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AR080167A1 - Macrociclos como inhibidores del factor xia - Google Patents

Macrociclos como inhibidores del factor xia

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Publication number
AR080167A1
AR080167A1 ARP110100435A AR080167A1 AR 080167 A1 AR080167 A1 AR 080167A1 AR P110100435 A ARP110100435 A AR P110100435A AR 080167 A1 AR080167 A1 AR 080167A1
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Argentina
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alkyl
group
independently selected
nhco2
conh
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English (en)
Inventor
James R Corte
Tianan Fang
Carl P Decicco
Donald J P Pinto
Karen A Rossi
Zilun Hu
Yoon Jeon
Joanne M Smallheer
Yufeng Wang
Wu Wang
Mimi L Quan
Original Assignee
Bristol Myers Squibb Co
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Publication of AR080167A1 publication Critical patent/AR080167A1/es

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    • 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
    • C07D487/06—Peri-condensed systems
    • 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
    • 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
    • C07D487/04—Ortho-condensed 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
    • C07D225/04—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D225/08—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • 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
    • C07D471/14—Ortho-condensed systems
    • 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
    • C07D487/14—Ortho-condensed 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
    • C07D487/16—Peri-condensed 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/08—Bridged systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Estos compuestos son inhibidores selectivos del Factor XIa o inhibidores duales de fXIa y calicreína de plasma. Reivindicacion 1: Un compuesto caracterizado porque tiene la formula (1) o un estereoisomero, un tautomero, una sal farmacéuticamente aceptable o un solvato del mismo, en la que: el anillo A es independientemente un carbociclo C3-10 o un carbociclo de 5 a 10 miembros que comprende: átomos de carbono y 1 - 4 heteroátomos seleccionados de entre N, NH, N(alquilo C1-4), O y S(O)p; el anillo B es independientemente un anillo de benceno o un heteroarilo de 5 a 6 miembros que comprende: átomos de carbono y 1 - 4 heteroátomos seleccionados de entre N, O y S(O)p; el anillo C es independientemente un anillo de benceno o un heterociclo de 5 a 10 miembros que comprende: átomos de carbono y 1 - 4 heteroátomos seleccionados del N, NH, N(alquilo C1-4), O y S(O)p; L1 se selecciona independientemente del grupo constituido por: un enlace, -CHR5-, -CHR5CHR5-, -CR5=CR5-, -CsC-, -OCH2-, -CHR5NH-, -CH2O-, -SCH2-, -SO2CH2-, -CH2NH- y -CR5R5-; L se selecciona independientemente del grupo constituido por: alquileno C3-8, alquenileno C3-8 y alquinileno C4-8, en el que dichos alquileno, alquenileno y alquinileno están sustituidos con 0 - 2 R7 y opcionalmente uno o varios de los átomos de carbono de dichos alquileno y alquenileno pueden estar reemplazados por O, S, NH, N(alquilo C1-4), CO, CONH, NHCO, OCONH, NHCO2, -NHCONH-, SO2NH, NHSO2, CON(alquilo C1-4) o N(alquilo C1-4)CO; Y se selecciona independientemente del grupo constituido por: CH2, CH(alquilo C1-4), C(alquilo C1-4)2, CO, O, S, NH, N(alquilo C1-4), N(CO2(alquilo C1-4)), -N(alquil C1-4)CH2-, -N(CO2(alquil C1-4))CH2-, -N(CH2CO2(alquil C1-4))CH2-, -CONH-, -NHCO-, -CONHCH2-, -CON(alquil C1-4)CH2-, -OCONH-, -OCON(alquilo C1-4)-, -NHCONH-, -SO2NH-, -NHCO2- y -NHSO2-; alternativamente, L-Y es alquileno C3-6-CH=N-; R1, en cada aparicion, se selecciona independientemente del grupo constituido por: halogeno, alquilo C1-6, alcoxi C1-4, alquiltio C1-4, haloalquilo C1-4, OH, OCH2F, OCHF2, OCF3, CN, NH2, NH(alquilo C1-4), N(alquilo C1-4)2, -CO2(alquilo C1-4), -CO(alquilo C1-4), -CH2NH2, -CONH2, -CONH(alquilo C1-4), -OCH2CO2H, NHCO(alquilo C1-4), -NHCO2(alquilo C1-4), -NHSO2(alquilo C1-4), -SO2NH2, -C(=NH)NH2 y fenilo sustituido con 0 - 2 Ra; R2 es independientemente un heterociclo de 5 a 7 miembros que comprende átomos de carbono y 1 - 4 heteroátomos seleccionados del N, NH, N(alquilo C1-4), O, y S(O)p, en el que dicho heterociclo está sustituido con 0 - 2 R2a; R2a, en cada aparicion, se selecciona independientemente del grupo constituido por: halogeno, alquilo C1-4, -CH2OH, alcoxi C1-4, OH, CF3, OCF3, CN, NH2, CO2H, CO2(alquilo C1-4), CO-alquilo C1-4, -CONH2, -CONH(alquilo C1-4), -CON(alquilo C1-4)2, -SO2(alquilo C1-4), -SO2NH2, -SO2NH(alquilo C1-4) y -SO2N(alquilo C1-4)2; R3 se selecciona independientemente del grupo constituido por: H, =O, halogeno, OH, NH2, CN, alquilo C1-4, alcoxi C1-4, haloalquilo C1-4, -CH2OH, CO2H, CO2(alquilo C1-4), -C(O)NH2, -C(O)NH(alquilo C1-4), -C(O)N(alquilo C1-4)2, -CH2CO2H y cicloalquilo C3-6; R4 se selecciona independientemente del grupo constituido por: H y alquilo C1-4; R5, en cada aparicion, se selecciona independientemente del grupo constituido por: H, halogeno, OH y alquilo C1-4; R6, en cada aparicion, se selecciona independientemente del grupo constituido por: halogeno, alquilo C1-4, CN, OH, CF3, CO2H, CO2(alquilo C1-4), -CH2CO2H, (CH2)2CO2H, -CH2CO2(alquilo C1-4), -(CH2)2CO2(alquilo C1-4), NH2, -CH2NH2, -NHCO(alquilo C1-4), -NHCOCF3, -NHCO2(alquilo C1-4), -NHCO2(CH2)2O(alquilo C1-4), -NHCO2(CH2)3O(alquilo C1-4), -NHCO2CH2CH(alquil C1-4)O(alquilo C1-4), -NHCO2(CH2)2OH, -NHCO2(CH2)2NH2, -NHCO2(CH2)2N(alquilo C1-4)2, -NHCO2CH2CO2H, -CH2NHCO2(alquilo C1-4), -NHC(O)NH(alquilo C1-4), NHC(O)N(alquilo C1-4)2 -NHSO2(alquilo C1-4), -SO2NH2, -SO2NH(alquilo C1-4), -SO2NH(CH2)2OH, -SO2NH(CH2)2O(alquilo C1-4), -CONH2, -CONH(alquilo C1-4), -CON(alquilo C1-4)2, -CH2CONH2 y -NHCO2(CH2)0-2R9; R7, en cada aparicion, se selecciona independientemente del grupo constituido por: halogeno, OH, NH2, CH2NH2, haloalquilo C1-4, OCH2F, OCHF2, OCF3, -NH(alquilo C1-4), -N(alquilo C1-4)2, alcoxi C1-4, CH2OH, CH2O(alquilo C1-4), CH2O(CH2)1-4O(alquilo C1-4), CO2H, CO2(alquilo C1-4), CO2(CH2)2O(alquilo C1-4), CO2(haloalquilo C1-4), CO2(CH2)2SO2(alquilo C1-4), CH2CO2H, CH2CO2(alquilo C1-4), CONH2, CONH(alquilo C1-4), CON(alquilo C1-4)2, -OCO(alquilo C1-4), CH2NH(CH2)2O(alquilo C1-4), -CONH(alcoxi C1-4), -CO2(CH2)2O(alquilo C1-4), -CO2(CH2)2N(alquilo C1-4)2, -CONH(CH2)2O(alquilo C1-4), -CONH(CH2)2N(alquilo C1-4)2, -CON(alquilo C1-4)(CH2)2O(alquilo C1-4), -CON(alquil C1-4)(CH2)2N(alquilo C1-4)2, alquilo C1-4, -CONHBn, -CONH(OBn), -(CO)0-1(CH2)0-3-carbociclo C3-6 y -(CH2)0-1-(CO)0-1-(W)0-1-(CH2)0-2-(heterociclo de 4 a 6 miembros que comprende átomos de carbonos y 1 - 4 heteroátomos seleccionados de entre N, NH, N(alquilo C1-4), O y S(O)p); en el que dichos carbociclo y heterociclo están sustituidos con 0 - 2 R8; R8, en cada aparicion, se selecciona independientemente del grupo constituido por: halogeno, OH, CHF2, CF3, alcoxi C1-4, CH2OH, CO2H, CO2(alquilo C1-4), CONH2 y alquilo C1-4; R9 es un heterociclo de 4 a 6 miembros que comprende: átomos de carbono y 1 - 4 heteroátomos seleccionados de N, NH, N(alquilo C1-4), N(CO2(alquilo C1-4)), O y S(O)p; Ra, en cada aparicion, se selecciona independientemente del grupo constituido por: halogeno, OH, CF3, alcoxi C1-4 y alquilo C1-4; W se selecciona independientemente del grupo constituido por: O, NH y N(alquilo C1-4); y p, en cada aparicion, se selecciona independientemente del grupo constituido por: 0, 1 y 2.
ARP110100435 2010-02-11 2011-02-11 Macrociclos como inhibidores del factor xia AR080167A1 (es)

Applications Claiming Priority (2)

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US30342310P 2010-02-11 2010-02-11
US40533810P 2010-10-21 2010-10-21

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AR080167A1 true AR080167A1 (es) 2012-03-21

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US (9) US8940720B2 (es)
EP (3) EP3786165A1 (es)
JP (3) JP5844287B2 (es)
KR (2) KR101843542B1 (es)
CN (3) CN102753555B (es)
AR (1) AR080167A1 (es)
AU (1) AU2011215898B2 (es)
BR (1) BR112012019925B1 (es)
CA (1) CA2789622C (es)
CL (1) CL2012002229A1 (es)
CO (1) CO6551666A2 (es)
EA (1) EA020528B1 (es)
ES (2) ES2822130T3 (es)
IL (1) IL221343B (es)
MX (1) MX2012008874A (es)
MY (1) MY162936A (es)
NZ (1) NZ602266A (es)
PE (2) PE20160841A1 (es)
PH (1) PH12012501589A1 (es)
SG (1) SG183153A1 (es)
TW (2) TWI577665B (es)
WO (2) WO2011100401A1 (es)
ZA (1) ZA201206758B (es)

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ES2714283T3 (es) 2014-09-04 2019-05-28 Bristol Myers Squibb Co Macrociclos de diamida que son inhibidores de FXIa
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TWI535452B (zh) * 2015-01-23 2016-06-01 長庚醫療財團法人 使用抗－ｃｄ４４中和抗體來治療和／或預防心房顫動
EP3310777B1 (en) 2015-06-19 2019-10-09 Bristol-Myers Squibb Company Diamide macrocycles as factor xia inhibitors
CN107849026B (zh) * 2015-07-29 2021-01-01 百时美施贵宝公司 携带烷基或环烷基p2′部分的因子xia大环抑制剂
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