HRP20100561T1 - Inhibitori interakcije između mdm2 i p53 - Google Patents

Inhibitori interakcije između mdm2 i p53 Download PDF

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HRP20100561T1
HRP20100561T1 HR20100561T HRP20100561T HRP20100561T1 HR P20100561 T1 HRP20100561 T1 HR P20100561T1 HR 20100561 T HR20100561 T HR 20100561T HR P20100561 T HRP20100561 T HR P20100561T HR P20100561 T1 HRP20100561 T1 HR P20100561T1
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6alkyl
hydroxy
hydrogen
substituted
heteroaryl
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Fernand Armand Lacrampe Jean
Meyer Christophe
Aim� Eddy Ligny Yannick
Christian Francis Csoka Imre
Van Hijfte Luc
Arts Janine
Schoentjes Bruno
Georges Wermuth Camille
Giethlen Bruno
Contreras Jean-Marie
Joubert Muriel
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Janssen Pharmaceutica Nv
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Abstract

Spoj formule (I), njegov N-oksidni oblik, adicijska sol ili stereokemijski izomerni oblik, naznačen time, dam je 0, 1, ili 2 i kada m je 0 tada je namjeravana direktna veza ; n je 0, 1, 2, ili 3 i kada n je 0 tada je namjeravana direktna veza ; p je 0, ili 1 i kada p je 0 tada je namjeravana direktna veza ; s je 0, ili 1 i kada s je 0 tada je namjeravana direktna veza ; t je 0 ili 1 i kada t je 0 tada je namjeravana direktna veza ; X je C(=O) ili CHR8; pri čemuR8 je vodik, C1-6alkil, C3-7cikloalkil, -C(=O)-NR17R18, hidroksikarbonil, arilC1-6alkiloksikarbonil, heteroaril, heteroarilkarbonil, heteroarilC1-6alkiloksikarbonil, piperazinilkarbonil, pirolidinil, piperidinilkarbonil, C1-6

Claims (25)

1. Spoj formule (I), [image] njegov N-oksidni oblik, adicijska sol ili stereokemijski izomerni oblik, naznačen time, da m je 0, 1, ili 2 i kada m je 0 tada je namjeravana direktna veza ; n je 0, 1, 2, ili 3 i kada n je 0 tada je namjeravana direktna veza ; p je 0, ili 1 i kada p je 0 tada je namjeravana direktna veza ; s je 0, ili 1 i kada s je 0 tada je namjeravana direktna veza ; t je 0 ili 1 i kada t je 0 tada je namjeravana direktna veza ; X je C(=O) ili CHR8; pri čemu R8 je vodik, C1-6alkil, C3-7cikloalkil, -C(=O)-NR17R18, hidroksikarbonil, arilC1-6alkiloksikarbonil, heteroaril, heteroarilkarbonil, heteroarilC1-6alkiloksikarbonil, piperazinilkarbonil, pirolidinil, piperidinilkarbonil, C1-6alkiloksikarbonil, C1-6alkil supstituiran sa supstituentom odabranim od hidroksi, amino, arila, i heteroarila; C3-7cikloalkil supstituiran sa supstituentom odabranim od hidroksi, amino, arila, i heteroarila; piperazinilkarbonil supstituiran sa hidroksi, hidroksiC1-6alkil, hidroksiC1-6alkiloksiC1-6alkil; pirolidinil supstituiran sa hidroksiC1-6alkil; ili piperidinilkarbonil supstituiran sa jednim ili dva supstituenta odabranim od hidroksi, C1-6alkila, hidroksiC1-6alkila, C1-6alkiloksiC1-6alkila, C1-balkil(dihidroksi)C1-6alkila ili C1-6alkiloksi(hidroksi)C1-6alkila; R17 i R18 su svaki nezavisno odabrani od vodika, C1-6alkila, di(C1-6alkil)aminoC1-6alkila, arilC1-6alkila, C1-6alkiloksiC1-6alkila, hidroksiC1-6alkila, hidroksiC1-6alkil(C1-6alkil) ili hidroksiC1-6alkil(arilC1-6alkil); [image] je -CR9=C< i tada je isprekidana crta veza, -CHR9-CH< ili -CHR9-N<; pri čemu svaki R9 je nezavisno vodik ili C1-6alkil; R1 je vodik, aril, heteroaril, C1-6alkiloksikarbonil, C1-12alkil, ili C1-12alkil supstituiran sa jednim ili dva supstituenta nezavisno odabrana od hidroksi, arila, heteroarila, amino, C1-6alkiloksi, mono- ili di(C1-6alkil)amino, morfolinila, piperidinila, pirolidinila, piperazinila, C1-6alkilpiperazinila, arilC1-6alkilpiperazinila, heteroarilC1-6alkilpiperazinila, C3-7cikloalkilpiperazinila i C3-7cikloalkilC1-6alkilpiperazinila; R2 je vodik, halo, C1-6alkil, C1-6alkiloksi, arilC1-6alkiloksi, heteroarilC1-6alkiloksi, feniltio, hidroksiC1-6alkilkarbonil, C1-6alkil supstituiran sa supstituentom odabranim od amino, arila i heteroarila; ili C3-7cikloalkil supstituiran sa supstituentom odabranim od amino, arila i heteroarila; R3 je vodik, C1-6alkil, heteroaril, C3-7cikloalkil, C1-6alkil supstituiran sa supstituentom odabranim od hidroksi, amino, arila i heteroarila; ili C3-7cikloalkil supstituiran sa supstituentom odabranim od hidroksi, amino, arila i heteroarila; R4 i R5 su svaki nezavisno vodik, halo, C1-6alkil, polihaloC1-6alkil, cijano, cijanoC1-6alkil, hidroksi, amino ili C1-6alkiloksi; ili R4 i R5 zajedno mogu po izboru tvoriti bivalentni radikal odabran od metilendioksi ili etilendioksi; R6 je vodik, C1-6alkiloksikarbonil ili C1-6alkil; kada p je 1 onda R7 je vodik, arilC1-6alkil, hidroksi ili heteroarilC1-6alkil; Z je radikal odabran od [image] [image] [image] pri čemu svaki R10 ili R11 su svaki nezavisno odabrani od vodika, halo, hidroksi, amino, C1-6alkila, nitro, polihaloC1-6alkila, cijano, cijanoC1-6alkila, tetrazoloC1-6alkila, arila, heteroarila, arilC1-6alkila, heteroarilC1-6alkila, aril(hidroksi)C1-6alkila, heteroaril(hidroksi)C1-6alkila, arilkarbonila, heteroarilkarbonila, C1-6alkilkarbonila, arilC1-6alkilkarbonila, heteroarilC1-6alkilkarbonila, C1-6alkiloksi, C3-7cikloalkilkarbonila, C3-7cikloalkil(hidroksi)C1-6alkila, arilC1-6alkiloksiC1-6alkila, C1-6alkiloksiC1-6alkiloksiC1-6alkila, C1-6alkilkarboniloksiC1-6alkila, C1-6alkiloksikarbonilC1-6alkiloksiC1-6alkila, hidroksiC1-6alkiloksiC1-6alkila, C1-6alkiloksikarbonilC2-6alkenila, C1-6alkiloksiC1-6alkila, C1-6alkiloksikarbonila, C1-6alkilkarboniloksi, aminokarbonila, hidroksiC1-6alkila, aminoC1-6alkila, hidroksikarbonila, hidroksikarbonilC1-6alkil i -(CH2)v-(C(=O)r)-(CHR19)uNR13R14; pri čemu v je 0, 1, 2, 3, 4, 5, ili 6 i kada v je 0 tada je namjeravana direktna veza; r je 0, ili 1 i kada r je 0 tada je namjeravana direktna veza; u je 0, 1, 2, 3, 4, 5, ili 6 i kada u je 0 tada je namjeravana direktna veza; R19 je vodik ili C1-6alkil; R12 je vodik, C1-6alkil, C3-7cikloalkil, C1-6alkil supstituiran sa supstituentom odabranim od hidroksi, amino, C1-6alkiloksi i aril; ili C3-7cikloalkil supstituiran sa supstituentom odabranim od hidroksi, amino, aril i C1-6alkiloksi; R13 i R14 su svaki nezavisno odabrani od vodika, C1-12alkila, C1-6alkilkarbonila, C1-6alkilsulfonila, arilC1-6alkilkarbonila, C3-7cikloalkila, C3-7cikloalkilkarbonila, -(CH2)k-NR15R16, C1-12alkila supstituiran sa supstituentom odabranim od hidroksi, hidroksikarbonil, cijano, C1-6alkiloksikarbonila, C1-6alkiloksi, aril ili heteroaril; ili C3-7cikloalkil supstituiran sa supstituentom odabranim od hidroksi, C1-6alkiloksi, arila, amino, arilC1-6alkila, heteroarila ili heteroarilC1-6alkila; ili R13 i R14 zajedno sa dušikom na koji su vezani mogu po izboru tvoriti morfolinil, piperidinil, pirolidinil, piperazinil, ili piperazinil supstituiran sa supstituentom odabranim od C1-6alkila, arilC1-6alkila, arilC1-6alkiloksikarbonila, heteroarilC1-6alkila, C3-7cikloalkil i C3-7cikloalkilC1-6alkila; pri čemu k je 0, 1, 2, 3, 4, 5, ili 6 i kada k je 0 tada je namjeravana direktna veza; R15 i R16 su svaki nezavisno odabrani od vodika, C1-6alkila, arilC1-6alkiloksikarbonila, C3-7cikloalkila, C1-12alkila supstituiran sa supstituentom odabranim od hidroksi, C1-6alkiloksi, arila, i heteroarila; i C3-7cikloalkil supstituiran sa supstituentom odabranim od hidroksi, C1-6alkiloksi, arila, arilC1-6alkila, heteroarila, i heteroarilC1-6alkila; ili R15 i R16 zajedno sa dušikom na koji su vezani mogu po izboru tvoriti morfolinil, piperazinil ili piperazinil supstituiran sa C1-6alkiloksikarbonil; aril je fenil ili naftalenil; svaki fenil ili naftalenil može po izboru biti supstituiran sa jednim, dva ili tri supstituenta svaki nezavisno odabran od halo, hidroksi, C1-6alkil, amino, polihaloC1-6alkil i C1-6alkiloksi; i svaki fenil ili naftalenil može po izboru biti supstituiran sa bivalentnim radikalom odabranim od metilendioksi i etilendioksi; heteroaril je piridinil, indolil, kvinolinil, imidazolil, furanil, tienil, oksadiazolil, tetrazolil, benzofuranil ili tetrahidrofuranil; svaki piridinil, indolil, kvinolinil, imidazolil, furanil, tienil, oksadiazolil, tetrazolil, benzofuranil, ili tetrahidrofuranil može po izboru biti supstituiran sa jednim, dva ili tri supstituenta svaki nezavisno odabran od halo, hidroksi, C1-6alkil, amino, polihaloC1-6alkil, aril, arilC1-6alkil ili C1-6alkiloksi; i svaki piridinil, indolil, kvinolinil, imidazolil, furanil, tienil, benzofuranil, ili tetrahidrofuranil može po izboru biti supstituiran sa bivalentnim radikalom odabranim od metilendioksi ili etilendioksi; s time da kada m je 1; supstituenti na fenilnom prstenu koji nisu R2 su na meta položaju; s je 0; i t je 0; tada Z je radikal odabran od (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8) ili (a-9).
2. Spoj prema zahtjevu 1 naznačen time, da X je C(=O) ili CHR8 pri čemu R8 je vodik, C1-6alkil, C3-7cikloalkil, aminokarbonil, mono- ili di(C1-6alkil)aminokarbonil, hidroksikarbonil, arilC1-6alkiloksikarbonil, heteroarilC1-6alkiloksikarbonil, C1-6alkiloksikarbonil, C1-6alkil supstituiran sa supstituentom odabranim od hidroksi, amino, arila, i heteroarila ili C3-7cikloalkil supstituiran sa supstituentom odabranim od hidroksi, amino, arila i heteroarila; R1 je vodik, aril, heteroaril, C1-12alkil, ili C1-12alkil supstituiran sa jednim ili dva supstituenta nezavisno odabrana od hidroksi, arila, heteroarila, amino, C1-6alkiloksi, mono- ili di(C1-6alkil)amino, morfolinila, piperidinila, pirolidinila, piperazinila, C1-6alkilpiperazinila, arilC1-6alkilpiperazinila,heteroarilC1-6alkilpiperazinila, C3-7cikloalkilpiperazinil i C3-7cikloalkilC1-6alkilpiperazinil; R3 je vodik, C1-6alkila, C3-7cikloalkila, C1-6alkil supstituiran sa supstituentom odabranim od hidroksi, amino, arila i heteroarila; ili C3-7cikloalkil supstituiran sa supstituentom odabranim od hidroksi, amino, arila i heteroarila; R4 i R5 su svaki nezavisno vodik, halo, C1-6alkil, polihaloC1-6alkil, hidroksi, amino ili C1-6alkiloksi; R4 i R5 zajedno mogu po izboru oblikovati bivalentni radikal odabran od metilendioksi ili etilendioksi; R6 je vodik ili C1-6alkil; kada p je 1 tada R7 je vodik, arilC1-6alkil ili heteroarilC1-6alkil; Z je radikal odabran od (a-1), (a-2), (a-3), (a-4), (a-5) i (a-6); svaki R10 ili R11 su svaki nezavisno odabrani od vodika, hidroksi, amino, C1-6alkila, nitro, polihaloC1-6alkila, cijano, cijanoC1-6alkila, tetrazoloC1-6alkila, arila, heteroarila, arilC1-6alkila, heteroarilC1-6alkila, aril(hidroksi)C1-6alkila, heteroaril(hidroksi)C1-6alkila, arilkarbonila, heteroarilkarbonila, arilC1-6alkilkarbonila, heteroarilC1-6alkilkarbonila, C1-6alkiloksi, C1-6alkiloksiC1-6alkila, C1-6alkiloksikarbonila, C1-6alkilkarboniloksi, aminokarbonila, hidroksiC1-6alkila, aminoC1-6alkila, hidroksikarbonila, hidroksikarbonilC1-6alkila i -(CH2)v-(C(=O)r)-(CH2)u-NR13R14; R13 i R14 su svaki nezavisno odabrani od vodika, C1-12alkila, C3-7cikloalkila, -(CH2)k-NR15R16, C1-12alkila supstituiranog sa supstituentom odabranim od hidroksi, C1-6alkiloksi, arila, i heteroarila; ili C3-7cikloalkil supstituiran sa supstituentom odabranim od hidroksi, C1-6alkiloksi, arila, arilC1-6alkila, heteroarila i heteroarilC1-6alkila; R13 i R14 zajedno sa dušikom na koji su vezani mogu po izboru tvoriti morfolinil, piperidinil, pirolidinil, piperazinil, ili piperazinil supstituiran sa supstituentom odabranim od C1-6alkila, arilC1-6alkila, heteroarilC1-6alkila, C3-7cikloalkila, i C3-7cikloalkilC1-6alkila; R15 i R16 su svaki nezavisno odabrani od vodika, C1-6alkila, C3-7cikloalkila, C1-12alkila supstituiranog sa supstituentom odabranim od hidroksi, C1-6alkiloksi, arila, i heteroarila; i C3-7cikloalkil supstituiran sa supstituentom odabranim od hidroksi, C1-6alkiloksi, arila, arilC1-6alkila, heteroarila i heteroarilC1-6alkila; heteroaril je piridinil, indolil, kvinolinil, imidazolil, furanil, tienil, benzofuranil, ili tetrahidrofuranil; i svaki piridinil, indolil, kvinolinil, imidazolil, furanil, tienil, benzofuranil, ili tetrahidrofuranil može po izboru biti supstituiran sa jednim, dva ili tri supstituenta svaki nezavisno odabran od halo, hidroksi, C1-6alkila, amino, polihaloC1-6alkila i C1-6alkiloksi, ili svaki piridinil, indolil, kvinolinil, imidazolil, furanil, tienil, benzofuranil ili tetrahidrofuranil može po izboru biti supstituiran sa bivalentnim radikalom odabranim od metilendioksi ili etilendioksi.
3. Spoj prema zahtjevu 1 naznačen time, da: R8 je vodik, -C(=O)-NR17R18, arilC1-6alkiloksikarbonil, C1-6alkil supstituiran sa hidroksi, piperazinilkarbonil supstituiran sa hidroksi, hidroksiC1-6alkil, hidroksiC1-6alkiloksiC1-6alkil, pirolidinil supstituiran sa hidroksiC1-6alkil ili piperidinilkarbonil supstituiran sa jednim ili dva supstituenta odabranim od hidroksi, C1-6alkil, hidroksiC1-6alkil, C1-6alkiloksiC1-6alkil, C1-6alkil(dihidroksi)C1-6alkil ili C1-6alkiloksi(hidroksi)C1-6alkil; R17 i R18 su svaki nezavisno odabrani od vodika, C1-6alkila, di(C1-6alkil)aminoC1-6alkila, arilC1-6alkila, C1-6alkiloksiC1-6alkil ili hidroksiC1-6alkila; [image] je -CR9=C< i tada je isprekidana crta veza, -CHR9-CH< ili -CHR9-N<; R1 je vodik, heteroaril, C1-6alkiloksikarbonil, C1-12alkil ili C1-12alkil supstituiran sa heteroaril; R2 je vodik, halo, C1-6alkil, C1-6alkiloksi, arilC1-6alkiloksi ili feniltio; R3 je vodik, C1-6alkil ili heteroaril; R4 i R5 su svaki nezavisno vodik, halo, C1-6alkil, cijano, cijanoC1-6alkil, hidroksi ili C1-6alkiloksi; kada p je 1 tada R7 je arilC1-6alkil ili hidroksi; Z je radikal odabran od (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-8), (a-9), (a-10) i (a-11); svaki R10 ili R11 su svaki nezavisno odabrani od vodika, halo, hidroksi, amino, C1-6alkila, nitro, polihaloC1-6alkila, cijano, cijanoC1-6alkila, tetrazoloC1-6alkila, arila, heteroarila, heteroarilC1-6alkila, aril(hidroksi)C1-6alkila, arilkarbonila, C1-6alkilkarbonila, C3-7cikloalkilkarbonila, C3-7cikloalkil(hidroksi)C1-6alkila, arilC1-6alkiloksiC1-6alkila, C1-6alkiloksiC1-6alkiloksiC1-6alkila, C1-6alkilkarboniloksiC1-6alkila, C1-6alkiloksikarbonilC1-6alkiloksiC1-6alkila, hidroksiC1-6alkiloksiC1-6alkila, C1-6alkiloksikarbonilC2-6alkenila, C1-6alkiloksiC1-6alkila, C1-6alkiloksikarbonila, aminokarbonila, hidroksiC1-6alkila, aminoC1-6alkila, hidroksikarbonila, hidroksikarbonilC1-6alkila i -(CH2)v-(C(=O)r)-(CHR19)u-NR13R14; v je 0 ili 1; u je 0 ili 1; R12 je vodik ili C1-6alkil; R13 i R14 su svaki nezavisno odabrani od vodika, C1-12alkila, C1-6alkilkarbonila, C1-6alkilsulfonila, arilC1-6alkilkarbonila, C3-7cikloalkilkarbonila, -(CH2)k-NR15R16, C1-12alkila supstituiranog sa supstituentom odabranim od hidroksi, hidroksikarbonil, cijano, C1-6alkiloksikarbonil ili aril; R13 i R14 zajedno sa dušikom na koji su vezani mogu po izboru tvoriti morfolinil, pirolidinil, piperazinil ili piperazinil supstituiran sa supstituentom odabranim od C1-6alkil ili arilC1-6alkiloksikarbonil; k je 2; R15 i R16 su svaki nezavisno odabrani od vodika, C1-6alkila ili arilC1-6alkiloksikarbonila; R15 i R16 zajedno sa dušikom na koji su vezani mogu po izboru tvoriti morfolinil ili piperazinil, ili piperazinil supstituiran sa C1-6alkiloksikarbonil; aril je fenil ili fenil supstituiran sa halo; heteroaril je piridinil, indolil, oksadiazolil ili tetrazolil; i svaki piridinil, indolil, oksadiazolil ili tetrazolil može po izboru biti supstituiran sa jednim supstituentom odabranim od C1-6alkila, arila ili arilC1-6alkila.
4. Spoj prema bilo kojem od prethodnih zahtjeva, naznačen time da m je 0; n je 1; p je 0; s je 0; t je 0.
5. Spoj prema bilo kojem od prethodnih zahtjeva, naznačen time da X je CHR8, a R8 je vodik.
6. Spoj prema bilo kojem od prethodnih zahtjeva, naznačen time da [image] je -CR9=C<, a R9 je vodik.
7. Spoj prema bilo kojem od prethodnih zahtjeva, naznačen time da R1 je vodik; R3 je vodik; R6 je vodik.
8. Spoj prema bilo kojem od prethodnih zahtjeva, naznačen time da R4 i R5 su svaki nezavisno vodik, C1-6alkil ili C1-6alkiloksi.
9. Spoj prema bilo kojem od prethodnih zahtjeva, naznačen time da Z je radikal odabran od (a-1), (a-2), (a-3) ili (a-4).
10. Spoj prema bilo kojem od prethodnih zahtjeva, naznačen time da R10 ili R11 su svaki nezavisno odabrani od vodika, hidroksi ili hidroksiC1-6alkila.
11. Spoj prema bilo kojem od prethodnih zahtjeva, naznačen time da R2 je vodik ili C1-6alkiloksi.
12. Spoj prema bilo kojem od prethodnih zahtjeva, naznačen time da m je 0; n je 1; p je 0; s je 0; t je 0; X je CHR8; R8 je vodik; [image] je -CR9=C<; svaki R9 je vodik; R1 je vodik; R2 je vodik ili C1-6alkiloksi; R3 je vodik; R4 i R5 su svaki nezavisno vodik, C1-6alkil ili C1-6alkiloksi; R6 je vodik; Z je radikal odabran od (a-1), (a-2), (a-3) ili (a-4); i R10 ili R11 su svaki nezavisno odabrani od vodika, hidroksi ili hidroksiC1-6alkila.
13. Spoj prema zahtjevu 1, 2 ili 3 naznačen time da spoj je odabran od Spoja br. 1, Spoja br.21, Spoja br. 4, Spoja br. 5, Spoja br. 36, No. 69, Spoja br. 110, Spoja br. 111, Spoja br. 112, Spoja br. 229 i Spoja br. 37 [image] njihovog N-oksidnog oblika, adicijske soli ili stereokemijskog izomernog oblika.
14. Spoj prema bilo kojem od prethodnih zahtjeva, naznačen time da spoj je [image] ili njegova farmaceutski prihvatljiva sol.
15. Spoj prema zahtjevu 14 naznačen time, da spoj je [image]
16. Spoj prema bilo kojem od zahtjeva 1 do 15 naznačen time, da je za upotrebu kao lijek.
17. Spoj prema bilo kojem od zahtjeva 1 do 15 naznačen time, da je za liječenje raka.
18. Farmaceutski pripravak naznačen time, da sadrži farmaceutski prihvatljiv nosač i kao aktivnu tvar terapeutski učinkovitu količinu spoja prema zahtjevu 1 do 15.
19. Upotreba spoja prema bilo kojem od zahtjeva 1 do 15 naznačena time, da je za proizvodnju lijeka za liječenje raka.
20. Upotreba prema zahtjevu 19 naznačena time, da rak je odabran od karcinoma pluća (npr. adenokarcinoma i uključujući rak pluća ne-malih stanica), raka gušterače (npr. karcinoma gušterače, kao što su, primjerice egzokrini karcinomi gušterače), karcinoma crijeva (npr. kolorektalnog karcinoma, kao što su, primjerice, adenokarcinomi debelog crijeva i adenomi debelog crijeva), raka jednjaka, oralnog planocelularnog karcinoma, karcinoma jezika, karcinoma želuca, karcinoma nazofarinksa, hematopoetskih tumora limfnih čvorova (npr. akutne limfocitne leukemije, B-limfoma, Burkittovog limfoma), mijeloične leukemije (na primjer, akutne mijeloične leukemije (AML)), folikularnog karcinoma štitnjače, mijelodisplastičnog sindroma (MDS), tumora mezenkimalnog podrijetla (npr. fibrosarkoma i rabdomiosarkoma), melanoma, teratokarcinoma, neuroblastoma, tumora mozga, glioma, benignog tumora kože (npr. keratoakantoma), karcinoma dojke (npr. uznapredovanog raka dojke), karcinoma bubrega, karcinoma jajnika, karcinoma grlića maternice, endometrijskog karcinoma, karcinoma mjehura, raka prostate uključujući uznapredovale bolesti, karcinoma testisa, osteosarkoma, raka glave i vrata, epidermalnog karcinoma.
21. Upotreba prema zahtjevu 20 naznačena time, da rak je odabran od raka pluća ne-malih stanica, karcinoma dojke, raka debelog crijeva npr. kolorektalnog karcinoma, akutne mijeloične leukemije, karcinoma jajnika, karcinoma mjehura, raka prostate, glioma.
22. Pripravak naznačen time da je kombinacija anti-tumorskog sredstva i spoja prema bilo kojem od zahtjeva 1 do 15.
23. Kombinacija prema zahtjevu 22 naznačena time, da je anti-tumorsko sredstvo odabrano od kompleksa platine na primjer cisplatina, karboplatina ili oksaliplatina; spojeva taksana npr. paklitaksel ili docetaksel; inhibitora topoizomeraze I kao što su kamptotecin spojevi na primjer irinotekan ili topotekan; inhibitora topoizomeraze II kao što su anti-tumorski podofilotoksin derivati na primjer etopozid ili tenipozid; anti-tumorskih vinca alkaloida primjerice vinblastin, vinkristin ili vinorelbin; anti-tumorskih nukleozidnih derivata npr. 5-fluorouracila, gemcitabina ili capecitabina; alkilirajućih sredstava kao što su dušični iperit ili nitrozoureja primjerice ciklofosfamid, klorambucil, karmustin ili lomustin; anti-tumorskih derivata antraciklina na primjer daunorubicina, doksorubicina, idarubicina ili mitoksantrona; HER2 protutijela na primjer trastuzumaba; antagonista receptora estrogena ili selektivnih modulatora receptora estrogena na primjer tamoksifen, toremifen, droloksifen, faslodeks ili raloksifen; inhibitora aromataze kao što egzemestan anastrozol, letrazol i vorozol; diferencirajućih sredstava kao što su retinoidi, vitamin D i sredstva za blokiranje metabolizma retinoične kiseline (RAMBA) na primjer akutan; inhibitora DNK metil transferaze na primjer azacitidin; inhibitora kinaze na primjer flavopiridol, imatinib mesilat ili gefitinib; inhibitora farneziltransferaze; HDAC inhibitora; inhibitora staze ubikvitin-proteazoma na primjer Velcade; ili Yondelis.
24. Proizvod naznačen time, da sadrži kao prvi aktivni sastojak spoj prema bilo kojem od zahtjeva 1 do 15 i kao drugi aktivni sastojak anti-tumorsko sredstvo, kao kombinirani pripravak za istovremenu, odvojenu ili sekvencijalnu upotrebu kod liječenja pacijenata oboljelih od raka.
25. Postupak za pripravu spoja prema zahtjevu 1, naznačen time, da sadrži a) reakciju međuprodukta formule (II) sa međuproduktom formule (III) pri čemu W je prikladna odlazna skupina kao što je, na primjer, halo, [image] pri čemu su varijable kako je definirano u zahtjevu1; b) pretvorbu spoja formule (I) pri čemu X je C(=O), ovdje se nazivaju spojevi formule (I-b), u spojeve formule (I), pri čemu X je CH2, ovdje se nazivaju spojevi formule (I-a), u prisutnosti litij aluminij hidrida u pogodnom otapalu, [image] pri čemu su varijable kako je definirano u zahtjevu1; c) reakciju odgovarajućeg karboksaldehida formule (IV), sa međuproduktom formule (V), u prisutnosti odgovarajućeg reakcijskog sredstva, u pogodnom otapalu, [image] pri čemu su varijable kako je definirano u zahtjevu1; d) reakciju međuprodukta formule (II) odgovarajućim karboksaldehidom formule (VI) uz stvaranje spoja formule (I), pri čemu t je 1, ovdje se nazivaju spojevi formule (I-c), [image] pri čemu su varijable kako je definirano u zahtjevu1; e) reakciju međuprodukta formule (VII) sa litij aluminij hidridom u pogodnom otapalu, uz stvaranje spoja formule (I), pri čemu s je 1, ovdje se nazivaju spojevi formule (I-d). [image] pri čemu su varijable kako je definirano u zahtjevu1.
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