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AR066887A1 - Agentes antihipertensivos de benzoimidazol de accion dual - Google Patents

Agentes antihipertensivos de benzoimidazol de accion dual

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Publication number
AR066887A1
AR066887A1 ARP080102406A ARP080102406A AR066887A1 AR 066887 A1 AR066887 A1 AR 066887A1 AR P080102406 A ARP080102406 A AR P080102406A AR P080102406 A ARP080102406 A AR P080102406A AR 066887 A1 AR066887 A1 AR 066887A1
Authority
AR
Argentina
Prior art keywords
alkyl
alkylene
cycloalkyl
aryl
alkylenearyl
Prior art date
Application number
ARP080102406A
Other languages
English (en)
Inventor
Paul Allegretti
Seok-Ki Choi
Darren Mcmurtrie
Paul R Fatheree
Roland Gendron
Robert Murray Mckinnell
Ryan Hudson
Keith Jendza
Original Assignee
Theravance Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Theravance Inc filed Critical Theravance Inc
Publication of AR066887A1 publication Critical patent/AR066887A1/es

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    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/535—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Estos compuestos tienen una actividad antagonista del receptor AT1 y una actividad inhibidora de neprilisina. La invencion también se refiere a intermediarios para preparar tales compuestos y métodos de preparacion del compuesto. Reivindicacion 1: Un compuesto de la formula 1: caracterizado porque: r es 0, 1 o 2; Ar es un grupo arilo seleccionado del grupo de formulas (2): R1 está seleccionado de -COOR1a, -NHSO2R1b, -SO2NHR1d, -SO2OH, -C(O)NH-SO2R1c, -P(O)(OH)2, -CN, -OCH(R1e)-COOH, tetrazol-5-ilo, y el grupo de formulas (3) R1a es H, -alquilo C1-6, -alquilenarilo C1-3, -alquilenheteroarilo C1-3, -cicloalquilo C3-7, -CH(alquil C1-4)OC(O)R1aa, -alquilen C0-6-morfolina, y el grupo de formulas (4)R1aa es -O-alquilo C1-6, -O-cicloalquilo C3-7, -NR1abR1ac o -CH(NH2)CH2COOCH3; R1ab y R1ac están seleccionados, de modo independiente, de H, -alquilo C1-6 y bencilo o se toman juntos como -(CH2)3-6-; R1b es R1c o -NHC(O)R1c; R1c es -alquilo C1-6, -alquilen C0-6-O-R1ca, -alquilen C1-5-NR1cbR1cc, -alquilenarilo C0-4 o -alquilenheteroarilo C0-4; R1ca es H, -alquilo C1-6 o -alquilen C1-6-O-alquilo C1-6; R1cb y R1cc están seleccionados, de modo independiente, de H y -alquilo C1-6 o se toman juntos como -(CH2)2-O-(CH2)2- o -(CH2)2-N[C(O)CH3]-(CH2)2-; R1d es H, R1c, -C(O)R1c o -C(O)NHR1c; R1e es -alquilo C1-4 o arilo; n es 0, 1, 2 o 3; cada R2 está seleccionado, de modo independiente, de halo, -NO2, -alquilo C1-6, -alquenilo C2-6, -cicloalquilo C3-6, -CN, -C(O)R2a, -alquilen C0-5- OR2b, -alquilen C0-5-NR2CR2d, -alquilenarilo C0-3 y -alquilenheteroarilo C0-3; donde R2a está seleccionado de H, -alquilo C1-6, -cicloalquilo C3-6, -OR2b y -NR2cR2d; R2b está seleccionado de H, -alquilo C1-6, -cicloalquilo C3-6 y -alquilenarilo C0-1; y R2c y R2d están seleccionados, de modo independiente, de H, -alquilo C1-4 y -alquilenarilo C0-1; R3 está seleccionado de -alquilo C1-10, -alquenilo C2-10, -alquinilo C3-10, -alquilen C0-3-cicloalquilo C3-7, -alquenilen C2-3-cicloalquilo C3-7, -alquinilen C2-3-cicloalquilo C3-7, -alquilen C0-5-NR3a-alquilen C0-5-R3b, -alquilen C0-5-O-alquilen C0-5-R3b, -alquilen C0-5-S-alquilen C1-5-R3b y -alquilenarilo C0-3; donde R3a está seleccionado de H, -alquilo C1-6, -cicloalquilo C3-7 y -alquilenarilo C0-3 y R3b está seleccionado de H, -alquilo C1-6, -cicloalquilo C3-7, -alquenilo C2-4, -alquinilo C2-4 y arilo; X es -alquileno C1-12-, donde al menos un resto -CH2- en el alquileno está reemplazado con un resto -NR4a-C(O)- o -C(O)-NR4a-, donde R4a está seleccionado de H, -OH y -alquilo C1-4; R5 está seleccionado de -alquilen C0-3-SR5a, -alquilen C0-3- C(O)NR5bR5c, -alquilen C0-3-NR5b-C(O)R5d, -NH-alquilen C0-1-P(O)(OR5e)2, -alquilen C0-3-P(O)OR5eR5f, -alquilen C0-2-CHR5g-COOH, -alquilen C0-3, C(O)NR5h-CHR5i-COOH y -alquilen C0-3-S-SR5j donde R5a es H o -C(O)-R5aa; R5aa es -alquilo C1-6, -alquilen C0-6-cicloalquilo C3-7, -aminocicloalquilo C4-7, -alquilenarilo C0-6, -alquilenheteroarilo C0-6, -alquilen C0-6-morfolina, -alquilen C0-6-piperazin-CH3, -alquilen C0-6-piperidina, -alquilen C0-6-piperidin-CH3, -CH[N(R5ab)2]-aa, donde aa es una cadena lateral de aminoácido, -alquilen C0-6-CH[N(R5ab)2]-R5ac, -2-pirrolidina, -2-tetrahidrofurano, -alquilen C0-6-OR5ab, -O-alquilenarilo C0-6, -alquilen C1-2-OC(O)-alquilo C1-6, -alquilen C1-2-OC(O)-alquilenarilo C0-6, -O-alquilen C1-2- OC(O)O-alquilo C1-6, -alquilen C-4COOH o -arilen-COOH; R5ab es, de modo independiente, H o -alquilo C1-6; R5ac es H, -alquilo C1-6, -CH2-cicloalquilo C3-7 o -COOH; R5b está seleccionado de H, -OH, -OC(O)R5ba, -CH2COOH, -O- bencilo, -piridilo u -OC(S)NR5bbR5bc; R5ba es H, -alquilo C1-6, arilo, -OCH2-arilo, -CH2O-arilo o -NR5bbR5bc; R5bb y R5bc están seleccionados, de modo independiente, de H y -alquilo C1-4; R5c es H, -alquilo C1-6 o -C(O)R5ca; R5ca es -alquilo C1-6, -cicloalquilo C3-7, arilo o heteroarilo; R5d es H, -alquilo C1-4, -alquilenarilo C0-3, -NR5daR5db, -CH2SH u -O-alquilo C1-6; R5da y R5db están seleccionados, de modo independiente, de H y -alquilo C1-4 R5e es H, -alquilo C1-6, -alquilenarilo C1-3, -alquilenheteroarilo C1-3, -cicloalquilo C3-7, -CH(CH3)OC(O)R5ea, y el grupo de formulas (5) R5ea es -O-alquilo C1-6, -O-cicloalquilo C3-7, -NR5ebR5ec o -CH(NH2)CH2COOCH3; R5eb y R5ec están seleccionados, de modo independiente, de H, -alquilo C1-4 y -alquilenarilo C1-3 o se toman juntos como -(CH2)-3-6; R5f está seleccionado de H, -alquilo C1-4, -alquilenarilo C0-3, -alquilen C1-3-NR5faR5fb y -alquilen C1-3(aril)-alquilen C0-3-NR5faR5fb; R5fa y R5fb están seleccionados, de modo independiente, de H y -alquilo C1-4: R5g es H, -alquilo C1-6, -alquilenarilo C1-3 o -CH2-O-(CH2)2-OCH3; R5h es H o -alquilo C1-4 R5i es H, -alquilo C1-4 o -alquilenarilo C0-3; y R5j es -alquilo C1-6, arilo o -CH2CH(NH2)COOH; R6 está seleccionado de -alquilo C1-6, -CH2O(CH2)2OCH3, -alquilen C1-6-O-alquilo C1-6, -alquilenarilo C0-3, -alquilenheteroarilo C0-3 y -alquilen C0-3-cicloalquilo C3-7 y R7 es H o se toma junto con R6 para formar -cicloalquilo C3-8 en donde: cada grupo -CH2- en -(CH2)r- está opcionalmente sustituido con 1 o 2 sustituyentes seleccionados, de modo independiente, de -alquilo C1-4 y fluoro; cada átomo de carbono en el resto alquileno en X está opcionalmente sustituido con uno o varios grupos R4b y un resto -CH2- en X puede estar reemplazado por un grupo seleccionado de -cicloalquileno C4-8, -CR4d=CH- y -CH=CR4d-; en donde R4b está seleccionado de -alquilen C0-5-COOR4c, -alquilo C1-6, -alquilen C0-1-CONH2, -alquilen C1-2-OH, -alquilen C0-3-cicloalquilo C3-7, 1H-indol-3-ilo, bencilo e hidroxibencilo; R4c es H o -alquilo C1-4 y R4d está seleccionado de -CH2-tiofeno y fenilo; cada alquilo y cada arilo en R1-3, R4a-4d y R5-6 está opcionalmente sustituido con 1 a 7 átomos de fluor; cada anillo en Ar y cada arilo y heteroarilo en R1-3 y R5-6 está opcionalmente sustituido con 1 a 3 sustituyentes seleccionados, de modo independiente, de -OH, -alquilo C1-6, -alquenilo C2-4, -alquinilo C2-4, -CN, halo, -O-alquilo C1-6, -S-alquilo C1-6, -S(O)-alquilo C1-6, -S(O)2-alquilo C1-4, -fenilo, -NO2, -NH2, -NH-alquilo C1-6 y -N(alquilo C1-6) 2 en donde cada alquilo, alquenilo y alquinilo está opcionalmente sustituido con 1 a 5 átomos de fluor; y sus sales farmacéuticamente aceptables.
ARP080102406A 2007-06-05 2008-06-05 Agentes antihipertensivos de benzoimidazol de accion dual AR066887A1 (es)

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US (2) US8637676B2 (es)
EP (1) EP2162442B1 (es)
JP (1) JP2010529121A (es)
CN (1) CN101675036B (es)
AR (1) AR066887A1 (es)
CA (1) CA2684886A1 (es)
CL (1) CL2008001636A1 (es)
ES (1) ES2401677T3 (es)
TW (1) TWI406850B (es)
WO (1) WO2008153857A1 (es)

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JP2010529121A (ja) 2010-08-26
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US9198899B2 (en) 2015-12-01
CN101675036A (zh) 2010-03-17
CL2008001636A1 (es) 2008-11-03
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US8637676B2 (en) 2014-01-28
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