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AR110782A1 - Derivados de tirosinamida como inhibidores de rho-quinasa - Google Patents

Derivados de tirosinamida como inhibidores de rho-quinasa

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Publication number
AR110782A1
AR110782A1 ARP180100188A ARP180100188A AR110782A1 AR 110782 A1 AR110782 A1 AR 110782A1 AR P180100188 A ARP180100188 A AR P180100188A AR P180100188 A ARP180100188 A AR P180100188A AR 110782 A1 AR110782 A1 AR 110782A1
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AR
Argentina
Prior art keywords
alkyl
aryl
heteroaryl
heterocycloalkyl
alkoxy
Prior art date
Application number
ARP180100188A
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English (en)
Inventor
Arnaud Jean Francois Auguste Cheguillaume
Gurdip Bhalay
Patrizia Tisselli
David Edward Clark
Alessandro Accetta
Christine Edwards
Anna Maria Capelli
Fabio Rancati
Original Assignee
Chiesi Farm Spa
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Publication date
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Publication of AR110782A1 publication Critical patent/AR110782A1/es

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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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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
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
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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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
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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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • 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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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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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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Abstract

Compuestos de fórmula (1) inhibidores de la rho-quinasa, que son derivados de tirosinamida, métodos para preparar dichos compuestos, composiciones farmacéuticas que los contienen y el uso terapéutico de los mismos. Dichos compuestos pueden ser útiles en el tratamiento de numerosos trastornos asociados con mecanismos relacionados con las enzimas ROCK, como por ejemplo enfermedades pulmonares que incluyen asma, enfermedad pulmonar obstructiva crónica (EPOC), fibrosis pulmonar idiopática (IPF) e hipertensión arterial pulmonar (PAH). Reivindicación 1: Un compuesto caracterizado porque es de fórmula (1), donde X¹, y X² son en cada caso independientemente un grupo CH o un átomo de nitrógeno; p es cero o un entero entre 1 y 3; cada R, cuando está presente, es un halógeno; R⁰ y R¹ se seleccionan independientemente entre el grupo que consiste en -H, halógeno, -NR⁷R⁸, -CN, C₁₋₆ alquilo, C₁₋₆ haloalquilo, C₁₋₆ hidroxialquilo, C₁₋₆ aminoalquilo, C₁₋₆ alcoxi-C₁₋₆ alquilo, C₃₋₁₀ cicloalquilo, C₂₋₆ alquenilo, C₅₋₇ cicloalquenilo, C₂₋₆ alquinilo, C₂₋₆ hidroxialquinilo, arilo, heteroarilo y C₃₋₆ heterocicloalquilo donde cada uno de dichos arilo, heteroarilo y C₃₋₆ heterocicloalquilo está a su vez opcionalmente e independientemente sustituido con uno o más grupos seleccionados entre halógeno, -OH, -CN, -NR⁷R⁸, -CH₂NR⁷R⁸, C₁₋₆ alquilo, C₁₋₆ haloalquilo, C₁₋₆ hidroxialquilo, C₂₋₆ alquenilo, C₂₋₆ alquinilo, C₂₋₆ hidroxialquinilo; R² y R³, que son iguales o diferentes, se seleccionan entre el grupo que consiste en -H, C₁₋₆ alquilo, C₁₋₆ haloalquilo, C₁₋₆ hidroxialquilo, C₁₋₆ aminoalquilo, C₁₋₆ alcoxi-C₁₋₆ alquilo, C₃₋₁₀ cicloalquilo, C₃₋₈ heterocicloalquilo, arilo, heteroarilo, aril-C₁₋₆ alquilo, heteroaril-C₁₋₆ alquilo, C₃₋₈ cicloalquil-C₁₋₆ alquilo, C₃₋₈ heterocicloalquil-C₁₋₆ alquilo, cada uno de dichos arilo, heteroarilo, cicloalquilo, heterocicloalquilo está opcionalmente sustituido a su vez con uno o más grupos seleccionados en forma independiente entre halógeno, -CN, -OH, C₁₋₈ alquilo, C₁₋₆ haloalquilo, C₁₋₁₀ alcoxi, arilo, aril-C₁₋₆ alquilo, carbamoílo, C₁₋₆ aminoalquilo, C₁₋₆ hidroxialquilo; o R² y R³, en la alternativa, tomados junto con el átomo de nitrógeno al cual están unidos, para formar un radical mono o bicíclico saturado o heterocíclico parcialmente saturado, preferentemente un radical monocíclico de 4 a 6 miembros, donde al menos un átomo de carbono adicional del anillo en dicho radical heterocíclico está opcionalmente reemplazado con al menos un heteroátomo adicional seleccionado de forma independiente entre N, S ó O y/o o puede tener un grupo sustituyente -oxo (=O), donde dicho radical heterocíclico incluye además opcionalmente disustitución espiro así como también sustitución en dos átomos adyacentes o vecinos formando un anillo saturado, parcialmente saturado o aromático, cíclico o heterocíclico de 5 a 6 miembros adicional; estando dicho radical heterocíclico a su vez opcionalmente sustituido con uno o más grupos seleccionados entre el grupo que consiste en halógeno, hidroxilo, -NR⁷R⁸, -CH₂NR⁷R⁸, C₁₋₆ alquilo, C₁₋₆ haloalquilo, C₁₋₆ hidroxialquilo, C₂₋₆ alquenilo, C₂₋₆ alquinilo, C₂₋₆ hidroxialquinilo, C₁₋₆ alcoxi-C₁₋₆ alquilo, C₁₋₆ alcanoilo, carbamoílo, C₃₋₆ cicloalquil-carbonilo, C₃₋₆ heterocicloalquil-carbonilo, aril-C₁₋₆ alquilo, arilalcanoilo, arilsulfonilo, heteroaril-C₁₋₆ alquilo, heteroaril-carbonilo, heteroariloxilo, C₃₋₆ cicloalquilo, C₃₋₈ cicloalquil-C₁₋₆ alquilo, C₃₋₆ heterocicloalquil-C₁₋₆ alquilo, arilo y heteroarilo donde cada uno de dichos cicloalquilo, arilo y heteroarilo está opcionalmente sustituido con halógeno, C₁₋₈ alquilo, C₁₋₁₀ alcoxi, C₁₋₆ alquiltio, C₁₋₆ aminoalquilo, C₁₋₆ aminoalcoxilo, carbamoílo, C₁₋₆ alquil-sulfonilo; R⁴ y R⁵ se seleccionan en forma independiente en cada caso del grupo que consiste en H, C₁₋₆ alquilo, C₁₋₆ haloalquilo, C₁₋₆ hidroxialquilo, C₁₋₆ aminoalquilo, C₁₋₆ alcoxilo, C₁₋₆ alcoxi-C₁₋₆ alquilo, C₃₋₆ cicloalquil-C₁₋₆ alquilo, C₃₋₆ heterocicloalquil-C₁₋₆ alquilo, C₃₋₆ cicloalquil-carbonilo, C₃₋₆ heterocicloalquil-carbonilo, arilo, heteroarilo y C₃₋₆ heterocicloalquilo; donde cualquiera de dichos C₃₋₆ cicloalquilo, arilo, heteroarilo y C₃₋₆ heterocicloalquilo a su vez está opcionalmente e independientemente sustituido con uno o más grupos seleccionados entre halógeno, -OH, C₁₋₆ alquilo; R⁶ se selecciona entre el grupo que consiste en -H, C₁₋₆ alquilo, C₁₋₆ haloalquilo; R⁷ y R⁸ se seleccionan en forma independiente en cada caso del grupo H, C₁₋₆ alquilo, C₁₋₆ haloalquilo, C₁₋₆ hidroxialquilo, C₁₋₆ aminoalquilo, C₁₋₆ alcoxilo, C₁₋₆ alcoxi-C₁₋₆ alquilo, C₃₋₆ heterocicloalquil-C₁₋₆ alquilo, arilo, heteroarilo y C₃₋₆ heterocicloalquilo; donde cualquiera de dichos arilo, heteroarilo y C₃₋₆ heterocicloalquilo a su vez está opcionalmente e independientemente sustituido con uno o más grupos seleccionados entre halógeno, -OH, C₁₋₆ alquilo; o R⁷ y R⁸ se toman junto con el átomo de nitrógeno al cual están unidos, para formar un radical heterocíclico de 4 a 6 miembros, donde al menos un átomo de carbono adicional del anillo en dicho radical heterocíclico puede estar reemplazado por al menos un grupo seleccionado entre N, S ó O; donde dicho radical heterocíclico puede estar opcionalmente sustituido con un grupo seleccionado entre H, -CN, halógeno, -oxo, -NR⁷R⁸, C₁₋₆ alquilo, C₁₋₆ haloalquilo, C₁₋₆ hidroxialquilo, C₁₋₆ aminoalquilo, C₁₋₆ alcoxilo, C₁₋₆ alcoxi-C₁₋₆ alquilo, alcanoilo; o sus sales aceptables farmacéuticamente y solvatos.
ARP180100188A 2017-01-30 2018-01-26 Derivados de tirosinamida como inhibidores de rho-quinasa AR110782A1 (es)

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