AR039571A1 - BICYCLIC HETEROCICLES, MEDICATIONS CONTAINING THESE COMPOUNDS, THEIR EMPLOYMENT, AND PROCEDURES FOR THEIR PREPARATION - Google Patents

BICYCLIC HETEROCICLES, MEDICATIONS CONTAINING THESE COMPOUNDS, THEIR EMPLOYMENT, AND PROCEDURES FOR THEIR PREPARATION

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AR039571A1
AR039571A1 ARP030101330A ARP030101330A AR039571A1 AR 039571 A1 AR039571 A1 AR 039571A1 AR P030101330 A ARP030101330 A AR P030101330A AR P030101330 A ARP030101330 A AR P030101330A AR 039571 A1 AR039571 A1 AR 039571A1
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Himmelsbach Franz Dr
Jung Birgit Dr
Solca Flavio Dr
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Boehringer Ingelheim Pharma GmbH Co KG
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Boehringer Ingelheim Pharma GmbH Co KG
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Abstract

Heterociclos bicíclicos de la fórmula general (1) en la cual Ra, Rb, Rc, A, B, C, D, E, y X están definidos como en la reivindicación 1, sus tautómeros, sus estereoisómeros, sus mezclas y sus sales, en especial sus sales fisiológicamente tolerables con ácidos inorgánicos u orgánicos, que presentan valiosas propiedades farmacológicas, en especial una acción inhibidora sobre la transducción de senal mediada por tirosincinasas, a su empleo en el tratamiento de enfermedades, en especial enfermedades tumorales e hiperplasia benigna de próstata (BPH), enfermedades de los pulmones y de las vías respiratorias, y a su preparación. Reivindicación 1: heterociclos bicíclicos de formula general (1) donde Ra significa un átomo de hidrógeno o un grupo alquilo C1-4, Rb significa a fenilo, bencilo o 1-feniletilo, donde el núcleo fenilo está substituido en cada caso por los grupos R1 a R3, en donde R1 y R2, los cuales pueden ser idénticos o diferentes, en cada caso significan un átomo de hidrógeno, flúor, cloro, bromo o iodo, un grupo alquilo C1-4, hidroxi, alcoxi C1-4, alquenilo C2-3 o alquinilo C2-3, un grupo arilo, ariloxi, arilmetilo o arilmetoxi, un grupo heteroarilo, heteroariloxi, heteroarilmetilo o heteroarilmetoxi, un grupo metilo o metoxi substituido por 1 a 3 átomos flúor o un grupo ciano, nitro o amino, y R3 significa un átomo hidrógeno, flúor, cloro o bromo, un metilo o un grupo trifluorometilo, Rc significa un átomo de hidrógeno o un átomo de flúor, cloro o bromo, un hidroxi o un grupo alquiloxi C1-4, un grupo metoxi substituido por 1 a 3 átomos de flúor, un grupo etiloxi substituido por 1 a 5 átomos de flúor, un grupo alquiloxi C2-4 el cual está substituido por un grupo R4, donde R4 significa un grupo hidroxi, alquiloxi C1-3, cicloalquiloxi C3-6, cicloalquil C3-6-alquiloxi C1-3, amino, alquilamino C1-3, di-(alquil C1-3)amino, bis-(2-alquiloxi C1-3-etil)-amino, bis-(3-alquiloxi C1-3-propil)-amino, pirrolidin-1-il, piperidin-1-ilo, homopiperidin-1-il, morfolin-4-il, homomorfolin-4-il, piperazin-1-il, 4-(alquil C1-3)-piperazin-1-ilo, homopiperazin-1-ilo o 4-(alquil C1-3)-homopiperazin-1-il grupo, un grupo alquiloxi C2-4 el cual está substituido por el grupo E, donde E está definido de la manera que se indica e continuación, un grupo cicloalquiloxi C3-7 o cicloalquil C3-7-alquiloxi C1-4, un grupo tetrahidrofuran-3-iloxi, tetrahidropiran-3-iloxi o tetrahidropiran-4-iloxi, un grupo tetrahidrofuranil-alquiloxi C1-4 o tetrahidropiranil-alquiloxi C1-4, un grupo pirrolidin-3-iloxi, piperidin-3-iloxi o piperidin-4-iloxi-, un grupo 1-(alquil C1-3)-pirrolidin-3-iloxi, 1-(alquil C1-3)-piperidin-3-iloxi o 1-(alquil C1-3)-piperidin-4-iloxi-, un grupo alcoxi C1-4 el cual está sustituido por un grupo pirrolidinilo, piperidinilo o homopiperidinilo substituido en la position 1 por el grupo R5, donde R5 significa un átomo de hidrógeno o un grupo alquilo C1-3, o un grupo alcoxi el cual está sustituido por un grupo morfolinilo o homomorfolinilo substituido en la posición 4 por el radical R5, siendo R5 tal como se ha definido antes, A significa un grupo imino o alquilimino C1-4, B significa un grupo carbonil o sulfonil, C significa un grupo 1,3-alenileno, 1,1-vinileno o 1,2-vinileno los cuales pueden estar substituidos en cada caso por uno o dos grupos metilo o por un grupo trifluorometilo, un grupo etinileno o un grupo 1,3-butadien-1,4-ileno los cuales pueden estar substituidos por uno o dos grupos metilo o por un grupo trifluorometilo, D significa un grupo alquileno C1-4 lineal o ramificado, E significa un grupo pirrolidin-1-ilo donde dos átomos de hidrógeno del esqueleto carbonado han sido reemplazados por un puente de alquileno de cadena lineal, conteniendo este puente de 2 a 6 átomos de carbono si los dos átomos de hidrógeno se encuentran sobre el mismo átomo de carbono, o 1 a 5 átomos de carbono si los dos átomos de hidrógeno se encuentran sobre átomos de carbono vecinos, o 2 a 4 átomos de carbono si los dos átomos de hidrógeno se encuentran sobre átomos de carbono que están separados por un átomo, pudiendo estar sustituidos en cada caso los grupos pirrolidin-1-ilo antes mencionados, además, con uno o dos grupos alquilo C1-3, un grupo piperidin-1-ilo o homopiperidin-1-ilo, donde en cada caso dos átomos de hidrógeno del esqueleto carbonado han sido reemplazados por un puente de alquileno de cadena lineal, conteniendo este puente de 2 a 6 átomos de carbono si los dos átomos de hidrógeno se encuentran sobre el mismo átomo de carbono, o 1 a 5 átomos de carbono si los dos átomos de hidrógeno se encuentran sobre átomos de carbono vecinos, o 1 a 4 átomos de carbono si los dos átomos de hidrógeno se encuentran sobre átomos de carbono que están separados por un átomo, o bien conteniendo de 1 a 3 átomos de carbono si los dos átomos de hidrógeno se encuentran sobre átomos de carbono que están separados por dos átomos, pudiendo estar sustituidos en cada caso los grupos piperidin-1-ilo- y homopiperidin-1-ilo antes mencionados, además con uno o dos grupos alquilo C1-3, un grupo piperazin-1-ilo o homopiperazin-1-io, en el cual, en cada caso dos átomos de hidrógeno del esqueleto carbonado han sido reemplazados por un puente de alquileno lineal, conteniendo este puente de 2 a 6 átomos de carbono si los dos átomos de hidrógeno se encuentran sobre el mismo átomo de carbono, o 1 a 5 átomos de carbono si los dos átomos de hidrógeno se encuentran sobre átomos de carbono vecinos, o 1 a 4 átomos de carbono si los dos átomos de hidrógeno se encuentran sobre átomos de carbono que están separados por un átomo, o bien conteniendo de 1 a 3 átomos de carbono si los dos átomos de hidrógeno se encuentran sobre átomos de carbono que están separados por dos átomos, pudiendo estar sustituidos en cada caso los grupos piperazin-1-ilo- y homopiperazin-1-ilo antes mencionados, además con uno o dos grupos alquilo C1-3, un grupo morfolin-4-ilo o homomorfolin-4-ilo, donde en cada caso dos átomos de hidrógeno del esqueleto carbonado han sido reemplazados por un puente de alquileno lineal conteniendo este puente de 2 a 6 átomos de carbono si los dos átomos de hidrógeno se encuentran sobre el mismo átomo de carbono, o 1 a 5 átomos de carbono si los dos átomos de hidrógeno se encuentran sobre átomos de carbono vecinos, o 1 a 4 átomos de carbono si los dos átomos de hidrógeno se encuentran sobre átomos de carbono que están separados por un átomo, o bien conteniendo de 1 a 3 átomos de carbono si los dos átomos de hidrógeno se encuentran sobre átomos de carbono que están separados por dos átomos, pudiendo estar sustituidos en cada caso los grupos morfolin-4-ilo- y homomorfolin-4-ilo antes mencionados, además con uno o dos grupos alquilo C1-3, y X significa un grupo metino substituido por un grupo ciano o un átomo de nitrógeno, debiéndose entender por los grupos arilo citados en la definición de los radicales antes mencionados, en cada caso, un grupo fenilo que está mono- o disustituido con R6, pudiendo ser los sustituyentes iguales o diferentes, y representando R6 un átomo de hidrógeno, un átomo de flúor, de cloro, de bromo, o de yodo, o bien un grupo alquilo C1-3, hidroxi, alquiloxi C1-3, difluorometilo, trifluorometilo, difluorometoxi, o ciano, debiéndose entender por los grupos heteroarilo citados en la definición de los radicales antes mencionados, un grupo piridinilo, piridazinilo, pirimidinilo, o pirazinilo estando en cada caso los grupos heteroarilo antes mencionados mono-, o disustituidos con el radical R6, pudiendo ser los sustituyentes iguales o diferentes, y estando R6 definido como se ha mencionado antes, y si no se ha indicado otra cosa, pudiendo ser de cadena lineal o ramificados los grupos alquilo antes mencionados, sus tautómeros, sus estereoisómeros, sus mezclas y sus sales.Bicyclic heterocycles of the general formula (1) in which Ra, Rb, Rc, A, B, C, D, E, and X are defined as in claim 1, their tautomers, their stereoisomers, their mixtures and their salts, especially its physiologically tolerable salts with inorganic or organic acids, which have valuable pharmacological properties, especially an inhibitory action on signal transduction mediated by tyrosine kinase, for use in the treatment of diseases, especially tumor diseases and benign prostatic hyperplasia (BPH), diseases of the lungs and respiratory tract, and their preparation. Claim 1: bicyclic heterocycles of general formula (1) wherein Ra means a hydrogen atom or a C1-4 alkyl group, Rb means phenyl, benzyl or 1-phenylethyl, wherein the phenyl nucleus is substituted in each case by the groups R1 to R3, wherein R1 and R2, which may be identical or different, in each case mean a hydrogen atom, fluorine, chlorine, bromine or iodine, a C1-4 alkyl group, hydroxy, C1-4 alkoxy, C2 alkenyl -3 or C2-3 alkynyl, an aryl, aryloxy, arylmethyl or arylmethoxy group, a heteroaryl, heteroaryloxy, heteroarylmethyl or heteroarylmethoxy group, a methyl or methoxy group substituted by 1 to 3 fluorine atoms or a cyano, nitro or amino group, and R3 means a hydrogen, fluorine, chlorine or bromine atom, a methyl or a trifluoromethyl group, Rc means a hydrogen atom or a fluorine, chlorine or bromine atom, a hydroxy or a C1-4 alkyloxy group, a methoxy group substituted by 1 to 3 fluorine atoms, a substituted ethyloxy group po r 1 to 5 fluorine atoms, a C2-4 alkyloxy group which is substituted by a group R4, where R4 means a hydroxy group, C1-3 alkyloxy, C3-6 cycloalkyloxy, C3-6 cycloalkyl-C1-3 alkyloxy group, amino, C1-3 alkylamino, di- (C1-3 alkyl) amino, bis- (2-C1-3 alkyloxy-ethyl) -amino, bis- (3-C1-3-propyl) -amino, pyrrolidin-1 -il, piperidin-1-yl, homopiperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl, piperazin-1-yl, 4- (C1-3 alkyl) -piperazin-1-yl, homopiperazin- 1-yl or 4- (C1-3 alkyl) -homopiperazin-1-yl group, a C2-4 alkyloxy group which is substituted by the group E, where E is defined in the manner indicated and then a group C 3-7 cycloalkyloxy or C 3-7 cycloalkyl-C 1-4 alkyloxy, a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy or tetrahydropyran-4-yloxy group, a tetrahydrofuranyl-C 1-4 alkyloxy or tetrahydropyranyl-C 1-4 alkyloxy group , a pyrrolidin-3-yloxy, piperidin-3-yloxy or piperidin-4-yloxy group, a 1- (C1-3 alkyl) -pyrrolidin-3-yloxy group, 1- (a C1-3 alkyl) -piperidin-3-yloxy or 1- (C1-3 alkyl) -piperidin-4-yloxy-, a C1-4 alkoxy group which is substituted by a pyrrolidinyl, piperidinyl or homopiperidinyl group substituted at the position 1 by the group R5, where R5 means a hydrogen atom or a C1-3 alkyl group, or an alkoxy group which is substituted by a morpholinyl or homomorpholinyl group substituted at the 4-position by the radical R5, where R5 is as defined above, A means an imino or C1-4 alkylimino group, B means a carbonyl or sulfonyl group, C means a 1,3-alenylene, 1,1-vinyl or 1,2-vinyl group which can be substituted in each case by one or two methyl groups or by a trifluoromethyl group, an ethynylene group or a 1,3-butadiene-1,4-ylene group which may be substituted by one or two methyl groups or by a trifluoromethyl group, D means a linear or branched C1-4 alkylene group, E means a pyrrolidin-1-yl group where two hydrologic atoms The carbon skeleton has been replaced by a linear chain alkylene bridge, this bridge containing 2 to 6 carbon atoms if the two hydrogen atoms are on the same carbon atom, or 1 to 5 carbon atoms if the two hydrogen atoms are on neighboring carbon atoms, or 2 to 4 carbon atoms if the two hydrogen atoms are on carbon atoms that are separated by an atom, the pyrrolidin-1- groups may be substituted in each case In addition, with one or two C1-3 alkyl groups, a piperidin-1-yl or homopiperidin-1-yl group, where in each case two hydrogen atoms of the carbon skeleton have been replaced by an alkylene bridge of linear chain, this bridge containing 2 to 6 carbon atoms if the two hydrogen atoms are on the same carbon atom, or 1 to 5 carbon atoms if the two hydrogen atoms are on neighboring carbon atoms, or 1 to 4 carbon atoms if the two hydrogen atoms are on carbon atoms that are separated by one atom, or contain 1 to 3 carbon atoms if the two hydrogen atoms are on carbon atoms that are separated by two atoms, the aforementioned piperidin-1-yl and homopiperidin-1-yl groups may be substituted in each case, in addition to one or two C1-3 alkyl groups, a piperazin-1- group ilo or homopiperazin-1-io, in which, in each case two hydrogen atoms of the carbon skeleton have been replaced by a linear alkylene bridge, this bridge containing 2 to 6 carbon atoms if the two hydrogen atoms meet on the same carbon atom, or 1 to 5 carbon atoms if the two hydrogen atoms meet on neighboring carbon atoms, or 1 to 4 carbon atoms if the two hydrogen atoms meet on carbon atoms that are separated by an atom, or containing 1 to 3 carbon atoms if the two hydrogen atoms are on carbon atoms that are separated by two atoms, the piperazin-1-yl- and homopiperazin groups may be substituted in each case -1-yl mentioned above, in addition to one or two C1-3 alkyl groups, a morpholin-4-yl or homomorpholin-4-yl group, where in each case two hydrogen atoms of the carbon skeleton have been replaced by a bridge of linear alkylene containing this bridge of 2 to 6 carbon atoms if the two hydrogen atoms are on the same carbon atom, or 1 to 5 carbon atoms if the two hydrogen atoms are on neighboring carbon atoms, or 1 at 4 carbon atoms if the two hydrogen atoms are on carbon atoms that are separated by one atom, or containing 1 to 3 carbon atoms if the two hydrogen atoms are on carbon atoms which are separated by two atoms, the aforementioned morpholin-4-yl- and homomorpholin-4-yl groups may be substituted in each case, in addition to one or two C1-3 alkyl groups, and X means a methine group substituted by a cyano group or a nitrogen atom, it being understood by the aryl groups mentioned in the definition of the aforementioned radicals, in each case, a phenyl group that is mono- or disubstituted with R6, the substituents being the same or different, and representing R6 a hydrogen atom, a fluorine, chlorine, bromine, or iodine atom, or a C1-3 alkyl, hydroxy, C1-3 alkyloxy, difluoromethyl, trifluoromethyl, difluoromethoxy, or cyano group. heteroaryl groups mentioned in the definition of the aforementioned radicals, a pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl group being in each case the above-mentioned heteroaryl groups mono-, or disubstituted with the radical R6, may be the same or different substituents, and R 6 being defined as mentioned above, and if not otherwise indicated, the above-mentioned alkyl groups, their tautomers, their stereoisomers, their mixtures and their salts being able to be straight chain or branched.

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