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AR079026A1 - Antagonistas de espiro -oxindol de mdm2 - Google Patents

Antagonistas de espiro -oxindol de mdm2

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Publication number
AR079026A1
AR079026A1 ARP100104201A ARP100104201A AR079026A1 AR 079026 A1 AR079026 A1 AR 079026A1 AR P100104201 A ARP100104201 A AR P100104201A AR P100104201 A ARP100104201 A AR P100104201A AR 079026 A1 AR079026 A1 AR 079026A1
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Argentina
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optionally substituted
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hydrogen
alkyl
cycloalkyl
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Univ Michigan
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Application filed by Univ Michigan filed Critical Univ Michigan
Publication of AR079026A1 publication Critical patent/AR079026A1/es

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10Spiro-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/4523Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic 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
    • A61K31/496Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/53751,4-Oxazines, e.g. morpholine
    • A61K31/53771,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/66Phosphorus compounds
    • A61K31/675Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/04Antineoplastic agents specific for metastasis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00General protective or antinoxious agents
    • A61P39/02Antidotes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/20Spiro-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic 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
    • C07D491/02Heterocyclic 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
    • C07D491/10Spiro-condensed systems
    • C07D491/107Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D495/00Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10Spiro-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02Phosphorus compounds
    • C07F9/547Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oncology (AREA)
  • Toxicology (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Indole Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Los compuestos y composiciones proporcionadas en la presente memoria se refieren a espiro-oxindoles que funcionan como antagonistas de la interaccion entre p53 y MDM2, y a su uso como agentes terapéuticos para el tratamiento del cáncer y otras enfermedades. Reivindicacion 1: Un compuesto que tiene la Formula (1): en la que: R1a, R1b, R1c y R1d se seleccionan independientemente entre el grupo que consiste en hidrogeno, halogeno, hidroxi, amino, nitro, ciano, alcoxi, ariloxi, alquilo opcionalmente sustituido, haloalquilo, cicloalquilo opcionalmente sustituido, alquenilo opcionalmente sustituido, cicloalquenilo opcionalmente sustituido, arilo opcionalmente sustituido, heteroarilo opcionalmente sustituido, carboxamido y sulfonamido; R2 se setecciona entre el grupo que consiste en arilo opcionalmente sustituido y heteroarilo opcionalmente sustituido; R3 se selecciona entre el grupo que consiste en alquilo opcionalmente sustituido, (cicloalquil)alquilo opcionalmente sustituido, cicloalquilo opcionalmente sustituido, alquenilo opcionalmente sustituido, cicloalquenilo opcionalmente sustituido, arilo opcionalmente sustituido y heteroarilo opcionalmente sustituido; R4 se selecciona entre el grupo que consiste en hidrogeno y alquilo C1-6 opcionalmente sustituido; R5 se selecciona entre el grupo (2): en el que: cada R6 y R6b se selecciona independientemente entre el grupo que consiste en hidrogeno y alquilo C1-6 opcionalmente sustituido; R7 se selecciona entre el grupo que consiste en hidrogeno, alquilo C1-6 opcionalmente sustituido y cicloalquilo opcionalmente sustituido; cada uno de R8a y R8b se selecciona independientemente entre el grupo que consiste en hidrogeno, alquilo C1-6 opcionalmente sustituido y cicloalquilo opcionalmente sustituido; o R8a y R8b tomados junto con el carbono al que están unidos forman un cicloalquilo opcionalmente sustituido de 3 a 8 miembros; W1 se selecciona entre el grupo que consiste en -OR9a y -NR9bR9c; R9a es hidrogeno; R9b se selecciona entre el grupo que consiste en hidrogeno, alquilo opcionalmente sustituido, cicloalquilo opcionalmente sustituido, arilo opcionalmente sustituido, heteroarilo opcionalmente sustituido, -SO2R9d y -CONR9eR9f; R9c se selecciona entre el grupo que consiste en hidrogeno, alquilo opcionalmente sustituido, cicloalquilo opcionalmente sustituido, arilo opcionalmente sustituido y heteroarilo opcionalmente sustituido; o R9b y R9c tomados junto con el átomo de nitrogeno al que están unidos forman un heterociclo opcionalmente sustituido de 4 a 8 miembros; R9d se selecciona entre el grupo que consiste en alquilo opcionalmente sustituido y cicloalquilo opcionalmente sustituido; cada uno de R9e y R9f se selecciona independientemente entre el grupo que consiste en hidrogeno, alquilo opcionalmente sustituido y cicloalquilo opcionalmente sustituido; o R9e y R9f tomados junto con el átomo de nitrogeno al que están unidos forman un heterociclo opcionalmente sustituido de 4 a 8 miembros; W2 se selecciona entre el grupo que consiste en -OR10 y -NR11aR11b; R10 es hidrogeno; o uno de R9a y R10 es hidrogeno y el otro es un grupo metabolicamente escindible; con la condicion de que cuando W1 es -OR9a y W2 es -OR10 entonces al menos uno de R7, R8a y R8b sea distinto de hidrogeno; R11a se selecciona entre el grupo que consiste en hidrogeno, alquilo opcionalmente sustituido, cicloalquilo opcionalmente sustituido, arilo opcionalmente sustituido, heteroarilo opcionalmente sustituido, -SO2R11c y -CONR11dR11e; Rb se selecciona entre el grupo que consiste en hidrogeno, alquilo opcionalmente sustituido, cicloalquilo opcionalmente sustituido, arilo opcionalmente sustituido y heteroarilo opcionalmente sustituido; o R11a y R11b tomados junto con el átomo de nitrogeno al que están unidos forman un heterociclo opcionalmente sustituido de 4 a 8 miembros; R11c se selecciona entre el grupo que consiste en alquilo opcionalmente sustituido y cicloalquilo opcionalmente sustituido; cada uno de R11d y R11e se selecciona independientemente entre el grupo que consiste en hidrogeno, alquilo opcionalmente sustituido y cicloalquilo opcionalmente sustituido; o R11d y R11e junto con el átomo de nitrogeno al que están unidos forman un heterociclo opcionalmente sustituido de 4 a 8 miembros; n es 1, 2, 3, 4 o 5; cada R12a, R12b, R12c y R12d se selecciona independientemente entre el grupo que consiste en hidrogeno y alquilo C1-6 opcionalmente sustituido; R13 se selecciona entre el grupo que consiste en hidrogeno y alquilo C1-6 opcionalmente sustituido; R14 se selecciona entre el grupo que consiste en hidrogeno, alquilo C1-6 opcionalmente sustituido y cicloalquilo opcionalmente sustituido; Z se selecciona entre el grupo que consiste en -OR15 y -NR16aR16b; o Z y R14 tomados juntos forman un grupo carbonilo; R15 se selecciona entre el grupo que consiste en hidrogeno y un grupo metabolicamente escindible; R16b se selecciona entre el grupo que consiste en -SO2R16c y -CONR16dR16e; R16b se selecciona entre el grupo que consiste en hidrogeno y alquilo opcionalmente sustituido; R16c se selecciona entre el grupo que consiste en alquilo opcionalmente sustituido, cicloalquilo opcionalmente sustituido, arilo opcionalmente sustituido y heteroarilo opcionalmente sustituido; cada uno de R16d y R16e se selecciona independientemente entre el grupo que consiste en hidrogeno, alquilo opcionalmente sustituido, cicloalquilo opcionalmente sustituido, arilo opcionalmente sustituido y heteroarilo opcionalmente sustituido; o R16d y R16e tomados junto con el átomo de nitrogeno al que están unidos forman un heterociclo de 4 a 8 miembros; o es 1, 2 o 3; p es 0, 1, 2 o 3; cada R17a, R17b, R17c y R17d se selecciona independientemente entre el grupo que consiste en hidrogeno y alquilo C1-6 opcionalmente sustituido; R18 se selecciona entre el grupo que consiste en hidrogeno y alquilo C1-6 opcionalmente sustituido; R19 se selecciona entre el grupo que consiste en hidrogeno, alquilo C1-6 opcionalmente sustituido y cicloalquilo opcionalmente sustituido; R20 se selecciona entre el grupo que consiste en hidrogeno, alquilo C1-6 opcionalmente sustituido y cicloalquilo opcionalmente sustituido; cada uno de R21a y R21b es hidrogeno; o uno de R21a y R21b es hidrogeno y el otro es un grupo metabolicamente escindible; q es 0, 1, 2 o 3; r es 1, 2 o 3; X se selecciona entre el grupo que consiste en O, S y NR'; Y se selecciona entre el grupo que consiste en O, S y NRö; R' se selecciona entre el grupo que consiste en hidrogeno, alquilo opcionalmente sustituido, aralquilo y cicloalquilo opcionalmente sustituido; Rö se selecciona entre el grupo que consiste en hidrogeno, alquilo opcionalmente sustituido, aralquilo y cicloalquilo opcionalmente sustituido; y --- representa un enlace sencillo o un doble enlace, o una sal farmacéuticamente aceptable, solvato o profármaco de los mismos.
ARP100104201A 2009-11-12 2010-11-12 Antagonistas de espiro -oxindol de mdm2 AR079026A1 (es)

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US26068509P 2009-11-12 2009-11-12
US26366209P 2009-11-23 2009-11-23

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AR079026A1 true AR079026A1 (es) 2011-12-21

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US (3) US8518984B2 (es)
EP (1) EP2499145B1 (es)
JP (1) JP2013510860A (es)
KR (1) KR20120099462A (es)
CN (2) CN102712650B (es)
AR (1) AR079026A1 (es)
AU (1) AU2010319595B2 (es)
BR (1) BR112012011317A2 (es)
CA (1) CA2780547C (es)
CL (1) CL2012001250A1 (es)
CO (1) CO6501131A2 (es)
CR (1) CR20120313A (es)
DO (1) DOP2012000131A (es)
EC (1) ECSP12011943A (es)
GT (1) GT201200147A (es)
IL (1) IL219706A (es)
MA (1) MA33815B1 (es)
MX (1) MX2012005507A (es)
NI (1) NI201200083A (es)
NZ (1) NZ600430A (es)
PE (1) PE20121282A1 (es)
RU (1) RU2553269C2 (es)
TN (1) TN2012000161A1 (es)
TW (1) TWI508967B (es)
UA (1) UA107814C2 (es)
UY (1) UY33029A (es)
WO (1) WO2011060049A2 (es)
ZA (1) ZA201203323B (es)

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