ES2480390T3 - 2,6-metano-3-benzazocinas 8-carboxamido sustituidas y morfanos 3-carboxamido sustituidos como ligandos de los receptores opioides - Google Patents

2,6-metano-3-benzazocinas 8-carboxamido sustituidas y morfanos 3-carboxamido sustituidos como ligandos de los receptores opioides Download PDF

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ES2480390T3
ES2480390T3 ES06800266.6T ES06800266T ES2480390T3 ES 2480390 T3 ES2480390 T3 ES 2480390T3 ES 06800266 T ES06800266 T ES 06800266T ES 2480390 T3 ES2480390 T3 ES 2480390T3
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alkyl
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heteroaryl
carboxamide
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Mark Wentland
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Abstract

Compuesto de fórmula: donde es un residuo arilo o heteroarilo de uno a tres anillos; refiriéndose "arilo" y "heteroarilo" a un anillo aromático de 5 o 6 miembros aromático o heteroaromático conteniendo de 0 a 3 heteroátomos seleccionados entre O, N o S; a un sistema de anillo bicíclico de 9 o 10 miembros aromático o heteroaromático conteniendo de 0 a 3 heteroátomos seleccionados entre O, N o S; o a un sistema de anillo tricíclico de 13 o 14 miembros aromático o heteroaromático conteniendo de 0 a 3 heteroátomos seleccionados entre O, N o S; A es (CH2)n, pudiendo reemplazarse uno o más CH2 por -O-, cicloalquilo o -CR1aR1b; siendo cicloalquilo un subconjunto de alquilo e incluyendo grupos hidrocarburo cíclicos de 3 a 8 átomos de carbono; R1a y R1b se seleccionan independientemente entre hidrógeno, halógeno, alquilo(C1-C6), alcoxi(C1- C4) y alquiltio(C1-C6); R2 y R2a son ambos hidrógeno o R2 y R2a juntos son >=O; R3 se selecciona entre hidrógeno y un hidrocarburo(C1-C8); heterociclilo, heterociclilalquilo e hidroxialquilo, donde heterociclo significa un grupo cicloalquilo o arilo en el que uno a dos átomos de carbono se reemplaza por un heteroátomo tal como oxígeno, nitrógeno o azufre; R4 se selecciona entre hidrógeno, hidroxilo, amino, alcoxi(C1-C4), alquilo(C1-C20) y alquilo(C1-C20) sustituido con hidroxi o carbonilo; R5 es alquilo(C1-C6); R6 es alquilo(C1-C6); R7 se selecciona entre hidrógeno e hidroxilo; o R4, R5, R6 y R7 pueden formar conjuntamente de uno a tres anillos, dichos anillos teniendo sustituciones adicionales opcionales, donde la sustitución adicional opcional significa que hasta tres átomos de H se han reemplazado por halógeno, hidroxilo, alcoxi(C1-C4), carboxi, carboalcoxi; carboxamido, ciano, carbonilo, NO2; -NR1R2; alquiltio, sulfóxido, sulfona, acilamino, amidino, fenilo, bencilo, heteroarilo, fenoxi, benciloxi, heteroariloxi, o fenilo, bencilo, heteroarilo, fenoxi, benciloxi, heteroariloxi sustituidos.

Description

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Ensayos de Unión de [35S]-GTPS. En un volumen final de 0,5 ml se incubaron 12 concentraciones diferentes de cada compuesto de ensayo con 15 g (), 10 g () o 7,5 g () de membranas celulares de CHO que expresaban de forma estable el receptor opioide ,  o  humano. El tampón de ensayo era Tris-HCl 50 mM, pH 7,4, MgCl2 3 mM, EGTA 0,2 mM, GDP 3 M y NaCl 100 mM. La concentración final de [35S]-GTPS era de 5 0,080 nM. La unión no específica se midió mediante adición de GTPS 10 M. La unión se inició por la adición de las membranas. Después de 60 minutos de incubación a 30ºC, las muestras se filtraron a través de filtros de fibra de vidrio Schleicher & Schuell nº 32. Los filtros se lavaron tres veces con Tris-HCl 50 mM, pH 7,5 y se realizó un recuento en 2 ml de fluido de centelleo Ecoscint A. Los datos son la media Emáx y valores EC50  SEM de al menos tres experimentos independientes, realizados por triplicado. Para el cálculo 10 de los valores Emáx, la unión de [35S]-GTPS basal se ajustó al 0%. Para determinar la actividad antagonista de un compuesto sobre los receptores opioides , se incubaron membranas de CHO que expresaban el receptor opioide  con 12 concentraciones diferentes del compuesto en presencia de 200 nM del agonista  DAMGO. Para determinar la actividad antagonista de un compuesto sobre los receptores opioides , se incubaron membranas de CHO que expresaban el receptor opioide  con el compuesto en presencia de 100
15 nM del agonista  U50,488. Para determinar si un compuesto era antagonista de los receptores , se incubaron membranas de CHO que expresaban el receptor  con 12 concentraciones diferentes del compuesto en ensayo en presencia de 10 nM del agonista selectivo de  SNC 80.
Tabla 1 Subseries de ciclazocina (Ejemplos Comparativos)
Ki (nM  SE (error estándar))
Ejp. nº
Isómero óptico Q [3H] DAMGO () [3H] Naltrindol () [3H] U69,593 ()
15
()- CONH(CH2)2(4-C6H4C6H5) 0,048  0,0014 0,94  0,045 0,33  0,015
42
()- CONH(CH2)2(4-C6H4C6H5) 0,30  0,036 0,74  0,019 1,8  0,19
43
()- CONH(CH2)2(4-C6H4C6H5) 0,26  0,006 0,70  0,073 2,3  0,048
16
(-)- CONH(CH2)2(4-C6H4C6H5) 0,017  0,004 0,32  0,08 0,046  0,01
16
(-) CONH(CH2)2(4-C6H4C6H5) 0,25  0,31 0,24  0,014 0,35  0,009
17
()- CONH(CH2)2(4-C6H4C6H5) 7,8  2,0 21  0,74 11  1,3
17
() CONH(CH2)2(4-C6H4C6H5) 6,4  0,50 9,9  0,44 8,5  1,07
18
()- CONH(CH2)2(4-C6H4C6H5) 5,8  0,31 72  11 2,7  0,21
19
() CON(CH2)(CH2)2(4-C6H4C6H5) 6,7  1,7 12  2,4 11  0,44
44
()- CONH-c-C3H4-(4-C6H4C6H5) (trans) 13  0,69 20  2,9 36  6,8
45
()- CONH-c-C3H4-(4-C6H4C6H5) (cis) 12  2,4 20  1,4 21  4,8
46
()- CONHCH2CH(CH3)(4-C6H4C6H5) 18  1,1 12  0,11 5  1,0
47
() CONHCH(CH3)CH2(4-C6H4C6H5) 7,8  0,99 7,6  0,51 11  0,24
48
()- CONH(CH2)2(4-C6H4-4-CH3OC6H4) 0,084  0,012 0,18  0,022 1,5  0,10
49
()- CONH(CH2)2(4-C6H4-4-ClC6H4) 0,20  0,038 0,71  0,046 3,2  0,67
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68
() CONHCH(R-CH3)C6H5 62  3,3 > 10 M 64  4,3
69
() CONHCH2CH2-3-pir 120  3,6 54  1,3 97  3,1
13
()- CONH(CH2)2(4-Br-3piridinilo)
14
() CONHCH2CH2-(4-Br-2-pir)
Tabla 2 Subseries ceto (Ejemplos Comparativos)
R6 = CH3 (cetociclazocina) R6 = CH2CH3 (EKC)
Ejp.
Q = [3H] DAMGO () [3H] Naltrindol () [3H] U69,593 ()
20
CONH(CH2)2(4-C6H4C6H5 (KC) 3,1  1,3 3,9  1,4 1,3  0,072
21
CONH(CH2)2(4-C6H4C6H5 (EKC) 4,9  0,20 13  2,5 5,1  0,18
Tabla 3 Otros precursores de opioides
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Claims (1)

  1. -
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ES06800266.6T 2005-07-21 2006-07-21 2,6-metano-3-benzazocinas 8-carboxamido sustituidas y morfanos 3-carboxamido sustituidos como ligandos de los receptores opioides Active ES2480390T3 (es)

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US7557119B2 (en) 2009-07-07
US20150051194A1 (en) 2015-02-19
US20090247562A1 (en) 2009-10-01
US9156821B2 (en) 2015-10-13
US20110306603A1 (en) 2011-12-15
US20160257677A1 (en) 2016-09-08
AU2006272773A1 (en) 2007-02-01
WO2007014137A3 (en) 2007-03-29
EP2266959B1 (en) 2013-05-01
ES2422579T3 (es) 2013-09-12
EP1924559B1 (en) 2014-04-16
US8026252B2 (en) 2011-09-27
CA2615774A1 (en) 2007-02-01
CA2615774C (en) 2014-12-09
EP1924559A2 (en) 2008-05-28
US8541586B2 (en) 2013-09-24
JP5266051B2 (ja) 2013-08-21
US20130345251A1 (en) 2013-12-26
JP2009502808A (ja) 2009-01-29
AU2006272773B2 (en) 2012-03-08
US20070021457A1 (en) 2007-01-25
EP2266959A1 (en) 2010-12-29
WO2007014137A2 (en) 2007-02-01

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