DK2906551T3 - Krystallinske former af en faktor-xia-hæmmer - Google Patents

Krystallinske former af en faktor-xia-hæmmer Download PDF

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DK2906551T3
DK2906551T3 DK13780287.2T DK13780287T DK2906551T3 DK 2906551 T3 DK2906551 T3 DK 2906551T3 DK 13780287 T DK13780287 T DK 13780287T DK 2906551 T3 DK2906551 T3 DK 2906551T3
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crystalline
oxopiperazin
tetrahydroisoquinoline
acryloyl
methyl
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DK13780287.2T
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Marta Dabros
Chenkou Wei
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Bristol Myers Squibb Co
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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    • A—HUMAN NECESSITIES
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    • A61K9/4841—Filling excipients; Inactive ingredients
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
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Claims (14)

  1. KRYSTALLINSKE FORMER AF EN FAKTOR-XIA-HÆMMER
    1. Form HC1:SA-1 (opløst mono-HCl-salt) af krystallinsk (S,E)-4-(2-(3-(3-chlor-2-fluor-6-(lH-tetrazol-l-yl)phenyl)acryloyl)-5-(4-methyl-2-oxopiperazin-l-yl)-l,2,3,4-tetrahydroisoquinolin-l-carboxamid)benzoesyre, der er kendetegnet ved et pulverrøntgendiffraktionsmønster, der omfatter fire eller flere 2Θ værdier (CuKa λ= 1,5418 Å): 6,0, 8,3, 8,7, 12,3, 16,2, 16,7, 17,5, 19,9 og 20,4.
  2. 2. Form HC1:SA-1 (opløst mono-HCl-salt) af krystallinsk (S,E)-4-(2-(3-(3-chlor-2-fluor-6-(lH-tetrazol-l-yl)phenyl)acryloyl)-5-(4-methyl-2-oxopiperazin-l-yl)-l,2,3,4-tetrahydroisoquinolin-l-carboxamid)benzoesyre ifølge krav 1, der er kendetegnet ved enhedscelleparametre, der svarer til følgende: Celledimensioner: a = 8,3746(2) Å b= 20,2236(5) Å c = 21,3099(6) Å α = 90° β = 90° γ = 90° Afstandsgruppe: P2(l)2(l)2(l) Molekyler/asymmetrisk enhed: 1 hvor måling af den krystallinske form sker ved en temperatur på 23 °C.
  3. 3. Form HC1:SA-1 ifølge krav 2, der er kendetegnet ved fraktionelle atomkoordinater som opført nedenfor, hvor U(eq) er defineret som én tredjedel af sporet af den ortogonaliserede U1J tensor:
  4. 4. Form HC1:SA-1 (opløst mono-HCl-salt) af krystallinsk (S,E)-4-(2-(3-(3-chlor-2-fluor-6-(lH-tetrazol- l-yl)phenyl)acryloyl)-5-(4-methyl-2-oxopiperazin- 1-yl)-1,2,3,4-tetrahydroisoquinolin-1-carboxamid)benzoesyre ifølge krav 1 til 3, der er kendetegnet ved enhedscelleparametre som opført nedenfor:
  5. 5. Form H.5-1 (hemihydrat) af krystallinsk (S,E)-4-(2-(3-(3-chlor-2-fluor-6-(lH-tetrazol-l- yl)phenyl)acryloyl)-5-(4-methyl-2-oxopiperazin- 1-yl)-1,2,3,4-tetrahydroisoquinolin-1-carboxamid)benzoesyre, der er kendetegnet ved et pulverrøntgendiffraktionsmønster, der omfatter fire eller flere 2Θ værdier (CuKa λ= 1,5418 Å): 5,9, 7,2,12,0, 15,7, 17,2, 18,9, 20,3, 24,2 og 26,1.
  6. 6. Form H.5-1 (hemihydrat) af krystallinsk (S,E)-4-(2-(3-(3-chlor-2-£luor-6-(lH-tetrazol-l- yl)phenyl)acryloyl)-5-(4-methyl-2-oxopiperazin-l-yl)-l,2,3,4-tetrahydroisoquinolin-l-carboxamid)benzoesyre ifølge krav 5, der er kendetegnet ved enhedscelleparametre, der svarer til følgende: Celledimensioner: a = 13,6547(3) Å b= 18,7590(3) Å c = 24,7370(5) Å a= 90° β = 90° γ = 90° Afstandsgruppe: 12(1)2(1)2(1) Molekyler/asymmetrisk enhed: 1 Densitet (beregnet): 1,401 Mg/m3 hvor måling af den krystallinske form sker ved en temperatur på 23 °C.
  7. 7. Form H.5-1 ifølge krav 6, der er kendetegnet ved fraktionelle atomkoordinater som opført nedenfor, hvor U(eq) er defineret som én tredjedel af sporet af den ortogonaliserede U1J tensor.
  8. 8. Form P13 af krystallinsk (S,E)-4-(2-(3-(3-chlor-2-fluor-6-(lH-tetrazol-l-yl)phenyl)acryloyl)-5-(4-methyl-2-oxopiperazin-l-yl)-l,2,3,4-tetrahydroisoquinolin-l-carboxamid)benzoesyre, der er kendetegnet ved et pulverrøntgendiffraktionsmønster, der omfatter fire eller flere 2Θ værdier (CuKa λ= 1,5418 A): 8,4, 8,9, 12,7 og 17,9.
  9. 9. Form ifølge et hvilket som helst af kravene 1, 5, og 8, der har en renhed, der er større end 90 procent.
  10. 10. Farmaceutisk sammensætning, der omfatter en terapeutisk effektiv mængde af krystallinsk Form H.5-1 (hemihydrat) af (S,E)-4-(2-(3-(3-chlor-2-fluor-6-(lH-tetrazol-l-yl)phenyl)acryloyl)-5-(4-methyl-2- oxopiperazin-l-yl)-l,2,3,4-tetrahydroisoquinolin-l-carboxamid)benzoesyre og en farmaceutisk acceptabel bærer; eller, der omfatter en terapeutisk effektiv mængde af krystallinsk Form P13 af (S,E)-4-(2-(3-(3-chlor-2-fluor-6-(lH-tetrazol-l-yl)phenyl)acryloyl)-5-(4-methyl-2-oxopiperazin-l-yl)-l,2,3,4-tetrahydroisoquinolin-l-carboxamid)benzoesyre og en farmaceutisk acceptabel bærer; eller, der omfatter en terapeutisk effektiv mængde af krystallinsk Form HCFSA-1 (opløst mono-HCl-salt) af (S,E)-4-(2-(3-(3-chlor-2-fluor-6-(lH-tetrazol-l-yl)phenyl)acryloyl)-5-(4-methyl-2-oxopiperazin-l-yl)-l,2,3,4-tetrahydroisoquinolin-l-carboxamid)benzoesyre og en farmaceutisk acceptabel bærer.
  11. 11. Krystallinsk form ifølge et hvilket som helst af kravene 1-9 eller sammensætning ifølge krav 10 til anvendelse i behandling af en tromboembolisk forstyrrelse.
  12. 12. Krystallinsk form eller sammensætning til anvendelse ifølge krav 11, hvor den tromboembolisk forstyrrelse er valgt fra gruppen bestående af arterielle kardiovaskulære tromboemboliske forstyrrelser, venøse kardiovaskulære tromboemboliske forstyrrelser og tromboemboliske forstyrrelser i hjertekamrene.
  13. 13. Krystallinsk form eller sammensætning til anvendelse ifølge krav 11, hvor den tromboemboliske forstyrrelse er valgt fra ustabilt angina, et akut koronært syndrom, atrieflimren, første myokardieinfarkt, tilbagevendende myokardieinfarkt, iskæmisk pludselig død, transient iskæmisk attack, apopleksi, aterosklerose, periferisk okklusiv arteriesygdom, venetrombose, dyb venetrombose, tromboflebit, arterieemboli, koronær arteriel trombose, cerebral arteriel trombose, cerebral emboli, nyreemboli, lungeemboli og trombose som følge af (a) protesehjerteklapper eller andre implantater, (b) fastliggende katetre, (c) stenter, (d) kardiopulmonal bypass, (e) hæmodialyse eller (f) andre procedurer, hvor blod eksponeres for en kunstig overflade, der fremmer trombose.
  14. 14. Fremgangsmåde til fremstilling af krystallinske former af (S,H)-4-(2-(3-(3-chlor-2-fluor-6-(lIF tetrazol- l-yl)phenyl)acryloyl-5-(4-methyl-2-oxopiperazin-1 -yl)-1,2,3,4,-tetrahydroisoquinolin-1-carboxamidjbenzoesyre (forbindelse (I)), der omfatter et trin med opslæmning af forbindelse (I) i et opløsningsmiddel, der er udvalgt fra: acetone, methanol, ethanol, CH2C12, DMF, NMP, MEK, 2-BuOH, IPA, IpOAc, MTBE, EtOAc og BuOAc.
DK13780287.2T 2012-10-12 2013-10-11 Krystallinske former af en faktor-xia-hæmmer DK2906551T3 (da)

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PCT/US2013/064423 WO2014059203A1 (en) 2012-10-12 2013-10-11 Crystalline forms of a factor xia inhibitor

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