ES2548887T3 - Inhibidores de neprilisina - Google Patents

Inhibidores de neprilisina Download PDF

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Publication number
ES2548887T3
ES2548887T3 ES11805709.0T ES11805709T ES2548887T3 ES 2548887 T3 ES2548887 T3 ES 2548887T3 ES 11805709 T ES11805709 T ES 11805709T ES 2548887 T3 ES2548887 T3 ES 2548887T3
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alkyl
phenyl
halo
optionally substituted
cycloalkyl
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ES11805709.0T
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Cameron Smith
Melissa Fleury
Roland Gendron
Ryan Hudson
Adam D. Hughes
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Theravance Biopharma R&D IP LLC
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Theravance Biopharma R&D IP LLC
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    • 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
    • C07D471/04—Ortho-condensed systems
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    • 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
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    • 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
    • A61K31/415—1,2-Diazoles
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    • 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
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    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
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    • 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
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    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • 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
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    • 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
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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  • Thiazole And Isothizaole Compounds (AREA)

Abstract

Un compuesto de fórmula I:**Fórmula** en la que: R1 es -OR7; R2 es H; X es seleccionado entre pirazol, triazol, benzotriazol, tetrazol, oxazol, isoxazol, tiazol, piridazina, pirimidina y piridiltriazol; R3 está ausente o es seleccionado entre H; halo; -alquilen C0-5-OH; -NH2; -alquilo C1-6; -CF3; -cicloalquilo C3-7; - alquileno C0-2 O-alquilo C1-6; -C(O)R20; -alquilen C0-1-COOR21; -C(O)NR22R23; -NHC(O)R24; >=O; -NO2; - C(CH3)>=N(OH); fenilo opcionalmente sustituido con uno o dos grupos seleccionados independientemente entre halo, -OH, -CF3, -OCH3, -NHC(O)CH3 y fenilo; naftalenilo; piridinilo; pirazinilo; pirazol opcionalmente sustituido con metilo; tiofenilo opcionalmente sustituido con metilo o halo; furanilo; y -CH2-morfolinilo; y R3, cuando está presente, está unido a un átomo de carbono; R4 está ausente o es seleccionado entre H; -OH; -alquilo C1-6; -alquilen C1-2-COOR35; -CH20C(O)CH(R36)NH2; - OCH2OC(O)CH(R36)NH2; -OCH2OC(O)CH3; -CH2OP( O)(OH)2; -CH2CH(OH)CH2OH; -CH[CH(CH3)2]-NHC(O)Oalquilo C1-6; piridinilo; y fenilo o bencilo opcionalmente sustituido con uno o más grupos seleccionados entre halo, -COOR35, -OCH3, -OCF3 y -SCF3; y R4, cuando está presente, está unido a un átomo de nitrógeno o de carbono; o R3 y R4 son tomados conjuntamente para formar -fenilen-O-(CH2)1-3- o -fenilen-OCH2-CHOH-CH2-; a es 0 o 1; R5 es seleccionado entre halo, -CH3, -CF3 y -CN; b es 0 o un número entero de 1 a 3; cada R6 es seleccionado independientemente entre halo, -OH, -CH3, -OCH3 y -CF3; R7 es seleccionado entre H, -alquilo C1-8, -alquilen C1-3-arilo C6-10, -alquilen C1-3-heteroarilo C1-9-, -cicloalquilo C3-7, -[(CH2)2O ]1-3CH3, -alquilen C1-6-OC(O)R10, -alquilen C1-6-NR12R13, -alquilen C1-6-C(O)R31, -alquilenmorfolinilo C0-6; -alquilen C1-6-SO2-alquilo C1-6;**Fórmula** R10 es seleccionado entre -alquilo C1-6, -O-alquilo C1-6, -cicloalquilo C3-7, -O-cicloalquilo C3-7, fenilo, -O-fenilo, - NR12R13, -CH[CH(CH3)2]-NH2, -CH[CH(CH3)2]-NHC(O)O-alquilo C1-6 y -CH(NH2)CH2COOCH3; y R12 y R13 son seleccionados independientemente entre H, -alquilo C1-6 y bencilo; o R12 y R13 son tomados conjuntamente como -(CH2)3-6-, -C(O)-(CH2)3- o -(CH2)2O(CH2)2-; y R31 es seleccionado entre -O-alquilo C1-6, -O-bencilo y -NR12R13; R32 es -alquilo C1-6 o -alquilen C0-6-arilo C6-10; R20 es seleccionado entre H y -alquilo C1-6; R21 y R35 son seleccionados independientemente entre H, -alquilo C1-6, -alquilen C1-3-arilo C6-10, -alquilen C1-3- heteroarilo C1-9, -cicloalquilo C3-7, -[(CH2)2O]1-3CH3, -alquilen C1-6-OC(O)R25; -alquilen C1-6-NR27R28, -alquilen C1-6- C(O)R33, -alquilenmorfolinilo C0-6, -alquilen C1-6-SO2-alquilo C1-6,**Fórmula** R25 es seleccionado entre -alquilo C1-6-, -O-alquilo C1-6, -cicloalquilo C3-7, -O-cicloalquilo C3-7, fenilo, -O-fenilo, - NR27R28, -CH[CH(CH3)2]-NH2, -CH[CH(CH3)2]-NHC(O)O-alquilo C1-6 y -CH(NH2)CH2COOCH3; R27 y R28 son seleccionados independientemente entre H, -alquilo C1-6 y bencilo; o R27 y R28 son tomados conjuntamente como -(CH2)3-6-, -C(O)-(CH2)3- o -(CH2)2O(CH2)2-; R33 es seleccionado entre -O-alquilo C1-6, -O-bencilo y -NR27R28; y R34 es -alquilo C1-6 o -alquilen C0-6-arilo C6-10; R22 y R23 son seleccionados independientemente entre H, -alquilo C1-6, -CH2COOH, -(CH2)2OH; -(CH2)2OCH3, - (CH2)2SO2NH2, -(CH2)2 N(CH3)2, -alquilen C0-1-cicloalquilo C3-7 y -(CH2)2-imidazolilo; o R22 y R23 son tomados conjuntamente para formar un -heterociclo C3-5 saturado o parcialmente insaturado opcionalmente sustituido con halo, -OH, -COOH o -CONH2; y que contiene opcionalmente un átomo de oxígeno en el anillo; R24 es seleccionado entre -alquilo C1-6; -alquilen C0-1-O-alquilo C1-6; fenilo opcionalmente sustituido con halo o - OCH3; y -heteroarilo C1-9; y R36 es seleccionado entre H, -CH(CH3)2, fenilo y bencilo; en la que cada grupo alquilo en R1, R3 y R4 está opcionalmente sustituido con 1 a 8 átomos de flúor; y; en la que el engarce metileno en el bifenilo está opcionalmente sustituido con uno o dos grupos -alquilo C1-6 o ciclopropilo; o una sal farmacéuticamente aceptable del mismo

Description

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El resto R10 se selecciona entre:
5 -alquilo C1-6, por ejemplo, -CH3 y -CH2CH3; -O-alquilo C1-6, por ejemplo, -OCH3, -O-CH2CH3 y -O-CH(CH3)2; -cicloalquilo C3-7, por ejemplo, ciclopentilo); -O-cicloalquilo C3-7, por ejemplo, -O-ciclopropilo, -O-ciclohexilo y -O-ciclopentilo; fenilo; -O-fenilo;
10 -NR12R13; -CH[CH(CH3)2]-NH2; -CH[CH(CH3)2]-NHC(O)O-alquilo C1-6, por ejemplo, -CH[CH(CH3)2]-NHC(O)OCH3; y -CH(NH2)CH2COOCH3.
Los restos R12 y R13 se seleccionan independientemente entre H, -alquilo C1-6 (por ejemplo, CH3) y bencilo. De manera alternativa, los restos R12 y R13 pueden tomarse juntos como -(CH2)3-6-, -C(O)-(CH2)3-o -(CH2)2O(CH2)2-, por 15 ejemplo para formar un grupo tal como:
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El resto R31 se selecciona entre –O-alquilo C1-6, por ejemplo, -OCH3, -O-bencilo y -NR12R13, por ejemplo, -N(CH3)2, y
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El resto R32 es -alquilo C1-6 (por ejemplo, -CH3 y -C(CH3)3) o -alquilen C0-6-arilo C6-10.
20 Además, cada grupo alquilo en R1 está opcionalmente sustituido con 1 a 8 átomos de flúor. Por ejemplo, cuando R7 es -alquilo C1-8, R1 también puede ser un grupo tal como -OCH(CH3)CF3,-OCH2CF2CF3, -OCH(CF3)2, -O(CH2)2CF3, -OCH(CH2F)2, -OC(CF3)2 CH3 y -OCH(CH3)CF2CF3.
En una realización, R7 se selecciona entre H, -alquilo C1-8, -alquilen C1-3-arilo C6-10, -alquilenmorfolinilo C0-6 y
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25 en la que R32 es -alquilo C1-6; y en la que cada grupo alquilo está opcionalmente sustituido con 1 a 8 átomos de flúor. En otras realizaciones estos compuestos tienen fórmula III.
En una realización, R7 es H. En otras realizaciones estos compuestos tienen fórmula III.
En otra realización, R7 se selecciona entre -alquilo C1-8, -alquilen C1-3-arilo C6-10, -alquilen C1-3-heteroarilo C1-9, cicloalquilo C3-7, -[(CH2)2O]1-3CH3, -alquilen C1-6-OC(O)R10, -alquilen C1-6-NR12R13, -alquilen C1-6-C(O)R31,
30 alquilenmorfolinilo C0-6; -alquilen C1-6-SO2-alquilo C1-6;
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En una realización, R7 es -alquilen C1-6-OC(O)R10, tal como -O-CH(CH3)OC(O)-O-ciclohexilo:
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haciendo el compuesto un éster de cilexetilo; o R7 es -alquilenmorfolinilo C0-6 tal como -O-(CH2)2-morfolinilo:
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haciendo el compuesto un éster de 2-morfolinoetilo o mofetilo; o R7 es
tal como -O-CH2-5-metil-[1,3]dioxol-2-ona:
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10 haciendo el compuesto un éster de medoxomilo.
R2 es H.
El punto de unión para el resto "X" es en cualquier átomo del anillo de nitrógeno o carbono disponible. Tenga en cuenta que en algunas realizaciones, R3 y/o R4 pueden estar ausentes. Cuando está presente, R3 está en cualquier átomo de carbono disponible. Cuando está presente, R4 está en cualquier átomo de nitrógeno o átomo de carbono
15 disponible. X puede ser:
anillos de pirazol, tales como:
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ejemplos específicos de los cuales incluyen:
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anillos de oxazol:
ejemplos específicos de los cuales incluyen:
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anillos de isoxazol:
ejemplos específicos de los que incluyen:
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anillos de tiazol:
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ejemplos específicos de los cuales incluyen:
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anillos de piridazina:
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CH2OC(O)CH3, -CH2-C(O)O-CH2OC(O)CH3, -C(O)O-CH2OC(O)O-CH3, -CH2-C(O)O-CH2OC(O)O-CH3, -C(O)O-CH(CH3)OC(O)O-CH2CH3, -C(O)O-CH(CH3)OC(O)O-CH(CH3)2, -C(O)O-CH2CH(CH3)OC(O)-ciclopentilo, -C(O)OCH2OC(O)O-ciclopropilo, -C(O)O-CH(CH3)-OC(O)-O-ciclohexilo, -C(O)O-CH2OC(O)O-ciclopentilo, -C(O)OCH2CH(CH3)OC(O)-fenilo, -C(O)O-CH2OC(O)O-fenilo, -C(O)O-CH2-piridina, -C(O)O-CH2-pirrolidina, -C(O)O(CH2)2-morfolinilo, -C(O)O-(CH2)3-morfolinilo y -C(O)O-(CH2)2-SO2-CH3; -C(O)NR22R23, por ejemplo, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -C(O)NH-(CH2)2CH3, -C(O)NH-CH2COOH, -C(O)NH-(CH2)2-OH, -C(O)NH-(CH2)2-N(CH3)2, -C(O)NH-ciclopropilo, -C(O)NH-(CH2)2-imidazolilo, -C(O)N(CH3)-CH2CH(CH3)2 y -C(O)N(CH3)[(CH2)2OCH3]; -NHC(O)R24, por ejemplo, -NHC(O)-CH2CH3, -NHC(O)-(CH2)3CH3, -NHC(O)O-CH2CH3, -NHC(O)-CH2-OCH3, NHC(O)-2-metoxifenilo, -NHC(O)-2-clorofenilo y -NHC(O)-2-piridina; =O; -NO2; -C(CH3)=N(OH); fenilo opcionalmente sustituido con uno o dos grupos seleccionados independientemente entre halo, -OH, -CF3, -OCH3, -NHC(O)CH3 y fenilo (por ejemplo, fenilo, 2-clorofenilo, 2-fluorofenilo, 2-hidroxifenilo, 2-trifluorometilfenilo, 2-metoxifenilo, 3-clorofenilo, 3-fluorofenilo, 3-metoxifenilo, 3-NHC(O)CH3-fenilo, 4-clorofenilo, 4-fluorofenilo, 4metoxifenilo, 4-bifenilo, 2,5-diclorofenilo, 2,5-dimetoxifenilo, 2,4-diclorofenilo, 2-metoxi, 5-fluorofenilo y 3,4diclorofenilo); naftalenilo; piridinilo; pirazinilo; pirazolilo opcionalmente sustituido con metilo; tiofenilo opcionalmente sustituido con metilo o halo (por ejemplo, cloro); furanilo; y -CH2-morfolinilo.
El resto R20 se selecciona entre H y -alquilo C1-6 (por ejemplo, -CH3). El resto R21 se selecciona entre:
H; -alquilo C1-6, por ejemplo, -CH3 y -CH2CH3; -alquilen C1-3-C6-10arilo; -alquilen C1-3-heteroarilo C1-9, por ejemplo, -CH2-piridina; -cicloalquilo C3-7; -[(CH2)2O]1-3CH3, por ejemplo, -(CH2)2OCH3; -alquilen C1-6-OC(O)R25, por ejemplo, -CH2OC(O)CH3, -CH2OC(O)O-CH3, -CH2OC(O)O-CH3, -CH(CH3)OC(O)O-CH2CH3, -CH(CH3)OC(O)O-CH(CH3)2, -CH2CH(CH3)OC(O)-ciclopentilo, -CH2OC(O)O-ciclopropilo, -CH(CH3)OC(O)-O-ciclohexilo, -CH2OC(O)O-ciclopentilo, -CH2CH(CH3)OC(O)-fenilo y -CH2OC(O)O-fenilo; -alquilen C1-6-NR27R28, por ejemplo, -CH2-pirrolidina; -alquilen C1-6-C(O)R33; -alquilenmorfolinilo C0-6, por ejemplo, -(CH2)2-morfolinilo y -(CH2)3-morfolinilo:
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-alquilen C1-6-SO2-alquilo C1-6, por ejemplo, -(CH2)2-SO2-CH3;
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Los restos R22 y R23 se seleccionan independientemente entre:
5 H; -alquilo C1-6, por ejemplo, -CH3 y -(CH2)2CH3; -CH2COOH; -(CH2)2OH; -(CH2)2OCH3;
10 -(CH2)2SO2NH2; -(CH2)2 N(CH3)2; -alquilen C0-1-cicloalquilo C3-7, por ejemplo, ciclopropilo y -CH2-ciclopropilo; y -(CH2)2-imidazolilo.
R22
y R23 también pueden tomarse juntos para formar un -heterociclo C3-5 saturado o parcialmente saturado
15 opcionalmente sustituido con halo, -OH, -COOH o -CONH2 y que contiene opcionalmente un átomo de oxígeno en el anillo. Los -heterociclos C3-5 saturados incluyen azetidina, pirrolidina, piperidina y morfolina, tal que los grupos R3 ejemplares incluyen:
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20 Los -heterociclos C3-5 parcialmente insaturados incluyen 2,5-dihidro-1H-pirrol, tal que los grupos R3 ejemplares incluyen:
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El resto R24 se selecciona entre:
-alquilo C1-6, por ejemplo, -CH2CH3 y -(CH2)3CH3;
25 -alquilen C0-1-O-alquilo C1-6-, por ejemplo, -O-CH2CH3 y -CH2-OCH3; fenilo opcionalmente sustituido con halo o -OCH3, por ejemplo, -2clorofenilo o -2-metoxifenilo; y -heteroarilo C1-9, por ejemplo, 2-piridina.
R25 se selecciona entre:
-alquilo C1-6-, por ejemplo, -CH3, -CH2CH3 y -(CH2)3CH3; 30 -O-alquilo C1-6, por ejemplo, -OCH3, -OCH2CH3 y -OCH(CH3)2;
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-cicloalquilo C3-7, por ejemplo, ciclopentilo;
-O-cicloalquilo C3-7, por ejemplo, -O-ciclopropilo, -O-ciclopentilo y -O-ciclohexilo; fenilo;
-O-fenilo;
-NR27R28;
-CH[CH(CH3)2]-NH2;
-CH[CH(CH3)2]-NHC(O)O-alquilo C1-6, por ejemplo, -CH[CH(CH3)2]-NHC(O)OCH3; y
-CH(NH2)CH2COOCH3.
R27 y R28 se seleccionan independientemente entre H, -alquilo C1-6 y bencilo, o R27 y R28 se toman juntos como (CH2)3-6-, -C(O)-(CH2)3-o -(CH2)2O(CH2)2-; R33 se selecciona entre –O-alquilo C1-6, -O-bencilo y -NR27R28; y R34 es alquilo C1-6-(por ejemplo, -CH3 y -C(CH3)3) o –alquilen C0-6-arilo C6-10.
Además, cada grupo alquilo en R3 está opcionalmente sustituido con 1 a 8 átomos de flúor. Por ejemplo, cuando R3 es -alquilen C0-1-COOR21 y R21 es -alquilo C1-6, R3 también puede ser un grupo tal como -COOCH(CH3)CF3, -COOCH2CF2CF3, -COOCH(CF3)2, -COO(CH2)2CF3, -COOCH(CH2F)2, -COOC(CF3)2CH3 y -COOCH(CH3)CF2CF3.
En una realización, R3 está ausente o se selecciona entre H; halo; -alquilen C0-5-OH; -alquilo C1-6; -cicloalquilo C3-7; alquilen C0-2-Oalquilo C1-6; -C(O)R20; -alquilen C0-1-COOR21; -C(O)NR22R23; -NHC(O)R24; =O; fenilo opcionalmente sustituido con uno o dos grupos seleccionados independientemente entre halo, -OH y -OCH3; piridinilo; y pirazinilo; R20 es -alquilo C1-6; R21 es H; R22 es H o -alquilo C1-6; R23 se selecciona entre -alquilo C1-6, -(CH2)2OH, -(CH2)2OCH3, -(CH2)2SO2NH2 y –alquilen C0-1-cicloalquilo C3-7; o R22 y R23 se toman juntos para formar un –heterociclo C3-5 saturado o parcialmente insaturado opcionalmente sustituido con halo u -OH y que contiene opcionalmente un átomo de oxígeno en el anillo; y R24 es fenilo sustituido con -OCH3. En otras realizaciones estos compuestos tienen fórmula
III.
En una realización, R3 está ausente o se selecciona entre H; halo; -alquilen C0-5-OH; -NH2; -alquilo C1-6; -CF3; cicloalquilo C3-7; -alquilen C0-2-O-alquilo C1-6; -C(O)R20; -alquilen C0-1-COOR21; -C(O)NR22R23; -NHC(O)R24; =O; -NO2; -C(CH3)=N(OH); fenilo opcionalmente sustituido con uno o dos grupos seleccionados independientemente entre halo, -OH, -CF3, -OCH3, -NHC(O)CH3 y fenilo; naftalenilo; piridinilo; pirazinilo; pirazolilo opcionalmente sustituido con metilo; tiofenilo opcionalmente sustituido con metilo o halo; furanilo; y -CH2-morfolinilo; y R21 es H. En otras realizaciones estos compuestos tienen fórmula III.
En otra realización, R3 es -alquilen C0-1-COOR21 y R21 se selecciona entre -alquilo C1-6, -alquilen C1-3-arilo C6-10, alquilen C1-3-heteroarilo C1-9, -cicloalquilo C3-7, -[(CH2)2O]1-3CH3, -alquilen C1-6-OC(O)R25; -alquilen C1-6-NR27R28, alquilen C1-6-C(O)R33, -alquilenmorfolinilo C0-6, -alquilen C1-6-SO2-alquilo C1-6,
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En un aspecto de la invención, estos compuestos pueden encontrar una utilidad particular como profármacos o como intermedios en los procedimientos sintéticos descritos en el presente documento. En otras realizaciones estos compuestos tienen fórmula III.
El resto R4 puede estar ausente. Cuando está presente, R4 está unido a un átomo de nitrógeno o carbono en el grupo "X" y se selecciona entre:
H; -OH; -alquilo C1-6, por ejemplo, -CH3; -alquilen C1-2-COOR35 , por ejemplo, -CH2COOH y -(CH2)2-COOH; -CH2OC(O)CH(R36)NH2, por ejemplo, -CH2OC(O)CH[CH(CH3)2]NH2; -OCH2OC(O)CH(R36)NH2, por ejemplo, -OCH2OC(O)CH[CH(CH3)2]NH2; -OCH2OC(O)CH3; -CH2OP(O)(OH)2; -CH2CH(OH)CH2OH; -CH[CH(CH3)2]-NHC(O)O-alquilo C1-6; piridinilo; y fenilo o bencilo opcionalmente sustituido con uno o más grupos seleccionados entre halo, -COOR35, -OCH3, -OCF3 y -SCF3 (por ejemplo, 4-clorofenilo, 3-metoxifenilo, 2,4-diclorofenilo, 3,4-diclorofenilo, 2-cloro, 5-fluorofenilo, 3-trifluorometoxi, 4-clorofenilo, 3-trifluorometilsulfanilo, 4-clorofenilo, 2,6-diflúor, 4-clorofenilo, 2-clorobencilo, 3clorobencilo, 4-clorobencilo, 3-carboxibencilo, 4-carboxibencilo, 3-metoxibencilo, 2-cloro, 5-fluorobencilo, 3-cloro, 5-fluorobencilo, 2-flúor, 4-clorobencilo, 3-cloro, 4-fluorobencilo, 3-OCF3, 4-clorobencilo, 3-SCF3, 4-clorobencilo,
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R32
es -alquilo C1-6; R20 es -alquilo C1-6; R21 es H; R22 es H o -alquilo C1-6; R23 se selecciona entre –alquilo C1-6, (CH2)2OH, -(CH2)2OCH3, -(CH2)2SO2NH2 y –alquilen C0-1-cicloalquilo C3-7; o R22 y R23 se toman juntos para formar un -heterociclo C3-5 saturado o parcialmente insaturado opcionalmente sustituido con halo u -OH y que contiene opcionalmente un átomo de oxígeno en el anillo; R24 es fenilo sustituido con -OCH3; y R35 es H; y en el que cada grupo alquilo en R1 está opcionalmente sustituido con 1 a 8 átomos de flúor.
Todavía en otra realización, R2 es H; X se selecciona entre pirazol, triazol, benzotriazol, tetrazol, oxazol, isoxazol, tiazol, piridazina y pirimidina; R3 está ausente o se selecciona entre H; halo; -alquilen C0-5-OH; -alquilo C1-6; cicloalquilo C3-7-; -alquilen C0-2-O-alquilo C1-6; -C(O)R20; -alquilen C0-1-COOR21; -C(O)NR22R23; -NHC(O)R24; =O; fenilo sustituido con uno o dos grupos seleccionados independientemente entre halo, -OH y -OCH3; piridinilo; y pirazinilo; R4 se selecciona entre H, -OH y fenilo opcionalmente sustituido con un grupo halo; a es 0; o a es 1 y R5 es halo; b es 0; o b es 1 y R6 es halo o -CH3; o b es 2 y cada R6 es independientemente halo, -OH, -CH3 o -OCH3; R20 es -alquilo C1-6; R21 es H; R22 es -alquilo C1-6; R23 es -alquilo C1-6 o –alquilen C0-1-cicloalquilo C3-7; o R22 y R23 se toman juntos para formar un -heterociclo C3-5 saturado opcionalmente sustituido con halo u -OH; y R24 es fenilo sustituido con -OCH3.
Un grupo particular de compuestos de fórmula I junto con compuestos no relacionados dentro del ámbito de la presente invención se desvelan en la Solicitud Provisional de Estados Unidos Nº 61/423,175, presentada el 15 de diciembre de 2010, que desvela compuestos de fórmula II:
imagen38
en la que: R1 es -OR7 y -NR8R9; R7 se selecciona entre H; -alquilo C1-6; -alquilen C1-3-arilo C6-10;-alquilen C1-3heteroaarilo C1-9; -cicloalquilo C3-7; -(CH2)2OCH3; -alquilen C1-6-OC(O)R10; -CH2-piridina; -CH2-pirrolidina; -alquilen C06-morfolina; -alquilen C1-6-SO2-lquilo C1-6;
imagen39
en la que R10 se selecciona entre -alquilo C1-6, -O-alquilo C1-6, -cicloalquilo C3-7, -O-cicloalquilo C3-7, fenilo, -O-fenilo, -NR12R13 y -CH(NH2)CH2COOCH3; y R12 y R13 se seleccionan independientemente entre H, -alquilo C1-6-y bencilo, o
R12
y R13 se toman juntos como -(CH2)3-6-; R8 se selecciona entre H; -OH; -OC(O)R14; -CH2COOH; -O-bencilo; piridilo; y -OC(S)NR15R16; en la que R14 se selecciona entre H, -alquilo C1-6-, -arilo C6-10, -OCH2-arilo C6-10, -CH2Oarilo C6-10 y -NR15R16; y R15 y R16 se seleccionan independientemente entre H y -alquilo C1-4; R9 se selecciona entre H; -alquilo C1-6; y -C(O)R17; en la que R17 se selecciona entre H; -alquilo C1-6; -cicloalquilo C3-7; -arilo C6-10; y heteroarilo C1-9; R2 es H o se toma junto con R1 para formar -OCHR18R19-o -NHC(O)-; en la que R18 y R19 se seleccionan independientemente entre H, -alquilo C1-6 y –O-cicloalquilo C3-7, o R18 y R19 se toman juntos para formar =O; X es un -heteroarilo C1-9 o un –heterociclo C3-5 parcialmente insaturado; R3 está ausente o se selecciona entre H; halo; -alquilen C0-5-OH; -NH2; -alquilo C1-6; -cicloalquilo C3-7; -alquilen C0-1-O-alquilo C1-6-; -C(O)R20; -alquilen C0-1C(O)OR21; -C(O)NR22R23; -NHC(O)R24; fenilo opcionalmente sustituido con un grupo seleccionado entre halo, -CF3, -OCH3, -NHC(O)CH3 y fenilo; naptilo; piridina; pirazina; pirazol opcionalmente sustituido con metilo; tiofeno opcionalmente sustituido con metilo; y furano; y R3, cuando está presente, está unido a un átomo de carbono; R20 se selecciona entre H y -alquilo C1-6; R21 se selecciona entre H; -alquilo C1-6; -alquilen C1-3-arilo C6-10; -alquilen C1-3
22
imagen40
imagen41
imagen42
imagen43
imagen44
imagen45
imagen46
imagen47
imagen48
imagen49
imagen50
imagen51
imagen52
imagen53
imagen54
imagen55
imagen56
imagen57
imagen58
imagen59
imagen60
imagen61
E11805709
30-09-2015
Ej.
R1 R3 R4 Fórmula EM m/z: [M+H]+
calculado
encontrado
1
-OH -COOH H C21H20N4O6 425,14 425,2
2
-OH -C(O)NH(CH2)2-OH H C23H25N5O6 468,18 468,4
3
-OH -C(O)NH(CH2)2-SO2NH2 H C23H26N6O7S 531,16 531,4
4
-OH -C(O)NH-ciclopropilo H C24H25N5O5 464,19 464,4
5
-OH -C(O)N(CH3)-(CH2)2-OCH3 H C25H29N5O6 496,21 496,6
6
-OH -C(O)N(CH3)2 H C23H25N5O5 452,19 452,4
7
-OH -C(O)N(CH3)CH2-CH(CH3)2 H C26H3N5O5 494,23 494,6
8
-OH H C24H25N5O5 464,19 464,4
9
-OH H C25H27N5O5 478,20 478,4
10
-OH H C25H27N5O6 494,20 494,4
11
-OH H C25H27N5O6 494,20 494,4
12
-OH H C25H27N5O6 494,20 494,4
13
-OH H C25H25N5O5 476,19 476,4
14
-OH H C26H29N5O5 492,22 492,4
15
-OH H C25H27N5O6 494,20 494,4
16
-OH fenilo H C26H24N4O4 457,18 457,4
45
imagen62
imagen63
imagen64
imagen65
imagen66
imagen67
imagen68
imagen69
imagen70
imagen71
imagen72
imagen73
E11805709
30-09-2015
Ej.
R1 R3 R4 Fórmula EM m/z: [M+H]+
calculado
encontrado
11
-OH H C25H26ClN5O5 512,16 512,4
12
-OH H C24H24ClN5O5 498,15 498,6
13
-OH -C(O)N(CH3)2 H C23H24ClN5O5 486,15 486,4
14
-OH H C25H26ClN5O6 528,16 528,2
15
-OH 2-clorofenilo H C26H22Cl2N4O4 525,10 525,4
16
-OH -C(O)N(CH3)-[CH2CH(CH3)2] H C26H30ClN5O5 528,19 528,2
17
-OH -C(O)N(CH3)-ciclopropilo H C26H28ClN5O5 526,18 526,4
18
-OH imagen74 H C24H23ClFN5O5 516,14 516,4
19
-OH 2-hidroxifenilo H C26H23ClN4O5 507,14 507,2
20
-OH 2-metoxifenilo H C27H25ClN4O5 521,15 521,2
21
-OH H C25H22ClN5O4 492,14 492,2
22
-OH -(CH2)3CH3 H C24H27ClN4O4 471,17 471,2
23
-OH -COOH H C21H19ClN4O6 459,10 459,2
24
-OH H C24H21ClN6O4 493,13 493,2
25
-OH -C(O)CH3 H C22H21ClN4O5 457,12 457,2
26
-OH -CH2OCH3 H C22H23ClN4O5 459,14 459,2
27
-OH -C(CH3)2OH H C23H25ClN4O5 473,15 473,2
11. Ácido (R)-3-{N-(3’-clorobifenil-4-ilmetil)-N’-[5-(pirrolidina-1-carbonil)-2H-pirazol-3-carbonil]-hidrazino}-2-hidroxipropiónico
5 12. Ácido (R)-3-[N’-[5-(Azetidin-1-carbonil)-2H-pirazol-3-carbonil]-N-(3’-clorobifenil-4-ilmetil)-hidrazino]-2-hidroxipropiónico
58
imagen75
imagen76
imagen77
imagen78
imagen79
imagen80
imagen81
imagen82
imagen83
imagen84
imagen85
Ej.
R1 R3 R4 b R6 Fórmula EM m/z: [M+H]+
calculado
encontrado
1
-OH -OH H 2 2'-Me, 5'-Cl C21H20ClN3O6 446,10 446,4
2
-OH -OH H 2 2'-OMe, 5'-Cl C21H20ClN3O7 462,10 462,2
3
-OCH2-CH3 -OH H 2 2'-OMe, 5'-Cl C23H24ClN3O7 490,13 490,4
4
-OH -OH H 2 2'-OMe, 5'-F C21H20FN3O7 446,13 446,4
5
-OH -OH H 2 2'-OH, 5'-F C20H18FN3O7 432,11 432,4
6
-OH -OH H 2 2'-OH, 5'-Cl C20H18ClN3O7 448,08 448,0
7
-OH -OH H 2 2'-OH, 3'-Cl C20H18ClN3O7 448,08 448,0
8
-OH -OH H 2 2'-F, 5'-Cl C20H17ClFN3O6 450,08 450,2
9
-OH -OCH3 H 2 2'-F, 5'-Cl C21H19ClFN3O6 464,09 464,0
10
-OCH2-CH3 -OCH3 H 2 2'-F, 5'-Cl C23H23ClFN3O6 492,13 492,2
11
-OCH-(CH3)2 -OCHh3 H 2 2'-F, 5'-Cl C24H25ClFN3O6 506,14 506,4
12
-OCH2-CH-(CH3)2 -OCH3 H 2 2'-F, 5'-Cl C25H27ClFN3O6 520,16 520,2
13
-OH H 2 2'-F, 5'-Cl C26H20ClF2N3O5 528,11 528,0
14
-OH -CH2-CH3 H 2 2'-F, 5'-Cl C22H21ClFN3O5 462,12 462,0
15
-OH H 2 2'-F, 5'-Cl C27H23ClFN3O6 540,13 540,2
16
-OH H 2 2'-F, 5'-Cl C26H20Cl2FN3O5 544,08 544,0
17
-OH H 2 2’-F, 5’-Cl C26H20Cl2FN3O5 544,08 544,0
18
-OH H 2 2’-F, 5’-Cl C26H20ClF 2N3O5 528,11 528,2
69 (continuación)
Ej.
R1 R3 R4 b R6 Fórmula EM m/z: [M+H]+
calculado
encontrado
19
-O-CH2-CH3 H 2 2’-F, 5’-Cl C28H24ClF2N3O5 556,14 556,2
20
H 2 2’-F, 5’-Cl C32H31ClF2N4O6 641,19 641,2
21
-OH -OH H 2 2’-F, 3’-Cl C20H17ClFN3O6 450,08 450,2
22
-OH -OH H 2 2’, 5’-diCl C20H17Cl2N3O6 466,05 466,2
23
-OH -OH H 3 2’-F, 3’-Me, 5’-Cl C21H19ClFN3O6 464,09 464,4
24
-OH -OH H 2 3’-F, 5’-Cl C20H17ClFN3O6 450,08 450,2
25
-OH -OH H 2 3’, 5’-diCl C20H17Cl2N3O6 466,05 466,2
26
-OH -OH H 2 3’, 5’-diF C20H17F2N3O6 434,11 434,4
27
-OH -OH H 2 3’-OH, 5’-Cl C20H18ClN3O7 448,08 448,0
28
-OH -OH H 3 2’-Me, 3’, 5’-diCl C21H19Cl2N3O6 480,07 480,2
29
-OH -Cl H 2 2’-F, 5’-Cl C20H16Cl2FN3O5 468,05 468,2
30
-OH -CH2CH-(CH3)2 H 2 2’-F, 5’-Cl C24H25ClFN3O5 490,15 490,2
31
-OH -(CH2)2CH3 H 2 2’-F, 5’-Cl C23H23ClFN3O5 476,13 476,2
32
-OH -CH(CH3)2 H 2 2’-F, 5’-Cl C23H23ClFN3O5 476,13 476,4
33
-OH -C(CH3)3 H 2 2’-F, 5’-Cl C24H25ClFN3O5 490,15 489,8
1.
Ácido (R)-3-[N-(5’-cloro-2’-metil-bifenil-4-ilmetil)-N’-(3-hidroxi-isoxazol-5-carbonil)-hidrazino]-2-hidroxi-propiónico
2.
Ácido (R)-3-[N-(5’-cloro-2’-metoxi-bifenil-4-ilmetil)-N’-(3-hidroxi-isoxazol-5-carbonil)-hidrazino]-2-hidroxi-propiónico
5 3. Éster etílico del ácido (R)-3-[N-(5’-cloro-2’-metoxi-bifenil-4-ilmetil)-N’-(3-hidroxi-isoxazol-5-carbonil)-hidrazino]-2hidroxi-propiónico
4.
Éster etílico del ácido (R)-3-[N-(5’-fluoro-2’-metoxi-bifenil-4-ilmetil)-N’-(3-hidroxi-isoxazol-5-carbonil)-hidrazino]-2hidroxi-propiónico
5.
Ácido (S)-3-[N-(5’-fluoro-2’-hidroxi-bifenil-4-ilmetil)-N’-(3-hidroxi-isoxazol-5-carbonil)-hidrazino]-2-hidroxi-propiónico
10 6. Ácido (S)-3-[N-(5’-cloro-2’-hidroxi-bifenil-4-ilmetil)-N’-(3-hidroxi-isoxazol-5-carbonil)-hidrazino]-2-hidroxi-propiónico
7.
Ácido (R)-3-[N-(3’-cloro-2’-hidroxi-bifenil-4-ilmetil)-N’-(3-hidroxi-isoxazol-5-carbonil)-hidrazino]-2-hidroxi-propiónico
8.
Ácido (R)-3-[N-(5’-cloro-2’-fluoro-bifenil-4-ilmetil)-N’-(3-hidroxi-isoxazol-5-carbonil)-hidrazino]-2-hidroxi-propiónico
9.
Ácido (R)-3-[N-(5’-cloro-2’-fluoro-bifenil-4-ilmetil)-N’-(3-metoxi-isoxazol-5-carbonil)-hidrazino]-2-hidroxi-propiónico
10. Éster etílico del ácido (R)-3-[N-(5’-Cloro-2’-fluoro-bifenil-4-ilmetil)-N’-(3-metoxi-isoxazol-5-carbonil)-hidrazino]-215 hidroxi-propiónico
11.
Éster isopropílico del ácido (R)-3-[N-(5’-Cloro-2’-fluoro-bifenil-4-ilmetil)-N’-(3-metoxi-isoxazol-5-carbonil)hidrazino]-2-hidroxi-propiónico
12.
Éster isobutílico del ácido (R)-3-[N-(5’-Cloro-2’-fluoro-bifenil-4-ilmetil)-N’-(3-metoxi-isoxazol-5-carbonil)-hidrazino]2-hidroxi-propiónico
20 13. Ácido (R)-3-{N-(5’-cloro-2’-fluoro-bifenil-4-ilmetil)-N’-[3-(3-fluoro-fenil)-isoxazol-5-carbonil]-hidrazino}-2-hidroxipropiónico
14.
Ácido (R)-3-[N-(5’-cloro-2’-fluoro-bifenil-4-ilmetil)-N’-(3-etil-isoxazol-5-carbonil)-hidrazino]-2-hidroxi-propiónico
15.
Ácido (R)-3-{N-(5’-cloro-2’-fluoro-bifenil-4-ilmetil)-N’-[3-(2-metoxi-fenil)-isoxazol-5-carbonil]-hidrazino}-2-hidroxi
propiónico 25 16. Ácido (R)-3-{N-(5’-cloro-2’-fluoro-bifenil-4-ilmetil)-N’-[3-(3-cloro-fenil)-isoxazol-5-carbonil]-hidrazino}-2-hidroxi
70
imagen86
Ej.
R1 R3 R4 b R6 Fórmula EM m/z: [M+H]+
calculado
encontrado
35
-OH -C(O)-N(CH3)2 H 2 2’-F, 5’-Cl C23H23ClFN5O5 504,14 504,2
36
-OH H 2 2’-F, 5’-Cl C25H21ClFN5O4 510,13 510,2
37
-OCH2-CH3 H 2 2’-F, 5’-Cl C27H25ClFN5O4 538,16 538,4
38
-OH H 2 2’-F, 5’-Cl C26H22ClFN4O5 525,13 525,2
39
-OH imagen87 H 2 2’-F, 5’-Cl C27H24ClFN4O5 539,14 539,2
40
-OH -C(CH3)2-OH H 2 2’-F, 5’-Cl C23H24ClFN4O5 491,14 491,2
41
-OH H 2 2’-F, 5’-Cl C26H20Cl3FN4O4 577,05 577,0
42
-OH -(CH2)3CH3 H 2 2’-F, 5’-Cl C24H26ClFN4O4 489,16 489,2
43
-OH ciclopropilo H 2 2’-F, 5’-Cl C23H22ClFN4O4 473,13 473,2
44
-OH -CH(CH3)2 H 2 2’-F, 5’-Cl C23H24ClFN4O4 475,15 475,2
45
-OH -C(O)CH3 H 2 2’-F, 5’-Cl C22H20ClFN4O5 475,11 475,2
46
-OCH2-CH3 -C(O)CH3 H 2 2’-F, 5’-Cl C24H24ClFN4O5 503,14 503,2
47
-OH -C(O)CH3 H 2 2’-Me, 5’-Cl C23H23ClN4O5 471,14 471,4
48
-OH -C(O)CH3 H 2 2’, 5’-diCl C22H20Cl2N4O5 491,08 491,0
49
-OH H 2 2’-F, 5’-Cl C28H25ClFN5O6 582,15 582,2
35. Ácido (R)-3-[N-(5’-cloro-2’-fluoro-bifenil-4-ilmetil)-N’-(5-dimetilcarbamoil-2H-pirazol-3-carbonil)-hidrazino]-2hidroxi-propiónico
5 36. Ácido (R)-3-[N-(5’-cloro-2’-fluoro-bifenil-4-ilmetil)-N’-(5-piridm-2-il-2H-pirazol-3-carbonil)-hidrazino]-2-hidroxipropiónico
37.
Éster etílico del ácido (R)-3-[N-(5’-cloro-2’-fluoro-bifenil-4-ilmetil)-N’-(5-piridm-2-il-2H-pirazol-3-carbonil)hidrazino]-2-hidroxi-propiónico
38.
Ácido (R)-3-{N-(5’-cloro-2’-fluoro-bifenil-4-ilmetil)-N’-[5-(2-hidroxi-fenil)-2H-pirazol-3-carbonil]-hidrazino}-2-hidroxipropiónico
5 39. Ácido (R)-3-{N-(5’-Cloro-2’-fluoro-bifenil-4-ilmetil)-N’-[5-(2-metoxi-fenil)-2H-pirazol-3-carbonil]-hidrazino}-2-hidroxipropiónico
72
40. Ácido (R)-3-{N-(5’-cloro-2’-fluoro-bifenil-4-ilmetil)-N’-[5-(1-hidroxi-1-metiletil)-2H-pirazol-3-carbonil]-hidrazino}-2hidroxi-propiónico
41.
Ácido (R)-3-{N-(5’-cloro-2’-fluoro-bifenil-4-ilmetil)-N’-[5-(2,5-dicloro-fenil)-2H-pirazol-3-carbonil]-hidrazino}-210 hidroxi-propiónico
42.
Ácido (R)-3-[N’-(5-butil-2H-pirazol-3-carbonil)-N-(5’-cloro-2’-fluoro-bifenil-4-ilmetil)-hidrazino]-2-hidroxi-propiónico
43.
Ácido (R)-3-[N-(5’-cloro-2’-fluoro-bifenil-4-ilmetil)-N’-(5-ciclopropil-2H-pirazol-3-carbonil)-hidrazino]-2-hidroxipropiónico
44.
Ácido (R)-3-[N-(5’-cloro-2’-fluoro-bifenil-4-ilmetil)-N’-(5-isopropil-2H-pirazol-3-carbonil)-hidrazino]-2-hidroxi15 propiónico
45.
Ácido (S)-3-[N’-(5-acetil-2H-pirazol-3-carbonil)-N-(5’-cloro-2’-fluoro-bifenil-4-ilmetil)-hidrazino]-2-hidroxi-propiónico
46.
Éster etílico del ácido (S)-3-[N’-(5-Acetil-2H-pirazol-3-carbonil)-N-(5’-cloro-2’-fluoro-bifenil-4-ilmetil)-hidrazino]-2hidroxi-propiónico
47. Ácido (S)-3-[N’-(5-acetil-2H-pirazol-3-carbonil)-N-(5’-cloro-2’-metil-bifenil-4-ilmetil)-hidrazino]-2-hidroxi-propiónico 20 48. Ácido (S)-3-[N’-(5-acetil-2H-pirazol-3-carbonil)-N-(2’,5’-dicloro-bifenil-4-ilmetil)-hidrazino]-2-hidroxi-propiónico
49. Ácido (R)-3-{N-(5’-cloro-2’-fluoro-bifenil-4-ilmetil)-N’-[5-(2-metoxi-benzoilamino)-2H-pirazol-3-carbonil]-hidrazino}2-hidroxi-propiónico
imagen88
Ej.
R1 R3 R4 b R6 Fórmula EM m/z: [M+H]+
calculado
encontrado
50
-OH H 2 2’-F, 5’-Cl C24H20ClFN6O4 511,12 511,2
51
-OH -OH 2 2’-F, 5’-Cl C25H21ClFN5O5 526,12 526,4
52
-OH -OH 2 2’-F, 5’-Cl C26H21ClF2N4O5 543,12 543,6
53
-OH ciclo-propilo -CH2-COOH 2 2’-F, 5’-Cl C25H24ClFN4O6 531,14 531,0
54
-OH -CH-(CH3)2 -CH2-COOH 2 2’-F, 5’-Cl C25H26ClFN4O6 533,15 533,2
55
-OH -(CH2)3-CH3 -CH2-COOH 2 2’-F, 5’-Cl C26H28ClFN4O6 547,17 547,0
56
-OH -C(CH3)2-OH -CH2-COOH 2 2’-F, 5’-Cl C25H26ClFN4O7 549,15 549,0
57
-OH -o-CH2CH3 H 2 2’-F, 5’-Cl C22H22ClFN4O5 477,13 477,2
25
50. Ácido propiónico
(R)-3-[N-(5’-cloro-2’-fluoro-bifenil-4-ilmetil)-N’-(5-pirazin-2-il-1H-pirazol-3-carbonil)-hidrazino]-2-hidroxi
73
imagen89
imagen90
imagen91
imagen92
imagen93
imagen94
imagen95
imagen96
imagen97
(continuación)
Ej.
pKi imagen98 Ej. pKi
2-21
7,0-7,9 8-22 ≥ 9,0
1
> 9,0 8-1 > 9,0
2-22
6,0-6,9 8-23 8,0-8,9
2-23
6,0-6,9 8-24 8,0-8,9
2-24
6,0-6,9 8-25 > 9,0
2-25
6,0-6,9 8-26 7,0-7,9
3A
n.d. 8-27 > 9,0
3B
> 9,0 8-28 7,0-7,9
3C
n.d. 8-29 8,0-8,9
3D
n.d. 8-30 > 9,0
3E
n.d. 8-31 > 9,0
3F
n.d. 8-32 > 9,0
3G
n.d. 8-33 8,0-8,9
3H
n.d. 8-34 8,0-8,9
31
n.d. 8-35 > 9,0
3J
n.d. 8-36 > 9,0
3K
> 9,0 8-37 n.d.
3L
n.d. 8-38 > 9,0
3 M
n.d. 8-39 > 9,0
4-1
8,0-8,9 8-40 > 9,0
4-2
8,0-8,9 8-41 > 9,0
4-3
8,0-8,9 8-42 > 9,0
4-4
> 9,0 8-43 > 9,0
4-5
> 9,0 8-44 > 9,0
4-6
n.d. 8-45 > 9,0
4-7
n.d. 8-46 n.d.
4-8
n.d. 8-47 8,0-8,9
4-9
8,0-8,9 8-48 8,0-8,9
4-10
8,0-8,9 8-49 > 9,0
4-11
> 9,0 8-50 > 9,0
4-12
> 9,0 8-51 8,0-8,9
4-13
> 9,0 8-52 8,0-8,9
4-14
> 9,0 8-53 8,0-8,9
83 (continuación)
Ej.
pKi Ej. pKi
4-15
> 9,0 8-54 8,0-8,9
4-16
> 9,0 8-55 8,0-8,9
4-17
> 9,0 8-56 8,0-8,9
4-18
> 9,0 8-57 8,0-8,9
4-19
8,0-8,9 8-58 > 9,0
4-20
8,0-8,9 8-59 > 9,0
1
> 9,0 8-1 > 9,0
4-21
8,0-8,9 8-60 > 9,0
4-22
> 9,0 8-61 n.d.
4-23
> 9,0 8-62 n.d.
4-24
8,0-8,9 8-63 n.d.
4-25
> 9,0 8-64 > 9,0
4-26
8,0-8,9 8-65 8,0-8,9
4-27
8,0-8,9 8-66 8,0-8,9
4-28
7,0-7,9 8-67 ≥ 9,0
4-29
≥ 9,0 8-68 8,0-8,9
4-30
8,0-8,9 8-69 > 9,0
4-31
8,0-8,9 8-70 n.d.
4-32
8,0-8,9 8-71 n.d.
4-33
n.d. 8-72 n.d.
4-34
> 9,0 8-73 > 9,0
4-35
> 9,0 8-74 > 9,0
4-36
7,0-7,9 8-75 > 9,0
4-37
7,0-7,9 8-76 > 9,0
4-38
> 9,0 8-77 n.d.
4-39
8,0-8,9 8-78 n.d.
4-40
8,0-8,9 8-79 n.d.
4-41
8,0-8,9 8-80 > 9,0
4-42
8,0-8,9 8-81 7,0-7,9
5-1
8,0-8,9 8-82 > 9,0
5-2
7,0-7,9 8-83 > 9,0
5-3
8,0-8,9 8-84 n.d.
5-4
> 9,0 9A > 9,0
84
imagen99
imagen100

Claims (1)

  1. imagen1
    imagen2
    imagen3
    imagen4
    imagen5
    imagen6
    imagen7
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Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100518998C (zh) * 2005-09-29 2009-07-29 宝山钢铁股份有限公司 薄带连铸结晶辊加热方法和装置
ES2548887T3 (es) 2010-12-15 2015-10-21 Theravance Biopharma R&D Ip, Llc Inhibidores de neprilisina
ES2550324T3 (es) 2010-12-15 2015-11-06 Theravance Biopharma R&D Ip, Llc Inhibidores de neprilisina
EP2675792B1 (en) * 2011-02-17 2016-01-06 Theravance Biopharma R&D IP, LLC Substituted aminobutyric derivatives as neprilysin inhibitors
RU2604522C2 (ru) * 2011-02-17 2016-12-10 ТЕРЕВАНС БАЙОФАРМА Ар энд Ди АйПи,ЭлЭлСи Замещенные аминомасляные производные в качестве ингибиторов неприлизина
EP2714662B1 (en) 2011-05-31 2017-10-11 Theravance Biopharma R&D IP, LLC Neprilysin inhibitors
EP2714660B1 (en) 2011-05-31 2018-09-26 Theravance Biopharma R&D IP, LLC Neprilysin inhibitors
TWI560172B (en) 2011-11-02 2016-12-01 Theravance Biopharma R&D Ip Llc Neprilysin inhibitors
US9271965B2 (en) 2012-03-28 2016-03-01 Theravance Biopharma R&D Ip, Llc Crystalline forms of (R)-3-[N-(3'-chlorobiphenyl-4-ylmethyl)-N'-(3-hydroxyisoxazole-5-carbonyl)hydrazino]-2-hydroxyproprionic acid isopropyl ester
JP6088047B2 (ja) * 2012-05-31 2017-03-01 セラヴァンス バイオファーマ アール＆ディー アイピー， エルエルシー 一酸化窒素ドナーであるネプリライシン阻害剤
CA2873328A1 (en) 2012-06-08 2013-12-12 Theravance Biopharma R&D Ip, Llc Neprilysin inhibitors
US9108934B2 (en) 2012-06-08 2015-08-18 Theravance Biopharma R&D Ip, Llc Neprilysin inhibitors
NZ704741A (en) 2012-08-08 2017-10-27 Theravance Biopharma R&D Ip Llc Neprilysin inhibitors
EP2964616B1 (en) 2013-03-05 2017-05-03 Theravance Biopharma R&D IP, LLC Neprilysin inhibitors
JP2017507921A (ja) 2014-01-30 2017-03-23 セラヴァンス バイオファーマ アール＆ディー アイピー， エルエルシー ネプリライシン阻害剤
JP2017504625A (ja) 2014-01-30 2017-02-09 セラヴァンス バイオファーマ アール＆ディー アイピー， エルエルシー ネプリライシン阻害剤としての５−ビフェニル−４−ヘテロアリールカルボニルアミノ−ペンタン酸誘導体
ES2923002T3 (es) 2015-02-11 2022-09-22 Theravance Biopharma R&D Ip Llc Acido (2S,4R)-5-(5'-cloro-2'-fluorobifenil-4-il)-4-(etoxioxailamino)-2-hidroximetil-2-metilpentanoico como inhibidor de la neprilisina
RU2715241C2 (ru) 2015-02-19 2020-02-26 ТЕРЕВАНС БАЙОФАРМА Ар энд Ди АйПи, ЭлЭлСи (2r,4r)-5-(5′-хлор-2′-фторбифенил-4-ил)-2-гидрокси-4-[(5-метилоксазол-2-карбонил)амино]пентановая кислота
WO2017156009A1 (en) 2016-03-08 2017-09-14 Theravance Biopharma R&D Ip, Llc Crystalline(2s,4r)-5-(5'-chloro-2'-fluoro-[1,1'-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoic acid and uses thereof
EP3548039B1 (en) 2016-12-04 2023-07-19 Alavi Khorassani Moghadam, Marcel Victor Ribavirin for use in the treatment of a mitochondrial disease
TWI794385B (zh) 2018-01-03 2023-03-01 美商藝康美國公司 作為腐蝕抑制劑之苯并三唑衍生物
UY38072A (es) 2018-02-07 2019-10-01 Novartis Ag Compuestos derivados de éster butanoico sustituido con bisfenilo como inhibidores de nep, composiciones y combinaciones de los mismos

Family Cites Families (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4189604A (en) 1975-07-22 1980-02-19 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Bestatin
US4206232A (en) 1976-05-10 1980-06-03 E. R. Squibb & Sons, Inc. Relieving hypertension with carboxyalkylacylamino acids
IL58849A (en) 1978-12-11 1983-03-31 Merck & Co Inc Carboxyalkyl dipeptides and derivatives thereof,their preparation and pharmaceutical compositions containing them
FR2480747A1 (fr) 1980-04-17 1981-10-23 Roques Bernard Derives d'acides amines et leur application therapeutique
US4906615A (en) 1980-12-18 1990-03-06 Schering Corporation Substituted dipeptides as inhibitors of enkephalinases
US4722810A (en) 1984-08-16 1988-02-02 E. R. Squibb & Sons, Inc. Enkephalinase inhibitors
US4939261A (en) 1984-06-08 1990-07-03 Ciba-Geigy Corporation N-substituted butyramide derivatives useful for treatment of conditions responsive to inhibition of enkephalinase
EP0225292A3 (en) 1985-12-06 1988-11-30 Ciba-Geigy Ag Certain n-substituted butyramide derivatives
US4929641B1 (en) 1988-05-11 1994-08-30 Schering Corp Mercapto-acylamino acid antihypertensives
KR880007441A (ko) 1986-12-11 1988-08-27 알렌 제이.스피겔 스피로-치환된 글루타르아미드 이뇨제
FR2623498B1 (fr) 1987-11-24 1990-04-06 Bioprojet Soc Civ Nouveaux composes enantiomeres derives d'amino-acides, leur procede de preparation et leurs applications therapeutiques
GB8820844D0 (en) 1988-09-05 1988-10-05 Pfizer Ltd Therapeutic agents
US5599951A (en) 1989-09-15 1997-02-04 Societe Civile Bioprojet Amino acid derivatives, the process for their preparation and their applications to therapy
US5294632A (en) 1991-05-01 1994-03-15 Ciba-Geigy Corporation Phosphono/biaryl substituted dipetide derivatives
US5155100A (en) 1991-05-01 1992-10-13 Ciba-Geigy Corporation Phosphono/biaryl substituted dipeptide derivatives
US5217996A (en) 1992-01-22 1993-06-08 Ciba-Geigy Corporation Biaryl substituted 4-amino-butyric acid amides
US5508272A (en) 1993-06-15 1996-04-16 Bristol-Myers Squibb Company Compounds containing a fused bicycle ring and processes therefor
DE19510566A1 (de) 1995-03-23 1996-09-26 Kali Chemie Pharma Gmbh Benzazepin-, Benzoxazepin- und Benzothiazepin-N-essigsäurederivate sowie Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel
CA2218716A1 (en) 1995-04-21 1996-10-24 Novartis Ag N-aroylamino acid amides as endothelin inhibitors
US6660756B2 (en) 2001-03-28 2003-12-09 Pfizer Inc. N-phenpropylcyclopentyl-substituted glutaramide derivatives as inhibitors of neutral endopeptidase
GB0119305D0 (en) 2001-04-12 2001-10-03 Aventis Pharma Gmbh Mercaptoacetylamide derivatives,a process for their preparation and their use
EP2385037A1 (en) * 2003-06-24 2011-11-09 Chemtura Corporation Fungicidal phenoxyphenylhydrazine derivatives
WO2006027680A1 (en) 2004-09-10 2006-03-16 Pfizer Limited 3-(1-carbamoylcyclohexyl) propionic acid derivatives as inhibitors of neutral endopeptidase enzyme
ATE429417T1 (de) * 2005-02-10 2009-05-15 Medivir Ab Hiv-protease-inhibitoren
AR057882A1 (es) 2005-11-09 2007-12-26 Novartis Ag Compuestos de accion doble de bloqueadores del receptor de angiotensina e inhibidores de endopeptidasa neutra
WO2007106708A2 (en) 2006-03-10 2007-09-20 Novartis Ag Combinations of the angiotensin ii antagonist valsartan and the nep inhibitor daglutril
KR101580067B1 (ko) 2007-01-12 2015-12-23 노파르티스 아게 5-바이페닐-4-아미노-2-메틸 펜탄산의 제조 방법
TWI448284B (zh) 2007-04-24 2014-08-11 Theravance Inc 雙效抗高血壓劑
PE20091364A1 (es) 2008-01-17 2009-10-13 Novartis Ag Proceso para la preparacion de inhibidores de nep
ME01923B (me) * 2009-05-28 2015-05-20 Novartis Ag Supstituisani derivati aminopropionske kiseline kao inhibitori neprilizina
SG176010A1 (en) * 2009-05-28 2011-12-29 Novartis Ag Substituted aminobutyric derivatives as neprilysin inhibitors
JO2967B1 (en) 2009-11-20 2016-03-15 نوفارتس ايه جي Acetic acid derivatives of carbamoyl methyl amino are substituted as new NEP inhibitors
CN102712585B (zh) 2010-01-22 2015-06-24 诺华股份有限公司 中性内肽酶抑制剂中间体和其制备方法
US8673974B2 (en) 2010-11-16 2014-03-18 Novartis Ag Substituted amino bisphenyl pentanoic acid derivatives as NEP inhibitors
US8993631B2 (en) 2010-11-16 2015-03-31 Novartis Ag Method of treating contrast-induced nephropathy
ES2548887T3 (es) 2010-12-15 2015-10-21 Theravance Biopharma R&D Ip, Llc Inhibidores de neprilisina
ES2550324T3 (es) 2010-12-15 2015-11-06 Theravance Biopharma R&D Ip, Llc Inhibidores de neprilisina
RU2604522C2 (ru) * 2011-02-17 2016-12-10 ТЕРЕВАНС БАЙОФАРМА Ар энд Ди АйПи,ЭлЭлСи Замещенные аминомасляные производные в качестве ингибиторов неприлизина
EP2675792B1 (en) * 2011-02-17 2016-01-06 Theravance Biopharma R&D IP, LLC Substituted aminobutyric derivatives as neprilysin inhibitors
EP2714662B1 (en) 2011-05-31 2017-10-11 Theravance Biopharma R&D IP, LLC Neprilysin inhibitors
EP2714660B1 (en) 2011-05-31 2018-09-26 Theravance Biopharma R&D IP, LLC Neprilysin inhibitors
WO2012166389A1 (en) 2011-05-31 2012-12-06 Theravance, Inc. Neprilysin inhibitors
TWI560172B (en) 2011-11-02 2016-12-01 Theravance Biopharma R&D Ip Llc Neprilysin inhibitors
US9271965B2 (en) 2012-03-28 2016-03-01 Theravance Biopharma R&D Ip, Llc Crystalline forms of (R)-3-[N-(3'-chlorobiphenyl-4-ylmethyl)-N'-(3-hydroxyisoxazole-5-carbonyl)hydrazino]-2-hydroxyproprionic acid isopropyl ester
JP6088047B2 (ja) 2012-05-31 2017-03-01 セラヴァンス バイオファーマ アール＆ディー アイピー， エルエルシー 一酸化窒素ドナーであるネプリライシン阻害剤
US9108934B2 (en) 2012-06-08 2015-08-18 Theravance Biopharma R&D Ip, Llc Neprilysin inhibitors
CA2873328A1 (en) 2012-06-08 2013-12-12 Theravance Biopharma R&D Ip, Llc Neprilysin inhibitors
NZ704741A (en) 2012-08-08 2017-10-27 Theravance Biopharma R&D Ip Llc Neprilysin inhibitors

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