AR057990A1 - Imidazolinas 4,4,5,5 tetrasustituidas y un proceso para su sintesis - Google Patents

Imidazolinas 4,4,5,5 tetrasustituidas y un proceso para su sintesis

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Publication number
AR057990A1
AR057990A1 ARP060105272A ARP060105272A AR057990A1 AR 057990 A1 AR057990 A1 AR 057990A1 AR P060105272 A ARP060105272 A AR P060105272A AR P060105272 A ARP060105272 A AR P060105272A AR 057990 A1 AR057990 A1 AR 057990A1
Authority
AR
Argentina
Prior art keywords
ch2ch3
piperidinyl
och3
morpholinyl
ch2ch2oh
Prior art date
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ARP060105272A
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English (en)
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Hoffmann La Roche
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Publication date
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Publication of AR057990A1 publication Critical patent/AR057990A1/es

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D233/22—Radicals substituted by 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D233/26—Radicals substituted by carbon atoms having three bonds to hetero atoms
    • 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
    • C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic 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
    • C07D487/04—Ortho-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Los compuestos descriptos muestran actividad como agentes antitumorales. Estas imidazolinas son inhibidores de la interaccion entre P53 y MDM2 (proteínas). Reivindicacion 1: Un compuesto de formula (1), en la que X1 y X2 son halogeno, acetileno, ciano, trifluorometilo o nitro; R1 y R2 se seleccionan de entre el grupo que consiste en -H, -CH3, - CH2CH3, -CH2OH y -CH2OCH3 con la condicion de que y no sean ambos hidrogeno; R3 es -H o -C(=O)-R7; y cuando R6 es hidrogeno entonces, R4 es -OCH3, - OCH2CH3, -OCH2CH2F, -OCH2CH2OCH3, u -OCH(CH3)2; R5 es -H, -halogeno, -CH3, -CF3, -OCH3, -C(CH3)2, -ciclopropilo, ciano, -C(CH3)3, -C(CH3)2OR (en la que R es -H, -CH3, -CH2-CH3, -C(CH3)2CH-OR (en la que R es -H, -CH3, -CH(CH3)2, -CH2CH2OH o - CH2CH2OCH3), -C(CH3)2CN, -C(CH3)2COR (en la que R es -CH3), -C(CH3)2COOR (en la que R es -H, -CH3, -CH2CH3 o -CH-(CH3)2), -C(CH3)2CONRaRb (en la que Ra es -H, -CH3, y Rb es -H o -CH3), -SR (en la que R es -CH3 o -CH2CH3),o -SO2R (en la que R es - CH3, -CH2CH3, 1-pirrolidina, -NH-terc-butilo o -N(CH3)2); y cuando R6 no es hidrogeno entonces R4 es -OCH3, -OCH2CH3, -OCH2CH2F, -OCH2CH2OCH3, o -OCH(CH3)2; R5 es hidrogeno, -CI, -OCH3, terc-butiIo o -N(CH3)2; R6 es -CI, ciclopropilo, -SO2R (en la que R es -CH3, -CH2CH3, 1-pirrolidina, -NH-terc-butilo, -NH2, o -N(CH3)2); y R7 se selecciona del grupo que consiste en i) -CH3, -CH(CH3)2, -CH2CH(CH3)2, ciclopropilo, ciclobutilo, -CH2CH2Ph, 2-furanilo, fenilo o fenilo sustituido por cloro, -OCH3 o ciano, ii) 4-morfolinilo, 1-piperidinilo, 4-tiomorfolinilo o 4-tiomorfolinil-1,1-dioxido, iii) -NRc2 (en la que Rc es hidrogeno, -CH3, -CH2CH3. -CH2CH2OH, -CH2CH2OCH3 o -CH2CH(OH)CH2OH), iv) una piperazina sustituida de la formula (2), en la que R se selecciona del grupo que consiste en a) hidrogeno, b) alquilo inferior, c) -CH(CH3)2, d) -CH(CH2CH3)2, e) ciclopentilo, f) -CH2CH(OH)CH3, g) -CH2CF3, h) -CH2CH(OH)CF3, i) -CH2C(CH3)2OH, j) -CH2-[4-N-metilpiperidinilo], k) -CH2CH2Rd (en la que Rd es -OH, -OCH3, -OCH2CH2OH, -OCH2CH2OCH3, -CN, -CF3, -SO2CH3, -SO2NH2, -SO2N(CH3)2, -CONH2, -CON(CH3)2, -NH2, -NHCOCH3, -NHSO2CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, 1-pirrolidinilo, 1-piperidinilo, 4-morfolinilo, 2-isotiazolidinil-1 1-dioxido, o 2-tetrahidrofuranilo), l) -CH2CH2CH2Re (en la que Re es -OH, -OCH3, -SO2CH3, -SO2CH2CH3, -SO2N(CH3)2, -CN, -N(CH3)2, -N(CH2CH2CH3)2, 1-imidazolilo, 1-pirrolidinilo, 1-piperidinilo, 4-morfolinilo, -COOCH3, -COOCH2CH3, -COOC(CH3)3, -CON(CH3)2, -CO-Rf (en la que Rf es -CH3, -CH2CH3, ciclopropilo, fenilo, 2-tienilo, 3-tienilo, 2-furanilo, 3-furanilo), -COCH2-Rg (en la que Rg es 1-1, -NHCH2CH2OH, -NHCH2CH2OCH3, -NHCH2CH2N(CH3)2, 1-piperidinilo, 1-(piperidinil-4-metanol), 4-morfolinilo, o -N(CH3)-(3- (1-metilpirrolidinilo)), m) CH2CORh (en la que Rh es -OCH3, -OCH2CH3, -NH2, - NHCH2CH(CH3)2, -NHCH2CF3, -NH-ciclopropilo, -NH-terc-butilo, -NHCH2CH2CH2OH, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2OH)2, -N(CH2CH2OCH3)2, -N(CH3)CH2CH2OH, -N(CH3)CH2CH2OCH3, - NHCH2CH2OCH3, 1-pirrolidinilo, 1-piperidinilo, 1-(piperidinil-4-metanol), 1-(piperidinil-3-carboxamida), 4-morfolinilo, 4-tiomorfolinilo, 4-tiomorfolinil-1,1-dioxido, 1-piperazinilo, 1-(4-acetilpiperazinilo), 1-(3-oxopiperazinilo), n) -SO2Ri (en la que Ri es -CH3, -CH2CH3, -CH(CH3)2, fenilo, 4-metilfenilo, 4-propilfenilo, -CF3, 2-tienilo, 3-tienilo, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH2OCH3, -N(CH2CH2OCH3)2, 1-pirrolidinilo, 1-piperidinilo, 4-morfolinilo, 1-piperazil-4-etanol, 1-(4- acetilpiperazinilo), 1-(3-oxopiperazinilo)), o) -CORj (en la que Rj es -CH3, -CH2CH3, -CH(CH3)2, 2-tetrahidrofuranilo, 2-tienilo, 3-tienilo, -NH2, -NHCH3, -N(CH3)2, 1-pirrolidinilo, 1-piperidinilo, 4-morfolinilo, 1-piperazinil-4-etanol, 1-(4- acetilpiperazinilo), o 1-(3-oxopiperazinilo)), p) 4-tetrahidro-2H-tiopiranil-1,1-dioxido, q) 4-piperidinil-1-acetilo, r) 4-piperidinil-1-dimetilcarboxamida, y s) 3-tetrahidro-tiofenil-1,1-dioxido; v) una oxopiperazina sustituida de la formula (3), en la que R es -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2OH o - CH2CH2OCH3; y vi) una piperidina sustituida de la formula (4), en la que R es -H, -COOCH3, -COOCH2CH3, -CONH2, -OH, -CH2OH, -CH2CH2OH, -CH2N(CH2CH3)2, -CH2-(1-piperazinilo), -CH2-(1-(3- oxopiperazinilo)),-NH2, -NHCOCH3, -NHCOCH2NH2, -NHCOCH2NHCH3, -NHCOCH2N(CH3)2, -NHCOCH2N(CH2CH2OH)2, -NHCOCH2N(CH2CH2OCH3)2, -NHCOCH2NHCH2CH2OH, -NHCOCH2-(1-(4-acetilpiperazinilo)), -NHCOCH2-(1-(3-oxopiperazinilo)), -NHCOCH2-(1- piperidinacarboxamida), -NHCOCH2-(N,N-dietil-1-piperidinilcarboxamida), -NHCOCH2-(1-(3-hidroxipiperidinilo)), -NHCOCH2-(1-(piperidinil-4-metanol)), -NHCON(CH3)2, -NHCSNHCH3, -NHCSNHPh, -NHCH2CONH2, 1 -pirrolidinilo, 1-piperidinilo, 1-(4- metilpiperazinilo), o 4-morfolinilo; y las sales y ésteres farmacéuticamente aceptables de los mismos.
ARP060105272A 2005-12-01 2006-11-29 Imidazolinas 4,4,5,5 tetrasustituidas y un proceso para su sintesis AR057990A1 (es)

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US74122305P 2005-12-01 2005-12-01
US85274706P 2006-10-19 2006-10-19

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US (1) US7851626B2 (es)
EP (3) EP2130822A1 (es)
JP (1) JP4870778B2 (es)
KR (2) KR20100129331A (es)
CN (1) CN101316823B (es)
AR (1) AR057990A1 (es)
AU (1) AU2006319248B2 (es)
BR (1) BRPI0619236A2 (es)
CA (1) CA2630410C (es)
CR (1) CR9980A (es)
ES (1) ES2538714T3 (es)
HK (1) HK1126216A1 (es)
MA (1) MA31550B1 (es)
NO (1) NO20082389L (es)
NZ (1) NZ568285A (es)
RU (1) RU2442779C2 (es)
TW (1) TWI326681B (es)
WO (1) WO2007063013A1 (es)

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