HRP20150592T1 - Organoborni esterski spojevi i njihove farmaceutske kompozicije - Google Patents

Organoborni esterski spojevi i njihove farmaceutske kompozicije Download PDF

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HRP20150592T1
HRP20150592T1 HRP20150592TT HRP20150592T HRP20150592T1 HR P20150592 T1 HRP20150592 T1 HR P20150592T1 HR P20150592T T HRP20150592T T HR P20150592TT HR P20150592 T HRP20150592 T HR P20150592T HR P20150592 T1 HRP20150592 T1 HR P20150592T1
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pharmaceutical composition
weight
present
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HRP20150592TT
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Eric L. Elliott
Abu J. Ferdous
Michael J. Kaufman
Sonja A. Komar
Debra L. Mazaik
Quentin J. Mccubbin
Phoung M. Nguyen
Vaithianathan Palaniappan
Raymond D. Skwierczynski
Nobel T. Truong
Csanad M. Varga
Peter N. Zawaneh
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Millennium Pharmaceuticals, Inc
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Application filed by Millennium Pharmaceuticals, Inc filed Critical Millennium Pharmaceuticals, Inc
Publication of HRP20150592T1 publication Critical patent/HRP20150592T1/hr

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Claims (25)

1. Spoj formule (II): [image] ili njegova farmaceutski prihvatljiva sol, u kojem: A je 0; Ra je izobutil; Ra1 je vodik; P je Rc-C(O)-; Rc je -RD; -RD je 2,5-diklorofenil; svaki od Rb1 i Rb2 nezavisno je vodik, -CO2H, -OH ili supstituirani ili nesupstituirani alifatik, aril, heteroaril ili heterociklil grupa; svaki od Rb3 i Rb4 nezavisno je vodik, -CO2H, ili supstituirani ili nesupstituirani alifatik, aril, heteroaril ili heterociklil grupa; ili Rb2 i Rb4 su svaki nezavisno vodik, i Rb1 i Rb3, uzeti zajedno sa atomima ugljika za koje su vezani, formiraju nesupstituirani ili supstituirani fuzionirani 4- do 8-člani ne-aromatični prsten koji ima 0-3 heteroatoma u prstenu izabrana iz grupe koju čine O, N i S, pri čemu navedeni prsten može biti izborno fuzioniran za nesupstituirani ili supstituirani 4- do 8-člani ne-aromatični prsten, ili 5- do 6- člani aromatični prsten koji ima 0-3 heteroatoma u prstenu izabrana iz grupe koju čine O, N i S; ili Rb2 i Rb4 su odsutni, i Rb1 i Rb3, uzeti zajedno sa atomima ugljika za koje su vezani, formiraju nesupstituirani ili supstituirani fuzionirani 5- do 6-člani aromatični prsten koji ima 0-3 heteroatoma u prstenu izabrana iz grupe koju čine O, N i S, gdje navedeni prsten može biti izborno fuzioniran za nesupstituirani ili supstituirani 4- do 8-člani ne-aromatični prsten, ili 5- do 6-člani aromatični prsten koji ima 0-3 heteroatoma u prstenu izabrana iz grupe koju čine O, N i S; i n je 0 ili 1.
2. Spoj prema patentnom zahtjevu 1, naznačen time što svaki od Rb3 i Rb4 nezavisno je vodik, C1-6 alifatik, ili -(CH2)p-CO2H; i p je 0, 1, ili 2.
3. Spoj prema patentnom zahtjevu 2, naznačen time što -OC(O)(CRb1Rb2)nCRb3Rb4O- je grupa porijeklom iz limunske kiseline.
4. Spoj prema patentnom zahtjevu 3, u značajno čistom kristalnom obliku.
5. Spoj prema patentnom zahtjevu 3, naznačen formulom (III), (IIIa), (IV), (IVa): [image] ili njegova smjesa.
6. Spoj prema patentnom zahtjevu 3, naznačen formulom (III) ili (IV): [image] [image] ili njegova smjesa.
7. Spoj prema patentnom zahtjevu 6, naznačen formulom (III): [image]
8. Spoj formule (I): [image] ili njegova farmaceutski prihvatljiva sol, u kojem: A je 0; Ra je izobutil; Ra1 je vodik; P je Rc-C(O)-; Rc je -RD; -RD je 2,5-diklorofenil; i Z1 i Z2 zajedno formiraju grupu porijeklom iz limunske kiseline, gdje je atom vezan za bor u svakom slučaju atom kisika i gdje je grupa formirana uklanjanjem iz limunske kiseline atoma vodika iz grupe karboksilne kiseline i atoma vodika iz hidroksil grupe direktno vezanog za atom ugljika u alfa ili beta položaju u odnosu na grupu karboksilne kiseline.
9. Farmaceutska kompozicija koja sadrži spoj prema bilo kojem od patentnih zahtjeva 1 do 8, ili njegovu farmaceutski prihvatljivu sol i farmaceutski prihvatljiv nosač.
10. Farmaceutska kompozicija prema patentnom zahtjevu 9, koja sadrži spoj prema bilo kojem od patentnih zahtjeva 1 do 8 ili njegov kristalni oblik, punitelj i izborno lubrikant; pri čemu farmaceutska kompozicija izborno dalje sadrži aditiv za poboljšanje protoka, i izborno dalje sadrži pufer, izborno gdje je farmaceutska kompozicija oralni farmaceutski oblik doze, na primjer kapsula.
11. Farmaceutska kompozicija prema patentnom zahtjevu 10, naznačena time što farmaceutska kompozicija sadrži: a) oko 0.2% do oko 3% spoja prema bilo kojem od patentnih zahtjeva 1 do 8, ili njegovog kristalnog oblika, oko 86.5% do oko 99.8% punitelja izborno do oko 1.5% lubrikanta, izborno do oko 5% aditiva za poboljšanje protoka, i izborno do oko 5% pufera, prema težini kao postotak ukupne težine; b) oko 0.2% do oko 3% spoja prema bilo kojem od patentnih zahtjeva 1 do 8, ili njegovog kristalnog oblika; oko 97% do oko 99.8% punitelja; i izborno do oko 1.5% lubrikanta, prema težini kao postotak ukupne težine; ili c) oko 25% do oko 2% spoja prema bilo kojem od patentnih zahtjeva 1 do 8, ili njegovog kristalnog oblika; i oko 98% do oko 99.75% punitelja, prema težini kao postotak ukupne težine.
12. Farmaceutska kompozicija prema patentnom zahtjevu 10, naznačena time što a) spoj prema bilo kojem od patentnih zahtjeva 1 do 8 ili njegov kristalni oblik, je prisutan u količini od oko 0.2% do oko 3%, prema težini kao postotak ukupne težine, na primjer količina od oko 0.25% do oko 2%, prema težini kao postotak ukupne težine; i/ili b) punitelj je prisutan u količini od oko 86.5% do oko 99.8%, prema težini kao postotak ukupne težine, na primjer gdje je punitelj prisutan u količini od oko 97% do oko 99.8%, prema težini kao postotak ukupne težine, ili gdje je punitelj prisutan u količini od oko 98% do oko 99.75%, prema težini kao postotak ukupne težine; i/ili c) gdje je lubrikant, kada je prisutan, prisutan u količini do oko 1.5%, prema težini kao postotak ukupne težine, na primjer u količini od oko 1%, prema težini kao postotak ukupne težine; i/ili d) aditiv za poboljšanje protoka, kada je prisutan, je prisutan u količini do oko 5%, prema težini kao postotak ukupne težine, na primjer u količini od oko 1%, prema težini kao postotak ukupne težine; i/ili e) pufer, kada je prisutan, je prisutan u količini do oko 5%, prema težini kao postotak ukupne težine, na primjer u količini od oko 2%, prema težini kao postotak ukupne težine.
13. Farmaceutska kompozicija prema patentnom zahtjevu 10, naznačena time što a) punitelj je izabran iz grupe koju čine celuloza u prahu, mikrokristalna celuloza, silicificirana mikrokristalna celuloza, mikrokristalna celuloza sa niskim sadržajem vlage, natrijev škrob glikolat, preželatinizirani škrob, i njihove smjese, poželjno gdje je punitelj izabran iz grupe koju čine mikrokristalna celuloza sa niskim sadržajem vlage, natrijev škrob glikolat, preželatinizirani škrob, i njihove smjese; i/ili b) lubrikant, kada je prisutan, je izabran iz grupe koju čine magnezijev stearat, gliceril behenat, hidrogenizirano biljno ulje, talk, cinkov stearat, kalcijev stearat, saharoza stearat, natrijev stearil fumarat, i njihove smjese, poželjno gdje lubrikant je magnezijev stearat; i/ili c) sredstvo za poboljšanje protočnosti, kada je prisutno, je talk.
14. Farmaceutska kompozicija prema patentnom zahtjevu 10, naznačena time što: -OC(O)(CRb1Rb2)nCRb3Rb4O- ili Z1 i Z2 formiraju grupu porijeklom iz limunske kiseline; punitelj je izabran iz grupe koju čine mikrokristalna celuloza sa niskim sadržajem vlage, natrijev škrob glikolat, preželatinizirani škrob, i njihove smjese; lubrikant, kada je prisutan, je magnezijev stearat; sredstvo za poboljšanje protočnosti, kada je prisutno, je talk; i pufer, kada je prisutan, je natrijev citrat.
15. Farmaceutska kompozicija prema patentnom zahtjevu 14, koja sadrži kristalni oblik 2.
16. Farmaceutska kompozicija prema patentnom zahtjevu 9, koja sadrži spoj prema bilo kojem od patentnih zahtjeva 1 do 8 ili njegov kristalni oblik, sredstvo za povećanje volumena; i pufer.
17. Farmaceutska kompozicija prema patentnom zahtjevu 16, naznačena time što je sredstvo za povećanje volumena prisutno u količini od oko 1% tež./vol. do oko 5% tež./vol., na primjer količini od oko 3 % tež./vol.
18. Farmaceutska kompozicija prema patentnom zahtjevu 15, naznačena time što agens punjenja je glicin, i/ili što pufer je natrijev citrat, i limunska kiselina.
19. Farmaceutska kompozicija koja sadrži spoj prema bilo kojem od patentnih zahtjeva 1 do 8 u liofiliziranom prahu, izborno dalje sadrži sredstvo za povećanje volumena, i pufer, poželjno gdje agens punjenja je glicin i/ili gdje pufer je natrijev citrat i limunska kiselina.
20. Farmaceutska kompozicija prema patentnom zahtjevu 16 ili 17 naznačena time što: -OC(O)(CRb1Rb2)nCRb3Rb4O- ili Z1 i Z2 formiraju grupu porijeklom iz limunske kiseline; agens punjenja je glicin; i pufer je natrijev citrat i limunska kiselina.
21. Postupak za pripremu farmaceutske kompozicije spoja (I) prema patentnom zahtjevu 8 kao liofilizirani prah, pri čemu postupak sadrži korake: spajanja: i. vodene smjese otapala; ii. spoja (I) iii. glicina; iv. natrijevog citrata i limunske kiseline; formira se smjesa; i liofilizacije smjese.
22. Postupak pripreme farmaceutske kompozicije spoja formule (I) prema patentnom zahtjevu 8 kao liofiliziranog praha, pri čemu postupak sadrži korake: spajanja: i. vodene smjese otapala; ii. spoja formule (VIII) [image] gdje su A, Ra, Ra1, P, Rc i RD kao što su definirani u patentnom zahtjevu 8; iii. glicina; i iv. limunske kiseline; formira se smjesa; i liofilizacije smjese.
23. Postupak za pripremu farmaceutske kompozicije spoja (I) prema patentnom zahtjevu 8 kao tekućeg farmaceutskog oblika doze, pri čemu navedeni postupak sadrži korak rekonstitucije liofiliziranog praha spoja (I) sa vodom za injekciju.
24. Tekuća farmaceutska kompozicija koja sadrži spoj prema bilo kojem od patentnih zahtjeva 1 do 8, pufer i izborno modifikator toničnosti, izborno gdje modifikator toničnosti, kada je prisutan, je natrijev klorid i/ili gdje je pufer natrijev citrat, i limunska kiselina, poželjno gdje: -OC(O)(CRb1Rb2)nCRb3Rb4O- ili Z1 i Z2 formiraju grupu porijeklom iz limunske kiseline; pufer je natrijev citrat i limunska kiselina; i modifikator toničnosti, kada je prisutan, je natrijev klorid.
25. Farmaceutska kompozicija prema bilo kojem od patentnih zahtjeva 9 do 24 za uporabu u postupku za liječenje kancera.
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