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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
Authority
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
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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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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