DK2688873T3 - Bis(fluoralkyl)-1,4-benzodiazepinonforbindelser - Google Patents

Bis(fluoralkyl)-1,4-benzodiazepinonforbindelser Download PDF

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DK2688873T3
DK2688873T3 DK12711102T DK12711102T DK2688873T3 DK 2688873 T3 DK2688873 T3 DK 2688873T3 DK 12711102 T DK12711102 T DK 12711102T DK 12711102 T DK12711102 T DK 12711102T DK 2688873 T3 DK2688873 T3 DK 2688873T3
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compound
trifluoropropyl
phenyl
oxo
dihydro
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DK12711102T
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Claude Quesnelle
Soong-Hoon Kim
Francis Lee
Ashvinikumar Gavai
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Bristol Myers Squibb Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/24—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Claims (15)

  1. BIS(ELUORALKYL)-l,4-BENZODIAZEPINONFORBINDELSER
    1. Forbindelse med formlen (I):
    hvor: Rt er -CH2CF3 eller -CH2CH2CF3; R2 er -CH2CF3, -CH2CH2CF3 eller -CH2CH2CH2CF3; R3 er H, -CH3, -CD·,, -CHD2 eller -CH2D; hver Ra uafhængigt er F, Cl, -CN, -OCH3 og/eller -NHCH2CH2OCH3; og z er nul, 1 eller 2.
  2. 2. Forbindelse ifølge krav 1, hvor: Ri er -CH2CF3 eller -CH2CH2CF3 og R2 er -CH2CF3 eller -CH2CH2CF3.
  3. 3. Forbindelse ifølge krav 1, hvor: z er nul eller 1.
  4. 4. Forbindelse ifølge krav 1, hvor: Ri er -CH2CH2CF3 og R2 er -CH2CH2CF3.
  5. 5. Forbindelse ifølge krav 4, hvor: z er nul eller 1.
  6. 6. Forbindelse ifølge krav 1, hvor: z er 1 eller 2.
  7. 7. Forbindelse ifølge krav 1 udvalgt fra: (2R,35)-N-((35)-l-methyl-2-oxo-5-phenyl-2,3-dihydro-lH- l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluorpropyl)succinamid (1); (2R,35)-N-((35)-2-Oxo-5-phenyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluorpropyl)succinamid (2); (2R,35)-N-((35)-l-methyl-2-oxo-5-phenyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-2-(2,2,2-trifluorethyl)-3-(3,3,3-trifhiorpropyl)succinamid (3); (2R,35)-N-((35)- l-methyl-2-oxo-5-phenyl-2,3-dihydro-1 Η-1,4- benzodiazepin-3-yl)-3-(2,2,2-trifluorethyl)-2-(3,3,3-trifluorpropyl)succinamid (4); (2R,3S)-N-((3S)-1- f2I I1)mcthyl-2-oxo-5-phcnyl-2,3-dihydro-1//-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3- trifluorpropyl)succinamid (5); (2i?,35)-N-((3S)-7-chlor-l-methyl-2-oxo-5-phenyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluorpropyl)succinamid (6); (2R,3S)-N-((3S)-8-mcthoxy-l-methyl-2-oxo-5-phenyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluorpropyl)succinamid (7); (2R.3S)-N-((3S)-8-fluor- l-methyl-2-oxo-5-phenyl-2,3-dihydro-1 Η-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluorpropyl)succinamid (8); (2R,3S)-N-((3S)-7-methoxy-l-methyl-2-oxo-5-phenyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluorpropyl)succinamid (9); (2/?,35)-N-((35')-7-fluor-l-methyl-2-oxo-5-phenyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluorpropyl)succinainid (10); (2R,35')-N-((35')-8-chlor-l-methyl-2-oxo-5-phenyl-2,3-dihydro-1 Η-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluorpropyl)succinainid (11); (2R,35')-N-((3S)-9-mcthoxy-2-oxo-5-phenyl-2,3-dihydro-1II-1,4- benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluorpropyl)succinamid (12); (2R,35')-N-((3S)-8-mcthoxy-2-oxo-5- phenyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifhiorpropyl)succinamid (13); (2R,3S)-N- ((35)-7-methoxy-2-oxo-5-phenyl-2,3-dihydrolH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluorpropyl)succinainid (14); (2R,3S)-N-((3S)-8-cyano-9-methoxy-2-oxo-5-phenyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluorpropyl)succinainid (15); (2R,35)-N-((3S)-8,9-dichlor-2-oxo-5- phcnyl-2,3-dihydro-lI I-1,4-bcnzodiazcpin-3-yl)-2,3-bis(3,3,3-trifluorpropyl)succinamid (16); (2R,3S)-N-((35)-9-fluor-2-OXO-5-phcnyl-2,3-dihydro-IH-1,4-bcnzodia/,epin-3-yl )-2,3-bis(3,3,3-trifhiorpropyl)succinamid (17); (2/i,35)-N-((35)-9-chlor-2-oxo-5-phenyl-2,3-dihydro-lH-1,4- benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluorpropyl)succinamid (18); (21i,35)-N-((35)-2-Oxo-5-phenyl-2,3- dihydro-lH-l,4-benzodiazepin-3-yl)-3-(4,4,4-lrifluorbutyl)-2-(3,3,3-lrifluorpropyl)succinamid (19); <2R.3S)-N 1 -((3,S')-8-niethoxy-2-oxo-5-phcnyl-2,3-dihydro-lH-l,4-bcnz,odiazcpin-3-yl)-3-(4,4,4-trifluorbutyl)-2-(3,3,3-trifluorpropyl)succinamid (20); og (2R,3S)-N-((3S)-9-((2-methoxyethyl)amino)-2-oxo-5-phenyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluorpropyl)succinainid (21).
  8. 8. Forbindelse ifølge krav 1, hvor: R3 er H eller -CH3.
  9. 9. Forbindelse ifølge krav 8 udvalgt fra:
  10. 10. Forbindelse ifølge krav 9, hvor forbindelsen er:
  11. 11. Forbindelse ifølge krav 10, hvor forbindelsen er i krystallinsk form N-l, der er kendetegnet ved ét af følgende: a) et simuleret pulverrøntgendiffraktionsmønster i alt væsentligt som vist i figur 1 og/eller ved et observeret PXRD-mønster som i alt væsentligt vist i figur 1; b) et røntgendiffraktionsmønster omfattende fire eller flere, fortrinsvis fem eller flere, 2Θ værdier (CuKa λ^1,5418 Å) udvalgt ffa: 5,7+0,2, 7,5+0,2, 10,3+0,2, 10,7+0,2, 15,2±0,2, 16,8±0,2, 20,2+0,2 og 20,7+0,2, hvor PXRD-mønsteret af form N-l måles ved en temperatur på ca. 20 °C; c) enhedscelleparametre i alt væsentligt lig med følgende: Celledimensioner: a = 9,41 Å b = 17,74 Å c = 31,94 Å α = 90,0° β = 98,4° γ = 90,0° rumgruppe: P21 Molekyler af forbindelsen/den asymmetriske enhed: 4 hvor enhedscelleparametrene af form N-l måles ved en temperatur på ca. -10 °C; og/eller d) fraktionsatomkoordinater i alt væsentligt som opført i tabel 1 ved en temperatur på ca. 25°C, Tabel 1
  12. 12. Farmaceutisk sammensætning omfattende en forbindelse ifølge ét af kravene 1 til 11; og et farmaceutisk acceptabelt bærestof.
  13. 13. Forbindelse ifølge et af kravene 1 til 11, til anvendelse i terapi.
  14. 14. Forbindelse ifølge et af kravene 1 til 11, til anvendelse i behandlingen af cancer.
  15. 15. Kombination af en forbindelse ifølge et hvilket som helst af kravene 1 til 11; og ét eller flere supplerende midler udvalgt fra dasatinib, paclitaxel, tamoxifen, dexamethason og carboplatin, til anvendelse i behandlingen af cancer, til sekventiel eller samtidig anvendelse.
DK12711102T 2011-03-22 2012-03-22 Bis(fluoralkyl)-1,4-benzodiazepinonforbindelser DK2688873T3 (da)

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JP (1) JP5873923B2 (da)
KR (1) KR101948347B1 (da)
CN (1) CN103717576B (da)
AR (1) AR085471A1 (da)
AU (1) AU2012230904B2 (da)
BR (1) BR112013024059B1 (da)
CA (1) CA2830902C (da)
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CO (1) CO6771446A2 (da)
CY (1) CY1116423T1 (da)
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EA (1) EA022530B1 (da)
ES (1) ES2534080T3 (da)
HK (1) HK1189218A1 (da)
HR (1) HRP20150273T1 (da)
IL (1) IL228534A (da)
MA (1) MA35036B1 (da)
MX (1) MX2013010420A (da)
MY (1) MY161233A (da)
PE (1) PE20140626A1 (da)
PL (1) PL2688873T3 (da)
PT (1) PT2688873E (da)
RS (1) RS53843B1 (da)
SG (1) SG193555A1 (da)
SI (1) SI2688873T1 (da)
SM (1) SMT201500091B (da)
TN (1) TN2013000372A1 (da)
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