HRP20120154T1 - HETEROCIKLIČKI INHIBITORI MEK-a I METODE NJIHOVE UPORABE - Google Patents

HETEROCIKLIČKI INHIBITORI MEK-a I METODE NJIHOVE UPORABE Download PDF

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HRP20120154T1
HRP20120154T1 HR20120154T HRP20120154T HRP20120154T1 HR P20120154 T1 HRP20120154 T1 HR P20120154T1 HR 20120154 T HR20120154 T HR 20120154T HR P20120154 T HRP20120154 T HR P20120154T HR P20120154 T1 HRP20120154 T1 HR P20120154T1
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Croatia
Prior art keywords
compound
dihydropyridine
oxo
fluoro
carboxamide
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HR20120154T
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English (en)
Inventor
L. Marlow Allison
Wallace Eli
Seo Jeongbeob
P. Lyssikatos Joseph
Woon Yang Hong
Blake Jim
Anthony Storey Richard
Jane Booth Rebecca
David Pittam John
Leonard John
Richard Fielding Mark
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Array Biopharma
Astrazeneca Ab
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Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=37943261&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=HRP20120154(T1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Array Biopharma, Astrazeneca Ab filed Critical Array Biopharma
Publication of HRP20120154T1 publication Critical patent/HRP20120154T1/hr

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Abstract

Spoj formule IV: ili njegova farmaceutski prihvatljiva sol, naznačen time da: R1 je Cl ili F; R3 je H, Me, Et, OH, MeO-, EtO-, HOCH2CH2O-, HOCH2C(Me)2O-, (S)-MeCH(OH)CH2O-, (R)-HOCH2CH(OH) CH2O-, ciklopropil-CH2O-, HOCH2CH2-,R7 je metil ili etil, pri čemu su navedeni metil i etil po izboru supstituirani s jednim ili s više F; R8 je Br, I ili SMe iR9 je H, C1-C4 alkil, Cl ili CN, pri čemu je navedeni alkil po izboru supstituiran s jednom ili s više skupina neovisno odabranih između F ili CN, pod uvjetom kada) R1 je F, R8 je Br, R9 je H i R7 je ili Me ili Et, tada R3 ne može biti HOCH2CH2O; b) R1 je F, R8 je I, R9 je H i R3 je MeO, tada R7 ne može biti Me; c) R1 je F, R8 je Me, R9 je H i R3 je HOCH2CH2O, tada R7 ne može biti Me id) R1 je F, R8 je Br, R9 je H i R3 je ciklopropil-CH2O, tada R7 ne može biti Me. Patent sadrži još 34 patentna zahtjeva.

Claims (35)

1. Spoj formule IV: [image] ili njegova farmaceutski prihvatljiva sol, naznačen time da: R1 je Cl ili F; R3 je H, Me, Et, OH, MeO-, EtO-, HOCH2CH2O-, HOCH2C(Me)2O-, (S)-MeCH(OH)CH2O-, (R)-HOCH2CH(OH) CH2O-, ciklopropil-CH2O-, HOCH2CH2-, [image] R7 je metil ili etil, pri čemu su navedeni metil i etil po izboru supstituirani s jednim ili s više F; R8 je Br, I ili SMe i R9 je H, C1-C4 alkil, Cl ili CN, pri čemu je navedeni alkil po izboru supstituiran s jednom ili s više skupina neovisno odabranih između F ili CN, pod uvjetom kad a) R1 je F, R8 je Br, R9 je H i R7 je ili Me ili Et, tada R3 ne može biti HOCH2CH2O; b) R1 je F, R8 je I, R9 je H i R3 je MeO, tada R7 ne može biti Me; c) R1 je F, R8 je Me, R9 je H i R3 je HOCH2CH2O, tada R7 ne može biti Me i d) R1 je F, R8 je Br, R9 je H i R3 je ciklopropil-CH2O, tada R7 ne može biti Me.
2. Spoj prema 1. patentnom zahtjevu, naznačen time da R9 je H, Me, Et, Cl ili CN.
3. Spoj formule V: [image] ili njegova farmaceutski prihvatljiva sol, naznačen time da: R3 je HOCH2CH2O ili (S)-MeCH(OH)CH2O i R9 je H, CH3, F ili Cl, pod uvjetom kad R9 je Cl, tada R3 ne može biti HOCH2CH2O.
4. Spoj naznačen time da je odabran između: 2-(2-fluoro-4-(metiltio)fenilamino)-N-(2-hidroksietoksi)-1-metil-6-okso-1,6-dihidropiridin-3-karboksamid; (S)-2-(2-fluoro-4-(metiltio)fenilamino)-N-(2-hidroksipropoksi)-1-metil-6-okso-1,6-dihidropiridin-3-karboksamid; 2-(2-fluoro-4-(metiltio)fenilamino)-N-(2-hidroksietoksi)-1,5-dimetil-6-okso-1,6- dihidropiridin-3-karboksamid; (S)-2-(2-fluoro-4-(metiltio)fenilamino)-N-(2-hidroksipropoksi)-1,5-dimetil-6-okso-1,6-dihidropiridin-3-karboksamid; 5-fluoro-2-(2-fluoro-4-(metiltio)fenilamino)-N-(2-hidroksietoksi)-1-metil-6-okso-1,6-dihidropiridin-3-karboksamid; (S)-5-fluoro-2-(2-fluoro-4-(metiltio)fenilamino)-N-(2-hidroksipropoksi)-1-metil-6-okso-1,6-dihidropiridin-3-karboksamid i (S)-5-kloro-2-(2-fluoro-4-(metiltio)fenilamino)-N-(2-hidroksipropoksi)-1-metil-6-okso-1,6-dihidropiridin-3-karboksamid.
5. Spoj formule VI: [image] ili njegova farmaceutski prihvatljiva sol, naznačen time da: R1 je Cl ili F; R3 je H, HOCH2CH2O ili (S)-MeCH(OH)CH2O i R9 je H, Me, F ili Cl.
6. Spoj prema 5. patentnom zahtjevu, naznačen time da R1 je F, R3 je HOCH2CH2O- i R9 je metil, ili njegova farmaceutski prihvatljiva sol.
7. Spoj prema 5. patentnom zahtjevu, naznačen time da je taj spoj: 2-(2-kloro-4-jodofenilamino)-N-(2-hidroksietoksi)-1-metil-6-okso-1,6-dihidropiridin-3-karboksamid; (S)-2-(2-kloro-4-jodofenilamino)-N-(2-hidroksipropoksi)-1-metil-6-okso-1,6-dihidropiridin-3-karboksamid; 2-(2-fluoro-4-jodofenilamino)-1,5-dimetil-6-okso-1,6-dihidropiridin-3-karboksamid; 2-(2-fluoro-4-jodofenilamino)-N-(2-hidroksietoksi)-1-metil-6-okso-1,6-dihidropiridin-3-karboksamid; (S)-2-(2-fluoro-4-jodofenilamino)-N-(2-hidroksipropoksi)-1-metil-6-okso-1,6-dihidropiridin-3-karboksamid; (S)-2-(2-fluoro-4-jodofenilamino)-N-(2-hidroksipropoksi)-1,5-dimetil-6-okso-1,6-dihidropiridin-3-karboksamid; 2-(2-kloro-4-jodofenilamino)-N-(2-hidroksietoksi)-1,5-dimetil-6-okso-1,6-dihidropiridin-3-karboksamid; 5-kloro-2-(2-fluoro-4-jodofenilamino)-N-(2-hidroksietoksi)-1-metil-6-okso-1,6-dihidropiridin-3-karboksamid; (S)-2-(2-kloro-4-jodofenilamino)-N-(2-hidroksipropoksi)-1,5-dimetil-6-okso-1,6-dihidropiridin-3-karboksamid; ili (S)-5-kloro-2-(2-fluoro-4-jodofenilamino)-N-(2-hidroksipropoksi)-1-metil-6-okso-1,6-dihidropiridin-3-karboksamid.
8. Spoj prema 5. patentnom zahtjevu, naznačen time da je spoj odabran između: 5-fluoro-2-(2-fluoro-4-jodofenilamino)-N-(2-hidroksietoksi)-1-metil-6-okso-1,6-dihidropiridin-3-karboksamid; i (S)-5-fluoro-2-(2-fluoro-4-jodofenilamino)-N-(2-hidroksipropoksi)-1-metil-6-okso-1,6-dihidropiridin-3-karboksamid.
9. Spoj prema 5. patentnom zahtjevu, naznačen time da je spoj 2-(2-fluoro-4-jodofenilamino)-N-(2-hidroksietoksi)-1,5-dimetil-6-okso-1,6-dihidropiridin-3-karboksamid.
10. Kristalni oblik spoja formule XI [image] bitno u obliku oblika 2, 2-(2-fluoro-4-jodofenilamino)-N-(2-hidroksietoksi)-1,5-dimetil-6-okso-1,6-dihidropiridin-3-karboksamid naznačen time da uzorkom rendgenske difrakcije koja ima karakterizirajuće šiljke na oko 9.5 i 12.6 na skali 2θ.
11. Kristalni oblik spoja formule XI prema 10. patentnom zahtjevu naznačen time da uzorkom rendgenske difrakcije koja ima karakterizirajuće šiljke na oko 9.5, 12.6, 14.7 i 19.6 na 2θ�skali.
12. Kristalni oblik spoja formule XI prema 10. patentnom zahtjevu naznačen time da uzorkom rendgenske difrakcije bitno kako je prikazan na slici 10.
13. Kristalni oblik spoja formule XI [image] bitno u obliku oblika 1, 2-(2-fluoro-4-jodofenilamino)-N-(2-hidroksietoksi)-1,5-dimetil-6-okso-1,6-dihidropiridin-3-karboksamid naznačen time da uzorkom rendgenske difrakcije koja ima karakterizirajuće šiljke na oko 9.2 i 13.0 na skali 2θ�.
14. Kristalni oblik spoja formule XI prema 13. patentnom zahtjevu naznačen time da uzorkom rendgenske difrakcije koja ima karakterizirajuće šiljke na oko 9.2, 13.0, 18.3, 21.0 i 21.7 na skali 2θ�
15. Kristalni oblik spoja formule XI prema 13. patentnom zahtjevu naznačen time da uzorkom rendgenske difrakcije bitno kako je prikazan na slici 11.
16. Spoj prema bilo kojem od patentnih zahtjeva od 1 do 15 naznačen time da je za uporabu kao lijek.
17. Spoj prema bilo kojem od patentnih zahtjeva od 1 do 15 naznačen time da je za uporabu kao lijek za liječenje hiperproliferativnog poremećaja ili upalnog stanja.
18. Uporaba spoja prema bilo kojem od patentnih zahtjeva od 1. do 15. naznačena time da je u pripravi lijeka za liječenje hiperproliferativnog poremećaja ili upalnog stanja.
19. Farmaceutska sastavina koja sadržava spoj prema bilo kojem od patentnih zahtjeva od 1. do 15. naznačena time da je zajedno s farmaceutski prihvatljivim nosačem.
20. Metoda priprave spoja prema 1. patentnom zahtjevu, naznačena time da ta metoda obuhvaća: reakciju spoja formule 108 ili 109 [image] i R3NH2, pri čemu je R3 onakav kako je definiran 10. patentnim zahtjevom, u prisutnosti ili (i) veznog reagensa ili (ii) amidne baze, kad je R3 onakav kako je definiran 10. patentnim zahtjevom, uz iznimku da R3 nije H ili Me.
21. Metoda priprave spoja prema 5. patentnom zahtjevu, naznačena time da ta metoda obuhvaća: (a) bromiranje spoja formule 105 [image] pri čemu je R alkil, za dobivanje spoja 106 [image] (b) reakciju spoja 106 i Zn(Me)2 u prisutnosti paladija kao katalizatora i jednog liganda, te po izboru u prisutnosti baze, za dobivanje spoja 107 [image] (c) reakciju spoja 107 i anilina formule [image] u prisutnosti paladija kao katalizatora, liganda fosfina i amidne baze, za dobivanje spoja 108 [image] (d) po izboru hidroliziranje spoja 108 pod osnovnim uvjetima za dobivanje spoja 109 [image] i (e) reakciju ili spoja 108 ili spoja 109 i R3NH2 ili u prisutnosti (i) veznog reagensa kad je R3 onakav kako je definiran 5. patentnim zahtjevom ili (ii) amidne baze kad je R3 onakav kako je definiran 5. patentnim zahtjevom, uz iznimku da R3 nije H, za dobivanje toga spoja iz 5. patentnog zahtjeva.
22. Metoda prema 21. patentnom zahtjevu, naznačena time da je spoj 105 pripravljen metodom koja obuhvaća: (a) reakciju spoja 103 [image] i vodene otopine natrijeva hidroksida za dobivanje spoja 104 [image] i (b) reakciju spoja 104 i RX, pri čemu je R Me, a X je halid, u prisutnosti baze za dobivanje spoja 105.
23. Metoda priprave spoja iz 3.patentnog zahtjeva, naznačena time da R9 je Me i pri čemu ta metoda obuhvaća: (a) bromiranje spoja formule 105 [image] pri čemu je R alkil, za dobivanje spoja 106 [image] (b) reakciju spoja 106 i Zn(Me)2 u prisutnosti paladija kao katalizatora i jednog liganda te po izboru u prisutnosti baze, za dobivanje spoja 107 [image] (c) reakciju spoja 107 i anilina formule [image] u prisutnosti amidne baze, za dobivanje spoja 108 [image] (d) po izboru hidroliziranje spoja 108 pod osnovnim uvjetima za dobivanje spoja 109 [image] i (e) reakciju ili spoja 108 ili spoja 109 i R3NH2, pri čemu je R3 onakav kako je definiran 3. patentnim zahtjevom, u prisutnosti veznog reagensa ili amidne baze, za dobivanje toga spoja iz 3. patentnog zahtjeva.
24. Metoda priprave spoja iz 3. patentnog zahtjeva, naznačena time da R9 je Cl, i pri čemu navedena metoda obuhvaća: (a) reakciju spoja formule 112 [image] i anilina formule [image] u prisutnosti jedne amidne baze za dobivanje spoja 117 [image] (b) kloriranje spoja 117 za dobivanje spoja 118 [image] i (c) po izboru hidroliziranje spoja 118 za dobivanje spoja 118A [image] (d) reakciju ili spoja 118 ili spoja 118A i (S)-MeCH(OH)CH2ONH2 ili HOCH2CH2ONH2 u prisutnosti veznog reagensa ili jedne amidne baze za dobivanje toga spoja iz 3. patentnog zahtjeva.
25. Metoda priprave spoja iz 3. patentnog zahtjeva, naznačena time da R9 je H ili F, i pri čemu ta metoda obuhvaća: (a) obradu spoja formule 140 [image] pri čemu je R9 H ili F, s NaOH otopljenim u vodi za dobivanje spoja 141 [image] (b) reakciju spoja 141 i CH3X, pri čemu je X halid, u prisutnosti jedne baze za dobivanje spoja 142 [image] (c) reakciju spoja 142 i anilina formule [image] u prisutnosti jedne amidne baze za dobivanje spoja 143 [image] (d) po izboru hidroliziranje spoja 143 za dobivanje spoja 144 [image] i (e) reakciju ili spoja 143 ili spoja 144 i R3NH2, pri čemu je R3 onakav kako je definiran 3. patentnim zahtjevom, u prisutnosti jednog veznog reagensa ili jedne amidne baze za dobivanje toga spoja iz 3. patentnog zahtjeva.
26. Metoda prema bilo kojem patentnom zahtjevu od 20. do 25., naznačena time da je navedeni vezni reagens 1-(3-dimetilaminopropil)-3-etilkarbodiimid hidroklorid, 1-hidroksibenzotriazol-6-sulfonamidometil hidroklorid, ili benzotriazol-1-iloksitripirolidinofosfonij heksafluorofosfat.
27. Postupak za pripremu spoja formule XI bitno u obliku oblika 1,2-(2-fluoro-4-jodofenilamino)-N-(2-hidroksietoksi)-1,5-dimetil-6-okso-1,6-dihidropiridin-3-karboksamid prema 13. patentnom zahtjevu, naznačen time da obuhvaća: a) stavljanje u kontakt (2-viniloksietoksi)-amida 2-(2-fluoro-4-jodofenilamino)-1,5-dimetil-6-okso-1,6-dihidropiridin-3-karboksilne kiseline i kiselinske mješavine dostatno dugo kako bi se taj spoj pretvorio u 2-(2-fluoro-4-jodofenilamino)-N-(2-hidroksietoksi)-1,5-dimetil-6-okso-1,6-dihidropiridin-3-karboksamid; b) dopuštanje da se materijal iz faze a) kristalizira iz organskog otapala koje sadržava zametak oblika 1, 2-(2-fluoro-4-jodofenilamino)-N-(2-hidroksietoksi)-1,5-dimetil-6-okso-1,6-dihidropiridin-3-karboksamid i c) izoliranje obrasca 1, 2-(2-fluoro-4-jodofenilamino)-N-(2-hidroksietoksi)-1,5-dimetil-6-okso-1,6-dihidropiridin-3-karboksamida.
28. Postupak prema 27. patentnom zahtjevu, naznačen time da je kiselinska mješavina iz faze a) sustav vodenih otapala kiseline i etil acetata.
29. Postupak prema 27. ili prema 28. patentnom zahtjevu, naznačen time da je organsko otapalo iz faze b) etil acetat.
30. Postupak priprave spoja formule XI bitno u obliku oblika 1, 2-(2-fluoro-4-jodofenilamino)-N-(2-hidroksietoksi)-1,5-dimetil-6-okso-1,6-dihidropiridin-3-karboksamid prema 13. patentnom zahtjevu, naznačen time da obuhvaća: a) miješanje oblika 2, 2-(2-fluoro-4-jodofenilamino)-N-(2-hidroksietoksi)-1,5-dimetil-6-okso-1,6-dihidropiridin-3-karboksamid i malih količina oblika 1, 2-(2-fluoro-4-jodofenilamino)-N-(2-hidroksietoksi)-1,5-dimetil-6-okso-1,6-dihidropiridin-3-karboksamida u organskom otapalu i b) izoliranje oblika 1, 2-(2-fluoro-4-jodofenilamino)-N-(2-hidroksietoksi)-1,5-dimetil-6-okso-1,6-dihidropiridin-3-karboksamid.
31. Metoda prema 30. patentnom zahtjevu, naznačena time da je organsko otapalo etil acetat.
32. Metoda prema 30. ili prema 31. patentnom zahtjevu, naznačena time da se faza a) izvodi na temperaturi od oko 50 do 60 ̊C.
33. Postupak za pripravu spoja formule X1 bitno u obliku oblika 2,2-(2-fluoro-4-jodofenilamin)-N-(2-hidroksietoksi)-1,5-dimetil-6-okso-1,6-dihidropiridin-3-karboksamid prema 10. patentnom zahtjevu, naznačen time da obuhvaća: a) stavljanje u kontakt (2-viniloksietoksi)-amid 2-(2-fluoro-4-jodofenilamino)-1,5-dimetil-6-okso-1,6-dihidropiridin-3-karboksilne kiseline i kiselinske mješavine dostatno dugo da bi se spoj pretvorio u 2-(2-fluoro-4-jodofenilamino)-N-(2-hidroksietoksi)-1,5-dimetil-6-okso-1,6-dihidropiridin-3-karboksamid; b) dopuštanje da se materijal iz faze a) kristalizira iz organskog otapala i c) izoliranje oblika 2, 2-(2-fluoro-4-jodofenilamino)-N-(2-hidroksietoksi)-1,5-dimetil-6-okso-1,6-dihidropiridin-3-karboksamid.
34. Postupak prema 33. patentnom zahtjevu, naznačen time da u fazi b) organsko otapalo sadržava zametak oblika 2, 2-(2-fluoro-4-jodofenilamino)-N-(2-hidroksietoksi)-1,5-dimetil-6-okso-1,6-dihidropiridin-3-karboksamid.
35. Postupak prema 33. patentnom zahtjevu, naznačen time da je organsko otapalo u fazi b) etil acetat.
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