ME02601B - Novi derivati indolizina, postupak njihove pripreme i farmaceutski preparati koji ih sadrže za liječenje karcinoma - Google Patents

Novi derivati indolizina, postupak njihove pripreme i farmaceutski preparati koji ih sadrže za liječenje karcinoma

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Publication number
ME02601B
ME02601B MEP-2017-28A MEP201728A ME02601B ME 02601 B ME02601 B ME 02601B ME P201728 A MEP201728 A ME P201728A ME 02601 B ME02601 B ME 02601B
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ME
Montenegro
Prior art keywords
dihydro
formula
compound
hydroxyphenyl
group
Prior art date
Application number
MEP-2017-28A
Other languages
German (de)
English (en)
French (fr)
Inventor
Diguarher Thierry Le
Patrick Casara
Jérôme-Benoît Starck
Jean-Michel Henlin
James Edward Paul Davidson
James Brooke Murray
Christopher John Graham
I-Jen Chen
Olivier Geneste
John Hickman
Stéphane Depil
Tiran Arnaud Le
Miklos Nyerges
Nanteuil Guillaume De
Original Assignee
Servier Lab
Vernalis R&D Ltd
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Filing date
Publication date
Application filed by Servier Lab, Vernalis R&D Ltd filed Critical Servier Lab
Publication of ME02601B publication Critical patent/ME02601B/me

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Claims (32)

1. Spoj formule (I) naznačen time, da ♦ X i Y predstavljaju atom ugljika ili atom dušika, pri čemu se podrazumijeva da ne mogu istovremeno predstavljati dva atoma ugljika ili dva atoma dušika ♦ Het polovica skupine predstavlja po izboru supstiturani aromatski ili ne-aromatski prsten sastavljen od 5, 6 ili 7 članova prstena, koji dodatno osim dušika predstavljenog s X ili s Y, može sadržati od jedan do 3 heteroatoma neovisno odabrana od kisika, sumpora i dušika, pri čemu se podrazumijeva da navedeni dušik može biti supstituiran sa skupinom koja predstavlja atom vodika, ravnu ili razgrananu (C1-C6)alkilnu skupinu ili skupinu -C(O)-O-Alk, pri čemu je Alk ravna ili razgranana (C1-C6)alkilna skupina, ♦ R1 i R2 neovisno jedan od drugog predstavljaju atom vodika ili ravnu ili razgrananu (C1-C6)alkilnu skupinu ili R1 i R2 tvore s atomom dušika koji ih nosi heterocikloalkil sastavljen od 4 do 7 članova prstena, koji može sadržati, osim atoma dušika, drugi heteroatom odabran od kisika, sumpora, SO2 i NR gdje R predstavlja atom vodika, ravnu ili razgrananu (C1-C6)alkilnu skupinu, (C1-C6)alkilsulfonilnu skupinu, ravnu ili razgrananu (C1-C6)polihaloalkilnu skupinu ili skupinu -C(O)-O-Alk, pri čemu je Alk ravna ili razgranana (C1-C6)alkilna skupina, ♦ R3 predstavlja ravnu ili razgrananu (C1-C6)alkilnu skupinu, (C2-C6)alkenilnu skupinu, (C2-C6)alkinilnu skupinu, cikloalkilnu skupinu, ravnu ili razgrananu (C4-C10)cikloalkil-(C1-C6)alkilnu skupinu, arilnu skupinu ili heteroarilnu skupinu, ♦ R4 predstavlja aril, heteroaril, cikloalkil ili ravnu ili razgrananu (C1-C6)alkilnu skupinu, ♦ R5 predstavlja atom vodika ili atom halogena, ♦ Ra, Rb, Rc i Rd neovisno jedan od drugog predstavljaju atom vodika, atom halogena, ravnu ili razgrananu (C1-C6)alkilnu skupinu, ravnu ili razgrananu (C1-C6)alkoksi skupinu, hidroksi skupinu, ravnu ili razgrananu (C1-C6)polihaloalkilnu skupinu ili trifluorometoksi skupinu ili supstituente od jednog od parova (Ra,Rb), (Rb,Rc) ili (Rc,Rd) koji zajedno s ugljikovim atomima koji ih nose tvore prsten sastavljen od 5 do 7 članova prstena, koji mogu sadržati od jedan do 3 heteroatoma odabrana od kisika, sumpora i dušika, pri čemu se podrazumijeva da navedeni dušik može biti supstituiran skupinom predstavljenom atomom hidrogena, ravnom ili razgrananom (C1-C6)alkilnom skupinom ili skupinom -C(O)-O-Alk pri čemu je Alk ravna ili razgranana (C1-C6)alkilna skupina, gdje se podrazumijeva da jedan ili više atoma ugljika prstena koji su ovdje definirani mogu biti deuterirani, kada se podrazumijeva da: - "aril" znači fenilna, naftilna, bifenilna ili indenilna skupina, - "heteroaril" znači bilo koja mono- ili bi-ciklička skupina koja se sastoji od 5 do 10 članova prstena, koji imaju najmanje jednu aromatsku polovicu i sadrže od 1 do 3 heteroatoma odabrana od kisika, sumpora i dušika, - "cikloalkil" znači bilo koja mono- ili bi-ciklička ne-aromatska karbociklička skupina koja se sastoji od 4 do 10 članova prstena, pri čemu je moguće da tako definirane alkilne, arilne, heteroarilne, cikloalkilne i heterocikloalkilne skupine budu supstituirane sa od 1 do 3 skupine odabrane od po izboru supstituiranog ravnog ili razgrananog (C1-C6)alkila, (C3-C6)spiro, ravnog ili razgrananog (C1-C6)alkoksi, (C1-C6)alkil-S-, hidroksi, okso (ili N-oksid gdje je prikladno), nitro, cijano, -COOR', NR'R", ravnog ili razgrananog (C1-C6)polihaloalkila, trifluorometoksi, (C1-C6)alkilsulfonila ili halogena, pri čemu se podrazumijeva da R' i R" neovisno jedan od drugog predstavljaju atom vodika ili ravnu ili razgrananu (C1-C6)alkilnu skupinu, gdje je moguće da Het polovica skupine koja je ranije gore definirana, može supstituirati skupinom odabranom od ravnog ili razgrananog (C1-C6)alkila, hidroksi, NR1'R1" i halogena, gdje se podrazumijeva da R1' i R1" imaju iste definicije kao ranije spomenute skupine R' i R", njihove enantiomere i dijastereoizomere i njihove adicijske soli s farmaceutski prihvatljivom kiselinom ili lužinom.
2. Spoj formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da skupina predstavlja jednu od sljedećih skupina: 5,6,7,8-tetrahidroindolizin po izboru supstituiran s hidroksi, indolizin, 1,2,3,4-tetrahidropirolo[1,2-α]pirazin, terc-butil 3,4-dihidro-pirolo[1,2-α]pirazin-2(1H)-karboksilat, 3,4-dihidro- 1H-pirolo[2,1-c][1,4]oksazinom, 2,3-dihidro-1H-pirolizinom po izboru supstituiranim s hidroksi, 6,7,8,9-tetrahidro-5H-pirolo[1,2-α]azepinom ili pirolo[1,2-α]pirazinom.
3. Spoj formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da R1 i R2 svaki predstavlja alkilnu skupinu po izboru supstituiranu s metoksi ili R1 i R2 zajedno s dušikom koji ih nosi tvore heterocikloalkil odabran od sljedećih skupina: morfolina po izboru supstituiranog s jednim ili više ravnih ili razgrananih (C1-C6)alkil(a), oksidomorfolina, tiomorfolin 1,1-dioksida, 1,4-oksazepana, 3-metoksipirolidina, 3,3-difluoropirolidina, 3-metoksiazetidina, 3-fluoroazetidina, oksopiperazina ili piperazina, od kojih su zadnje dvije skupine supstituirane s ravnom ili razgrananom (C1-C6)alkilnom skupinom, ravnom ili razgrananom (C1-C6)-polihaloalkilnom skupinom ili metilsulfonilnom skupinom.
4. Spoj formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da Ra i Rd svaki predstavlja atom vodika a (Rb,Rc) zajedno s atomom ugljika koji ih nosi tvore 1,3-dioksolan skupinu, jedan od ugljikovih atoma koji su po izboru deuterirani, 1,4-dioksan skupinu, 1,4-dioksepan skupinu ili Ra, Rc i Rd svaki predstavlja atom vodika a Rb predstavlja halogen, metil, metoksi, etoksi, trifluorometil ili trifluorometoksi.
5. Spoj formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da R4 predstavlja 4-hidroksifenilnu skupinu, 3-fluoro-4-hidroksifenilnu skupinu ili 5-hidroksipirimidin skupinu.
6. Spoj formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da R3 predstavlja skupinu odabranu od fenila, indola, indolina, 1,2,3,4-tetrahidrokinolina, 3,4-dihidro-2H-1,4-benzoksazina, indana, 1H-indazola, 1H-pirolo[2,3-b]piridina, pirimidina, ciklobutilmetila, ciklopropilmetila, 1H-pirazola, piridina, piridazina, te skupine po izboru imaju jedan ili više supstituenata odabranih od halogena, ravnog ili razgrananog (C1-C6)alkila, cijano i ravnog ili razgrananog (C1-C6)alkoksi.
7. Spoj formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da je odabran od sljedeće skupine: - N-(4-hidroksifenil)-3-{6-[((3S)-3-(4-morfolinilmetil)-3,4-dihidro-2(1H)-izokinolinil)karbonil]-1,3-benzodioksol-5-il}-N-fenil-5,6,7,8-tetrahidro-1-indolizin karboksamida, - 3-{5-kloro-2-[((3S)-3-(4-morfolinilmetil)-3,4-dihidro-2(1H)-izokinolinil)-karbonil]fenil}-N-(4-hidroksifenil)- N-(1-metil-1H-indol-5-il)-5,6,7,8-tetrahidro-1-indolizin karboksamida, - N-(4-hidroksifenil)-N-(1-metil-1H-indazol-5-il)-3-{2,2-dideuterio-6-[((3S)-3-(4-morfolinilmetil)-3,4-dihidro- 2(1H)-izokinolinil)karbonil]-1,3-benzodioksol-5-il}-5,6,7,8-tetrahidro-1-indolizin karboksamida, - N-(4-hidroksifenil)-N-(1-metil-1H-indazol-5-il)-3-(6-{[(3S)-3-(morfolin-4-ilmetil)-3,4-dihidroizokinolin- 2(1H)-il]karbonil}-1,3-benzodioksol-5-il)-5,6,7,8-tetrahidroindolizin-1-karboksamida, - N-(4-hidroksifenil)-3-{7-[((3S)-3-(4-morfolinilmetil)-3,4-dihidro-2(1H-izokinolinil)karbonil]-2,3-dihidro- 1,4-benzodioksin-6-il}-N-fenil-5,6,7,8-tetrahidro-1-indolizin karboksamida, - N-(4-hidroksifenil)-N-(1-metil-1H-indol-5-il)-3-{6-[((3S)-3-[(4-metil-1-piperazinil)metil]-3,4-dihidro- 2(1H)-izokinolinil)karbonil]-1,3-benzodioksol-5-il}-1-indolizin karboksamida, - N-[4-(hidroksi)fenil]-N-(1-metil-1H-indol-5-il)-3-{6-[((3S)-3-(4-morfolinilmetil)-3,4-dihidro-2(H)-izokinolinil) karbonil]-1,3-benzodioksol-5-il}-5,6,7,8-tetrahidro-1-indolizin karboksamida, - N-(4-hidroksifenil)-3-{6-[((3S)-3-(4-morfolinilmetil)-3,4-dihidro-2(1H)-izokinolinil)karbonil]-1,3-benzodioksol- 5-il}-N-fenil-1-indolizin karboksamida, - 3-{5-kloro-2-[((3S)-3-(4-morfolinilmetil)-3,4-dihidro-2(1H)-izokinolinil)karbonil]fenil}-N-(4-hidroksifenil)- N-(1-metil-1H-indol-5-il)-1-indolizin karboksamida, - 6-{5-kloro-2-[((3S)-3-(4-morfolinilmetil)-3,4-dihidro-2(1H)-izokinolinil)-karbonil]fenil}-N-(3-fluoro-4- metilfenil)-N-(4-hidroksifenil)-3,4-dihidro-1H-pirolo[2,1-c][1,4]oksazin-8-karboksamida, - 3-(5-kloro-2-{[(3S)-3-(morfolin-4-ilmetil)-3,4-dihidroizokinolin-2(1H)-il]karbonil}fenil)-N-(4-hidroksifenil)- N-(1-metil-1H-pirazol-4-il)-5,6,7,8-tetrahidroindolizin-1-karboksamida, - N-(3-fluoro-4-metilfenil)-N-(4-hidroksifenil)-3-{6-[((3S)-3-(4-morfolinilmetil)-3,4-dihidro-2(1H)-izokinolinil) karbonil]-1,3-benzodioksol-5il}-5,6,7,8-tetrahidro-1-indolizin karboksamida, - N-[4-(hidroksi)fenil]-N-(1-metil-2,3-dihidro-1H-indol-5-il)-3-{6-[((3S)-3-(4-morfolinilmetil)-3,4-dihidro- 2(1H)-izokinolinil)karbonil]-1,3-benzodioksol-5-il}-5,6,7,8-tetrahidro-1-indolizin karboksamida, - 3-{5-kloro-2-[((3S-3-(4-morfolinilmetil)-3,4-dihidro-2(1H)-izokinolinil)karbonil]fenil}-N-(4-hidroksifenil)- N-(1-metil-2,3-dihidro-1H-indol-5-il)-5,6,7,8-tetrahidro-1-indolizin karboksamida, - N-(4-hidroksifenil)-N-(1-metil-1H-indol-5-il)-3-{6-[((3S)-3-(4-morfolinilmetil)-3,4-dihidro-2(1H)-izokinolinil) karbonil]-1,3-benzodioksol-5-il}-1-indolizin karboksamida, - 3-{5-kloro-2-[((3S)-3-(4-morfolinilmetil)-3,4-dihidro-2(1H)-izokinolinil)-karbonil]fenil}-N-(-4-hidroksifenil)- N-(1-metil-2,3-dihidro-1H-indol-5-il)-1 indolizin karboksamida, - 6-{5-kloro-2-[((3S)-3-(4-morfolinilmetil)-3,4-dihidro-2(1H)-izokinolinil)-karbonil]fenil}-N-(4-hidroksifenil)- N-fenil-3,4-dihidro-1H-pirolo[2,1-c]-[1,4]oksazin-8-karboksamida, - N-(3-fluorofenil)-N-(4-hidroksifenil)-3-(6-{[(3S)-3-(morfolin-4-ilmetil)-3,4-dihidroizokinolin-2(1H)-il]karbonil}-1,3-benzodioksol-5-il)-5,6,7,8-tetrahidroindolizin-1-karboksamida, njihovih enantiomera i dijastereoizomera i njihove adicijske soli s farmaceutski prihvatljivom kiselinom ili lužinom.
8. Spoj formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da je odabran od sljedeće skupine: - N-(4-hidroksifenil)-3-{6-[((3S)-3-(4-morfolinilmetil)-3,4-dihidro-2(1H)-izokinolinil)karbonil]-1,3-benzodioksol-5-il}-N-fenil-5,6,7,8-tetrahidro-1-indolizin karboksamida, - 3-{5-kloro-2-[((3S)-3-(4-morfolinilmetil)-3,4-dihidro-2(1H)-izokinolinil)-karbonil]fenil}-N-(4-hidroksifenil)-N-(1-metil-1H-indol-5-il)-5,6,7,8-tetrahidro-1-indolizin karboksamida, - N-(4-hidroksifenil)-N-(1-metil-1H-indazol-5-il)-3-{2,2-dideuterio-6-[((3S)-3-(4-morfolinilmetil)-3,4-dihidro-2(1H)-izokinolinil)karbonil]-1,3-benzo-dioksol-5-il)-5,6,7,8-tetrahidro-1-indolizin karboksamida, - N-(4-hidroksifenil)-N-(1-metil-1H-indazol-5-il)-3-(6-{[(3S)-3-(morfolin-4-ilmetil)-3,4-dihidroizokinolin-2(1H)-il]karbonil}-1,3-benzodioksol-5-il)-5,6,7,8-tetrahidroindolizin-1-karboksamida, - N-(4-hidroksifenil)-3-{7-[((3S-3-(4-morfolinilmetil)-3,4-dihidro-2(1H)-izokinolinil)karbonil]-2,3-dihidro-1,4-benzodioksin-6-il}-N-fenil-5,6,7,8-tetrahidro-1-indolizin karboksamida, - N-(4-hidroksifenil)-N-(1-metil-1H-indol-5-il)-3-{6-[((3S)-3-[(4-metil-1-piperazinil)metil]-3,4-dihidro- 2(1H)-izokinolinil)karbonil]-1,3-benzodioksol-5-il}-1-indolizin karboksamida, - N-[4-(hidroksi)fenil]-N-(1-metil-1H-indol-5-il)-3-{6-[((3S)-3-(4-morfolinilmetil)-3,4-dihidro-2(1H)-izokinolinil)karbonil]-1,3-benzodioksol-5-il}-5,6,7,8-tetrahidro-1-indolizin karboksamida, - N-(4-hidroksifenil)-3-{6-[((3S)-3-(4-morfolinilmetil)-3,4-dihidro-2(1H)-izokinolinil)karbonil]-1,3-benzodioksol-5-il}-N-fenil-1-indolizin karboksamida, - 3-{5-kloro-2-[((3S)-3-(4- morfolinilmetil)-3,4-dihidro-2(1H)-izokinolinil)karbonil]fenil}-N-(4-hidroksifenil)-N-(1-metil-1H-indol-5-il)-1-indolizin karboksamid, - 6-{5-kloro-2-[((3S)-3-(4-morfolinilmetil)-3,4-dihidro-2(1H)-izokinolinil)-karbonil]fenil}-N-(3-fluoro-4-metilfenil)-N-(4-hidroksifenil)-3,4-dihidro-1H- pirolo[2,1-c][1,4]oksazine-8-karboksamida, - 3-(5-kloro-2-{[(3S)-3-(morfolin-4-ilmetil)-3,4-dihidroizokinolin-2(1H)-il]karbonil}fenil)-N-(4-hidroksifenil)-N-(1-metil-1H-pirazol-4-il)-5,6,7,8-tetrahidroindolizin-1-karboksamida, njihovih enantiomera i dijastereoizomera i njihove adicijske soli s farmaceutski prihvatljivom kiselinom ili lužinom.
9. Spoj formule (I) u skladu s patentnim zahtjevom 8, naznačen time, da je N-(4-hidroksifenil)-3-{6-[((3S)-3-(4-morfolinilmetil)-3,4-dihidro-2(1H)-izokinolinil)karbonil]-1,3-benzodioksol-5-il}-N-fenil-5,6,7,8-tetrahidro-1-indolizin karboksamid.
10. Spoj formule (I) u skladu s patentnim zahtjevom 8, naznačen time, da je 3-{5-kloro-2-[((3S)-3-(4-morfolinilmetil)-3,4-dihidro-2(1H)-izokinolinil)karbonil]fenil}-N-(4-hidroksifenil)-N-(1-metil-1H-indol-5-il)-5,6,7,8-tetrahidro-1-indolizin karboksamid.
11. Spoj formule (I) u skladu s patentnim zahtjevom 8, naznačen time, da je N-(4-hidroksifenil)-N-(1-metil-1H-indazol-5-il)-3-{2,2-dideuterio-6-[((3S)-3-(4-morfolinilmetil)-3,4-dihidro-2(1H)-izokinolinil)karbonil]-1,3-benzodioksol-5-il}-5,6,7,8-tetrahidro-1-indolizin karboksamid.
12. Spoj formule (I) u skladu s patentnim zahtjevom 8, naznačen time, da je N-(4-hidroksifenil)-N-(1-metil-1H-indazol-5-il)-3-(6-{[(3S)-3-(morfolin-4-ilmetil)-3,4-dihidroizokinolin-2(1H)-il]karbonil}-1,3-benzodioksol-5-il)-5,6,7,8-tetrahidroindolizin-1-karboksamid.
13. Spoj formule (I) u skladu s patentnim zahtjevom 8, naznačen time, da je N-(4-hidroksifenil)-3-{7-[((3S)-3-(4-morfolinilmetil)-3,4-dihidro-2(1H)-izokinolinil)karbonil]-2,3-dihidro-1,4-benzodioksin-6-il}-N-fenil-5,6,7,8-tetrahidro-1-indolizin karboksamid.
14. Spoj formule (I) u skladu s patentnim zahtjevom 8, naznačen time, da je N-(4-hidroksifenil)-N(1-metil-1H-indol-5-il)-3-{6-[((3S)-3-[(4-metil-1-piperazinil)metil]-3,4-dihidro-2(1H-izokinolinil)karbonil]-1,3-benzodioksol-5-il}-1-indolizin karboksamid.
15. Spoj formule (I) u skladu s patentnim zahtjevom 8, naznačen time, da je N-[4-(hidroksi)fenil]-N-(1-metil-1H-indol-5-il)-3-{6-[((3S)-3-(4-morfolinilmetil)-3,4-dihidro-2(1H)-izokinolinil)karbonil]-1,3-benzodioksol-5-il}-5,6,7,8-tetrahidro-1-indolizin karboksamid.
16. Spoj formule (I) u skladu s patentnim zahtjevom 8, naznačen time, da je N-(4-hidroksifenil)-3-{6-[((3S)-3-(4-morfolinilmetil)-3,4-dihidro-2(1H)-izokinolinil)karbonil]-1,3-benzodioksol-5-il}-N-fenil-1-indolizin karboksamid.
17. Spoj formule (I) u skladu s patentnim zahtjevom 8, naznačen time, da je 3-{5-kloro-2-[((3S)-3-(4-morfolinilmetil)-3,4-dihidro-2(1H)-izokinolinil)karbonil]fenil}-N-(4-hidroksifenil)-N-(1-metil-1H-indol-5-il)-1-indolizin karboksamid.
18. Spoj formule (I) u skladu s patentnim zahtjevom 8, naznačen time, da je 6-{5-kloro-2-[((3S)-3-(4-morfolinilmetil)-3,4-dihidro-2(1H)-izokinolinil)karbonil]fenil}-N-(3-fluoro-4-metilfenil)-N-(4-hidroksifenil)-3,4-dihidro-1H-pirolo[2,1-c][1,4]oksazin-8-karboksamid.
19. Spoj formule (I) u skladu s patentnim zahtjevom 8, naznačen time, da je 3-(5-kloro-2-{[(3S)-3-(morfolin-4-ilmetil)-3,4-dihidroizokinolin-2(1H)-il]karbonil}fenil)-N-(4-hidroksifenil)-N-(1-metil-1H-pirazol-4-il)-5,6,7,8-tetrahidroindolizin-1-karboksamid.
20. Hidrokloridna sol spoja formule (I) u skladu s bilo kojim od patentnih zahtjeva 9 do 13 i 15 do 19.
21. Dihidrokloridna sol spoja formule (I) u skladu s patentnim zahtjevom 14.
22. Postupak za pripravu spoja formula (I) u skladu s patentnim zahtjevom 1, naznačen time, da je kao početni materijal korišten spoj formule (II): gdje su Ra, Rb, Rc i Rd definirani za formulu (I), koji spoj formule (II) se izlaže Heckovoj reakciji u vodenom ili organskom mediju u nazočnosti paladij katalizatora, lužine, fosfina i spoja formule (III): gdje su skupine X, Y i Het definirane za formulu (I), kako bi se dobio spoj formule (IV): gdje su Ra, Rb, Rc i Rd, X, Y i Het kako je definirano za formulu (I), aldehidna funkcija od kojeg se spoj formule (IV) oksidira u karboksilnoj kiselini da se stvori spoj formule (V): gdje su Ra, Rb, Rc i Rd, X, Y i Het kako je definirano za formulu (I), koji spoj formule (V) se potom izlaže spajanju peptida sa spojem formule (VI): gdje su R1, R2 i R5 kako je definirano za formulu (I), kako bi se dobio spoj formule (VII): pri čemu su Ra, Rb, Rc i Rd, R1, R2, R5, X, Y i Het kako je definirano za formulu (I), funkcija estera kojim je spoj formule (VII) hidroliziran kako bi se dobila karboksilna kiselina ili odgovarajući karboksilat, koji može biti pretvoren u derivat kiseline poput primjerice acil klorida ili odgovarajući anhidrid prije spajanja s aminom NHR3R4 gdje R3 i R4 imaju ista značenja kao i za formulu (I), kako bi se dobio spoj formule (I), koji spoj formule (I) može biti pročišćen u skladu s uobičajenom tehnikom separacije, koji se pretvara, ako je poželjno, u svoju adicijsku sol s farmaceutski prihvatljivom kiselinom ili lužinom i koji je po izboru separiran u svoje izomere u skladu s uobičajenom tehnikom separacije, pri čemu se podrazumijeva da, u bilo koje vrijeme koje se smatra prikladnim u smislu gore navedenog postupka, određene skupine (hidroksi, amino...) reagensi ili intermedijeri sinteze mogu biti zaštićeni a potom im se može skinuti zaštita sukladno zahtjevima sinteze.
23. Postupak u skladu s patentnim zahtjevom 22 za pripravu spoja formule (I) pri čemu je jedna od skupina R3 i R4 supstituirana s hidroksi funkcijom, naznačen time, da je amin NHR3R4 prije toga izložen zaštitnoj reakciji hidroksi funkcije prije spajanja s karboksilnom kiselinom dobivenom iz spoja formule (VII) ili s njegovim odgovarajućim derivatom kiseline, dobiveni zaštićeni spoj formule (I) naknadno se podliježe reakciji skidanja zaštite a potom se po izboru pretvara u jedan od njegovih adicijskih soli s farmaceutski prihvatljivom kiselinom ili lužinom.
24. Farmaceutski pripravak, naznačen time, da sadrži spoj formule (I) u skladu s bilo kojim od patentnih zahtjeva 1 do 19 ili njegova adicijska sol s farmaceutski prihvatljivom kiselinom ili lužinom u kombinaciji s jednim ili više farmaceutski prihvatljivih ekscipijensa.
25. Farmaceutski pripravak u skladu s patentnim zahtjevom 24, naznačen time, da se koristi kao pro-apoptotičko sredstvo.
26. Farmaceutski pripravak u skladu s patentnim zahtjevom 24, naznačen time, da se koristi u liječenju karcinoma, imunih i autoimunih bolesti.
27. Farmaceutski pripravak u skladu s patentnim zahtjevom 24, naznačen time, da se koristi u liječenju raka mokraćnog mjehura, mozga, dojke, uterusa, kroničnih limfoidnih leukemija, raka debelog crijeva, ezofagusa, jetre, limfoblastične leukemije, folikularnih limfoma, melanoma, malignih hemopatija, mijeloma, karcinoma jajnika, karcinoma pluća ne-malih stanica, raka prostate i raka pluća malih stanica.
28. Spoj formule (I) u skladu s bilo kojim od patentnih zahtjeva 1 do 19 ili njegova adicijska sol s farmaceutski prihvatljivom kiselinom ili lužinom, naznačen time, da se koristi u liječenju raka mokraćnog mjehura, mozga, dojke, uterusa, kroničnih limfoidnih leukemija, raka debelog crijeva, ezofagusa, jetre, limfoblastične leukemije, folikularnih limfoma, melanoma, malignih hemopatija, mijeloma, karcinoma jajnika, karcinoma pluća ne-malih stanica, raka prostate i raka pluća malih stanica.
29. Asocijacija spoja formule (I) u skladu s bilo kojim od patentnih zahtjeva 1 do 21 sa sredstvom protiv karcinoma, naznačen time, da je odabran od genotoksičnih sredstava, mitotskih otrova, antimetabolita, inhibitora proteazoma, inhibitora kinaze i antitijela.
30. Farmaceutski pripravak koji sadrži asocijaciju u skladu s patentnim zahtjevom 29, naznačen time, da je u kombinaciji s jednim ili više farmaceutski prihvatljivih ekscipijensa.
31. Asocijacija u skladu s patentnim zahtjevom 29, naznačen time, da se koristi u liječenju karcinoma.
32. Spoj formule (I) u skladu s bilo kojim od patentnih zahtjeva 1 do 21 naznačen time, da se koristi zajedno s radioterapijom u liječenju karcinoma.
MEP-2017-28A 2012-01-24 2013-01-23 Novi derivati indolizina, postupak njihove pripreme i farmaceutski preparati koji ih sadrže za liječenje karcinoma ME02601B (me)

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