AR060095A1 - Derivados de himbacina monociclicos y biciclicos utiles como antogonistas de los receptores de trombina - Google Patents

Derivados de himbacina monociclicos y biciclicos utiles como antogonistas de los receptores de trombina

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AR060095A1
AR060095A1 ARP070101263A ARP070101263A AR060095A1 AR 060095 A1 AR060095 A1 AR 060095A1 AR P070101263 A ARP070101263 A AR P070101263A AR P070101263 A ARP070101263 A AR P070101263A AR 060095 A1 AR060095 A1 AR 060095A1
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Argentina
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alkyl
group
hydrogen
ring
aminoalkyl
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Schering Corp
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Abstract

Reivindicacion 1: Un compuesto representado mediante la formula estructural (1), o una sal de dicho compuesto, aceptable para uso farmacéutico, donde la línea punteada representa un enlace doble o un enlace simple, segun lo permitido por el requerimiento de valencia; con la condicion de que R10 esté ausente cuando el carbono al cual se une R10 sea parte de un enlace doble; B es -(CH2)n3-, -(CH2)-O-, -(CH2)S-, -(CH2)-NR6-, -C(O)NR6-, -NR6C(O)-, ciclopropileno, (CH2)n4CR12=CR12a(CH2)n5- o -(CH2)n4CsC(CH2)n5- donde n3 es 0-5, n4 y n5 son independientemente 0-2, y R12 y R12a se seleccionan independientemente del grupo formado por hidrogeno, alquilo y halogeno; G y J se seleccionan independientemente del grupo formado por -(CR1R2)-, - O-, -C(O)-, -S-, -S(O)- y -S(O)2-; con la condicion de que la seleccion de. G y J no de como resultado átomos de oxígeno o de azufre adyacentes y que por lo menos un átomo de carbono aparezca entre dichos átomos de oxigeno, nitrogeno o azufre; cada n es 0, 1 o 2 con la condicion de que la suma de variables n sea 1, 2 o 3; Het es un grupo heteroaromático mono-, bi- o tricíclico de 5 a 14 átomos compuesto por 1 a 13 átomos de carbono y 1 a 4 heteroátomos seleccionados independientemente del grupo formado por N, O y S, con la condicion de que no haya átomos de oxigeno o de azufre adyacentes presentes en el grupo heteroaromático, donde un nitrogeno del anillo puede formar un N-oxido o un grupo cuaternario con un grupo alquilo, donde Het está unido a B por un miembro del anillo del átomo de carbono, y donde el grupo Het está sustituido con 1 a 4 porciones W, donde cada W se selecciona independientemente del grupo formado por hidrogeno; alquilo; fluoroalquilo; difluoroalquilo; trifluoroalquilo; cicloalquilo; heterocicloalquilo; heterocicloalquilo sustituido con alquilo o alquenilo; R21-aril-alquilo; R21-aril-alquenilo; heteroarilo; heteroarilalquilo; heteroarilalquenilo; hidroxialquilo; dihidroxialquilo; aminoalquilo; alquilaminoalquilo; di-(alquil)-aminoalquilo; tioalquilo; alcoxi; alqueniloxi; halogeno; -NR4R5; -CN; -OH; -C(O)OR17; -COR16; -OS(O2)CF3; -CH2OCH2CF3; alquiltio; -C(O)NR4R5; -OCHR6-fenilo; fenoxialquilo; -NHCOR16; -NHC(O)OR16; -NHSO2R16; bifenilo; - OC(R6)2COOR7; -C(R6)2C(O)NR4R5; alcoxi sustituido con alquilo, amino o -NHC(O)OR17; R21-arilo; R21-heteroarilo; alquilo opcionalmente sustituido con -NR1R2, -NR1COR2, -NR1CONR1R2, NR1C(O)OR2, -NR1S(O)2R2, -NR1S(O)2NR1R2, -C(O)OR1, -CONR1R2, heteroarilo, hidroxialquilo o -S(O)2-alquilo; o -C(O)NR4R5 donde los carbonos adyacentes en el anillo Het pueden formar opcionalmente un anillo con un grupo metilendioxi; R1 y R2 se seleccionan independientemente del grupo formado por hidrogeno, alquilo, fluoroalquilo, difluoroalquilo, trifluoroalquilo, cicloalquilo, alquenilo, alcoxi, arilalquilo, arilalquenilo, heteroarilalquilo, heteroarilalquenilo, hidroxi, hidroxialquilo, alcoxialquilo, aminoalquilo, arilo y tioalquilo; o R1 y R2 cuando se unen a nitrogeno, tomados en conjunto, forman un anillo heterocíclico mono o bicíclico de 4 a 10 átomos, con 1-3 heteroátomos seleccionados entre -O-, -N-, -S-, -S(O)-, -S(O)2- y -C(O)-, con la condicion de anillo heterocíclico está no sustituido o sustituido con uno o más grupos seleccionados entre alquilo, halogeno, hidroxi, alcoxi, ariloxi y arilalcoxi; R3 es R1, fluoroalcoxi, difluoroalcoxi, trifluoroalcoxi, cicloalquiloxi, alqueniloxi, alcoxi, arilalcoxi, aril-alqueniloxi, heteroarilalcoxi, heteroarilalqueniloxi, hidroxialcoxi, alcoxialcoxi, aminoalcoxi, ariloxi o tioalcoxi; R8 es R34-alquilo, R34-aquenilo, R34-aIquinilo, R40-heterocicloalquilo, R38-arilo, R38-aralquilo, R42-cicloalquilo, R42-cicloalquenilo, -OH, - OC(O)R43, -C(O)OR43, -C(O)R43, -C(O)NR43R44, -NR43R44, -NR43C(O)R44, NR43C(O)OR44, NR43C(O)NR44R45, -NHS(O)2R43, -OC(O)NR43R44, R37-alcoxi, R37-alqueniloxi, R37-alquiniloxi, R40-heterocicloalquiloxi, R42-cicloalquiloxi, R42-cicloalqueniloxi, R42- cicloalquil-NH-, -NHSO2NHR16 o -CH(=NOR17); o R3 y R8 en conjunto son =NOR17; R6 es hidrogeno, alquilo o fenilo; R7 es hidrogeno o alquilo; cada R13 se selecciona Independientemente entre hidrogeno, alquilo, cicloalquilo, haloalquilo, halogeno, - (CH2)n6NHC(O)OR16b, -(CH2)n6NHC(O)R16b, -(CH2)n6NHC(O)NR4R5, -(CH2)n6NHSO2R16, -(CH2)n6NHSO2NR4R5, y -(CH2)n6C(O)NR28R29, donde n6 es 0-4; cada R14 se selecciona independientemente del grupo formado por hidrogeno, alquilo, -OH, alcoxi, arilalquilo, heteroarilo, heteroarilalquilo, heterociclilo, heterociclilalquilo, halogeno, haloalquilo, -(CH2)n6NHC(O)OR16b, -(CH2)n6NHC(O)R16b, -(CH2)n6NHC(O)NR4R5, -(CH2)n6NHSO2R16, -(CH2)n6NHSO2NR4R5, y -(CH2)n6C(O)NR28R29, donde n6 es 0-4; donde R4 y R5 se seleccionan independientemente del grupo formado por hidrogeno, alquilo, fenilo, bencilo y cicloalquilo, o R4 y R5 en conjunto pueden formar un anillo con el nitrogeno al cual están unidos, donde dicho anillo formado por R4 y R5 es opcionalmente sustituido con =O, OH, OR1 o -C(O)OH; o R13 y R14 tomados en conjunto forman un anillo espirocíclico o un anillo heteroespirocíclico de 3-6 átomos en el anillo, donde dicho anillo heteroespirocíclico contiene de 2 a 5 átomos en el anillo de carbono y 1 o 2 heteroátomos en el anillo seleccionados del grupo formado por O, S y N; R16 se selecciona independientemente del grupo formado por hidrogeno, alquilo fenilo y bencilo; R16a se selecciona independientemente del grupo formado por hidrogeno, alquilo, fenilo y bencilo; R16b es hidrogeno, alcoxi, alquilo, alcoxialquil-, R22-O-C(O)-alquil-, cicloalquilo, R21-arilo, R21-arilalquilo, haloalquilo, alquenilo, alquenilo sustituido con halo, alquinilo, alquinilo sustituido con halo, R21- heteroarilo, (R21-heteroaril)-alquil-, (R21-heterocicloalquil)-alquil-, R28R29N-alquil-, R28R29N-C(O)-alquil-, R28R29N-C(O)O-alquil-, R28OC(O)N(R29)-alquil-, R28S(O)2N(R29)-alquil-, R28R29N-C(O)-N(R29)-alquil-, R28R29N-S(O)2N(R29)-alquil-, R28- C(O)N(R29)-alquil-, R28R29N-S(O)2-alquil-, HOS(O)2-alquil-, (OH)2P(O)2-alquil-, R28-S-alquil-, R28-S(O)2-alquil- o hidroxialquilo; R17 se selecciona independientemente del grupo formado por hidrogeno, alquilo, fenilo y bencilo; R18 y R19 son hidrogeno, alquilo, arilo, R21-arilo, heteroarilo, cicloalquilo, heterociclilo, alcoxialquilo, haloalcoxialquilo, ariloxialquilo, arilalcoxialquilo, heteroariloxialquilo, heteroarilalcoxialquilo, cicloalquiloxialquilo, (heterociclil)alquiloxialquilo, alcoxialquiloxialquilo, -S(O)2-alquilo, -C(NH)NR1R2 o alquilo sustituido con una o dos porciones seleccionadas entre cicloalquilo, halogeno, hidroxi, -NR1R2, -NR1C(O)R2, -NR1C(O)NR1R2, -NR1C(O)OR2, -NR1S(O)2R2, - NR1S(O)2NR1R2, -C(O)OH, -C(O)OR1 y -C(O)NR1R2; o R18 y R19 junto con el nitrogeno al cual están unidos, forman un anillo heterocíclico mono o bicíclico de 4 a 10 átomos, que tiene 1-3 heteroátomos en el anillo seleccionados entre -O-, -N-, -S-, - S(O)-, -S(O)2- y -C(O)-, con la condicion de que los átomos de S y O no sean adyacentes entre sí, estando el anillo no sustituido o sustituido con uno o más grupos seleccionados entre alquilo, halogeno, hidroxi, alcoxi, ariloxi, arilalcoxi, -NR1R2, - NR1COR2, -NR1C(O)NR1R2, -NR1C(O)OR2, -NR1S(O)2R2, -NR1S(O2)NR1R2, -C(O)OR1, -CONR1R2 y alquilo sustituido con -NR1R2, -NR1COR2, -NR1CONR1R2, -NR1C(O)OR2, -NR1S(O)2R2, -NR1S(O)2NR1R2, -C(O)OR1 o -CONR1R2; R21 es de 1 a 3 porciones y cada R21 se selecciona independientemente del grupo formado por hidrogeno, -CN, -CF, -OCF3, halogeno, -NO2, alquilo, -OH, alcoxi, alquilamino-, di-(alquil)amino-, -NR25R26-alquil-, hidroxialquil-, -C(O)OR17, -COR17, -NHCOR16, -NHS(O)2R16, -C(NH)-NH2, - NHS(O)2CH2CF3, -C(O)NR25R26, -NR25-C(O)-NR25R26, -S(O)R16, -S(O)2R16, -SR16, -SO2NR4R5 y -CONR4 R5; o dos porciones R21 adyacentes pueden formar un grupo metilendioxi; R22 es hidrogeno, alquilo, fenilo, bencilo, -COR16, CONR18R19, -COR23, -S(O)R31, - S(O)2R31, -S(O2)NR24R25 o -C(O)OR27; R23 es -C(NH2)(r35)(R36), donde R35 y R36 se seleccionan independientemente del grupo formado por hidrogeno, alquilo, y alquilo sustituido con R37, donde R37 se selecciona del grupo formado por HO-, HS-, CH2S-, - NH2, fenilo, p-hidroxifenilo e indolilo; o R23 es alquilo; haloalquilo; alquenilo; haloalquenilo; alquinilo; cicloalquilo; cicloalquilalquilo; cicloalquilo sustituido con 1 a 3 sustituyentes seleccionados del grupo formado por alcoxialquilo, alquilo, halogeno, hidroxi, alcoxi, ariloxi, arilalcoxi, -NR1R2, -NR1C(O)R2, -NR1C(O)NR1R2, -NR1C(O)OR2, -NR1S(O)2R2, -NR1S(O)2NR1R2, -C(O)OR1 y -CONR1R2; arilo; aralquilo; heteroarilo; heterocicloalquilo; alquilo sustituido con -NR1R2, -NR1COR2, - NR1CONR1R2, -NR1C(O)OR2, -NR1S(O2)R2, -NR1S(O2)NR1R2, -C(O)OR1, -CONR1R2 y -SO3H; R24, R25 y R26 se seleccionan independientemente del grupo formado por hidrogeno, alquilo, haloalquilo, alquenilo, alquinilo, arilo, aralquilo, cicloalquilo, halocicloalquilo alcoxialquilo, hidroxi y alcoxi; R27 es de 1 a 3 porciones y cada R27 se selecciona del grupo formado por hidrogeno, alquilo, y cicloalquilo, donde R27 es opcionalmente sustituido con -OH, -C(O)OH, halogeno y alcoxi; R28 y R29 se seleccionan independientemente del grupo formado por hidrogeno, alquilo, alcoxi, arilalquilo, heteroarilo, heteroarilalquilo, hidroxialquilo, alcoxialquilo, heterociclilo, heterociclilalquilo, y haloalquilo; o R28 y R29 tomados en conjunto forman un anillo espirocíclico o un anillo heteroespirocíclico que tiene 3-6 átomos del anillo; R32 y R33 se seleccionan independientemente del grupo formado por hidrogeno, R34-alquilo, R34-alquenilo, R34-alquinilo, R40-heterocicloalquilo, R38-arilo, R38- aralquilo, R42-cicloalquilo, R42-cicloalquenilo, -OH, -OC(O)R43, -C(O)OR43, -C(O)R43, -C(O)NR43R44, -NR43R44, -NR43C(O)R44, -NR43C(O)OR44, -NR43C(O)NR44R45, -NHS(O)2R43, -OC(O)NR43R44, R37-alcoxi, R37-alqueniloxi, R37-alquiniloxi, R40- heterocicloalquiloxi, R42-cicloalquiloxi, R42-ciclo-alqueniloxi, R42-cicloalquil-NH-, -NHSO2NHR16 y -CH(=NOR17); o R32 y R33 se combinan para formar una estructura anular Q, de formula (2
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