SI21100B - Polimorfa analoga epotilona - Google Patents

Polimorfa analoga epotilona Download PDF

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SI21100B
SI21100B SI200120055A SI200120055A SI21100B SI 21100 B SI21100 B SI 21100B SI 200120055 A SI200120055 A SI 200120055A SI 200120055 A SI200120055 A SI 200120055A SI 21100 B SI21100 B SI 21100B
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temperature
mixture
analog
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hours
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SI21100A (sl
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John Dimarco
Jack Gougoutas
Imre Vitez
Martha Davidovich
Michael Galella
Zhenrong Guo
Denis Favreau
Timothy Malloy
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Bristol Myers Squibb Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—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
    • 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
    • C07D491/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

V skladu s pričujočim izumom sta podana dva kristalna polimorfa analoga epotilona, predstavljenega s formulo (I), ki sta poimenovana oblika A in oblika B, podane pa so tudi njune mešanice. Poleg tega so podane tudi metode za izdelovanje novih polimorfov, terapevstke metode njihove uporabe ter farmacevtske dozirne oblike, ki navedena polimorfa vsebujejo.

Claims (21)

  1. -1- SI 21100 Polimorfa analoga epotilona Patentni zahtevki 1. Kristalni polimorf analoga epotilona, predstavljenega s formulo Me
    I ki vključuje obliko Δ, označeno s: parametri osnovne celice, ki so okvirno enaki naslednj im: Dimenzije celice a=14,152(6) A b=30,72(2) A c=6,212(3) A Prostornina=2701 (4) A3 Prostorska konfiguracija Ρ2χ2ι2ι Ortorombska Število molekul v osnovni celici 4 Gostota (izračunana) (g/cm3) 1,247 Tališče 182-185° C (razkroj); ter značilnimi koničnimi jakostmi prašne rentgenske difrakcije pri vrednosti dve theta (CuKa λ=1,5406 A pri 22° C) : 5, 69, 6, 76, 8,38, 11,43, 12,74, 13,62, 14,35, 15,09 15, 66, 16,43, 17,16, 17,66, 18,31, 19,03, 19,54, 20,57 21, 6, 21,29, 22,31, 23,02, 23,66, 24,18, 24,98, 25,50 -2- 26,23, 26,23, 26,46, 27,59, 28,89, 29,58, 30,32, 31,08 in 31,52; ali obliko B, označeno s: parametri osnovne celice, naslednj im: ki so okvirno enaki Dimenzije celice a=16,675(2) A b=28,083(4) A c=6,054(1) A Prostornina=2835(1) A1 2 3 Prostorska konfiguracija P2i2i2! Ortorombska Število molekul v osnovni celici 4 Gostota (izračunana) (g/cm3) 1,187 Tališče 191-199° C (razkroj) značilnimi koničnimi jakostmi prašne rentgenske difrakcije pri vrednosti dve theta (CuKa λ=1,5406 A pri 22° C): 6,17, 10,72, 12,33, 14,17, 14,93, 15,88, 16,17, 17,11, 17,98, 19,01, 19,61, 20,38, 21,55, 21,73, 22,48, 23,34, 23, 93, 24,78, 25,15, 25,90, 26, 63, 27,59, 28,66, 29,55, 30,49 in 31,22.
  2. 2. Kristalni polimorf analoga epotilona, predstavljenega s formulo
    1 2 ki vključuje obliko A, označeno s prašno rentgensko difrakcijo, kakršna je v bistvu prikazana na sliki 1 3 spodaj in z ramanskim spektrom, kakršen je v bistvu prikazan na sliki 5 spodaj; ali obliko B, označeno s prašno rentgensko difrakcijo, kakršna je v bistvu 3 prikazana na sliki 2 spodaj, in z Ramanovim spektrom, kakršen je v bistvu prikazan na sliki 6 spodaj:
    SLIKA 1
    -4 -
    [2Τ| SLIKA 2
    SLIKA 6 Ramanov zamik (cm-1) -5-
  3. 3. Kristalni polimorf analoga epotilona, predstavljenega s formulo
    I ki vključuje obliko A, označeno s topnostjo v vodi, ki znaša 0,1254, s topnostjo v 3-% vodni raztopini polisorbata 80, ki znaša 0,2511, s tališčem z razkrojem med 182-185° C in toploto raztopine 20,6 kJ/mol; ali obliko B, označeno s topnostjo v vodi, ki znaša 0,1907, s topnostjo v 3-% vodni raztopini polisorbata 80, ki znaša 0,5799, s tališčem z razkrojem med 191-199° C ter toploto raztopine 9,86 kJ/mol.
  4. 4. Kristalni polimorf po zahtevkih 1, 2 ali 3, pri čemer je navedeni polimorf oblika A.
  5. 5. Kristalni polimorf po zahtevkih 1, 2 ali 3, pri čemer je navedeni polimorf oblika B.
  6. 6. Kristalna snov, ki vključuje zmes oblik A in B po zahtevkih 1, 2 ali 3.
  7. 7. Postopek za izdelavo kristalnega polimorfa, ki je oblika A analoga epotilona, predstavljenega s formulo I zahtevka 1, pri čemer navedeni postopek vključuje segretj e brozge navedenega s formulo I predstavljenega analoga v od okvirno 8 do okvirno 16 ml etilacetata na gram navedenega analoga na približno 75° C, vzdrževanje -6- take temperature približno eno uro, dodajanje določene količine cikloheksana v okvirnem razmerju 1:2 do 2:2 do etilacetata, čakanje, da se mešanica ohladi do temperature okolja, vzdrževanje mešanice z mešanjem okvirno od 12 do 96 ur, nadaljnjo ohladitev mešanice na približno 5° C v teku okrog dveh ur in pridobitev kristalne oblike A iz navedene mešanice.
  8. 8. Postopek po zahtevku 7, pri čemer je količina dodanega cikloheksana v razmerju 1:2 do količine etilacetata, uporabljenega za tvorbo navedene brozge.
  9. 9. Postopek po zahtevku 7, pri čemer se navedena brozga navedenega s formulo I predstavljenega analoga v etilacetatu segreje do približno 75° C, nakar se cepi s kristali in se ohranja okrog 30 minut pri tej temperaturi, nakar se ji doda navedena količina cikloheksana, medtem ko se temperatura vzdržuje pri okvirno 70° C, nakar se mešanica ohladi na temperaturo okolja, se jo okrog 18 ur z mešanjem ohranja pri tej temperaturi in zatem ohladi na približno 5° C v teku približno dveh ur, nakar se iz navedene mešanice dobi kristalna oblika A.
  10. 10. Postopek po zahtevku 7, pri čemer se navedena brozga navedenega s formulo I predstavljenega analoga v etilacetatu segreje na okrog 75° C najmanj eno uro, dokler ne nastane raztopina, nakar se navedena raztopina ohladi na približno 50° C v teku približno dveh ur, pri čemer se pri temperaturi približno 60° C cepi z navedenimi kristali, zatem se raztopina v teku približno treh ur ohladi na približno 30° C, zatem se temperatura raztopine zniža na -10° C v teku približno treh ur, v okviru katerih se v enournem obdobju po kapljicah doda -7- navedena količina cikloheksana, zatem se dobljena mešanica ohranja pri -10° C približno eno uro, nakar se iz navedene mešanice dobi kristalna oblika A.
  11. 11. Postopek za izdelavo kristalnega polimorfa, ki je oblika B s formulo I zahtevka 1 predstavljenega analoga epotilona, pri čemer navedeni postopek vključuje segrevanje brozge navedenega s formulo I predstavljenega analoga v okvirno 40 do 50 ml etilacetata na gram navedenega analoga na okvirno 75° C do 80° C, ohranjanje te temperature približno eno uro, da nastane raztopina, ohranjanje raztopine pri tej temperaturi še približno 30 minut, ohlajanje raztopine na približno 30° C v teku približno dveh ur, nadalje znižanje temperature raztopine na -10° C v teku približno ene ure, med katero se v približno tridesetminutnem obdobju po kapljicah doda količina cikloheksana v okvirnem razmerju 1:2 do 2:2 do etilacetata, dobljena mešanica se še približno dve uri ohranja pri temperaturi -10° C, nakar se iz nje dobi kristalna oblika B.
  12. 12. Postopek po zahtevku 11, pri čemer se navedena brozga navedenega s formulo I predstavljenega analoga v etilacetatu segreje na približno 78° C, tako da nastane raztopina, nakar se raztopina ohladi na približno 10° C v teku približno dveh ur, pri čemer se pri temperaturi 10° C cepi s kristali, zatem se temperatura raztopine zniža na -10° C v teku približno dveh ur, v okviru katerih se v približno tridesetminutnem obdobju po kapljicah doda navedena količina cikloheksana, nato se še približno dve uri ohranja temperatura dobljene mešanice pri -10° C, nakar se iz mešanice dobi kristalna oblika B. -8-
  13. 13. Postopek za izdelavo kristalnega polimorfa, ki je oblika B s formulo I zahtevka 1 predstavljenega analoga epotilona, pri čemer navedeni postopek vključuje segrevanje brozge navedenega s formulo I predstavljenega analoga v okrog 10 do okrog 20 ml toluena na gram navedenega analoga na okrog 75° C do 80° C, ohranjanje temperature približno 30 minut, ohladitev mešanice na približno 20° C, ohranjanje temperature še okrog 18 ur med mešanjem in nazadnje pridobitev kristalne oblike B iz navedene mešanice.
  14. 14. Farmacevtski pripravek, ki kot aktivno sestavino vključuje učinkovito količino kristalnega polimorfa po zahtevkih 1, 2 ali 3 in eno ali več farmacevtsko sprejemljivih podlag, polnil ali topil.
  15. 15. Farmacevtski pripravek po zahtevku 14, pri čemer je navedeni kristalni polimorf oblika A.
  16. 16. Farmacevtski pripravek po zahtevku 14, pri čemer je navedeni kristalni polimorf oblika B.
  17. 17. Farmacevtski pripravek po zahtevku 14, pri čemer je navedeni kristalni polimorf zmes oblik A in B.
  18. 18. Uporaba učinkovite količine kristalnega polimorfa po zahtevkih 1, 2 ali 3 za izdelavo zdravila za zdravljenje raka ali drugih proliferativnih bolezni v sesalcu, ki tako zdravilo potrebuje.
  19. 19. Uporaba po zahtevku 18, pri čemer je navedeni kristalni polimorf oblika A.
  20. 20. Uporaba po zahtevku 18, pri čemer je navedeni kristalni polimorf oblika B. se navedeni
  21. 21. Uporaba po zahtevku 18, pri čemer kristalni polimorf vnaša parenteralno.
SI200120055A 2000-08-16 2001-08-01 Polimorfa analoga epotilona SI21100B (sl)

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US22559000P 2000-08-16 2000-08-16
PCT/US2001/024540 WO2002014323A2 (en) 2000-08-16 2001-08-01 Polymorphs of an epothilone analog

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