ES2602331T3 - Pirazin-carboxamidas de tipo amilorida como bloqueantes de ENaC - Google Patents
Pirazin-carboxamidas de tipo amilorida como bloqueantes de ENaC Download PDFInfo
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- ES2602331T3 ES2602331T3 ES08860731.2T ES08860731T ES2602331T3 ES 2602331 T3 ES2602331 T3 ES 2602331T3 ES 08860731 T ES08860731 T ES 08860731T ES 2602331 T3 ES2602331 T3 ES 2602331T3
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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- 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
- C07D403/12—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 chain containing hetero atoms as chain links
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- 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
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- 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
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- C07D471/12—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 three hetero rings
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- 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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- 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
- C07D487/10—Spiro-condensed systems
Abstract
Compuesto según la fórmula la**Fórmula** en la que R6 y R11 son ambos H; R7, R8, R9, y R10 se seleccionan cada uno independientemente de H; SO2R16; arilo opcionalmente sustituido con uno o más grupos Z; un grupo carbocíclico C3-C10 opcionalmente sustituido con uno o más grupos Z; grupo heterocíclico C3-C14 opcionalmente sustituido con uno o más grupos Z; alquilo C1-C8 sustituido con un grupo arilo opcionalmente sustituido con uno o más grupos Z, un grupo carbocíclico C3-C10 opcionalmente sustituido con uno o más grupos Z o un grupo heterocíclico C3-C14 opcionalmente sustituido con uno o más grupos Z; R16 se selecciona de alquilo C1-C8, arilo y un grupo heterocíclico de 3 a 14 miembros; Z se selecciona independientemente de OH, arilo, O-arilo, aralquilo C7-C14, O-aralquilo C7-C14, alquilo C1-C6, alcoxilo C1-C6, NR19(SO2)R21, (SO2)NR19R21, (SO2)R20, NR19C(O)R20, C(O)NR19R20, NR19C(O)NR20R18, NR19C(O)OR20, NR19R21, C(O)OR19, C(O)R19, SR19, OR19, oxo, CN, NO2 y halógeno, en los que los grupos alquilo, alcoxilo, aralquilo y arilo están sustituidos cada uno opcionalmente con uno o más sustituyentes seleccionados de OH, halógeno, haloalquilo C1-C4 y alcoxilo C1-C4; R18, R19 y R20 se seleccionan cada uno independientemente de H y alquilo C1-C6; R21 se selecciona de alquilo C1-C8, arilo y un grupo heterocíclico de 3 a 14 miembros; n es 0 o 2; con la condición de que cuando n es 0, al menos uno de R6, R7, R8, R9, R10 y R11 es distinto de H.
Description
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Physiol (2005).
Los bloqueantes del canal de sodio epitelial, incluyendo los compuestos de fórmula (I), también son útiles como agentes coterapéuticos para su uso en combinación con otros principios activos, tales como principios activos antiinflamatorios, broncodilatadores, antihistamínicos o antitusivos, particularmente en el tratamiento de fibrosis quística o enfermedades obstructivas o inflamatorias de las vías respiratorias tales como las mencionadas anteriormente en el presente documento, por ejemplo, como potenciadores de la actividad terapéutica de tales fármacos o como medio para reducir la dosificación requerida o los posibles efectos secundarios de tales fármacos.
El bloqueante del canal de sodio epitelial puede mezclarse con otro principio activo en una composición farmacéutica fijada o puede administrarse por separado, antes, de manera simultánea a o después del otro principio activo.
Por consiguiente, la invención incluye como aspecto adicional una combinación de bloqueante del canal de sodio epitelial con agentes osmóticos (solución salina hipertónica, dextrano, manitol, xilitol) + modificadores de la función de CFTR, tanto de tipo natural como mutantes (correctores + potenciadores), por ejemplo, los descritos en los documentos WO 2007/021982, WO 2006/099256, WO 2006/127588, WO 2004/080972, WO 2005/026137, WO 2005/035514, WO 2005/075435, WO 2004/111014, WO 2006/101740, WO 2004/110352, WO 2005/120497 y US 2005/0176761, un principio activo antiinflamatorio, broncodilatador, antihistamínico, antitusivo, antibiótico o de ADNasa, estando dicho bloqueante del canal de sodio epitelial y dicho principio activo en la misma composición o diferentes composiciones.
Los antibióticos adecuados incluyen antibióticos de macrólido, por ejemplo, tobramicina (TOBI™).
Los principios activos de ADNasa adecuados incluyen dornasa alfa (Pulmozyme™), una disolución altamente purificada de desoxriribonucleasa I humana recombinante (rhADNasa), que escinde selectivamente el ADN. La dornasa alfa se usa para tratar la fibrosis quística.
Otras combinaciones útiles de bloqueantes del canal de sodio epitelial con fármacos antiinflamatorios son aquellas con antagonistas de receptores de quimiocinas, por ejemplo, CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR7, CCR-8, CCR-9 y CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularmente antagonistas de CCR-5, tales como los antagonistas de Schering-Plough SC-351125, SCH-55700 y SCH-D; los antagonistas de Takeda, tales como cloruro de N-[[4-[[[6,7-dihidro-2-(4-metil-fenil)-5H-benzo-ciclohepten-8-il]carbonil]amino]fenil]metil]tetrahidro-N,N-dimetil-2H-pirano-4-aminio (TAK-770); y los antagonistas de CCR-5 descritos en los documentos USP 6.166.037 (particularmente las reivindicaciones 18 y 19), WO 00/66558 (particularmente la reivindicación 8), WO 00/66559 (particularmente la reivindicación 9), WO 04/018425 y WO 04/026873.
Los fármacos antiinflamatorios adecuados incluyen esteroides, en particular, glucocorticosteroides, tales como budesonida, dipropionato de beclametasona, propionato de fluticasona, ciclesonida o furoato de mometasona, o los esteroides descritos en los documentos WO 02/88167, WO 02/12266, WO 02/100879, WO 02/00679 (especialmente los de los ejemplos 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, 99 y 101), WO 03/35668, WO 03/48181, WO 03/62259, WO 03/64445, WO 03/72592, WO 04/39827 y WO 04/66920; agonistas de receptores de glucocorticoides no esteroideos, tales como los descritos en los documentos DE 10261874, WO 00/00531, WO 02/10143, WO 03/82280, WO 03/82787, WO 03/86294, WO 03/104195, WO 03/101932, WO 04/05229, WO 04/18429, WO 04/19935 y WO 04/26248; antagonistas de LTD4, tales como montelukast y zafirlukast; inhibidores de PDE4, tales como cilomilast (Ariflo® GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofilline (Almirall Prodesfarma), PD189659/PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SelCID(TM) CC-10004 (Celgene), VM554/UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo), y los dados a conocer en los documentos WO 92/19594, WO 93/19749, WO 93/19750, WO 93/19751, WO 98/18796, WO 99/16766, WO 01/13953, WO 03/104204, WO 03/104205, WO 03/39544, WO 04/000814, WO 04/000839, WO 04/005258, WO 04/018450, WO 04/018451, WO 04/018457, WO 04/018465, WO 04/018431, WO 04/018449, WO 04/018450, WO 04/018451, WO 04/018457, WO 04/018465, WO 04/019944, WO 04/019945, WO 04/045607 y WO 04/037805; antagonistas de receptores de adenosina A2B tales como los descritos en los documentos WO 02/42298; y agonistas de receptores beta-2-adrenérgicos, tales como albuterol (salbutamol), metaproterenol, terbutalina, salmeterol fenoterol, procaterol, y especialmente, formoterol, carmoterol y sales farmacéuticamente aceptables de los mismos, y compuestos (en forma libre o de sal o de solvato) de fórmula (I) del documento WO 0075114, especialmente un compuesto de fórmula:
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Condiciones generales
Los CL-EM se registran usando una columna Phenomenex Gemini de 50 mm x 3,0 mm, 3 um. Los métodos a pH bajo usan un gradiente de acetonitrilo al 5-95% en agua -0,1% de TFA, los métodos a alto pH usan un gradiente de acetonitrilo al 5-95% en agua -0,1% de NH3-[M+H]+ se refiere a pesos moleculares monoisotópicos.
9-BBN 9-Borabiciclo[3.3.1]nonano
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Se prepara este compuesto según Cragoe, Edward J., Jr.; Woltersdorf, Otto W., Jr.; De Solms, Susan Jano. Heterocyclic-substituted pyrazinoylguanidines, and a pharmaceutical composition containing them. Documento EP 17152, página 4.
Método 2
Etapa 1
Se trata una suspensión con agitación de éster metílico del ácido 3,5-diamino-6-cloro-pirazin-2-carboxílico (110 g, 542,9 mmol) en MeOH (500 ml) a 5-10ºC (baño de hielo) gota a gota con una suspensión de hidróxido de litio (46,6 g, 1111 mmol) en agua (500 ml). Se calienta la mezcla de reacción hasta 50ºC durante 5 horas, luego se enfría hasta temperatura ambiente y se agita durante la noche. Se recoge el precipitado resultante mediante filtración y se seca en un horno de vacío para proporcionar litio-ácido 3,5-diamino-6-cloro-pirazin-2-carboxílico como la sal de litio (dihidratada); [M-Li]-187.
Etapa 2
Se trata una suspensión con agitación de de S-metil-iso-sulfato de tiourea (10 g, 35,9 mmol) en tolueno (75 ml) con NaOH 4 M (15 ml) a temperatura ambiente. A la mezcla bifásica se le añade dicarbonato de di-terc-butilo (3,27 g, 15 mmol) en una porción. Se agita la mezcla de reacción a temperatura ambiente durante 1 hora, luego se calienta hasta 60ºC durante la noche. Se separa la parte orgánica, se lava con disolución de salmuera, entonces se seca sobre Na2SO4, se filtra y se concentra a vacío para dar un aceite viscoso, que cristaliza a alto vacío para proporcionar amino(metiltio)metilencarbamato de terc-butilo como un sólido incoloro.
Etapa 3
Se trata una suspensión con agitación de litio-ácido 3,5-diamino-6-cloro-pirazin-2-carboxílico (22,6 g, 98,03 mmol) en DMF (400 ml) en porciones con HATU (41 g, 107,83 mmol), bajo una atmósfera inerte de nitrógeno. Se agita la mezcla de reacción a temperatura ambiente durante 2 horas y entonces se añade en porciones amino(metiltio)metilencarbamato de terc-butilo (20,5 g, 107,83 mmol) a lo largo de un periodo de 10 minutos. Se agita la mezcla de reacción a temperatura ambiente durante 1,5 horas más, luego se calienta hasta 50ºC y se agita durante la noche. Se filtra en caliente el precipitado resultante, lavando con agua y se seca en un horno de vacío (40ºC) durante la noche para proporcionar (3,5-diamino-6-cloropirazin-2-carboxamido)(metiltio)metilencarbamato de terc-butilo; [M+H]+ 361.
Etapa 4
Se prepara una suspensión de (3,5-diamino-6-cloropirazin-2-carboxamido)(metiltio)metilencarbamato de terc-butilo (50 g, 139 mmol) en DCM (500 ml). Se disuelve TFA (53,4 ml, 693 mmol) en DCM (100 ml) y se añade gota a gota a lo largo de 45 min para formar una disolución de color marrón. Se agita la disolución a temperatura ambiente durante la noche, tiempo después del cual se ha formado un precipitado de color amarillo. Se recoge el sólido mediante filtración, y se seca a vacío para producir el compuesto del título; [M+H]+ 261,1.
Producto intermedio D
(S)-3-(4-metoxi-fenil)-propano-1,2 diamina
Se prepara (S)-2-amino-3-(4-metoxi-fenil)-propionamida según el procedimiento descrito en la página 3880, método
2.1.3 del Journal of Physical Chemistry B, 108(12), 3879-3889; 2004 y se reduce de manera análoga al producto intermedio C.
Producto intermedio G
4-Amino-1-bencil-piperidin-4-carbonitrilo
Etapa 1
A una disolución de cloruro de amonio (1,73 g, 32,3 mmol) en agua (20 ml) se le añade una disolución de amoniaco al 30% (2 ml) seguido por 1-bencil-4-piperidona. Después de 20 minutos, se añade en porciones cianuro de sodio (1,47 g, 30 mmol) a lo largo de 15 minutos. Después de agitar durante una hora, se añade agua (50 ml) y se extraen los productos con DCM (3 x 50 ml), se secan (MgSO4) se filtran y se concentran a vacío. La purificación mediante cromatografía sobre sílice eluyendo con EtOAc al 50-100% en iso-hexano proporciona 4-aminometil-1-bencilpiperidin-4-ilamina; [M+H]+ 216.
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Se trata una disolución de N-(difenilmetilen)aminoacetonitrilo (5,14 g, 23,4 mmol) en DCM (12 ml) con (R)-4-[4-(3bromo-propil)-fenoximetil]-2,2-dimetil-[1,3] dioxolano (8,1 g, 24 mmol) en DCM (12 ml) y se enfría hasta 0ºC. Se le añade NaOH acuoso al 48% (20 ml) seguido por cloruro de benciltrietilamonio (530 mg, 2,4 mmol) y se permite que la mezcla resultante se caliente hasta temperatura ambiente. Después de agitación vigorosa durante 4 horas, se diluye la mezcla con DCM (100 ml) y se retira la parte acuosa. Se lava la fase orgánica con agua (2 x 50 ml), salmuera, se seca (MgSO4), se filtra y se concentra a vacío. Se purifica el producto en bruto mediante cromatografía sobre sílice eluyendo con de iso-hexano/dietil éter 15:1 a iso-hexano/dietil éter 4:1 para producir 2-(benzhidrilidenamino)-5-[4-((R)-2,2-dimetil-[1,3]dioxolan-4-ilmetoxi)-fenil]pentanonitrilo como un aceite de color amarillo; 1H-RMN (CDCl3): mezcla de diastereoisómeros 1,39 (3H, s), 1,43 (3H,s), 1,71 (2H, m), 1,80-1,98 (2H, m), 2,52 (2H, tr, J = 7,0 Hz) 3,90,(2H, m), 4,02 (1H, m), 4,10 -4,22 (2H, m), 4,47 (1H, pent, J = 6,9 Hz), 6,82 (2H, d, J = 7,4 Hz), 7,05 (2H, d, J = 7,4 Hz), 7,19 (2H, m), 7,35 (2H, tr, J = 7,2 Hz), 7,40-7,50 (4H, m), 7,60 (2H, d, J = 7,1 Hz).
Etapa 6
A una disolución de 2-(benzhidriliden-amino)-5-[4-((R)-2,2-dimetil-[1,3]dioxolan-4-ilmetoxi)-fenil]pentanonitrilo (7,2 g, 15,5 mmol) en THF (50 ml) se le añade a HCl 2 M (ac.) (5 ml). Se calienta la disolución a 40ºC durante 4 horas y entonces se permite que se enfríe hasta temperatura ambiente. Se ajusta el pH a pH 9-10 usando disolución acuosa saturada de hidrogenocarbonato de sodio y se elimina el disolvente orgánico a vacío. Se disuelve el residuo en bruto en EtOAc (100 ml) y se lava con agua, salmuera, se seca (MgSO4), se filtra y se concentra a vacío. Se purifica el residuo resultante mediante cromatografía sobre sílice eluyendo con iso-hexano/ EtOAc de 5:1 a 1:1 y trietilamina al 1% para producir 2-amino-5-[4-((R)-2,2-dimetil-[1,3]dioxolan-4-ilmetoxi)-fenil]-pentanonitrilo como un aceite incoloro que solidifica; 1H-RMN (CDCl3): mezcla de diastereoisómeros 1,39 (3H, s), 1,43 (3H,s), 1,70-1,87 (4H, m), 2,60 (2H, tr, J = 7,1 Hz), 3,62 (1H, a), 3,90 (2H, m), 4,00-4,18 (2H, m), 4,48 (1H, pent, J = 6,9 Hz), 6,82 (2H, d, J = 7,4 Hz), 7,10 (2H, d, J = 7,4 Hz). [M+H]+ 305.
Etapa 7
Se hace pasar una disolución de 2-amino-5-[4-((R)-2,2-dimetil-[1,3]dioxolan-4-ilmetoxi)-fenil]-pentanonitrilo (1,7 g, 4,28 mmol) en una disolución de amoniaco 2 M en metanol (50 ml) a través de un aparato H-CUBE dotado con un catalizador CatCart de níquel Raney a 50ºC y una presión de hidrógeno de 50 bar y una velocidad de flujo de 1,5 ml/min. Después de 5 horas de ciclos continuos de la disolución, se concentra la mezcla de reacción a vacío para dar 5-[4-((R)-2,2-dimetil-[1,3]dioxolano-4-ilmetoxi)-fenil]-pentano-1,2-diamina como un aceite de color amarillo claro; [M+H]+ 309.
Producto intermedio I
5-(4-Metoxi-fenil)-pentano-1,2-diamina
Se prepara este compuesto de manera análoga al producto intermedio H sustituyendo (3-[4-((R)-2,2-dimetil[1,3]dioxolan-4-ilmetoxi)-fenil]-propan-1-ol por 4-(4-metoxifenil)-1-butanol.
Producto intermedio K
(4-((R)-4,5-Diamino-pentil)-fenol
Etapas 1 y 2
Se prepara el éster etílico del ácido (R)-2-terc-butoxicarbonilamino-5-(4-terc-butoxi-fenil)-pentanoico según el procedimiento de Ding, Chuanyong.; Ma, Rujian.; Rong, Guobin. Preparation of w-Phenyl-(2S)-N-Boc-amino Acid Ethyl esters; Chinese Journal of Organic Chemistry vol. 26(12) 2006, 1694 &1695, sustituyendo Boc-L-piroglutamato de etilo por Boc-D-piroglutamato de etilo y bromometil-benceno por 1-bromo-4-terc-butoxi-benceno en el ejemplo 2a, usando las etapas de preparación 2.2, 2.3 y 2.5; [M+H]+ 394.
Etapa 3
Se disuelve éster etílico del ácido (R)-2-terc-butoxicarbonilamino-5-(4-terc-butoxi-fenil)-pentanoico (179 g, 460 mmol) en NH3 7 M en MeOH (400 ml, 2800 mmol) y se agita a temperatura ambiente durante 4 días. Se concentra la reacción a vacío manteniendo la temperatura por debajo de 30ºC para proporcionar éster terc-butílico del ácido [(R)4-(4-terc-butoxi-fenil)-1-carbamoil-butil]-carbámico [M+H]+ 364.
Etapa 4
Se agita una disolución de éster terc-butílico del ácido [(R)-4-(4-terc-butoxi-fenil)-1-carbamoil-butil]-carbámico (167 g,
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