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AR053566A1 - Compuestos espiriciclicos antagonistas de los receptores de trombina - Google Patents

Compuestos espiriciclicos antagonistas de los receptores de trombina

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Publication number
AR053566A1
AR053566A1 ARP060101216A ARP060101216A AR053566A1 AR 053566 A1 AR053566 A1 AR 053566A1 AR P060101216 A ARP060101216 A AR P060101216A AR P060101216 A ARP060101216 A AR P060101216A AR 053566 A1 AR053566 A1 AR 053566A1
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Argentina
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alkyl
group
ring
alkylxyalkyl
independently selected
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ARP060101216A
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Schering Corp
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Abstract

Composiciones farmacéuticas que contienen los mismos y un método para tratar enfermedades asociadas con trombosis, aterosclerosis, restenosis, hipertension, angina de pecho, arritmia, insuficiencia cardíaca, y cáncer administrando dichos compuestos. También se reivindica la terapia de combinacion con otro agentes cardiovasculares. Reivindicacion 1: Un compuesto representado mediante la formula estructural (1) o una sal farmacéuticamente aceptable de dicho compuesto, donde ------ representa un enlace doble o un enlace simple, segun lo permitido mediante el requerimiento de valencia, con la condicion de que R10 está ausente cuando el C al cual R10 está unido es parte de un enlace doble; B es -(CH2)n3-, -(CH2)-O-, -(CH2) S-, -(CH2)NR6-, - C(O)NR6-, -NR6C(O)-, D , -(CH2)n4CR12=CR12a-(CH2)n5- o -(CH2)n4C:::C-(CH2)n5-, donde n3 es 0-5, n4 y n5 son independientemente 0-2, y R12 y R12a son independientemente seleccionados del grupo formado por H, alquilo y halogeno; A, E, G, J, K, M y U se seleccionan independientemente del grupo formado por -N(R54)-, -(CR1R2)-, -O- >C=O, -S-, -S(O)-, -S(O)2- y >N= R1; con las condiciones de que la seleccion de A, E, G, J, K, M y U no da como resultado átomos de O o S adyacentes y que al menos un átomo de C aparezca entre dichos átomos de O, N o S; cada n es 0, 1 o 2 co la condicion de que todas las variables n no pueden ser 0 y que el total de variables n no pueden ser superior a 7; Het es un grupo heteroaromático mono-, bi- o tricíclico de 5 a 14 átomos compuesto por 1 a 13 átomos de C y 1 a 4 heteroátomos seleccionados independientemente del grupo formado por N, O y S, con la condicion de que no haya átomos de O o S adyacentes presentes en el grupo heteroaromático, donde un N del anillo puede formar un N-oxido o un grupo cuaternario con un grupo alquilo, donde Het está unido a B mediante un miembro del anillo de átomos de C, y donde el grupo Het está sustituido con 1 a 4 porciones, W, donde cada W se selecciona independientemente del grupo formado por H, alquilo, fluoralquilo, difluoralquilo, trifluoralquilo, cicloalquilo, heterocicloalquilo, heterocicloalquilo sustituido con alquilo o alquenilo; alquenilo, R21-arilalquilo, R21-aril-alquenilo, heteroarilo, heteroarilalquilo, heteroarilalquenil, 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, -NHSO2R16, bifenilo, -OC(R6) 2COOR7, -OC(R6)2C(O)NR4R5, alcoxi sustituido con alquilo, amino o -NHC(O)OR17, arilo, arilo sustituido con 1 a 3 sustituyentes seleccionados independientemente del grupo formado por alquilo, halogeno, alcoxi, metilendioxi, ácido carboxílico, carboxamida, amina, urea, amida, sulfonamida, -CN, -CF3, -OCF3, -OH, alquilamino-,di(alquilamino-, -NR25R26alquil-, hidroxialquil-, -C(O)OR17, -COR17, - NHCOR16, -NHS(O)2R16, - NHS(O)2CH2CF3, -C(O)NR25R26, -NR25-C(O)-NR25R26, -S(O)R16, -S(O)2R16 y -SR16, o alquilo opcionalmente sustituido con -NR1R2, -NR1COR2, -NR1CONR1R2, -NR1C(O)OR2, -NR1S(O)2R2, -NR1S(O)2NR1R2, -C(O)OH, -C(O)OR1, -CONR1R2heteroarilo, hidroxialquilo, alquilo o -S(O)2-alquilo, -C(O)NR4R5 o heteroarilo, donde los C adyacentes en el anillo Het pueden formar opcionalmente un anillo con un grupo metilendioxi; R1 y R2 se seleccionan independientemente del grupo formado por H, alquilo, fluoralquilo, difluoralquilo, trifluoralquilo, cicloalquilo, alquenilo, alcoxi, arilalquilo, arilalquenilo, heteroarilalquilo, heteroarilalquenilo, hidroxi, hidroxialquilo, alcoxialquilo, aminoalquilo, arilo y tioalquilo; o R1 y R2 cuando se unen a N, en forma conjunta, 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 que los átomos del anillo S y O no estén adyacentes entre sí, donde dicho anillo heterocíclico esta insustituido o sustituido con uno o más grupos seleccionados entre alquilo, halogeno, hidroxi, alcoxi, ariloxi y arilalcoxi; R6 es H, alquilo o fenilo; R7 es H alquilo; cada R13 se selecciona independientemente entre H, 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 H, 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 H, alquilo, fenilo, bencilo y cicloalquilo, o R4 y R5 juntos pueden formar un anillo con el N al cual están unidos, donde dicho anillo formado por R4 y R5 está opcionalmente sustituido con =O, OH, OR1 o -C(O)OH; o R13 y R14 tomados en forma conjunta forman un anillo espirocíclico o un anillo heteroespirocíclico de 3-6 átomos del anillo, donde dicho anillo heteroespirocíclico contiene 2 a 5 átomos del anillo de C y 1 o 2 heteroátomos del anillo seleccionados de grupo formado por O, S y N; R16 se selecciona independientemente del grupo formado por H, alquilo, fenilo y bencilo; R16a se selecciona independientemente del grupo formado por H, alquilo, fenilo y bencilo; R16b es H, alcoxi, alquilo, alcoxialquil-, R22-O-C-(O)-alquil-, cicloalquilo, R21-arilo, R21-arilalquilo, haloalquilo, alquenilo, alquenilo halo sustituido, alquinilo, alquinilo halo sustituido, 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 H, alquilo, fenilo y bencilo; R18 y R19 son H, 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 19 junto con el N al cual están unidos, forman un anillo heterocíclico mono o bicíclico de 4 a 10 átomos, que tiene 1-3 heteroátomos del anillo seleccionados entre -O-, -N-, -S-, -S(O)-, -S(O)2- y >C=O, con la condicion de que los átomos S y O no estén adyacentes uno de otro, estando el anillo no sustituido o sustituido co uno o mas grupos seleccionados entre alquilo, halogeno, hidroxi, alcoxi, ariloxi, arilalcoxi, -NR1R2, -NR1COR2, -NR1C(O)NR1R2, -NR1C(O)R2, - NR1S(O)2R2, -NR1S(O2)NR1R2, -C(O)OR1, -C(O)NR1R2 y alquilo sustituido con -NR1R2, -NR1COR2, -NR1CONR1R2, -NR1C(O)OR2, - NR1S(O)2R2, -NR1S(O)2NR1R2, -C(O)OR1 o -CONR1R2; R21 es 1 a 3 porciones y cada R21 se selecciona independientemente del grupo formado por H, -CN, -CF3, -OCF3, halogeno, -NO2, alquilo, -OH, alcoxi, alquilamino, di-(alquil)amino, -NR25R26alquil-, hidroxialquil-, -C(O)OR17, -COR17, -NHCOR16, -NHS(O)2R16, -C(NH)-NH2, -NHS(O)2CH2CF3, -C(O)NR25R26, -NR25-C(O)-NR25R26, - S(O)2R16, -S(O)2R16, -SR16; -SO2NR4R5 y -CONR4R5; o dos porciones R21 adyacentes pueden formar un grupo metilendioxi; R22 es H, alquilo, fenilo, bencilo, -COR16, -CONR18R19, -COR23, -S(O)R31, -S(O)2R31, -S(O2)NR24R25 o -C(O)OR27; R23 es -C(NH2)(R36)- R35, donde R35 y R36 se seleccionan independientemente del grupo formado por , 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)OH, -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)OH, -C(O)OR1,-CONR1R2 y -SO3H; R24, R25 y R26 se seleccionan independientemente del grupo formado por H, alquilo, haloalquilo, alquenilo, alquinilo, arilo, aralquilo, cicloalquilo, halocicloalquilo, alcoxialquilo, hidroxi y alcoxi; R27 es 1 a 3 porciones y cada R27 se selecciona del grupo formado por H, alquilo, y cicloalquilo, donde R27 está opcionalmente sustituido con -OH, -C(O)OH, halogeno y alcoxi; R28 y R29 se seleccionan independientemente del grupo formado por H, alquilo, alcoxi, arilalquilo, heteroarilo, heteroarilalquilo, hidroxialquilo, alcoxialquilo, heterociclilo, heterociclilalquilo, y haloalquilo; o R28 y R29 tomados en forma conjunta 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 H, R34- alquilo, R34-alquenilo, R34-alquinilo, R40-heterocicloalquilo, R38-arilo, R38-aralquilo, R42-cicloalquilo, 42-cicloalquenilo, -OH, -OC(O) R43, -C(O)OR43, -C(O)R43, -C(O)NR43R44, -NR43R44, -NR43C(O)R44, - 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 de anillo Q que aparece como se muestra en la formula (2) donde R9 es H, OH, alcoxi, halogeno o hal
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