AR071112A1 - Derivados de benzopirano y benzoxepina inhibidores de quinasaspi3k, utiles como agentes anticancer,y composiciones farmaceuticas que los contienen. - Google Patents

Derivados de benzopirano y benzoxepina inhibidores de quinasaspi3k, utiles como agentes anticancer,y composiciones farmaceuticas que los contienen.

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Publication number
AR071112A1
AR071112A1 ARP090101126A ARP090101126A AR071112A1 AR 071112 A1 AR071112 A1 AR 071112A1 AR P090101126 A ARP090101126 A AR P090101126A AR P090101126 A ARP090101126 A AR P090101126A AR 071112 A1 AR071112 A1 AR 071112A1
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Argentina
Prior art keywords
alkylene
nr10r11
co2h
ch2oh
heterocyclyl
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ARP090101126A
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English (en)
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Genentech Inc
Hoffmann La Roche
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Publication of AR071112A1 publication Critical patent/AR071112A1/es

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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/425—Thiazoles
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    • 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
    • A61K31/4365—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 having sulfur as a ring hetero atom, e.g. ticlopidine
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
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    • 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
    • A61K31/495—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
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
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    • 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
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    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic 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
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    • C07D495/12—Heterocyclic 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 three hetero rings
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    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/14—Ortho-condensed systems

Abstract

Son utiles para inhibir quinasas lipídicas que incluyen p110 alfa y otras isoformas de PI3K, y para tratar trastornos tales como cáncer mediado por quinasas lipídicas. Reivindicacion 1: Un compuesto seleccionado de formula 1 y sus estereoisomeros, isomeros geométricos, tautomeros, o sales aceptables para uso farmacéutico, donde: Z1 es CR1 o N; Z2 es CR2 o N; Z3 es CR3 o N; Z4 es CR4 o N; donde (i) X1 es N y X2 es S, (ii) X1 es S y X2 es N, (iii) X1 es CR7 y X2 es S, o (iv) X1 es S y X2 es CR7; R1, R2, R3, R4, y R7 se seleccionan independientemente entre H, F, CI, Br, I, -CN, -CF3, -CH2OR10, -CH2R10, -alquileno C1-12NR10R11, -alquileno C1-12NR12C(=O)R10, -alquileno C1-12C(=O)OR10, -alquileno C1-12OR10, -CO2R10, -C(=O)N(R10)OR11, -NO2, -NR10R11, -OR10, -S(O)2R10, -C(=O)NR10R11, -C(=O)NR10(alquileno C1-12)NR10R11, -C(=O)NR10(alquileno C1-12)NR10C(=O)OR11, -C(=O)NR10(alquileno C1-12)NR10C(=O)R11, -C(=O)NR10(alquileno C1-12)R10, -C(=NR10)NR10R11, -NR12C(=O)R10, -NR12C(=O)OR11, -NR12C(=O)NR10R11, -NR12C(=O)(alquileno C1-12)NR10R11, -NR12(alquileno C1-12)NR10R11, -NR12(alquileno C1-12)OR10, -NR12(alquileno C1-12)C(=O)NR10R11, -C=CR10, -CH=CHR10, heterociclilo C2-20, heteroarilo C1-20, y fenilo, donde heterociclilo, heteroarilo, y fenilo están opcionalmente sustituidos con uno o más grupos seleccionados entre F, CI, Br, I, -CH2OH, -(CH2)2OH, -CH2CO2H, -CN, -CH2NH2, -(CH2)2N(CH3)2, -CH3, -C(=O)CH3, -C(=O)NHCH3, -CO2H, -CH2CO2CH3, -NH2, -OCH3, -S(O)2CH3, 4-metilpiperazin-1-ilo, y 4-morfolinilo, y donde alquileno está opcionalmente sustituido con uno o más F; A se selecciona entre -C(O)NR5R6, heterociclilo C2-20 y heteroarilo C1-20 donde heterociclilo C2-20 y heteroarilo C1-20 están opcionalmente sustituidos con uno o más grupos seleccionados independientemente entre F, CI, Br, I, -CH2OH, -CH2CO2H, -CH(CH3)CH2OCH3, -CN, alquilo C1-12, -alquileno C1-12NR10R11, -alquileno C1-12OR10, -CH3, -C(=O)CH3, -C(=O)NHCH3, -C(=O)N(CH3)2, -CO2H, -CO2CH3, -CH2CO2CH3, -NH2, -NHC(=O)CH3, -OCH3, -S(O)2CH3, 1-metilpiperid-4-ilo, 4-metilpiperazin-1-ilo, 4-morfolinilo, isopropilo, isobutilo, ciclopropilo, ciclopropilmetilo, ciclobutilo, triazolilmetilo, bencilo, y fenilo, donde alquilo, alquileno, bencilo y fenilo están opcionalmente sustituidos con uno o más grupos seleccionados independientemente entre F, CI, Br, I, -CF3, -CH2OH, -CH2CO2H, -CN, -CH2NH2, -CH3, -C(=O)CH3, -C(=O)NHCH3, -CO2H, -CH2CO2CH3, -NH2, -OH, -OCH3, -S(O)2CH3, 1-metilpiperid-4-ilo, (4-metilpiperazin-1-il)carboxamida, -CH2(1H-1,2,4-triazol-5-il), 4-metilpiperazin-1-ilo, y 4-morfolinilo; R5 se selecciona entre H, alquilo C1-12, opcionalmente sustituido con uno o más grupos seleccionados independientemente entre F, CI, Br, I, -CN, -CO2H, -CONH2, -CONHCH3, -NH2, -NO2, -N(CH3)2, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -OCH2CH3, -S(O)2NH2, y -S(O)2CH3; R6 se selecciona entre alquilo C1-12, carbociclilo C3-12, heterociclilo C2-20, heteroarilo C1-20, y arilo C6-20, cada uno opcionalmente sustituido con uno o más grupos seleccionados independientemente entre F, CI, Br, I, -CH2OH, - CH2C6H5, -CN, -CF3, -CO2H, -C(=O)NR10R11, -NH2, -NO2, -N(CH3)2, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -OCH2CH3, -S(O)2NH2, -S(O)2CH3, -C(=O)NR10(alquileno C1-12)NR10R11, morfolin-4-ilo, piperidin-1-ilo, piperazinilo, piperazin-4-il-2-ona, piperazin-4-il-3-ona, pirrolidin-1-ilo, tiomorfolin-4-ilo, S-dioxotiomorfolin-4-ilo, -C:::CR13, -CH=CHR13, y -C(=O)NR10R11 o R5 y R6 junto con el átomo de nitrogeno al cual están unidos forman morfolin-4-ilo, piperidin-1-ilo, piperazinilo, piperazin-4-il-2-ona, piperazin-4-iI-3-ona, pirrolidin-1-ilo, tiomorfolin-4-ilo o S-dioxotiomorfolin-4-ilo, cada uno opcionalmente sustituido con uno o más grupos seleccionados entre F, CI, Br, I, -CH2OH, -CH2C6H5, -CN, -CF3, -CO2H, -CONH2, -CONHCH3, -NO2, - N(CH3)2, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -OCH2CH3, -S(O)2NH2, y -S(O)2CH3; R7 se selecciona entre H y F; R10, R11 y R12 se seleccionan independientemente entre H, alquilo C1-12, alquilen C1-12-heterociclilo C2-20, alquilen C1-12-arilo C6-20, alquenilo C2-8, alquinilo C2-8, carbociclilo C3-12, heterociclilo C2-20, arilo C6-20, y heteroarilo C1-20, donde alquilo C1-12, alquenilo C2-8, alquinilo C2-8, carbociclilo C3-12, heterociclilo C2-20, arilo C6-20, y heteroarilo C1-20 están opcionalmente sustituidos con uno o más grupos seleccionados independientemente entre F, CI, Br, I, -CH2OH, -CH2C6H5, -CN, -CF3, -CO2H, -CONH2, -CONHCH3, -NO2, -N(CH3)2, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -OCH2CH3, 2-oxopirrolidin-1-ilo, -S(O)2NH2, y -S(O)2CH3; o R10 y R11 junto con el átomo de nitrogeno al cual están unidos forman un anillo de heterociclilo C2-20 o heteroarilo C1-20 cada uno opcionalmente sustituido con uno o más grupos seleccionados independientemente entre F, CI, Br, I, -CH3, -CH2OH, -CH2C6H5, -CN, -CF3, -CO2H, -CONH2, -CONHCH3, -NO2, -N(CH3)2, -NHCOCH3, -NHS(O)2CH3, -OH, oxo, -OCH3, -OCH2CH3, -S(O)2NH2, y -S(O)2CH3; y R13 se selecciona entre H, F, CI, Br, I, -CH3, -CH2CH3, -CN, -CF3, -CH2N(CH3)2, -CH2OH, -CO2H, -CONH2, -CON(CH3)2, -NO2, y -S(O)2CH3. Reivindicacion 32: Un compuesto seleccionado de la formula (2) y sus estereoisomeros, isomeros geométricos, tautomeros, o sales aceptables para uso farmacéutico, donde: R1, R2, R3, y R4 se seleccionan independientemente entre H, F, CI, Br, I, -CN, -CF3, -CH2OR10, -CH2R10, -CH2NR10R11, -(alquileno C1-12)C(=O)OR10, -CO2R10, -C(=O)N(R10)OR11, -NO2, -NR10R11, -OR10, -S(O)2R10, -C(=O)NR10R11, -C(=O)NR10(alquileno C1-12)NR10R11, -C(=O)NR10(alquileno C1-12)NR10C(=O)OR11, -C(=O)NR10(alquileno C1-12)NR10C(=O)R11, -C(=O)NR10(alquileno C1-12)R10, -NR12C(=O)R10, -NR12C(=O)OR11, -NR12C(=O)NR10R11, -NR12(alquileno C1-12)NR10R11, -NR12(alquileno C1-12)OR10, -NR12(alquileno C1-12)C(=O)NR10R11, -C:::CR10, -CH=CHR10, heterociclilo C2-20, heteroarilo C1-20, y fenilo, donde heterociclilo, heteroarilo, y fenilo están opcionalmente sustituidos con uno o más grupos seleccionados entre -CH2OH, -CH2CO2H, -CN, -CH2NH2, -C(=O)CH3, -CO2H, -CH2CO2CH3; -NH2, -S(O)2CH3, 4-metilpiperazin-1-ilo, y 4-morfolinilo; R5 se selecciona entre alquilo C1-12, opcionalmente sustituido con uno o más grupos seleccionados independientemente entre F, CI, Br, I, -CN, -CO2H, -CONH2, -CONHCH3, -NH2, -NO2, -N(CH3)2, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -OCH2CH3, -S(O)2NH2, y -S(O)2CH3; R6 se selecciona entre carbociclilo C3-12, heterociclilo C2-20, heteroarilo C1-20, y arilo C6-20, cada uno opcionalmente sustituido con uno o más grupos seleccionados independientemente entre F, CI, Br, I, -CH2OH, -CH2C6H5, -CN, -CF3, -CO2H, -CONHCH3, -NH2, -NO2, -N(CH3)2, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -OCH2CH3, -S(O)2NH2, -S(O)2CH3, morfolin-4-ilo, piperidin-1-ilo, piperazinilo, piperazin-4-il-2-ona, piperazin-4-il-3-ona, pirrolidin-1-ilo, tiomorfolin-4-ilo, S-dioxotiomorfolin-4-ilo, -C:::CR13, -CH=CHR13, y -C(=O)NR10R11 o R5 y R6 junto con el átomo de nitrogeno al cual están unidos forman morfolin-4-ilo, piperidin-1-ilo, piperazinilo, piperazin-4-il-2-ona, piperazin-4-iI-3-ona, pirrolidin-1-ilo, tiomorfolin-4-ilo, S-dioxotiomorfolin-4-ilo, cada uno opcionalmente sustituido con uno o más grupos seleccionados entre F, CI, Br, I, -CH2OH, -CH2C6H5, -CN, -CF3, -CO2H, -CONH2, -CONHCH3, -NO2, - N(CH3)2, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -OCH2CH3, -S(O)2NH2, y -S(O)2CH3;cada uno R7 se selecciona independientemente entre H, F, Cl, Br, I, -CH2OH, -CH3, -CN, -CF3, -CO2H, -CONH2, -CONHCH3, -NO2, -N(CH3)2, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -OCH2CH3, -S(O)2NH2, y -S(O)2CH3; o ambos R7 juntos son =O; R8 se selecciona entre H y F; R10, R11 y R12 se seleccionan independientemente entre H, alquilo C1-12, alquenilo C2-8, alquinilo C2-8, carbociclilo C3-12, heterociclilo C2-20, arilo C6-20, y heteroarilo C1-20, donde alquilo C1-12, alquenilo C2-8, alquinilo C2-8, carbociclilo C3-12, heterociclilo C2-20, arilo C6-20, y heteroarilo C1-20 están opcionalmente sustituidos con uno o más grupos seleccionados independientemente entre F, CI, Br, I, -CH2OH, -CH2C6H5, -CN, -CF3, -CO2H, -CONH2, -CONHCH3, -NO2, -N(CH3)2, -NHCOCH3, -NHS(O)2CH3, -OH, -OCH3, -OCH2CH3, -S(O)2NH2, y -S(O)2CH3; o R10 y R11 junto con el átomo de nitrogeno al cual están unidos forman un anillo de heterociclilo C2-20 opcionalmente sustituido con uno o más grupos seleccionados independientemente entre F, CI, Br, I, -CH3, -CH2OH, -CH2C6H5, -CN, -CF3, -CO2H, -CONH2, -CONHCH3, -NO2, -N(CH3)2, -NHCOCH3, -NHS(O)2CH3, -OH, oxo, -OCH3, -OCH2CH3, -S(O)2NH2, y -S(O)2CH3; R13 se selecciona entre H, F, CI, Br, I, -CH3, -CH2CH3, -CN, -CF3, -CH2N(CH3)2, -CH2OH, -CO2H, -CONH2, -CON(CH3)2, -NO2, y -S(O)2CH3; n es 1 o 2; y Y es O, S, N-NR10R11; con las siguientes condiciones: cuando n es 1, Y es O, y R1, R2, R3, R7, R8 son cada uno H, entonces R4 no es H o CH3 y cuando n es 1, entonces ambos R7 en forma conjunta no son =O.
ARP090101126A 2008-03-31 2009-03-30 Derivados de benzopirano y benzoxepina inhibidores de quinasaspi3k, utiles como agentes anticancer,y composiciones farmaceuticas que los contienen. AR071112A1 (es)

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