AR088023A1 - COMPUESTOS CON ACTIVIDAD ANTAGONISTA DE LOS RECEPTORES MUSCARINICOS Y ACTIVIDAD AGONISTA DEL RECEPTOR b2 ADRENERGICO - Google Patents

COMPUESTOS CON ACTIVIDAD ANTAGONISTA DE LOS RECEPTORES MUSCARINICOS Y ACTIVIDAD AGONISTA DEL RECEPTOR b2 ADRENERGICO

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AR088023A1
AR088023A1 ARP120102064A ARP120102064A AR088023A1 AR 088023 A1 AR088023 A1 AR 088023A1 AR P120102064 A ARP120102064 A AR P120102064A AR P120102064 A ARP120102064 A AR P120102064A AR 088023 A1 AR088023 A1 AR 088023A1
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Argentina
Prior art keywords
alkyl
group
cycloalkyl
heteroaryl
absent
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ARP120102064A
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English (en)
Inventor
Rizzi Andrea
Amari Gabriele
Biagetti Matteo
Linney Ian
Rancati Fabio
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Chiesi Farma Spa
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Publication of AR088023A1 publication Critical patent/AR088023A1/es

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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
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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
    • A61K31/439—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
    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • A—HUMAN NECESSITIES
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/10—Separation; Purification; Stabilisation; Use of additives
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
    • C07C215/50—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22—Bridged ring systems

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

Compuestos que actúan como antagonistas de los receptores muscarínicos a la vez que como agonistas del receptor b2 adrenérgico, procesos para su preparación, composiciones que los comprenden, usos terapéuticos y combinaciones con otros ingredientes farmacéuticamente activos. Útiles para asma, bronquitis crónica o enfermedad pulmonar obstructiva crónica (COPD). Reivindicación 1: Un compuesto caracterizado porque es de fórmula general (1) donde Q es un grupo seleccionado del grupo de fórmulas (2); Z es H o OH; Y se selecciona entre los grupos divalentes de fórmula (3) ó (4), donde A¹ y A² en forma independiente están ausentes o se seleccionan entre el grupo que consiste en alquileno C₁₋₁₂, cicloalquileno C₃₋₈ y heterocicloalquileno C₃₋₈ opcionalmente sustituido con uno o más sustituyentes seleccionados entre el grupo que consiste en alquilo C₁₋₆, arilalquilo C₁₋₆ y heteroarilalquilo C₁₋₆; B se encuentra ausente o se selecciona entre el grupo que consiste en cicloalquileno C₃₋₈, heterocicloalquileno C₃₋₈, arileno, heteroarileno o es un grupo de fórmula (5) opcionalmente sustituido con uno o más grupos seleccionados entre halógenos, nitrilo, alquilo C₁₋₆, alcoxi C₁₋₆ y arilalquilo C₁₋₆; C se encuentra ausente o se selecciona entre el grupo que consiste en -O-, -CO-, -OC(O)-, -C(OO)-, -S-, -S(O)-, -S(O)₂-, -N(R⁷)-, -N(CO)R⁷-, -N(CO)NHR⁷-, -N(SO₂)R⁷- o es uno de los restos del grupo de formulas (6), donde R⁷ es H o se selecciona entre el grupo que consiste en alquilo C₁₋₈ lineal o ramificado, cicloalquilo C₃₋₈, heterocicloalquilo C₃₋₈, arilo, arilalquilo C₁₋₆, alcoxi C₁₋₆alquilo C₁₋₆ y heteroarilo y R⁸ es alcoxi C₁₋₈carbonilo; D se encuentra ausente o se selecciona entre el grupo que consiste en alquileno C₁₋₁₂, -C(CH₃)₂-, arileno, alquenileno C₂₋₁₂, heteroarileno, heterocicloalquileno C₃₋₈ y alquinileno C₂₋₆; n es 0 o un entero entre 1 y 3; E se encuentra ausente o se selecciona entre -O-, -NR⁷-, -OC(O)- y -S-; G es arileno o heteroarileno, opcionalmente sustituido con uno o más sustituyentes seleccionados entre el grupo que consiste en átomos de halógeno, -OH, oxo (=O), -SH, -NO₂, -CN, -CON(R⁶)₂, -NH₂, -NHCOR⁶, -CO₂R⁶, alquil C₁₋₁₀sulfanilo, alquil C₁₋₁₀sulfinilo, alquil C₁₋₁₀sulfonilo, alquilo C₁₋₁₀, arilo, haloarilo, heteroarilo y alcoxi C₁₋₁₀; R¹ y R² son en forma independiente H o se seleccionan entre el grupo que consiste en alquilo C₁₋₈, cicloalquilo C₃₋₈, heterocicloalquilo C₃₋₈, arilo, heteroarilo, arilalquilo C₁₋₆, heteroarilalquilo C₁₋₆ y cicloalquil C₃₋₈alquilo C₁₋₆, opcionalmente sustituido con uno o más átomos de halógeno o grupos alquilo C₁₋₈ o, tomados junto con el átomo de carbono al cual están unidos, R¹ y R² pueden formar un cicloalquilo C₃₋₈, donde R¹ y R² no son simultáneamente H; M es -O- o -N(R³)-; R³ es H o se selecciona entre el grupo que consiste en alquilo C₁₋₈, cicloalquilo C₃₋₈, arilo y heteroarilo; R⁴ es un resto seleccionado del grupo de fórmula (7); R⁵ es un grupo de fórmula (8), donde p es 0 o un entero entre 1 y 4; q es 0 o un entero entre 1 y 4; P se encuentra ausente o se selecciona entre un grupo divalente seleccionado entre O, S, SO, SO₂, CO, NR⁶, CH=CH, N(R⁶)SO₂, N(R⁶)COO, N(R⁶)C(O), SO₂N(R⁶), CO(O)N(R⁶) y C(O)N(R⁶); W se selecciona entre el grupo que consiste en H, alquilo C₁₋₆, cicloalquilo C₃₋₈, arilo y heteroarilo, opcionalmente sustituido con uno o más sustituyentes seleccionados entre el grupo que consiste en átomos de halógeno, -OH, oxo (=O), -SH, -NO₂, -CN, -CON(R⁶)₂, -NH₂, -NHCOR⁶, -CO₂R⁶, alquil C₁₋₁₀sulfanilo, alquil C₁₋₁₀sulfinilo, alquil C₁₋₁₀sulfonilo, alquilo C₁₋₁₀ y alcoxi C₁₋₁₀; X⁻ es un anión fisiológicamente aceptable; R⁶ es H o se selecciona entre el grupo que consiste en alquilo C₁₋₁₀, haloalquilo C₁₋₆, alquinilo C₂₋₆, alquenilo C₂₋₆, cicloalquilo C₃₋₈, cicloalquil C₃₋₈alquilo C₁₋₆, heteroarilo y arilo opcionalmente sustituido con uno o más sustituyentes seleccionados entre el grupo que consiste en átomos de halógeno, -OH, oxo (=O), -SH, -NO₂, -CN, -CONH₂, -COOH, alcoxi C₁₋₁₀carbonilo, alquil C₁₋₁₀sulfanilo, alquil C₁₋₁₀sulfinilo, alquil C₁₋₁₀sulfonilo, alquilo C₁₋₁₀ y alcoxi C₁₋₁₀; y sales aceptables farmacéuticamente o solvatos del mismo.
ARP120102064A 2011-06-10 2012-06-08 COMPUESTOS CON ACTIVIDAD ANTAGONISTA DE LOS RECEPTORES MUSCARINICOS Y ACTIVIDAD AGONISTA DEL RECEPTOR b2 ADRENERGICO AR088023A1 (es)

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EP11169537 2011-06-10
EP12165283 2012-04-24

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