HRP20030427A2 - Novel 7-azaindoles, use thereof as phosphodiesterase 4 inhibitors and method for producing the same - Google Patents
Novel 7-azaindoles, use thereof as phosphodiesterase 4 inhibitors and method for producing the same Download PDFInfo
- Publication number
- HRP20030427A2 HRP20030427A2 HR20030427A HRP20030427A HRP20030427A2 HR P20030427 A2 HRP20030427 A2 HR P20030427A2 HR 20030427 A HR20030427 A HR 20030427A HR P20030427 A HRP20030427 A HR P20030427A HR P20030427 A2 HRP20030427 A2 HR P20030427A2
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- Croatia
- Prior art keywords
- alkyl
- azaindol
- amide
- glyoxylic acid
- compounds
- Prior art date
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Description
Područje tehnike
Izum se odnosi na supstituirane 7-azaindole opće formule 1
[image]
postupke za sintezu istih, farmaceutske pripravke koji sadrže ove spojeve, kao i farmaceutsku uporabu ovih spojeva koji su inhibitori fosfodiesteraze 4, kao aktivnih sastojaka za liječenje bolesti na koje se može utjecati inhibicijom djelovanja fosfodiesteraze 4 u stanicama odgovornih za imunitet (poput makrofaga i limfocita) putem inventivnih spojeva.
Stanje tehnike
Aktivacija receptora stanične opne pomoću odašiljača dovodi do aktiviranja sustava “drugog glasnika”. Adenilat ciklaza sintetizira aktivni, ciklički AMP (cAMP) ili ciklički GMP (cGMP) iz AMP i GMP. To dovodi do, na primjer, opuštanja u stanicama glatkih mišića ili do inhibicije oslobađanja ili sinteze posrednika kod upale stanica. “Drugi glasnik” cAMP i cGMP je razgrađen fosfodiesterazom (PDE). Do sada je poznato 11 obitelji PDE enzima (PDE1 do PDE11), koji se razlikuju po svojem specifičnom supstratu (cAMP, cGMP ili oba) i ovisnosti o drugim supstratima (poput kalmodulina). Ovi izoenzimi imaju različite funkcije u tijelu i različito se reagiraju u individualnim tipovima stanica (Beavo, J.A., M. Conti and R.J. Heaslip, Multiple cyclic nucleotide phosphodiesterases. Mol. Pharmacol. 1994, 46:399 – 405; Hall, I. P., Isoenzyme selective phosphodiesterase inhibitors: potential clinical uses, Br. J. clin. Pharmacol, 1993, 35:1-7). Inhibicija različitih PDE tipova izoenzima rezultira nagomilavanjem cAMP i/ili cGMP u stanicama, što se može terapijski iskoristiti (Torphy, T.J., G.P. Livi, S.B. Christensen, Novel Phosphodiesterase Inhibitors for the therapy of Asthma, Drug News and Perspectives 1993, 6:203-214).
U stanicama važnim za alergijske upale (limfociti, mastociti, eozinofilni granulociti, makrofage), predominatni PDE izoenzim je tip 4 (Torphy, J.T. and B.J. Undem, Phosphodiesterase inhibitors: new opportunities for the treatment of asthma. Thorax 1991, 46:512-523). Inhibicija PDE 4 putem prikladnih inhibitora se stoga smatra važnim početkom za liječenje brojnih alergijom izazvanih bolesti (Schudt, CH., G. Dent and K. Rabe, Phosphodiesterase Inhibitors, Academic Press London 1996).
Važno svojstvo inhibitora fosfodiesteraze 4 je inhibicija oslobađanja čimbenika nekroze tumora α (TNFα) iz upalnih stanica. TNFα je važan pro-upalni citokin, koji utječe na brojne biološke procese. TNFα se oslobađa, primjerice, iz aktiviranih makrofaga, aktiviranih T limfocita, mastocita, bazofila, fibroblasti, stanica endotela i astrocita u mozgu. On sam ima aktivirajuće djelovanje na neutrofile, eozinofile, fibroblasti i stanice endotela, a kao rezultat toga se oslobađaju različiti medijatori za uništavanje tkiva. U monocitima, makrofagama i T limfocitima, TNFα izazivaju povećanu proizvodnju daljnjih pro-upalnih citokina poput GM-CSF (granulocy-macrophage colony-stimulating factor) ili interleukin-8. Zbog svojstva pospješivanja upale i kataboličkog učinka, TNFα igra središnju ulogu u brojnim bolestima, poput upala dišnih putova, upala zglobova, endotoksičnog šoka, odbacivanja tkiva, AIDS-a i brojnih drugih imunoloških bolesti. Sukladno tome, inhibitori fosfodiesteraze 4 su također prikladni za liječenje takvih bolesti, koje su povezane sa TNFα.
Kronične opstruktivne plućne bolesti (COPD) raširene su u populaciji i također imaju veliku ekonomsku važnost. Na primjer, COPD bolesti su odgovorne za otprilike 10 do 15% troškova svih bolesti u razvijenim zemljama, a oko 25% cjelokupne smrtnosti u SAD može se pripisati ovom uzroku (Norman, P.: COPD: New developments and therapeutic opportunities, Drug News Perspect. 11 (7), 431-437, 1998); međutim, kada nastupa smrt, većina pacijenata su stariji od 55 godina (Nolte, D.: Chronic Bronchitis – a National Disease of Multifactorial Origin. Atemw.-Lungenkrkh. 20 (5), 260-267, 1994). Svjetska zdravstvena organizacija (WHO) procjenjuje kako će u sljedećih 20 godina COPD biti treći najčešći uzročnik smrti.
Sindrom kronične obstruktivne bolesti pluća (COPD) je kombinacija različitih sindroma kroničnog bronhitisa sa simptomima produktivnog kašlja i progresivne i nepovratne deterioracije funkcije pluća (posebice kod izdisanja). Tijek bolesti je epizodan i često kompliciran bakterijskim infekcijama (Rennard, S.I.: COPD: Overview of definitions, Epidemiology, and factors influencing its development. Chest, 113 (4) Suppl. 235S-241S, 1998). U tijeku bolesti, plućna funkcija se polagano smanjuje, pluća sve više postaju emfizemska, a poteškoće s disanjem kod pacijenata su očigledne. Bolest očito smanjuje kvalitetu života bolesnika (skraćivanje daha, niska tolerancija na napor), a bitno skraćuje i životni vijek (bolesnika). Ne glede na vanjske čimbenike, glavni čimbenik rizika je pušenje (Kummer, F.; Asthma and COPD, Atemw.-Lungenkrkh. 20 (5), 299-302, 1994; Rennard S.I.: COPD: Overview of definitions, Epidemiology, and factors influencing its development. Chest, 113 (4) Suppl., 235S-241S, 1998), stoga muškarci češće oboljevaju od žena. Ova slika će se u budućnosti promijeniti obzirom na promjenu navika i povećanjem broja žena koje puše.
Predmetno liječenje cilja samo na ublažavanje simptoma, bez interveniranja na slučajeve progresije bolesti. Uporaba beta 2 agonista s produljenim djelovanjem (poput Salmeterola), moguće u kombinaciji s muskarinergijskim antagonistima (poput Ipratropiuma) poboljšava funkciju pluća širenjem bronhija i koristi se rutinski (Norman, P.: COPD: New developments and therapeutic opportunities, Drug News Perspect. 11 (7), 431-437, 1998). Bakterijske infekcije, koje se moraju liječiti s antibioticima, igraju značajnu ulogu u COPD epizodama (Wilson, R.: The role of infections in COPD, Chest, 113 (4) Suppl., 242S-248S, 1998; Grossman, R.F.: The value of antibiotics and the outcomes of antibiotic therapy in exacerbation of COPD, Chest 113 (4) Suppl., 249S-155S, 1998). Liječenje ove bolesti još uvijek je nezadovoljavajuće, posebice u odnosu na kontinuirano umanjenje funkcije pluća. Novi pristupi liječenjima, koji napadaju posrednike upale, molekule proteaza ili adhezije, mogli bi biti vrlo obećavajući (Barnes, P.J.: Chronic obstructive disease: new opportunities for drug development, TiPS 10 (19), 415-423, 1998).
Neovisno o bakterijskim infekcijama koje mogu stvoriti komplikacije, kronična upala, koja je vođena neutrofilnim granulocitima, nađena je u bronhijama.
Među ostalima, medijatori i enzimi, koje oslobođaju neutrofilni granulociti, postaju odgovorni za strukturne promjene primjećene u respiratornom traktu (emfizem). Inhibicija djelovanja neutrofilnih granulocita je stoga racionalna polazna točka za prevenciju ili usporavanje progresije COPD (slabljenje parametara funkcije pluća). Važan stimulant za aktiviranje granulocita je pro-upalni citokin TNFα (čimbenik nekroze tumora). Na primjer, poznato je kako TNFα stimulira nastajanje slobodnih kisikovih radikala putem neutrofilnih granulocita (Jersmann, H.P.A., D.A. Rathjen and A. Ferrante: Enhancement of LPS-induced neutrophil oxygen radical production by TNFα, Infection and Immunity, 4, 1744-1747, 1998). PDE4 inhibitori mogu vrlo učinkovito inhibirati oslobađanje TNFα iz velikog broja stanica i stoga spriječiti aktivnost neutrofilnih granulocita. Nespecifični PDE inhibitor, pentoksifilin, ima sposobnost inhibirati nastajanje kisikovih radikala, kao i sposobnost fagocitoze neutrofilnih granulocita (Wenisch, C., K. Zedtwitz-Liebenstein, B. Parschalk and W. Graninger: Effect of pentoxifylline in vitro on neutrophil reactive oxygen production and phagocytic ability, assesed by flow cytometry, Clin. Drug. Invest., 13 (2): 99-104, 1997).
Različiti PDE 4 inhibitori su već poznati. To su prvenstveno derivati ksantina, analozi roliprama ili derivati nitrakvazona (studija u Karlsson, J.-A. and D. Aldos, Phosphodiesterase 4 inhibitors for the treatment of asthma, Exp. Opin. Ther. Patents 1997, 7:989-1003). Do sada nije bilo moguće dovesti bilo koji od ovih spojeva na razinu kliničke primjene. Treba naglasiti kako poznati PDE 4 inhibitori također imaju različite nuspojave, poput morske bolesti i jutarnje mučnine i povraćanja; do sada (te nuspojave) nije bilo moguće spriječiti na odgovarajući način.
Iz tog razloga, neophodno je pronalaženje novih PDE 4 inhibitora s boljom terapijskom primjenom.
Uporaba 7-azaindola za razvitak novih aktivnih sastojaka za različite indikacije do sada su opisane samo u relativno malom broju slučajeva.
U japanskom patentu JP 10120681 (Fujisawa Pharmaceutical Co., Ltd.) predstavljeni su 5- i 7-azaindoli opće formule
[image]
u kojima R1 može predstavljati vodik ili kratke alkilne skupine, R2 može predstavljati vodik, halogen, kratke alkilne skupine, cikloalkilne skupine, alkilkarbonilne skupine ili alkanoilne skupine, R3 predstavlja alkanoilne skupine, zaštićene skupine karboksilne kiseline, cijano skupine ili supstituirane karbamoil skupine. L predstavlja kratki alkilenski most. Q predstavlja supstituirane aromatske i heterocikličke skupine. Između A1 i A2, jedan predstavlja dušik, a drugi CH. Ovi spojevi se razlikuju od inventivnih spojeva prvenstveno u odnosu na supstituente R2 i R3,a djelomično u odnosu na R1 i A2. Spojevi koji su opisani predstavljeni su kao inhibitori cGMP specifične fosfodiesteraze (PDE 5). Razne bolesti srčane cirkulacije, bronhitisa, astme, rinitisa, impotencije, komplikacija dijabetesa i glaukoma navedeni su kao područja prijave.
Sintezu raznih 3-aminoalkil-4-azaindola i 3-aminoalkil-7-azaindola opisali su L.N. Yakhontov, S.S. Liberman, D.M. Krasnokutskaya i dr. u Khim.-Farm. Zh. 8 (11), 1974, 5-9.
Za 3-(2-aminoetil)-7-azaindol, opisan je depresivni ili antidepresivni učinak. Učinak smanjenog krvnog tlaka primjećen je kod 3-aminometil-7-azaindola.
A.J. Verbiscar, u J. Med. Chem. 15 (2), 1972, 149-152 opisuje spoj formule
[image]
za koji je utvrđen učinak protiv malarije.
U patentima US 650223 (Sterling Drug, Inc.), opisana je sinteza raznih 2-(imidazolin-2-il)-alkil-7-azaindola ili 3-(imidazolin-2-il)-alkil-7-azaindola iz odgovarajućih 2- ili 3-cijanoalkil-7-azaindola, te uporaba ovih spojeva kao vazokonstriktora.
7-azaindoli nisu prethodno bili poznati kao inhibitori PDE 4.
Opis izuma
Izum se odnosi na 7-azaindole opće formule
[image]
u kojoj
n može biti 1 ili 2, a
R1 predstavlja
-C1 do –C10 ravnu ili razgrananu alkilnu skupinu, po izboru supstituiranu jednom ili više puta sa sljedećim: –OH, -SH, -NH2, -NHC1 do –NHC6 alkil, -N(C1 do C6-alkil)2,-NHC6 do –NHC14 aril, -N(C6 do C14 aril)2, -N(C1 do C6 alkil)(C6 do C14 aril), -NO2, -CN, -F, -Cl, -Br, -J, -O-C1 do –O-C6 alkil, -O-C6 do –O-C14 aril, -S-C1 do –S-C6 alkil, -S-C6 do –S-C14 aril, -SO3H, -SO2C1 do –SO2C6 alkil, -SO2C6 do –SO2C14 aril, -OSO2C1 do –OSO2C6 alkil, -OSO2C6 do –OSO2C14 aril, -COOH, -(CO)C1 do –(CO)C5 alkil, s mono-, di- ili tricikličkim, zasićenim ili mono-nezasićenim ili multi-nezasićenim karbocikličkim spojevima s 3 do 14 elemenata prstena, s mono-, di- ili tricikličkim zasićenim ili mono-nezasićenim ili multi-nezasićenim heterocikličkim skupinama s 5 do 15 elemenata prstena i 1 do 6 heteroatoma, za koje je poželjno da su N, O i S,
C6 do C14 arilne skupine i karbociklički i heterociklički supstituenti redom mogu biti mono-supstituirani ili multi-supstituirani s R4,
-C2 do C10 alkenil, mono-nezasićeni ili multi-nezasićeni, ravni ili razgranani, po izboru mono-suptituiran ili multi-supstituiran s –OH, -SH, -NH2, -NHC1 do –NHC6 alkil, -N(C1 do C6-alkil)2, -NHC6 do NHC14 aril, -N(C6 do C14 aril)2, -N(C1 do C6 alkil)(C6 do C14 aril), -NO2, -CN, -F, -Cl, -Br, -J, -O-C1 do –O-C6 alkil, -O-C6 do –O-C14 aril, -S-C1 do –S-C6 alkil, -S-C6 do –S-C14 aril, -SO3H, -SO2C1 do –SO2C6 alkil, -SO2C6 do –SO2C14 aril, -OSO2C1 do –OSO2C6 alkil, -OSO2C6 do –OSO2C14 aril, -COOH, -(CO)C1 do –(CO)C5 alkil, s mono-, di- ili tricikličkim zasićenim ili mono-nezasićenim ili mutli-nezasićenim karbocikličkim spojevima s 3 do 14 elemenata prstena, s mono-, di ili tricikličkim zasićenim ili mono-nezasićenim ili mutli-nezasićenim heterocikličkim skupinama s 5 do 15 elemenata prstena i 1 do 6 heteroatoma, za koje je poželjno da budu N, O i S,
C6 do C14 arilne skupine i karbociklički i heterociklički supstituenti redom mogu biti mono-suptituirani ili multi-supstituirani s R4,
R2 i R3 mogu biti isti ili različiti, samo jedan od dva predstavlja vodik, a nadalje, R2 i R3 mogu predstavljati
-C1 – C5 alkil, po izboru mono-suptituirani ili multi-supstituirani s –OH, -SH, -NH2, -NHC1 do –NHC6 alkil, -N(C1 do C6-alkil)2, -NO2, -CN, -F, -Cl, -Br-, -J, -O-C1 do –O-C6 alkil, -S-C1 do –S-C6 alkil-fenil, -piridil, -fenil, po izboru mono-suptituirani ili multi-supstituirani s –OH, -SH, -NH2, -NHC1 do -NHC3 alkil, -N(C1 do C3-alkil)2, -NO2, -CN, -COOH, -COOC1 do –COOC3 alkil, -F, -Cl, Br-, -O-C1 do –O-C3 alkil, -S-C1 do -S-C3 alkil, -piridil, po izboru mono-suptituiran ili multi-supstituiran s –NO2, -CN, -COOH, -COOC1 do –COOC3 alkil, -Cl, -Br-, -O-C1 do –O-C3 alkil, -S-C1 do –S-C3 alkil, kao i
[image]
Zajedno, NR2R3 skupina može predstavljati
[image]
u kojoj R4 predstavlja
-H, -OH, -SH, -NH2, -NHC1 do –NHC6 alkil, -N(C1 do C6 alkil)2, NHC6 do NHC14 aril, N(C6 do C14 aril)2, -N(C1 do C6 alkil)(C6 do C14 aril), -NHCOC1 do –NHCOC6 alkil, -NO2, -CN, -COOH, -COOC1 do –COOC6 alkil, -(CO)C1 do –(CO)C6 alkil, -(CS)C1 do –(CS)C6 alkil, -F, -Cl, -Br, -J, -O-C1 do –O-C6 alkil, -O-C6 do –O-C14 aril, -S-C1 do –S-C6 alkil, -S-C6 do –S-C14 aril, -SOC1 do –SOC6 alkil, -SO2C1 do –SO2C6 alkil.
U inventivnim 7-azaindolima formule 1, poželjno je da ostatak R1 bude ostatak C1 do C10 alkila. Takav ostatak može biti ravni, razgranani ili ciklički, a poželjno je ravni. Posebice su poželjni alkilni ostaci koji imaju 1 do 6, a još je poželjnije 1 do 4, ugljikova atoma. U daljnjem poželjnom utjelovljenju R1 je C2 do C10 ostatak alkenila, poželjno je C2 do C6, a još je poželjniji C2 do C4 ostatak alkenila. Ostatak alkenila može biti mono- ili multi-nezasićeni, primjerice di-nezasićeni ili trostruko nezasićeni. Ostatak alkenila može biti ravan, razgranan ili ciklički ostatak ugljikovodika. Posebice su poželjni ostaci R1, pri čemu je ostatak alkila ili alkenila mono- ili multi-supstituiran, na primjer, disupstituiran, trisupstituiran, tetrasupstituiran ili pentasupstituiran. U posebno poželjnom utjelovljenju, ostatak R1 je supstituirani C1 alkil (tj. metil) ostatak. Između gore navedenih supstituenata alkilne ili alkenilne skupine supstituenata ostatka R1 posebno su poželjni –OH, -F, -Cl, -Br, -J, -C1 do C4 alkoksi. Nadalje, supstituenti su poželjni, kada po izboru nazočni alkilni ostatak ima 1 do 4 ugljikova atoma, a po izboru nazočni ostatak arila ima 6 do 10 ugljikovih atoma. Među karbociklima, poželjan je ostatak fenila, posebice supstituirani fenilov ostatak za kojeg je poželjno da je supstituiran s –F, -Cl, -Br, -J, C1 do C6 alkoksi ili hidroksi. Među heterociklima, poželjni su oni koji imaju najmanje jedan heteroatom odabran od N, O ili S. Među heterociklima je posebno poželjan ostatak piridila, kao i ostatak izoksazola, posebice ostatak 3,5-dimetil izoksazola. Primjer kondenziranog karbocikličkog supstituenta je ostatak naftila.
U posebno poželjnom utjelovljenju, R1 je skupina koja sadrži ostatak cikličkog ugljikovodika, poput ciklopropil metila, ravnog ugljikovodika, poput n-heksila, ravnog ugljikovodika supstituiranog s ostatkom alkoksi, poput 2-metoksietila, razgrananog ostatka ugljikovodika, poput izobutila, nezasićenog ostatka ugljikovodika, poput 2-metilpropen-3-il-a ili ostatka ugljikovodika koji sadrži aromatsku skupinu, čiji ostatak po izboru može biti supstituiran, poput 4-fluorobenzila, 3-metoksibenzila, 4-metoksibenzila, 4-klorobenzila, 4-metilbenzila, 3-hidroksibenzila ili 4-hidroksibenzila, skupine koja se sastoji od heteroaromatskog ugljikovodika, poput 4-piridilmetila ili 3,5-dimetilizooksazol-4-metila ili skupine koja se sastoji od kondenziranog aromatskog ugljikovodika, poput 1-naftilmetila.
U poželjnom utjelovljenju, supstituenti na dušikovom atomu, R2 i R3 mogu po izboru biti supstituirani C1 do C5 ostatak alkila, poželjno je C1 do C3, a posebice je poželjan ostatak C1 (tj. metil) alkila.
Jedan od ostataka R2 i/ili R3 posebice predstavljaju ostatak koji se sastoji od heteroaromatskog ugljikovodika, poput 4-piridilmetila, pri čemu rečeni heteroaromatski ugljikovodik nadalje može biti supstituiran, poželjno je s halogenom, poput 3,5-dikloro-4-piridila. U drugom poželjnom utjelovljenju R2 i/ili R3 je ostatak morfolina. Dalje su poželjni ostaci R2 i R3 koji sadrže aromatski ugljikovodik za kojeg je poželjno da je supstituiran, posebice, s halogenom ili karboksi, poput 2,6-diklorofenila, 4-karboksifenila, 4-etoksikarbonil fenila, 3,4-dimetoksifenila. U daljnjem poželjnom utjelovljenju i R2 i R3 su metoksietil. U drugom poželjnom utjelovljenju R2 ili R3 predstavljaju ostatak
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ili skupina –NR2R3 zajedno predstavlja
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Nadalje, izum se odnosi na fiziološki tolerirane soli spojeva formule 1.
Fiziološki tolerirane soli dobivaju se na uobičajeni način neutraliziranjem baza s anorganskim ili organskim kiselinama ili neutraliziranjem kiselina s anorganskim ili organskim bazama. Kao anorganske kiseline u obzir dolaze klorovodična kiselina, sumporna kiselina, fosforna kiselina ili bromovodična kiselina, a kao organske kiseline, primjerice, karboksilna, sulfo ili sulfonska kiselina, poput octene kiseline, tartarne kiseline, mliječne kiseline, propionske kiseline, glikolne kiseline, malonske kiseline, jabučne kiseline, fumarne kiseline, tanične kiseline, sukcinske kiseline, alginske kiseline, benzojeve kiseline, 2-fenoksibenzojeve kiseline, 2-acetoksibenzojeve kiseline, cimetne kiseline, bademove kiseline, limunske kiseline, jabučne kiseline, salicilne kiseline, 3-aminosalicilne kiseline, askorbinske kiseline, embonijske kiseline, nikotinske kiseline, izonikotinske kiseline, oksalne kiseline, aminokiselina, metansulfonske kiseline, etansulfonske kiseline, 2-hidroksietansulfonske kiseline, etan-1,2-disulfonske kiseline, benzensulfonske kiseline, 4-metilbenzensulfonske kiseline ili naftalen-2-sulfonske kiseline. Kao anorganske baze u obzir dolaze, primjerice natrij hidroksid, kalij hidroksid, amonijak, a kao organske baze, amini, poželjno je tercijarni amini poput trimetilamina, trietilamina, piridina, N,N-dimetilanilina, kinolina, izokinolina, α-pikolina, β-pikolina, γ-pikolina, kinaldina ili pirimidina.
Pored toga, fiziološki tolerirane soli spojeva formule 1 mogu se dobiti pretvaranjem derivata koji sadrže tercijarne amino skupine, na poznati način sa sredstvima za kvarterniziranje, u analogne kvarterne amonijeve soli. Kao sredstva za kvarterniziranje u obzir dolaze, primjerice, alkil halidi, poput metil jodida, etil bromida i n-propil klorida, ali također i aril alkil halidi, poput benzil klorida ili 2-feniletil bromida.
Nadalje, od spojeva formule 1 koji imaju nesimetrični ugljikov atom, izum se odnosi na oblik D, oblik L i mješavinu D, L, te u slučaju nekoliko nesimetričnih ugljikovih atoma, na diastereoizomeričke oblike. Oni spojevi formule 1, koji sadrže nesimetrične ugljikove atome i obično se dobivaju kao racemati, mogu se odvojiti u optički aktivne izomere na poznat način, primjerice optički aktivnom kiselinom. Međutim, također je moguće upotrijebiti optički aktivnu polaznu tvar od samog početka, a odgovarajući optički aktivan ili diasteroizomerički spoj se potom dobiva kao konačni produkt.
Kod inventivnih spojeva utvrđeno je kako imaju farmakološki važna svojstva, koja se mogu koristiti u terapijske svrhe.
Inventivni spojevi su inhibitori oslobađanja TNFα.
Ovi spojevi stoga mogu biti korišteni za inhibiciju oslobađanja TNFα.
Stoga je cilj ovog izuma da se spojevi formule 1 i njihove soli, kao i farmaceutski pripravci koji sadrže ove spojeve ili soli istih, mogu koristiti za liječenje bolesti kod kojih je korisna inhibicija TNFα.
Ove bolesti uključuju, primjerice upalu zglobova, uključujući artritis i reumatoidni artritis, kao i druge bolesti artritisa poput reumatoidnog spondilitisa i osteoartritisa. Daljnje mogućnosti prijave su liječenje pacijenata koji pate od osteoporoze, sepse, septičkog šoka, gram negativne sepse, sindroma toksičkog šoka, sindroma otežanog disanja, astme ili drugih kroničnih plućnih bolesti, bolesti resorpcije kosti ili reakcije na transplantate ili druge autoimunološke bolesti, poput lupus erythematosus, multipla skleroze, glomerulonefritisa i uveitisa, dijabets melitusa ovisnog o insulinu i kronične demijelinacije.
Osim toga, inventivni spojevi se također mogu koristiti za liječenje infekcija, poput virusnih i parazitskih infekcija, primjerice za liječenje malarije, leishmanijaze, infekcijom izazvane vrućice, infkecijom izazvanog bola u mišićima, AIDS-a i kaheksije.
Inventivni spojevi su inhibitori fosfodiesteraze 4.
Inventivni spojevi se stoga mogu koristiti za inhibiciju fosfodiesteraze 4.
Stoga je cilj ovog izuma da se spojevi formule 1 i soli istih, kao i farmaceutski pripravci koji sadrže ove spojeve ili njihove soli, mogu koristiti za liječenje bolesti kod kojih je korisna inhibicija fosfodiesteraze 4.
Prema tome, inventivni spojevi mogu se rabiti kao bronhodilatori i za profilaksu astme. Spojevi formule 1 nadalje su inhibitori nakupljanja eozinofila kao i njihova djelovanja. Sukladno tome, inventivni spojevi se također mogu koristiti u slučaju bolesti, u kojoj eozinofili igraju ulogu. Ove bolesti primjerice uključuju upalne bolesti respiratornog trakta poput bronhijalne astme, alergijskog rinitisa, alergijskog konjunktivitisa, atopičnog dermatitisa, ekcema, alergijskog angiitisa, upale izazvane eoziofilima poput eoziofilnog fasciitisa, eoziofilne upale pluća i PIE sindroma (plućna infiltracija s eozinofiliom), urtikarije, ulceroznog kolitisa, Crohnove bolesti i proliferacijskih bolesti kože, poput psorijaze i keratoze.
Cilj ovog izuma je da spojevi formule 1 i njihove soli mogu inhibirati oslobađanje TNFα in vitro kao i LPS-izazvanu plućnu neutrofilnu infiltraciju kod štakora in vivo.
Sveobuhvatnost ovih utvrđenih farmakološki važnih svojstava potvrđuje kako ovi spojevi formule 1 i njihove soli, kao i farmaceutski pripravci koji sadrže ove spojeve ili njihove soli, mogu biti korišteni u terapiji za liječenje kroničnih opstruktivnih bolesti pluća.
Nadalje, inventivni spojevi imaju neuroprotekcijska svojstva i mogu se koristiti za liječenje bolesti, za koje je korisna neuroprotekcija. Takve bolesti su, primjerice senilna demencija (Alzheimerova bolest), gubitak pamćenja, Parkinsonova bolest, depresije, udari i Claudikatio intermittens.
Daljnja moguća primjena inventivnih spojeva jest za profilaksu i liječenje bolesti prostate, poput dobroćudne hiperplazije prostate, polakisurije, nokturije kao i liječenja inkontinencije, kolika izazvanih urinarnim kalkulusom, te spolnih poremećaja kod muškaraca i žena.
Konačno, inventivni spojevi se također mogu koristiti za inhibiciju prekomjerne ovisnosti o lijekovima usljed opetovane uporabe analgetika, poput morfija, kao i smanjivanja razvoja tolerance kada se ovi analgetici opetovano rabe.
Za pripravu medicinskih lijekova, učinkovita doza inventivnih spojeva ili njihovih soli koristi se uz uobičajene adjuvanse, nosače i aditive.
Doziranje aktivnog sastojka može se mijenjati ovisno o načinu primjene, dobi, težini pacijenta, prirodi i ozbiljnosti bolesti koja se treba liječiti i sličnim čimbenicima.
Dnevna doza se može primjeniti kao jedna doza, koja se uzima odjednom, ili se podijeli u dvije ili više doza dnevno, obično u količini od 0,001 do 100 mg.
Oralni, parenteralni, transdermalni, lokalni, inhalacijski i intranazalni pripravci su poželjni oblici za primjenu.
Mogu se rabiti uobičajeni farmaceutski oblici pripravka, poput tableta, premazanih tableta, kapsula, raspršivih praškova, zrnaca, vodenih otopina, vodenih ili uljnih suspenzija, sirupa, likvora ili kapljica.
Kruti oblici medicinskih lijekova mogu sadržati inertne komponente i nosače, poput kalcij karbonata, kalcij fosfata, natrij fosfata, laktoze, škroba, manitola, alginata, želatine, guar-brašna, magnezijevog ili aluminijevog stearata, metilceluloze, talka, visoko raspršive silike, silikonskog ulja, masnih kiselina velike molekulske mase (poput stearinske kiseline), želatina, agar agara, ulja biljnog i životinjskog podrijetla i krutih polimera velike molekulske mase (poput poletilen glikola); preparati prikladni za oralnu primjenu po izboru mogu sadržavati dodatne pojačivače okusa i/ili zaslađivače.
Tekući oblici medicinskih lijekova mogu biti sterilizirani i/ili po izboru mogu sadržati adjuvanse poput prezervativa, stabilizatora, sredstava za vlaženje, penetranata, emulgatora, sredstava za raspršivanje, solubilizatora, soli, šećera ili šećernih alkohola za kotrolu osmotskog tlaka ili za potrebe puferiranja i/ili regulatora viskoziteta.
Takovi aditivi su, primjerice, tartratni ili citratni puferi, etanol, kompleksirajućih sredstava (poput etilendiamintetraoctene kiseline i netoksičnih soli iste). Za kontroliranje viskoziteta, u obzir dolaze polimeri velike molekulske mase, poput tekućeg polietilen oksida, mikrokristalnih celuloza, poput karboksimetilceluloze, polivinilpirolidona, dekstrana ili želatina. Kruti nosači su, na primjer, škrob, laktoza, manitol, metilceluloza, talk, visoko raspršive silike/kremene zemlje, masne kiseline velike molekulske mase (poput stearinske kiseline), želatine, agar agar, kalcijev fosfat, magnezijev stearat, životinjska i biljna ulja, te kruti polimeri velike molekulske mase, poput polietilen glikola.
Uljne suspenzije za parenteralnu ili lokalnu primjenu mogu sadržavati biljna, sintetička ili polusintetička ulja, poput tekućih masnih estera sod kojih svaki ponaosob ima 8 do 22 ugljikova atoma u lancima masnih kiselina, poput palmitinske, laurinske, tridecil, margarinske, sterainske, arašidne, miristinske, behenske, pentadecil, linolinske, elaidinske, brasidne, Eruka ili oleinske kiseline, esterificirane s monohidridnim ili trihidridnim alkoholima s 1 do 6 ugljikovih atoma, poput metanola, etanola, propanola, butanola, pentanola ili njihovih izomera, glikola ili glicerola. Takvi masni esteri su, primjerice uobičajeni komercijalni miglioli, izopropil miristat, izopropil palmitat, izopropil stearat, PEG 6-kapronska kiseline, kaprilni/kapronski esteri zasićenih masnih alkohola, polioksietilen glicerol trioleata, etil oleat, voštani masni esteri poput sintetičkih masnoća iz pačje trtične žlijezde, izopropil esteri masnih kiselina kokosovog ulja, oleil oleat, decil oleat, etil laktat, dibutil ftalat, diizopropil adipat, esteri masnih kiselina poliola itd. Jednako prikladna su silikonska ulja različitog viskoziteta ili masni alkoholi poput izotridecil alkohola, 2-oktildodekanola, ketil stearil alkohola ili oleil alkohola, masne kiseline poput oleinske kiseline. Nadalje, mogu se koristiti biljna ulja poput ricinusovog ulja, bademovog ulja, maslinovog ulja, suncokretovog ulja, pamučnog ulja, kikirikijevog ulja ili sojinog ulja.
Kao otapala, u obzir dolaze sredstva za želatiniziranje i rastvarači, voda ili otapala koja se miješaju s vodom. Na primjer, u obzir dolaze alkoholi, poput etanola ili izopropanola, benzil alkohola, 2-oktildodekanola, polietilen glikola, ftalata, adipata, propilen glikola, glicerina, dipropilen glikola, tripropilen glikola, voska, metil celosolva, celosolva, estera, morfolina, dioksana, dimetilsulfoksida, dimetilformamida, tetrahidrofurana, cikloheksanona, itd.
Kao sredstva za stvaranje filma, mogu se koristiti esteri celuloze, koji se mogu otopiti ili nabubriti u vodi kao i organska otapala, poput hidroksipropilmetilceluloze, metilceluloze, etilceluloze ili topljivih vrsta škroba.
Također su mogući i miješani oblici između sredstava za želatiniziranje i sredstava za tvorbu filma. Povrh svega, ovdje se rabe ionske makromolekule, poput natrijeve karboksimetilceluloze, poliakrilne kiseline, polimetakrilne kiseline i njihovih soli, natrijevog amilopektin semiglikolata, alginske kiseline ili propilen glikol alginata, kao što je natrijeva sol, gumiarabika, ksantan guma, guar-brašno ili Carageen guma.
Kao slijedeća pomoćna sredstva u formulaciji može se koristiti sljedeće: glicerin, parafin različitog viskoziteta, trietanolamin, kolagen, alantoin, novantisol kiselina. Uporaba surfaktanata, emulgatora ili sredstava za vlaženje, poput natrijevog lauril sulfata, eter sulfata masnog alkohola, dinatrijevog N-lauril-β-imino dipropionata, polietoksiliranog ricinusovog ulja ili sorbitan monooleata, sorbitan monostearata, polisorbata (poput Tween), ketil alkohola, lecitina, glicerin monostearata, polioksietilen stearata, alkilfenol poliglikol etera, ketiltrimetilamonijevog klorida ili monoalkil ili dialkil poliglikol etera ortofosforne monoetanolaminske soli. Stabilizatori poput montmorilonita ili koloidne silike za stabiliziranje emulzije ili za prevenciju raspadanja aktivnih tvari, poput antioksidansa, primjerice tokoferola ili butilhidroksianisola, ili prezervativa poput p-hidroksibenzoat estera, također mogu biti potrebni za pripravu željenih formulacija.
Pripravci za parenteralnu primjenu tekođer mogu postojati i u odvojenim oblicima jedinica za doziranje, poput ampula ili bočica. Poželjna je uporaba otopine aktivnog sastojka, posebice vodenih otopina i, povrh svega, izotoničke otopine; međutim, također se rabe i suspenzije. Ovi oblici za uštrcavanje mogu biti dostupni kao konačni pripravci ili pripravljeni izravno prije uporabe miješanjem aktivnog spoja, poput liofilizata, po izboru s drugim krutim tvarima, sa željenim otapalom ili sredstvom za suspediranje.
Intranazalni pripravci mogu postojati kao vodene ili uljne otopine ili kao vodene ili uljne suspenzije. Oni također mogu postojati kao liofilizati, koji su pripravljeni s prikladnim otapalima ili sredstvima za suspendiranje prije uporabe.
Proizvodnja, punjenje u posude i prodaja pripravaka odvija se pod uobičajenim protumikrobskim i antiseptičkim uvjetima.
Izum se nadalje odnosi na postupak za pripravu inventivnih spojeva.
Sukladno izumu, spojevi opće formule 1, u kojima R1, R2, R3 imaju gore navedena značenja, a n = 1
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sintetizirani su tako da 7-azaindol-3-karboksilne kiseline formule 2, u kojoj R1 ima istovjetno značenje
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pretvoreni su na poznat način s kiselnskim kloridima, poželjno je s tionil kloridom ili oksalil kloridom, u početku u analognu 7-azaindol-3-karboksilnu kiselinu formule 3
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Naknadno, izdvojeni kloridi 7-azaindol-3-karboksilne kiseline formule 3 pretvoreni su reakcijom s primarnim ili sekundarnim aminom u inventivne spojeve opće formule 1, u kojoj R1, R2, R3 imaju gore navedena značenja, a n = 1. Reakcija se odvija u nazočnosti pomoćne baze. Mogu se koristiti pomoćne baze, prekomjerni amin, korišten kao reaktant, tercijarni amin, poželjno je piridin ili trietilamin, kao i anorganske baze, poželjno je alkalijski hidrooksidi ili alkalijski hidridi.
Sukladno izumu, spojevi opće formule 1, u kojima R1, R2 i R3 imaju gore navedena značenja, a n = 2
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sintetizirani su tako da su 7-azaindoli formule 4, u kojoj R1 ima istovjetno značenje
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pretvoreni na poznat način počevši od acilirianja s oksalil kloridom u analogne 7-azaindol-3-il kloride glioksilne kiseline formule 5.
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Naknadno, iz 7-azaindol-3-il klorida glioksilne kiseline formule 5, oblikuju se inventivni spojevi opće formule 1, u kojima R1, R2 i R3 imaju gore navedena značenja, a n=2, rekacijom s primarnim ili sekundarnim aminom. Reakcija se dalje odvija u nazočnosti pomoćne baze. Kao pomoćne baze, mogu se koristiti višak amina, korištenog kao reaktant, tercijarnog amina, poželjno je piridina ili trietilamina, kao i anorganskih baza, poželjno je alkalijskih hidroksida ili alkalijskih hidrida.
Primjeri
Primjeri metoda za sintetiziranje inventivnih spojeva formule 1 sa n = 1
Primjer 1
N-(4-piridilmetil)-1-ciklopropilmetil-7-azaindol-3-amid karboksilne kiseline
1-Ciklopropilmetil-7-azaindol-3-karboksilna kiselina (1,87 g, 8,6 mmola) suspendirana je u 15 mL diklorometana. Dok se hladi s vodom, dodaje se 1,8 mL oksalil klorida (17,4 mmola). Reakcijska smjesa se miješa 8 sati tijekom kojeg vremena se iskristalizira 1-ciklopropilmetil-7-azaindol-3 klorid karboksilne kiseline. Izolira se i otopi u 18 mL tetrahidrofurana (THF).
Natrijev hidrid (60%, 1,14 g) suspendiran je u 21 mL THF-a. Dok se miješa na oko 10ºC, u kapljicama je dodana otopina od 0,93 g 4-aminometilpiridina (8,6 mmola) u 21 mL THF. Nakon otprilike 15 minuta, prethodno pripravljena otopina 1-ciklopropilmetil-7-azaindol-3-klorida karboksilne kiseline u kapljicama se dodaje u reakcijsku smjesu. Naknadno se sve refluksira 3 sata. Nakon hlađenja, reakcijska smjesa se miješa s 36 mL etil acetata i 36 mL vode. Faze se razdvajaju, a organska faza se pere s vodom. Otapalo se destilira, a ostatak ponovno kristalizira iz etanola.
Prinos: 1,3 g (50% teoretskog)
Točka taljenja: 187º - 189ºC
Uporabom gore opisanog postupka sinteze, može se sintetizirati veliki broj drugih spojeva formule 1 sa n = 1, od kojih su sljedeći navedeni primjerično:
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Primjeri postupaka sintetiziranja inventivnih spojeva formule 1 sa n =2
Primjer 12
N-(3,5-dikloropiridin-4-il)-[1-(3-netoksibenzil)-7-azaindol-3-il]-amid glioksilne kiseline
1-(3-metoksibenzil)-7-azaindol (3,57 g, 15 mmola) otopljeno je u 50 mL t-butil metil etera. Otopina od 1,54 mL oksalil klorida (18 mmola) u 10 mL t-butil metil etera dodana je u kapljicama na 0ºC uz miješanje. Naknadno, smjesa se refluksira 2 sata, nakon čega se otapalo destilira pod vakuumom. Dobiveni 1-(3-metoksibenzil)-7-azaindol-3-il klorid glioksilne kiseline dobiven je kao ostatak u krutom obliku, koji se suspendira u 50 mL tetrahidrofurana (THF).
U suspenziju od 2 g natrijevog hidrida u 20 mL THF-a, u kapljicama se dodaje 2,4 g 4-amino-3,5-dikloropiridina (15 mmola) u 30 mL THF na –5ºC. Smjesa se potom drži na 20oC uz miješanje. Naknadno, prethodno pripravljena suspenzija od 1-(3-metoksibenzil)-7-azaindol-3-il klorida glioksilne kiseline dodaje se u kapljicama na oko 0ºC. Na kraju se reakcijska smjesa refluksira 4 sata, nakon čega se otapalo uklanja pod vakuumom. Ostatak se miješa s 50 mL etil acetata i 50 mL vode. Faze se razdvajaju, a organska faza se pere s vodom. Otapalo se destilira pod vakuumom, a ostatak ponovno kristalizira iz izopropanola.
Prinos: 3,5 g (51,5% teoretskog)
Točka taljenja: 165º – 167ºC
Uporabom gore opisanog postupka sinteze, mogu se sintetizirati brojni drugi spojevi formule 1 s n = 2, od kojih su sljedeći navedeni primjerično:
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Inventivni spojevi su snažni inhibitori fosfodiesteraze 4 i oslobađanja TNFα. Terapijski potencijal potvrđen je in vivo, primjerice, inhibicijom rekacije kasne astmatične faze (eozinofilija), kao i učinkom na propustljivost krvnih žila izazvane alergenom aktivno senzibiliziranog smeđeg norveškog štakora.
Inhibicija fosfodiesteraze
Aktivnost PDE 4 utvrđena je u enzimskim pripravcima iz humanih polimorfonuklearnih limfocita (PMNL), a aktivnost PDE 2, 3 i 5 je utvrđena s PDE-om iz humanih trombocita. Ljudska krv je protu-koagulirana s citratom. Centrifugiranjem na 700 x g 20 minuta na sobnoj temperaturi, plazma bogata trombocitima u supernatantu se odvaja od eritrocita i leukocita. Trombociti se liziraju ultrazvukom i koriste u pokusima PDE 3 i PDE 5. Za određivanje aktivnosti PDE 2, pročišćava se frakcija citosolnih trombocita na anionskom izmjenjivačkom stupcu putem NaCl gradijenta i dobivena je vršna vrijednost PDE 2 za pokus. PMNL-ovi za određivanje PDE4 izolirani se naknadnim taloženjem dekstrana, a potom slijedi centrifugiranje sastojaka s Ficoll-Paque. Nakon što su stanice dvaput oprane, eritrociti koji su još uvijek sadržani, lizirani su tijekom 6 minuta na 4 ̊C dodavanjem 10 mL hipotoničnog pufera (155 mM NH4Cl, 10 mM NaHCO3, 0,1 mM EDTA, pH=7,4). PMNL-ovi koji su još uvijek nedirnuti, operu se dva puta s PBS i liziraju ultrazvukom. Supernatant dobiven jednosatnim centrifugiranjem na 4 ̊C na 48,000 x g sadrži citosolnu frakciju PDE 4 i koristi se za mjerenja PDE 4.
Aktivnost fosfodiesteraze određuje se uporabom postupka opisnog od Thompson i dr. uz neke izmjene (Thompson, W.J. and M.M. Appleman, Assay of cyclic nucleotide phosphodiesterase and resolution of multiple molecular forms of the enzyme, Adv. Cycl. Nucl. Res. 1979, 10, 69-92).
Reakcijska smjesa sadrži 50 mM tris hidroklorida (pH 7,4), 5 mM magnezij klorida, inhibitore u različitim koncentracijama, odgovarajuće enzimske pripravke kao i druge komponente potrebne za određivanje individualnih izoenzima (vidi niže). Reakcija je započeta dodavanjem supstrata, 0,5 μM [3H]-cAMP ili [3H]-cGMP (otprilike 6000 CPM po testu). Konačna zapremina je 100 ml. Testne tvari se miješaju kao prethodno spravljene otopine u DMSO. DMSO koncentracija u reakcijskoj smjesi iznosi 1% v/v. Koncentracija DMSO ne utječe na PDE aktivnost. Nakon što je reakcija započela dodavanjem supstrata, uzorci se inkubiraju 30 minuta na 37ºC. Reakcija se zaustavlja zagrijavanjem epruveta 2 minute na 110ºC. Uzorci ostaju daljnjih 10 minuta u ledu. Nakon dodavanja 30 μL 5' - nukleotidaze (1 mg/mL, iz suspenzije zmije otrovnice Crotalus adamanteus) slijedi 10-minutna inkubacija na 37ºC. Uzorci se zaustavljaju na ledu, u svaki se dodaje 400 μL smjese Dowex-a, vode i etanola (1 + 1 + 1), dobro se izmiješa i ponovno inkubira 15 minuta na ledu. Reakcijske posude se centrifugiraju 20 minuta na 3000 x g. Alikvoti supernatanta (200 μL) se izravno prenose u posude za scintilaciju. Nakon dodavanja 3 mL scintilatora, uzorci se mjere beta brojilom.
[3H]-cAMP se koristi kao supstrat za određivanje aktivnosti PDE 4, 3 i 2, a [3H]-cGMP se koristi kao supstrat za određivanje aktivnosti PDE 5. Enzimske aktivnosti, koje su svakom pojedinačnom slučaju ne-specifične, određene su u nazočnosti 100 μM Roliprama za određivanje PDE 4, te u nazočnosti 100 μM IBMX za određivanje PDE 3 i 5 i oduzete od testnih vrijednosti. Inkubacijske formulacije pokusa za PDE 3 sadržavale su 10 μM Roliprama, kako bi se spriječila moguća kontaminacija od strane PDE 4. PDE 2 je testiran SPA analizom dobavljača Amersham Company. Analiza se izvodi u nazočnosti aktivatora PDE 2 (5 μM cGMP).
Za inventivne spojeve, utvrđene su vrijednosti IC50 u rasponu od 10-9 do 10-5 M za inhibiciju fosfodiesteraze 4. Selektivnost prema PDE tipovima 2, 3 i 5 kreće se u rasponu faktora 100 do 10,000.
Primjerima su rezultati inhibicije PDE 4 sažeti u sljedećoj Tablici za odabrane primjere:
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Inhibicija oslobađanja TNFα iz stanica polipa nosa
Pokusni aranžmani u osnovi odgovaraju postupku koji su opisali Campbell, A.M. i J. Bousquet (Anti-allergic of H1-blockers, Int. Arch. Allergy Immunol., 1993, 101, 308-310). Polipi nosa tvore početni materijal (materijal od pacijenta koji je podvrgnut kirurškom zahvatu).
Tkivo se pere s RPMI 1640 i naknadno digestira s proteazom (2,0 mg/mL), kolagenazom (1,5 mg/mL), hijaluronidazom (0,75 mg/mL) i DNAzom (0,05 mg/mL) dva sata na 37ºC (1 g tkiva i 4 mL RPMI 1640 s enzimima). Dobivene stanice, smjesa epitelijalnih stanica, monocita, makrofaga, limfocita, fibroblasti i granulocita, filtrira se i pere ponavljanim centrifugiranjem u otopini kulture i pasivno senzibilizira dodavanjem humanog IgE, a stanična supsenzija se dovodi do koncentracije od 2 milijuna stanica/mL u RPMI 1640 (nadopunjeno antibioticima, 10%-tnim serumom telećeg fetusa, 2 mM glutamina i 25 mM Hepesa). Ova suspenzija se prenosi na pločice sa zasijanim kulturama od 6 jamica (1 ml/jamica). Stanice su prethodno inkubirane 30 minuta s testnim tvarima u različitim konačnim koncentracijama i naknadno stimulirane kako bi oslobodile TNFα dodavanjem anti-IgE (7,2 μg/mL). Najveće oslobađanje u mediju kutlure događa se nakon otprilike 18 sati. Tijekom ovog perioda, stanice se inkubiraju na 37ºC i 5% ugljičnog dioksida. Medij kulture (supernatant) odvaja se centrifugiranjem (pet minuta na 4000 okretaja u minuti) i drži na –70ºC dok se ne odredi citokin. TNFα u supernatantu određuje se takozvanim sendvič ELISA-ma (osnovni materijal Pharmingen), s kojima se mogu utvrditi koncentracije citokina u rasponu od 30 do 1000 pg/mL.
Stanice koje nisu stimulirane s anti IgE, teško da mogu proizvesti bilo kakav TNFα; s druge strane, stimulirane stanice izlučuju velike količine TNFα, koji se može smanjiti, primjerice putem PDE 4 inhibitora kao funkcija doze. Iz postotka inhibicije (TNFα oslobađanje od stanica, stimuliranih s anti IgE = 100%) tvari testiranih na različitim koncentracijama, izračunat je IC50 (koncentracija na 50% inhibicije).
Za inventivne spojeve, određene su vrijednosti IC50 koji iznose od 10-7 do 10-5 M.
Rezultati inhibicije oslobađanja od TNFα primjerično su sažeti za odabrane primjere u sljedećoj Tablici:
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Inhibicija kasne faze eozinofilije 48 sati nakon inhalacijskog izlaganja ovalbuminu uporabom aktivno senzibiliziranih smeđih norveških štakora
Inhibicija infiltracije plućne eozinofilije inventivnim tvarima testirano je na mužjaku smeđeg norveškog štakora (200 – 250 g), koji se aktivno senzibilizira na ovalbumin (OVA). Štakori se senzibiliziraju subkutanim uštrcavanjem suspenzije od 10 μg OVA zajedno s 20 mg aluminijevog hidroksida kao adjuvansa u 0,5 mL fiziološke slane otopine po životinji na dan 1, 14 i 21. Pored toga, životinje istovremeno dobivaju Bordetella pertussis vakcinsku otopinu koja se uštrcava i.p. u količini od 0,25 mL po životinji. 28. dana pokusa, životinje se pojedinačno stavljaju u otvorene 1L kutije od pleksiglasa, koje su povezane napravom za izlaganje glave i nosa. Životinje se izlažu aerosolu od 1,0% suspenzije ovalbumina (izlaganje alergenu). Ovalbumin aerosol je proizveden raspršivačem (Bird Micronebulizer, Palm Springs CA, USA), koji se pokreće stlačenim zrakom (0,2 MPa). Vrijeme izlaganja je jedan sat, normalne kontrole također su nebulizirane jedan sat s aerosolom od 0,9% slane otopine.
Četrdeset osam sati nakon izlaganja alergenu, došlo je do masovne migracije eozinofilnih granulocita u pluća životinja. Za to vrijeme, životinje se anesteziraju s većom količinom etil uretana (1,5 g/kg tjelesne težine ), a izvodi se bronhoalveolarno ispiranje (lavage) (BAL) s 3 x 4 mL Hankove balansne otopine. Ukupan zbroj stanica i broj eozinofilnih granulocita izvučene BAL tekućine naknadno je određen instrumentom za automatsku diferencijaciju stanica (Bayer Diagnostics Technicon H1E). Za svaku životinju, eozinofili (EOS) u BAL izračunavaju se u milijun/životinji: EOS/μl x izvučena BAL (mL) = EOS/životinji.
Za svaki test, koriste se 2 kontrolne skupine (raspršivanje s fiziološkom slanom otopinom i raspršivanje s OVA otopinom).
Postotak inhibicije eozinofilije iz pokusne skupine, tretirane s tvari, izračunat je u skladu sa sljedećom formulom:
{(( OVAC – SC) – (OVAD – SC)) / (OVAC – SC)} x 100% = % inhibicija
(SC = kontrolna skupina tretirana s vehikulom izložena djelovanju 0,9%-tne slane otopine; OVAC = kontrolna skupina tretirana s vehikulom izložena 1%-tnoj suspenziji ovalbumina; OVAD = pokusna skupina tretirana supstancom koja je izložena 1%-tnoj suspenziji ovalbumina).
Testne tvari su davane intraperitonealno ili oralno kao suspenzija u 10%-tnom polietilen glikolu 300 i 0,5%-tnoj 5-hidroksietilcelulozi dva sata prije izlaganja alergenu. Kontrolne skupine su tretirane vehikulom u skladu s konkretnim oblikom primjene testne tvari.
Inventivni spojevi inhibiraju kasnu fazu eozinofilije nakon intraperitonealne primjene od 10mg/kg (u rasponu od) 30% do 100%, a nakon oralne primjene od 30 mg/kg, (u rasponu od) 30% do 75%.
Sukladno tome, inventivni spojevi su posebice prikladni za proizvodnju lijekova za liječenje bolesti koje su povezane s djelovanjem eozinofila.
Primjerom su rezultati inhibicije eozinofilije za odabrane primjere sažeti u sljedećoj Tablici:
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Inhibicija lipopolisaharidom(LPS)-izazvane plućne neutrofilije u Lewis štakora
Inhibicija plućne neutrofilne infiltracije inventivnim tvarima testirano je na mužjacima Lewis štakora (250-350 g). Na dan pokusa, životinje su pojedinačno stavljane u otvorene 1L kutije od pleksiglasa, koje su spojene na napravu s otvorima za izlaganje glave i nosa. Životinje su bile izložene aerosolu lipopolisaharidne suspenzije (100 μg LPS/mL 0,1% otopine hidroksilamina) u PBS-u (LPS provociranje). LPS/hidroksilamin aerosol je raspršen nebulizatorom (Bird Micronebulizer, Palm Springs CA, SAD), koji se pokreće stlačenim zrakom (0,2 MPa). Vrijeme izlaganja je 40 minuta, normalne kontrolne skupine su nebulizirane također 40 minuta s aerosolom od 0,1% otopine hidroksilamina u PBS-u.
Šest sati nakon provociranja LPS, došlo je do maksimalne, masivne migracije neutrofilnih granulocita u pluća životinja. Tada su životinje anestezirane s prekomjernim etil uretanom (1,5 g/kg tjelesne težine i.p.), a izvedeno je bronhoalveolarno ispiranje (lavage) (BAL) sa 3 x 4 mL Hankove balansne otopine. Ukupan zbroj stanica i broj neutrofilnih granulocita u izvučenoj BAL tekućini se naknadno određuje instrumetnom za automatsku diferencijaciju stanica (Bayer Diagnostics Technicon H1E). Za svaku životinju, neutrofili (NEUTRO) u BAL se izračunavaju u milijunima/životinji: NEUTRO/μg x izvučena BAL (mL) = NEUTRO/životinji.
Za svaki test, korištene su 2 kontrolne skupine (nebulizacija sa 0,1%-tnom otopinom hidroskilamina u PBS i nebulizacija sa 100 μg LPS/mg 0,1%-tne otopine hidroksilamina u PBS-u).
Postotak inhibicije neutrofilije kod pokusne skupine, tretirane sa supstancom, izračunat je u skladu sa slijedećom formulom:
{(( LPSC – SC) – (LPSD – SC)) / (LPSC – SC)} x 100% = % inhibicija
SC = kontrolna skupina tretirana s vehikulom izložena djelovanju 0,1%-tne otopine hidroksilamina; LPSC = kontrolna skupina tretirana s vehikulom izložena djelovanju LPS-a (100 μg/mL 0,1%-tne otopine hidroksilamina); LPSD = pokusna skupina tretirana sa supstancom izložena LPS-u (100 μg/mL 0,1%-tne otopine hidroksilamina).
Testne tvari su davane oralno kao suspenzije u 10%-tnom polietilen glikolu 300 i 0,5%-tnoj 5-hidroksietilcelulozi dva sata prije LPS provociranja. Kontrolne skupine su tretirane vehikulom u skladu s konkretnim oblikom primjene testne tvari.
Inventivni spojevi inhibiraju neutrofiliju nakon oralne primjene od 1 mg/kg (u rasponu od) 30% do 100%, pa su, sukladno tome, posebice prikladni za proizvodnju lijekova za liječenje bolesti koje su povezane s djelovanjem neutrofila.
Primjerom su rezultati inhibicije neutrofilije za odabrane primjere sažeti u sljedećoj Tablici:
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Claims (19)
1. 7-azaindoli opće formule 1
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naznačeni time, da
n može biti 1 ili 2, a
R1 predstavlja
-C1 do –C10 ravni ili razgranani alkil, nesupstituirani ili supstituirani jedan ili više puta s -OH, -SH, -NH2, -NHC1 do –NHC6 alkil, -N(C1 do C6 alkil)2, -NHC6 do –NHC14 aril, -N(C6 do C14 aril)2, -N(C1 do C6 alkil) (C6 do C14 aril), -NO2, -CN, -F, -Cl, -Br, -J, -O-C1 do –O-C6 alkil, -O-C6 do –O-C14 aril, -S-C1 do –S-C6 alkil, -S-C6 do –S-C14 aril, -SO3H, -SO2C1 do –SO2C6 alkil, -SO2C6 do –SO2C14 aril, -OSO2C1 do –OSO2C6 alkil, -OSO2C6 do –OSO2C14 aril, -COOH, -(CO)C1 do –(CO)C5 alkil, sa mono-, di- ili tricikličkim, zasićenim ili mono-nezasićenim ili multinezasićenim karbocikličkim spojevima s 3 do 14 elemenata prstena, s mono-, di- ili tricikličkim zasićenim ili mono-nezasićenim ili multinezasićenim heterocikličkim skupinama s 5 do 15 elemenata prstena i 1 do 6 hetero atoma, za koje je poželjno da su N, O i S,
C6 do C14 arilne skupine, a karbociklički i heterociklički suptituenti redom mogu biti nesupstituirani ili mono-supstituirani ili multi-supstituirani s R4.
-C2 do –C10 alkenil, mono-nezasićeni ili multi-nezasićeni, ravni ili razgranani, nesupstituirani ili mono-suptituirani ili multi-suptituirani ss sljedećim: –OH, -SH, -NH2, -NHC1 do –NHC6 alkil, -N(C1 do C6 alkil)2, -NHC6 do NHC14 aril, -N(C6 do C14 aril)2, -N(C1 do C6 alkil)(C6 do C14 aril), -NO2, -CN, -F, -Cl, -Br, -J, -O-C1 do –O-C6 alkil, -O-C6 do –O-C14 aril, -S-C1 do –S-C6 alkil, -S-C6 do S-C14 arilom, -SO3H, -SO2C1 do –SO2C6 alkilom, -SO2C6 do -SO2C14 aril, -OSO2C1 do –OSO2C6 alkil, -OSO2C6 do –OSO2C14 aril, -COOH, -(CO)C1 do –(CO)C5 alkil, s mono-, di- ili tricikličkim, zasićenim ili mono-nezasićenim ili multi-nezasićenim karbocikličkim spojevima s 3 do 14 elemenata prstena, s mono-, di- ili tricikličkim zasićenim ili mono-nezasićenim ili multi-nezasićenim heterocikličkim skupinama s 5 do 15 elemenata prstena i 1 do 6 hetero atoma, koji su poželjno N, O, i S,
C6 do C14 su arilne skupine, a karbociklički i heterociklički supstituenti redom mogu biti nesupstituirani ili mono-suptituirani ili multi-supstituirani s R4.
R2 i R3 mogu biti isti ili različiti, a samo jedan od dva predstavlja vodik i nadalje, R2 i R3 mogu predstavljati –C1 – C5 alkil,
nesupstituiran ili mono-suptituiran ili multi-supstituiran sa sljedećim: –OH, -SH, -NH2, -NHC1 do -NHC6 alkil, -N(C1 do C6-alkil)2, -NO2, -CN, -F, -Cl, -Br-, -J, -O-C1 do –O-C6 alkil, -S-C1 do –S-C6 alkil, -fenil, -piridil,
-fenil,
nesupstituiran ili mono-suptituiran ili multi-supstituiran sa sljedećim: –OH, -SH, -NH2, -NHC1 do –NHC3 alkil, -N(C1 do C3 alkil)2, -NO2, -CN, -COOH, -COOC1 do –COOC3 alkil, -F, -Cl, -Br-, -O-C1 do –O-C3 alkil, -S-C1 do –S-C3 alkil,
-piridil,
nesupstituirani ili mono-suptituirani ili multi-supstituirani sa sljedećim: –NO2, -CN, -COOH, -COOC1 do –COOC3 alkil, -Cl, -Br-, -O-C1 do -O-C3 alkil, -S-C1 do –S-C3 alkil
kao i
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Nadalje, -NR2R3 skupina može zajedno predstavljati
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a R4 predstavlja
-H, -OH, -SH, -NH2, -NHC1 do –NHC6 alkil, -N (C1 do C6 alkil)2, -NHC6 do –NHC14 aril, -N(C6 do C14 aril)2, -N(C1 do C6 alkil)(C6 do C14 aril), -NHCOC1 do –NHCOC6 alkil, -NO2, -CN, -COOH, -COOC1 do –COOC6 alkil, -(CO)C1 do –(CO)C6 alkil, -(CS)C1 do –(CS)C6 alkil, -F, -Cl, -Br-, -J, -O-C1 do –O-C6 alkil, -O-C6 do –O-C14 aril, -S-C1 do –S-C6 alkil, -S-C6 do –S-C14 aril, -SOC1 do –SOC6 alkil, -SO2C1 do –SO2C6 alkil,
pod uvjetom da, ako je n = 1, R1, R2, R3 nisu istovremeno
R1 = -C1 do –C6 alkil,
R2 = -H ili –C1 do –C6 alkil, a
R3 =
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gdje su R i R' neovisno –C1 do –C6 alkil, mogućei mono-suptituirani ili multi-supstituirani s halogenom, -C2 do –C6 alkenil, -C3 do –C6 cikloalkiloksi, -C3 do C6 cikloalkil, -C1 do C6 alkoksi, -C2 do –C6 alkinil, -C3 do –C6 cikloalkil, -C3 do –C6 cikloalkil, -C1 do C6 alkil, -C1 do –C6 alkiltio, -C3 do –C6 cikloalkiltio, -C3 do –C6 cikloalkil, -C1 do –C6 alkiltio, C1 do C6 alkoksi, hidroksi-, halogen-, nitro-, -CF3, -C2F5, -OCF3, -SCF3, -SO2CF3, -SO2F, formil-, C2 do C6 alkanoil, cijano-, moguće supstituirani fenil- ili tienil-, -NR''2, -CONR''2, -COOR''
ili
R + R' su zajedno 5-eročlani karbocikl ili heterocikl,
a
R'' = -H ili –C1 do –C6 alkil.
2. Fiziološki tolerirane soli spojeva formule 1 iz zahtjeva 1, naznačene time, da su baze neutralizirane s anorganskim ili organskim kiselinama, ili su kiselinama neutraliziranim s anorganskim ili organskim bazama, ili su tercijarni amini kvarternizirani do kvarternih amonijevih soli.
3. Spojevi formule 1 iz zahtjeva 1 ili 2, naznačeni time, što sadrže asimetrični ugljikov atom u obliku D, obliku L ili u obliku mješavine D, L ili u slučaju nekoliko asimetričnih uljikovih atoma, u dijastereoizomeričkim oblicima.
4. Spoj formule 1 iz bilo kojeg zahtjeva 1 do 3, naznačen time, da je n= 1, odabran iz slijedećih spojeva:
N-(4-piridilmetil)-1-ciklopropilmetil-7-azaindol-3-amid karboksilne kiseline
N-(3,5-dikloropiridin)-1-izobutil-7-azaindol-3-amid karboksilne kiseline
N-(3,5-dikloropiridin-4-il)-1-heksil-7-azaindol-3-amid karboksilne kiseline
N-(3,5-dikloropiridin-4-il)-1-ciklopropilmetil-7-azaindol-3-amid karboksilne kiseline
N-(4-piridilmetil)-1-(4-fluorobenzil)-7-azaindol-3-amid karboksilne kiseline
N-(3,5-dikloropiridin-4-il)-1-(4-fluorobenzil) -7-azaindol-3-amid karboksilne kiseline
N-(3,5-dikloropiridin-4-il)-1-(4-metoksibenzil)-7-azaindol-3-amid karboksilne kiseline
N-(4-piridilmetil)-1-(4-klorobenzil)-7-azaindol-3-amid karboksilne kiseline
1-(4-fluorobenzil)- 7-azaindol-3-morfolid karboksilne kiseline
N-(2,6-diklorofenil)-1-(2-metilpropen-3-il)-7-azaindol-3-amid karboksilne kiseline, te
N-(3,5-dikloropiridin-4-il)-1-(4-piridilmetil)-7-azaindol-3-amid karboksilne kiseline.
5. Spoj formule 1 iz bilo kojeg zahtjeva 1 do 3, naznačen time da je n = 2, a odabran je iz sljedećih spojeva:
N-(3,5-dikloropiridin-4-il)-(1-(3-metoksibenzil)-7-azaindol-3-il)-amid glioksilne kiseline
N-(4-piridil)-(1-(4-fluorobenzil)-7-azaindol-3-il)-amid hidroklorid glioksilne kiseline
N-(3,5-dikloropiridin-4-il)-(1-(4-fluorobenzil)-7-azaindol-3-il)-amid glioksilne kiseline
N-(4-piridil)-(1-(4-klorobenzil)-7-azaindol-3-il)-amid hidroklorid
N-(3,5-dikloropiridin-4-il)-(1-(4-klorobenzil)-7-azaindol-3-il)-amid glioksilne kiseline
N-(3,5-dikloropiridin-4-il)-(1-(4-metoksibenzil)-7-azaindol-3-il)-amid glioksilne kiseline
N-(2,6-diklorofenil)-(1-(4-klorobenzil)-7-azaindol-3-il)-amid glioksilne kiseline
N-(4-karboksifenil)-(1-(4-fluorobenzil)-7-azaindol-3-il)-amid glioksilne kiseline
N-(4-etoksikarbonilfenil)-(1-(4-fluorobenzil)-7-azaindol-3-il)-amid glioksilne kiseline
N-(3,4-dimetoksifenil)-(1-(4-fluorobenzil)-7-azaindol-3-il)-amid glioksilne kiseline
N-(3,5-dikloropiridin-4-il)-(1-(4-metilbenzil)-7-azaindol-3-il)-amid glioksilne kiseline
N-(3,5-dikloropiridin-4-il)-(1-(4-hidroksibenzil)-7-azaindol-3-il)-amid glioksilne kiseline
N-(3,5-dikloropiridin-4-il)-(1-(3-hidroksibenzil)-7-azaindol-3-il)-amid glioksilne kiseline
N-(3,5-dikloropiridin-4-il)-(1-ciklopropilmetil-7-azaindol-3-il)-amid glioksilne kiseline
N-(3,5-dikloropiridin-4-il)-(1-heksil-7-azaindol-3-il)-amid glioksilne kiseline
N-(3,5-dikloropiridin-4-il)-(1-izobutil-7-azaindol-3-il)-amid glioksilne kiseline
N-(3,5-dikloropiridin-4-il)-(1-(2-metilpropen-3-il)-7-azaindol-3-il)-amid glioksilne kiseline
N-(3,5-dikloropiridin-4-il)-(1-(2-metoksietil)-7-azaindol-3-il)-amid glioksilne kiseline
N-(3,5-dikloropiridin-4-il)-(1-(1-naftilmetil)-7-azaindol-3-il)-amid glioksilne kiseline
N-(3,5-dikloropiridin-4-il)-(1-(4-pridilmetil)-7-azaindol-3-il)-amid glioksilne kiseline
N-(3,5-dikloropiridin-4-il)-(1-(3,5-dimetilizoksazol-4-ilmetil)-7-azaindol-3-il)-amid glioksilne kiseline
N,N-bis(2-metoksietil)-(1-(4-fluorobenzil)-7-azaindol-3-il)-amid glioksilne kiseline
(1-(4-fluorobenzil)-7-azaindol-3-il)-morfolid glioksilne kiseline
(1-(4-fluorobenzil)-7-azaindol-3-il)-glioksilna kiselina (S,S-dioksi-tiomorfolid)
(1-(4-fluorobenzil)-7-azaindol-3-il)- glioksilna kiselina (4-metilpiperazid)
N-(6-metiluracil-5-il)-(1-(4-fluorobenzil)-7-azaindol-3-il)-amid glioksilne kiseline
N-(3,6-dimetiluracil-5-il)-(1-(4-fluorobenzil)-7-azaindol-3-il)-amid glioksilne kiseline
N-(1,3,6-trimetiluracil-5-il)-(1-(4-fluorobenzil)-7-azaindol-3-il)-amid glioksilne kiseline
i
N-(1,2,4-4H-triazol-3-il)-(1-(4-fluorobenzil)-7-azaindol-3-il)-amid glioksilne kiseline.
6. Postupak sintetiziranja spojeva formule 1 iz bilo kojeg od zahtjeva 1 do 4, uz n = 1, naznačen time, da su 7-azaindol-3-karboksilne kiseline pretvorene pomoću kiselinskih klorida u analogne kloride 7-azaindol-3-karboksilne kiseline, a potom se reakcijom s primarnim ili sekundarnim aminima u inventivne spojeve formule 1, uz n = 1.
7. Sinteza spojeva formule 1 postupkom iz zahtjeva 6, naznačena time, da se koristi tionil klorid ili oksalil klorid kao kiselinski klorid za sintezu klorida 7-azaindol-3-karbokiseline kiseline.
8. Sinteza spojeva formule 1 postupkom iz bilo kojeg od zahtjeva 6 ili 7, naznačena time, da su kloridi 7-azaindol-3-karboksilne kiseline reagirali s primarnim ili sekundarnim aminima u nazočnosti pomoćne baze, poželjno je u nazočnosti viška amina korištenog kao reaktanta, tercijarnog amina, poput piridina ili trietilamina, kao i anorganskih baza, poželjno je alkalnih hidroksida ili alkalnih hidrida.
9. Postupak za sintezu spojeva formule 1 iz bilo kojeg od zahtjeva 1 do 3 i 5, uz n = 2, naznačen time, da su 7-azaindoli pretvoreni u analogne kloride 7-azaindol-3-il-glioksilne kiseline s oksalil kloridom, a potom u spojeve formule 1 s n = 2 putem reakcije s primarnim ili sekundarnim aminima.
10. Sinteza spojeva formule 1 postupkom iz zahtjeva 9, naznačena time, da klorid 7-azaindol-3-il glioksilne kiseline reagira s primarnim ili sekundarnim aminima u nazočnosti pomoćne baze, poželjno je u nazočnosti viška amina korištenog kao reaktanta, tercijarnog amina, poput piridina ili trietilamina, kao i anorganskih baza, poželjno je alkalnih hidroksida ili alkalnih hidrida.
11. Uporaba spojeva formule 1 iz bilo kojeg od zahtjeva 1 do 5 kao terapijski aktivnih sastojaka, naznačena time da je korisna za pripravu medicinskih lijekova za liječenje bolesti kod kojih je inhibicija TNFα terapijski korisna.
12. Uporaba spojeva formule 1 iz bilo kojeg od zahtjeva 1 do 5 kao terapijski aktivnih sastojaka, naznačena time, da je korisna za pripravu medicinskih lijekova za liječenje bolesti za koju je inhibicija fosfodiesteraze 4 terapijski korisna.
13. Uporaba spojeva formule 1 iz zahtjeva 1 do 5 kao terapijski aktivnih sastojaka, naznačena time, da je korisna za pripravu lijekova za liječenje bolesti, koje su povezane s učinkom eozinofila.
14. Uporaba spojeva formule 1 iz zahtjeva 1 do 5 kao terapijski aktivnih sastojaka, naznačena time, da je korisna za pripravu lijekova za liječenje bolesti, da je povezana s učinkom neutrofila.
15. Uporaba spoja iz bilo kojeg zahtjeva 1 do 5 kao aktivne tvari za pripravu lijeka za liječenje ili/i prevenciju bolesti, naznačena time, kod kojih je inhibicija TNFα korisna, posebice upale zglobova, artritisa, reumatoidnog artritisa, bolesti artritisa, reumatoidnog spondilitisa, osteoartritisa, osteoporoze, sepse, septičnog šoka, gram-negativne sepse, sindroma toksičnog šoka, sindroma otežanog disanja, astme, kronične plućne bolesti, bolesti resorpcije kosti, reakcije odacivanja transplantata, autoimunološke bolesti, lupus erythematosus, multipla skleroze, glomerulonefritisa, uveitisa, dijabetes mellitusa ovisnog o inzulinu, kronične demijelizacije, virusnih bolesti, virusnih infekcija, parazitskih infekcija, malarije, leishmaniasisa, zaraze izazvane vrućicom, zaraze izazvane bolom u mišićima, AIDS, kaheksije, bolestima koje mogu biti liječene inhibicijom fosfodiesteraze 4, astme, bolesti u kojima eozinofili igraju ulogu, bronhijalne astme, alergijskog rinitisa, alergijskog konjunktivitisa, atopičkog dermatitisa, ekcema, alergijskog angiitisa, eozinofilom izazvanih upala, eozinofilnog fasciitisa, eozinofilne upale pluća, sindroma PIE, urtikarije, ulceroznog kolitisa, Crohn-ove bolesti, proliferativne bolesti kože, psorijaze, keratoze, kronične obstruktivne bolesti pluća, bolesti koje mogu biti liječene neuroprotekcijom, senilne demencije, Alzheimer-ove bolesti, gubitka pamćenja, Parkinsonove bolesti, depresije, udara, claudikatio intermittens, bolesti prostate, dobroćudne hiperplazije prostate, polakisurije, nokturije, inkontinencije, kolika, urolitičkih kolika, spolnih poremećaja kod muškaraca i žena, kao i bronhodilatori, za inhibiranje razvoja ovisnosti o lijeku, te za smanjenje razvoja tolerance.
16. Medicinski lijekovi koji sadrže jedan ili više spojeva iz bilo kojeg zahtjeva 1 do 5, naznačeni time, da su kao dodatak uobičajenim, fiziološkim toleriranim nosačima i/ili razrjeđivačima ili adjuvansima.
17. Postupak za pripravu medicinskog lijeka iz zahtjeva 16, naznačen time, da se jedan ili više spojeva iz bilo kojeg zahtjeva 1 do 5, zajedno s uobičajenim farmaceutskim nosačima i/ili razrjeđivačima ili drugim adjuvansima, procesiraju u farmaceutski pripravak i/ili se dovode u terapijski uporabljivi oblik.
18. Uporaba spojeva opće formule 1 iz bilo kojeg od zahtjeva 1 do 5 i/ili farmaceutskih pripravaka iz zahtjeva 16 ili 17, naznačena time, da se rečeni spojevi rabe sami ili u kombinaciji jedni s drugima ili u kombinaciji s nosačima i/ili razrjeđivačima ili drugim adjuvansima.
19. Spoj opće formule 1 u skladu s bilo kojim od zahtjeva 1 do 3, naznačen time, da je to spoj N-(3,5-dikloropiridin-4-il)-[(1-(4-fluorobenzil)-7-azaindol-3-il)]-amid glioksilne kiseline.
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US20040014761A1 (en) * | 1997-10-28 | 2004-01-22 | Place Virgil A. | Treatment of female sexual dysfunction with phosphodiesterase inhibitors |
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US20050054691A1 (en) * | 2003-08-29 | 2005-03-10 | St. Jude Children's Research Hospital | Carboxylesterase inhibitors |
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