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ES2625256T3 - Compuestos de tetrahidroisoquinolina sustituidos como inhibidores del factor XIA - Google Patents

Compuestos de tetrahidroisoquinolina sustituidos como inhibidores del factor XIA Download PDF

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ES2625256T3
ES2625256T3 ES12778913T ES12778913T ES2625256T3 ES 2625256 T3 ES2625256 T3 ES 2625256T3 ES 12778913 T ES12778913 T ES 12778913T ES 12778913 T ES12778913 T ES 12778913T ES 2625256 T3 ES2625256 T3 ES 2625256T3
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alkylene
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Michael J. Orwat
Donald J.P. Pinto
Leon M. Smith Ii
Shefali SRIVASTAVA
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Bristol Myers Squibb Co
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    • C07D401/14—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 three or more hetero rings
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    • C07D401/10—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 carbon chain containing aromatic rings
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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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
    • A61K31/472—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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    • A61K31/535—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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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
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    • A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • 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
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • 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
    • C07D471/10—Spiro-condensed systems
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    • 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
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    • 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
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Abstract

Un compuesto de acuerdo con la fórmula (I):**Fórmula** o un estereoisómero, un tautómero, una sal farmacéuticamente aceptable o un solvato del mismo, en la que: el anillo A es un carbociclo C3-6; el anillo B es un heterociclo de 4 a 7 miembros que contiene átomos de carbono y 0-3 heteroátomos adicionales seleccionados entre el grupo que consiste en N, NR6, O y S(O)p; opcionalmente, el anillo B forma un anillo condensado o un anillo espiro con un heterociclo de 4 a 7 miembros que contiene átomos de carbono y 1-3 heteroátomos seleccionados entre el grupo que consiste en NR6, O y S(O)p; el anillo B, incluyendo el anillo condensado o el anillo espiro, está sustituido con 1-3 R5; L se selecciona entre el grupo que consiste en: -CHR10CHR10-, -CR10>=CR10-, -CºC-, -CHR10NH-, -NHCHR10-, - SCH2-, -CH2S-, -SO2CH2-, -CH2SO2-, -NHCH2- y -CH2NH-; R1, en cada aparición, se selecciona entre el grupo que consiste en: H, halo, alquilo C1-6, alcoxi C1-4, alquiltio C1-4, OH, SH, CHF2, CF3, OCF3, CN, NH2, CO-alquilo C1-4, CO2(alquilo C1-4), -CH2CO2H, -CH2CO2(alquilo C1-4), - CH2NH2, -CONH2, -CONH(alquilo C1-4), -NHCO(alquilo C1-4), -NHCO2(alquilo C1-4), -NHSO2(alquilo C1-4) y - SO2NH2 y -C(>=NH)NH2; R2 se selecciona entre el grupo que consiste en: H, halo, CN, OH, alquilo C1-6, alcoxi C1-4, haloalquilo C1-6, haloalcoxi C1-6, CO(alquilo C1-4), CONH2, CO2H, CH2NH2 y un heterociclo de 5 a 7 miembros que comprende átomos de carbono y 1-4 heteroátomos seleccionados entre N, NRc, O y S(O)p, en donde dicho heterociclo está sustituido con 0-2 R2a; R2a, en cada aparición, se selecciona entre el grupo que consiste en: H, halo, alquilo C1-4, alcoxi C1-4, OH, CF3, OCF3, CN, NH2, CO2H, CO2(alquilo C1-4), CO(alquilo C1-4), -CONH2, -CH2OH, -CH2O-alquilo C1-4, -CH2NH2-, 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 entre el grupo que consiste en: alquilo C1-6 sustituido con 1-3 R3a, -(CH2)n-carbociclo C3-10 sustituido con 0-3 R3a o -(CH2)n-heterociclo de 5-10 miembros que contiene átomos de carbono y 1-4 heteroátomos seleccionados entre el grupo que consiste en N, NR7, O y S(O)p; en donde dicho heterociclo está sustituido con 0-3 R3a; R3a, en cada aparición, se selecciona entre el grupo que consiste en: >=O, halo, alquilo C1-4, OH, alcoxi C1-4, CN, NH2, CO2H, CO2(alquilo C1-4), CONH2, CONH(alquilo C1-6), CON(alquilo C1-4)2, -CONH-alquilen C1-4-CO2(alquilo C1-4), -CONHCO2-alquilo C1-4, -CONH-alquilen C1-4-NHCO(alquilo C1-4), -CONH-alquilen C1-4-CONH2, -NHCO alquilo C1-4, -NHCO2(alquilo C1-4), -alquilen C1-4-NHCO2-alquilo C1-4, Rf, CONHRf y -CO2Rf; R4, en cada aparición, se selecciona entre el grupo que consiste en: H, halo y alquilo C1-4; R5, en cada aparición, se selecciona entre el grupo que consiste en: H, >=O, halo, alquilo C1-4, OH, CN, NH2, - N(alquilo C1-4)2, NO2, alcoxi C1-4, -OCO(alquilo C1-4), -O-alquilen C1-4-O(alquilo C1-4), -O-alquilen C1-4-N(alquilo C1- 4)2, -CO2H, -CO2(alquilo C1-4), -CONH2, -(CH2)2CONH2, -CONR9(alquilo C1-4), -CONR9-alquilen C1-4-O(alquilo C1- 4), -CON(alquilo C1-4)2, -CONR9-alquilen C1-4-N(alquilo C1-4)2, -CON(alquil C1-4)-alquilen C1-4-O(alquilo C1-4), - CONR9-alquilen C1-4-CO2(alquilo C1-4), -NR9CO-alquilo C1-4, -NR9CO2-alquilo C1-4, -NR9CONH(alquilo C1-4), - NR9CONR9-alquilen C1-4-CO2-alquilo C1-4, -NR9-alquilen C1-4-N(alquilo C1-4)2, R8, -OR8, -O-alquilen C1-4-R8, - COR8, -CO2R8, -CONR9R8, -NR9COR8, -NR9CO2R8 y -NR9CON R9R8; R6 se selecciona entre el grupo que consiste en: H, alquilo C1-4, -CO2(alquilo C1-4), -CO(alquilo C1-4), -CONH2, - CO-alquilen C1-4-N(alquilo C1-4)2, -(CH2)2N(alquilo C1-4)2, -CONR9(alquilo C1-4), -CONR9-alquilen C1-4-O(alquilo C1- 4), -CONR9-alquilen C1-4-N(alquilo C1-4)2, -CONR9-alquilen C1-4-CO2(alquilo C1-4), -CON(alquilo C1-4)2, R8, -COR8, - CO2R8 y -CONR9R8; R7, en cada aparición, se selecciona entre el grupo que consiste en: H, alquilo C1-4, CO-alquilo C1-4, CO2(alquilo C1-4), CO2Bn, -CONH-alquilen C1-4-CO2-alquilo C1-4, fenilo, bencilo y -CO2-alquilen C1-4-arilo; R8, en cada aparición, se selecciona entre el grupo que consiste en: -(CH2)n-carbociclo C3-10 sustituido con 0-3 Re y -(CH2)n-heterociclo de 5-10 miembros que contiene átomos de carbono y 1-4 heteroátomos seleccionados entre el grupo que consiste en N, NRd, O y S(O)p; en donde dichos carbociclo y heterociclo están opcionalmente sustituidos con >=O; R9, en cada aparición, se selecciona entre el grupo que consiste en: H y alquilo C1-4; R10, en cada aparición, se selecciona entre el grupo que consiste en: H, halo, OH y alquilo C1-4; Rc se selecciona, independientemente en cada aparición, entre el grupo que consiste en: H, alquilo C1-4, COalquilo C1-4, CO2-alquilo C1-4 y CO2Bn; Rd se selecciona, independientemente en cada aparición, entre el grupo que consiste en: H, alquilo C1-4, CO(alquilo C1-4), COCF3, CO2(alquilo C1-4), -CONH-alquilen C1-4-CO2-alquilo C1-4, CO2Bn, Rf y CONHRf; Re se selecciona, independientemente en cada aparición, entre el grupo que consiste en: >=O, halo, alquilo C1-4, alcoxi C1-4, OCF3, NH2, NO2, N(alquilo C1-4)2, CO(alquilo C1-4), CO(haloalquilo C1-4), CO2(alquilo C1-4), CONH2, - CONH(alquilo C1-4), -CONHPh, -CON(alquilo C1-4)2, -CONH-alquilen C1-4-O(alquilo C1-4), -CONH-alquilen C1-4- N(alquilo C1-4)2, -CONH-alquilen C1-4-CO2(alquilo C1-4), -NHCO2(alquilo C1-4), Rf, CORf, CO2Rf y CONHRf; Rf se selecciona, independientemente en cada aparición, entre el grupo que consiste en: -(CH2)n-cicloalquilo C3-6, -(CH2)n-fenilo y -(CH2)n-heterociclo de 5 a 6 miembros que contiene átomos de carbono y 1-4 heteroátomos seleccionados entre el grupo que consiste en N, NRc, O y S(O)p; en donde cada resto del anillo está sustituido con 0-2 Rg; Rg se selecciona, independientemente en cada aparición, entre el grupo que consiste en: >=O, halo, alquilo C1-4, OH, alcoxi C1-4 y NHCO(alquilo C1-4); n, en cada aparición, se selecciona entre 0, 1, 2, 3 y 4; y p, en cada aparición, se selecciona entre 0, 1 y 2.
ES12778913T 2011-10-14 2012-10-12 Compuestos de tetrahidroisoquinolina sustituidos como inhibidores del factor XIA Active ES2625256T3 (es)

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PCT/US2012/059969 WO2013056060A1 (en) 2011-10-14 2012-10-12 Substituted tetrahydroisoquinoline compounds as factor xia inhibitors

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