AR041769A1 - Analogos quimericos de somatostatina-dopamina y usos de los mismos - Google Patents

Analogos quimericos de somatostatina-dopamina y usos de los mismos

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AR041769A1
AR041769A1 ARP040101233A ARP040101233A AR041769A1 AR 041769 A1 AR041769 A1 AR 041769A1 AR P040101233 A ARP040101233 A AR P040101233A AR P040101233 A ARP040101233 A AR P040101233A AR 041769 A1 AR041769 A1 AR 041769A1
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alkenyl
heteroalkyl
alkynyl
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Sod Conseils Rech Applic
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Abstract

Se describen análogos quiméricos de somatostatina-dopamina, y métodos relacionados con su uso terapéutico para el tratamiento de neoplasia, acromegalia y otras indicaciones. Reivindicación 2: El análogo quimérico de la declaración 1, donde dicho análogo quimérico comprende la fórmula (1) donde: X es H, Cl, Br, I F, -CN, alquilo C1-10, heteroalquilo C1-10, alquenilo C2-10, alquinilo C2-10, alquilo C1-10 sustituido, heteroalquilo C1-10 sustituido, alquenilo C2-10 sustituido, o alquinilo C2-10 sustituido; R1 es H, alquilo C1-10, heteroalquilo C1-10, alquenilo C2-10, alquinilo C2-10, alquilo C1-10 sustituido, heteroalquilo C1-10 sustituido, alquenilo C2-10 sustituido o alquinilo C2-10 sustituido, o -CN; R2 y R3 son, independientemente, H o están ausentes, a condición de que cuando R2 y R3 está ausente existe un doble enlace entre los átomos de C a los cuales están unidos; R4 es H, alquilo C1-10, heteroalquilo C1-10, alquenilo C2-10, alquinilo C2-10, alquilo C1-10 sustituido, heteroalquilo C1-10 sustituido, alquenilo C2-10 sustituido, o alquinilo C2-10 sustituido; Y es -O-, -C(O), -S-, -S-(CH2)s-C(O), -S(O)-, -S(O)2-, -SC(O)-,-OC(O)-, -N(R5)-C(O)-, o -N(R6)-; L es -(CH2)p-C(O)-, cuando Y es -S-, -S(O)-, -S/(O)2-, -O- o -N(R6)-; o L es -C(O)-(CR7R8)q-C(O)-, cuando Y es -N(R6)-, -O-, o -S-; L es (aminoácido)t cuando Y es -C(O)-, SC(O)-, -OC(O)-, -S-(CH2)s-C(O)-, o N(R5)-C(O)-; W es -CR9,R10-; R5 y R6 son, independientemente, H, alquilo C1-10, alquilo C1-10 sustituido; heteroalquilo C1-10, heteroalquilo C1-10 sustituido, alquenilo C2-10, alquenilo C2-10 sustituido, alquinilo C2-10, alquinilo C2-10 sustituido, arilo, alquilarilo, o alquilarilo sustituido; R7, R8, R9 y R10 son, independientemente, H, F, Cl, Br, I, alquilo C1-10, alquilo C1-10 sustituido, heteroalquilo C1-10, heteroalquilo C1-10 sustituido, alquenilo C2-10, alquenilo C2-10 sustituido, alquinilo C2-10, alquinilo C2-10 sustituido, arilo, arilalquilo, o arilalquilo sustituido; R7 y R8 se pueden unir, opcionalmente, para formar un sistema de anillos; R9 y R10 se pueden unir, opcionalmente, para formar un sistema de anillos; i es 1-10, a condición de que cuando i es 1, R1 no es H, alquilo C1-4, alilo, alquenilo o -CN, R4 no es H o -CH3, R5, R6, R7 y R8 no son, independientemente, H o alquilo C1-5, L no es -(Doc)t-, X no es H, Cl, Br, I, F, -CN, o alquilo C1-5, o R9 y R10 no son, independientemente, H; m es 0 o 1; n es 0-10; p es 1-10; q es 1-5; s es 1-10; t es 1-10; Z es un ligando de un receptor de somatostatina, como mínimo; o una sal farmacéuticamente aceptable de los mismos; y donde cada sección encerrada entre paréntesis está, independientemente para cada ocurrencia, unida a un terminal N o un grupo de aminas interno o a un grupo hidroxilo de Z. Reivindicación 3: El análogo quimérico de la declaración 1, donde dicho análogo quimérico comprende la fórmula (2) donde: X es H, Cl, Br, I F, -CN, alquilo C1-10, heteroalquilo C1-10, alquenilo C2-10, alquinilo C2-10, alquilo C1-10 sustituido, heteroalquilo C1-10 sustituido, alquenilo C2-10 sustituido, o alquinilo C2-10 sustituido; R1 es H, alquilo C1-10, heteroalquilo C1-10, alquenilo C2-10, alquinilo C2-10, alquilo C1-10 sustituido, heteroalquilo C1-10 sustituido, alquenilo C2-10 sustituido o alquinilo C2-10 sustituido, o -CN; R2 y R3 son, independientemente, H o están ausentes, a condición de que cuando R2 y R3 está ausente existe un doble enlace entre los átomos de C a los cuales están unidos; R4 es H, alquilo C1-10, heteroalquilo C1-10, alquenilo C2-10, alquinilo C2-10, alquilo C1-10 sustituido, heteroalquilo C1-10 sustituido, alquenilo C2-10 sustituido, o alquinilo C2-10 sustituido; R5 es H, alquilo C1-10, heteroalquilo C1-10, alquenilo C2-10, alquinilo C2-10, alquilo C1-10 sustituido, heteroalquilo C1-10 sustituido, alquenilo C2-10 sustituido, alquinilo C2-10 sustituido, o un grupo de la fórmula (CH2)rN(R11,R12); Y es -O-, -C(O)-, -S-, -SC(O)-, -OC(O)-, -N(R6)-C(O)-, -N(R7)-, o -N(R8)-(CH2)s-C(O)-; L es -(CH2)p-C(O)-, cuando Y es -S-,-O- o -N(R7)-; o L es -C(O)-(CR9R10)q-C(O)-, cuando Y es -N(R7)-, -O- o -S-; o L es (aminoácido)t, cuando Y es -C(O)-, SC(O)-, -OC(O)-, N(R8)-(CH2)s-C(O)-, o -N(R6)-C(O); W es -CR9,R10-; R6, R7 y R8 son, independientemente, H, alquilo C1-10, alquilo C1-10 sustituido, heteroalquilo C1-10, heteroalquilo C1-10 sustituido, alquenilo C2-10, alquenilo C2-10 sustituido, alquinilo C2-10, alquinilo C2-10 sustituido, arilo, alquilarilo, o alquilarilo sustituido; R9 y R10 son, independientemente, H, Cl, Br, I, F, alquilo C1-10, alquilo C1-10 sustituido, heteroalquilo C1-10, heteroalquilo C1-10 sustituido, alquenilo C2-10, alquenilo C2-10 sustituido, alquinilo C2-10, alquinilo C2-10 sustituido, arilo, arilalquilo, o arilalquilo sustituido; R9 y R10 se pueden unir, opcionalmente, para formar un sistema de anillos; R11 y R122 son, independientemente, H, alquilo C1-10 sustituido, heteroalquilo C1-10, heteroalquilo C1-10 sustituido, alquenilo C2-10, alquenilo C2-10 sustituido, alquinilo C2-10, alquinilo C2-10 sustituido, arilo, alquilarilo, o alquilarilo sustituido; i es 1-10, a condición de que cuando i es 1, R1 no es H, alquilo C1-4,.alilo, alquenilo o -CN, R4 no es H o -CH3, R5 no es grupo alquilo C1-5 o un grupo de la fórmula -(CH2)rN(CH3)v, R6, R7, R8, R9 y R10 no son, independientemente, H o alquilo C1-5, L no es -(Doc)t-, o X no es H, Cl, Br, I, F, -CN, o alquilo C1-5; m es 0 o1; n es 2-10; p es 1-10; q es 1-5; r es 1-8; s es 1-10; t es 1-10; v es 2-4; Z es un ligando de un receptor de somatostatina, como mínimo; o una sal farmacéuticamente aceptable de los mismos; y donde cada sección encerrada entre paréntesis está, independientemente para cada ocurrencia, unida a un terminal N o un grupo de aminas interno o a un grupo hidroxilo de Z. Reivindicación 4: El análogo quimérico de la declaración 1, donde dicho análogo quimérico comprende la fórmula (3) donde R2 es -N(R11)N(R12,R13), -N(R6R7), o -COOH; R4 y R5 son, independientemente, H, alquilo C1-10, alquilo C1-10 sustituido, heteroalquilo C1-10, heteroalquilo C1-10 sustituido, alquenilo C2-10, alquenilo C2-10 sustituido, alquinilo C2-10, alquinilo C2-10 sustituido, arilo, arilalquilo, o arilalquilo sustituido o R8-C(O)-; W es -CR9R10 o (CH2)q-NH-(CH2)r-; R1, R6, R7, R8, R11, R12 y R13 son, independientemente, H, alquilo C1-10, alquilo C1-10 sustituido, heteroalquilo C1-10, heteroalquilo C1-10 sustituido, alquenilo C2-10, alquenilo C2-10 sustituido, alquinilo C2-10, alquinilo C2-10 sustituido, arilo, arilalquilo, o arilalquilo sustituido; R9 y R10 son, independientemente, H, -OH, -CN, -NO2,F, Cl, Br, I, alquilo C1-10, alquilo C1-10 sustituido, heteroalquilo C1-10, heteroalquilo C1-10 sustituido, alquenilo C2-10, alquenilo C2-10 sustituido, alquinilo C2-10, alquinilo C2-10 sustituido, alquilarilo, o alquilarilo sustituid, o arilo; X es alquilo c1-10, alquilo C1-10 sustituido, heteroalquilo c1-10, heteroalquilo C1-10 sustituido, alquenilo C2-10, alquenilo c2-10 sustituido, alquinilo C2-10, alquinilo C2-10 sustituido, alquilarilo, alquilarilo sustituido, arilo o acilo; Q es C o N; a condición de que cuando Q es N, R2 está ausente; i es 1-10; n es 1-6; q es 1-6; r es 1-8; Z es un ligando de un receptor de somatostatina, como mínimo; o una sal farmacéuticamente aceptable de los mismos, y donde cada sección encerrada entre paréntesis está, independientemente para cada ocurrencia, unida a un terminal N o un grupo de aminas interno o a un grupo hidroxilo de Z. Reivindicación 5: El análogo quimérico de la declaración 1, donde dicho análogo quimérico comprende la fórmula (4) donde R1 y R2 son, independientemente, H, alquilo C1-10, alquilo C1-10 sustituido; heteroalquilo C1-10, heteroalquilo C1-10 sustituido, alquenilo C2-10, alquenilo C2-10 sustituido, alquinilo C2-10, alquinilo C2-10 sustituido, arilo, alquilarilo, o alquilarilo sustituido; R3, R4, R5, R6 y R7 son, independientemente, H, -OH, -CN, NO2, F, Cl, Br, I, alquilo C1-10, alquilo C1-10 sustituido; heteroalquilo C1-10, heteroalquilo C1-10 sustituido, alquenilo C2-10, alquenilo C2-10 sustituido, alquinilo C2-10, alquinilo C2-10 sustituido, arilo, alquilarilo, o alquilarilo sustituido; W es -CR4R5-; Y es -(CR6R7)m-C(O)- o acilo; m es 0-10; n es 1-6; Z es un ligando de un receptor de somatostatina, como mínimo; o una sal farmacéuticamente aceptable de los mismos, y donde cada sección encerrada entre paréntesis está, independientemente para cada ocurrencia, unida a un terminal N o un grupo de aminas interno o a un grupo hidroxilo de Z. Reivindicación 6: El análogo quimérico de la declaración 1, donde dicho análogo quimérico comprende la fórmula (5), donde P es -N(R3R4)m o H, Y es N o S; W es -CR5R6-; Y es -(CR7R8)m-C(O)-; R1, R3 y R4 son, independientemente, H, alquilo C1-10, alquilo C1-10 sustituido, heteroalquilo C1-10, heteroalquilo C1-10 sustituido, alquenilo C2-10, alquenilo C2-10 sustituido, alquinilo C2-10, alquinilo C2-10 sustituido, arilo, alquilarilo, o alquilarilo sustituido; R2, R5, R6, R7 y R8 son independientemente, H, -OH, -CN, NO2, F, Cl, Br, I, alquilo C1-10, alquilo C1-10 sustituido; heteroalquilo C1-10, heteroalquilo C1-10 sustituido, alquenilo C2-10, alquenilo C2-10 sustituido, alquinilo C2-10, alquinilo C2-10 sustituido, arilo, alquilarilo, o alquilarilo sustituido; i es 1-10; m es 0-10; n es 0-6; -OH, -CN, NO2, F, Cl, Br, I, alquilo C1-10, alquilo C1-10 sustituido; heteroalquilo C1-10, heteroalquilo C1-10 sustituido, alquenilo C2-10, alquenilo C2-10 sustituido, alquinilo C2-10, alquinilo C2-10 sustituido, arilo, alquilarilo, o alquilarilo sustituido; i es 1-10; m es 0-10; n es 0-6, Z es un ligando de un receptor de somatostatina, como mínimo; o una sal farmacéuticamente aceptable de los mismos, y donde cada sección encerrada entre paréntesis está, independientemente para cada ocurrencia, unida a un terminal N o un grupo de aminas interno o a un grupo hidroxilo de Z. Reivindicación 7: El análogo quimérico de la declaración 1, donde dicho análogo quimérico comprende la fó
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