HRP20171200T1 - Novi derivati benzimidazola kao antagonisti ep4 - Google Patents

Novi derivati benzimidazola kao antagonisti ep4 Download PDF

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HRP20171200T1
HRP20171200T1 HRP20171200TT HRP20171200T HRP20171200T1 HR P20171200 T1 HRP20171200 T1 HR P20171200T1 HR P20171200T T HRP20171200T T HR P20171200TT HR P20171200 T HRP20171200 T HR P20171200T HR P20171200 T1 HRP20171200 T1 HR P20171200T1
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ethyl
carbazol
carboxylic acid
benzimidazole
alkyl
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Olaf Peters
Nico BRÄUER
Thorsten Blume
Antonius Ter Laak
Ludwig Zorn
Jens Nagel
Stefan KAULFUSS
Gernot Langer
Joachim Kuhnke
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Bayer Pharma Aktiengesellschaft
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Claims (13)

1. Spojevi opće formule (I)  [image] naznačeni time da R1a, R1b neovisno jedan od drugoga predstavljaju H, C1-C5-alkil, C2-C5-alkenil, C2-C5-alkinil, C3-C6-cikloalkil-(CH2)m, C3-C6-heterocikloalkil-(CH2)n, C1-C5-alkoksi-C1-C3-alkil, C3-C6-cikloalkoksi-C1-C3-alkil, amino-C1-C3-alkil, C1-C5-alkilamino-C1-C3-alkil, C1-C5-dialkilamino-C1-C3-alkil ili cijano, gdje je proizvoljno prisutna heterociklička jedinica poželjno odabrana iz skupine koju čine oksetan, tetrahidrofuran, tetrahidropiran, 1,4-dioksan, morfolin, azetidin, pirolidin, piperazin i piperidin i gdje proizvoljno prisutni radikali alkil, cikloalkil ili heterocikloalkil mogu biti mono- ili polisupstituirani, identično ili različito s halogenom, C1-C5-alkil, hidroksil, karboksil, karboksi-C1-C5-alkil, C1-C5-alkoksikarbonil-C1-C5-alkil ili C1-C5-alkilsulfonil, R4 predstavlja H, F, Cl, C1-C2-alkil, C3-C5-cikloalkil, C1-C2-alkoksi ili C3-C4-cikloalkilmetil, gdje odgovarajuća alkil ili cikloalkil jedinica može biti mono- ili polisupstituirana, istovjetno ili različito s halogenom ili hidroksilom, A predstavlja RO-CO(CH2)p, gdje R predstavlja H ili C1-C2-alkil, m je 0, 1, 2 ili 3, n je 0, 1, 2 ili 3, p je 0, i B je odabran od slijedećih struktura, [image] [image] R6 , predstavlja H, F, Cl, CH3, CF3 CH3O ili CF3O, R7, R8 svaki puta neovisno jedan od drugoga predstavljaju H, F, Cl, cijano, SF5, C1-C3-alkil, C3-C5-cikloalkil, C1-C2-alkoksi ili C3-C4-cikloalkilmetil, gdje odgovarajuća alkil ili cikloalkil jedinica može biti mono- ili polihalogenirana, i R9 predstavlja C1-C5-alkil, C2-C5-alkenil, C2-C5-alkinil, C3-C6-cikloalkil-(CH2)n, C3-C6-heterocikloalkil-(CH2)n, ili C1-C7-alkoksi-C2-C5-alkil, gdje je proizvoljno prisutna heterociklička jedinica odabrana iz skupine koju čine oksetan, tetrahidrofuran, tetrahidropiran, morfolin, pirolidin i piperidin i gdje proizvoljno prisutne jedinice alkil, cikloalkil ili heterocikloalkil mogu biti mono- ili polisupstituirane, istovjetno ili različito s halogenom, C1-C2-alkilom, C1-C2-alkoksi ili karboksilom, i njihovi izomeri, dijastereomeri, enantiomeri, solvati i soli ili klatrati ciklodekstrina.
2. Spojevi prema zahtjevu 1, naznačeni time da R1a predstavlja H ili C1-C5-alkil, R1b predstavlja H, C1-C5-alkil, C2-C5-alkenil, C3-C6-cikloalkil-(CH2)m, C3-C6-heterocikloalkil-(CH2)n, C1-C5-alkoksi-C1-C3-alkil ili C1-C5-dialkilamino-C1-C3-alkil, gdje proizvoljno prisutna heterociklička jedinica je poželjno odabrana iz skupine koju čine oksetan, tetrahidrofuran, 1,4-dioksan, morfolin i pirolidin i gdje proizvoljno prisutni radikali alkil- ili cikloalkil mogu biti mono- ili polisupstituirani, istovjetno ili različito, s C1-C5-alkilom, hidroksilom, ili C1-C5-alkilsulfonilom, R4 predstavlja H, F, Cl, C1-C2-alkil ili C1-C2-alkoksi, A predstavlja RO-CO(CH2)p, gdje R predstavlja H ili C1-C2-alkil, m je 0 ili 1, n je 0 ili 1, p je 0, i B je odabran od slijedećih struktura, [image] [image] R6 predstavlja H, F, CH3 ili CH3O, R7, R8 svaki puta neovisno jedan od drugoga predstavljaju H, F, Cl, C1-C3-alkil ili C1-C2-alkoksi, i R9 predstavlja C1-C5-alkil, C2-C5-alkenil, C2-C5-alkinil, C3-C6-cikloalkil-(CH2)n ili C1-C7-alkoksi-C2-C5-alkil, i njihovi izomeri, dijastereomeri, enantiomeri, solvati i soli ili klatrati ciklodekstrina.
3. Spojevi prema zahtjevu 1, naznačeni time da R1a predstavlja H ili metil, R1b predstavlja H, C1-C2-alkil, vinil, ciklopropil-(CH2)m, C3-C6-heterocikloalkil-(CH2)n, metoksi-C1-C2-alkil ili (N,N-dimetilamino)-metil, gdje je proizvoljno prisutna heterociklička jedinica poželjno odabrana iz skupine koju čine oksetan, tetrahidrofuran, 1,4-dioksan, morfolin i pirolidin i gdje proizvoljno prisutni radikali alkil ili cikloalkil mogu biti mono- ili polisupstituirani, istovjetno ili različito, s metilom, hidroksilom, ili metilsulfonilom, R4 predstavlja H, F, Cl, metil ili metoksi, A predstavlja RO-CO(CH2)p, gdje R predstavlja H ili C1-C2-alkil, m je 0 ili 1, n je 0 ili 1, p je 0, i B je odabran od slijedećih struktura, [image] [image] R6 predstavlja H, F, CH3 ili CH3O, R7, R8 svaki puta neovisno jedan od drugoga predstavljaju H, F, Cl, metil ili metoksi, i R9 predstavlja C1-C3-alkil, alil, propargil, C3-C4-cikloalkil-(CH2)n ili metoksietil, i njihovi izomeri, dijastereomeri, enantiomeri, solvati i soli ili klatrati ciklodekstrina.
4. Spojevi prema zahtjevu 1, naznačeni time da R1a predstavlja H ili metil, R1b predstavlja H, C1-C2-alkil, vinil, ciklopropil-(CH2)m, C3-C6-heterocikloalkil-(CH2)n, metoksi-C1-C2-alkil ili (N,N-dimetilamino)-metil, gdje je proizvoljno prisutna heterociklička jedinica poželjno odabrana iz skupine koju čine oksetan, tetrahidrofuran, 1,4-dioksan, morfolin i pirolidin i gdje proizvoljno prisutni radikali alkil ili cikloalkil mogu biti mono- ili polisupstituirani, istovjetno ili različito, s metilom, hidroksilom, ili metilsulfonilom, R4 predstavlja H, F, Cl, metil ili metoksi, A predstavlja RO-CO(CH2)p, gdje R predstavlja H, m je 0 ili 1, n je 0 ili 1, p je 0, i B je odabran od slijedećih struktura, [image] [image] R6 predstavlja H, F, CH3 ili CH3O, R7, R8 svaki puta neovisno jedan od drugoga predstavljaju H, F, Cl, metil ili metoksi, i R9 predstavlja C1-C3-alkil, alil, propargil, C3-C4-cikloalkil-(CH2)n ili metoksietil, i njihovi izomeri, dijastereomeri, enantiomeri, solvati i soli ili klatrati ciklodekstrina.
5. Spojevi prema zahtjevu 1, naznačeni time da R1a predstavlja H, R1b predstavlja metoksimetil, R4 predstavlja H, F, Cl, metil ili metoksi, A predstavlja RO-CO(CH2)p, gdje R predstavlja H, n je 0 ili 1, p je 0, i B je odabran od slijedećih struktura, [image] R6 , predstavlja H, F, CH3 ili CH3O, R7, R8 svaki puta neovisno jedan od drugoga predstavljaju H, F, Cl, metil ili metoksi, i R9 predstavlja C1-C3-alkil, alil, propargil, C3-C4-cikloalkil-(CH2)n ili metoksietil, i njihovi izomeri, dijastereomeri, enantiomeri, solvati i soli ili klatrati ciklodekstrina.
6. Spoj prema zahtjevu 1 naznačen time da je odabran iz skupine koja sadrži slijedeće spojeve: 1. metil 1-alil-2-(9-etil-9H-karbazol-3-il)-1H-benzimidazol-5-karboksilat 2. 1-alil-2-(9-etil-9H-karbazol-3-il)-1H-benzimidazol-5-karboksilna kiselina 3. metil 2-(9-etil-9H-karbazol-3-il)-1-(2-metoksietil)-1H-benzimidazol-5-karboksilat 4.2-(9-etil-9H-karbazol-3-il)-1-(2-metoksietil)-1H-benzimidazol-5-karboksilna kiselina 5. metil 1-(ciklopropilmetil)-2-(9-etil-9H-karbazol-3-il)-1H-benzimidazol-5-karboksilat 6. 1-(ciklopropilmetil)-2-(9-etil-9H-karbazol-3-il)-1H-benzimidazol-5-karboksilna kiselina 7. metil 4-chloro-1-(ciklopropilmetil)-2-(9-etil-9H-karbazol-3-il)-1H-benzimid-azole-5-karboksilat 8. 4-kloro-1-(ciklopropilmetil)-2-(9-etil-9H-karbazol-3-il)-1H-benzimidazol-5-karboksilna kiselina 9. 1-(ciklopropilmetil)-2-(9-etil-9H-karbazol-3-il)-4-metil-1H-benzimidazol-5-karboksilna kiselina 10. 2-(9-etil-7-fluoro-9H-karbazol-3-il)-1-(2-metoksietil)-1H-benzimidazol-5-karboksilna kiselina 11. 2-(9-etil-5-fluoro-9H-karbazol-3-il)-1-(2-metoksietil)-1H-benzimidazol-5-karboksilna kiselina 12. 2-(9-etil-8-fluoro-9H-karbazol-3-il)-1-(2-metoksietil)-1H-benzimidazol-5-karboksilna kiselina 13. 1-(ciklopropilmetil)-2-[9-(2-metoksietil)-9H-karbazol-3-il]-1H-benzimidazol-5-karboksilna kiselina 14. 1-(ciklopropilmetil)-2-(9-etil-9H-pirido[2,3-b]indol-3-il)-1H-benzimidazol-5-karboksilna kiselina 15. 2-(9-etil-6-metoksi-9H-karbazol-3-il)-1-(2-metoksietil)-1H-benzimidazol-5-karboksilna kiselina 16. 2-(9-alil-9H-karbazol-3-il)-1-(ciklopropilmetil)-1H-benzimidazol-5-karboksilna kiselina 17. 1-(ciklopropilmetil)-2-(9-metil-9H-karbazol-3-il)-1H-benzimidazol-5-karboksilna kiselina 18. 1-(ciklopropilmetil)-2-[9-(ciklopropilmetil)-9H-karbazol-3-il]-1H-benzimidazol-5-karboksilna kiselina 19. 2-[9-(ciklopropilmetil)-9H-karbazol-3-il]-1-(2-metoksietil)-1H-benzimidazol-5-karboksilna kiselina 20. etil-2-(9-etil-9H-karbazol-3-il)-1-[2-(pirolidin-1-il)etil]-1H-benzimidazol-5-karboksilat 21. 2-(9-etil-9H-karbazol-3-il)-1-[2-(pirolidin-1-il)etil]-1H-benzimidazol-5-karboksilna kiselina 22. 2-(5-etil-5H-pirido[3,2-b]indol-2-il)-1-(2-metoksietil)-1H-benzimidazol-5-karboksilna kiselina 23. 1-(ciklopropilmetil)-2-(9-etil-6-metoksi-9H-karbazol-3-il)-1H-benzimidazol-5-karboksilna kiselina 24. 2-(9-etil-9H-karbazol-3-il)-1-[2-(morfolin-4-il)etil]-1H-benzimidazol-5-karboksilna kiselina 25. etil-1-[2-(dimetilamino)etil]-2-(9-etil-9H-karbazol-3-il)-1H-benzimidazol-5-karboksilat 26. 1-[2-(dimetilamino)etil]-2-(9-etil-9H-karbazol-3-il)-1H-benzimidazol-5-karboksilna kiselina 27. 2-(9-etil-9H-karbazol-3-il)-1-(2-hidroksietil)-1H-benzimidazol-5-karboksilna kiselina 28. etil-2-(9-etil-9H-karbazol-3-il)-1-izopropil-1H-benzimidazol-5-karboksilat 29. 2-(9-etil-9H-karbazol-3-il)-1-izopropil-1H-benzimidazol-5-karboksilna kiselina 30. 2-(9-etil-9H-karbazol-3-il)-1-metil-1H-benzimidazol-5-karboksilna kiselina 31. metil 1-etil-2-(9-etil-9H-karbazol-3-il)-1H-benzimidazol-5-karboksilat 32. 2-(9-alil-9H-karbazol-3-il)-1-(2-metoksietil)-1H-benzimidazol-5-karboksilna kiselina 33. etil 1-(2-metoksietil)-2-[9-(2-metoksietil)-9H-karbazol-3-il]-1H-benzimidazol-5-karboksilat 34. 1-(2-metoksietil)-2-[9-(2-metoksietil)-9H-karbazol-3-il]-1H-benzimidazol-5-karboksilna kiselina 35. etil 2-(9-etil-9H-karbazol-3-il)-1-(3-metoksipropil)-1H-benzimidazol-5-karboksilat 36. 2-(9-etil-9H-karbazol-3-il)-1-(3-metoksipropil)-1H-benzimidazol-5-karboksilna kiselina 37. 1-(ciklopropilmetil)-2-(9-etil-9H-karbazol-3-il)-6-metoksi-1H-benzimidazol-5-karboksilna kiselina 38. 2-(9-etil-9H-karbazol-3-il)-6-metoksi-1-(2-metoksietil)-1H-benzimidazol-5-karboksilna kiselina 39. 1-(ciklopropilmetil)-2-(9-etil-9H-karbazol-3-il)-4-metoksi-1H-benzimidazol-5-karboksilna kiselina 40. 2-(9-etil-9H-karbazol-3-il)-1-(2-metoksietil)-4-metil-1H-benzimidazol-5-karboksilna kiselina 41. 1-(ciklopropilmetil)-2-(9-etil-9H-pirido[2,3-b]indol-3-il)-4-metil-1H-benzimidazol-5-karboksilna kiselina 42. 1-(ciklopropilmetil)-2-(9-etil-9H-beta-karbolin-6-il)-1H-benzimidazol-5-karboksilna kiselina 43. 1-(ciklopropilmetil)-2-(5-etil-5H-pirido[4,3-b]indol-8-il)-1H-benzimidazol-5-karboksilna kiselina 44. 1-(ciklopropilmetil)-2-(9-etil-9H-karbazol-3-il)-6-metil-1H-benzimidazol-5-karboksilna kiselina 45. 2-(9-etil-9H-karbazol-3-il)-1-(2-metoksietil)-6-metil-1H-benzimidazol-5-karboksilna kiselina 46. 2-(9-etil-9H-karbazol-3-il)-6-fluoro-1-(2-metoksietil)-1H-benzimidazol-5-karboksilna kiselina 47. 1-(ciklopropilmetil)-2-(9-etil-9H-karbazol-3-il)-6-fluoro-1H-benzimidazol-5-karboksilna kiselina 48. 2-(9-etil-9H-karbazol-3-il)-4-fluoro-1-(2-metoksietil)-1H-benzimidazol-5-karboksilna kiselina 49. 1-(ciklopropilmetil)-2-(9-etil-9H-karbazol-3-il)-4-fluoro-1H-benzimidazol-5-karboksilna kiselina 50. 1-(ciklopropilmetil)-2-(9-etil-9H-pirido[2,3-b]indol-6-il)-1H-benzimidazol-5-karboksilna kiselina 51. 1-(2-ciklopropiletil)-2-(9-etil-9H-karbazol-3-il)-1H-benzimidazol-5-karboksilna kiselina 52. 1-(2-metoksietil)-2-(9-propil-9H-karbazol-3-il)-1H-benzimidazol-5-karboksilna kiselina 53. 1-(2-metoksietil)-2-[9-(prop-2-in-1-il)-9H-karbazol-3-il]-1H-benzimidazol-5-karboksilna kiselina 54. 1-(ciklopropilmetil)-2-(9-propil-9H-karbazol-3-il)-1H-benzimidazol-5-karboksilna kiselina 55. 1-[(2,2-Dimetilciklopropil)metil]-2-(9-etil-9H-karbazol-3-il)-1H-benzimidazol-5-karboksilna kiselina 56. etil 2-(9-etil-9H-karbazol-3-il)-1-(oksetan-3-ilmetil)-1H-benzimidazol-5-karboksilat 57. 2-(9-etil-9H-karbazol-3-il)-1-(oksetan-3-ilmetil)-1H-benzimidazol-5-karboksilna kiselina 58. 2-[9-(ciklobutilmetil)-9H-karbazol-3-il]-1-(2-metoksietil)-1H-benzimidazol-5-karboksilna kiselina 59. 2-[9-(ciklobutilmetil)-9H-karbazol-3-il]-1-(ciklopropilmetil)-1H-benzimidazol-5-karboksilna kiselina 60. 2-(9-etil-9H-karbazol-3-il)-1-[2-(trifluorometoksi)etil]-1H-benzimidazol-5-karboksilna kiselina 61. 1-(ciklopropilmetil)-2-(9-etil-1-metil-9H-beta-karbolin-3-il)-1H-benzimidazol-5-karboksilna kiselina 62. 2-(9-etil-9H-karbazol-3-il)-1-(oksetan-2-ilmetil)-1H-benzimidazol-5-karboksilna kiselina 63. 2-(9-etil-9H-karbazol-3-il)-1-(tetrahidrofuran-2-ilmetil)-1H-benzimidazol-5-karboksilna kiselina 64. 2-(9-etil-9H-karbazol-3-il)-1-[(2R)-2-hidroksi-3-metoksipropil]-1H-benzimidazol-5-karboksilna kiselina 65. 2-(9-etil-9H-karbazol-3-il)-1-[(2S)-2-hidroksi-3-metoksipropil]-1H-benzimidazol-5-karboksilna kiselina 66. 2-(9-etil-9H-karbazol-3-il)-1-[2-(metilsulfonil)etil]-1H-benzimidazol-5-karboksilna kiselina 67. 1-(2-ciklopropil-2-hidroksietil)-2-(9-etil-9H-karbazol-3-il)-1H-benzimidazol-5-karboksilna kiselina 68. 1-[(2S)-2,3-dihidroksipropil]-2-(9-etil-9H-karbazol-3-il)-1H-benzimidazol-5-karboksilna kiselina 69. 1-(1,4-dioksan-2-ilmetil)-2-(9-etil-9H-karbazol-3-il)-1H-benzimidazol-5-karboksilna kiselina 70. 1-(1,4-dioksan-2-ilmetil)-2-(9-etil-9H-karbazol-3-il)-1H-benzimidazol-5-karboksilna kiselina 71. 2-(9-etil-6-metil-9H-karbazol-3-il)-1-(2-metoksietil)-4-metil-1H-benzimidazol-5-karboksilna kiselina 72. 2-(6-kloro-9-etil-9H-karbazol-3-il)-1-(2-metoksietil)-4-metil-1H-benzimidazol-5-karboksilna kiselina 73. 2-(8-kloro-9-etil-9H-karbazol-3-il)-1-(2-metoksietil)-4-metil-1H-benzimidazol-5-karboksilna kiselina
7. Spoj s formulom (I), kako je definirano u jednom od zahtjeva 1 do 6, naznačen time da je za liječenje i/ili profilaksu bolesti.
8. Spoj s formulom (I), kako je definirano u jednom od zahtjeva 1 do 6, naznačen time da je za uporabu u postupku liječenja i/ili profilaksu endometrioze, leiomioma maternice, poremećaja krvarenja maternice, gdje poremećaji krvarenja mogu biti teško i dugotrajno krvarenje, privremeno nepravilno krvarenje i bol, dismenoreje, raka, gdje rak može biti rak pluća, crijeva, dojke, kože, rak prostate, jednjaka i leukemija, za liječenje arterioskleroze i policističnih bolesti bubrega.
9. Uporaba spoja prema zahtjevu 1, 2, 3, 4, 5 ili 6 naznačena time da je za proizvodnju lijeka za liječenje i/ili profilaksu bolesti.
10. Uporaba spoja, kako je definirano u jednom od zahtjeva 1 do 6, naznačena time da je za proizvodnju lijeka za liječenje i/ili profilaksu endometrioze, leiomioma maternice, poremećaja krvarenja maternice, gdje poremećaji krvarenja mogu biti teško i dugotrajno krvarenje, privremeno nepravilno krvarenje i bol, dismenoreje, raka, gdje rak može biti rak pluća, crijeva, dojke, kože, rak prostate, jednjaka i leukemija, za liječenje arterioskleroze i policističnih bolesti bubrega.
11. Lijek naznačen time da sadrži spoj, kako je definirano u jednom od zahtjeva 1 do 6, u kombinaciji s jednom ili više dodatnih aktivnih tvari, naročito sa selektivnim modulatorima estrogenskih receptora (SERM), antagonistima receptora estrogena (ER), inhibitorima aromataze, inhibitorima 17β-HSD1, inhibitorima steroidne sulfataze (STS), agonistima i antagonistima GnRH, antagonistima kisspeptin receptora (KISSR), selektivnim modulatorima androgenskih receptora (SARM), androgenima, inhibitorima 5α-reduktaze, selektivnima modulatorima receptora progesterona (SPRM), gestagenima, antigestagenima, oralnim kontracepcijskim sredstvima, inhibitorima mitogenom aktiviranih protein (MAP) kinaza i inhibitorima MAP kinaza (Mkk3/6, Mek1/2, Erk1/2), inhibitorima protein kinaza B (PKBα/β/γ; Akt1/2/3), inhibitorima fosfoinositid-3 kinaze (PI3K), inhibitorima kinaze ovisne o ciklinima (CDK1/2), inhibitorima puta inducibilnog signala hipoksije (HIF1alfa inhibitori, aktivatori prolilhidroksilaza), inhibitorima histonske deacetilaze (HDAC), antagonistima receptora prostaglandina F (FP) (PTGFR), antagonistima neurokinin 1 receptora, paracetamolom, selektivnim inhibitorima COX2 i/ili ne-selektivnim inhibitorima COX1/COX2.
12. Lijek naznačen time da sadrži spoj s formulom (I) kako je definirano u jednom od zahtjeva 1 do 6, u kombinaciji s inertnim, netoksičnim farmaceutskim pogodnim pomoćnim sredstvom.
13. Lijek prema zahtjevu 11 ili 12 naznačen time da je za liječenje i/ili profilaksu endometrioze, leiomioma maternice, poremećaja krvarenja maternice, gdje poremećaji krvarenja mogu biti teško i dugotrajno krvarenje, privremeno nepravilno krvarenje i bol, dismenoreje, raka, gdje rak može biti rak pluća, crijeva, dojke, kože, rak prostate, jednjaka i leukemija, za liječenje arterioskleroze i policističnih bolesti bubrega.
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