Pripremi se upotrebom sličnog postupka kao što je gore opisano u metodi M. Produkt se izolira kao bijela krutina (7 %): 1H NMR(400 MHz, CDCl3) δ 0.90-1.33 (12H, m), 2.55 (1H, m), 2.78-3.15 (2H, m), 4.80-5.50 (5H, m), 7.25 (1H, br s), 7.43 (2H, m), 7.55 (2H, m), 8.05 (2H, m), 8.36 (2H, m); 19F NMR (376 MHz, CDCl3) -232.00 (t), -232.03 (t).
Primjer 29
[3S/R]-5-fluor-4-okso-3-[(S)-3-metil-2-(karbazol)-karbamoiloksi-butirilamino]-pentanoična kiselina, metil ester
[image]
Pripremi se upotrebom sličnog postupka kao što je gore opisano u Metodi M. Produkt se izolira kao bijela krutina (81 %): δ 1H NMR(400 MHz, CDCl3) 1.20 (6H, m), 2.58 (1H, m), 2.80-3.05 (2H, m), 3.42, 3.16 (3H, 2 x s), 4.98-5.26 (3H, m), 5.41 (1H, m), 7.20 (1H, br s), 7.45 (2H, m), 7.55 (2H, m), 8.04 (2H, m), 8.35 (2H, m); 19F NMR (376 MHz, CDCl3) -231.99 (t), -232.00 (t); MS (ESI +ve) 457 (M+H).
Primjer 30
[3S/R]-5-fluor-4-okso-3-[(S)-3-metil-2-(karbazol)-karbamoiloksi-butirilamino]-pentanoična kiselina, kolesterol ester
[image]
Pripremi se upotrebom sličnog postupka kao što je gore opisano u Metodi N, koristeći karbonildiimidazol kao spajajući reagens. Produkt se izolira kao bijela krutina (12 %): 1H NMR(400 MHz, CDCl3) 6 0.65-2.35 (47H, m), 2.58 (1H, m), 2.75-3.15 (2H, m), 4.25 (0.5H, m), 4.48 (0.5H, m), 4.97-5.46 (5H, m), 7.30 (1H, m), 7.44 (2H, m), 7.58 (2H, m), 8.05 (2H, m), 8.33 (1H, m); 19F NMR (376 MHz, CDCl3) -231.91 (t), -232.03 (t). Odgovarajući ketal također se izolira kao bijela krutina (21 %): 1H NMR(400 MHz, CDCl3) δ 0.65-2.10 (48H, m), 2.35-3.15 (2H, 3xm) , 3.42-3.69 (1H, m), 4.10-4.96 (4H, m), 5.15-5.65 (2H, m), 6.78 (1H, m), 7.45 (2H, m), 7.57 (2H, m), 8.05 (2H, m), 8.34 (1H, m); 19F NMR (376 MHz, CDCl3) -230.57 (t), -230.67 (t).
Metode testiranja
Enzimsko ispitivanje
Ispitivanje inhibicije kaspaze bazira se na cijepanju fluoregeničnog substrata rekombinantnom, purificiranom humanom kaspazom -1, -3, -7 ili -8. To ispitivanje provedeno je u suštini na isti način kao što je izvjestio Garcia-Calvo et al. (J. Biol. Chem. 273 (1998), 32608-32613), koristeći specifičan substrat za svaki enzim. Substrat za kaspazu-1 je acetil-Tyr-Val-Ala-Asp-amino-4-metilkumarin. Supstrat za kaspazu -3, -7 i -8 je acetil-Asp-Glu-Val-Asp-amino-4-metilkumarin.
Uočeni put inaktivacije enzima uz određenu koncentraciju inhibitora, kobs, izračunat je direktnim stavljanjem podataka u jednadžbu izvedenu od Thornberry et al. (Biochemistry 33 (1994), 3943-3939) upotrebom nelinearne least-squares analize računalnog programa (PRISM 2.0; GraphPad sofrware). Da bi se dobio second order rate constant, kinact, k0bs vrijednosti su sudjelovale protiv njihovih pojedinih inhibitornih koncentracija, a kinact vrijednosti su kasnije izračunate kompjutorskom linearnom regresijom. Mnogi od prezentiranih spojeva tako su testirani na kaspazu-1, kinact vrijednosti između 25,000 i 1,500,000 M-1s-1; na kaspazu-3, kinact vrijednosti su između 9,000 i 1,500,000 M-1s-1; na kaspazu-8, vrijednosti su između 10,000 i 700,000 M-1s-1.
Inhibicija IL-1β sekrecije iz miješane populacije mononuklearnih stanica periferne krvi (PBMC)
Postupanje s pre-IL-1β kaspaze-1 može se mjeriti staničnom kulturom koristeći različite izvore stanica. Humane PBMC dobivene od zdravog donora osiguravaju mješanu populaciju limfocita i mononuklearnih stanica tako da produciraju spektar interleukina i citokina kao odgovor na brojne klase fizioloških stimulatora.
Eksperimentalni postupak
Test spoj rastopi se u dimetil sulfoksidu (DMSO; Sigma #D-2650) sa se dobije 100 mM stock otopine. To se razrijedi u kompletnom mediju koji sadržava RPMI koji sadržava 10% toplinom inaktiviranog FCS (Gibco BRL §10099-141), 2 mM L-glutamina (Sigma, #G-7513), 100 J penicilina i 100 μg/ml streptomicina (Sigma #P-7539). Finalna koncentracija omjera testiranog spoja je od 100 μM sve do 6 nM preko osam koraka razrjeđivanja. Najviša koncentracija testiranog spoja je ekvivalentna 0.1 % DMSO u ispitivanju.
Humani PBMC je izolirana iz Buffy Coats dobivene iz banke krvi koristeći centrifugiranje na Ficoll-Paque mediju za separaciju leukocita (Amersham, §17-1440-02) i analizom stanica provedenom u sterilnim pločama s 96 jažica ravnog dna (Nunc). Svaka jažica sadržava 100 μl suspenzije stanica, 1 x 105 stanica, 50 jal otopine spoja i 50 μl LPS (Sigma #L-3012) na 50 ng/ml finalne koncentracije. Kontrola sadržva stanice +/- LPS stimulirane i serijska razrjeđenja DMSO razrjeđenog spoja na isti način. Ploče se inkubiraju kroz 16-18 sati na 37 °C u 5% CO2 & vlažnoj atmosferi.
Nakon 16-18 sati supernatant se sakupi nakon centrifugiranja ploča na 100 x g na 18 °C kroz 15 min i analizira na sadržaj IL-1β. Mjerenje zrelih IL-1β u supernatantu provodi se upotrebom Quantikine kitom (R&D Systems) u skladu s uputom proizvođača. Nivoi zrelosti IL-1β od oko 600-1500 pg/ml su promatrani za PBMCs u jažicama pozitivne kontrole.
Inhibitorna snaga spojeva može se predtaviti IC50 vrijednosti, koja je koncentracija inhibitora na kojoj je određeno 50% zrelih IL-1β u supernatantu u komparaciji s pozitivnom kontrolom. Tablica 5 pokazuje inhibiciju sekrecije IL-1β od mononuklearnih stanica periferne krvi za odabrani spoj ovog izuma a determinirana je gore navedenom metodom.
Odabrani spojevi će biti testirani ovom analizom i prikazana inhibicija otpuštanja IL-1β s IC50 vrijednosti između 0.04 pM i 20 μM.
Ispitivanje anti-fas inducirane apoptoze
Apoptoza stanica može biti inducirana vezanjem fas liganda (FasL) na njegov receptor, CD95 (Fas). CD95 je jedan iz porodice srodnih receptora, poznatih kao receptor smrti, koji može biti okidač apoptoze u stanicama preko aktivacije kaskade enzima kaspaze. Proces je inicijaliziran vezanjem molekule adaptera FADD/MORT-1 na citoplazmatsko područje CD-95 receprtor-ligand kompleksa. Kaspaza-8 zatim veže FADD i postaje aktivirana, inicijacija kaskade rezultat takvog uključivanja aktivacije nizvodne kaspaze i . posljedične apoptoze stanice. Apoptoza može isto biti induicrana u stanicama istiskivanjem CD95 eg Jurkat E6.1 T stanice linije limfoma stanice, koristeći protutijela, radije nego FasL, za crosslink površine stanice CD95. Anti-fas-inducirana apoptoza je isto pokrenuta aktivacijom kaspaze-8. To je osigurano na osnovu na osnovu analize stanica provjerenih spojeva za inhibiciju kaspaze-8-posredovane apoptotičkim putem.
Eksperimentalni postupak
Jurkat E6.1 stanice su kultivirane u kompletnom mediju koji sadržava RPMI-1640 (Sigma No) + 10 % telećeg fetalnog seruma (Gibco BRL No. 10099-141) + 2 mM L-glutamina (Sigma No. G-7513). Stanice se skupljaju u logaritamskoj fazi rasta. 100 ml stanica sa 5-8xl05 stanica/ml se transferira u sterilne 50 ml Falkon epruvete za centrifugiranje i centrifugira kroz 5 minuta na 100xg na sobnoj temperaturi. Supernatant se odstrani a spojene stanice se resuspendiraju u 25 ml kompletnog medija. Stanice se broje i s kompletnim medijem podesi gustoća na 2x106 stanica/ml.
Ispitivani spoj se rastopi u dimetil sulfoksidu (DMSO) (Sigma No. D-2650) da se dobije 100 mM stok otopine. Ta se razrijedi na 400 pM u kompletnom mediju, potom serijski razrijedi u pločama s 96 jažica kojima je prije dodano stanica za ispitivanje ploče.
100 μL suspenzije stanica (2xl06 stanica) doda se u svaku jažicu sterilne 96-jažica round-buttomed cluster plate (Costar No. 3790). 50 μl otopine spoja odgovarajućeg razrjedenja i 50 μl anti fas-protutijela, klon CH-11 (Kamiya No.MC-060) za finalnu koncentraciju od 10 ng/ml, dada se u jažice. U kontrolne jažice postavljeno je manje protutijela i manje spoja sa serijskim razrjeđenjem DMSO kao sredstvo kontrole. Ploče su inkubiraju kroz 16-18 sati na 37 °C u 5% CO2 i 95% vlažnosti.
Apoptoza stanica se mjeri kvantifikacijom DNA fragmentacije koristeći "Cell Death detection Assay" od Boehringer-Mannheim, No. 1544 675. Nakon inkubacije od 16-18 sati ispitivane ploče se centrifugiraju na 100xg na sobnoj temperaturi kroz 5 min. 150 μl supernatanta se odstrani i zamjeni s 150 μl svježeg kompletnog medija. Stanice se potom sakupe i doda 200 μl lysis bufera iz kita za ispitivanje u svaku jažicu. Stanice se trituriraju da se osigura kompletna liza i inkubiraju 30 min. na 4 °C. Ploče se potom centrifugiraju na 1900xg kroz 10 min a supernatant se razrijedi 1:20 i doda se bufer za inkubaciju. 100 μl ove otopine se potom ispita u skladu s uputom proizvođača koja se nalazi uz kit. OD405nm je mjeren 20 minuta nakon dodavanja finalnog supstarata u SPECTRAmax Plus čitač ploča (Molecular Devices).
OD405nm je unesen nasuprot koncentracije spoja i IC50 vrijednosti za spojeve izračunate koristeći curve-fitting program SOFTmax Pro (Molecular Device) koristeći četiri parametra.
Odabrani spojevi su ispitani ovom analizom i pokazana je inhibicija fas-inducirane apoptoze Jurkat stanica s IC50 vrijednosti između 0.001 pM i 0.15 μM.
Opisana su brojna ostvarenja ovog izuma, i očito je da se osnovni primjeri mogu promjeniti kako bi se osiguralo drugo ostvarenje, koje koristi spojeve i metode ovog izuma.
Zbog toga, biti će procjenjeno da cilj ovog izuma će biti definiran dodatnim zahtjevima radije nego s specifičnim ostvarenjima, koja su predstavljena primjerima.
Claims (38)
1. Postupak za tretiranje bolesti pacijenata koje su ublažene tretiranjem s inhibitorima kaspaze, obuhvaćaju aplikaciju pacijentima ako je potreban takav tretman terapijski učinkovite količine spoja formule I:
[image]
ili njihovi farmaceutski -prihvatljivih derivata
naznačen time, da
Z je kisik ili sumpor;
R1 je vodik, -CHN2, -R, -CH2OR, -CH2SR, ili -CH2Y;
R je alifatski C1-12, aril, aralkil, heterociklil, ili heterociklilalkil;
Y je elektronegativna ostatna skupina;
R2 je CO2H; CH2CO2H; ili njihovi esteri, amidi ili izosteri;
R3 je skupina sposobna za pristajanje u S2 sub-mjesto kaspaze; i
R4 i R5 zauzimaju zajedno s interventnim dušikom oblik mono-, bi- ili tricikličnog hetero sustava prstena koji ima 1-6 heteroatoma odabranih od dušika, kisika ili sumpora.
2. Postupak zahtjeva 1, naznačen time, da spoj ima jednu ili više sljedećih osobina:
(i) Z je kisik.
(ii) R1 je vodik, -R, -CH2OR, -CH2SR, ili -CH2Y.
(iii) R2 je C02H ili njihovi esteri, amidi ili izosteri.
(iv) R3 je skupina čija je molekulska masa sve do oko 140 daltona, ili
(v) R4 i R5 zauzimaju zajedno s interventnim oblikom dušika monociklični, biciklični ili triciklični sustav prstena gdje svaki prsten sustava ima 5-7 atoma prstena.
3. Postupak zahtjeva 2, naznačen time, da spoj ima jednu ili više sljedećih osobina:
(i) Z je kisik.
(ii) R1 je vodik, -R, -CH2OR, -CH2SR, ili -CH2Y.
(iii) R2 je C02H ili njihovi esteri, amidi ili izoesteri.
(iv) R3 je skupina čija je molekulska masa sve do oko 140 daltona, ili
(v) R4 i R5 zauzimaju zajedno s interventnim oblikom dušika monociklični, biciklični ili triciklični heterociklični ili heteroaril sustav prstena gdje svaki prstem sustava ima 5-7 atoma prstena.
4. Postupak zahtjeva 3, naznačen time, da je R1 -CH2Y.
5. Postupak zahtjeva 4, naznačen time, da R1 je -CH2F, a R3 je C1-4 alkil skupina.
6. Postupak zahtjeva 5, naznačen time, da R4 i R5 zauzimaju zajedno s interventnim oblikom dušika biciklični ili triciklični heterociklični ili heteroaril sustav prstena gdje svaki prsten sustava ima 5-7 atoma prstena.
7. Postupak zahtjeva 6, naznačen time, da R4 i R5 zauzimaju zajedno s interventnim oblikom dušika triciklični heterociklični ili heteroaril sustav prstena gdje svaki prsten sustava ima 5-7 atoma prstena.
8. Postupak zahtjeva 7, naznačen time, da je sredina prstena tricikličnog sustava prstena pet ili šest-člani prsten.
9. Postupak zahtjeva l, naznačen time, da spoj ima jednu ili više slijedećih osobina
(i) Z je kisik.
(ii) R1 je -CH2OR, -CH2SR, ili -CH2Y.
(iii) R2 je C02H ili njihov ester, amid ili izoster.
(iv) R3 jeC1-4 alkil, ili
(v) R4 i R5 zauzimaju zajedno s interventnim oblikom dušika oblik prstena odabran od indola, izoindola, indolina, indazola, purina, dihidropiridina, benzimidazola, imidazola, imidazolina, pirola, pirolidina, pirolina, pirazola, pirazolina, pirazo-lidina, triazola, piperidina, morfolina, tiomerfolina, piperazina, karbazola, fenotiazina, fenoksazina, dihidrofenazina, dihidrocinolina, dihidrokvinoksalina, tetrahidrokvinolina, tetrahidroizokvinolina, dihidro-nafthiridina, tetrahidronafthidrina, dihidroakridina, p-karbolina, pirido[4,3-b]indola, 2,3,9-triazafluorena, 9-tia-2,10-diaazantracena, 3,6,9-triazafluorena, tieno-[3,2-b]pirola, ili dihidrofenantridin.
10. Postupak zahtjeva 9, naznačen time, da spoj ima jednu ili više slijedećih osobina
(i) Z je kisik.
(ii) R1 je -CH2OR, -CH2SR, ili -CH2Y.
(iii) R2 je CO2H ili njihov ester, amid ili izoster.
(iv) R3 je C1-4 alkil, ili
(v) R4 i R5 zauzimaju zajedno s interventnim oblikom dušika prstena odabranim indola, izoindola, indolina, indazola, benzimidazola, imidazola, pirolidina, pirazola, triazola, piperidina, morfolina, tiomorfolina, piperazina, karbazola, fenotiazina, fenokazina, dibenzoazepina, dihidro-dibenzoazepina, dihidrofenazina, dihidrocinolina, dihidrokvinoksalina, tetrahidrokvinolina, tetrahidroizokvinolina, dihidro-nafthiridina, tetrahidronafthiridina, dihidroakridina, p-karbolina, pirido[4,3-b]indola, 2,3,9-triazafluorena, 9-tia-2,10-diazaantracena, 3,6,9-triazafluorena, tieno-[3,2-b]pirola ili dihidrofenantridin.
11. Postupak zahtjeva 10, naznačen time, da spoj ima jednu ili više slijedećih osobina
(i) Z je kisik.
(ii) R1 je -CH2OR, -CH2SR, ili -CH2Y.
(iii) R2 je CO2H ili njihov ester, amid ili izoster.
(iv) R3 jeC1-4 alkil, ili
(v) R4 i R5 zauzimaju zajedno s interventnim oblikom dušika substituirani ili nesubstituirani oblik prstena odabran od karbazola, fenotiazina, indola, indolina, 5H-dibenzo[b,f]azepina, 10,11-dihidro-5H-dibenzo[b,f]-azepina, β-karbolina, pirido[4,3-b]indola, 2,3,9-triazafluorena, 9-tia-2,10-diazaantracena, 3,6,9-triazafluorena, tieno-[3,2-b]pirola ili dihidrofenantridin.
12. Postupak zahtjeva 11, naznačen time, da Z je kisik; R1 je -CH2OR, -CH2SR, ili -CH2Y; R2 je CO2H ili njihov ester, amid ili izoester; R3 je C1-4 alkil; a R4 i R5 zauzimaju zajedno s interventnim oblikom dušika substituirani ili nesubstituirani oblik prstena odabran od karbazola, fenotiazina, indola, indolina, 5H-dibenzo[b,f]azepina, 10,11-dihidro-5H-dibenzo [b,f]-azepina, (5-karbolina, pirido[4,3-b]indola, 2,3,9-triazafluorena, 9-tia-2,10-diazaantracena, 3,6,9-triazafluorena, tieno-[3,2-b]pirola, ili dihidrofenantridina.
13. Postupak zahtjeva 12, naznačen time, da R1 je -CH2Y.
14. Postupak zahtjeva 11, naznačen time, da R1 je -CH2F.
15. Postupak zahtjeva 1, naznačen time, da je spoj odabran od spojeva navedenih u Tablici 1.
16. Postupak zahtjeva 1, naznačen time, da je spoj odabran od sljedećih:
[image]
17. Postupak u skladu sa svakim od zahtjeva 1-16, naznačen time, da su bolesti ili tretmani odabrani od bolesti posredovanih s IL-1, bolesti posredovane apoptozom, upalne bolesti, autoimune bolesti, poremećaje destrukcije kosti, proliferativne poremećaje, infekcijske bolesti, degenerativne bolesti, bolesti povezane sa smrti stanica, bolesti povezane prekomjernim dnevnim unošenje alkohola, bolesti uzrokovane virusima, uveitis, infalmatorni peritonitis, osteoartritis, pankreatitis, astma, iscrpljenost odraslih respiratornim sindromom, glomerulonefritis/ reumatoidni artritis, sistemski lupus erittematosus, skleroderma, kronični tiroiditis, Grav-ova bolest, autoimuni gastritis, diabetes, autoimuna hemolitička anemija, autoimuna neutropenija, trombo-citopenija, kronični aktivni hepatitis, miastenija gravis, upalna bolest crijeva, Crohn-ova bolest, psorijaza, atopički dermatitis, scarring, graft vs host bolest, odbacivanje organa nakon transplantacije, osteoporoza, leukemija i s njom povezani poremećaji, mijelodisplastični sindrom, poremećaji povezani s multiplim mielomom, akutna mijelogena leukemija, kronična mijelogena leukemija, metastatički melanom, Kaposi-jev sarkom, multipli mijelom, hemoragični šok, sepsa, septički šok, opekline, šigeloza, Alzheimer-ova bolest, Parkinson-ova bolest, Huntington-ova bolest, Kennedy-eva bolest, prionska bolest, cerebralna ishemija, epilepsija, ishemija miokarda, akutne i kronične bolesti srca, infarkt miokarda, kongestivno zatajivanje srca, ateroskleroza, transplantiranje premosnice koronarne arterije, atrofija spinalne muskulature, amiotrofična lateralna skleroza, multipla skleroza, encefalitis povezan s HlV-m, aging, alopecija, neurološka oštećenja radi udara, ulcerativni kolitis, traumatske oštećenje mozga, oštećenje leđne moždine, hepatitis-B, hepatitis-C, hepatitis-G, žuta groznica, denga groznica, ili japanski encefalitis, različiti oblici bolesti jetre, bolest bubrega, poliaptična bolest bubrega, bolest gastričnog i duodenalnog ulcera povezana s H.pvlori, HIV-infekcije, tuberkuloza, meningitis, tretiranje komplikacija povezanih s transplantiranjem premosnice koronarne arterije i kao imunoterapija za tretiranje različitih oblika karcinoma.
18. Postupak u skladu sa svakim od zahtjeva 1-16, naznačen time, da se spoj koristi u tretiranju komplikacija povezanih s transplantacijom premosnica koronarnih arterija.
19. Postupak u skladu sa svakim od zahtjeva 1-16, naznačen time, da se spoj koristi u čuvanju stanica, navedenom metodom koja obuhvaća korak kupanja stanica u otopini spoja ili njihovih farmaceutski prihvatljivih derivata.
20. Postupak u skladu sa svakim od zahtjeva 1-16, naznačen time, da se spoj koristi za transplantaciju organa ili čuvanje krvnih pripravaka.
21. Postupak u skladu sa svakim od zahtjeva 1-16, naznačen time, da se spoj koristi kao komponenta imunoterapije za tretiranje karcinoma.
22. Spoj formule I:
[image]
ili njegovi farmaceutski-prihvatljivi derivati
naznačen time, da
Z je kisik ili sumpor;
R1 je vodik, -CHN2, -R, -CH2OR, -CH2SR, ili -CH2Y;
R je alifatski C1-12, aril, aralkil, heterociklil, ili heterociklilalkil;
Y je elektronegativna ostatna skupina;
R2 je CO2H; CH2CO2H; ili njihov ester, amid ili izoster;
R3 je skupina sposobna za pristajanje u S2 sub-mjesto kaspaze; i
R4 i R5 uzimaju zajedno s interventnim dušikom oblik mono-, bi- ili triciklični hetero sustav prstena koji imaju 1-6 heteroatoma odabranih od dušika, kisika ili sumpora.
23. Spoj iz zahtjeva 22 naznačen time, da spoj ima jednu ili više sljedećih osobina:
(i) Z je kisik.
(ii) R1 je vodik, -R, -CH2OR, -CH2SR, ili -CH2Y.
(iii) R2 je CO2H ili njihov ester, amid ili izoster.
(iv) R3 je skupina čija je molekulska masa sve do oko 140 daltona, ili
(v) R4 i R5 zauzimaju zajedno s interventnim oblikom dušika monociklični, biciklični ili triciklični sustav prstena gdje svaki prstem sustava ima 5-7 atoma prstena.
24. Spoj iz zahtjeva 23 naznačen time, da spoj ima jednu ili više sljedećih osobina:
(i) Z je kisik.
(ii) R1 je vodik, -R, -CH2OR, -CH2SR, ili -CH2Y.
(iii) R2 je CO2H ili njihov ester, amid ili izoster.
(iv) R3 je skupina čija je molekulska masa sve do oko 140 daltona, ili
(v) R4 i R5 zauzimaju zajedno s interventnim oblikom dušika monociklični, biciklični ili triciklični heterociklični ili heteroaril sustav prstena gdje svaki prsten sustava ima 5-7 atoma prstena.
25. Spoj iz zahtjeva 24 naznačen time, da R1 je -CH2Y.
26. Spoj iz zahtjeva 25 naznačen time, da R1 je -CH2F a R3 je C1-4 alkil skupina.
27. Spoj iz zahtjeva 26 naznačen time, da R4 i R5 zauzimaju zajedno s interventnim oblikom dušika biciklični ili triciklični heterociklični ili heteroaril sustav prstena gdje svaki prsten sustava ima 5-7 atoma prstena.
28. Spoj iz zahtjeva 27 naznačen time, da R4 i R5 zauzimaju zajedno s interventnim oblikom dušika triciklični heterociklični ili heteroaril sustav prstena gdje svaki prsten sustava ima 5-7 atoma prstena.
29. Spoj iz zahtjeva 28 naznačen time, da sredina prstena sustava tricikličnog prstena je pet- ili šest-člani prsten.
30. Postupak zahtjeva 22, naznačen time, da spoj ima jednu ili više slijedećih osobina
(i) Z je kisik.
(ii) R1 je -CH2OR, -CH2SR, ili -CH2Y.
(iii) R2 je CO2H ili njihov ester, amid ili izoster.
(iv) R3 je C1-4 alkil, ili
(v) R4 i R5 zauzimaju zajedno s interventnim oblikom dušika oblik prstena odabran od indola, izoindola, indolina, indazola, purina, dihidropiridina, benzimidazola, imidazola, imidazolina, pirola, pirolidina, pirolina, pirazola, pirazolina, pirazo-lidina, triazola, piperidina, morfolina, tiomerfolina, piperazina, karbazola, fenotiazina, fenoksazina, dihidrofenazina, dihidrocinolina, dihidrokvinoksalina, tetrahidrokvinolina, tetrahidroizokvinolina, dihidro-nafthiridina, tetrahidronafthidrina, dihidroakridina, β-karbolina, pirido[4,3-b]indola, 2,3,9-triazafluorena, 9-tia-2,10-diaazantracena, 3,6,9-triazafluorena, tieno-[3,2-b]pirola, ili dihidrofenantridin.
31. Postupak zahtjeva 30, naznačen time, da spoj ima jednu ili više slijedećih osobina
(i) Z je kisik.
(ii) R1 je -CH2OR, -CH2SR, ili -CH2Y.
(iii) R2 je CO2H ili njihov ester, amid ili izoester.
(iv) R3 jeC1-4 alkil, ili
(v) R4 i R5 zauzimaju zajedno s interventnim oblikom dušika prstena odabranim od indola, izoindola, indolina, indazola, benzimidazola, imidazola, pirolidina, pirazola, triazola, piperidina, morfolina, tiomorfolina, piperazina, karbazola, fenotiazina, fenokazina, dibenzoazepina, dihidro-dibenzoazepina, dihidrofenazina, dihidrocinolina, dihidrokvinoksalina, tetrahidrokvinolina, tetrahidroizokvinolina, dihidro-nafthiridina, tetrahidronafthiridina, dihidroakridina, β-karbolina, pirido[4,3-b]indola, 2,3,9-triazafluorena, 9-tia-2,10-diazaantracena, 3,6,9-triazafluorena, tieno-[3,2-b]pirola ili dihidrofenantridin.
32. Postupak zahtjeva 31, naznačen time, da spoj ima jednu ili više slijedećih osobina
(i) Z je kisik;
(ii) R1 je -CH2OR, -CH2SR, ili -CH2Y;
(iii) R2 je CO2H ili njihov ester, amid ili izoster;
(iv) R3 je C1-4 alkil; ili
(v) R4 i R5 zauzimaju zajedno s interventnim oblikom dušika substituirani ili nesubstituirani oblik prstena odabran od karbazola, fenotiazina, indola, indolina, 5H-dibenzo[b,f]azepina, 10,11-dihidro-5H-dibenzo[b,f]-azepina, β-karbolina, pirido[4,3-b]indola, 2,3,9-triazafluorena, 9-tia-2,10-diazaantracena, 3,6,9-triazafluorena, tieno-[3,2-b]pirola ili dihidrofenantridin.
33. Postupak zahtjeva 32, naznačen time, da Z je kisik; R1 je -CH2OR, -CH2SR, ili -CH2Y; R2 je CO2H ili njihov ester, amid ili izoester; R3 je C1-4 alkil; a R4 i R5 zauzimaju zajedno s interventnim oblikom dušika substituirani ili nesubstituirani oblik prstena odabran od karbazola, fenotiazina, indola, indolina, 5H-dibenzo[b,f]azepina, 10,11-dihidro-5H-dibenzo[b,f]-azepina, β-karbolina, pirido[4,3-b]indola, 2,3,9-triaza fluorena, 9-tia-2,10-diazaantracena, 3,6,9-triazafluorena, tieno-[3,2-b]pirola, ili dihidrofenantridin.
34. Postupak zahtjeva 33, naznačen time, da R1 je -CH2Y.
35. Postupak zahtjeva 34, naznačen time, da R1 je -CH2F.
36. Postupak zahtjeva 22, naznačen time, da je spoj odabran od spojeva navedenih u Tablici 1.
37. Postupak zahtjeva 22, naznačen time, da je spoj odabran od sljedećih:
[image]
38. Farmaceutska kompozicija naznačena time, da sadržava spoj u skladu sa svakim od zahtjeva 22-37 i farmaceutski prihvatljivih nosača.
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Families Citing this family (40)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE363465T1 (de) | 1999-04-09 | 2007-06-15 | Cytovia Inc | Caspase inhibitoren und ihre verwendung |
ATE409688T1 (de) | 1999-08-27 | 2008-10-15 | Cytovia Inc | Substituierte alpha-hydroxy-säuren als caspase- hemmer und ihre verwendung |
SK13922002A3 (sk) * | 2000-03-29 | 2003-09-11 | Vertex Pharmaceuticals Incorporated | Karbamátové inhibítory kaspázy a ich použitie |
PE20011350A1 (es) | 2000-05-19 | 2002-01-15 | Vertex Pharma | PROFARMACO DE UN INHIBIDOR DE ENZIMA CONVERTIDORA DE INTERLEUCINA-1ß (ICE) |
US20040192889A1 (en) * | 2001-03-30 | 2004-09-30 | Dale Bredesen | Cytotoxic peptides and peptidomimetics based thereon, and methods for use thereof |
EP1392289A2 (en) * | 2001-05-23 | 2004-03-03 | Vertex Pharmaceuticals Incorporated | Caspase inhibitors and uses thereof |
AU2003211052A1 (en) * | 2002-02-11 | 2003-09-04 | Vertex Pharmaceuticals Incorporated | Phospholipids as caspase inhibitor prodrugs |
US7960398B2 (en) | 2002-04-19 | 2011-06-14 | Vertex Pharmaceuticals Incorporated | Regulation of TNF-alpha |
EP1447093A1 (en) * | 2003-02-14 | 2004-08-18 | Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts | Inhibition of the CD95 ligand/receptor system for the treatment of neurological disorders and injuries |
EP1607101A4 (en) * | 2003-02-24 | 2007-10-24 | Daiichi Seiyaku Co | INHIBITOR OF DEGRADATION OF PROTEIN INTERACTING WITH HEPATITIS B VIRUS PROTEIN X |
AU2003902704A0 (en) * | 2003-05-29 | 2003-06-19 | Crc For Waste Management And Pollution Control Limited Of Unsw | Process for producing a nanoscale zero-valent metal |
PT1725548E (pt) * | 2004-03-12 | 2015-04-16 | Vertex Pharma | Processo e intermediários para a preparação de inibidores de caspase de acetal de ácido aspártico |
US7544855B2 (en) * | 2004-04-23 | 2009-06-09 | Buck Institute | Transgenic mouse whose genome comprises an APP having a mutation at amino acid 664 |
WO2005115362A1 (en) * | 2004-05-15 | 2005-12-08 | Vertex Pharmaceuticals Incorporated | Treating seizures using ice inhibitors |
KR100619440B1 (ko) | 2004-05-20 | 2006-09-08 | 한기종 | 포름아마이드 유도체 제조방법 |
EP2295054A1 (en) | 2004-05-27 | 2011-03-16 | Vertex Pharmaceuticals Incorporated | Ice inhibitors for the treatment of autoinflammatory diseases |
KR100619439B1 (ko) | 2004-05-27 | 2006-09-08 | 한기종 | 포밀기 도입된 아민유도체의 제조방법 |
US8012751B2 (en) * | 2005-03-31 | 2011-09-06 | Wisconsin Alumni Research Foundation | Differentiation of pluripotent embryonic stem cells |
ATE529430T1 (de) * | 2005-07-28 | 2011-11-15 | Vertex Pharma | Caspase-hemmer-propharmaka |
JP4976304B2 (ja) | 2005-10-07 | 2012-07-18 | パナソニック株式会社 | 音響信号処理装置、音響信号処理方法およびプログラム |
AU2006349611A1 (en) | 2005-11-30 | 2008-05-02 | Massachusetts Institute Of Technology | Pathogen-detecting cell preservation systems |
US9539303B2 (en) * | 2006-04-24 | 2017-01-10 | Celgene Corporation | Treatment of Ras-expressing tumors |
EP2043672A4 (en) * | 2006-07-07 | 2009-10-21 | Univ Leland Stanford Junior | SELECTIVE CASPASE INHIBITORS |
WO2008021745A2 (en) * | 2006-08-16 | 2008-02-21 | Itherx Pharmaceuticals, Inc. | Hepatitis c virus entry inhibitors |
EP2054076A2 (en) * | 2006-08-21 | 2009-05-06 | United Therapeutics Corporation | Combination therapy for treatment of viral infections |
WO2008106167A1 (en) * | 2007-02-28 | 2008-09-04 | Conatus Pharmaceuticals, Inc. | Combination therapy comprising matrix metalloproteinase inhibitors and caspase inhibitors for the treatment of liver diseases |
US8828950B2 (en) * | 2007-05-01 | 2014-09-09 | Cedars-Sinai Medical Center | Caspase inhibitors in the treatment of infection-associated preterm delivery |
KR101009588B1 (ko) * | 2008-06-04 | 2011-01-20 | 거진산업주식회사 | 미세여과막을 이용한 부유고형물 처리장치 |
JP2012051804A (ja) * | 2008-12-26 | 2012-03-15 | Kyoto Univ | Eg5阻害剤 |
KR101010350B1 (ko) * | 2009-03-26 | 2011-01-25 | 삼성중공업 주식회사 | 역세척 여과장치 |
WO2012061786A1 (en) | 2010-11-05 | 2012-05-10 | Brandeis University | Ice cleaved alpha-synuclein a biomarker |
TW201236239A (en) * | 2010-11-16 | 2012-09-01 | Solvay | Rechargeable metal or metal-ion cell |
EP2490021A1 (en) | 2011-02-18 | 2012-08-22 | Biotempt B.V. | Modulators of PRR and GPCR signalling |
US9956260B1 (en) | 2011-07-22 | 2018-05-01 | The J. David Gladstone Institutes | Treatment of HIV-1 infection and AIDS |
EP3142649B1 (en) | 2014-05-12 | 2019-07-24 | Conatus Pharmaceuticals, Inc. | Treatment of the complications of chronic liver disease with caspase inhibitor emricasan |
WO2017079566A1 (en) | 2015-11-05 | 2017-05-11 | Conatus Pharmaceuticals, Inc. | Caspase inhibitors for use in the treatment of liver cancer |
KR20180101418A (ko) | 2015-12-31 | 2018-09-12 | 코나터스 파마슈티칼스, 인크. | 간 질환의 치료에서의 카스파제 억제제의 사용 방법 |
BR112019005985A2 (pt) | 2016-10-05 | 2019-06-25 | Novartis Ag | composições de combinação compreendendo agonistas de fxr para tratar ou prevenir uma doença ou distúrbio fibrótico, cirrótico |
WO2018216012A1 (en) * | 2017-05-24 | 2018-11-29 | Ramot At Tel-Aviv University Ltd. | Chemiluminescent probes for imaging/detection of proteases |
WO2022123062A1 (en) | 2020-12-11 | 2022-06-16 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Blocking caspase and/or fasl for preventing fatal outcome in covid-19 patients |
Family Cites Families (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU7775991A (en) | 1990-04-04 | 1991-10-30 | Immunex Corporation | Interleukin 1beta protease |
CA2111100C (en) | 1991-08-30 | 2004-11-02 | Roy A. Black | Interleukin-1 beta protease and interleukin-1 beta protease inhibitors |
EP0618223A3 (en) | 1993-03-08 | 1996-06-12 | Sandoz Ltd | Peptides, the release of Interleukin 1-Bêta, useful as anti-inflammatory agents. |
AU5122196A (en) | 1995-03-31 | 1996-10-16 | Takeda Chemical Industries Ltd. | Cysteine protease inhibitor |
EP0900791A1 (en) | 1995-12-27 | 1999-03-10 | Ono Pharmaceutical Co., Ltd. | Tetrazole derivatives and drugs containing the same as the active ingredient |
JP3492703B2 (ja) | 1996-09-12 | 2004-02-03 | アイドゥン ファーマシューティカルズ,インコーポレイテッド | システインプロテアーゼのICE/ced―3ファミリーの阻害剤としてのC―末端変性(N―置換)―2―インドリルジペプチド |
EP0946502B1 (en) * | 1996-10-11 | 2002-12-18 | Warner-Lambert Company | Sulfonamide interleukin-beta converting enzyme inhibitors |
AU738341B2 (en) | 1996-10-11 | 2001-09-13 | Abbott Gmbh & Co. Kg | Asparate ester inhibitors of interleukin-1beta converting enzyme |
US6184210B1 (en) | 1997-10-10 | 2001-02-06 | Cytovia, Inc. | Dipeptide apoptosis inhibitors and the use thereof |
CN1138472C (zh) * | 1997-10-10 | 2004-02-18 | 西托维亚公司 | 二肽型编程性细胞死亡抑制剂及其用途 |
KR20010041905A (ko) | 1998-03-16 | 2001-05-25 | 시토비아 인크. | 디펩티드 카스파제 억제제 및 이의 용도 |
US6242422B1 (en) | 1998-10-22 | 2001-06-05 | Idun Pharmacueticals, Inc. | (Substituted)Acyl dipeptidyl inhibitors of the ice/ced-3 family of cysteine proteases |
AU3876600A (en) | 1999-03-16 | 2000-10-04 | Cytovia, Inc. | Substituted 2-aminobenzamide caspase inhibitors and the use thereof |
ATE363465T1 (de) | 1999-04-09 | 2007-06-15 | Cytovia Inc | Caspase inhibitoren und ihre verwendung |
ATE409688T1 (de) | 1999-08-27 | 2008-10-15 | Cytovia Inc | Substituierte alpha-hydroxy-säuren als caspase- hemmer und ihre verwendung |
SK13922002A3 (sk) * | 2000-03-29 | 2003-09-11 | Vertex Pharmaceuticals Incorporated | Karbamátové inhibítory kaspázy a ich použitie |
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