AR038955A1 - PIRIMIDINONE AND PIRIDONA SUBSTITUTED COMPOUNDS AND METHODS FOR USE - Google Patents

PIRIMIDINONE AND PIRIDONA SUBSTITUTED COMPOUNDS AND METHODS FOR USE

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AR038955A1
AR038955A1 ARP970105716A ARP970105716A AR038955A1 AR 038955 A1 AR038955 A1 AR 038955A1 AR P970105716 A ARP970105716 A AR P970105716A AR P970105716 A ARP970105716 A AR P970105716A AR 038955 A1 AR038955 A1 AR 038955A1
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Argentina
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radicals
alkyl
optionally substituted
alkylthio
cyano
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ARP970105716A
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Spanish (es)
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Michael J Malone
Nathan B Mantlo
Jeffery A Zablocki
Ulrike D Spohr
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Amgen Inc
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Abstract

Los compuestos de pirimidinona y piridona sustituidos seleccionados son efectivos para la profilaxis y tratamiento de enfermedades, tales como enfermedades mediadas por TNF-alfa, IL-1beta, IL-6 y/o IL-8, y otras afecciones, tales como dolor y diabetes. Nuevos compuestos, análogos, prodrogas y sales farmacéuticamente aceptables de las mismas, composiciones farmacéuticas y métodos para la profilaxis y el tratamiento de enfermedades y otras afecciones y condiciones que involucran inflamación, dolor, diabetes y lo similar. Procesos para preparar estos compuestos así como productos intermedios útiles en estos procesos. Reivindicación 1: Un compuesto de la fórmula (1) o una sal farmacéuticamente aceptable del mismo, donde X es O, S ó NR5; el grupo molecular (2) es elegido del grupo de fórmulas (3) siempre que el número total combinado de radicales arilo, heteroarilo, cicloalquilo y heterociclilo en -VC(R)W- sea 0-3; U es NR21 ó CHR21; n es un entero de 1-3; R1 y R2 son independientemente -Y ó -Z-Y, y R3 y R4 son cada uno independientemente -Z-Y; siempre que R4 no sea un radical arilo sustituido, (aril sustituido)metilo ó (aril sustituido)etilo, y el número total de radicales arilo, heteroarilo, cicloalquilo y heterociclilo en cada -Y y -Z-Y sea 0-3; donde cada Z es independientemente: (1) un radical alquilo, alquenilo ó alquinilo sustituido optativamente por (a) 1-3 radicales de amino, alquilamino, dialquilamino, alcanoilamino, alcoxicarbonilamino, alquilsulfonilamino, hidroxi, alcoxi, alquiltio, ciano ó halo, y (b) 1-2 radicales de heterociclilo, arilo o heteroarilo sustituidos optativamente por 1-3 radicales de amino, alquilamino, dialquilamino, alcanoilamino, alcoxicarbonilamino, alquilsulfonilamino, hidroxi, alcoxi, alquiltio, halo, alquilo ó haloalquilo; (2) un radical heterociclilo sustituido optativamente por 1-3 radicales de amino, alquilamino, dialquilamino, alcanoilamino, alcoxicarbonilamino, alquilsulfonilamino, hidroxi, alcoxi, alquiltio, alquilo ó haloalquilo; o (3) un radical arilo ó heteroarilo sustituido optativamente por 1-3 radicales de amino, alquilamino, dialquilamino, alcanoilamino, alcoxicarbonilamino, alquilsulfonilamino, hidroxi, alcoxi, alquiltio, ciano, halo, alquilo ó haloalquilo; cada Y es independientemente: (1) un radical hidrógeno; (2) un radical halo, ciano ó nitro; (3) un radical -C(O)-R20, -C(O)-OR21, -C(O)-NR5R21 ó -C(NR5)-NR5R21; (4) un radical -OR21, -O-C(O)-R21, -O-C(O)-NR5R21 u -O-C(O)-NR22-S(O)2-R20; (5) un radical -SR21, -S(O)-R20, -S(O)2-R20, -S(O)2-NR5R21, -S(O)2NR22-C(O)-R21, -S(O)2-NR22-C(O)-OR20 ó -S(O)2-NR22-C(O)NR5R21; ó (6) un radical -NR5R21, -NR22-C(O)-R21, -NR22-C(O)-OR20, -NR22-C(O)NR5R21, -NR22-C(NR5)-NR5R21, -NR22-S(O)2-R20 ó -NR22S(O)2-NR5R21; donde cada R5 es independientemente (1) radicales hidrógeno; (2) radicales alquilo, alquenilo ó alquinilo sustituidos optativamente por 1-3 radicales de amino, alquilamino, dialquilamino, hidroxi, alcoxi, alquiltio, ciano ó halo; ó (3) radicales arilo, heteroarilo, aralquilo, heteroaralquilo, heterociclilo, heterociclilalquilo, cicloalquilo ó cicloalquilalquilo sustituidos optativamente por 1-3 radicales de amino, alquilamino, dialquilamino, hidroxi, alcoxi, alquiltio, ciano, alquilo ó haloalquilo; donde cada R20 es independientemente (1) un radical alquilo, alquenilo ó alquinilo optativamente sustituidos por 1-3 radicales de -CO2R23 amino, alquilamino, dialquilamino, alcanoilamino, alcoxicarbonilamino, N-(alcoxicarbonil)-N-(alquil)amino, aminocarbonilamino, alquilsulfonilamino, hidroxi, alcoxi, alquiltio, alquilsulfinilo, alquilsulfonilo, ciano, halo ó aralcoxi, aralquiltio, aralquilsulfonilo, cicloalquilo, heterociclilo, arilo ó heteroarilo optativamente sustituidos por 1-3 radicales de amino, alquilamino, dialquilamino, alcanoilamino, alcoxicarbonilamino, alquilsulfonilamino, alcanoilo, alcoxicarbonilo, hidroxi, alcoxi, alquiltio, alquilsulfinilo, alquilsulfonilo, ciano, halo, alquilo ó haloalquilo; (2) un radical heterociclilo sustituido optativamente por 1-3 radicales de amino, alquilamino, dialquilamino, alcanoilamino, alcoxicarbonilamino, alquilsulfonilamino, alcoxicarbonilo, hidroxi, alcoxi, alquiltio, ciano, alquilo ó haloalquilo; o (3) radicales arilo ó heteroarilo sustituidos optativamente por 1-3 radicales de amino, alquilamino, dialquilamino, alcanoilamino, alcoxicarbonilamino, alquilsulfonilamino, alcoxicarbonilo, hidroxi, alcoxi, alquiltio, ciano, halo, azido, alquilo ó haloalquilo; cada R22 es independientemente un radical hidrógeno ó R20; cada R22 es independientemente (1) un radical hidrógeno; (2) un radical alquilo sustituido optativamente por un radical de heterociclilo, arilo ó heteroarilo sustituido optativamente por 1-3 radicales de amino, alquilamino, dialquilamino, alcanoilamino, alcoxicarbonilamino, alquilsulfonilamino, hidroxi, alcoxi, alquiltio, alquilsulfinilo, alquilsulfonilo, ciano, halo, alquilo ó haloalquilo; ó (3) radicales heterociclilo, arilo ó heteroarilo sustituidos optativamente por 1-3 radicales de amino, alquilamino, dialquilamino, alcanoilamino, alcoxicarbonilamino, alquilsulfonilamino, hidroxi, alcoxi, alquiltio, alquilsulfinilo, alquilsulfonilo, ciano, halo, alquilo ó haloalquilo; y cada R23 es independientemente hidrógeno ó alquilo, ó arilo, heteroarilo, aralquilo ó heteroaralquilo sustituido optativamente por 1-3 radicales de amino, alquilamino, dialquilamino, alcanoilamino, alcoxicarbonilamino, alquilsulfonilamino, hidroxi, alcoxi, alquiltio, alquilsulfinilo, alquilsulfonilo, ciano, halo, alquilo ó haloalquilo; y R11 y R12 son independientemente un radical arilo ó heteroarilo sustituido optativamente por 1-3 radicales de (1) R30; (2) radicales halo ó ciano; (3) radicales -C(O)-R30, -C(O)-OR29, -C(O)-NR31R32 ó -C(NR31)NR31R32; (4) radicales -OR29, -O-C(O)-R29, -O-C(O)-NR31R32 ó -O-C(O)-NR33S(O)2-R30; (5) radicales -SR29, -S(O)-R30, -S(O)2-R30, -S(O)2-NR31R32, -S(O)2-NR33-C(O)-R30, -S(O)2-NR33-C(O)-OR30 ó -S(O)2-NR33-C(O)-NR31R32; ó (6) -NR31R32, -NR33-C(O)-R29, -NR33-C(O)-OR30, -NR33-C(O)-NR31R32, -NR33-C(NR31)-NR31R32, -NR33-S(O)2-R30 ó -NR33S(O)2-NR31R32; siempre que (1) R11 no sea un radical 4-piridilo, 4-pirimidinilo, 4-quinolilo ó 6-isoquinolinilo sustituido optativamente por 1-2 sustituyentes; y (2) el número total de radicales arilo, heteroarilo, cicloalquilo y heterociclilo sustituidos en cada uno de R11 y R12 sea 0-1; donde cada R30 es independientemente (1) un radical alquilo, alquenilo ó alquinilo optativamente sustituido por 1-3 radicales de -NR31R31, -CO2R23, hidroxi, alcoxi, alquiltio, alquilsulfinilo, alquilsulfonilo, ciano, halo ó aralcoxi, aralquiltio, aralquilsulfonilo, heterociclilo, arilo ó heteroarilo optativamente sustituidos por 1-3 radicales de los radicales amino, alquilamino, dialquilamino, alcanoilamino, alcoxicarbonilamino, alquilsulfonilamino, hidroxi, alcoxi, alquiltio, alquilsulfinilo, alquilsulfonilo, ciano, halo, alquilo ó haloalquilo; (2) un radical heterociclilo sustituido optativamente por 1-3 radicales de amino, alquilamino, dialquilamino, alcanoilamino, alcoxicarbonilamino, alquilsulfonilamino, hidroxi, alcoxi, alquiltio, ciano, halo, alquilo ó haloalquilo; o (3) radicales arilo ó heteroarilo optativamente sustituidos por 1-3 radicales de amino, alquilamino, dialquilamino, alcanoilamino, alcoxicarbonilamino, alquilsulfonilamino, hidroxi, alcoxi, alquiltio, ciano, alquilo ó haloalquilo; cada R29 es independientemente un radical hidrógeno ó R30; cada R31 y R32 es independientemente (1) radicales hidrógeno; (2) un radical alquilo sustituido optativamente por un radical cicloalquilo, arilo, heterociclilo ó heteroarilo sustituido optativamente por 1-3 radicales de los radicales amino, alquilamino, dialquilamino, alcanoilamino, alcoxicarbonilamino, alquilsulfonilamino, hidroxi, alcoxi, alquiltio, ciano, alquilo ó haloalquilo; ó (3) un radical arilo, heteroarilo, heterociclilo ó cicloalquilo sustituido optativamente por 1-3 radicales de los radicales amino, alquilamino, dialquilamino, alcanoilamino, alcoxicarbonilamino, alquilsulfonilamino, hidroxi, alcoxi, alquiltio, ciano, alquilo ó haloalquilo; y donde cada R33 es independientemente (1) un radical hidrógeno; ó (2) un radical alquilo sustituido optativamente por un radical de los radicales heterociclilo, arilo ó heteroarilo optativamente sustituido por 1-3 radicales de amino, alquilamino, dialquilamino, alcanoilamino, alcoxicarbonilamino, alquilsulfonilamino, hidroxi, alcoxi, alquiltio, ciano, alquilo ó haloalquilo.Selected substituted pyrimidinone and pyridone compounds are effective for the prophylaxis and treatment of diseases, such as diseases mediated by TNF-alpha, IL-1 beta, IL-6 and / or IL-8, and other conditions, such as pain and diabetes. . New compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for the prophylaxis and treatment of diseases and other conditions and conditions involving inflammation, pain, diabetes and the like. Processes to prepare these compounds as well as intermediate products useful in these processes. Claim 1: A compound of the formula (1) or a pharmaceutically acceptable salt thereof, wherein X is O, S or NR5; the molecular group (2) is chosen from the group of formulas (3) provided that the combined total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in -VC (R) W- is 0-3; U is NR21 or CHR21; n is an integer of 1-3; R1 and R2 are independently -Y or -Z-Y, and R3 and R4 are each independently -Z-Y; provided that R4 is not a substituted aryl radical, (substituted aryl) methyl or (substituted aryl) ethyl, and the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in each -Y and -Z-Y is 0-3; where each Z is independently: (1) an alkyl, alkenyl or alkynyl radical optionally substituted by (a) 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano or halo radicals, and (b) 1-2 heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, halo, alkyl or haloalkyl radicals; (2) a heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkyl or haloalkyl; or (3) an aryl or heteroaryl radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl or haloalkyl radicals; each Y is independently: (1) a hydrogen radical; (2) a halo, cyano or nitro radical; (3) a radical -C (O) -R20, -C (O) -OR21, -C (O) -NR5R21 or -C (NR5) -NR5R21; (4) a radical -OR21, -O-C (O) -R21, -O-C (O) -NR5R21 or -O-C (O) -NR22-S (O) 2-R20; (5) a radical -SR21, -S (O) -R20, -S (O) 2-R20, -S (O) 2-NR5R21, -S (O) 2NR22-C (O) -R21, -S (O) 2-NR22-C (O) -OR20 or -S (O) 2-NR22-C (O) NR5R21; or (6) a radical -NR5R21, -NR22-C (O) -R21, -NR22-C (O) -OR20, -NR22-C (O) NR5R21, -NR22-C (NR5) -NR5R21, -NR22 -S (O) 2-R20 or -NR22S (O) 2-NR5R21; where each R5 is independently (1) hydrogen radicals; (2) alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3 amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, cyano or halo radicals; or (3) aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or cycloalkylalkyl radicals optionally substituted by 1-3 amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl radicals; where each R20 is independently (1) an alkyl, alkenyl or alkynyl radical optionally substituted by 1-3 radicals of -CO2R23 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, N- (alkoxycarbonyl) -N- (alkyl) amino, aminocarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo or aralkoxy, aralkylthio, aralkylsulfonyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkylaminolamino, alkylaminolamino, alkylaminolamino, alkylaminolamino, alkylaminolamino, alkylaminolamino, alkylaminolamino, alkylaminolamino, alkylaminolamino, alkylaminolamino, alkylaminolamino, alkylaminolamino, alkylaminolamino , alkoxycarbonyl, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; (2) a heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, halo, azido, alkyl or haloalkyl radicals; each R22 is independently a hydrogen radical or R20; each R22 is independently (1) a hydrogen radical; (2) an alkyl radical optionally substituted by a heterocyclyl, aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo , alkyl or haloalkyl; or (3) heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl radicals; and each R23 is independently hydrogen or alkyl, or aryl, heteroaryl, aralkyl or heteroaralkyl optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo , alkyl or haloalkyl; and R11 and R12 are independently an aryl or heteroaryl radical optionally substituted by 1-3 radicals of (1) R30; (2) halo or cyano radicals; (3) radicals -C (O) -R30, -C (O) -OR29, -C (O) -NR31R32 or -C (NR31) NR31R32; (4) radicals -OR29, -O-C (O) -R29, -O-C (O) -NR31R32 or -O-C (O) -NR33S (O) 2-R30; (5) radicals -SR29, -S (O) -R30, -S (O) 2-R30, -S (O) 2-NR31R32, -S (O) 2-NR33-C (O) -R30, - S (O) 2-NR33-C (O) -OR30 or -S (O) 2-NR33-C (O) -NR31R32; or (6) -NR31R32, -NR33-C (O) -R29, -NR33-C (O) -OR30, -NR33-C (O) -NR31R32, -NR33-C (NR31) -NR31R32, -NR33- S (O) 2-R30 or -NR33S (O) 2-NR31R32; provided that (1) R11 is not a 4-pyridyl, 4-pyrimidinyl, 4-quinolyl or 6-isoquinolinyl radical optionally substituted by 1-2 substituents; and (2) the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted in each of R11 and R12 is 0-1; where each R30 is independently (1) an alkyl, alkenyl or alkynyl radical optionally substituted by 1-3 radicals of -NR31R31, -CO2R23, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo or aralkoxy, aralkylthio, aralkylsulfonyl, heterocyclyl , aryl or heteroaryl optionally substituted by 1-3 radicals of the amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl radicals; (2) a heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl or haloalkyl; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl radicals; each R29 is independently a hydrogen radical or R30; each R31 and R32 is independently (1) hydrogen radicals; (2) an alkyl radical optionally substituted by a cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 radicals of the amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or (3) an aryl, heteroaryl, heterocyclyl or cycloalkyl radical optionally substituted by 1-3 radicals of the amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl radicals; and where each R33 is independently (1) a hydrogen radical; or (2) an alkyl radical optionally substituted by a radical of the heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl

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