ES2647927T3 - Conjugados enlazadores del fármaco auriestatina - Google Patents

Conjugados enlazadores del fármaco auriestatina Download PDF

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ES2647927T3
ES2647927T3 ES14182732.9T ES14182732T ES2647927T3 ES 2647927 T3 ES2647927 T3 ES 2647927T3 ES 14182732 T ES14182732 T ES 14182732T ES 2647927 T3 ES2647927 T3 ES 2647927T3
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alkyl
group
heterocycle
aryl
carbocycle
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Peter Senter
Svetlana Doronina
Timothy Bovee
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Seagen Inc
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Seattle Genetics Inc
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Abstract

Un compuesto que tiene la fórmula: L-(LU-D)p o una de sus sales o solvatos farmacéuticamente aceptables; en la que L es la unidad de ligando, LU es una unidad enlazadora y D es una unidad de fármaco, L es un péptido, un polipéptido o una proteína que se unen específicamente a una población de células diana; LU tiene la fórmula -Aa-Ww-, Ww es una secuencia de w seleccionada independientemente de aminoácidos dirradicales, que comprende un aminoácido natural unido a un aminoácido no natural, en donde el W proximal a la unidad de fármaco (W1) está unido mediante un enlace peptídico a la unidad de fármaco, con la condición de que W1 no pueda formar una amida secundaria con el aminoácido del extremo C de D y que el enlace peptídico pueda escindirse mediante una proteasa intracelular, w es un número entero comprendido entre 2 y 12, A es una unidad ensanchadora, y a es 1 o 2; p es un número entero de 1 a 20; y D tiene la fórmula:**Fórmula** en la que la línea ondulada indica el enlace peptídico con LU; R1 y R2 se seleccionan independientemente entre el grupo que consiste en -H y alquilo-C1-C8, con la condición de que ambos R1 y R2 no sean -H; R3 se selecciona entre el grupo que consiste en -H, -alquilo C1-C8, carbociclo-C3-C8, -arilo, -alquil C1-C8 arilo, -X1-(carbociclo C3-C8), heterociclo-C3-C8 y -X1- (heterociclo C3-C8); R4 se selecciona entre el grupo que consiste en -H, -alquilo C1-C8, -carbociclo C3-C8, -arilo, -X1-arilo, -alquil C1-C8-(carbociclo C3-C8), -heterociclo C3-C8 y -X130 -(heterociclo C3-C8); R5 se selecciona entre el grupo que consiste en -H y metilo; o R4 y R5 forman conjuntamente un anillo carbocíclico y tiene la fórmula -(CRaRb)n- en la que Ra y Rb se seleccionan independientemente entre el grupo que consiste de -H y -alquilo C1-C8 y n se selecciona del grupo que consiste en 2, 3, 4, 5 y 6; R6 se selecciona entre el grupo que consiste en -H y alquilo C1-C8; R7 se selecciona entre el grupo que consiste en -H, -alquilo C1-C8, carbociclo C3-C8, -arilo, -X1-arilo, -X1-(carbociclo C3-C8), -heterociclo C3-C8 y -X1-(heterociclo C3-C8); cada R8 se selecciona independientemente del grupo que consiste en H, -OH, -alquilo C1-C8, -carbociclo C3-C8 y -O-(alquilo C1-C8); R12 se selecciona entre H, -alquilo C1-C8, arilo, -X1-arilo, carbociclo C3-C8, -X1-(heterociclo C3-C8), -alquileno C1-C8, NH2, -heterociclo C3-C8 y -X1-(heterociclo C3-C8), y cada X1 es independientemente -alquileno C1-C10.

Description

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evita esta reactividad. Se pueden encontrar ejemplos de grupos protectores en T.W. Green y P.G.M. Wuts, Protective Groups in Organic Synthesis, 3ª Edición, John Wiley & Sons, Nueva York, 1999, y Harrison y Harrison et al., Compendium of Synthetic Organic Methods, Volúmenes 1-8 (John Wiley and Sons, 1971-1996). Los grupos protectores de hidroxi representativos incluyen grupos acilo, éteres de bencilo y tritilo, éteres de tetrahidropiranilo, éteres de trialqulsililo y alilo. Los grupos protectores de amino representativos incluyen, grupos formilo, acetilo, trifluoroacetilo, bencilo, benciloxicarbonilo (CBZ), terc-butoxicarbonilo (Boc), trimetil sililo (TMS), 2-trimetilsilil-etanosulfonilo (SES), tritilo y tritilo sustituido, aliloxicarbonilo, 9-fluorenilmetiloxicarbonilo (FMOC), nitro-veratriloxicarbonilo (NVOC), y similares.
Los ejemplos de "grupo protector de hidroxilo" incluyen, pero sin limitación, metoximetil éter, 2-metoxietoximetil éter, éteres de tetrahidropiranilo, éter de bencilo, éter de p-metoxibencilo, éter de trimetilsililo, éter de trietilsililo, éter de triisopropilsililo, éter de t-butildimetilsililo, éter de trifenilmetilsililo, éster de acetato, ésteres de acetato sustituidos, pivaloato, benzoato, metanosulfonato y p-toluensulfonato.
"Grupo saliente" se refiere a un grupo funcional que puede estar sustituido por otro grupo funcional. Dichos grupos salientes son bien conocidos en la materia, y los ejemplos incluyen, pero sin limitación, un haluro (por ejemplo, cloruro, bromuro, yoduro), metanosulfonilo (mesilo), p-toluensulfonilo (tosilo), trifluorometilsulfonilo (triflato), y trifluorometilsulfonato.
La frase "sal farmacéuticamente aceptable", tal como se usa en el presente documento, se refiere a sales orgánicas o inorgánicas farmacéuticamente aceptables de un compuesto (por ejemplo, un fármaco, un compuesto enlazador de fármaco, o un conjugado del ligando enlazador de fármacos). El compuesto contiene normalmente al menos un grupo amino, y de acuerdo con ello, las sales de adición de ácido se pueden formar con este grupo amino. las sales ilustrativas incluyen, pero sin limitación, sulfato, citrato, acetato, oxalato, cloruro, bromuro, yoduro, nitrato, bisulfato, fosfato, fosfato ácido, isonicotinato, lactato, salicilato, citrato ácido, tartrato, oleato, tanato, pantotenato, bitartrato, ascorbato, succinato, maleato, gentisinato, fumarato, gluconato, glucuronato, sacarato, formato, benzoato, glutamato, metanosulfonato, etanosulfonato, bencenosulfonato, p-toluenosulfonato, y pamoato (es decir, sales de 1,1’-metileno-bis-(2-hidroxi-3-naftoato)) Una sal farmacéuticamente aceptable puede implicar la inclusión de otra molécula tal como un ion acetato, un ion succinato u otro contraión. El contraión puede ser cualquier resto orgánico o inorgánico que estabilice la carga del compuesto progenitor. Además, una sal farmacéuticamente aceptable puede tener más de un átomo cargado en su estructura. Los casos en los que múltiples átomos cargados son parte de la sal farmacéuticamente aceptable pueden tener múltiples contraiones. De este modo, una sal farmacéuticamente aceptable puede tener uno o más átomos cargados y/ uno o más contraiones.
"Solvato farmacéuticamente aceptable" o "solvato" se refiere a una asociación de una o más moléculas de disolvente y un compuesto de la invención, por ejemplo, un conjugado de ligandos enlazadores de fármacos y compuestos enlazadores de fármacos, Los ejemplos de disolventes que forman solvatos farmacéuticamente aceptables incluyen, pero sin limitación, agua, isopropanol, etanol, metanol, DMSO, acetato de etilo, ácido acético, y etanolamina.
Las siguientes abreviaturas se usan en el presente documento y tienen las definiciones indicadas: Boc es N-(t-butoxicarbonilo), cit es citrulina, dap es dolaproína, DCM es diclorometano, DIEA es N,N-diisopropiletilamina, dil es dolaisoleucina, DMF es N,N-dimetilformamida, DMSO es dimetilsulfóxido, doe es dolafenina, dov es N,N-dimetilvalina, DTNB es 5,5’-ditiobis(ácido 2-nitrobenzoico), DTPA e ácido dietilentriaminopentaacético, DTT es ditiotreitol, Fmoc es N-(9-fluorenil-metoxicarbonilo), gly es glicina, HATU es hexafluorofosfato de 0-(7-azabenzotriazol-1-il)-N,N,N',N'-tetrametiluronio, HBTU es hexafluorofosfato de 2-[1H-benzotriazol-1-il]-1,1,3,3-tetrametilamino; HOBt es 1-hidroxibenzotriazol, HPLC es cromatografía líquida de alta presión, ile es isoleucina, lys es lisina, MeOH es metanol, MeVal es N-metil-valina, PAB es p-aminobencilol, PBS es solución salina tamponada con fosfato (pH 7,4), Ph es fenilo, phe es L-fenilalanina, PyBrop es hexafluorofosfato de bromo tris-pirrolidino fosfonio, TFA es ácido trifluoroacético, UV es ultravioleta, y val es valina.
Las siguientes abreviaturas de enlazadores se usan en el presente documento y tienen las definiciones indicadas: Val Cit o vc es un sitio dipéptido de valina-citrulina en el enlazador de la proteasa escindible; PABC es p-aminobencilcarbamoílo; (Me)vc es N-metil-valina citrulina, en el que el enlace peptídico del enlazador se ha modificado para evitar su escisión por la catepsina B; y MC(PEG)6-OH es maleimidocaproil-polietilenglicol.
Las siguientes abreviaturas de fármacos citotóxicos se usan en el presente documento y tienen las definiciones indicadas: "Auriestatina F" o "AF" es N,N-dimetilvalina-valina-dolaisoleucina(dil)-dolaproína(dap)-fenilalanina. "MMAF" es N-metilvalina-valina-dolaisoleucina(dil)-dolaproína(dap)-fenilalanina (PM 731,5).
Compuestos y conjugados
Se describe en el presente documento una serie de compuestos y conjugados que contienen un resto de fármaco (D) unido mediante su extremo C a una unidad enlazadora. La unidad enlazadora puede actuar para proporcionar una liberación adecuada de D.
Por ejemplo, se describen en el presente documento compuestos enlazadores de fármacos que tienen la Fórmula I:
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(ligando enlazador de fármaco) en líneas celulares positivas para CD70+, 786O, Caki-1, L428, UMRC-3, LP-1, U251, y una línea celular CDR70+, HCT-116, como control. Además, el conjugado hlF6-vc-PABC-MMAF se utilizó como control. Las Tablas 4 y 5 muestran la actividad in vitro de conjugados Auristatina-Dipéptido-h1F6 seleccionados (el péptido tiene dos aminoácidos) comparada con el conjugado de h1F6-vc-PABC-MMAF de control. Los conjugados contienen aproximadamente 4 fármacos por anticuerpo.
Tabla 4: Valores de CI50 (ng/ml) para los conjugados Auristatina-Dipéptido-h1F6 (~4 fármacos/anticuerpo) con células CD70+
imagen60
10 Los resultados de estos estudios se muestran en la Tabla 4. En este ejemplo, los conjugados Auristatina F-dipéptido con el anticuerpo h1F6 muestran por lo general una actividad comparable a la del control, un conjugado h1F6-vc-PABC-MMAF. Estos resultados demuestran que las auristatinas se pueden conjugar a través del grupo carboxilo del extremo C con un enlazador que comprende unidades de aminoácido para generar ADC activos. La
15 potencia de dichos conjugados varía dependiendo de la secuencia de los aminoácidos de los enlazadores. Los conjugados con enlazadores de fármaco que comprenden aminoácidos no naturales como β-alanina y fenilglicina unidos a la fenilalanina de la auristatina demostraron una actividad reducida, debido potencialmente a la escisión enzimática ineficaz de dichos sustratos. El enlazador de fármaco AF-Prolina-(D)Lisina proporcionó un ADC fuertemente inactivo, muy probablemente debido a la imposibilidad, o dificultar extrema, de la escisión proteolítica del
20 enlace amida secundario entre la fenilalanina y la prolina.
Tabla 5: Resumen de los valores de CI50 (ng/ml) para los conjugados Auristatina-Péptido-h1F6 (~4 fármacos/anticuerpo) con células CD70+
Enlazador de fármaco en el conjugado+
CI50 (ng/ml)
786-O
Caki-1 Caki-2 L428 HCT-116 (CD70-)
AF-Gln-(D)Lys
12 11 14 209 >1000
AF-Arg-(D)Lys
8 10 8 47 >1000
AF-Cit-(D)Lys
10 11 16 47 >1000
AF-Tyr-(D)Lys
9 11 12 10 >1000
AF-Lys-(D)Lys
9 8 9 37 >1000
AF-Asn-Pro
11 12 32 23 >1000
AF-Met-Pro
8 15 25 8 >1000
AF-Met-(D)Met
4 5 13 4 >1000
AF-Met-(D)Val
5 6 32 8 >1000
AF-Met-(D)Asp
8 10 35 11 >1000
AF-hPhe-(D)Asp
10 >1000 >1000 29 >1000
AF-Asn-(D)Asp
7 7 71 14 >1000
AF-Asn-(D)Lys-(D)Lys
9 10 30 22 >1000
AF-Met-(D)Lys-(D)Lys
8 12 25 >1000 >1000
AM-Tyr-(D)Asp
32 23 71 30 >1000
AM-Met-(D)Lys
56 39 251 1000 >1000
AM-Asn-(D)Lys
20 20 47 26 >1000
AM-Asn
30 31 63 32 >1000
AW-Tyr-(D)Asp
18 16 33 21 >1000
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AF,
Asn-(D)Lys 10 6 9 32 479
MMAF
9 7 7 19 110
+ La unidad ensanchadora de la unidad enlazadora es como se indica en los Ejemplos anteriores.
Los datos muestran que los ADC de MMAF y AF tienen una potencia in vitro e in vivo similar independiente de qué fármaco se utilizó con los enlazadores que contienen dipéptido. Los conjugados que contienen MMAF parecen ser menos bien tolerados que los correspondientes ADC que contienen Auristatina F. Ambos conjugados
5 MMAF-Met-(D)Lys y MMAF-Asn-(D)Lys-h1F6 dieron como resultado pérdidas de animales a dosis de 100 mg/kg mientras que los correspondientes conjugados AF fueron bien tolerados a esta dosis.
Ejemplo 66 -Comparación entre la eficacia y la tolerabilidad de conjugados Auristatina-Dipéptido-Anticuerpo seleccionados
10 La eficacia y tolerabilidad (MTD) de los conjugados Auristatina-Dipéptido-Anticuerpo se compararon usando diferentes enlazadores, que tenían aminoácidos D o L en la segunda posición de aminoácido de la unidad enlazadora. Los estudios de eficacia y tolerabilidad se llevaron a cabo de manera general como se describe en los Ejemplos 58 y 64, respectivamente. Los resultados que se muestran en la siguiente Tabla 8 y en las Figuras 12-13.
15
Tabla 8. Resumen de los valores de CI50 (ng/ml) para conjugados Auristatina-Dipéptido-h1F6 seleccionados
Fármaco
Enlazador+ Valores de CI50 (ng/ml)
786-O
Caki-1 L-428 UMRC-3 LP-1
AF,
Met-(D)Lys 12 9 158 182 >1000
Met-(L)Lys
7 4 3 22 95
AF,
Asn-(D)Lys 10 6 9. 32 479
Asn-(L)Lys
9 8 8 26 501
La unidad ensanchadora de la unidad enlazadora es como se indica en los Ejemplos anteriores.
Los enlazadores de fármacos con un L-aminoácido en la segunda posición proporciona los ADC mejor tolerados para 20 ambos enlazadores ensayados, como se muestra en la Figura 13, aunque la potencia in vitro e in vivo de estos conjugados fue comparable.
Ejemplo 67 -Comparación entre la eficacia y la tolerabilidad de conjugados Auristatina-Péptido-Anticuerpo con enlazadores de monopéptido o dipéptido.
25 Las eficacias y tolerabilidades (MTD) de los conjugados Auristatina-Dipéptido-Anticuerpo se compararon usando enlazadores de monopéptido o dipéptido. Los estudios de eficacia y tolerabilidad se llevaron a cabo de manera general como se describe en los Ejemplos 58 y 64, respectivamente. Los resultados que se muestran en la siguiente Tabla 9 y en las Figuras 14-15.
30
Tabla 9. Resumen de los valores de CI50 (ng/ml) para conjugados h1F6-fármaco(4) seleccionados
o
Enlazador+ 786-O Caki-1 L-428 UMRC-3 LP-1
AF,
Met-(D)Lys Met 12 8 9 6 158 3 182 17 >1000 110
AF,
Asn-(D)Lys Asn 10 10 6 6 9 9 32 28 479 209
Valores de CI50 (ng/ml) Fármac
+ La unidad ensanchadora de la unidad enlazadora es como se indica en los Ejemplos anteriores.
Los resultados de los estudios muestran que los conjugados que solamente tienen un aminoácido en el enlazador eran
35 significativamente menos bien tolerados en comparación con los correspondientes conjugados que tienen enlazadores dipéptidos (Figura 15). AF-Asn-h1F6 y AF-Met-h1F6 fueron tóxicos a una dosis de 50 mg/kg mientras que los correspondientes AF-Asn-(D)Lys y AF-Met-(D)Lys fueron tolerados a 100 mg/kg. Estos datos respaldan el uso de al menos dos aminoácidos en los enlazadores de péptidos para los conjugados Auristatina-Péptido-Anticuerpo unidos por el extremo C.
40
Ejemplo general 68 -Preparación de enlazadores de fármacos de Auristatina-AA1-AA2 con aril-maleimidas
Los enlazadores de fármacos de Auristatina-péptido con aril-maleimidas en la unidad ensanchadora se prepararon por sustitución del éster de NHS del ácido 3-maleimidopropiónico en la etapa (j) del Ejemplo 10, como se modifica en el
45 Ejemplo 24, por el éster de NHS de p-maleimidobenzoilo.
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