ME02635B - 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

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Publication number
ME02635B
ME02635B MEP-2017-63A MEP201763A ME02635B ME 02635 B ME02635 B ME 02635B ME P201763 A MEP201763 A ME P201763A ME 02635 B ME02635 B ME 02635B
Authority
ME
Montenegro
Prior art keywords
formula
compound
dimethyl
morpholin
hydroxyphenyl
Prior art date
Application number
MEP-2017-63A
Other languages
German (de)
English (en)
French (fr)
Inventor
Tiran Arnaud Le
Diguarher Thierry Le
Jérôme-Benoît Starck
Jean-Michel Henlin
Anne-Françoise Guillouzic
Nanteuil Guillaume De
Olivier Geneste
Imre Fejes
Janos Tatai
Miklos Nyerges
James Edward Paul Davidson
James Brooke Murray
I-Jen Chen
Didier Durand
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.)
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Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=50023639&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=ME02635(B) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Servier Lab, Vernalis R&D Ltd filed Critical Servier Lab
Publication of ME02635B publication Critical patent/ME02635B/me

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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • C07D401/02—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
    • C07D401/10—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 carbon chain containing aromatic rings
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    • C07D401/02—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
    • 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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    • 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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  • Psychiatry (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pyrrole Compounds (AREA)
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Claims (35)

1. Spoj formule (I): 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 (I) u skladu s patentnim zahtjevom 1, naznačen time, da A1 predstavlja atom vodika ili metilnu skupinu.
3. Spoj formule (I) 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-1-il)metil, 2-(morfolin-4-il)etil, [2-(morfolin-4-il)etoksi]metil, hidroksimetil,[2-(dimetilamino)etoksi]metil, heksahidropirazino[2,1-c][1,4]oksazin-8(1H)-ilmetil, 1-oksa-6-azaspiro[3.3]hept-6-ilmetil, 3-(morfolin-4-il)propilnu ili trifluorometilnu skupinu.
5. Spoj formule (I): 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-b]piridina, 2,3-dihidro-1H-pirolo[2,3-b]piridina, 1H-benzimidazola, 1H-pirola, 1H-pirolo[2,3- c]piridina, 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-(1-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)-1,2- dimetil-N-(piridin-4-il)-1H-pirol-3-karboksamida, - 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-benzoadioksol-5-il)-1H-pirol-3-karboksamida, - N-(4-hidroksifenil)-1,2-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-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-1H-pirazol-4-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-(1-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)-1H-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-1H-pirol-3-il)-N-(4-hidroksifenil)-1,2-dimetil-1H-pirol-3-karboksamida, - 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-karboksamida, - 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-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, - N-(5-cijano-1,2-dimetil-1H-pirol-3-il)-5-(5-fluoro-2-{[(3S)-3-(morfolin-4-il-metil)-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-2-metil-1-(trideuteriometil)-1H-pirol-3-il]-N-(4-hidroksifenil)-1,2-dimetil-1H-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)-1,2-dimetil-N-(1-metil-1H-pirazol-4-il)-1H-pirol-3-karboksamid.
8. Spoj formule (I) 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)-1,2-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 (I) u skladu s patentnim zahtjevom 6, naznačen time, da je N-(4-hidroksifenil)-1,2-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 (I) 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)-1,2-dimetil-N-(1-metil-1H-pirazol-4-il)-1H-pirol-3-karboksamid.
12. 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)-1,2-dimetil-N-(1-metil-1H-pirolo[2,3-b]piridin-5-il)-1H-pirol-3-karboksamid.
13. 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)-1,2-dimetil-N-(piridin-4-il)-1H-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-1-metil-1H-pirol-3-il)-N-(4-hidroksifenil)-1,2-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)-1,2-dimetil-N-(1-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-ilmetil)-3,4-dihidroizokinolin-2(1H)-il]karbonil}fenil)-N-[5-cijano-2-metil-1-(trideuteriometil)-1H-pirol-3-il]-N-(4-hidroksifenil)-1,2-dimetil-1H-pirol-3-karboksamid.
20. Postupak za pripravu spojeva formule (I) u skladu s patentnim zahtjevom 1, naznačen time, da je kao početni materijal korišten spoj formule (II): 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): 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): 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): 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): pri čemu su T i R5 definirani za formulu (I), kako bi se dobio spoj formule (VII): 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 (I) u skladu s bilo kojim od patentnih zahtjeva 1 do 19 ili njegove adicijske soli s farmaceutski prihvatljivom kiselinom ili lužinom, naznačen time, da je 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, mijeloma, raka jajnika, raka pluća ne-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 ne-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 farmaceutksi 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 farmaceutksi 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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