AR039555A1 - Derivados n,n'-sustituidos de 1,3-diamino-2-hidroxipropano - Google Patents

Derivados n,n'-sustituidos de 1,3-diamino-2-hidroxipropano

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Publication number
AR039555A1
AR039555A1 ARP020104299A ARP020104299A AR039555A1 AR 039555 A1 AR039555 A1 AR 039555A1 AR P020104299 A ARP020104299 A AR P020104299A AR P020104299 A ARP020104299 A AR P020104299A AR 039555 A1 AR039555 A1 AR 039555A1
Authority
AR
Argentina
Prior art keywords
group
oxide
alkoxy
optionally substituted
alkyl
Prior art date
Application number
ARP020104299A
Other languages
English (en)
Original Assignee
Upjohn Co
Elan Pharm Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Upjohn Co, Elan Pharm Inc filed Critical Upjohn Co
Publication of AR039555A1 publication Critical patent/AR039555A1/es

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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D263/00Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/22Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07C233/36Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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Abstract

Estos compuestos tienen actividad como inhibidores de la b-secretasa y, en consecuencia, son útiles para el tratamiento de varios trastornos como el mal de Alzheimer. Reivindicación 1: Un compuesto de la fórmula (1) o una sal farmacéuticamente aceptable de los mismos, donde R1 es: (I) alquilo C1-6, opcionalmente sustituido por uno, dos ó tres sustituyentes seleccionados del grupo que consiste en alquilo C1-3, cicloalquilo C1-8 (opcionalmente sustituido por alquilo C1-3 y alcoxi C1-3), -F, -Cl, -Br, -I, -OH, -SH, -CsN, -CF3, alcoxi C1-3, -NR1-aR1-b, y -OC=O-NR1-aR1-b, donde R1-a y R1-b son, independientemente en cada caso, -H ó alquilo C1-6, (II) -CH2-S(O)0-2-(alquilo C1-6), (III) -CH2-CH2-S(O)0-2-(alquilo C1-6), (IV) alquenilo C2-6 con uno ó dos enlaces dobles, opcionalmente sustituido por uno, dos ó tres sustituyentes seleccionados del grupo que consiste en -F, -Cl, -OH, -SH, -CsN, -CF3, alcoxi C1-3, -NR1-aR1-b donde R1-a y R1-b son -H ó alquilo C1-6, (V) alquinilo C2-6 con uno ó dos enlaces triples, opcionalmente sustituido por uno, dos ó tres sustituyentes seleccionados del grupo que consiste en -F, -Cl, -OH, -SH, -CsN, -CF3, alcoxi C1-3, -NR1-aR1-b donde R1-a y R1-b son -H ó alquilo C1-6, (VI) -(CH2)n1-(R1-arilo) donde n1 es cero ó uno y donde R1-arilo es fenilo, naftilo, indanilo, indenilo, dihidronaftilo, ó tetralinilo cada uno de los cuales está opcionalmente sustituido por uno, dos, tres, cuatro, ó cinco de los siguientes sustituyentes en el anillo arilo: (A) alquilo C1-6 opcionalmente sustituido por uno, dos ó tres sustituyentes seleccionados del grupo que consiste en alquilo C1-3, -F, -Cl, -Br, -I, -OH, -SH, -NR1-aR1-b, -CsN, -CF3, y alcoxi C1-3, (B) alquenilo C2-6 opcionalmente sustituido por uno, dos ó tres sustituyentes seleccionados del grupo que consiste en -F, -Cl, -OH, -SH, -CsN, -CF3, alcoxi C1-3, y NR1-aR1-b, (C) alquinilo C2-6 opcionalmente sustituido por uno, dos ó tres sustituyentes seleccionados del grupo que consiste en -F, -Cl, -OH, -SH, -CsN, -CF3, alcoxi C1-3, y -NR1-aR1-b, (D) -F, Cl, -Br e -I, (E) haloalcoxi C1-6, (F) alcoxi C1-6, (G) -NRN-2RN-3, (H) -OH, (I) -CsN, (J) cicloalquilo C3-7, opcionalmente sustituido por uno, dos ó tres sustituyentes seleccionados independientemente entre sí del grupo que consiste en -F, -Cl, -OH, -SH, -CsN, -CF3, alcoxi C1-3, y -NR1-aR1-b, (K) -CO-(alquilo C1-4), (L) -SO2-NR1-aR1-b, (M) -CO-NR1-aR1-b, (N) -SO2-(alquilo C1-4), (VII) -(CH2)n1-(R1-heteroarilo), donde R1-heteroarilo está seleccionado del grupo que consiste en piridinilo, pirimidinilo, quinolinilo, benzotienilo, indolilo, indolinilo, piridazinilo, pirazinilo, isoindolilo, isoquinolilo, quinazolinilo, quinoxalinilo, ftalazinilo, imidazolilo, isoxazolilo, pirazolilo, oxazolilo, tiazolilo, indolizinilo, indazolilo, benzotiazolilo, bencimidazolilo, benzofuranilo, furanilo, tienilo, pirrolilo, oxadiazolilo, tiadiazolilo, triazolilo, tetrazolilo, oxazolopiridinilo, imidazopiridinilo, isotiazolilo, naftiridinilo, cinnolinilo, carbazolilo, beta-carbolinilo, isocromanilo, cromanilo, tetrahidroisoquinolinilo, isoindolinilo, isobenzotetrahidrofuranilo, isobenzotetrahidrotienilo, isobenzotienilo, benzoxazolilo, piridopiridinilo, benzotetrahidrofuranilo, benzotetrahidrotienilo, purinilo, benzodioxolilo, triazinilo, fenoxazinilo, fenotiazinilo, pteridinilo, benzotiazolilo, imidazopiridinilo, imidazotiazolilo, dihidrobencisoxazinilo, bencisoxazinilo, benzoxazinilo, dihidrobencisotiazinilo, benzopiranilo, benzotiopiranilo, cumarinilo, isocumarinilo, cromonilo, cromanonilo, tetrahidroquinolinilo, dihidroquinolinilo, dihidroquinolinonilo, dihidroisoquinolinonilo, dihidrocumarinilo, dihidroisocumarinilo, isoindolinonilo, benzodioxanilo, benzoxazolinonilo, piridinilo N-óxido, pirrolilo N-óxido, pirimidinilo N-óxido, piridazinilo N-óxido, pirazinilo N-óxido, quinolinilo N-óxido, indolilo N-óxido, indolinilo N-óxido, isoquinolilo N-óxido, quinazolinilo N-óxido, quinoxalinilo N-óxido, ftalazinilo N-óxido, imidazolilo N-óxido, isoxazolilo N-óxido, oxazolilo N-óxido, tiazolilo N-óxido, indolizinilo N-óxido, indazolilo N-óxido, benzotiazolilo N-óxido, bencimidazolilo N-óxido, pirrolilo N-óxido, oxadiazolilo N-óxido, tiadiazolilo N-óxido, triazolilo N-óxido, tetrazolilo N-óxido, benzotiopiranilo S-óxido, y benzotiopiranilo S,S-dióxido, donde el grupo R1-heteroarilo está enlazado con -(CH2)n1- mediante cualquier átomo del anillo del grupo RN-heteroarilo principal sustituido por hidrógeno, de modo tal que el nuevo enlace con el grupo R1-heteroarilo reemplace el átomo de hidrógeno y su enlace, donde el heteroarilo está opcionalmente sustituido por uno, dos, tres, cuatro, ó cinco de: (1) alquilo C1-6 opcionalmente sustituido por uno, dos ó tres sustituyentes seleccionados del grupo que consiste en alquilo C1-3, -F, -Cl, -Br, -I, -OH, -SH, -NR1-aR1-b, -CsN, -CF3, y alcoxi C1-3, (2) alquenilo C2-6 con uno ó dos enlaces dobles, opcionalmente sustituido por uno, dos ó tres sustituyentes seleccionados del grupo que consiste en -F, -Cl, -OH, -SH, -CsN, -CF3, alcoxi C1-3, y NR1-aR1-b, (3) alquinilo C2-6 con uno ó dos enlaces triples, opcionalmente sustituido por uno, dos ó tres sustituyentes seleccionados del grupo que consiste en -F, -Cl, -OH, -SH, -CsN, -CF3, alcoxi C1-3, y -NR1-aR1-b, (4) -F, -Cl, -Br y -I, (5) haloalcoxi C1-6, (6) alcoxi C1-6, (7) -NRN-2RN-3, (8) -OH, (9) -CsN, (10) cicloalquilo C3-7, opcionalmente sustituido por uno, dos ó tres sustituyentes independientemente seleccionados del grupo que consiste en -F, -Cl, -OH, -SH, -CsN, -CF3, alcoxi C1-3, y -NR1-aR1-b, (11) -CO-(alquilo C1-4), -SO2-NR1-aR1-b, (13)-CO-NR1-aR1-b, (14) -SO2-(alquilo C1-4), con la condición de que, cuando n1 es cero, R1-heteroarilo no está enlazado con la cadena de carbonos por medio del nitrógeno, (VIII) -(CH2)n1-(R1-heterociclo) donde n1 es tal como se definió con anterioridad y R1-heterociclo está seleccionado del grupo que consiste en morfolinilo, tiomorfolinilo, tiomorfolinilo S-óxido, tiomorfolinilo S,S-dióxido, piperazinilo, homopiperazinilo, pirrolidinilo, pirrolinilo, tetrahidropiranilo, piperidinilo, tetrahidrofuranilo, tetrahidrotienilo, homopiperidinilo, homomorfolinilo, homotiomorfolinilo, homotiomorfolinilo S,S-dióxido, oxazolidinonilo, dihidropirazolilo, dihidropirrolilo, dihidropirazinilo, dihidropiridinilo, dihidropirimidinilo, dihidrofurilo, dihidropiranilo, tetrahidrotienilo S-óxido, tetrahidrotienilo S,S-dióxido, homotiomorfolinilo S-óxido, ditianilo, piranilo, dihidrofuranilo, pirrolidinonilo, imidazolidinonilo, imidazolidinondionilo, donde cada uno de los anteriores está fusionado opcionalmente con un anillo de benceno, piridina o pirimidina, y donde el grupo R1-heterociclo está enlazado con cualquier átomo del grupo R1-heterociclo principal sustituido por hidrógeno, de modo tal que el nuevo enlace con el grupo R1-heterociclo reemplaza el átomo de hidrógeno y su enlace, donde el heterociclo está opcionalmente sustituido por uno, dos, tres ó cuatro: (1) alquilo C1-6 opcionalmente sustituido con uno, dos ó tres sustituyentes independientemente seleccionados del grupo que consiste en alquilo C1-3, -F, -Cl, -Br, -I, -OH, -SH, -NR1-aR1-b, -CsN, -CF3, y alcoxi C1-3, (2) alquenilo C2-6 opcionalmente sustituido con uno, dos ó tres sustituyentes seleccionados del grupo que consiste en -F, -Cl, -OH, -SH, -CsN, -CF3, alcoxi C1-3, -NR1-aR1-b, (3) alquinilo C2-6 opcionalmente sustituido con uno, dos ó tres sustituyentes independientemente seleccionados del grupo que consiste en -F, -Cl, -OH, -SH, -CsN, -CF3, alcoxi C1-3, y NR1-aR1-b, (4) -F, -Cl, -Br y -I, (5) alcoxi C1-6, (6) haloalcoxi C1-6, (7) -NRN-2RN-3, (8) -OH, (9) -CsN, (10) cicloalquilo C3-7, opcionalmente sustituido por uno, dos ó tres sustituyentes seleccionados independientemente entre sí del grupo que consiste en -F, -Cl, -OH, -SH, -CN, -CF3, alcoxi C1-3, y -NR1-aR1-b, (11) -CO-(alquilo C1-4), (12) -SO2-NR1-aR1-b, (13) -CO-NR1-aR1-b, (14) -SO2-(alquilo C1-4), (15) =O, con la condición de que, cuando n1 es cero, R1-heterociclo no está enlazado con la cadena de carbonos por medio del nitrógeno; donde R2 está seleccionado del grupo que consiste en: (I) -H, (II) alquilo C1-6, opcionalmente sustituido por uno, dos ó tres sustituyentes seleccionados independientemente entre sí del grupo que consiste en alquilo C1-3, -F, -Cl, -Br, -I, -OH, -SH, -CsN, -CF3, alcoxi C1-3, y -NR1-aR1-b, (III) -(CH2)0-4-R30, donde R30 es R1-arilo, R1-heteroarilo, ó R1-heterociclo, (IV) alquenilo C2-6 con uno ó dos enlaces dobles, opcionalmente sustituido por uno, dos ó tres sustituyentes seleccionados independientemente entre sí del grupo que consiste en -F, -Cl, -OH, -SH, -CsN, -CF3, alcoxi C1-3, y -NR1-aR1-b, (V) alquinilo C2-6 opcionalmente sustituido por uno, dos ó tres sustituyentes seleccionados independientemente entre sí del grupo que consiste en -F, -Cl, -OH, -SH, -CsN, -CF3, alcoxi C1-3, y NR1-aR1-b, (VI) -(CH2)0-4-cicloalquilo C3-7, opcionalmente sustituido por uno, dos ó tres sustituyentes seleccionados independientemente entre sí del grupo que consiste en -F, -Cl, -OH, -SH, -CsN, -CF3, alcoxi C1-3, y -NR1-aR1-b, donde R3 está seleccionado del grupo que consiste en: (I) -H, (II) alquilo C1-6, opcionalmente sustituido por uno, dos ó tres sustituyentes seleccionados del grupo que consiste en alquilo C1-3, -F, -Cl, -Br, -I, -OH, -SH, -CsN, -CF3, alcoxi C1-3, y -NR1-aR1-b, (III) -(CH2)0-4-R30, (IV) alquenilo C2-6, (V) alquinilo C2-6, (VI) -(CH2)0-4-cicloalquilo C3-7, opcionalmente sustituido por uno, dos ó tres sustituyentes seleccionados independientemente entre sí del grupo que consiste en -F, -Cl, -OH, -SH, -CsN, -CF3, alcoxi C1-3, y -NR1-aR1-b, ó R2 y R3 se toman juntos con el átomo de carbono al que están unidos para formar un carbociclo de tres, cuatro, cinco, seis, y siete átomos de carbono, donde opcionalmente un átomo de carbono está reemplazado por un heteroátomo seleccionado del grupo que consiste en -O-, -S-, -SO2-, -NRN-2-; RN es: (I) RN-1-XN-donde XN está seleccionado del g
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