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AR034004A1 - DERIVATIVES OF AMIDOALQUIL-PIPERIDINA AND AMIDOALQUIL-PIPERAZINA AND ITS USE IN THE MANUFACTURE OF MEDICINES - Google Patents

DERIVATIVES OF AMIDOALQUIL-PIPERIDINA AND AMIDOALQUIL-PIPERAZINA AND ITS USE IN THE MANUFACTURE OF MEDICINES

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AR034004A1
AR034004A1 ARP010105017A AR034004A1 AR 034004 A1 AR034004 A1 AR 034004A1 AR P010105017 A ARP010105017 A AR P010105017A AR 034004 A1 AR034004 A1 AR 034004A1
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Argentina
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alkyl
heterocycloalkyl
heteroaryl
halogenated
alkoxy
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Spanish (es)
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Ortho Mcneil Pharm Inc
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Priority to ARP010105017 priority Critical patent/AR034004A1/en
Publication of AR034004A1 publication Critical patent/AR034004A1/en

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Abstract

Derivados de amidoalquil-piperidina y amidoalquil-piperazina de la fórmula (1) en la cual: a es un número entero seleccionado de 0 a 2; R10 está seleccionado del grupo que consiste en alquilo C1-6, arilo, cicloalquilo C3-8, aralquilo, heteroarilo, heteroarilo- alquilo C1-6, heterocicloalquilo y heterocicloalquilo alquilo C1-6; en el cual el grupo arilo, cicloalquilo, aralquilo, heteroarilo o heterocicloalquilo puede ser opcionalmente sustituido con uno a cuatro sustituyentes independientemente seleccionados de halógeno, hidroxi, alquilo C1-6, alquilo C1-6 halogenado, alcoxi C1-6, alcoxi C1-6 halogenado, nitro, ciano, amino, alquilamino C1-4, di(alquilo C1-4) amino, alquilsulfonilo C1-6, alcoxisulfonilo C1-6 o alquilsulfonilo C1-6 halogenado. X está seleccionado del grupo que consiste en CH, C(alquilo C1-6) y N; m es un número entero seleccionado de 0 y 1; L1 está seleccionado del grupo que consiste en alquilo C1-6; Y1 está seleccionado del grupo que consiste en C(O) y C(S); R1 y R2 están cada uno independientemente seleccionados del grupo que consiste en hidrógeno, alquilo C1-6, arilo, aralquilo, cicloalquilo C3-8, , cicloalquilo C3-8 -alquilo C1-6, heteroarilo, heteroarilo-alquilo C1-6, heterocicloalquilo y heterocicloalquilo-alquilo C1-6; donde el arilo, aralquilo, cicloalquilo, heteroarilo o heterocicloalquilo pueden estar opcionalmente sustituidos con uno o más sustituyentes independientemente seleccionados de halógeno, hidroxi, alquilo C1-6-alcoxi C1-6, alquilo C1-6 halogenado, alcoxi C1-6 halogenado, nitro, ciano, amino, alquilamino C1-4, di(alquilo C1-4) amino, heteroarilo o heterocicloalquilo; alternativamente, R1 y R2 pueden estar tomados conjuntamente con el átomo de nitrógeno al cual están unidos para formar una estructura de anillo monocíclico de 5 a 6 miembros seleccionado del grupo que consiste en pirrolidinilo, piperidinilo, piperazinilo, morfolinilo y tiomorfolinilo; Y2 está seleccionado del grupo que consiste de CH2, C(O), C(S) y SO2; R3 está seleccionado del grupo que consiste de arilo, aralquilo, cicloalquilo C3-8, heteroarilo, heterocicloalquilo, cicloalquilo C3-8-alquilo C1-6 y heterocicloalquilo-alquilo C1-6; donde el arilo, aralquilo, cicloalquilo, heteroarilo o heterocicloalquilo pueden estar opcionalmente sustituidos con uno o más sustituyentes independientemente seleccionados de halógeno, hidroxi, alquilo C1-6, alcoxi C1-6, alquilo C1-6 halogenado, alcoxi C1-6 halogenado, nitro, ciano, amino, alquilamino C1-4, di(alquilo C1-4) amino o -(L2)n-R4; n es un número entero seleccionado entre 0 y 1; L2 está seleccionado del grupo que consiste en alquilo C1-8, alquenilo C2-8, alquinilo C2-8, C(O), C(S), SO2, y (A)0-1-Q-(B)0-1; donde A y B está cada uno independientemente seleccionado de alquilo C1-6, alquenilo C2-6 y alquinilo C2-6; donde Q está seleccionado del grupo que consiste en NH, O y S; donde R5 está seleccionado del grupo que consiste en hidrógeno, alquilo C1-6, arilo, aralquilo, cicloalquilo C3-8, heteroarilo, heterocicloalquilo, C(O)-alquilo C1-6, C(O)-arilo, C(O)-aralquilo, C(O)-heteroarilo, C(O)-heterocicloalquilo, SO2-alquilo C1-6, SO2-arilo, SO2-aralquilo, SO2-heteroarilo, SO2-heterocicloalquilo y -CHR6R7; donde el arilo, aralquilo, cicloalquilo, heteroarilo o heterocicloalquilo pueden estar opcionalmente sustituidos con uno o más sustituyentes independientemente seleccionados de halógeno, hidroxi, alquilo C1-6, alcoxi C1-6, alquilo C1-6 halogenado, alcoxi C1-6 halogenado, nitro, ciano, amino, alquilamino C1-4 o di(alquilo C1-4) amino; donde R6 y R7 están cada uno independientemente seleccionados del grupo que consiste en hidrógeno, alquilo C1-6, arilo, aralquilo, cicloalquilo C3-8, heteroarilo, heterocicloalquilo, C(O)-alquilo C1-6, C(O)-arilo, C(O)-cicloalquilo C3-8, C(O)-heteroarilo y C(O)-heterocicloalquilo, donde el arilo, aralquilo, cicloalquilo, heteroarilo o heterocicloalquilo pueden estar opcionalmente sustituidos con uno o más sustituyentes independientemente seleccionados de halógeno, hidroxi, alquilo C1-6, alcoxi C1-6, alquilo C1-6 halogenado, alcoxi C1-6 halogenado, nitro, ciano, amino, alquilamino C1-4 o di(alquilo C1-4) amino; R4 está seleccionado del grupo que consiste en arilo, aralquilo, cicloalquilo C3-8, heteroarilo y heterocicloalquilo; donde el arilo, aralquilo, cicloalquilo, heteroarilo o heterocicloalquilo pueden estar opcionalmente sustituidos con uno o más sustituyentes independientemente seleccionados de halógeno, hidroxi, alquilo C1-6, alcoxi C1-6, alquilo C1-6 halogenado, alcoxi C1-6 halogenado, nitro, ciano, amino, alquilamino C1-4 o di(alquilo C1-4) amino; con la condición de que cuando a es 0; X es CH; m es 1; L1 es CH2; R3 es fenilo; n es 0; y R4 es fenilo, donde el grupo fenilo puede estar opcionalmente sustituido con un sustituyentes seleccionado entre halógeno, hidroxi, alquilo C1-6, alcoxi C1-6, alquilo C1-6 halogenado, alcoxi C1-6 halogenado, nitro, ciano, amino, alquilamino C1-4 o di(alquilo C1-4) amino, y donde el grupo R4 está unido al grupo R3 en posición para; entonces R1 y R2 están cada uno independientemente seleccionado del grupo que consiste en hidrógeno, alquilo C2-6, arilo, aralquilo, cicloalquilo C3-8, cicloalquilo C3-8-alquilo C1-6, heteroarilo, heteroarilo-alquilo C1-6, heterocicloalquilo y heterocicloalquilo-alquilo C1-6; en el cual el arilo, aralquilo, cicloalquilo, heteroarilo o heterocicloalquilo puede estar opcionalmente sustituido con uno o más sustituyentes independientemente seleccionados de halógeno, hidroxi, alquilo C1-6, alcoxi C1-6, alquilo C1-6 halogenado, alcoxi C1-6 halogenado, nitro, ciano, amino, alquilamino C1-4, di(alquilo C1-4) amino, heteroarilo o heterocicloalquilo; alternativamente, R1 y R2 pueden tomarse conjuntamente con el átomo de nitrógeno al cual están unidos para formar una estructura de anillo monocíclico de 5 a 6 miembros seleccionados del grupo que consiste en pirrolidinilo, piperidinilo, piperazinilo, morfolinilo y tiomorfolinilo; con la condición adicional de que cuando a es 0; X es N; m es 1; L1 es CH2; Y2 es C(O) o C(S); n es 1; L2 es O; R4 es fenilo, donde el fenilo puede estar opcionalmente sustituido con uno o más sustituyentes independientemente seleccionados de halógeno, hidroxi, alquilo C1-6, alcoxi C1-6, alquilo C1-6 halogenado, alcoxi C1-6 halogenado, nitro, ciano, amino, alquilamino C1-4 o di(alquilo C1-4)amino; y R1 y R2 están cada uno independientemente seleccionados del grupo que consiste en hidrógeno y alquilo C1-6; entonces R3 está seleccionado del grupo que consiste en arilo, aralquilo, cicloalquilo C3-8, heteroarilo distinto de tienopiridinilo, heterocicloalquilo, cicloalquilo C3-8-alquilo C1-6, y heterocicloalquilo-alquilo C1-6; donde el arilo, aralquilo, cicloalquilo, heteroarilo o heterocicloalquilo pueden estar opcionalmente sustituidos con uno o más sustituyentes independientemente seleccionados de halógeno, hidroxi, alquilo C1-6, alcoxi C1-6, alquilo C1-6 halogenado, alcoxi C1-6 halogenado, nitro, ciano, amino, alquilamino C1-4, di(alquilo C1-4) amino o -(L2)n-R4; con la condición adicional de que cuando a es 0; X es N; m es 1; L1 es CH2; Y2 es C(O) o C(S); n es 0; R1 y R2 se toman conjuntamente con el nitrógeno al cual están unidos para formar pirrolidinilo; y R4 es piridilo; entonces R3 está seleccionado del grupo que consiste en arilo, aralquilo, cicloalquilo C3-8, heteroarilo, heterocicloalquilo distinto de tiazolidinilo; cicloalquilo C3-8-alquilo C1-6 y heterocicloalquilo-alquilo C1-6; donde el arilo, aralquilo, cicloalquilo, heteroarilo o heterocicloalquilo pueden estar opcionalmente sustituidos con uno o más sustituyentes independientemente seleccionados de halógeno, hidroxi, alquilo C1-6, alcoxi C1-6, alquilo C1-6 halogenado, alcoxi C1-6 halogenado, nitro, ciano, amino, alquilamino C1-4, di(alquilo C1-4) amino o -(L2)n-R4; con la condición adicional de que cuando R1 y R2 están cada uno independientemente seleccionados del grupo que consiste en hidrógeno y alquilo C1-6, o R1 y R2 están tomados conjuntamente con el átomo de nitrógeno al cual están unidos para formar morfolinilo o pirrolidinilo; a es 0; X es N; m es 1; L1 es CH2; Y2 es C(O) o C(S); n es 0; y R4 es fenilo, donde el fenilo puede estar opcionalmente sustituido con uno o más sustituyentes independientemente seleccionados de alquilo C1-6, alcoxi C1-6, alquilo C1-6 halogenado, alcoxi C1-6 halogenado, o nitro; entonces R3 está seleccionado del grupo que consiste en arilo, aralquilo, heteroarilo, heterocicloalquilo, cicloalquilo C3-8-alquilo C1-6 y heterocicloalquilo-alquilo C1-6; donde el arilo, aralquilo, cicloalquilo, heteroarilo o heterocicloalquilo pueden estar opcionalmente sustituidos con un sustituyente seleccionado de halógeno, hidroxi, alquilo C1-6, alcoxi C1-6, alquilo C1-6 halogenado, alcoxi C1-6 halogenado, nitro, ciano, amino, alquilamino C1-4 o di(alquilo C1-4) amino y sales farmacéuticamente aceptables de los mismos. Tales compuestos son útiles en el tratamiento de trastornos tales como depresión, demencia, esquizofrenia, desórdenes bipolares, ansiedad, émesis, dolor agudo o neuropático, picazón, migrana y desórdenes del movimiento. También se da a conocer el uso de dichos compuestos en la fabricación de medicamentos.Amidoalkyl-piperidine and amidoalkyl-piperazine derivatives of the formula (1) in which: a is an integer selected from 0 to 2; R 10 is selected from the group consisting of C 1-6 alkyl, aryl, C 3-8 cycloalkyl, aralkyl, heteroaryl, heteroaryl-C 1-6 alkyl, heterocycloalkyl and heterocycloalkyl C 1-6 alkyl; wherein the aryl, cycloalkyl, aralkyl, heteroaryl or heterocycloalkyl group may be optionally substituted with one to four substituents independently selected from halogen, hydroxy, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy halogenated, nitro, cyano, amino, C1-4 alkylamino, di (C1-4 alkyl) amino, C1-6 alkylsulfonyl, C1-6 alkoxysulfonyl or halogenated C1-6 alkylsulfonyl. X is selected from the group consisting of CH, C (C1-6 alkyl) and N; m is an integer selected from 0 and 1; L1 is selected from the group consisting of C1-6 alkyl; Y1 is selected from the group consisting of C (O) and C (S); R1 and R2 are each independently selected from the group consisting of hydrogen, C1-6 alkyl, aryl, aralkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C1-6 alkyl, heteroaryl, heteroaryl-C1-6 alkyl, heterocycloalkyl and heterocycloalkyl-C1-6 alkyl; wherein the aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl may be optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-6 alkyl-C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, nitro , cyano, amino, C 1-4 alkylamino, di (C 1-4 alkyl) amino, heteroaryl or heterocycloalkyl; alternatively, R1 and R2 may be taken together with the nitrogen atom to which they are attached to form a 5- to 6-membered monocyclic ring structure selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl; Y2 is selected from the group consisting of CH2, C (O), C (S) and SO2; R 3 is selected from the group consisting of aryl, aralkyl, C 3-8 cycloalkyl, heteroaryl, heterocycloalkyl, C 3-8 cycloalkyl-C 1-6 alkyl and heterocycloalkyl-C 1-6 alkyl; wherein the aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl may be optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, nitro , cyano, amino, C1-4 alkylamino, di (C1-4 alkyl) amino or - (L2) n-R4; n is an integer selected from 0 to 1; L2 is selected from the group consisting of C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C (O), C (S), SO2, and (A) 0-1-Q- (B) 0- one; where A and B are each independently selected from C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl; where Q is selected from the group consisting of NH, O and S; where R 5 is selected from the group consisting of hydrogen, C 1-6 alkyl, aryl, aralkyl, C 3-8 cycloalkyl, heteroaryl, heterocycloalkyl, C (O) -C 1-6 alkyl, C (O) -aryl, C (O) -aralkyl, C (O) -heteroaryl, C (O) -heterocycloalkyl, SO2-C1-6 alkyl, SO2-aryl, SO2-aralkyl, SO2-heteroaryl, SO2-heterocycloalkyl and -CHR6R7; wherein the aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl may be optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, nitro , cyano, amino, C1-4 alkylamino or di (C1-4 alkyl) amino; where R 6 and R 7 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, aryl, aralkyl, C 3-8 cycloalkyl, heteroaryl, heterocycloalkyl, C (O) -C 1-6 alkyl, C (O) -aryl , C (O) -C3-8cycloalkyl, C (O) -heteroaryl and C (O) -heterocycloalkyl, where aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl may be optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, nitro, cyano, amino, C1-4 alkylamino or di (C1-4 alkyl) amino; R4 is selected from the group consisting of aryl, aralkyl, C3-8 cycloalkyl, heteroaryl and heterocycloalkyl; wherein the aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl may be optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, nitro , cyano, amino, C1-4 alkylamino or di (C1-4 alkyl) amino; with the proviso that when a is 0; X is CH; m is 1; L1 is CH2; R3 is phenyl; n is 0; and R4 is phenyl, where the phenyl group may be optionally substituted with a substituent selected from halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, nitro, cyano, amino, C1-4 alkylamino or di (C1-4 alkyl) amino, and where the R4 group is attached to the R3 group in position for; then R1 and R2 are each independently selected from the group consisting of hydrogen, C2-6 alkyl, aryl, aralkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C1-6 alkyl, heteroaryl, heteroaryl-C1-6 alkyl, heterocycloalkyl and heterocycloalkyl-C1-6 alkyl; wherein the aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl may be optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy , nitro, cyano, amino, C1-4 alkylamino, di (C1-4 alkyl) amino, heteroaryl or heterocycloalkyl; alternatively, R1 and R2 may be taken together with the nitrogen atom to which they are attached to form a 5-6 membered monocyclic ring structure selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl; with the additional condition that when a is 0; X is N; m is 1; L1 is CH2; Y2 is C (O) or C (S); n is 1; L2 is O; R4 is phenyl, where the phenyl may be optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, nitro, cyano, amino , C1-4 alkylamino or di (C1-4 alkyl) amino; and R1 and R2 are each independently selected from the group consisting of hydrogen and C1-6 alkyl; then R3 is selected from the group consisting of aryl, aralkyl, C3-8 cycloalkyl, heteroaryl other than thienopyridinyl, heterocycloalkyl, C3-8 cycloalkyl-C1-6 alkyl, and heterocycloalkyl-C1-6 alkyl; wherein the aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl may be optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, nitro , cyano, amino, C1-4 alkylamino, di (C1-4 alkyl) amino or - (L2) n-R4; with the additional condition that when a is 0; X is N; m is 1; L1 is CH2; Y2 is C (O) or C (S); n is 0; R1 and R2 are taken together with the nitrogen to which they are attached to form pyrrolidinyl; and R4 is pyridyl; then R3 is selected from the group consisting of aryl, aralkyl, C3-8 cycloalkyl, heteroaryl, heterocycloalkyl other than thiazolidinyl; C3-8 cycloalkyl-C1-6 alkyl and heterocycloalkyl-C1-6 alkyl; wherein the aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl may be optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, nitro , cyano, amino, C1-4 alkylamino, di (C1-4 alkyl) amino or - (L2) n-R4; with the additional condition that when R1 and R2 are each independently selected from the group consisting of hydrogen and C1-6 alkyl, or R1 and R2 are taken together with the nitrogen atom to which they are attached to form morpholinyl or pyrrolidinyl; a is 0; X is N; m is 1; L1 is CH2; Y2 is C (O) or C (S); n is 0; and R4 is phenyl, where the phenyl may be optionally substituted with one or more substituents independently selected from C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, or nitro; then R3 is selected from the group consisting of aryl, aralkyl, heteroaryl, heterocycloalkyl, C3-8 cycloalkyl-C1-6 alkyl and heterocycloalkyl-C1-6 alkyl; wherein the aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl may be optionally substituted with a substituent selected from halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, nitro, cyano, amino, C1-4 alkylamino or di (C1-4 alkyl) amino and pharmaceutically acceptable salts thereof. Such compounds are useful in the treatment of disorders such as depression, dementia, schizophrenia, bipolar disorders, anxiety, emesis, acute or neuropathic pain, itching, migraine and movement disorders. The use of such compounds in the manufacture of medicaments is also disclosed.

ARP010105017 2001-10-26 2001-10-26 DERIVATIVES OF AMIDOALQUIL-PIPERIDINA AND AMIDOALQUIL-PIPERAZINA AND ITS USE IN THE MANUFACTURE OF MEDICINES AR034004A1 (en)

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ARP010105017 AR034004A1 (en) 2001-10-26 2001-10-26 DERIVATIVES OF AMIDOALQUIL-PIPERIDINA AND AMIDOALQUIL-PIPERAZINA AND ITS USE IN THE MANUFACTURE OF MEDICINES

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ARP010105017 AR034004A1 (en) 2001-10-26 2001-10-26 DERIVATIVES OF AMIDOALQUIL-PIPERIDINA AND AMIDOALQUIL-PIPERAZINA AND ITS USE IN THE MANUFACTURE OF MEDICINES

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