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AR054611A1 - Antagonistas del receptor de trombina y composicion farmaceutica - Google Patents

Antagonistas del receptor de trombina y composicion farmaceutica

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Publication number
AR054611A1
AR054611A1 ARP050104221A ARP050104221A AR054611A1 AR 054611 A1 AR054611 A1 AR 054611A1 AR P050104221 A ARP050104221 A AR P050104221A AR P050104221 A ARP050104221 A AR P050104221A AR 054611 A1 AR054611 A1 AR 054611A1
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AR
Argentina
Prior art keywords
alkyl
group
hydrogen
nr1r2
independently selected
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ARP050104221A
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English (en)
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Schering Corp
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Abstract

Composiciones farmacéuticas que contienen al compuesto, estos compuestos son utiles en el tratamiento de enfermedades asociadas con la trombosis ateroesclerosis, restenosis, hipertension, angina de pecho, arritmia, insuficiencia cardíaca y cáncer. También son utiles en terapia combinatoria con otros agentes cardiovasculares. Reivindicacion 1: Un compuesto representado por la formula estructural (1) o una sal farmacéuticamente aceptable de dicho compuesto, donde la línea punteada representa un enlace doble o un enlace simple, segun lo permita lo que demanda la valencia; con la condicion de que R3 esté ausente cuando el carbono al cual se uniría R3 es parte de un doble enlace; B es -(CH2)n3-, -(CH2)-O-, -(CH2)S-, -(CH2)-NR6-, -C(O)NR6-, - NR6C(O)-, ciclopropileno, -(CH2)n4CR12=CR12a(CH2)n5- donde n3 es 0-5, n4 y n5 son independientemente 0-2; y R12 y R12a son independientemente seleccionados del grupo constituido por hidrogeno, alquilo y halogeno; E es >C(=O)-, o -S(O)m-, donde m es 0, 1 o 2; A, G, M y J son independientemente seleccionados del grupo constituido por -N(R54)-, -(CR1R2)-, -O-, >C(=O)-, -S-, -S(O)-, -S(O)2-, y >N(=R1)-; X es >C=, -CH- o -N- con la condicion de que la seleccion de A, G, M y X no dé lugar a átomos de oxígeno o azufre adyacentes; cada n es 0, 1 o 2, con la salvedad de que todas las variables n no pueden ser 0; Het es un grupo heteroaromático mono-, bi- o tricíclico de 5 a 14 átomos, compuesto por 1 a 13 átomos de carbono y de 1 a 4 heteroátomos independientemente seleccionados del grupo constituido por N, O y S, con la condicion de que no haya átomos de oxigeno o azufre 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 átomo de carbono miembro del anillo y donde el grupo Het está sustituido con 1 a 4 porciones, W, donde cada W se selecciona independientemente del grupo que consiste en hidrogeno, alquilo, fluoroalquilo, difluoroalquilo, trifluoroalquilo, cicloalquilo, heterocicloalquilo, heterocicloalquilo sustituido con alquilo o alquenilo, alquenilo, R21-arilalquilo, R21-arilalquenilo, heteroarilo; heteroarilalquilo, heteroarilalquenilo, hidroxialquilo, dihidroxialquilo, aminoalquilo, alquilaminoalquilo, di-(alquil)aminoa!quilo, 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 independientemente seleccionados del grupo constituido por alquilo, halogeno, alcoxi, metilendioxi, ácido carboxílico, carboxamida, amina, urea, amida, sulfonamida, -CN, -CF3, -OCF3, -OH, alquilamino-, di-(alquil)amino-, -NR25R26alquilo-, hidroxialquilo-, -C(O)OR17, -COR7, -NHCOR16, -NHS(O)2R16, -NHS(O)2CH2CF3, -C(O)NR25R26, - NR25-C(O)-NR25R26, -S(O)R13, -S(O)2R13 y -SR13 o bien alquilo optativamente 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 carbonos adyacentes en el anillo de Het pueden formar, optativamente, un anillo con un grupo metilendioxi; R1y R2 son independientemente seleccionados del grupo constituido por hidrogeno, alquilo, fluoroalquilo, difluoroalquilo, trifluoroalquilo, cicloalquilo, alquenilo, alcoxi, arilalquilo, arilalquenilo, heteroarilalquilo, heteroarilalquenilo, hidroxi, hidroxialquilo, alcoxialquilo, aminoalquilo, arilo y tioalquilo, o bien R1 y R2, cuando están unidos a nitrogeno, juntos 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 de S y O del anillo no estén adyacentes entre si, donde dicho anillo heterocíclico no está sustituido o está sustituido con uno o más grupos seleccionados entre alquilo, halogeno, hidroxi, alcoxi, ariloxi y arilalcoxi; R3 es aralcoxi, ariloxi, heteroarilo, heteroaralcoxi, -CN, -NO2, -O-arilo, - O-heteroarilo, N3, -C(O)NR18R19, -C(=NR1)NR1R2, -N(R1)C=(NR1)NR1R2, -N=C(R1)NR1R2, -NR18C(O)R19, -NR18C(O)NR18R19, -NR18C(O)OR19, -NR18S(O)2R19, -NR18S(O)2NR18R19, -NHNR18R19, -NR18NR18R19 o -alquil-NR18R19; R6 es hidrogeno, alquilo o fenilo; R7 es hidrogeno o alquilo; cada R13 es independientemente seleccionado entre hldrogeno, 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 es independientemente seleccionado del grupo constituido 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 son independientemente seleccionados del grupo constituido por hidrogeno, alquilo, fenilo, bencilo y cicloalquilo, o R4 y R5 pueden formar, juntos, un anillo con el nitrogeno al cual están unidos, donde dicho anillo formado por R4 y R5 está optativamente sustituido con =O, OH, OR1 o -C(O)OH; o bien R13 y R14 juntos forman un anillo espirocíclico o heteroespirocícllco de 3-6 átomos de anillo, donde dicho anillo heteroespirociclico contiene de 2 a 5 átomos de carbono de anillo y 1 o 2 heteroátomos seleccionados del grupo constituido por O, S y N; R16 es independientemente seleccionado del grupo constituido por hidrogeno, alquilo, fenilo y bencilo; R16a es independientemente seleccionado del grupo constituido por hidrogeno, alquilo fenilo y bencilo; R16b es hidrogeno, alcoxi, alquilo, alcoxialquilo, R-O-C(O)-alquilo-, cicloalquilo, R21- arilo, R21-arilalquilo, haloalquilo, alquenilo, alquenilo sustituido con halo, alquinilo, alquinilo sustituido con halo, R21-heteroarilo, (R21-heteroaril)-alquilo-, (R21-heterocicloalquil)-alquilo-, R28R29N-alquilo-, R28R29N-C(O)-alquilo-, R28R29N- C(O)O-alquilo-, R28OC(O)N(R29)-alquilo-, R28S(O)2N(R29)-alquilo-, R28R29N-C(O)-N(R29)-alquilo-, R28R29N-S(O)2N(R29)-alquilo-, R28-C(O)N(R29)alquilo-, R28R29N-S(O)2-alquilo-, HOS(O)2-alquilo-, (OH)2P(O)2-alquilo-, R28-S-alquilo-, R28-S(O)2-alquilo- o hidroxialquilo, R17 es independientemente seleccionado del grupo constituido 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 del grupo constituido por 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 bien 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 de 1-3 heteroátomos del anillo seleccionados entre -O-, -N-, -S-, -S(O)2-. y >C(=O)-, con la condicion de que los átomos de S y O no estén adyacentes entre si, donde el anillo no está sustituido o está sustituido con uno o más grupos seleccionados del grupo constituido por 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 representa de 1 a 3 porciones y cada R21 es independientemente seleccionado del grupo constituido por hidrogeno, -CN, -CF3, - OCF3, halogeno, -NO2, alquilo, -OH, alcoxi, alquilamino-, di-(alquil)amino-, -NR25R26alquiIo-, hidroxialquilo-, -C(O)OR17, -COR17, -NHCOR16, -NHS(O)2R16, -C(NH)-NH2, -NHS(O)2CH2CF3, -C(O)NR25R26, -NR25-C(O)-NR25R26, -S(O)R13, -S(O)2R13, -SR13; - SO2NR4R5 y -CONR4R5 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)OR21; R23 es -C(NH2)R35R36, donde R35 y R36 son independientemente seleccionados del grupo constituido por hidrogeno , alquilo y alquilo sustituido con R37, donde R37 es seleccionado del grupo constituido 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 constituido 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; heteroclcloalquilo, 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 son independientemente seleccionados del grupo constituido por hidrogeno, alquilo, haloalquilo, alquenilo, alquinilo, arilo, aralquilo, cicloalquilo, halocicloalquilo, alcoxialquilo, hidroxi y alcoxi; R27 representa de 1 a 3 porciones, y cada R27 es seleccionado del grupo constituido por hidrogeno, alquilo y cicloalquilo, donde R27 está optativamente sustituido con -OH, -C(O)OH, halogeno y alcoxi; R28 y R29 son independientemente seleccionados del grupo constituido por hidrogeno, alquilo, alcoxi, arilalquilo, heteroarilo, heteroarilalquilo, hidroxialquilo, alcoxialquilo, heterociclilo, heterociclilalquilo y haloalquilo, o R28 y R29 juntos, forman un anillo espirocíclico o un anillo heteroespirocíclico con 3-6 átomos en el anillo; R32 y R33 son independientemente seleccionados del grupo constituido p
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