AR091981A1 - Dihidropiridona p1 como inhibidores del factor xia - Google Patents

Dihidropiridona p1 como inhibidores del factor xia

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Publication number
AR091981A1
AR091981A1 ARP130102764A ARP130102764A AR091981A1 AR 091981 A1 AR091981 A1 AR 091981A1 AR P130102764 A ARP130102764 A AR P130102764A AR P130102764 A ARP130102764 A AR P130102764A AR 091981 A1 AR091981 A1 AR 091981A1
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Argentina
Prior art keywords
independently selected
optionally substituted
alkyl
heterocycle
carbocycle
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ARP130102764A
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English (en)
Inventor
R Corte James
J Gilligan Paul
J P Pinto Donald
R Erwing William
Fang Tianan
Yang Wu
G Clark Charles
Delucca Indawati
K Dilger Andrew
B Pabbisetty Kumar
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Bristol Myers Squibb Co
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Publication of AR091981A1 publication Critical patent/AR091981A1/es

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—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
    • 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
    • C07D471/08—Bridged 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
    • A61K31/435—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
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/15—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing halogen
    • C07C53/16—Halogenated acetic acids
    • C07C53/18—Halogenated acetic acids containing fluorine
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—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
    • C07D471/12—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 three hetero rings
    • C07D471/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms

Abstract

Estos compuestos son inhibidores selectivos del factor XIa o inhibidores duales de FXIa y calicreína plasmática. También composiciones farmacéuticas que comprenden estos compuestos y a métodos para tratar trastornos tromboembólicos y/o inflamatorios mediante su uso. Reivindicación 1: Un compuesto caracterizado por la fórmula (1) o un estereoisómero, un tautómero o una sal de aquel aceptable desde el punto de vista farmacéutico, en donde: el anillo A se selecciona independientemente de un arilo de 6 miembros y un heterociclo de 5 a 6 miembros, en donde el arilo y el heterociclo se sustituyen opcionalmente, cuando la valencia lo permite, con uno o más R⁴; el anillo B se selecciona independientemente de un arilo de 6 miembros y un heterociclo de 5 a 10 miembros, en donde el arilo y el heterociclo se sustituyen opcionalmente, cuando la valencia lo permite, con uno o más R³; el anillo C se selecciona independientemente de los compuesto de fórmula (2) y (3); - - - - es un enlace opcional; G¹ se selecciona independientemente de carbociclo C₃₋₁₀ y un heterociclo de 5 a 10 miembros, en donde el carbociclo y el heterociclo se sustituyen opcionalmente, cuando la valencia lo permite, con uno o más R⁸; X se selecciona independientemente de alquileno C₄₋₈ y alquenileno C₄₋₈, en donde el alquileno y el alquenileno se sustituyen con R¹ y R²; de manera alternativa, uno o más de los átomos de carbono del alquileno y alquenileno se pueden reemplazar por O, C=O, S(O)ₚ, S(O)ₚNH, NH y N(alquilo C₁₋₄); X¹ se selecciona independientemente de CR⁷ y N; Y se selecciona independientemente de -NH-C(O)- y -C(O)-NH-; R¹ y R² se seleccionan independientemente de H, halógeno, haloalquilo, alquilo C₁₋₆ (opcionalmente sustituido con R⁶), hidroxilo y alcoxi (opcionalmente sustituido con R⁶), y cicloalquilo C₃₋₆ opcionalmente sustituido con R⁶; opcionalmente, cuando R¹ y R² se unen al mismo átomo de carbono, forman juntos un grupo oxo o cicloalquilo C₃₋₆; opcionalmente, cuando R¹ y R² se unen a átomos de carbono adyacentes entre sí, forman juntos un enlace o un carbociclo; R³ se selecciona independientemente de H, NO₂, =O, halógeno, haloalquilo, alquilo C₁₋₄ (opcionalmente sustituido con R⁶), alquenilo C₂₋₄ (opcionalmente sustituido con R⁶), alquinilo C₂₋₄ (opcionalmente sustituido con R⁶), CN, -(CH₂)ₙ-OR⁵, -(CH₂)ₙ-NR⁵R⁵, -(CH₂)ₙ-C(O)OR⁵, -(CH₂)ₙ-NR⁹C(O)OR⁵, -(CH₂)ₙ-NR⁹C(O)R⁵, -(CH₂)ₙ-NR⁹C(N-CN)NHR⁵, -(CH₂)ₙ-NR⁹C(NH)NHR⁵, -(CH₂)ₙ-N=CR⁹NR⁵R⁵, -(CH₂)ₙ-NR⁹C(O)NR⁵R⁵, -(CH₂)ₙ-C(O)NR⁵R⁵, (CH₂)ₙ-NR⁹C(S)NR⁹C(O)R⁵, -(CH₂)ₙ-S(O)ₚR¹², -(CH₂)ₙ-S(O)ₚNR⁵R⁵, -(CH₂)ₙ-NR⁹S(O)ₚNR⁵R⁵, -(CH₂)ₙ-NR⁹S(O)ₚR¹², -(CH₂)ₙ-carbociclo C₃₋₁₀ y -(CH₂)ₙ-heterociclo de 4 a 10 miembros, en donde el carbociclo y el heterociclo se sustituyen opcionalmente con R⁶; opcionalmente, dos grupos R³ adyacentes en el carbociclo y heterociclo pueden formar un anillo opcionalmente sustituido con R⁶; R⁴ se selecciona independientemente de H, OH, NH₂, halógeno, CN, alquilo C₁₋₄, haloalquilo C₁₋₄, alcoxi C₁₋₄, -CH₂OH, -CO₂H, -CH₂CO₂H, -CO₂(alquilo C₁₋₄), -C(O)NH₂, -C(O)NH(alquilo C₁₋₄), -C(O)N(alquilo C₁₋₄)₂, S(O)₂NH₂, cicloalquilo C₃₋₆, arilo y un heterociclo de 5 a 6 miembros, en donde el cicloalquilo, arilo y heterociclo se sustituyen opcionalmente con R⁶; R⁵ se selecciona independientemente de H, alquilo C₁₋₄ (opcionalmente sustituido con halógeno, hidroxilo, alcoxi, carboxi, alcoxicarbonilo, amino, amino sustituido), -(CH₂)ₙ-carbociclo C₃₋₁₀ y -(CH₂)ₙ-heterociclo de 4 a 10 miembros, en donde el carbociclo y el heterociclo se sustituyen opcionalmente con R⁶; de manera alternativa, R⁵ y R⁵, junto con el átomo de nitrógeno al que están unidos, forman un anillo heterocíclico opcionalmente sustituido con R⁶; R⁶ se selecciona independientemente de -(CH₂)ₙ-OH, =O, -(CH₂)ₙNH₂, -(CH₂)ₙCN, halógeno, alquilo C₁₋₆, -(CH₂)ₙ-C(=O)OH, -(CH₂)ₙ-C(=O)O-alquilo C₁₋₄, -(CH₂)ₙ-O-alquilo C₁₋₄, -(CH₂)ₙ-carbociclo C₃₋₁₀, -(CH₂)ₙ-heterociclo de 4 a 10 miembros y -O-heterociclo de 4 a 10 miembros, en donde el carbociclo y el heterociclo se sustituyen opcionalmente con R¹⁰; R⁷ se selecciona independientemente de H, hidroxilo, alcoxi, halógeno, alquilo C₁₋₃; R⁸ se selecciona independientemente de H, halógeno, CN, NH₂, alquilo C₁₋₆, haloalquilo, haloalquilcarbonilamina, alquilcarbonilo, alcoxi, haloalcoxi, -(CH₂)ₙ-arilo, -(CH₂)ₙ-cicloalquilo C₃₋₆ y -(CH₂)ₙ-heterociclo de 4 - 6 miembros; opcionalmente, dos grupos R⁸ adyacentes en el carbociclo y heterociclo pueden formar un anillo opcionalmente sustituido con R¹⁰; R⁹ es H o alquilo C₁₋₆; R¹⁰ se selecciona independientemente de alquilo C₁₋₆ (opcionalmente sustituido con R¹¹), alquenilo C₂₋₆, alquinilo C₂₋₆, -(CH₂)ₙ-cicloalquilo C₃₋₆ (opcionalmente sustituido con R¹¹), -O-heterociclo de 4 a 10 miembros (opcionalmente sustituido con R¹¹), F, Cl, Br, CN, NO₂, =O, CO₂H, -(CH₂)ₙ-O-alquilo C₁₋₅, -(CH₂)ₙ-OR¹¹ y -(CH₂)ₙ-NR¹¹R¹¹; R¹¹, en cada caso, se selecciona independientemente de H, alquilo C₁₋₅, -(CH₂)ₙ-OH, cicloalquilo C₃₋₆ y fenilo, o R¹¹ y R¹¹, junto con el átomo de nitrógeno al que están unidos, forman un anillo heterocíclico opcionalmente sustituido con alquilo C₁₋₄; R¹² es alquilo C₁₋₆ opcionalmente sustituido con R¹¹; m es un entero seleccionado independientemente de 0 y 1; n, en cada caso, es un entero seleccionado independientemente de 0, 1, 2, 3 y 4; p, en cada caso, es un entero seleccionado independientemente de 0, 1 y 2; siempre que se excluyan los compuestos de fórmula (4) en donde el anillo A se selecciona independientemente del grupo de fórmulas (5); - - - - es un enlace opcional; R¹ se selecciona independientemente de H, hidroxilo y alquilo C₁₋₄; R², en cada caso, se selecciona independientemente de H e hidroxilo; R⁴ se selecciona independientemente de H, OH, F, O-alquilo C₁₋₄ y CN; R⁸ᵃ se selecciona independientemente de H, F, Cl y Br; R⁸ᵇ se selecciona independientemente de H y F; y R⁸ᶜ se selecciona independientemente de H, F y Cl.
ARP130102764A 2012-08-03 2013-08-02 Dihidropiridona p1 como inhibidores del factor xia AR091981A1 (es)

Applications Claiming Priority (2)

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US201261679197P 2012-08-03 2012-08-03
US201361787081P 2013-03-15 2013-03-15

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US (2) US9409908B2 (es)
EP (1) EP2880026B1 (es)
JP (1) JP6082463B2 (es)
KR (1) KR20150038372A (es)
CN (2) CN104507924B (es)
AR (1) AR091981A1 (es)
AU (1) AU2013296259A1 (es)
BR (1) BR112015002081A2 (es)
CA (1) CA2880866A1 (es)
CY (1) CY1119004T1 (es)
DK (1) DK2880026T3 (es)
EA (1) EA028581B1 (es)
ES (1) ES2623175T3 (es)
HR (1) HRP20170506T1 (es)
HU (1) HUE032622T2 (es)
IL (1) IL237011A0 (es)
LT (1) LT2880026T (es)
MX (1) MX361759B (es)
PL (1) PL2880026T3 (es)
PT (1) PT2880026T (es)
RS (1) RS55975B1 (es)
SG (1) SG11201500271UA (es)
SI (1) SI2880026T1 (es)
TW (1) TW201410667A (es)
UY (1) UY34960A (es)
WO (1) WO2014022767A1 (es)

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