AR092108A1 - Piridazina 1,4 disustituida, analogos de la misma y metodos para tratar las enfermedades relacionadas con deficiencia del smn - Google Patents

Piridazina 1,4 disustituida, analogos de la misma y metodos para tratar las enfermedades relacionadas con deficiencia del smn

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AR092108A1
AR092108A1 ARP130102863A ARP130102863A AR092108A1 AR 092108 A1 AR092108 A1 AR 092108A1 AR P130102863 A ARP130102863 A AR P130102863A AR P130102863 A ARP130102863 A AR P130102863A AR 092108 A1 AR092108 A1 AR 092108A1
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AR
Argentina
Prior art keywords
alkyl
substituted
independently selected
alkoxy
mono
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ARP130102863A
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English (en)
Inventor
Noel Chin Donovan
Dales Natalie
Fazal Aleem
Brian Hurley Timothy
Kerrigan John
Obrien Gary
Shu Lei
Sung Moo
Kim Cheung Atwood
Sun Robert
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Novartis Ag
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Application filed by Novartis Ag filed Critical Novartis Ag
Publication of AR092108A1 publication Critical patent/AR092108A1/es

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    • A61K31/50—Pyridazines; Hydrogenated pyridazines
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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Abstract

El presente proporciona una combinación de agentes farmacológicamente activos y una composición farmacéutica. Reivindicación 1: Un compuesto o sal del mismo según la fórmula (1), A es 2-hidroxi-fenilo que se sustituye por 0, 1, 2, ó 3 sustituyentes seleccionados independientemente a partir de alquilo C₁₋₄, en donde 2 grupos alquilo C₁₋₄ pueden combinarse con los átomos a los que están unidos para formar un anillo de 5 - 6 miembros y se sustituye por 0 ó 1 sustituyentes seleccionados a partir de oxo, oxima e hidroxilo, haloalquilo C₁₋₄, dihaloalquilo C₁₋₄, trihaloalquilo C₁₋₄, alcoxilo C₁₋₄, alcoxi C₁₋₄-cicloalquilo C₃₋₇, haloalcoxilo C₁₋₄, dihaloalcoxilo C₁₋₄, trihaloalcoxilo C₁₋₄, hidroxilo, ciano, halógeno, amino, mono- y di-alquil C₁₋₄amino, heteroarilo, alquilo C₁₋₄ sustituido por hidroxilo, alcoxilo C₁₋₄ sustituido por arilo, amino, -C(O)NH-alquilo C₁₋₄-heteroarilo, -NHC(O)-heteroarilo-alquilo C₁₋₄-, alquilo C₁₋₄C₍O₎NH₋ₕₑₜₑʳₒₐʳⁱₗₒ, ₐₗqᵘⁱₗₒ C₁₋₄NHC(O)-heteroarilo, cicloalquilo de 3 - 7 miembros, cicloalquenilo de 5 - 7 miembros o heterociclo de 5, 6 ó 9 miembros que contiene 1 ó 2 heteroátomos independientemente seleccionados a partir de S, O y N, en donde heteroarilo tiene 5, 6 ó 9 átomos de anillo, 1, 2 ó 3 heteroátomos de anillo seleccionados a partir de N, O y S y sustituido por 0, 1, ó 2 sustituyentes seleccionados independientemente a partir de oxo, hidroxilo, nitro, halógeno, alquilo C₁₋₄, alquenilo C₁₋₄, alcoxilo C₁₋₄, cicloalquilo C₃₋₇, alquil C₁₋₄-OH, trihaloalquilo C₁₋₄, mono- y di-alquil C₁₋₄amino, -C(O)NH₂, -NH₂, -NO₂, hidroxi-alquil C₁₋₄amino, hidroxialquilo C₁₋₄, heterocicloalquilo C₁₋₄ de 4 - 7 miembros, aminoalquilo C₁₋₄ y mono- y di-alquil C₁₋₄aminoalquilo C₁₋₄; o A es 2-naftilo opcionalmente sustituido en la posición 3 por hidroxilo y adicionalmente sustituido por 0, 1, ó 2 sustituyentes seleccionados a partir de hidroxilo, ciano, halógeno, alquilo C₁₋₄, alquenilo C₂₋₄, alcoxilo C₁₋₅, en donde el alcoxilo no es sustituido o se sustituye por hidroxilo, alcoxilo C₁₋₄, amino, N(H)C(O)alquilo C₁₋₄, N(H)C(O)₂alquilo C₁₋₄, alquileno heterociclo de 4 a 7 miembros, heterociclo de 4 a 7 miembros y mono- y di-alquil C₁₋₄amino; o A es heteroarilo de 6 miembros que tiene 1 - 3 átomos de nitrógeno de anillo, tal heteroarilo de 6 miembros es sustituido por fenilo o un heteroarilo que tiene 5 ó 6 átomos de anillo, 1 ó 2 heteroátomos de anillo seleccionados independientemente a partir de N, O y S y sustituido por 0, 1, ó 2 sustituyentes seleccionados independientemente a partir de alquilo C₁₋₄, mono- y di-alquil C₁₋₄amino, hidroxi-alquil C₁₋₄amino, hidroxialquilo C₁₋₄, aminoalquilo C₁₋₄ y mono- y di-alquil C₁₋₄amino-alquilo C₁₋₄; o A es heteroarilo bicíclico que tiene 9 a 10 átomos de anillo, y 1, 2, ó 3 heteroátomos de anillo seleccionados independientemente a partir de N, O ó S, tal heteroarilo bicíclico se sustituye por 0, 1, ó 2 sustituyentes seleccionados independientemente a partir de ciano, halógeno, hidroxilo, alquilo C₁₋₄, alquenilo C₂₋₄, alquinilo C₂₋₄, alcoxilo C₁₋₄ y alcoxilo C₁₋₄ sustituido por hidroxilo, alcoxilo C₁₋₄, amino y mono- y di-alquil C₁₋₄amino; o A es heteroarilo tricíclico que tiene 12 ó 13 átomos de anillo, y 1, 2, ó 3 heteroátomos de anillo seleccionados independientemente a partir de N, O ó S, tal heteroarilo tricíclico se sustituye por 0, 1, ó 2 sustituyentes seleccionados independientemente a partir de ciano, halógeno, hidroxilo, alquilo C₁₋₄, alquenilo C₂₋₄, alquinilo C₂₋₄, alcoxilo C₁₋₄, alcoxilo C₁₋₄ sustituido por hidroxilo, alcoxilo C₁₋₄, amino, mono- y di-alquil C₁₋₄amino y heteroarilo, en donde dicho heteroarilo tiene 5, 6 ó 9 átomos de anillo, 1, 2 ó 3 heteroátomos de anillo seleccionados a partir de N, O y S y sustituido por 0, 1, ó 2 sustituyentes seleccionados independientemente a partir de oxo, hidroxilo, nitro, halógeno, alquilo C₁₋₄, alquenilo C₁₋₄, alcoxilo C₁₋₄, cicloalquilo C₃₋₇, alquil C₁₋₄-OH, trihaloalquilo C₁₋₄, mono- y di-alquil C₁₋₄amino, -C(O)NH₂, -NH₂, -NO₂, hidroxi-alquil C₁₋₄amino, hidroxialquilo C₁₋₄, heterocicloalquilo C₁₋₄ de 4 - 7 miembros, aminoalquilo C₁₋₄ y mono- y di-alquil C₁₋₄aminoalquilo C₁₋₄; B es un grupo de la fórmula (2), en donde m, n y p son independientemente seleccionados a partir de 0 ó 1; R, R¹, R², R³, y R⁴ son independientemente seleccionados a partir del grupo que consta de hidrógeno, alquilo C₁₋₄, tal alquilo se sustituye opcionalmente por hidroxilo, amino o mono- y di-alquil C₁₋₄amino; R⁵ y R⁶ son independientemente seleccionados a partir de hidrógeno y flúor; o R y R³, tomados en combinación forman un anillo heterocíclico condensado de 5 ó 6 miembros que tiene 0 ó 1 heteroátomos adicionales de anillo seleccionados a partir de N, O ó S; R¹ y R³, tomados en combinación forman un grupo alquileno C₁₋₃; R¹ y R⁵, tomados en combinación forman un grupo alquileno C₁₋₃; R³ y R⁴, tomados en combinación con el átomo de carbono al que están unidos, forman un cicloalquilo C₃₋₆ espirocíclico; X es CRARB, O, NR⁷ o un enlace; R⁷ es hidrógeno, o alquilo C₁₋₄; RA y RB son independientemente seleccionados a partir de hidrógeno y alquilo C₁₋₄, o RA y RB, tomados en combinación, forman un grupo alquileno C₂₋₅ divalente; Z es CR⁸ o N; cuando Z es N, X es un enlace; R⁸ es hidrógeno o tomados en combinación con R⁶ forman un enlace doble; o B es un grupo de la fórmula (3), en donde p y q son independientemente seleccionados a partir del grupo que consta de 0, 1, y 2; R⁹ y R¹³ son independientemente seleccionados a partir de hidrógeno y alquilo C₁₋₄; R¹⁰ y R¹⁴ son independientemente seleccionados a partir de hidrógeno, amino, mono- y di-alquil C₁₋₄amino y alquilo C₁₋₄, tal alquilo se sustituye opcionalmente por hidroxilo, amino o mono- y di-alquil C₁₋₄amino; R¹¹ es hidrógeno, alquilo C₁₋₄, amino o mono- y di-alquil C₁₋₄amino; R¹² es hidrógeno o alquilo C₁₋₄; o R⁹ y R¹¹, tomados en combinación forman un azaciclo saturado que tiene 4 a 7 átomos de anillo, el cual es opcionalmente sustituido por 1 - 3 grupos alquilo C₁₋₄; o R¹¹ y R¹², tomados en combinación forman un azaciclo saturado que tiene 4 a 7 átomos de anillo, el cual es opcionalmente sustituido por 1 - 3 grupos alquilo C₁₋₄.
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