ES2655391T3 - Inhibidores isoindolinona de fosfatidilinositol 3-quinasa - Google Patents

Inhibidores isoindolinona de fosfatidilinositol 3-quinasa Download PDF

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Publication number
ES2655391T3
ES2655391T3 ES10805555T ES10805555T ES2655391T3 ES 2655391 T3 ES2655391 T3 ES 2655391T3 ES 10805555 T ES10805555 T ES 10805555T ES 10805555 T ES10805555 T ES 10805555T ES 2655391 T3 ES2655391 T3 ES 2655391T3
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aliphatic
cycloaliphatic
alkyl
elements
hydrogen
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Alex Aronov
Jon H. Come
Robert J. Davies
Albert C. Pierce
Jian Wang
Suganthini Nanthakumar
Jingrong Cao
Upul K. Bandarage
Elaine Krueger
Amaud Le Tiran
Yusheng Liao
David Messersmith
Philip N. Collier
Ronald Grey
Hardwin O'dowd
James A. Henderson
Anne-Laure Grillot
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Vertex Pharmaceuticals Inc
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Vertex Pharmaceuticals Inc
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    • 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
    • A61K31/435—Heterocyclic 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
    • A61K31/4353—Heterocyclic 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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic 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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/435—Heterocyclic 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • C07D401/02—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 two hetero rings
    • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D471/00—Heterocyclic 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
    • C07D471/02—Heterocyclic 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 two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic 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
    • C07D471/12—Heterocyclic 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
    • C07D471/20—Spiro-condensed systems
    • 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
    • C07D491/12—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 three hetero rings
    • C07D491/20—Spiro-condensed systems

Abstract

Compuesto que presenta la fórmula: **(Ver fórmula)** o una sal farmacéuticamente aceptable del mismo, en la que: X1 es N, X2 es N, CH o C-CH3, R1 es un pirazol-4-ilo sustituido opcionalmente con 1 o 2 apariciones de R1a, R1a es cloro, flúor, alifático C1-8, -(CH2)0-2cicloalifático C3-6, -(CH2)0-2-heterocíclico de 5 a 6 elementos que presenta hasta dos heteroátomos seleccionados de entre nitrógeno, oxígeno o azufre, -CN, -C(O)-alifático C1-4, -C(O)NH(alifático C1-4), -C(O)N(alifático C1-4)2, -C(O)O-alifático C1-4, -S(O)2NH(alifático C1-4), - S(O)2N(alifático C1-4)2 o -S(O)2-alifático C 1-4, en los que hasta 3 átomos de carbono no contiguos de dicho alifático o cicloalifático de R1a pueden sustituirse por -O-, -S- o -N(R1b)- y en los que cada uno de dicho alifático, cicloalifático o heterocíclico de R1a se sustituye opcional e independientemente con hasta 4 apariciones de JR, cada JR es independientemente flúor, oxo, -(CH2)0-2CN, -(CH2)0-2CF3 -C(O)R1b, -C(O)N(R1b)2, -C(O)O(R1b), -N(R1b)2, -N(R1b)C(O)R1b, -(CH2)0-2OR1b, fenilo o un heteroarilo de 5 a 6 elementos, heterociclo de 4 a 6 elementos o heteroarilo o heterociclilo bicíclico fusionado de 9 a 11 elementos, presentando cada uno de dichos anillos heteroarilo o heterociclilo que presentan hasta 3 átomos seleccionados de entre nitrógeno, oxígeno o azufre, en el que cada uno de dichos grupos cicloalifático, fenilo, heteroarilo o heterociclilo se sustituyen opcionalmente con hasta 2 R1c, cada R1b se selecciona, independientemente de entre hidrógeno, alifático C1-8, -(CH2)0-1cicloalifático C3-6, -(CH2)0-1heterocíclico C4-6 que presenta hasta dos heteroátomos seleccionados de entre N o O, o dos R1b junto con el átomo al que se encuentran unidos forman un anillo heterocíclico de 5 a 6 elementos, en el que cada grupo alifático, cicloalifático o heterocíclico se sustituye opcionalmente con hasta tres átomos de F o hasta dos grupos -OH, -alquilo C1-2 o -O-alquilo C1-2, cada R1c es, independientemente, flúor, cloro, alifático C1-4, -(CH2)0-2OH, -CN, -C(O)-alifático C1-4 o -C(O)O-alifático C1-4, R2 es hidrógeno, F, Cl, CF3, alifático C1-2, cicloalifático C3-4, -N(CH3)2, -N(CH2)3,-OCF3, -OCHF2 o -O-alifático C1-2, R3 es hidrógeno, alifático C1-6, cicloalifático C3-6, heterocíclico C4-7 que presenta 1 o 2 átomos seleccionados de entre N o O, -(CH2)0-1CF3, -OH, -O-alifático C1-6, -O-cicloalifático C3-6, -O-heterociclilo C3-6 que presenta un átomo de oxígeno, -O(CH2)2O-alifático C1-2 o -O-alquilo C1-2-C(O)O-alifático C1-3 o bencilo, y R4 es hidrógeno o alquilo C1-6, en el que por lo menos uno de entre R3 y R4 no es hidrógeno, o R3 y R4 junto con el carbono al que se encuentran unidos forman un anillo cicloalifático de 3 a 6 elementos, un anillo heterocíclico de 3 a 6 elementos que presenta hasta dos átomos seleccionados de entre N o O, o un alquenilo C2, en el que cada uno de entre dichos grupos alifático, cicloalifático o heterociclilo de R3, R4 o R3 y R4 juntos se sustituyen opcionalmente con hasta tres átomos de F, o hasta dos grupos alquilos C1-2,-C(O)-alquilo C1-4, -C(O)O-alquilo C1-4, -OH o -O-alquilo C1-2, A es N o CRA, B es N o CRB, o A>=B es un átomo de azufre, C es N o CRC, D es N o CRD, E es N o CRE, en el que no más de dos de entre A, B, C, D o E son N, ...
ES10805555T 2009-12-22 2010-12-21 Inhibidores isoindolinona de fosfatidilinositol 3-quinasa Active ES2655391T3 (es)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US28900309P 2009-12-22 2009-12-22
US35063110P 2010-06-02 2010-06-02
US36920110P 2010-07-30 2010-07-30
US38758210P 2010-09-29 2010-09-29
PCT/US2010/061484 WO2011087776A1 (en) 2009-12-22 2010-12-21 Isoindolinone inhibitors of phosphatidylinositol 3-kinase

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ES2655391T3 true ES2655391T3 (es) 2018-02-19

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ES17187529T Active ES2842399T3 (es) 2009-12-22 2010-12-21 Inhibidores isoindolinona de fosfatidilinositol 3-quinasa
ES10805555T Active ES2655391T3 (es) 2009-12-22 2010-12-21 Inhibidores isoindolinona de fosfatidilinositol 3-quinasa

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US (4) US20120040950A1 (es)
EP (3) EP2516417B1 (es)
JP (4) JP5721187B2 (es)
KR (1) KR101758046B1 (es)
CN (1) CN102762548B (es)
AU (1) AU2010341573B2 (es)
BR (1) BR112012018386A8 (es)
CA (1) CA2785499C (es)
CL (1) CL2012001714A1 (es)
ES (2) ES2842399T3 (es)
HK (1) HK1253412A1 (es)
IL (1) IL220625A (es)
MX (2) MX350761B (es)
NZ (1) NZ600954A (es)
RU (1) RU2573569C2 (es)
SG (2) SG10201502073PA (es)
WO (1) WO2011087776A1 (es)

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