AR044043A1 - Fenacilo 2-hidroxi-3-diaminoalcanos - Google Patents

Fenacilo 2-hidroxi-3-diaminoalcanos

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Publication number
AR044043A1
AR044043A1 ARP040101346A ARP040101346A AR044043A1 AR 044043 A1 AR044043 A1 AR 044043A1 AR P040101346 A ARP040101346 A AR P040101346A AR P040101346 A ARP040101346 A AR P040101346A AR 044043 A1 AR044043 A1 AR 044043A1
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Argentina
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alkyl
optionally substituted
groups
group
alkoxy
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ARP040101346A
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Elan Pharm Inc
Upjohn Co
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Publication of AR044043A1 publication Critical patent/AR044043A1/es

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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
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    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
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    • 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
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    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
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    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Pyridine Compounds (AREA)
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  • Indole Compounds (AREA)
  • Quinoline Compounds (AREA)
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Abstract

La presente se refiere a fenacilo 2-hidroxi-3-diaminoalcanos. Estos compuestos incluyen inhibidores de la enzima b-secretasa que son útiles para el tratamiento del mal de Alzheimer y otras enfermedades similares, caracterizadas por la deposición de un péptido Ab en un mamífero. También son útiles en composiciones farmacéuticas y métodos de tratamiento para reducir la formación de un péptido Ab. También se describe el método de preparación de dichos compuestos. Reivindicación 1: Un compuesto de la fórmula (1) o una sal farmacéuticamente aceptable del mismo, en donde Z es [C(R4)(R4')]m-B; m es 1-3; en donde R4 y R4' son, de modo independiente en cada aparición, H, alquilo C1-6, (CH2)0-3(cicloalquilo C3-7), -(CH2)0-3OH, F, CF3, -OCF3, -O- fenilo, alcoxi C1-6, cicloalcoxi C3-7, arilo o heteroarilo, o en donde R4 y R4´ se toman juntos con el C al que están unidos para formar un anillo carbocíclico de 3-7 miembros en donde 1 a 3 C del anillo están opcionalmente sustituidos con O, -N(H, alquilo C1-6 o fenilo) o -S(O)0-2; en donde B es arilo, heteroarilo o heterociclilo, en donde dichos grupos están opcionalmente sustituidos con 1 o 2 grupos RB, en donde RB en cada aparición está seleccionado, de modo independiente, de halógeno, - OH, -OCF3, -O-fenilo, -CN, -NR100R101, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alcoxi C1-6, (CH2)0-3(cicloalquilo C3-7), en donde los grupos alquilo, alquenilo, alquinilo, alcoxi, cicloalquilo están opcionalmente sustituidos con 1 o 2 sustituyentes seleccionados de modo independiente del grupo integrado por alquilo C1-4, alcoxi C1-4, halógeno, -OH, -CN o -NR100R101; en donde R100 y R101 son en cada aparición, de modo independiente, H, alquilo C1-6 o fenilo; X es -(C=O)- o -(SO2)- ; R1 es alquilo C1-10 opcionalmente sustituido con 1, 2 o 3 grupos seleccionados de modo independiente de halógeno, -OH, =O, -SH, -CN, -CF3, -OCF3, -cicloalquilo C3-7, -alcoxi C1-4, amino, mono- dialquilamino, arilo, heteroarilo, heterocicloalquilo en donde cada grupo arilo está opcionalmente sustituido con 1, 2, o 3 grupos R50; en donde R50 está seleccionado de halógeno, OH, SH, CN, CO-(alquilo C1-4), -NR7R8, -S(O)0-2-(alquilo C1-4), alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alcoxi C1-6 y cicloalquilo C3-8; en donde los grupos alquilo, alquenilo, alquinilo, alcoxi y cicloalquilo están opcionalmente sustituidos con 1 o 2 sustituyentes seleccionados de modo independiente del grupo integrado por alquilo C1-4, halógeno, OH, -NR5R6, CN, haloalcoxi C1-4, NR7R8 y alcoxi C1-4; en donde R5 y R6 son, de modo independiente, H o alquilo C1-6; o en donde R5 y R6 y el N al que están unidos forman un anillo heterocicloalquilo de 5 o 6 miembros; y en donde R7 y R8 están seleccionados de modo independiente del grupo integrado por H, -alquilo C1-4 opcionalmente sustituido con 1, 2, o 3 grupos seleccionados de modo independiente del grupo integrado por -OH, -NH2, y halógeno; -cicloalquilo C3-6, -(alquil C1-4)-O-(alquilo C1-4); -alquenilo C2-4; y -alquinilo C2-4; en donde cada heteroarilo está opcionalmente sustituido con 1 o 2 grupos R50; en donde cada grupo heterocicloalquilo está opcionalmente sustituido con 1 o 2 grupos que son, de modo independiente , R50 u =O; R2 y R3 están seleccionados, de modo independiente, de -H; -F, -alquilo C1-6 opcionalmente sustituido con un sustituyentes seleccionado del grupo integrado por -F, -OH, -CºN, -CF3, alcoxi C1-3 y -NR5R6; -(CH2)0-2-R17; -(CH2)0-2-R18; -alquenilo C2-6 o alquinilo C2- 6, en donde cada uno está opcionalmente sustituido con un sustituyente independiente seleccionado del grupo integrado por -F, -OH, -CºN, -CF3, y alcoxi C1-3; -(CH2)0-2-cicloalquilo C3-7, opcionalmente sustituido un sustituyente independiente seleccionado del grupo integrado por -F, -OH, -CºN, -CF3, alcoxi C1-3 y -NR5R6; o R2 y R3 y el C al que están unidos forman un carbociclo de 3 a 7 átomos de C, en donde un átomo de C está opcionalmente reemplazado por un grupo seleccionado de -O-, - S-, -SO2- o -NR7; en donde R17 en cada aparición es un grupo arilo seleccionado de fenilo, 1-naftilo, 2-naftilo, indanilo, indenilo, dihidronaftilo y tetralinilo, en donde dichos grupos arilo están opcionalmente sustituidos con uno o dos grupos que son, de modo independiente, -alquilo C1-3; -alcoxi C1-4; CF3; o -alquenilo C2-6 o -alquinilo C2-6, cada uno de los cuales está opcionalmente sustituidos con un sustituyente seleccionado del grupo integrado por F, OH, alcoxi C1-3; o -halógeno; -OH, - CºN; -cicloalquilo C3-7; -CO-(alquilo C1-4); -SO2-(alquilo C1-4); en donde R18 es un grupo heteroarilo seleccionado de piridinilo, pirimidinilo, quinolinilo, indolilo, piridazinilo, pirazinilo, isoquinolilo, quinazolinilo, quinoxalinilo, ftalazinilo, imidazolilo, isoxazolilo, oxazolilo, tiazolilo, furanilo, tienilo, pirrolilo, oxadiazolilo o tiadiazolilo, en donde cada uno de dichos grupos heteroarilo está opcionalmente sustituido con uno o dos grupos que son, de modo independiente, -alquilo C1-6 opcionalmente sustituido con un sustituyente seleccionado del grupo integrado por OH, CºN, CF3, alcoxi C1-3, y -NR5R6; R15 está seleccionado del grupo integrado por H, alquilo C1-6, alcoxi C1-6, alcoxi C1-6 alquilo C1-6, hidroxialquilo C1-6, haloalquilo C1-6, cada uno de los cuales está insustituido o sustituido con 1, 2, 3 o 4 grupos seleccionados de modo independiente de halógeno, alquilo C1-6, hidroxi, alcoxi C1-6, NH2 y -R26-R27; en donde R26 está seleccionado del grupo integrado por un enlace, -C(O)-, -SO2-, -CO2-, -C(O)NR5-, y NR5C(O)-, en donde R27 está seleccionado del grupo integrado por alquilo C1-6, alcoxi C1-6, arilalquilo C1-6, heterocicloalquilo y heteroarilo, en donde cada uno de los anteriores está insustituido o sustituido con 1, 2, 3, 4 o 5 grupos que son, de modo independiente, alquilo C1-4, alcoxi C1-4, halógeno, haloalquilo, hidroxialquilo, -NR5R6, -C(O)NR5R6; Rc está seleccionado del grupo integrado por -(CH2)0-3-cicloalquilo (C3-8) en donde el cicloalquilo está opcionalmente sustituido con 1, 2, o 3 grupos seleccionados de modo independiente del grupo integrado por -R205, -CO2-(alquilo C1-4) y arilo, en donde el arilo está opcionalmente sustituido con 1 o 2 grupos R200 seleccionados de modo independiente; -(CR245R250)0-4-arilo; -(CR245R250)0-4-heteroarilo; -(CR245R250)0-4-heterocicloalquilo; -(CR245R250)0-4-aril-heteroarilo; -(CR245R250)0-4-aril-heterocicloalquilo; -(CR245R250)0-4-aril-arilo; -(CR245R250)0-4- heteroaril-arilo; -(CR245R250)0-4-heteroaril-heterocicloalquilo; -(CR245R250)0-4-heteroaril-heteroarilo;-(CR245R250)0-4-heterocicloalquil-heteroarilo; -(CR245R250)0-4-heterocicloalquil-heterocicloalquilo; -(CR245R250)0-4-heterocicloalquil-arilo; un anillo monocíclico o bicíclico de 5, 6, 7, 8, 9, o 10 C condensados a 1 o 2 grupos arilo, heteroarilo o heterocicloalquilo, en donde 1, 2 o 3 C del anillo monocíclico o bicíclico están opcionalmente reemplazados con-NH, -N(CO)0-1R215,-N(CO)0-1-R220, -O o -S(=O)0-2, y en donde el anillo monocíclico o bicíclico está opcionalmente sustituido con 1, 2 o 3 grupos que son, de modo independiente, -R205, -R245, -R250 u =O; -alquenilo C2-6 opcionalmente sustituidos con 1, 2 o 3 grupos R205; -alquinilo C2-6 opcionalmente sustituido con 1, 2 o 3 grupos R205; en donde cada grupo arilo unido directa o indirectamente al grupo -(CR245R250)0-4 está opcionalmente sustituido con 1, 2, 3 o 4 grupos R200; en donde cada grupo heteroarilo unido directa o indirectamente al grupo -(CR245R250)0-4 está opcionalmente sustituido con 1, 2, 3 o 4 R200; en donde cada heterocicloalquilo unido directa o indirectamente al grupo -(CR245R250)0-4 está opcionalmente sustituido con 1, 2, 3 o 4 R210; en donde R200 en cada aparición está seleccionado, de modo independiente, del grupo integrado por -alquilo C1-6 opcionalmente sustituido con 1, 2 o 3 grupos R205; -OH; -NO2; -halógeno; -CºN; -(CH2)0-4-CO-NR220R225; -(CH2)0-4-CO-(C1-8 alquilo); -(CH2)0-4-CO-(C2-8 alquenilo), -(CH2)0-4-CO-(C2-8 alquinilo); -(CH2)0-4-CO-(cicloalquilo C3-7); -(CH2)0-4-(CO)0-1-arilo; -(CH2)0-4-(CO)0-1-heteroarilo; -(CH2)0-4-(CO)0-1-heterocicloalquilo; -(CH2)0-4-CO2R215;-(CH2)0-4-SO2-NR220R225; -(CH2)0-4-S(O)0-2-(alquilo C1-8), - (CH2)0-4-S(O)0-2-(cicloalquilo C3-7); -(CH2)0-4-N(H o R215)-CO2R215; -(CH2)0-4-N(H o R215)-SO2-R220; -(CH2)0-4-N(H o R215)-CO-N(R215)2; -(CH2)0-4-N(-H o R215)-CO-R220; -(CH2)0-4-NR220R225; -(CH2)0-4-O-CO-(alquilo C1-6); -(CH2)0-4-O-(R215); -(CH2)0-4- S-(R215); -(CH2)0-4-O-(alquilo C1-6 opcionalmente sustituido con 1, 2, 3 o 5 -F); alquenilo C2-6 opcionalmente sustituido con 1 o 2 grupos R205; alquinilo C2-6 opcionalmente sustituido con 1 o 2 grupos R205, y -(CH2)0-4-cicloalquilo C3-7; en donde cada grupo arilo incluido dentro de R200 está opcionalmente sustituido con 1, 2 o 3 grupos que son, de modo independiente, R205, R210 o alquilo C1-6 sustituido con 1, 2 o 3 grupos que son, de modo independiente, R205 o R210; en donde cada grupo heterocicloalquilo incluido dentro de R200 está opcionalmente sustituido con 1, 2 o 3 grupos que son de modo independiente R210; en donde cada grupo heteroarilo incluido dentro de R200 está opcionalmente sustituido con 1, 2 o 3 grupos que son, de modo independiente, R205, R210 o alquilo C1-6 sustituido con 1, 2 o 3 grupos que son, de modo independiente, R205 o R210; en donde R205 en cada aparición está seleccionado de modo independiente, del grupo integrado por alquilo C1-6, alquenilo C2-6, alquinilo C2-6, haloalcoxi C1-6, -(CH2)0-3(cicloalquilo C3-7), halógeno, -(CH2)0-6-OH, -O-fenilo, -SH, -(CH2)0-6-CºN, -(CH2)0-6-C(=O)NR235R240, CF3, alcoxi C1-6 y NR235R240, en donde R210 en cada aparición está seleccionado, de modo independiente, del grupo integrado por alquilo C1-6 opcionalmente sustituido con 1, 2 o 3 grupos R205; alquenilo C2-6 opcionalmente sustituido con 1, 2 o 3 grupos R205; alquinilo C2-6 opcionalmente sustituido con 1, 2, o 3 grupos R205; halógeno, alcoxi C1-6, haloalcoxi C1-6, NR220R225; -OH, -CºN, cicloalquilo C3-7 opcionalmente sustituido con 1, 2 o 3 grupos R205
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