Patent CA-1338189-C (CA)
Title: 8,9-anellated-1,2,3,4-tetrahydro-.beta.-carboline derivatives
Inventor: HAMMINGA DERK
IPC: C07D471/16
Filed: 1988-07-15
Granted: 1996-03-26
Abstract: The invention relates to new 8,9-anellated-1,2,3,4-tetrahydro-.beta.-carboline derivatives of the formula   (1) wherein the symbols have the following meanings: R1 is straight or branched alkyl having 1-6 C-atoms, fluorinated or hydroxylated alkyl having 1-6 C-atoms, phenylalkyl having 1-6 C-atoms in the alkyl group, the phenyl group of which may optionally be substituted, or two alkyl groups R1 bonded to adjacent carbon atoms together constitute a ring of 5-7 carbon atoms, which ring may be substituted with alkyl groups having 1-3 C-atoms, or R1 is straight or branched alkenyl or alkynyl having 2-6 C-atoms, which groups may comprise one or more fluorine atoms, or cycloalkyl having 3-6 C-atoms which are substituted with 0-4 methyl groups, or R1 is straight or branched alkoxy or alkylthio having 1-6 C-atoms which may be substituted with one or more fluorine atoms or hydroxyl groups, or with one optionally sub-stituted phenyl group, or two alkoxy groups and/or al-kylthio groups bonded to two adjacent carbon atoms may form a ring consisting of 5-7 ring atoms which may be substituted with hydroxymethyl, alkoxy or alkoxyalkyl groups having 1-6 C-atoms, or R1 is a cycloalkoxy group or cycloalkylthio group having 3-6 C-atoms which may be substituted with 1-4 methyl groups, or R1 is straight or branched alkoxy-, alkylthio- or alkylsulphonylalkyl having 2-6 C-atoms which may comprise one or more fluorine atoms or hydroxyl groups, or R1 is an alkoxy-carbonylmethyl group having 1-6 C-atoms in the alkoxy group, or R1 is a group R8R9N-CO-CH2-, R8R9N-CO- or R8R9N-SO2 wherein R8 and R9 independently of each other are hydrogen, alkyl having 1-3 C-atoms, or, together with the nitrogen atom, form a heterocyclic 5- or 6-ring, or R1 is hydroxy, halogen, cyano, straight or branched alkoxycarbonyl having 1-6 C-atoms in the alkoxy group, cycloalkylsulphonyl having 3-8 C-atoms which may be substituted with 1-4 methyl groups; n  has the value 0-3; R2 + R3 together with the carbon atom and the nitrogen atom to which they are bonded and the intermediate carbon atom constitute a heterocyclic group consisting of 5-8 ring atoms which, in addition to the nitrogen atom already present, may comprise a second hetero atom from the group N, O, S, S-O or SO2, and which may be substituted with 1-3 alkyl groups having 1-4 C-atoms which can form a spiroalkyl group having 2-5 C-atoms, or the hetero group may be substituted with a phenyl group comprising 0-3 groups R10, wherein R10 is alkyl or alkoxy having 1-3 C-atoms, halogen, trifluoromethyl, cyano or hydroxy and two alkyl groups or alkoxy groups R10 bonded to adjacent carbon atoms may form a ring anellated with the phenyl group and consisting of 5-7 ring atoms, which ring may be substituted with alkyl or alkoxy having 1-3 C-atoms, or with akoxyalkyl having 1-6 C-atoms, and the ring formed by R2 + R3 may be anellated with a saturated or unsaturated carbocyclic or heterocy-clic ring consisting of 5- or 6-ring atoms which may be substituted with halogen or alkyl having 1-4 C-atoms;     R4 is hydrogen, straight or branched alkyl having 1-8 C-atoms, alkoxy- or alkylthioalkyl having 2-6 C-atoms, alkenyl or alkynyl having 2-8 C-atoms, which groups may be substituted with one or more fluorine atoms or hydroxy groups, or with one phenyl group containing 0-3 groups R10, or cycloalkyl group having 3-7 C-atoms, or R4 is cycloalkyl having 3-8 C-atoms which may be substituted with one or more fluorine atoms, alkyl groups having 1-4 C-atoms, cycloalkyl groups having 3-5 C-atoms, or R4 is cycloalkenyl having 5-7 C-atoms which may be substitutued with 1-4 methyl groups, or R4 is straight or branched alkoxycarbonylalkyl having 0-6 C-atoms in the alkoxy group and 1-3 C-atoms in the alkyl group, or R4 is a group R8R9N-CO-R11- or R8R9N-SO2-R11-, wherein R8 and R9 have the above-mentioned meanings and R11 is alkyl having 1-3 C-atoms, or R4 is alkylsulpho-nylalkyl having 1-3 C-atoms per alkyl group, or a phenylsulphonylalkyl group having 1-3 C-atoms in the alkyl group and the phenyl group comprises 0-3 groups R10, or R4 is a phenyl group substituted with 0-4 groups R12, wherein R12 is straight or branched alkyl having 1-6 C-atoms which may be substituted with one or more fluorine atoms or hydroxyl groups, or with one cyano group, or with straight or branched alkoxycarbonyl having 0-6 C-atoms in the alkoxy group, or with a group R8R9N-CO- or R8R9N-SO2-, wherein R8 and R9 have the above-mentioned meanings, or two groups R12 bonded to adjacent carbon atoms form a ring anellated with the phenyl group and consisting of 5-7 ring atoms, which ring may be substituted with 1-3 alkyl groups having 1-3 C-atoms, or R12 is straight or branched alkyl (1-4 C)-oxy-alkyl(0-3 C), alkyl (1-4 C)-thio-alkyl(0-3 C) or alkyl(1-4 C)-sulphonylalkyl(0-3 C) which groups may comprise one or more fluorine atoms or hydroxyl groups, or of which two alkoxy groups or alkylthio groups bonded to adjacent carbon atoms form a ring which consists of 5-7 ring atoms and may be substituted with alkyl or alkoxy having 1-3 C-atoms, or which hydroxymethyl, or with alkoxyalkyl having 2-6 C-atoms, or R12 is cycloalkoxy or cycloalkylthio having 3-7 C-atoms which may be substituted with 0-4 methyl groups, or R12 is cylcloakyl having 3-7 C-atoms in which one or more fluorine atoms or methyl groups may be present, or R12 is straight or branched alkoxycarbonyl having 1-6 C-atoms in the alkoxy group, a group R8R9N-CO- or R8R9N-SO2- wherein R8 and R9 have the above-mentioned meanings, or R12 is halogen or hydroxy, or R4 is mono- or bicyclic heteroaryl group in which N and/or O and/or S may be present as hetero atoms, and the ring(s) may be substituted with alkyl, alkoxy or alkylthio having 1-3 C-atoms, halogen keto oxygen atom, cyano and/or CF3;           R5 is hydrogen or straight or branched alkyl having 1-6 C-atoms; or R4 + R5, together with the carbon atom to which they are bonded, may form a carbocyclic or heterocyclic ring consisting of 5-7 ring atoms which may comprise N, O, S, SO or SO2 as hetero atoms;    R6 is hydrogen;          R7 is alkyl having 1-3 C-atoms, or one group R7 is an alkoxycarbonyl group having 1-3 C-atoms in the alkoxy group or the hydroxymethyl group; and has the value 0-4, and the salts and prodrugs thereof.      It has been found that these compounds have good fibrinolytic properties and may be used as orally active fibrinolytics.