SK12932001A3 - Farmaceutická kompozícia na prevenciu alebo liečenie choroby spojenej s nadmernou produkciou IL-12 - Google Patents
Farmaceutická kompozícia na prevenciu alebo liečenie choroby spojenej s nadmernou produkciou IL-12 Download PDFInfo
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- SK12932001A3 SK12932001A3 SK1293-2001A SK12932001A SK12932001A3 SK 12932001 A3 SK12932001 A3 SK 12932001A3 SK 12932001 A SK12932001 A SK 12932001A SK 12932001 A3 SK12932001 A3 SK 12932001A3
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- Slovakia
- Prior art keywords
- methyl
- oxo
- phenyl
- dihydro
- quinazolin
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Description
Farmaceutický preparát na prevenciu alebo liečbu ochorení združených s nadmernou produkciou IL-12
Oblasť techniky
Tento vynález sa týka použitia inhibítoru PDE4 alebo jeho farmakologicky prijateinej soli na výrobu lieku na prevenciu alebo liečbu ochorení združených s nadmernou tvorbou IL-12.
Doterajší stav techniky
Dendritické bunky sú profesionálne bunky prezentujúce antigén (APC), ktoré hrajú kíúčovú úlohu v imunitnom systéme, pretože majú jedinečnú schopnosť aktivovať naivné T-bunky. Dendritické bunky produkujú IL-12p70 po interakcii medzi CD40 na dendritickéj bunke a CD40L na aktivovanom T helper lymfocyte. IL-12 hrá ústrednú úlohu indukciou tvorby j^-interf erónu (IFN-7”j T lymfocyty a prirodzenými zabíjačmi (NK bunky), a zvyšovaním cytotoxickosti NK buniek podporovaním vývoja cytotoxických T buniek.
Interleukin-12 (IL-12) je cytokin produkovaný myelomonocytmi ako heterodimér tvorený dvoma disulfidicky viazanými reťazcami, p35 a p40, kódovanými oddelenými reťazcami. Na tvorbu biologicky aktívneho heterodiméru IL-12p70 je vyžadovaná simultánna expresia 2 génov.
Navyše bolo preukázané, že IL-12 riadi imunitnú odpoveď charakteru T-helper 1 (Thl) typu odpovedi, ktorá je charakterizovaná vysokou tvorbou ^*-interferónu a nízkou tvorbou IL-4. Pretože nadbytok buniek Thl typu sa vyskytuje pri rôznych patologických stavoch, typicky pri autoimunitnom ochorení, roztrúsenej skleróze, diabetes, artritíde a tiež pri autoimunitných demyelinizačných ochoreniach, existuje v odbore potreba zlúčenín majúcich schopnosť inhibovať tvorbu IL-12 v kontexte s týmito patologickými stavmi.
Bolo preukázané, že niektoré molekuly, ako sú napríklad salbutamol, 32-agonisty (Panina-Bordignon P. et al. 1997, J. Clin. Invest., 100 (6), 1513-1519), prostaglandin E2 (Kalinski P.et al., 1997, Journal of Immunology, 159(1), 28-35), a cholera toxín (Braun M.C. et al., 1999, Journal of Experimental Medicíne 189(3), 541-552), inhibujú tvorbu IL-12 dendritickými bunkami. Avšak tieto molekuly, predovšetkým cholera toxín a prostaglandin E2 nemôžu byt bezpečne použité na liečbu pacientov.
Existuje preto potreba liekov, ktoré môžu účinkovať na ochorenia, v ktorých hrá úlohu tvorba IL-12, ako sú napríklad autoimunitné ochorenia.
Opis vynálezu
Vynález je zameraný na použitie inhibítoru PDE4 na výrobu lieku na prevenciu a/alebo liečbu ochorení združených s nadmernou tvorbou IL-12, rovnako ako na spôsob liečby takých ochorení pomocou aspoň jedného inhĺbitoru PDE4.
Vynález sa tiež týka farmaceutického preparátu na prevenciu a/alebo liečbu ochorení združených s nadmernou tvorbou IL-12, tento preparát obsahuje účinné množstvo aspoň jedného PDE4 inhibítoru.
StručnÝ opis obrázkov
Obrázok 1 ilustruje inhibičný efekt inhibítorov PDE4 na LPS plus IFN-γindukovanú tvorbu cytokínu nezrelými DC bunkami DC bunky (2xl04 bunek/jamku) boli stimulované pomocou LPS a IFN-y* v kombinácii s indikovanými koncentráciami inhibítorov
PDE4 (Ariflo alebo Rolipram). Výsledky sú vyjadrené ako priemerná tvorba cytokínov v ng/ml kultúr v dublete (24-hodinové supernatanty). A: IL-12p70; B: TNF-α; C: IL-6. Produkcia cytokinov je vyjadrená v ng/ml.
Obrázok 2 ilustruje inhibičný efekt inhibítorov PDE4 na produkciu IL-12 nezrelými DC bunkami indukovanú pomocou CD40. DC bunky (2xl04 buniek/jamku) boli stimulované pomocou buniek J558-CD40L v prítomnosti 10 μΜ indukovaných inhibítorov PDE4 (Ariflo, Rolipram, Diazepino-indol alebo Pyrazolo[4,3-e]diazepín). Výsledky sú vyjadrené ako priemerná tvorba cytokínov v pg/ml 24-hodinového supernatantu). Uvedené údaje sú z jedného reprezentatívneho experimentu z troch experimentov s podobnými výsledkami.
Obrázok 3A ilustruje absenciu fenotypového efektu prítomnosti PDE4 inhibítorov počas vyzrievania dendritických buniek. Dendritické bunky boli vyzrievané počas 2 dní s LPS v prítomnosti alebo za absencie inhibítorov PDE4 Ariflo alebo Rolipram a analyzované na expresiu molekúl na bunkovom povrchu pomocou prietokovej cytometrie. V lavom rohu každého obrázku je uvedená priemerná intenzita fluorescencie (Mn).
Obrázok 3B ilustruje absenciu fenotypového efektu prítomnosti PDE4 inhibítorov počas vyzrievania dendritických buniek. Dendritické bunky boli vyzrievané počas 2 dní s vyzrievacími faktormi TNF-α plus IL-Ιβ (odkazované ako MF) v prítomnosti alebo za absencie inhibítorov PDE4 Ariflo alebo Rolipram a analyzované na expresiu molekúl na bunkovom povrchu pomocou prietokovej cytometrie. V la vo m rohu každého obrázku je uvedená priemerná intenzita fluorescencie (Mn).
Obrázok 4 ilustruje efekt PDE4 na produkciu cytokinu zrelými dendritickými bunkami. Vyzrievanie dendritických buniek bolo indukované pomocou IL-Ιβ/ΤΝΓ-α buď v neprítomnosti alebo v prítomnosti inhibítorov PDE4 alebo PGE2. Rozdielne vyzrievané dendritické bunky boli zberané po 48 hodinách, premyté, aby sa odstránili reziduálne faktory a stimulované pomocou J558-CD-40L a IFN-^. Koncentrácie cytokínov v 24-hodinových supernatantoch boli určené pomocou ELISA stanovenia. Výsledky sú vyjadrené ako priemerná produkcia cytokínov v ng/ml + SD z dubletových kultúr.
Detailný opis vynálezu inhibítoroch PDE4 je v odbore známe, že účinkujú priamo na T-bunky, hlavne inhibíciou proliferácie T-buniek, predovšetkým spätne väzbovým znížením proliferácie riadenej antigénom.
Vynálezcovia prekvapivo zistili, že inhibítory PDE4 majú priamy účinok na dendritické bunky inhibíciou ich kapacity produkovať zápalový cytokin IL-12 po následnej stimulácii týchto dendritických buniek, napríklad kombináciou LPS a IFN-/' alebo CD40L, povrchového receptoru T-buniek. Tiež preukázali, že hoci sú inhibítory PDE4 schopné inhibície produkcie IL-12 stimulovanými dendritickými bunkami, nenarušujú tieto inhibítory fenotyp zrelých dendritických buniek.
Ďalej bolo preukázané podlá vynálezu, že priama aktivita inhibítorov PDE4 na dendritické bunky bola schopná vyvolať zmeny v populácii T-helper buniek, špecifickejšie riadi priama aktivita inhibítorov PDE4 na dendritické bunky imunitnú odpoveď naivných T buniek v zmysle Th2 typu odpovedi po aktivácii zrelými dendritickými bunkami predliečenými inhibítorom PDE4 počas vyzrievania. Priama aktivita inhibítorov PDE4 na dendritické bunky navyše vyvoláva významné zníženie populácie Thl.
Prvý ciel vynálezu zahŕňa použitie aspoň jedného inhibítoru PDE4 alebo jeho farmaceutický prijatelnej soli na vý5 robu lieku na prevenciu a/alebo liečbu ochorení združených s nadmernou tvorbou IL-12.
Termín inhibítor PDE4 zahŕňa každú zlúčeninu, ktorá má schopnosť: inhibovat enzým PDE4 s hodnotou IC50 aspoň rovnakého radu ako je IC50 zmeraná za rovnakých experimentálnych podmienok pre Rolipram. Hodnota IC^q zodpovedá molárnej koncentrácii inhibítoru PDE4, ktorý je schopný 50% inhibície aktivity PDE4 v porovnaní s hodnotou aktivity PDE4 meranej s kontrolným tlmivým roztokom v neprítomnosti inhibítoru PDE4.
V ilustratívnej forme vynálezu môže byt inhibícia PDE4 meraná osobou oboznámenou s odborom podlá spôsobu opísaného Torphym et al. (1992, J. Pharm. Exp. Ther., 263, 1195-1205).
Najprednostnejšie je určenie hodnoty IC50 pre konkrétny inhibítor PDE4 dosiahnuté zmeraním aktivity enzýmu PDE4 ako za absencie inhibítoru PDE4, tak v jeho prítomnosti v koncentračnom rozmedzí inhibítoru medzi 0,01 nM a 100 μΜ a prednostne medzi 0,01 nM a 1 μΜ.
Enzým PDE4, ktorý je použitý na inhibičný test môže byt získaný z cytosolického extraktu z buniek ludskej bunkovej línie U937.
Hoci si vynálezcovia neželajú spojovat účinky inhibítorov PDE4 s žiadnou konkrétnou teóriou, veria, že priama aktivita týchto inhibítorov na produkciu IL-12 dendritickými bunkami nie je, alebo aspoň nie je iba, sprostredkovaná zvýšením intracelulárnej koncentrácie cAMP. Bolo skutočne preukázané, že iné inhibítory PDE, o ktorých je známe, že zvyšujú hladiny cAMP podobne ako inhibítory PDE7, nevykazujú žiadnu inhibičnú aktivitu na produkciu IL-12 dendritickými bunkami.
Výraz nadmerná produkcia IL-12 tu zahŕňa nežiadúcu produkciu IL-12 vo fyziologických situáciách, kde rozvoj imunitnej odpovedi v tele pacienta spôsobuje silnú zápalovú reakciu alebo vysokú aktiváciu T-helper buniek, ktorá poškodzuje zdravie pacienta a vedie k rôznym patologickým stavom zahŕňajúcich autoimunitné ochorenia.
Ochorenia združené s nadmernou produkciou IL-12 zahŕňajú autoimunitné ochorenia ako sú zápalové patologické stavy postihujúce priedušky, ako je napríklad bronchokonstrikcia, mnohopočetné orgánové zlyhanie, osteoartróza, septický šok (septikémia), zápalové choroby alebo poruchy, (chronické) zápalové ochorenia zažívacieho systému, vrátane čreva (hemoragická rektokolitída, ulcerózna kolitída, nešpecifické črevové zápaly) s autoimunitnou zložkou, chronická lymfatická leukémia, pečeňové zlyhanie, vrátane po nasledujúcom imunologickom a zápalovom pečeňovom poškodení, rejekcia štepu, Crohnova choroba, chronická obštrukčná bronchopneumopatia (chronická bronchitída, emfyzém, chronická obštrukčná choroba bronchopulmonálna), akútna píúcna príhoda, nervové poškodenie vyvolané ischémiou, ochorenie spôsobené reperfúznou ischémiou so vzťahom k vysokým hladinám TNF-α, akútny respiračný distress syndróm, akútna pankreatitída, autoimunitné demyelinizačné ochorenie, roztrúsená skleróza, diabetes I. typu, chronická/relabujúca alergická encefalomyelitída, autoimunitná encefalomyelitída, zápalová kolitída, artritída zahŕňajúca reumatoidnú artritídu, sarkoidóza, hypersenzitívna pneumonitída, autoimunitná uveitída, nešpecifické črevové zápaly, psoriáza, ekzém, kontaktná dernatitída, rovnako ako dalšie ludské ochorenia sprostredkované Th-l.
V prvej prednostnej forme vynálezu je inhibítor PDE4 vybraný zo skupiny zahŕňajúcej Rolipram a Ariflo.
V druhej prednostnej forme vynálezu je inhibítor PDE4 vybraný zo skupiny zahŕňajúcej zlúčeniny z diazepino-indolovej rodiny, prednostne [l,4]diazepino[6,7,l-Ai]indoly, ako sú napríklad zlúčeniny uvedené v patentovej prihláške PCT WO 97/36905 a WO 96/11690, rovnako ako ich metabolity uvedené v patentovej prihláške PCT WO 99/50270.
Prednostné [l,4]diazepino[6,7,l-hi]indolové zlúčeniny sú nasledujúce zlúčeniny:
(9-Hydroxy-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)amid (3R)-izochinolín-3-karboxylovej kyseliny
-(3R)-4-t-Butyloxykarbonylamino-N-(9-amino-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)benzamid
-(3R)-4-Amino-N-(9-amino-4-oxo-l-fenyl-3,4,6,7- tetrahydro [1.4] diazepino[6,7,1-hi]indol-3-yl)-3,5-dichlórbenzamid
-(3R)-4-Amino-N-(9-amino-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1.4] diazepino[6,7,l-hi]indol-3-yl)-5-chlór-2-metoxybenzamid
-(3R)-N-(9-Amino-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)izonikotínamid
-(3R)-3-t-Butyloxykarbonylamino-N-(9-amino-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)izonikotínamid (9-Amino-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)amid (3R)-izochinolín-3-karboxylovej kyseliny (9-Amino-4-oxo-l-feny1-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)amid (3R)-chinolín-3-karboxylovej kyseliny (9-Amino-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4Idiazepino[6,7,1-hi]indol-3-yl)amid (3R)-4,7-dimetylpyrazolo[5,1-c][1,2,4]triazín-3-karboxylovej kyseliny
-(3R)-4-Amino-3,5-dichlór-N-(9-dimetylamino-4-oxo-lfenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-y1)benzamid
-(3R)-N-(9-Amino-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-2-benzofuránkarboxamid [4-0xo-l-fenyl-9-(pyrolidin-l-yl)-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)amid -(3R)-4,7-dimetylpyrazolo[5,l-c][1,2,4]triazín karboxylovej kyseliny.
Medzi zlúčeninami uvedenými v patentovej prihláške PCT č. PCT/FR00/01174 (WO 00/66584) sú preferované 1-aminotriazolo[4,3-a]chinazolin-5-ony a/alebo -5-tiony a konkrétnejšie nasledujúce zlúčeniny:
1-(Azepan-l-yl)-7-chlór-4-(3-fenylalyl)-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
7-Bróm-l-dimetylamino-4-((E)-3-pyrid-3-ylalyl)-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on-l-(azepan-l-yl)-7-chlór-4-(4-chlórbenzyl)-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
1- (Azepan-l-yl) -7-chlór-4- (4-fluórbenzyl) -4H- [1,2,4]triazolo[4,3-a]chinazolin-5-on
1- (Azepan-l-yl) -7-chlór-4- (3,4-dimetoxybenzyl) -4H[ 1,2,4] triazolo[4,3-a]chinazolin-5-on
1- (Azepan-l-yl) -7-chlór-4- (3-pyridylmetyl) -4H- [1,2,4]triazolo[4,3-a]chinazolin-5-on
1- (Azepan-l-yl) -7-bróm-4- (4-chlórf enylmetyl) -4H- [1,2,4]triazolo[4,3-a]chinazolin-5-on
4- (1-Azepan-l-yl) -7-bróm-5-oxo-5H-[1,2,4] -triazolo[4,3-a]chinazolin-4-ylmetyl)benzonitril
1-(Azepan-l-yl)-7-bróm-4-(3,4-dimetoxybenzyl)-4H-[1,2,4] triazolo[4,3-a]chinazolin-5-on
1-(Azepan-l-yl)-7-bróm-4-(3-fenylalyl)-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on l-Azepan-l-yl-7-bróm-4-((E)-3-pyrid-3-ylalyl)-4H-[1,2,4] triazolo[4,3-a]chinazolin-5-on l-Azepan-l-yl-7-bróm-4-(3-pyrid-4-ylalyl)-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
7-Bróm-4-(4-metylbenzyl)-l-pyrolidin-l-yl-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
7-Bróm-4-(4-chlórbenzyl)-l-pyrolidin-l-yl-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
7-Bróm-4-(4-fluórbenzyl) -l-pyrolidin-l-yl-4H- [1,2,4]triazolo[4,3-a]chinazolin-5-on
4- (7-Bróm-5-oxo-l-pyrolidin-l-yl-5H- [1,2,4] triazolo[ 4,3-a ] chinazolin-4-ylmetyl) benzonitril
Metylester 4-(7-bróm-5-oxo-l-pyrolidin-l-yl-5H-[1,2,4]triazolo[ 4,3-a ]chinazolin-4-ylmetyl)benzoovej kyseliny
7-Bróm-4- (4-nitrobenzyl) -l-pyrolidin-l-yl-4H- [1,2,4]triazolo[4,3-a]chinazolin-5-on
7-Bróm-4- (4-metoxybenzyl) -l-pyrolidin-l-yl-4H- [1,2,4]triazolo[4,3-a]chinazolin-5-on
4- (7-Bróm-5-oxo-l-pyrolidin-l-yl-5H- [1,2,4] triazolo [ 4,3-a ] chinazolin-4-ylmetyl)fenylester kyseliny octovej
7-Bróm-4- (4-hydroxybenzyl) -l-pyrolidin-l-yl-4H- [1,2,4]triazolo[4,3-a]chinazolin-5-on
7-Bróm-4- (3,4-dimetoxybenzyl) -l-pyrolidin-l-yl-4H- [1,2,4]triazolo[4,3-a]chinazolin-5-on
1-(Pyrolidin-l-yl)-7-bróm-4-(3-fenylalyl-4H- [1,2,4]triazolo[4,3-a]chinazolin-5-on
7-Bróm-4-[(E)-3-(4-chlórfenyl)alyl]-1-pyrolidin-l-yl-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
7-Bróm-4- [ 3- (4-metoxyfenyl) alyl ] -l-pyrolidin-l-yl-4H[1,2,4]triazolo[4,3-a]chinazolin-5-on
7-Bróm-4-[3-pyrid-3-ylalyl)-l-pyrolidin-l-yl-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
7-Bróm-4- ((E)-3-pyrid-4-ylalyl) -l-pyrolidin-l-yl-4H[1,2,4]triazolo[4,3-a]chinazolin-5-on
7-Bróm-4- (3,4-dimetoxybenzyl) -l-piperid-l-yl-4H- [1,2,4]triazolo[4,3-a]chinazolin-5-on
1-(Piperid-l-yl)-7-bróm-4-(3-fenylalyl)-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
7-Bróm-l-dimetylamino-4-(4-metylbenzyl)-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
4-(7-Bróm-l-dimetylamino-5-oxo-5H-[1,2,4]triazolo[4,3-a]chinazolin-4-ylmetyl)benzonitril
7-Bróm-l-dimetylamino-4-(4-hydroxybenzyl)-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
Metylester 4-(7-bróm-l-dimetylamino-5-oxo-5H-[1,2,4]triazolo[4,3-a]chinazolin-4-ylmetyl)benzoovej kyseliny [4-(7-Bróm-l-dimetylamino-5-oxo-5H-[1,2,4]triazolo[4,3-a]chinazolin-4-ylmetyl)fenyl)acetonitril
7-Bróm-l-dimetylamino-4-(3-fenylalyl)-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
7-Brón-l-dimetylamino-4-(3-fenylprop-2-yny1) - 4H[1,2,4]triazolo[4,3-a]chinazolin-5-on l-Azepan-l-yl-7-metyl-4-(3-fenylalyl)-4H-[1,2,4]triazolo [4,3-a]chinazolin-5-on
4-(3,4-Dimetoxybenzyl)-7-metyl-l-pyrolidin-l-yl-4H-[1,2,4] triazolo[4,3-a]chinazolin-5-on [4-(7-Metyl-5-oxo-l-pyrolidin-l-yl-5H-[1,2,4]triazolo[4,3-a]chinazolin-4-ylmetyl)fenyl]octová kyselina
7-Metyl-4-(3-fenylalyl)-l-pyrolidin-l-yl-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on [4-(l-Dimetylamino-7-metyl-5-oxo-5H-[1,2,4]triazolo[4,3-a]chinazolin-4-yImety1)fenyl]octová kyselina l-Dimetylamino-7-metyl-4-((E)-3-fenylalyl)-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on l-Dimetylamino-7-metyl-4-(3-pyrid-3-ylalyl)-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on [4-(7-Bróm-5-oxo-l-perhydroazepin-l-yl-5H-[1,2,4]triazolo[4,3-a]chinazolin-3-ylmetyl)fenyl]octová kyselina
4-Benzyl-7-bróm-l-(pyrolidin-l-yl)-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
4-Benzyl-7-bróm-l-(2,5-dihydropyrol-l-yl)-4H-[1,2,4]triazolot 4,3-a]chinazolin-5-on
4-Benzyl-7-j odo-1-(pyrolidin-l-yl)-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on l-Azepan-l-yl-4-benzyl-7-metyl-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
4-(4-Aminobenzyl)-7-bróm-l-(pyrolidin-l-yl)-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
7-Amino-4-((E)-3-fenylalyl)-l-pyrolidin-l-yl-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
7-Amino-l-azepan-l-yl-4-benzyl-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
7-Amino-4-((E)-3-pyrid-3-ylalyl)-l-pyrolidin-l-yl-4H[1,2,4]triazolo[4,3-a]chinazolin-5-on
7-Amino-l-dimetylamino-4-((E)-3-fenylalyl)-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
4-Benzyl-7-metylamino-l-pyrolidin-l-yl-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
4-(7-Metylamino-5-oxo-l-pyrolidin-l-yl-5H-[1,2,4]triazolo[4,3-a]chinazolin-4-ylmetyl)benzonitril
4-Benzyl-8-metylamino-l-pyrolidin-l-yl-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
4-Benzyl-7-etylamino-l-pyrolidin-l-yl-4H-[1,2,4]triazolo [4,3-a]chinazolin-5-on
4-Benzyl-7-etylamino-l-pyrolidin-l-yl-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
4-Benzyl-7-izopropylamino-l-pyrolidin-l-yl-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
Metylester [4-(7-Bróm-5-oxo-l-pyrolidin-l-yl-5H-[1,2,4]triazolo[4,3-a]chinazolin-4-ylmetyl)fenyl]octovej kyseliny
2-[4-(7-Bróm-5-oxo-l-pyrolidin-l-yl-5H-{1,2,4]triazolo[4,3-a]chinazolin-4-ylmetyl)fenyl]-N-metylacetamid
2- [ 4- (7-Bróm-l-dimetylamino-5-oxo-5H- [1,2,4] triazolo[4,3-a]chinazolin-4-yImetyl)fenyl]acetamid
2-[4-(7-Bróm-5-oxo-l-pyrolidin-l-yl-5H-[1,2,4]triazolo[4,3-a]chinazolin-4-ylmetyl)fenyl]-N,N-dimetylacetamid
2-[4-(7-Bróm-5-oxo-l-pyrolidin-l-yl-5H-[1,2,4]triazolo[4,3-a]chinazolin-4-ylmetyl)fenyl]-N-hydroxyacetamid l-Dimetylamino-7-metyl-4-(3-pyrid-3-ylalyl)-4H- [1,2,4]triazolo[4,3-a]chinazolin-5-tión
Medzi zlúčeninami uvedenými hore sú osobitne preferované nasledujúce zlúčeniny:
7-Bróm-l-dimetylamino-4-((E)-3-pyrid-3-ylalyl)-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
1-(Azepan-l-yl)-7-chlór-4-(3,4-dimetoxybenzyl)-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
1-(Azepan-l-yl)-7-chlór-4-(3-pyridyImetyl)-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
4-(1-Azepan-l-yl)-7-bróm-5-oxo-5H-[1,2,4]triazolo[4,3-a]chinazolin-4-ylmetyl)benzonitril
1-(Azepan-l-yl)-7-bróm-4-(3,4-dimetoxybenzyl)-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
1-(Azepan-l-yl)-7-bróm-4-(3-fenylalyl)-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on l-Azepan-l-yl-7-bróm-4- ((E)-3-pyrid-3-ylalyl) -4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on l-Azepan-l-yl-7-bróm-4-(3-pyrid-4-ylalyl)-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
7-Bróm-4-(4-metylbenzyl)-l-pyrolidin-l-yl-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
7-Bróm-4-(4-chlórbenzyl)-l-pyrolidin-l-yl-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
7-Bróm-4-(3,4-dimetoxybenzyl)-l-pyrolidin-l-yl-4H-[1,2,4] triazolo[4,3-a]chinazolin-5-on
1-(Pyrolidin-l-yl)-7-bróm-4-(3-fenylalyl)-4H-[1,2,4]trlazolo[4,3-a]chinazolin-5-on
7-Bróm-4-(3-pyrid-3-ylalyl)-l-pyrolidin-l-yl-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
1-(Piperid-l-yl)-7-bróm-4-(3-fenylalyl)-4H-[1,2,4]triazolo [ 4 ,3-a]chinazolin-5-on
4-(7-Bróm-l-dimetylamino-5-oxo-5H-[1,2,4]triazolo[4,3-a]chinazolin-4-ylmetylJbenzonitril
Metylester 4-(Bróm-dimetylaminooxo-5H-[1,2,4]triazolo[4,3-a]chinazolin-4-ylmetyl)benzoovej kyseliny
7-Bróm-l-dimetylamino-4-(3-fenylalyl)-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
7-Bróm-l-dimetylamino-4-(3-fenylprop-2-ynyl)-4H[1,2,4]triazolo[4,3-a]chinazolin-5-on
1- Azepan-l-yl-7-metyl-4- (3-fenylalyl) -4H- [1,2,4] triazolo[4,3-a]chinazolin-5-on
4-(3,4-Dimetoxybenzyl)-7-metyl-l-pyrolidin-l-yl-4H-[1,2,4]· triazolo[4,3-a]chinazolin-5-on
7-Metyl-4-(3-fenylalyl)-l-pyrolidin-l-yl-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
7-Amino-4-((E)-3-fenylalyl)-l-pyrolidin-l-yl-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
7-Amino-4-((E)-3-pyrid-3-ylalyl)-l-pyrolidin-l-yl-4H[1,2,4]triazolo[4,3-a]chinazolin-5-on
4-Benzyl-7-metylamino-l-pyrolidin-l-yl-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-on
4-(7-Metylamino-5-oxo-l-pyrolidin-l-yl-5H-[1,2,4]triazolo[4,3-a]chinazolin-4-ylmetyl)benzonitril
Metylester [4-(7-bróm-5-oxo-l-pyrolidin-l-yl-5H-[1,2,4]triazolo[4,3-a]chinazolin-4-ylmetyl)fenyl]octovej kyseliny
2- [4-(7-Bróm-5-oxo-l-pyrolidin-l-yl-5H-[1,2,4]triazolo[4,3-a]chinazolin-4-ylmetyl)fenyl]-N-metylacetamid
2-[4-(7-Bróm-5-oxo-l-pyrolidin-l-yl-5H-[1,2,4]triazolo[4,3-a]chinazolin-4-ylmetyl)fenyl]-N,N-dimetylacetamid l-Dimetylamino-7-metyl-4-(3-pyrid-3-ylalyl)-4H-[1,2,4]triazolo[4,3-a]chinazolin-5-tión
Ďalšie preferované zlúčeniny sú také zlúčeniny, ktoré sú uvedené v prihláške PCT WO 98/49169 a najprednostnejšie sú preferované diazepinoindolóny a konkrétnejšie nasledujúce zlúčeniny:
(3S) 3-(2-Metyl-4-oxo-4H-chinazolin-3-yl)-1-fenyl-6,7-dihydro-3H-[1,4]diazepino[6,7,1-hi]indol-4-on
9-Metoxy-3-(2-metyl-4-oxo-4H-chinazolin-3-yl)-1-fenyl-6,7-dihydro-3H-[1,4]diazepino[6,7,1-hi]indol-4-on
2-Metyl-3-(9-metoxy-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolín-7-karboxylický metylester
2-Metyl-3-(9-metoxy-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolín-7-karboxylová kyselina
2-Metyl-3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolín-7-karboxylová kyselina
2-Metyl-3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolín-7-karboxylová kyselina
2-Metyl-3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolín-7-karboxylová kyselina
D glukamín 2-metyl-3-(9-metyl-4-oxo-l-fenyl-3,4,6,7tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo3,4-dihydrochinazolín-7-karboxylátová sol (3R) 2-Metyl-3- (9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[ 1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolín-7-karboxylová kyselina (3S) 2-Metyl-3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo- 3,4-dihydrochinazolín-7-karboxylová kyselina
2-Morfolin-4-yl-etylester 2-metyl-3-(9-metyl-4-oxo-l-fenyl3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo -3,4-dihydrochinazolín-7-karboxylovej kyseliny
2-Metyl-3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolín-7-karboxylátová sol 2-acetoxyetylu
2-Metyl-3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolín-7-karboxylátová sol 2-metoxyetylu
2-Metyl-3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolín-7-karboxylátová sol 2-hydroxyetylu
2-Mety1-3-(9-metyl-4-oxo-l-feny1-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolín-7-karboxylátová sol l-(2S)-glycerolu
2-Metyl-3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[ 6,7,1-hi ] indol-3-yl) -4-oxo-3,4-dihydrochinazolín-7-karboxylátová sol 2-2-hydroxy-3-morfolin-4-yl-propylu
9-Metyl-3-(2-metyl-4-oxo-4H-chinazolin-3-yl)-1-fenyl-6,7-dihydro-3H-[1,4]diazepino!6,7,1-hi]indol-4-on (3S) 9-Metyl-3-(2,5-dimetyl-4-oxo-4H-chinazolin-3-yl)-1-fenyl-6,7-dihydro-3H- [1,4 Jdiazepino [6,7,1-hi ] indol-4-on (3S) 9-Metyl-3- (2,6-dimetyl-4-oxo-4H-chinazolin-3-yl)-1-f enyl-6,7-dihydro-3H-[l,4]diazepino[6,7,l-hi]indol-4-on (3S) 9-Metyl-3-(2,6-dimetyl-4-oxo-4H-chinazolin-3-yl)-1-f enyl-6,7-dihydro-3H- [1,4 ]diazepino [6,7,1-hi ] indol-4-on (3S) 9-Metyl-3-(2,8-dimetyl-4-oxo-4H-chinazolin-3-yl)-1-f enyl-6,7-dihydro-3H- [1,4 ]diazepino [6,7,1-hi ] indol-4-on
3- (5-Metoxy-2-metyl-4-oxo-4H-chinazolin-3-yl)-9-metyl-1-fenyl-6,7-dihydro-3H-[1,4]diazepino[6,7,1-hi]indol-4-on
3-(7-Metoxy-2-metyl-4-oxo-4H-chinazolin-3-yl)-9-metyl-1-f enyl-6,7-dihydro-3H- [ 1,4 ]diazepino [6,7,1-hi ] indol-4-on
3-(6-Metoxy-2-metyl-4-oxo-4H-chinazolin-3-yl)-9-metyl-1-f enyl-6,7-dihydro-3H-[1,4]diazepino[6,7,1-hi]indol-4-on
3-(6-Bróm-2-metyl-4-oxo-4H-chinazolin-3-yl )-9-metyl-1-f enyl-6,7-dihydro-3H-[1,4]diazepino[6,7,1-hi]indol-4-on
3-(5-Hydroxymetyl-2-metyl-4-oxo-4H-chinazolin-3-yl)-9-metyl-l-fenyl-6,7-dihydro-3H-[1,4 Jdiazepino[6,7,1-hi] indol-4-on
Terciobutylový ester 2-metyl-3-(9-metyl-4-oxo-l-fenyl3,4,6,7-tertrahydro-3H-[1,4 jdiazepino[6,7,1-hi]indol-3yl)—4—oxo—3,4-dihydrochinazolín-5-karboxylovej kyseliny
2- Metyl-3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tertrahydro-3H-[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4dihydrochinazolín-5-karboxylová kyselina
3- (7-Hydroxymetyl-2-metyl-4-oxo-4H-china z o1in-3-yl) - 9 -metyl-l-fenyl-6,7-dihydro-3H-[1,4]diazepino[6,7,l-hi]indol-4-on (3S) 3-(5-Fluór-2-metyl-4-oxo-4H-chinazolin-3-yl)-9-metyl-l-fenyl-6,7-dihydro-3H-[1,4]diazepino[6,7,1-hi]indol-4-on
3-(5-Chlór-2-metyl-4-oxo-4H-chinazolin-3-yl)-9-metyl-1-fenyl-6,7-dihydro-3H-[1,4]diazepino[6,7,1-hi]indol-4-on (9-Metyl-3-oxo-4H-chinazolin-3-yl)-1-fenyl-6,7-dihydro-3H-[1,4]diazepino[6,7,1-hi]indol-4-on
Etylester 3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolín-2-karboxylovej kyseliny
Etylester 5-chlór-3-(9-metyl-4-oxo-l-fenyl-3,4,6,7tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4 dihydrochinazolín-2-karboxylovej kyseliny
Etylester [3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[ 1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolin-2-yl octovej kyseliny
3-(9-Metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolin-2-ylmetylester octovej kyseliny
9-Metyl-3-(2-metyloxymetyl-4-oxo-4H-chinazolin-3-yl)-1-fenyl-6,7-dihydro-3H-[1,4]diazepino[6,7,1-hi]indol-4-on
9-Metyl-3-(2-hydroxymetyl-4-oxo-4H-chinazolin-3-yl)-l-fenyl-6,7-dihydro-3H-[1,4]diazepino[6,7,1-hi]indol-4-on [[2-(2-Metoxyetoxy)etoxy] a [3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol3-yl)-4—oxo—3,4—dihydrochinazolin—2—yl]metyl]ester mono kyseliny jantárovej [2-(2-Metoxyetoxy)etoxy] a [3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)—4—oxo—3,4-dihydrochinazolin-2-yl]metyl]ester mono kyseliny octovej
3-(9-Metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino [6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolin-2-ylmetylester N-(2-morfolin-4-yl-etyl)kyseliny jantárové
3-(9-Metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino [6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolin-2-ylmetylester 2-morfolin-4-yletylester kyseliny jantárové
Metylester 6-t-butoxykarbonylamino-2-(3-[3-(9-metyl-4-oxo -1-feny1-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4—oxo-3,4-dihydrochinazolin-2-yl-metoxykarbonyl]propionylamino)hexánovej kyse1iny
Etylester 3-[3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[ 1,4]diazepino [6,7,1-hi ] indol-3-yl) -4-oxo-3,4-dihydrochinazolin-2-yl]propánovej kyseliny (3S) 3-(2-Metyl-4-oxo-4H-pyrido[3, 4-d]pyriπlidin-3-yl)-9-Inetyl-l-f enyl-6 ,7-dihydro-3H-[1,4]diazepino[6,7,1-hi]indol-l-on
3-(2-Metyl-4-oxo-4H-pteridin-3-yl)-9-metyl-l-fenyl-6,7-dihydro-3H-[1,4]diazepino[6,7,1-hi]indol-4-on
9-Amino-3-(2-metyl-4-oxo-4H-pyrido[3,4-d]pyridin-3-yl)-1-feny1-6,7-dihydro-3H-[1,4]diazepino[6,7,1-hi]indol-4-on
3-(2-Metyl-4-oxo-4H-chinazolin-3-yl)-9-nitro-l-fenyl-6,7-dihydro-3H-[1,4]diazepino[6,7,1-hi]indol-4-on
3-(2,5-Dimetyl-4-oxo-4H-chinazolin-3-yl)-9-nitro-lfenyl-6,7-dihydro-3H-[1,4]diazepino[6,7,1-hi]indol-4-on
3-(2,6-Dimetyl-4-oxo-4H-chinazolin-3-yl)-9-nitro-lfenyl-6,7-dihydro-3H-[1,4]diazepino[6,7,1-hi]indol-4-on
3-(2,7-Dimetyl-4-oxo-4H-chinazolin-3-yl)-9-nitro-l-fenyl-6,7-dihydro-3H-[1,4]diazepino[6,7,1-hi]indol-4-on
3-(2,8-Dimetyl-4-oxo-4H-chinazolin-3-yl)-9-nitro-lfenyl-6,7-dihydro-3H-[1,4]diazepino[6,7,1-hi]indol-4-on
3-(2,6,8-Trimetyl-4-oxo-4H-chinazolin-3-yl)-9-nitro-l-fenyl-6,7-dihydro-3H-[1,4]diazepino[6,7,1-hi]indol-4-on
3-(8-Bróm-2,6-dimetyl-4-oxo-4H-chinazolin-3-yl )-9-nitro-l-fenyl-6,7-dihydro-3H-[1,4]diazepino[6,7,l-hi]indol-4-on (3S) 3-(2-Metyl-4-oxo-4H-pyrido[3,4-pyrido]pyrimidin-3yl)-9-nitro-l-fenyl-6,7-dihydro-3H-[l,4]diazepino[5,7,l-hi] indol-4-on
5-Chlór-2-metyl-3-(9-nitro-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4 Jdiazepino[6,7,l-hiJindol-3-yl)-4-oxo-3,4-dihydrochinazolín (3S) 9-Amino-3-(2-metyl-4-oxo-4H-chinazolin-3-yl)-1fenyl-6,7-dihydro-3H-[1,4 Jdiazepino[6,7,l-hi]indol-4-on
Metylester 3-(9-amino-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,l-hi]indol-3-yl)-2-metyl-4-oxo-3,4-dihydrochinazolín-7-karboxylovej kyseliny a jeho enantioméry
3-(9-Amino-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4 Jdiazepino[6,7,l-hi]indol-3-yl)-2-metyl-4-oxo-3,4-dihydrochinazolín-7-karboxylová kyselina
9-Amino-3-(2-metyl-4-oxo-4H-chinazolin-3-yl)-1-fenyl-6,7-dihydro-3H-[1,4 Jdiazepino[6,7,l-hiJ indol-4-on
9-Amino-3-(2,5-dimetyl-4-oxo-4H-chinazolin-3-yl)-1fenyl-6,7-dihydro-3H-[1,4]diazepino[6,7,l-hi J indol-4-on
9-Amino-3-(2,6-dimetyl-4-oxo-4H-chinazolin-3-yl)-1-fenyl-6,7-dihydro-3H-[1,4 Jdiazepino[6,7,l-hi J indol-4-on
9-Amino-3-(2,8-dimetyl-4-oxo-4H-chinazolin-3-yl)-1-fenyl-6,7-dihydro-3H-[1,4]diazepino[6,7,l-hi J indol-4-on
9-Amino-3-(2,6,8-trimetyl-4-oxo-4H-chinazolin-3-yl)-1feny1-6,7-dihydro-3H- [1,4]diazepino[6,7,1-hi]indol-4-on
9-Amino-3-(5-chlôr-2-metyl-4-oxo-4H-chinazolin-3-yl)-1-fenyl-6,7-dihydro-3H-[1,4]diazepino[6,7,1-hi]indol-4-on
2-Metyl-3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]dlazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolín-7-karboxamid
2-Metyl-3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]dlazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolín-7-karbonitril
9-Metyl-3-[2-metyl-4-oxo-7-(lH-tetrazol-5-yl)-4H-chinazolin -3-yl]-1-fenyl-6,7-dihydro-3H-[1,4]diazepino[6,7,1-hi]indol -4-on
2-Metyl-3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1, 4 ] diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolín-7-N-metylkarboxamid
2-Metyl-3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolín-7-N-dimetylkarboxamid (2-Morfolin-4-yl-etyl)amid 2-metyl-3-(9-metyl-4-oxo-lfenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3yl)-4-ΟΧΟ-3,4-dihydrochinazolín-7-karboxylovej kyseliny (3-(Morfolin-4-yl-propyl)amid 2-metyl-3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-OXO-3,4-dihydrochinazolín-7-karboxylovej kyseliny
2- Metyl-3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolin -7-(2-amino)etylkarboxamid a jeho hydrochloridová soí
3- (7-[4-(2-Hydroxyetyl)-piperazin-l-karbonyl-l-karbonyl]-2-metyl-4-oxo-4H-chinazolin-3-yl)-9-metyl-l-fenyl-6,7-dihydro[l,4]diazepino[6,7,l-hi]indol-4-on a jeho hydrochloridová sol
Metylester (2S) 6-t-butoxykarbonylamino-2-([2-metyl-3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolín-7karbonyl]amino)hexánovej kyseliny
Metylester (2S) 6-amino-2-([2-metyl-3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-OXO-3,4-dihydrochinazolín-7-karbonyl]amino)hexánovej kyseliny
Pentafluórfenylester (2S) 2-metyl-3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-OXO-3,4-dihydrochinazolín-7-karbonyl]amino)karboxylovej kyseliny
N-(2-Metyl-3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolín-7-karboxyl)tyrozín
N-(2-Metyl-3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolín-7-karboxyl)alanín
N-(2-Metyl-3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolín-7-karboxyl)fenylalanín
N- (2-Metyl-3-(9-metyl-4-oxo-l-f enyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolín-7-karboxyl)glycín
N-(2-Metyl-3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolín-7-karboxyl)leucín
N-(2-Mety1-3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolín-7-karboxyl)aspartová kyselina
N-(2-Metyl-3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolín-7-karboxylJglutámová kyselina
N-(2-Metyl-3-(9-metyl-4-oxo-l-fenyl -3,4,6,7-tetrahydro [1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolín-7-karboxyl)lyzín
Etylester 2-[2-mety1-3-(9-metyl-4-oxo-l-fenyl-3,4,6,7tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4 -dihydrochinazolín-7-karbonyl)amino)-3-fenyl-(L)-propiónovej kyseliny
N-(2-Metyl-3-(9-metyl-4-oxo-l-fenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydrochinazolín-7-karboxylJprolín
Ďalšie preferované zlúčeniny sú zlúčeniny uvedené v prihláške PCT č. PCT/EP00/13380 ako substituované pyrazolo[4,3-e]diazepíny a najprednostnejšie ako nasledujúce zlúčeniny:
l-Etyl-5- (4-metoxy-f enyl) -3-metyl-6,7-dihydro-lH-pyrazolo [4,3-e][l,4]diazepin-8-on
5- (4-Brómfenyl) -l-etyl-3-metyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on
1,3-Dimetyl-5-fenyl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-on
5-(4-Metoxyfenyl)-l, 3-dimetyl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-on
5-(4-Brómfenyl)-1, 3-dimetyl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-on l-Etyl-3-metyl-5-naftalen-2-yl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-on
5-(3-Chlórtiofen-2-yl)-l-etyl-3-metyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on
3-(l-Etyl-3-metyl-8-oxo-l,6,7,8-tetrahydropyrazolo[4,3-e][l,4]diazepin-5-yl)propanoát demetyl l-Etyl-5-fenyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on
5-(4-Chlórfenyl)-l-etyl-3-metyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on
5-(4-Aminofenyl)-l-etyl-3-metyl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-on l-Etyl-5-(4-fluórfenyl)-3-metyl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-on
5-(3-Brómfenyl)-l-etyl-3-metyl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-on
3-(Metyl-5-fenyl)-l-propyl-3-metyl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-on l-Izopropyl-3-metyl-5-fenyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on (±) l-Etyl-3-metyl-5-fenyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on
1-(2-Hydroxyetyl)-3-metyl-5-fenyl-6,7-dihydro-lH-pyrazolo [4,3-e][l,4]diazepin-8-on l-Etyl-3-metyl-5-fenyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-tion l-Etyl-5-(4-metoxyfenyl)-6,7-dihydro-ΙΗ-pyrazolo[4,3-e][1,4] diazepin-8-on l-Etyl-5-(3-metoxyfenyl)-3-metyl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-on
5-(2-Aminofenyl)-l-etyl-3-metyl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-on l-Etyl-5-(2-metoxyfenyl)-3-metyl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-on l-Etyl-3-izopropyl-5-fenyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on
3-terc-Butyl-l-etyl-5-fenyl-6,7-dihydro-lH-pyrazolo[4,3-e] [1.4] diazepin-8-on l-Etyl-3-metyl-5-fenyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on, izomér 1 l-Etyl-3-metyl-5-fenyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-on, izomér 2
3-Metyl-5-fenyl-l-propyl-6,7-dihydro-lH-pyrazolo[4,3-e][1.4] diazepin-8-tion l-Etyl-3-metyl-5-p-tolyl-6,7-dihydro-lH-pyrazolo[4,3-eΙΕ 1 , 4 ] diazepin-8-on
5-(3-Aminofenyl)-l-etyl-3-metyl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-on
3-terc-Butyl-l-etyl-5-fenyl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-tion l-Etyl-3-izopropyl-5-fenyl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-tion
5-(4-Aminofenyl)-3-terc-butyl-l-etyl-6,7-dihydro-lHpyrazolot 4,3-e][1,4]diazepin-8-on
5-(4-Aminofenyl)-l-etyl-3-izopropyl-6,7-dihydro-lHpyrazolo[4,3-e][1,4]diazepin-8-on l-Etyl-5-(4-hydroxyfenyl)-3-metyl-6,7-dihydro-lH-pyrazolo [4,3-e][1,4]diazepin-8-on
5-(4-Aminofenyl)-3-metyl-l-propyl-6,7-dihydro-lH-pyrazolo [4,3-e][1,4]diazepin-8-on
3-Metyl-5-fenyl-1-(2,2,2-trifluóretyl)-6,7-dihydro-lHpyrazolo[4,3-e][l,4]diazepin-8-on
1,5-Dietyl-3-metyl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-on
5-Cyklohexyl-l-etyl-3-metyl-6,7-dihydro-lH-pyrazolo[4,3-e] [1,4]diazepin-8-on l-Etyl-3-metyl-5-pyridin-4-yl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on (±) l-Etyl-3-metyl-5-pyridin-4-yl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-on
5-terc-Butyl-l-etyl-3-metyl-4,5,6,7-tetrahydro-lH-pyrazolo [4,3-e][l,4]diazepin-8-on
5-(4-Dietylaminofenyl)-l-etyl-3-metyl-6,7-dihydro-lH-pytazolo[4,3-e][1,4]diazepin-8-on
3- Butyl-l-etyl-5-fenyl-6,7-dihydro-lH-pyrazolo[4,3-e][1.4] diazepin-8-on
N-[4-(l-Etyl-3-metyl-8-oxo-l,6,7,8-tetrahydropyrazolo[ 4,3-e][1,4]diazepin-5-yl)fenyl]acetamid
4- (l-Etyl-3-metyl-8-oxo-l,6,7,8-tetrahydropyrazolo[4,3-e][1.4] diazepin-5-yl)benzonitril
5- terc-Butyl-l-etyl-3-izopropyl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-on l-Etyl-3-Izopropyl-5-p-tolyl-6,7-dihydro-?lH-pyrazolo[4,3-e][1,4]diazepin-8-on
4- (l-Etyl-3-izopropyl-8-oxo-l ,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitril l-Etyl-3-izopropyl-5- (4-pyrolidin-l-yl-fenyl) -6,7-dihydro -ΙΗ-pyrazolo[4,3-e][l,4]diazepin-8-on
5- (2,4-Dimetoxyfenyl)-l-etyl-3-izopropyl-6,7-dihydro-lHpyrazolo[4,3-e][l,4]diazepin-8-on
5-terc-Butyl-3-izopropyl-l-propyl-6,7-dihydro-lH-pyrazolo [4,3-e][1,4]diazepin-8-on
3- Izopropyl-l-propyl-5-p-tolyl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-on
4- (3-lzopropyl-8-oxo-l-propyl-l,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitril
4- (3-Izopropyl-l-propyl-5-( 4-pyrolidin-l-yl-f enyl)-6,7dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-on
5- (2,4-Dimetoxyfenyl)-3-izopropyl-l-propyl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-on
3,5-Di-terc-Butyl-l-etyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on
3- terc-Butyl-l-etyl-5-p-tolyl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepín-8-on
4- (3-terc-Butyl-l-etyl-8-oxo-l,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitril
3-terc-Butyl-l-etyl-5- (4-pyrolidin-l-yl-f enyl) -6,7-dihydro -lH-pyrazolo[4,3-e][1,4]diazepin-8-on
3-terc-Butyl-5- (2,4-dimetoxy-f enyl)-l-etyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on
3,5-Di-terc-Butyl-l-propyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on
3- terc-Butyl-l-propyl-5-p-tolyl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-on
4- (3-terc-Butyl-8-oxo-l-propyl-l ,6,7,8-tetrahydropyrazolo[ 4,3-e][1,4]diazepin-5-yl)benzonitril
3-terc-Butyl-l-propyl-5- (4-pyrolidin-l-yl-f enyl )-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on
3-terc-Butyl-5- (2,4-dimetoxy-fenyl) -l-propyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on
3-Butyl-l-etyl-5-fenyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4 ] diazepin-8-tion l-Etyl-3-metyl-5-pyridin-3-yl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-on l-Etyl-3-metyl-5-pyridin-2-yl-6,7-dihydro-lH-pyrazolo[4,3—e][1,4]diazepin-8-on l-Etyl-3-metyl-5-fenyl-1,6-dihydropyrazolo[4,3-e][1,4 ] diazepin-8-ylkyánamid
N- [ 4- (l-Etyl-3-metyl-8-oxo-l ,6,7,8-tetrahydropyrazolo-[4,3-e] [l,4]diazepin-5-yl)fenyl] (fenylsulfonyl)benzénsulfónamid (l-Etyl-3-metyl-5-fenyl-1,6-dihydropyrazolo[ 4,3-e] [ 1,4 ]diazepin-8-yl)metylamín l-Etyl-3-izopropyl-5-fenyl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-ylidénkyánamid
3-terc-Butyl-l-etyl-5-f enyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-ylidénkyánamid l-Cyklopentyl-3-metyl-5-fenyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on l-Cyklopropylmetyl-3-metyl-5-fenyl-6,7-dihydro-lH-pyrazolo [4,3-e][l,4]diazepin-8-on l-Cyklobutylmetyl-3-metyl-5-fenyl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-on l-Alyl-3-metyl-5-fenyl-6,7-dihydro-lH-pyrazolo[ 4,3-e ] [ 1,4 ] diazepin-8-on l-Etyl-3-metyl-5- (4-trif Iuórmetylf enyl) -6,7-dihydro-lHpyrazolo[4,3-e][1,4]diazepin-8-on l-Etyl-3-izopropyl-5- (4-trif Iuórmetylf enyl) -6,7-dihydro-ΙΗ-pyrazolo[4,3-e][l,4]diazepin-8-on
3-terc-Butyl-l-etyl-5-(4-trifIuórmetylfenyl)-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on
3-Izopropyl-l-propyl-5-p-tolyl-6,7-dihydro-lH-pyrazolo-[4,3-e][1,4]diazepin-8-tion
3,5-Di-terc-butyl-l-propyl-6,7-dihydro-lH-pyrazolo[4,3-e] [1,4]diazepin-8-tion
5-terc-Butyl-3-izopropyl-l-propyl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-tion l-Etyl-3-izopropyl-5-p-tolyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-tion
5-terc-Butyl-l-etyl-3-izopropyl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-tion (+) 3-sek-Butyl-l-etyl-5-fenyl-6,7-dihydro -lH-pyrazolo[4,3-e][l,4]diazepin-8-on (±) 3-sek-Butyl-l-etyl-5-pyridin-4-yl-6,7-dihydro-lHpyrazolo[4,3-e][1,4]diazepin-8-on (±) 3-sek-Butyl-l-fenyl-l-propyl-4-yl-6,7-dihydro-lHpyrazolo[4,3-e][1,4]diazepin-8-on (±) 3-sek-Butyl-l-propyl-5-pyridin-4-yl-6,7-dihydro-lHpyrazolo[4,3-e][1,4]diazepin-8-on
3-Cyklohexyl-l-etyl-5-fenyl-4-yl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-on
3-Cyklohexyl-l-etyl-5-pyridin-4-yl-6,7-dihydro-lH-pyrazolo [4,3-e][i,4]diazepin-8-on
3-Cyklohexyl-5-fenyl-l-propyl-4-yl-6,7-dihydro-lH-pyrazolo [4,3-e][1,4]diazepin-8-on
3-Cyklohexyl-l-propyl-5-pyridin-4-yl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-on
3-Cyklohexylmetyl-l-etyl-5-pyridin-4-yl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on
3-Cyklohexylmetyl-5-f enyl-l-propyl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-on
3-Cyklohexylmetyl-l-propyl-5-pyridin-4-yl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on
3-Cyklohexylmetyl-l-etyl-5-fenyl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-on
Etylester l-etyl-8-oxo-5-fenyl-1,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepín-3-karboxylovéj kyseliny
5-terc-Butyl-l-etyl-3-izopropyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-ylidénkyánamid l-Etyl-3-izopropyl-5-p-tolyl-6,7-dihydro-lH-pyrazolo-[4,3-e][1,4]diazepin-8-ylidénkyánamid l-Etyl-3-izopropyl-5-(4-metoxyfenyl)-6,7-dihydro-lH-pyrazolo [4,3-e][1,4]diazepin-8-on l-Etyl-5-(4-metoxyfenyl)-3-metyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-tion l-Etyl-5-(4-metoxyfenyl)-3-metyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-ylidénkyánamid
3-Izopropyl-5- (4-metoxy-f enyl) -l-propyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]dia zepin-8-on
3-terc-Butyl-l-etyl-5- (4-metoxyf enyl) -6,7-dihydro-lHpyrazolo[4,3-e][1,4]diazepin-8-on
3-terc-Butyl-5- (4-metoxyf enyl) -l-propyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on l-Etyl-5- (4-hydroxyf enyl) -3-metyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-ylidénkyánamid (+) 3-sek-Butyl-l-etyl-5- (4-metoxyf enyl) -6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on (±) 3-sek-Butyl-5-(4-metoxyfenyl)-l-propyl-6,7-dihydro-ΙΗ-pyrazolo[4,3-e][l,4]diazepin-8-on l-Etyl-3-metyl-5-(3,4,5-trimetoxyfenyl)-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on l-Etyl-5-(3-hydroxyfenyl)-3-metyl-6,7-dihydro-lH-pyrazolo [4,3-e][l,4]diazepin-8-on l-Etyl-5-(2-hydroxyfenyl)-3-metyl-6,7-dihydro-lH-pyrazolo [4,3-e][l,4]diazepin-8-on l-Etyl-3-metyl-5-(2,3,4-trimetoxyfenyl)-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-on l-Etyl-3,5-Difenyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on l-Etyl-5-(4-hydroxyfenyl)-3-izopropyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on
5-(3-Hydroxyfenyl)-3-izopropyl-l-propyl-6,7-dihydro-ΙΗ-pyrazolo[4,3-e][1,4]diazepin-8-on
3-terc-Butyl-l-etyl-5-(4-hydroxyfenyl)-3-metyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on
5- (2,6-Dimetoxy-fenyl) -l-etyl-3-metyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on
3-Etoxymetyl-l-etyl-5-fenyl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-on
Sú preferované zlúčeniny ako substituované pyrazolo[4,3-e]diazepíny, konkrétnejšie potom nasledujúce zlúčeniny:
l-Etyl-3-izopropyl-5-fenyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on
3- terc-Butyl-l-etyl-5-fenyl-6,7-dihydro-lH-pyrazolo[4,3-e][1.4] diazepin-8-on l-Etyl-3-izopropyl-5-fenyl-6,7-dihydro-lH-pyrazolo[4,3-e][1.4] diazepin-8-tion
5-(4-Aminofenyl)-l-etyl-3-izopropyl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-on l-Etyl-5-(4-hydroxyfenyl)-3-metyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on
4- (l-Etyl-3-izopropyl-8-oxo-l,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitril
5-terc-Butyl-3-izopropyl-l-propyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on
4-(3-Izopropyl-8-oxo-l-propyl-l,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-5-ylJbenzonitril
3-terc-Butyl-l-etyl-5-p-tolyl-6,7-dihydro-lH-pyrazolo[4,3-e][l,4]diazepin-8-on
3-Butyl-l-etyl-5-fenyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-tion (±) 3-sek-Butyl-l-etyl-5-pyridin-4-yl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on (±) 3-sek-Butyl-l-propyl-5-pyridin-4-yl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on
3-Cyklohexyl-l-propyl-5-pyridin-4-yl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on
3-terc-Butyl-5-(4-metoxyfenyl)-l-propyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on l-Etyl-5-( 2-hydroxy-fenyl)-3-metyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on
3-terc-Butyl-l-etyl-5-(4-hydroxyfenyl)-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-on
1-Etyl-3-Izopropyl-5-fenyl-6,7-dihydro-lH-pyrazolo[4,3-e][1,4]diazepin-8-ylidénkyánamid
Podlá použitia definovaného hore je liek vo forme vhodnej na systémové alebo miestne podanie.
Liek môže byť upravený na inhalačné podanie a môže byt teda vo forme prášku alebo spreje.
Systémové podanie je preferované na liečbu ochorení, ako sú napríklad roztrúsená skleróza, diabetes, alergická a autoimunitná encefalomyelitída.
Inhibítory PDE4 použité v predkladanom vynáleze zahŕňajú solváty, hydráty a ich farmaceutický prijateľné soli.
Tam, kde je vhodné pripraviť soľ, zahŕňajú farmaceutický prijateľné soli acetát, benzénsulfonát, benzoát, bitartarát, kalciumacetát, kamzylát, karbonát, citrát, edetát, edizylát, estolát, ezylát, fumarát, gluceptát, glukonát, glutamát, glykoloylarsanilát, hexylresorcinát, hydrabamín, hydrobromid, hydrochlorid, hydrogenkarbonát, hydroxynaftoát, jodid, izetionát, laktát, laktobionát, malát, maleát, mandelát, mezylát, metylnitrát, metylsulfát, mucát, napzylát, nitrát, pamoát (embonát), pantotenát, fosfát/difosfát, polygalakturonát, salicylát, stearát, subacetát, sukcinát alebo hemi-sukcinát, sulfát alebo hemi-sulfát, tanát, tartarát alebo hemi-tartarát, teoklát, trietijodid, benzatin, chloroprokaín, hliník, amónium, tetrametylamónium, kalcium, lítium, magnézium, draslík, sodík a zinok. (Pozri tiež Farmaceutické soli, autorov Berge S.M. et al. (1997), J. Pharm. Sci., 66, 1-19, táto práce je týmto začlenená ako referencia).
Ďalší cieľ vynálezu zahŕňa farmaceutický preparát na prevenciu alebo liečbu ochorení združených s nadmernou produkciou IL-12 obsahujúceho účinné množstvo aspoň jedného inhibítoru fosfodiesterázy E4 (PDE4) alebo jeho farmaceutický prijateľnej soli v kombinácii s aspoň jedným farmaceutický prijateľným nosičom.
Výraz účinné množstvo inhibítoru PDE4 znamená podía vynálezu množstvo PDE4 inhibítoru v dávkovej jednotke umožňujúcej podanie od asi 2 mg do asi 1000 mg inhibítoru PDE4 denne dospelému pacientovi s normálnou hmotnosťou (tzn. 70 kg).
Prednostné inhibítory PDE4 na použitie vo farmaceutickom preparáte podía vynálezu sú také, ktoré sú definované hore v špecifikáciách.
Farmaceutický preparát podía vynálezu môže zahŕňať kombináciu dvoch alebo viacerých inhibítorov PDE4, prednostne od 2 do 4 a naj prednostnej š ie od 2 do 3 inhibítorov PDE4.
Farmaceutický preparát podía vynálezu je vo forme vhodnej na systémové alebo miestne podanie.
Farmaceutické preparáty inhibítoru PDE4 podía predkladaného vynálezu vrátane jednej z jeho solí sú produkované formuláciou tejto aktívnej zložky v dávkovej jednotkovej forme s aspoň jedným farmaceutický prijateíným nosičom alebo excipientom. Na prípravu farmaceutických preparátov z inhibítoru PDE4 použitého v tomto vynáleze môžu byť použité inertné, farmaceutický prijateíné nosiče búd v pevnej alebo tekutej forme.
Pevné dávkové formy na perorálne podanie zahŕňajú kapsuly tablety, prášky a granuly. V takých pevných dávkových formách je inhibítor PDE4 zmiešaný s aspoň jednou bežnou excipientnou látkou (alebo nosičom), ako sú napríklad citrát sodný alebo dikalcium fosfát alebo a) plniace alebo extendujúce látky, ako sú napríklad škroby, laktóza, sacharóza, glukóza, manitol a siliková kyselina, b) väzbové látky, ako sú napríklad karboxymetylcelulóza, algináty, želatína, polyvinylpyrolidón, sacharóza a akácia, c) zvlhčujúce látky, ako je napríklad glycerol, d) dezintegračné látky, ako sú napríklad agar-agar, kalcium karbonát, zemiakový a tapiokový škrob, kyselina algí41 nová, určité komplexné silikáty a karbonát sodný, e) látky spomalujúce roztoky, ako je napríklad parafín, f) látky urychĺújúce absorpciu, ako sú napríklad kvartérne amóniové zlúčeniny, g) zvlhčujúce látky, ako sú napríklad cetylalkohol a glycerolmonostearát, h) adsorpčné látky, ako sú napríklad kaolín a bentonit, a i) lubrikačné látky, ako sú napríklad talk, kalciumstearát, magnéziumstearát, pevné polyetylénové glykoly, laurylsulfát sodný alebo jeho zmesi. V prípade kapsúl tabliet a piluliek môžu dávkové formy obsahovať tiež tlmivé látky.
Pevné preparáty podobného typu môžu byť použité tiež ako plniace látky v mäkkých a tvrdých želatínových kapsulách pri použití excipientných látok, ako je laktóza rovnako ako vysokomolekulárne polyetylénglykoly a podobne.
Pevné dávkové formy, ako sú napríklad tablety, dražé, kapsuly, pilulky a granuly môžu byť pripravené potiahnuté a s obalmi, ako sú napríklad enterické a iné poťahy známe v odbore. Môžu mať tiež také zloženie, že uvolňujú s oneskorením inhibítor PDE4 v určitej časti črevového traktu. Polymérne látky a vosky sú príkladmi zapúzdrujúcich zložiek. Aktívna zložka môže byť tiež v mikroenkapsulovanej forme, pokial je to vhodné, s jednou alebo viacerými z hore uvedených excipientných látok.
Tekuté dávkové formy na perorálne podanie zahŕňajú farma ceuticky prijatelné emulzie, roztoky, suspenzie, sirupy a eli· xíry. Tekuté dávkové formy môžu navyše k inhibítoru PDE4 obsa hovať inertné riediace látky bežne používané v odbore, ako sú napríklad voda alebo iné rozpúšťadlá, solubilizačné látky a emulzifikujúce látky, ako sú napríklad etylalkohol, izopropyl alkohol, etylkarbonát, etylacetát, benzylalkohol a podobne.
Suspenzie môžu navyše k inhibítoru PDE4 obsahovať suspendujúce látky, ako sú napríklad etoxylované izostearylalkoholy, polyoxyetylénsorbitol a sorbitanestery, mikrokryštalickú celulózu, alumínium metahydroxid, bentonit, agar-agar a tragakant, alebo zmesi týchto látok a podobne.
Preparáty na rektálne podanie sú prednostne čapíky, ktoré môžu byt pripravené zmiešaním zlúčeniny, ktorá je predmetom predkladaného vynálezu s vhodnými neiritujúcimi excipientnými látkami alebo nosičmi, ako sú napríklad kakaové maslo, polyetylénglykol alebo vosk pre čapíky, ktoré sú v pevnej forme pri bežných teplotách, ale tekuté pri teplote tela a preto sa rozpúšťajú v rekte a uvolňujú aktívnu zložku.
Preparáty vhodné na parenterálne injekcie môžu obsahovať fyziologicky prijateíné sterilné vodné a nevodné roztoky, disperzie, suspenzie alebo emulzie, a sterilné prášky na rekonštitúciu v sterilných injekčných roztokoch alebo disperziách. Príklady vhodných tekutých nosičov, riediacich látok, rozpúšťacích látok alebo vehikul zahŕňajú vodu, etanol, polyoly (propylénglykol, polyetylénglykol, glycerol a podobne), a ich vhodné zmesi.
Tieto preparáty môžu tiež obsahovať adjuvansové látky, ako sú napríklad konzervačné, zvlhčujúce, emulzifikujúce a dispergujúce látky. Prevencia pred účinkami mikroorganizmov môže byť dosiahnutá rôznymi antibakteriálnymi a antifungáInými látkami, napríklad parabénmi, chlórbutanolom, fenolom, kyselinou sorbovou a podobne. Môže byt tiež žiadúce použiť izotonické látky, napríklad cukry, chlorid sodný a podobne.
Farmaceutický preparát je prednostne v jednotkovej dávkovacej forme. V takejto forme je preparát rozdelený do jednotkových dávok obsahujúcich príslušné množstvá inhibítoru PDE4. Jednotková dávková forma môže byť balený preparát, ba43 lenie obsahujúce diskrétne kvantity preparátu, napríklad balené tablety, kapsuly a prášky vo vialkách alebo v ampulách. Jednotková dávková forma môže byť tiež kapsula, tobolka alebo samotná tableta, alebo sa môže ísť o príslušné množstvo týchto balených foriem. Niektorými príkladmi dávkovacích jednotkových foriem sú tablety, kapsuly, pilulky, prášky, čapíky, vodné a nevodné perorálne roztoky a suspenzie, a parenterálne roztoky balené v nádobkách obsahujúcich bučí jednu alebo väčší počet dávkovacích jednotiek, ktoré môžu byť rozdelené do jednotlivých dávok.
Percento aktívnej zložky v predchádzajúcich preparátoch sa môže líšiť v širokom rozmedzí, ale z praktických účelov je aktívna zložka prednostne prítomná v koncentrácii aspoň 10 % v pevnom preparáte a aspoň 2 % v primárnom tekutom preparáte. Najlepšie preparáty sú také, v ktorých je prítomný oveía vyšší podiel aktívnej zložky, napríklad od 10 % do 90 % hmotnostných .
Vynález sa tiež týka spôsobu prevencie a/alebo liečby ochorení združených s nadmernou produkciou IL-12 zahŕňajúceho podanie účinného množstva aspoň jedného inhibítoru PDE4 alebo jeho farmaceutický prijateínej soli jedincovi potrebujúcemu túto liečbu. Výsledky experimentov skutočne ukazujú, že:
- Inhibítory PDE4 majú priamy efekt na buď nezrelé alebo zrelé DC bunky prostredníctvom inhibície produkcie IL-12p70 a ďalších zápalových cytokínov, ako sú napríklad TNF-α a do určitej miery IL-6.
- Inhibítory PDE4 inak nemodifikujú fenotyp týchto buniek.
- Prostredníctvom priameho inhibičného efektu inhibítorov PDE4 na tvorbu cytokínov bunkami DC je rovnováha Th-l verzus Th-2 diferenciácie naivných T buniek posunutá v smere Th-2 v neprospech Th-1 buniek.
Termín ''pacient” zahŕňa cicavca, predovšetkým človeka.
Všetko, čo je vyžadované na uskutočnenie spôsobu prevencie a liečby ochorení združených s nadmernou tvorbou IL-12 podlá predkladaného vynálezu, je podať aspoň jeden inhibítor PDE4 v množstve, ktoré je účinné na prevenciu alebo liečbu patologického stavu. Účinné množstvo inhibítoru PDE4, ktoré má byť použité, bude všeobecne od asi 2 mg do asi 1000 mg za deň pri dospelom pacientovi s normálnou hmotnosťou (tzn.
kg).
Vynález je ďalej ilustrovaný bez toho, aby bol obmedzený, príkladmi uvedenými ďalej.
Príklady uskutočnenia vvnálezu
Materiál a metodika
Cytokiny a činidlá
Inhibítory PDE4 Rolipram, Diazepino-indol, Pyrazolo[4,3-e]diazepín a Ariflo sú udržované ako 0,1 M rezervné roztoky v DMSO, uložené pri teplote -20’C a nariedené do kompletného média tesne pred použitím. Konečné riedenie l:104 pomocou DMSO je použité ako kontrola vehikulá vo všetkých experimentoch.
Ľudský rGM-CSF (špecifická aktivita (SA) 1,5 x 107 U/mg), a íudský rIL-4 (SA 2,9 x 107 U/mg, íudský rIFN-y^ (SA 2 x 107 U/mg) boli získané od spoločnosti RD Systems Európe (Oxon, Veíká Británia).
Vznik dendritických buniek (DC) z monocytov periférnej krvi
Venózna krv od zdravých darcov je odobraná venepunkciou do skúmaviek obsahujúcich heparín sodný (VT100H, Venoject, Terumo Európe, Leuven, Belgia). Mononukleárne bunky periférnej krvi (PBMC) sú izolované denzitnou centrifugáciou na Lamfoprepe (Nycomed, Torshov, Norsko). Následne sú PBMC centrifugované na Percoll (Pharmacia, Uppsala, Švédsko) gradiente tvorenom tromi denzitnými vrstvami (1,076, 1,059 a 1,045 g/ml). Ľahká denzitná frakcia plávajúca v strednej vrstve, ktorá obsahuje prevážne monocyty, je umiestnená do 24-jamkovéj kultivačnej doštičky (Costar, Cambridge, MA) pri denzite 5 x 105 buniek/jamku. Po 30 minútach inkubácie pri teplote 37°C sú odstránené neadherujúce bunky, adherujúce bunky sú kultivované v Iscovovom modifikovanom Dulbeccovom médie (Life Technologies, Paisley, Velká Británia) obsahujúcom gentamycín (86 μg/ml, Duchefa, Haarlem, Holandsko) a 1 % FCS (Hyclone, Logan UT) a suplementovanom GM-CSF (500 U/ml) a IL-4 (250 U/ml), aby mohli byť získané DC. Tretí deň sú médiá vrátane suplementačných látok obnovené. Šiesty deň sú získané nezrelé CDla+CD14” DC bunky.
V niektorých experimentoch sú monocyty purifikované z PBMC negatívnym výberom pri použití kitu na izoláciu monocytov (Miltenyi Biotec, Bergisch Gladbach, Nemecko). Získaná frakcia monocytov je potom spracovaná na in vitro kultiváciu v RPMI-1640 (Life Technologies, Paisley, Velká Británia) a obsahuje 10 % FCS, 1 % neesenciálnych aminokyselín, pyruvát sodný, 100 μg/ml kanamycínu (všetko od Life Technologies, Paisley, Velká Británia) a je suplementovaná rhGM-CSF (500 U/ml) a rh-IL-4 (250 U/ml) od spoločnosti RD Systems Európe, Oxon, Velká Británia. Tretí deň sú médiá vrátane suplementačných látok obnovené.
V obidvoch protokoloch sú získané podobné preparáty nezrelých CDla+CD14“ DC buniek.
Indukcia vyzrievania DC v prítomnosti alebo za absencie inhibítorov PDE4
Šiesty deň bolo vyvolané vyzrievanie CDla+ DC buniek dvojdennou expozíciou budf LPS (250 ng/ml, Difco, Detroit, MI), alebo kombináciou cytokínov rhIL-Ιβ (10 ng/ml) a TNF-a (25 ng/ml), získaných od Pharma Biotechnológie, Hannover, Nemecko. Vyzrievanie bolo indukované za absencie alebo v prítomnosti inhibítorov PDE4 (10 μΜ, keď to nie je uvedené inak), alebo PGE2 ( 106 M, Sigma, St. Louis, MA). Kde je indikované, boli DC bunky udržované za nevyzrievajúcich podmienok počas 2 dní.
Indukcia sekrécie cytokínov zrelými DC
8. deň boli zrelé DC bunky zobrané, extenzívne premyté a 2xl04 buniek/200 μΐ bolo stimulovaných pomocou CD40L-transfektovanej J558 bunkovej línie (2xl04 buniek/jamku) za absencie alebo v prítomnosti IFN-^flo3 U/ml) v 96-jamkových kultivačných doštičkách s plochým dnom (Costar, Cambridge, MA) v IMDM obsahujúcom 10% FCS. Supernatanty boli zberané po 24 hodinách a uskladnené pri teplote -20’C na stanovenie hladín IL-12p70 a TNF-α pomocou ELISA testu.
Analýza expresie molekúl bunkového povrchu pomocou prietokovej cytometrie
Boli použité nasledujúce myšie monoklonálne protilátky proti nasledujúcim ludským molekulám: CDla (OKT6, Ortho Diagnostic System, Beerse, Belgia), ICAM-1, CD86 (Pharmingen, San Diego, CA), CD83 (HB15a, IgG2b, Imunotech, Marseille, Francia) s následnou FITC-konjugovanou kozou anti-myšou monoklonálnou protilátkou (Jackson Immunoresearch Laboratories, West Grove, PA).
Meranie cytokínov
Merania hladín IL-12p70 v supernatantoch kultúr boli vykonaná špecifickým sendvičovým ELISA testom na pevnej fáze OptEIA^™) s ľudským IL-12p70 (Pharmingen San Diego, CA). Merania IL-6 a TNF-α boli uskutočnené pri použití párov špecifických monoklonáIných protilátok a rekombinantných cytokino/ých štandardov od spoločnosti BioSource International (Camarillo, CA). Detekčné limity týchto ELISA stanovení boli nasledujúce: IL-6, 20 pg/ml, IL-12p70, 3 pg/ml a TNF-a, pg/ml.
Izolácia CD4+ CD45RA+ CD45RO“ naivných T buniek, ko-kultúr s DC bunkami a indukcia pamäťových cytokínov vo vyzrievajúcich Th bunkách
Naivné Th bunky (ThN) boli izolované z leukocytov periférnej krvi kitom s negatívnou selekčnou ľudskou CD4+/CD45RO kolónkou (RD Systems Európe, Oxon, UK). Metóda viedla podľa prietokovej cytometrie k zisku vysoko purifikovaných (viac ako 98%) CD4+ CD45RA+ CD45RO“ ThN buniek. DC bunky, ktoré boli vyzrievané pomocou rhIL-Ιβ a TNFa, ako je opísané v odseku Indukcia vyzrievania DC v prítomnosti inhibítorov PDE4, boli extenzívne premývané, aby sa odstránili reziduálne inhibítory. ThN bunky (20000 buniek/jamku) boli ko-kultivované v 96-jamkových kultivačných jamkách s plochým dnom s 10000 DC na jamku v prítomnosti 1 ng/ml SEB. Piaty deň bol pridaný IL-2 (10 U/ml) a kultúry boli kultivované počas ďalších 9 dní. 14. deň boli zberané pokojové pamäťové Th bunky, premyté a restimulované počas 6 hodín pomocou 10 ng/ml PMA, 1 μg/ml ionomycínu a 10 μ9/πι1 Brefeldinu A (všetko od spoločnosti Sigma). Bunky boli fixované 4% paraformaldehydom permealizované pomocou PBS obsahujúcom BSA (0,5%) a saponín (0,5%), ofarbené monoklonálnymi protilátkami anti-IFN-α označenými pomocou FITC a anti-IL-4 označenými pomocou PE (Becton Dickinson) a analyzované pomocou
FACScan (Becton Dickinson).
Experimenty boli uskutočnené podlá techník opísaných hore v sekcii Materiál a Metodiky.
Príklad 1
Priamy efekt inhibítorov PDE4 na sekréciu cytokínov nezrelými dendritickými bunkami (DC)
Produkcia IL-12 DC bunkami môže byt indukovaná faktormi, ako napríklad LPS spolu s IFN-^ alebo ligáciou CD40 po kontakte CD40L-exprimujících T buniek.
Ako je uvedené na obrázku 1, nezrelé DC bunky stimulované pomocou LPS a IFN-X'v prítomnosti Rolipramu alebo Ariflo vykázali v porovnaní s DC bunkami v prostredí DMSO zníženú schopnosť produkovať IL-12p70 a TNF-α. Na druhej stranu nebola produkcia IL-6 nezrelými DC bunkami ovplyvnená žiadnym z inhibítorov.
Tento príklad teda demonštruje, že inhibítory PDE4 majú priamy efekt na dendritické bunky významným znížením sekrécie ich cytokínov.
Príklad 2
Porovnanie priameho efektu niekolkých inhibítorov PDE4 na sekréciu IL-12p70 nezrelými dendritickými bunkami
Produkcia IL-12 dendritickými bunkami bola stimulovaná s bunkami J558-CD40L za absencie akéhokolvek inhibítoru PDE alebo v prítomnosti 10 μΜ inhibítorov PDE4 (Ariflo, Rolipram, Diazepino-indol alebo Pyrazolo[4,3-e]diazepín). Údaje na obrázku 2 ukazujú, že všetky testované inhibítory PDE4 boli schopné inhibovať produkciu IL-12 stimulovanými dendritickými bunkami s inhibičnou aktivitou rovnakého radu.
Príklad 3
Prítomnosť inhibítorov PDE4 počas vyzrievania DC buniek nenarušuje fenotyp zrelých DC buniek
Proces vyzrievania DC buniek je spojený s objavením sa CD83 a spätne väzbovým zvýšením regulácie ko-stimulačných molekúl ako je CD86. Aby bolo možné zistiť, či by prítomnosť inhibítorov PDE4 počas vyzrievania DC buniek mohla ovplyvniť expresiu DC združeného markéru CDla, ko-stimulačných molekúl CD86 a ICAM-1 a DC maturačného markéru CD83 na bunkovom povrchu, bola vykonaná štúdia expresie týchto markérov po liečbe.
Ako je uvedené na obrázkoch 3A, neovplyvnila liečba inhibítorom PDE4 počas 2 dní expresiu povrchových molekúl indukovaných vyzrievacími faktormi (TNF-α plus IL-Ιβ, označovaných ako MF) alebo pomocou LPS v porovnaní s kontrolnými zrelými DC bunkami liečenými vehikulom. Výsledky teda ukazujú, že hoci inhibítory PDE4 modulujú tvorbu cytokinov DC bunkami, nezabránili tieto inhibítory ich fenotypovej maturácii indukovanej zápalovými cytokinmi alebo LPS.
Príklad 4
Efekt liečby inhibítorom PDE4 počas vyzrievania DC buniek na ich následnú sekréciu cytokinov
Bol študovaný účinok liečby DC buniek inhibítorom PDE4 iba počas ich in vitro vyzrievaní na ich schopnost produkovať cytokiny po následnej stimulácii. Ako kontrola bol použitý PDE2. Vyzrievanie DC buniek bolo indukované kombináciou zápa50 lových cytokínov (TNF-α plus IL-Ιβ) za absencie alebo v prítomnosti inhibítorov PDE4.
Ako je uvedené na obrázku 4, DC bunky vyzrievané v prítomnosti IL-Ιβ plus TNF-α a ďalej v prítomnosti inhibítorov PDE4 vykazovali zníženú kapacitu produkovať IL-12p70 a TNF-a (medzi 40-60 % inhibície) po následnej stimulácii J558-transfektovaných CD40L buniek.
Uvedeným experimentom bolo preukázané, že DC bunky vyzrievané v prítomnosti inhibítorov PDE4 inhibovali (ako je uvedeno na obr. 4) produkciu IL-6.
Príklad 5
Účinok inhibítorov PDE4 na diferenciáciu naivných T buniek
Experimenty boli vykonané podlá techník opísaných hore v sekcii Materiál a Metodika.
Naivné Th bunky (ThN) boli izolované z ludských leukocytov periférnej krvi a ko-kultivované s dendritickými bunkami vyzrievanými v prítomnosti rôznych inhibítorov PDE4. Diferenciácia naivných Th buniek na Thl a Th2 bola vizualizovaná intracelulárnym farbením T buniek značenými anti IFN- a anti IL-4 monoklonálnymi protilátkami a prietokovou cytometriou.
Inhibítory PDE4 boli pridané počas vyzrievaní dendritických buniek (DC) v prítomnosti IL-Ιβ plus TNF-α a (vyzrievacie faktory alebo MF). Po dvoch dňoch vyzrievania boli dendritické bunky premyté a použité na priming naivných T buniek.
Diferenciácia na Thr/Th2 bola hodnotená intracelulárnym farbením IFN-^pozitívnych a IL4 pozitívnych buniek a vyjadrená ako percentá pozitívnych buniek.
Výsledky sú uvedené v nasledujúcej tabulke 1
Tabulka 1
Experiment 1 Experiment 2 Experiment 3
IFN-}' (%) IL-4 (%) | IFN-^(%) IL-4 (%) | IFN-^(%) IL-4 (%) | ||||
MF-DC- DMSO | 14,1 | 12,6 | 42,5 | 0,9 | 37,7 | 1,7 |
MF-DC- Ariflo (10 μΜ) | 4,7 | 15,1 | 29,6 | 2,0 | 24,0 | 6,2 |
Mf-DC- | 7,2 | 13,5 | 35,4 | 1,1 | 24,5 | 5,7 |
Rolipram (10 μΜ)
Ako je vidieť v tabulke 1, vyzrievanie dendritických buniek v prítomnosti inhibítorov PDE4 podporilo diferenciáciu naivných T buniek do fenotypu podobnému Th2, ako bolo preukázané intracelulárnym IFN//IL4 farbením.
Priama aktivita inhibítorov PDE4 na dendritické bunky indukuje presnejšie zníženie tvorby IFN v Thl populácii.
Tieto výsledky ukazujú, že inhibítory PDE4 modulujú póla rizačnú kapacitu dendritických buniek a teda, že inhibítory PDE4 sú vysoko užitočné v liečbe akýchkolvek ochorení zahŕňajúcich tvorbu IL-12 dendritickými bunkami, a kde je produkované nežiadúce množstvo T buniek Th-1 typu.
Claims (8)
- PATENTOVÉ NÁROKY1. Použitie aspoň jedného inhibítoru PDE4 alebo jeho farmaceutický prijatelnej soli na výrobu lieku na prevenciu a/alebo liečbu ochorení združených s nadmernou tvorbou IL-12.
- 2. Použitie podlá patentového nároku 1, kde inhibítor PDE4 je vybraný zo skupiny obsahujúcej Rolipram, Ariflo, Diazepino-indolové zlúčeniny, prednostne [1,4]diazepino[6,7,1-Ai]indoly, l-aminotriazolo[4,3-a]chinazolin-5-ony a/alebo -5-tionové zlúčeniny, substituované pyrazolo[4,3-e]diazepíny a ich metabolity.
- 3. Použitie podlá akéhokolvek z patentových nárokov 1 a 2, kde ochorenie je vybrané zo skupiny obsahujúcej zápalové patologické stavy postihujúce priedušky, ako je napríklad bronchokonstrikcia, mnohopočetné orgánové zlyhanie, osteoartróza, septický šok (septikémia), zápalové choroby alebo poruchy, (chronické) zápalové ochorenia zažívacieho systému vrátane čreva (hemoragická rektokolitída, ulcerózna kolitída, nešpecifické črevové zápaly) s autoimunitnou zložkou, chronická lymfatická leukémia, pečeňové zlyhanie zahŕňajúce zlyhanie po následnom imunologickom a zápalovom pečeňovom poškodení, rejekcia štepu, Crohnova choroba, chronická obštrukčná bronchopneumoptia (chronická bronchitída, emfyzém, chronická obštrukčná choroba bronchopulmonálna), akútna plúcna príhoda, nervové poškodenie vyvolané ischémiou, ochorenia spôsobené reperfúznou ischémiou so vzťahom k vysokým hladinám TNF-a, akútny respiračný distress syndróm, akútna pankreatitída, autoimunitné demyelinizačné ochorenie, roztrúsená skleróza, diabetes I. typu, chronická/relabujúca alergická encefalomyelitída, autoimunitná encefalomyelitxda, zápalová kolitída, artritída zahŕňajúca reumatoidnú artritídu, sarkoidóza, hypersenzitivná pneumonitída, autoimunitná uveitída, nešpeci54 fické črevové zápaly, psoriáza, ekzém, kontaktná dermatitída, rovnako tak ako dalšie ludské ochorenia sprostredkované Th-1.
- 4. Použitie podía akéhokolvek z patentových nárokov 1 a 3, kde liek je vo forme vhodnej na systémové alebo lokálne podanie.
- 5. Farmaceutický preparát na prevenciu a/alebo liečbu ochorení združených s nadmernou tvorbou IL-12 obsahujúci účinné množstvo aspoň jedného inhibítoru fosfodiesterázy E4 (PDE4) alebo jeho farmaceutický prijatelnú sol v kombinácii s aspoň jedným farmaceutický prijateľným nosičom.
- 6. Farmaceutický preparát podlá patentového nároku 5, kde inhibítor PDE4 je vybraný zo skupiny obsahujúcej Rolipram, Ariflo, Diazepino-indolové zlúčeniny, prednostne [1,4]diazepino[6,7,l-hi]indoly, l-aminotriazolo[4,3-a]chinazolin-5-ony a/alebo -5-tionové zlúčeniny, substituované pyrazolo[4,3-e]diazepíny a ich metabolity.
- 7. Farmaceutický preparát podlá akéhokolvek z patentových nárokov 5 alebo 6 na prevenciu alebo liečbu ochorení vybraných zo skupiny obsahujúcej zápalové patologické stavy postihujúce priedušky, ako je napríklad bronchokonstrikcia, mnohopočetné orgánové zlyhanie, osteoartróza, septický šok (septikémia), zápalové choroby alebo poruchy, (chronické) zápalové ochorenia zažívacieho systému vrátane čreva (hemoragická rektokolitída, ulcerózna kolitída, nešpecifické črevové zápaly) s autoimunitnou zložkou, chronická lymfatická leukémia, pečeňové zlyhanie zahŕňajúce zlyhanie po následnom imunologickom a zápalovom pečeňovom poškodení, rejekcia štepu, Crohnova choroba, chronická obštrukčná bronchopneumoptia (chronická bronchitída, emfyzém, chronická obštrukčná choroba bronchopulmonálna), akútna plúcna príhoda, nervové poškodenie vyvolané ischémiou, ochorenia spôsobené reperfúznou ischémiou so vzťahom k vysokým hladinám TNF-α, akútny respiračný distress syndróm, akútna pankreatitída, autoimunitné demyelinizačné ochorenie, roztrúsená skleróza, diabetes I. typu, chronická/relabujúca alergická encefalomyelitída, autoimunitná encefalomyelitída, zápalová kolitída, artritída zahŕňajúca reumatoidnú artritídu, sarkoidóza, hypersenzitivná pneumonitída, autoimunitná uveitída, nešpecifické črevové zápaly, psoriáza, ekzém, kontaktná dermatitída, rovnako tak ako ďalšie ľudské ochorenia sprostredkované Th-1.
- 8. Farmaceutický preparát podľa akéhokoľvek z patentových nárokov 5 alebo 6, ktorý je vo forme vhodnej na systémové alebo lokálne podanie.
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EP00402560A EP1188438A1 (en) | 2000-09-15 | 2000-09-15 | Pharmaceutical composition for preventing or treating a disease associated with an excess of Il-12 production |
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KR (1) | KR20020021606A (sk) |
CN (1) | CN1348763A (sk) |
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CA2501940A1 (en) * | 2002-10-09 | 2004-04-22 | Tolerrx, Inc. | Molecules preferentially associated with effector t cells or regulatory t cells and methods of their use |
CN101547922B (zh) | 2006-10-04 | 2012-06-20 | 辉瑞产品公司 | 作为钙受体拮抗剂的吡啶并[4,3-d]嘧啶-4(3H)-酮衍生物 |
JP5509099B2 (ja) | 2008-03-07 | 2014-06-04 | アジェンデ・キミケ・リウニテ・アンジェリニ・フランチェスコ・ア・チ・エレ・ア・エフェ・ソシエタ・ペル・アチオニ | 新規な1−ベンジル−3−ヒドロキシメチルインダゾール誘導体並びにそのMCP−1、CX3CR1およびp40の発現に基づく疾患の治療への使用 |
US8461194B2 (en) | 2008-03-07 | 2013-06-11 | Aziende Chimiche Riunite Angelini Francesco A. C. R. A. F. S. P. A. | 1-benzyl-3-hydroxymethylindazole derivatives and use thereof in the treatment of diseases based on the expression of MCP-1, CX3CR1 and P40 |
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FR2725719B1 (fr) * | 1994-10-14 | 1996-12-06 | Jouveinal Inst Rech | Diazepino-indoles inhibiteurs de phosphodiesterases iv |
WO1996036626A1 (de) * | 1995-05-18 | 1996-11-21 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Cyclohexyldihydrobenzofurane |
FR2746800B1 (fr) * | 1996-03-29 | 1998-06-05 | Jouveinal Inst Rech | Diazepino-indoles inhibiteurs de phosphodiesterases 4 |
ATE256476T1 (de) * | 1996-11-15 | 2004-01-15 | Kennedy Inst Of Rheumatology | Unterdrückung von tnfalpha und il-12 in der therapie |
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FR2776660B1 (fr) * | 1998-03-27 | 2000-05-12 | Parke Davis | Diazepino-indoles de phosphodiesterases iv |
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- 2001-09-14 PL PL01349682A patent/PL349682A1/xx not_active Application Discontinuation
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EA200100876A3 (ru) | 2002-06-27 |
AU7033201A (en) | 2002-03-21 |
EP1188438A1 (en) | 2002-03-20 |
IL145366A0 (en) | 2002-06-30 |
WO2002022112A9 (en) | 2002-06-06 |
WO2002022112A3 (en) | 2004-02-26 |
AR030660A1 (es) | 2003-08-27 |
NO20014414L (no) | 2002-03-18 |
NO20014414D0 (no) | 2001-09-11 |
US20020119967A1 (en) | 2002-08-29 |
CZ20013275A3 (cs) | 2002-04-17 |
EA200100876A2 (ru) | 2002-04-25 |
JP2002316948A (ja) | 2002-10-31 |
CA2357155A1 (en) | 2002-03-15 |
HUP0103686A2 (en) | 2002-06-29 |
WO2002022112A2 (en) | 2002-03-21 |
CN1348763A (zh) | 2002-05-15 |
KR20020021606A (ko) | 2002-03-21 |
PL349682A1 (en) | 2002-03-25 |
PE20020465A1 (es) | 2002-06-06 |
HU0103686D0 (en) | 2001-11-28 |
NZ514107A (en) | 2001-09-28 |
BR0104005A (pt) | 2002-07-09 |
MXPA01009032A (es) | 2004-11-10 |
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