HRP20170349T1 - Novi derivati pirola, postupak njihove priprave i farmaceutski pripravci koji ih sadrže - Google Patents

Novi derivati pirola, postupak njihove priprave i farmaceutski pripravci koji ih sadrže Download PDF

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HRP20170349T1
HRP20170349T1 HRP20170349TT HRP20170349T HRP20170349T1 HR P20170349 T1 HRP20170349 T1 HR P20170349T1 HR P20170349T T HRP20170349T T HR P20170349TT HR P20170349 T HRP20170349 T HR P20170349T HR P20170349 T1 HRP20170349 T1 HR P20170349T1
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Croatia
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formula
compound
dimethyl
pyrrole
hydroxyphenyl
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HRP20170349TT
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Arnaud Le Tiran
Thierry Le Diguarher
Jérôme-Benoît STARCK
Jean-Michel Henlin
Anne-Françoise Guillouzic
Guillaume De Nanteuil
Olivier Geneste
Imre Fejes
Janos Tatai
Miklos Nyerges
James Edward Paul Davidson
James Brooke MURRAY
I-Jen Chen
Didier Durand
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Les Laboratoires Servier
Vernalis (R&D) Ltd.
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Publication of HRP20170349T1 publication Critical patent/HRP20170349T1/hr

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    • A61K31/47—Quinolines; Isoquinolines
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Claims (35)

1. Spoj formule (I): [image] naznačen time, da: ♦ A1 predstavlja atom vodika ili halogena, ravnu ili razgrananu (C1-C6)polihaloalkilnu skupinu, ravnu ili razgrananu (C1-C6)alkilnu skupinu ili cikloalkilnu skupinu, ♦ A2 predstavlja ravnu ili razgrananu (C1-C6)alkilnu skupinu po izboru supstituiranu sa skupinom odabranom od halogena, hidroksi, ravnog ili razgrananog (C1-C6)alkoksi, NR'R" i morfolina ili A2 predstavlja ravnu ili razgrananu (C1-C6)polihaloalkilnu skupinu ili ciklopropilnu skupinu, gdje se podrazumijeva da R' i R", svaki neovisno jedan o drugome, predstavljanju atom vodika ili ravnu ili razgrananu (C1-C6)alkilnu skupinu, ♦ T predstavlja atom vodika, ravnu ili razgrananu (C1-C6)alkilnu skupinu po izboru supstituiranu s jednim do tri atoma halogena, skupinu (C1-C4)alkil-NR1R2 ili skupinu (C1-C4)alkil-OR6, ♦ R1 i R2, svaki neovisno jedan o drugome, predstavljaju atom vodika ili ravnu ili razgrananu (C1-C6)alkilnu skupinu ili R1 i R2 tvore s dušikovim atomom koji ih nosi heterocikloalkil, ♦ R3 predstavlja arilnu ili heteroarilnu skupinu, pri čemu se podrazumijeva da jedan ili više ugljikovih atoma iz prethodnih skupina ili njihovi mogući supstituenti mogu biti deuterirani, ♦ R4 predstavlja fenilnu skupinu, 4-hidroksifenilnu skupinu, 3-fluoro-4-hidroksifenilnu skupinu, 2-hidroksipirimidinsku skupinu ili 3-hidroksipiridinsku skupinu, pri čemu se podrazumijeva da jedan ili više ugljikovih atoma iz prethodnih skupina ili njihovi mogući supstituenti mogu biti deuterirani, ♦ R5 predstavlja atom vodika ili atom halogena, ravnu ili razgrananu (C1-C6)alkilnu skupinu ili ravnu ili razgrananu (C1-C6)alkoksi skupinu, ♦ R6 predstavlja atom vodika ili ravnu ili razgrananu (C1-C6)alkilnu skupinu, ♦ Ra i Rd svaki predstavlja atom vodika i (Rb,Rc) zajedno s ugljikovim atomom koji ih nose tvore skupinu 1,3-dioksolana ili skupinu 1,4-dioksana ili Ra, Rc and Rd svaki predstavlja atom vodika i Rb predstavlja atom vodika ili halogena ili metoksi skupinu ili Ra i Rd svaki predstavlja atom vodika, Rb predstavlja atom vodika ili atom halogena i Rc predstavlja hidroski ili metoksi skupinu ili: Ra i Rd svaki predstavlja atom vodika, Rb predstavlja hidroksi ili metoksi skupinu i Rc predstavlja atom halogena, gdje se podrazumijeva kako: - "aril" znači fenilna, naftilna, bifenilna ili indenilna skupina, - "heteroaril" znači bilo koja mono- ili bi-ciklička skupina sastavljena od 5 do 10 članova prstena, koja ima najmanje jednu aromatsku polovicu i sastoji se od 1 do 4 heteroatoma odabrana od kisika, sumpora i dušika (uključujući kvaterne dušike), - "cikloalkil" znači bilo koja mono- ili bi-ciklička, ne-aromatska, karbociklička skupina koja se sastoji od 3 do 10 članova prstena, - "heterocikloalkil" znači bilo koja mono- ili bi-ciklička, ne-aromatska, kondenzirana ili spiro skupina koja se sastoji od 3 do 10 članova prstena i sadrži od 1 do 3 heteroatoma odabrana od kisika, sumpora, SO, SO2 i dušika, pri čemu je moguće za tako definirane arilne, heteroarilne, cikloalkilne i heterocikloalkilne skupine i skupine alkila, alkenil, alkinila i alkoksi da budu supstituirane s 1 do 3 skupine odabrane od ravnog ili razgrananog (C1-C6)alkila, (C3-C6)spiro, ravnog ili razgrananog (C1-C6)alkoksi, (C1-C6)alkil-S-, hidroksi, okso (ili N-oksida gdje je prikladno), nitro, cijano, -COOR', -OCOR', NR'R", ravnog ili razgrananog (C1-C6)polihaloalkila, trifluorometoksi, (C1-C6)alkilsulfonila, halogena, arila, heteroarila, ariloksi, ariltio, cikloalkila, heterocikloalkila po izboru supstituiranog s jednim ili više atoma halogena ili alkilnim skupinama, njegove enantiomere i dijastereoizomere i njihove adicijske soli s s farmaceutski prihvatljivom kiselinom ili lužinom.
2. Spoj formule (1) u skladu s patentnim zahtjevom 1, naznačen time, da A1 predstavlja atom vodika ili metilnu skupinu.
3. Spoj formule (1) u skladu s patentnim zahtjevom 1 ili 2, naznačen time, da A1 i A2 oba predstavljaju metilnu skupinu.
4. Spoj formule (I) u skladu s jednim od patentnih zahtjeva 1 do 3, naznačen time, da T predstavlja metil, aminometil, (morfolin-4-il)metil, (4-metilpiperazin-l-il)metil, 2-(morfolin-4-il)etil, [2-(morfolin-4-il)etoksi]metil, hidroksimetil,[2-(dimetilamino)etoksi]metil, heksahidropirazino[2,l-c][l,4]oksazin-8(1H)-ilmetil, l-oksa-6-azaspiro[3.3]hept-6-ilmetil, 3-(morfolin-4-il)propilnu ili trifluorometilnu skupinu.
5. Spoj formule (1): [image] u skladu s patentnim zahtjevom 1, naznačen time, da - A1, A2, Ra, Rb Rc Rd T, R4 i R5 jesu definirani u patentnim zahtjevima 1 do 4, - R3 predstavlja skupinu odabranu od fenila, 1H-pirazola, 1H -indola, 1H -indazola, piridina, pirimidina, 1H -pirolo[ 2,3-bipiridina, 2,3-dihidro-1H -pirolo[2,3-b]piridina, 1H -benzimidazola, 1H -pirola, 1H -pirolo[2,3-cipiridina, 1H -pirolo[3,2-b]piridina, 5H-pirolo[3,2-d]pirimidina, tiofena, pirazina, 1H -pirazolo[3,4-b]piridina, 1,2-oksazola i pirazolo[1,5-a]pirimidina, te skupine po izboru imaju jednog ili više supstituenata odabrana od halogena, ravnog ili razgrananog (C1-C6)alkila, ravnog ili razgrananog (C1-C6)alkoksi, cijano, ciklopropila, oksetana, tetrahidrofurana, -CO-O-CH3, trideuteriometila, 2-(morfolin-4-il)etila i 2-(morfolin-4-il)etoksi, njihovih enantiomera i dijastereoizomera te njihovih adicijskih soli s farmaceutski prihvatljivom kiselinom ili lužinom.
6. Spoj formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da je odabran iz sljedeće skupine: -5-(5-kloro-2-{[(3S)-3-(morfolin-4-ilmetil)-3,4-dihidroizokinolin-2(1H)-il]-karbonil}fenil)-N-(4-hidroksifenil) -1.2-dimetil-N-(l-metil-1H-pirazol-4-il)-1H-pirol-3-karboksamid, -5-(5-kloro-2-{[(3R)-3-metil-3,4-dihidroizokinolin-2(1H)-il]karbonil}fenil)-N-(4-hidroksifenil)-l,2-dimetil-N-(piridin-4-il)-1H-pirol-3-karboksamida, -yV-(4-hidroksifenil)-l,2-dimetil-N-(l-metil-1H-pirazol-4-il)-5-(6-{[(3S)-3-(morfolin-4-iImetil)-3,4-dihidroizokinolin-2( 1 H)-il]karbonil}-1,3-benzoadioksol-5-il)-1 H-pirol-3-karboksamida, - A'-(4-hidroksifenil)-l,2-dimetil-5-(6-{[(3R)-3-metil-3,4-dihidroizokinolin-2(1H)-il] karbonil}-1,3- benzodioksol -5-il)-N-(piridin-4-il)-l H-pirol-3-karboksamida, - 5-(5-fluoro-2-{[(3S)-3-(morfolin-4-ilmetil)-3,4-dihidroizokinolin-2(1H)-il]-karbonil}fenil)-N-(4-hidroksifenil)-1,2-dimetil-N-( 1 -metil-1 H-pirazol-4-il)-1 H-pirol-3-karboksamida, - 5-(5-kloro-2-{[(3S)-3-(morfolin-4-ilmetil)-3,4-dihidroizokinolin-2(1H)-il]-karbonil}fenil)-N-(4-hidroksifenil)-],2-dimetil-N-(l-metil-1H-pirolo[2,3-b]piridin-5-il)-1H-pirol-3-karboksamida, -5-(5-kloro-2-{[(3S)-3-(morfolin-4-ilmetil)-3,4-dihidroizokinolin-2(1H)-il]-karbonil}fenil)-N-(4-hidroksifenil)-1,2-dimetil-N-(piridin-4-il)-1 H-pirol-3-karboksamida, -5-(5-kloro-2-{[(3S)-3-(morfolin-4-ilmetil)-3,4-dihidroizokinolin-2(1H)-il]-karbonil}fenil)-N-(5-cijano-1-metil-1 H-pirol-3-il)-N-(4-hidroksifenil)-1,2-dimetil-1H-pirol-3-karboksamida, -A'-(5-cijano-l-metil-1H-piroI-3-il)-5-(5-fluoro-2-{[(3S)-3-(morfolin-4-ilmetil)-3,4-dihidroizokinolin-2(1H)-il]karbonil}fenil)-N-(4-hidroksifenil)-1,2-dimetil-1H-pirol-3-karboksamida, -5-(5-kloro-2-{[(3S)-3-(morfolin-4-ilmetil)-3,4-dihidroizokinolin-2(1H)-il]-karbonil}fenil)-N-(5-cijano-l,2-dimetil-1H-pirol-3-il)-N-(4-hidroksifenil)-l,2-dimetil-1H-pirol-3-karboksamida, -5-(5-kloro-2-{[(3S)-3-(morfolin-4-ilmetil)-3,4-dihidroizokinolin-2(1H)-il]-karbonil(fenil)-N-(4-hidroksifenil)-1,2-dimetil-N-( 1 -metil-2,3-dihidro-1H-pirolo[2,3-b]piridin-5-il)-1H-pirol-3-karboksamida, -.V-(5-cijano-l,2-dimetil-1H-pirol-3-il)-5-(5-fluoro-2-{[(3S)-3-(morfolin-4-il-metil)-3,4dihidroizokinolin-2(1H)-ilJkarbonil(fenil)-N-(4-hidroksifenil)-l,2-dimetil-l H-pirol-3-karboksamida, -5-(5-kloro-2-{[(3S)-3-(morfolin-4-ilmetil)-3,4-dihidroizokinolin-2(1H)-il]-karbonil}fenil)-N- [5-cijano-2-metil-l-(trideuteriometil)-1 H-pirol-3-il]-N-(4-hidroksifenil)-1,2-dimetil-1 H-pirol-3-karboksamida, njihovih enantiomera i dijastereoizomera te njihovih adicijskih soli s farmaceutski prihvatljivom kiselinom ili lužinom.
7. Spoj formule (I) u skladu s patentnim zahtjevom 6, naznačen time, da je 5-(5-kloro-2-{[(3S)-3- (morfolin-4-ilmetil)-3,4-dihidroizokinolin-2(1H)-il]karbonil}fenil)-N-(4-hidroksifenil)-l,2-dimetil-N-(l-metil-1H-pirazol-4-il)-1H-pirol-3-karboksamid.
8. Spoj formule (1) u skladu s patentnim zahtjevom 6, naznačen time, da je 5-(5-kloro-2-{[(3R)-3-metil-3,4- dihidroizokinolin-2(1H)-il]karbonil}fenil)-N-(4-hidroksifenil)-l,2-dimetil-N-(piridin-4-il)-1H-pirol-3-karboksamid.
9. Spoj formule (I) u skladu s patentnim zahtjevom 6, naznačen time, da je N-(4-hidroksifenil)-1,2- dimetil-N-(1-metil-1H-pirazol-4-il)-5-(6-[(3S)-3-(morfolin-4-ilmetil)-3,4-dihidroizokinolin-2(1H)-il]karbonil}-1,3-benzodioksol-5-il)-1H-pirol-3-karboksamid.
10. Spoj formule (1) u skladu s patentnim zahtjevom 6, naznačen time, da je N-(4-hidroksifenil)-l,2- dimetil-5-(6-{[(3R)-3-metil-3,4-dihidroizokinolin-2(1H)-il]karbonil}-1,3-benzodioksol-5-il)-N-(piridin-4-il)-1H-pirol-3 karboksamid.
11. Spoj formule (1) u skladu s patentnim zahtjevom 6, naznačen time, da je 5-(5-fluoro-2-{[(3S)-3- (morfolin-4-ilmetil)-3,4-dihidroizokinolin-2(1H)-il]karbonil}fenil)-N-(4-hidroksifenil)-l,2-dimetil-N-(l-metil-1H-pirazol-4-il)-1H-pirol-3-karboksamid.
12. Spoj formule (1) u skladu s patentnim zahtjevom 6, naznačen time, da je 5-(5-kloro-2-{[(3S)-3- (morfolin-4-ilmetil)-3,4-dihidroizokinolin-2(1H)-il]karbonil}fenil)-N-(4-hidroksifenil)-1,2-dimetil-N-(1 -metil-1H-pirolo[2,3-b]piridin-5-il)-1H-pirol-3-karboksamid.
13. Spoj formule (1) u skladu s patentnim zahtjevom 6, naznačen time, da je 5-(5-kloro-2-{[(3S)-3- (morfolin-4-ilmetil)-3,4-dihidroizokinolin-2(1H)-il]karbonil}fenil)-N-(4-hidroksifenil)-1,2-dimetil-N-(piridin-4-il)-lH-pirol-3-karboksamid.
14. Spoj formule (I) u skladu s patentnim zahtjevom 6, naznačen time, da je 5-(5-kloro-2-{[(3S)-3- (morfolin-4-ilmetil)-3,4-dihidroizokinolin-2(1H)-il]karbonil}fenil)-N-(5-cijano-l-metil-1H-pirol-3-il)-N-(4-hidroksifenil)-l,2-dimetil-1H-pirol-3-karboksamid.
15. Spoj formule (I) u skladu s patentnim zahtjevom 6, naznačen time, da je N-(5-cijano-1- metil-1H-pirol-3-il)-5-(5-fluoro-2-{[(3S)-3-(morfolin-4-ilmetil)-3,4-dihidroizokinolin-2(1H)-il]karbonil}fenil)-N-(4-hidroksifenil)-1,2-dimetil-1H-pirol-3-karboksamid.
16. Spoj formule (I) u skladu s patentnim zahtjevom 6, naznačen time, da je 5-(5-kloro-2-{[(3S)-3- (morfolin-4-ilmetil)-3,4-dihidroizokinolin-2(1H)-il]karbonil}fenil)-N-(5-cijano-1,2-dimetil-1H-pirol-3-il)-N-(4-hidroksifenil)-1,2-dimetil-1H-pirol-3-karboksamid.
17. Spoj formule (I) u skladu s patentnim zahtjevom 6, naznačen time, da je 5-(5-kloro-2-{[(3S)-3- (morfolin-4-ilmetil)-3,4-dihidroizokinolin-2(1H)-il]karbonil}fenil)-N-(4-hidroksifenil)-l,2-dimetil-N-(l-metil-2,3-dihidro-1H-pirolo[2,3-b]piridin-5-il)-1H-pirol-3-karboksamid.
18. Spoj formule (I) u skladu s patentnim zahtjevom 6, naznačen time, da je N-(5-cijano-1,2-dimetil-1H- pirol-3-il)-5-(5-fluoro-2-{[(3S)-3-(morfolin-4-ilmetil)-3,4-dihidroizokinolin-2(1H)-il]karbonil}fenil)-N-(4-hidroksifenil)-1,2-dimetil-1H-pirol-3-karboksamid.
19. Spoj formule (I) u skladu s patentnim zahtjevom 6, naznačen time, da je 5-(5-kloro-2-{[(3S)-3- (morfolin-4-ilinctil)-3,4-dihidroizokinolin-2(1H)-il]karbonil}fenil)-N-[5-cijano-2-metil-l-(trideuteriometil)-1H-pirol-3-il]-N-(4-hidroksifenil)-l,2-dimetil-1H-pirol-3-karboksamid.
20. Postupak za pripravu spojeva formule (I) u skladu s patentnim zahtjevom I, naznačen time, da je kao početni materijal korišten spoj formule (II): [image] pri čemu su Ra, Rb, Rc i Rd kako je definirano za formulu (I), koji spoj formule (II) je izložen Heckovoj reakciji u vodenom ili organskom mediju u nazočnosti paladijevog katalizatora, lužine, fosfina i spoja formule (III): [image] gdje su skupine A1 i A2 kako je definirano za formulu (I) i Alk predstavlja ravni ili razgranani (C1-C6)alkil, kako bi se dobio spoj formule (IV): [image] pri čemu su A1, A2, Ra, Rb. Rc i Rd definirani za formulu (I) i Alk je ranije gore definiran, funkcija aldehida kojim je spoj formule (IV) oksidiran u karboksilnu kiselinu kako bi se dobio spoj formule (V): [image] pri čemu su A1; A2, Ra, Rb, Rc i Rd defininirani za formulu (I) i Alk je ranije gore definiran, koji se spoj formule (V) potom izlaže spajanju peptida sa spojem formule (VI): [image] pri čemu su T i R5 definirani za formulu (I), kako bi se dobio spoj formule (VII): [image] pri čemu su A1, A2, Ra, Rb, Rc i Rd, T i R5 definirano za formulu (I) i Alk je ranije gore definiran, esterska funkcija kojom je hidraliziran spoj formule (VII) kako bi se dobila odgovarajuća karboksilna kiselina ili karboksilat, koji se može pretvoriti u derivat kiseline poput primjerice u acil-klorida ili anhidrid prije spajanja s NHR3R4 aminom, gdje R3 i R4 imaju ista značenja kao za formulu (I), kako bi se dobio spoj formule (I), koji se spoj formule (I) može pročišćavati u skladu s uobičajenim tehnikama separacije, koji se može pretvoriti, ako je poželjno, u svoje adicijske soli s farmaceutski prihvatljivom kiselinom ili lužinom i koji je po izboru razdvojen u svoje izomere u skladu s uobičajenim tehnikama separacije, gdje se podrazumijeva, da se bilo koje vrijeme smatra prikladnim u smislu gore opisanog postupka, izvjesne skupine (hidroksi, amino...) reagensa ili intermedijera sinteze mogu biti zaštićene a potom im se skida zaštita u skladu sa zahtjevima sinteze.
21. Postupak u skladu s patentnim zahtjevom 20 za pripravu spoja formule (I) gdje je jedna od skupina R3 ili R4 supstituirana s hidroksi funkcijom, naznačen time, da je amin NHR3R4 prije toga izložen reakciji štiteći hidroksi funkciju prije bilo kakvog spajanja s karboksilnom kiselinom dobivenom od spoja formule (VII) ili s odgovarajućim derivatom kiseline, dobiveni zaštićeni spoj formule (I) naknadno se podvrgava reakciji skidanja zaštite a potom se po izboru pretvara u jednu od njegovih adicijskih soli s farmaceutski prihvatljivom kiselinom ili lužinom.
22. Farmaceutski pripravak koji sadrži spoj formule (1) u skladu s bilo kojim od patentnih zahtjeva 1 do 19 ili njegove adicijske soli s farmaceutski prihvatljivom kiselinom ili lužinom, naznačen time, daje u kombinaciji s jednim ili više farmaceutski prihvatljivih ekscipijensa.
23. Farmaceutski pripravak u skladu s patentnim zahtjevom 22, naznačen time, da je za uporabu kao pro-apoptotičko sredstvo.
24. Farmaceutski pripravak u skladu s patentnim zahtjevom 22, naznačen time, da je za uporabu u liječenju karcinoma, autoimunih bolesti i bolesti imunog sustava.
25. Farmaceutski pripravak u skladu s patentnim zahtjevom 22, naznačen time, da je za uporabu u liječenju raka mjehura, mozga, dojki i maternice, kronične limfoidne leukemije, raka debelog crijeva, raka jednjaka i jetre, leukemije limfoblasta, ne-Hodgkinovog limfoma, melanoma, maligne hemopatije, mijcloma, raka jajnika, raka pluća nc-malih stanica, raka prostate i raka pluća malih stanica.
26. Uporaba farmaceutskog pripravka u skladu s patentnim zahtjevom 22, naznačena time, da je za proizvodnju lijeka za uporabu kao apoptotičkog sredstva.
27. Uporaba farmaceutskog pripravka u skladu s patentnim zahtjevom 22, naznačena time, da je za proizvodnju lijeka za liječenje karcinoma, bolesti imunog sustava i auto-imunih bolesti.
28. Uporaba farmaceutskog pripravka u skladu s patentnim zahtjevom 22, naznačena time, da je za proizvodnju lijeka namijenjenog za liječenje raka mjehura, mozga, dojki i maternice, kronične limfoidne leukemije, raka debelog crijeva, raka jednjaka i jetre, leukemije limfoblasta, ne-Hodgkinovog limfoma, melanoma, maligne hemopatije, mijeloma, raka jajnika, raka pluća nc-malih stanica, raka prostate i raka pluća malih stanica.
29. Spoj formule (I) u skladu s jednim od patentnih zahtjeva 1 do 19, ili njegova adicijska sol s farmaceutski prihvatljivom kiselinom ili lužinom, naznačen time, da se koristi u liječenju raka mjehura, mozga, dojki i maternice, kronične limfoidne leukemije, raka debelog crijeva, raka jednjaka i jetre, leukemije limfoblasta, ne-Hodgkinovog limfoma, melanoma, maligne hemopatije, mijeloma, raka jajnika, raka pluća ne-malih stanica, raka prostate i raka pluća malih stanica.
30. Uporaba spoja formule (I) u skladu s jednim od patentnih zahtjeva 1 do 19, ili njegova adicijska sol s farmaceutski prihvatljivom kiselinom ili lužinom, naznačen time, da je za proizvodnju lijeka namijenjenog za liječenje raka mjehura, mozga, dojki i maternice, kronične limfoidne leukemije, raka debelog crijeva, raka jednjaka i jetre, leukemije limfoblasta, ne-Hodgkinovog limfoma, melanoma, maligne hemopatije, mijeloma, raka jajnika, raka pluća ne-malih stanica, raka prostate i raka pluća malih stanica.
31. Kombinacija spoja formule (I) u skladu s bilo kojim od patentnih zahtjeva 1 do 19, naznačen time, da se kombinira s protutumorskim sredstvom koje je odabrano od genotoksičnih sredstava, mitotičkih otrova, antimetabolita, inhibitora proteazoma, inhibitora kinaze i protutijela.
32. Farmaceutski pripravak koji sadrži kombinaciju u skladu s patentnim zahtjevom 31, naznačen time, da se kombinira s jednim ili više farmaceutski prihvatljivih ekscipijensa.
33. Kombinacija u skladu s patentnim zahtjevom 31, naznačeno time, da je za uporabu u liječenju karcinoma.
34. Uporaba kombinacije u skladu s patentnim zahtjevom 31, naznačena time, da je za proizvodnju lijeka za uporabu u liječenju karcinoma.
35. Spoj formule (I) u skladu s bilo kojim od patentnih zahtjeva 1 do 19, naznačen time, da je za uporabu u kombinaciji s radioterapijom za liječenje karcinoma.
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