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 PDFInfo
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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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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]-GTPS. 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]-GTPS era de 5 0,080 nM. La unión no específica se midió mediante adición de GTPS 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]-GTPS 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
- 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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US70140705P | 2005-07-21 | 2005-07-21 | |
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PCT/US2006/028634 WO2007014137A2 (en) | 2005-07-21 | 2006-07-21 | 8-carboxamido-substituted-2 , 6-methano-3-benzazocines and 3 - carboxamido- substituted morphanes as opioid receptor binding agents |
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ES2480390T3 true ES2480390T3 (es) | 2014-07-28 |
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ES06800266.6T Active ES2480390T3 (es) | 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 |
ES10006594T Active ES2422579T3 (es) | 2005-07-21 | 2006-07-21 | 2,6-Metano-3-benzazocinas 8-carboxamido sustituidas y 3-carboxamido morfanos sustituidos como ligandos de los receptores opioides |
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US (6) | US7557119B2 (es) |
EP (2) | EP2266959B1 (es) |
JP (1) | JP5266051B2 (es) |
AU (1) | AU2006272773B2 (es) |
CA (1) | CA2615774C (es) |
ES (2) | ES2480390T3 (es) |
WO (1) | WO2007014137A2 (es) |
Families Citing this family (19)
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WO2002036573A2 (en) | 2000-10-31 | 2002-05-10 | Rensselaer Polytechnic Institute | 8- substituted-2, 6-methano-3-benzazocines and 3-substituted morphinanes as opioid receptor binding agents |
CA2615774C (en) | 2005-07-21 | 2014-12-09 | Rensselaer Polytechnic Institute | Large substituent, non-phenolic opioids |
AU2008286979B2 (en) | 2007-08-09 | 2013-03-28 | Rensselaer Polytechnic Institute | Quaternary opioid carboxamides |
EP2318372B9 (en) * | 2008-07-21 | 2015-05-06 | Rensselaer Polytechnic Institute | Large substituent, non-phenolic amine opioids |
US8946419B2 (en) | 2009-02-23 | 2015-02-03 | Mallinckrodt Llc | (+)-6-hydroxy-morphinan or (+)-6-amino-morphinan derivatives |
US8563724B2 (en) * | 2009-02-23 | 2013-10-22 | Mallinckrodt Llc | (+)-6-hydroxy-morphinan or (+)-6-amino-morphinan derivatives |
AU2010326676B2 (en) | 2009-12-04 | 2013-03-14 | Alkermes Pharma Ireland Limited | Morphinan derivatives for the treatment of drug overdose |
JP5964809B2 (ja) | 2010-03-22 | 2016-08-03 | レンセラール ポリテクニック インスティチュート | オピオイド受容体リガンドとしてのカルボキサミド基を含有するモルヒネ誘導体 |
NZ605234A (en) | 2010-07-08 | 2015-02-27 | Alkermes Pharma Ireland Ltd | Process for the synthesis of substituted morphinans |
FI3446565T3 (fi) | 2010-08-23 | 2024-01-30 | Alkermes Pharma Ireland Ltd | Menetelmiä antipsykoottisten lääkkeiden aiheuttaman painonnousun hoitamiseksi |
US9029543B2 (en) | 2011-04-05 | 2015-05-12 | Alkermes, Inc. | Process for the synthesis of quaternary amine compounds |
JP5981992B2 (ja) * | 2011-06-29 | 2016-08-31 | アルカーメス,インコーポレイテッド | 末梢作用オピオイド化合物 |
US9211293B2 (en) | 2011-12-15 | 2015-12-15 | Alkermes Pharma Ireland Limited | Opioid agonist antagonist combinations |
US9656961B2 (en) | 2013-05-24 | 2017-05-23 | Alkermes Pharma Ireland Limited | Methods for treating depressive symptoms |
EP3004114B1 (en) | 2013-05-24 | 2019-12-25 | Alkermes Pharma Ireland Limited | Morphan and morphinan analogues, and methods of use |
CN103992272B (zh) * | 2014-06-09 | 2016-05-11 | 安徽省逸欣铭医药科技有限公司 | 一种盐酸喷他佐辛酯、其制备方法及其用途 |
CN109288840A (zh) * | 2018-11-23 | 2019-02-01 | 中国科学院长春应用化学研究所 | 二元纳曲酮衍生物的应用 |
TWI719740B (zh) * | 2019-12-04 | 2021-02-21 | 大江生醫股份有限公司 | 植物發酵物的製備方法、以及該發酵物及其活性成分的應用 |
EP4243768A1 (en) | 2020-11-12 | 2023-09-20 | Alkermes Pharma Ireland Limited | Immediate release multilayer tablet |
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GB9912411D0 (en) * | 1999-05-28 | 1999-07-28 | Pfizer Ltd | Compounds useful in therapy |
DE10038709A1 (de) * | 2000-08-09 | 2002-02-28 | Aventis Pharma Gmbh | Substituierte und unsubstituierte Benzooxathiazole sowie daraus abgeleitete Verbindungen |
WO2002036573A2 (en) * | 2000-10-31 | 2002-05-10 | Rensselaer Polytechnic Institute | 8- substituted-2, 6-methano-3-benzazocines and 3-substituted morphinanes as opioid receptor binding agents |
AU2003281060A1 (en) | 2002-07-16 | 2004-02-02 | Rensselaer Polytechnic Institute | Process for conversion of phenols to carboxamides via the succinimide esters |
AU2003250117B2 (en) * | 2002-07-29 | 2007-05-10 | F. Hoffmann-La Roche Ag | Novel benzodioxoles |
US20080009478A1 (en) * | 2003-10-22 | 2008-01-10 | Arena Pharmaceuticals, Inc. | Benzazepine Derivatives and Methods of Prophylaxis or Treatment of 5Ht2c Receptor Associated Diseases |
BRPI0513075A (pt) * | 2004-08-05 | 2008-04-22 | Janssen Pharmaceutica Nv | moduladores gama-opióides tricìclicos |
MX2007005389A (es) | 2004-11-05 | 2007-12-07 | Rensselaer Polytech Inst | 4-hidroxibenzomorfanos. |
EP1833826B1 (en) | 2004-12-22 | 2009-05-27 | Janssen Pharmaceutica N.V. | Tricyclic delta-opioid modulators |
JP2008543866A (ja) * | 2005-06-16 | 2008-12-04 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | 三環式オピオイドモジュレーター |
CA2615774C (en) * | 2005-07-21 | 2014-12-09 | Rensselaer Polytechnic Institute | Large substituent, non-phenolic opioids |
JP5964809B2 (ja) * | 2010-03-22 | 2016-08-03 | レンセラール ポリテクニック インスティチュート | オピオイド受容体リガンドとしてのカルボキサミド基を含有するモルヒネ誘導体 |
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- 2006-07-21 JP JP2008523037A patent/JP5266051B2/ja active Active
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- 2006-07-21 AU AU2006272773A patent/AU2006272773B2/en active Active
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US8026252B2 (en) | 2011-09-27 |
AU2006272773B2 (en) | 2012-03-08 |
EP2266959A1 (en) | 2010-12-29 |
US20110306603A1 (en) | 2011-12-15 |
US8901148B2 (en) | 2014-12-02 |
US8541586B2 (en) | 2013-09-24 |
CA2615774A1 (en) | 2007-02-01 |
US9156821B2 (en) | 2015-10-13 |
EP1924559B1 (en) | 2014-04-16 |
WO2007014137A2 (en) | 2007-02-01 |
ES2422579T3 (es) | 2013-09-12 |
US20160257677A1 (en) | 2016-09-08 |
US7557119B2 (en) | 2009-07-07 |
US20090247562A1 (en) | 2009-10-01 |
EP2266959B1 (en) | 2013-05-01 |
AU2006272773A1 (en) | 2007-02-01 |
EP1924559A2 (en) | 2008-05-28 |
CA2615774C (en) | 2014-12-09 |
US20070021457A1 (en) | 2007-01-25 |
WO2007014137A3 (en) | 2007-03-29 |
JP2009502808A (ja) | 2009-01-29 |
JP5266051B2 (ja) | 2013-08-21 |
US20150051194A1 (en) | 2015-02-19 |
US20130345251A1 (en) | 2013-12-26 |
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