Patent EP-0035244-A2 (EP)
Inventor: BERGER LEO
IPC: C07D217/04
Filed: 1981-02-26
Abstract: For the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE 1.Cycloalka[4,5]pyrrolo[2,3-g]isoquinolines of the general formula see diagramm : EP0035244,P45,F1  wherein R1  signifies hydrogen, lower alkyl, lower alkanoyl, arylcarbonyl or aryl-lower alkyl, R2 signifies hydrogen, lower alkyl, lower hydroxyalkyl, aryl-lower hydroxyalkyl, lower alkoxy-lower alkyl, lower alkanoyloxy-lower alkyl, arylcarbonyloxy-lower alkyl, lower alkanoyl-lower alkyl, arylcarbonyl-lower alkyl, aryl-lower alkyl, lower alkenyl, (C3-6 )-cycloalkyl-lower alkyl, lower alkynyl, thienyl-lower alkyl, furyl-lower alkyl, arylcarboxamido-lower alkyl, aryl-lower alkenyl, lower alkenyloxy-lower alkyl, aryloxy-lower alkyl, aryl-lower alkyloxy-lower alkyl or aryl-N-imidazolonyl-lower alkyl, X signifies an oxygen or sulphur atom and n signifies the number 3, 4, 5 or 6, whereby the residues denoted as lower contain up to 7 carbon atoms and aryl signifies phenyl or phenyl substituted by halogen, trifluoromethyl, lower alkyl, lower alkoxy, nitro, amino, lower alkylamino or di(lower alkyl)amino, optical and geometric isomers of these compounds and pharmaceutically acceptable acid addition salts thereof. For the Contracting State : AT 1. A process for the manufacture of cycloalka[4,5]pyrrolo[2,3-g]isoquinolines of the general formula  see diagramm : EP0035244,P51,F1  wherein R1 signifies hydrogen, lower alkyl, lower alkanoyl, arylcarbonyl or aryl-lower alkyl, R2  signifies hydrogen, lower alkyl, lower hydroxyalkyl, aryl-lower hydroxyalkyl, lower alkoxy-lower alkyl, lower alkanoyloxy-lower alkyl, arylcarbonyloxy-lower alkyl, lower alkanoyl-lower alkyl, arylcarbonyl-lower alkyl, aryl-lower alkyl, lower alkenyl, (C3-6 )-cycloalkyl-lower alkyl, lower alkynyl, thienyl-lower alkyl, furyl-lower alkyl, arylcarboxamido-lower alkyl, aryl-lower alkenyl, lower alkenyloxy-lower alkyl, aryloxy-lower alkyl, aryl-lower alkyloxy-lower alkyl or aryl-N-imidazolonyl-lower alkyl, X signifies an oxygen or sulphur atom and n signifies the number 3, 4, 5 or 6, whereby the residues denoted as lower contain up to 7 carbon atoms and aryl signifies phenyl or phenyl substituted by halogen, trifluoromethyl, lower alkyl, lower alkoxy, nitro, amino, lower alkylamino or di(lower alkyl)amino, their optical and geometric isomers, as well as their pharmaceutically acceptable acid addition salts, characterized by a) for the manufacture of a compound of the general formula  see diagramm : EP0035244,P51,F2  wherein R''2 signifies lower alkyl, lower alkoxy-lower alkyl or (C3-6 )-cycloalkyl-lower alkyl and n has the above significance, treating a compound of the general formula  see diagramm : EP0035244,P52,F3 wherein R''2  and n have the above significance, with formaldehyde, or b) for the manufacture of a compound of the general formula Ia above, treating a compound of the general formula  see diagramm : EP0035244,P52,F4  wherein R''2  has the above significance, with a compound of the general formula  see diagramm : EP0035244,P52,F5  in the presence of a reduction agent or with a compound of the general formula  see diagramm : EP0035244,P52,F6  wherein n has the above significance, or a precursor of this, or c) for the manufacture of a compound of the general formula  see diagramm : EP0035244,P52,F7 wherein n has the above significance, N-demethylating a compound of general formula Ia above wherein R''2  signifies, methyl, or d) for the manufacture of a compound of the general formula  see diagramm : EP0035244,P53,F8  wherein R''1  signifies hydrogen, lower alkyl or aryl-lower alkyl and R'''2  signifies hydrogen, lower alkyl, lower alkoxy-lower alkyl, aryl-lower alkyl, lower alkenyl, (C3-6 )-cycloalkyl-lower alkyl, lower alkynyl, thienyl-lower alkyl, furyl-lower alkyl, lower alkenyloxy-lower alkyl, aryl-lower alkenyl, aryloxy-lower alkyl or aryl-lower alkyloxy-lower alkyl and n has the above significance, treating a compound of the general formula  see diagramm : EP0035244,P53,F9  wherein R''1 , R'''2  and n have the above significance, with phosphorus pentasulphide, or e) for the manufacture of a compound of the general formula  see diagramm : EP0035244,P53,F10  wherein R'2  signifies lower alkyl, lower hydroxyalkyl, aryl-lower hydroxyalkyl, lower alkoxy-lower alkyl, lower alkanoyloxy-lower alkyl, arylcarbonyloxy-lower alkyl, lower alkanoyl-lower alkyl, arylcarbonyl-lower alkyl, aryl-lower alkyl, lower alkenyl, (C3-6 )-cycloalkyl-lower alkyl, lower alkynyl, thienyl-lower alkyl, furyl-lower alkyl, arylcarboxamido-lower alkyl, aryl-lower alkenyl, lower alkenyloxy-lower alkyl, aryloxy-lower alkyl, aryl-lower alkyloxy-lower alkyl or aryl-N-imidazolonyl-lower alkyl and X and n have the above significance, substituting a compound of the general formula  see diagramm : EP0035244,P53,F11 wherein X and n have the above significance, at the isoquinoline nitrogen atom, or f) for the manufacture of a compound of the general formula  see diagramm : EP0035244,P54,F12  wherein R'1  signifies lower alkyl, lower alkanoyl, arylcarbonyl or aryl-lower alkyl and R 2-VI signifies lower alkyl, lower alkoxy-lower alkyl, lower alkanoyloxy-lower alkyl, arylcarbonyloxy-lower alkyl, lower alkanoyl-lower alkyl, arylcarbonyl-lower alkyl, aryl-lower alkyl, lower alkenyl, (C3-6 )-cycloalkyl-lower alkyl, thienyl-lower alkyl, lower alkynyl, furyl-lower alkyl, arylcarboxamido-lower alkyl, aryl-lower alkenyl, lower alkenyloxy-lower alkyl, aryloxy-lower alkyl, aryl-lower alkyloxy-lower alkyl or aryl-N-imidazolonyl-lower alkyl and X and n have the above significance, substituting a compound of the general formula  see diagramm : EP0035244,P54,F13 wherein R 2-VI, X and n have the above significance, at the pyrrole nitrogen atom, or g) for the manufacture of a compound of the general formula  see diagramm : EP0035244,P54,F14  wherein R 2-VI signifies lower hydroxyalkyl or aryl-lower hydroxyalkyl and R'1 , X and n have the above significance, cleaving off the protecting group in a compound of the general formula  see diagramm : EP0035244,P54,F15 wherein R 2-V signifies a lower hydroxyalkyl or aryl-lower hydroxyalkyl group protected at the hydroxy group and R'1 , X and n have the above significance, or h) for the manufacture of a compound of the general formula  see diagramm : EP0035244,P55,F16  wherein R 2-IV, X and n have the above significance, reducing the lower alkanoyl-lower alkyl or arylcarbonyl-lower alkyl group in a compound of the general formula  see diagramm : EP0035244,P55,F17  wherein R 2-VII signifies lower alkanoyl-lower alkyl or arylcarbonyl-lower alkyl and X and n have the above significance, or i) for the manufacture of a compound of the general formula  see diagramm : EP0035244,P55,F18  wherein X, n and R'1  have the above significance, cleaving off the ethoxycarbonyl group in a compound of the general formula  see diagramm : EP0035244,P55,F19  wherein X, n and R'1  have the above significance, and j) if desired, isomerizing a mixture of the cis- and trans isomers obtained to a final ratio which comprises predominantly the trans isomer, and/or k) if desired, separating the trans isomer from the mixture obtained, and/or l) if desired, resolving a racemate in to the optical antipodes, and/or m) if desired, converting a compound obtained or a non-pharmaceutically acceptable acid addition salt into a pharmaceutically acceptable acid addition salt.