IE50983B1

IE50983B1 - Cycloalka(4,5)pyrrolo(2,3-g)isoquinolines,process and intermediates for their preparation,and medicaments containing them

Info

Publication number: IE50983B1
Application number: IE430/81A
Authority: IE
Original assignee: Hoffmann La Roche
Priority date: 1980-02-28
Filing date: 1981-02-27
Publication date: 1986-09-03
Also published as: AR231640A1; NZ196363A; NO156371B; IL62223A0; DK87981A; HU185407B; NO156371C; EP0035244B1; MC1377A1; IL62223A; IE810430L; DE3170368D1; NO810683L; EP0035244A2; CA1160228A; PH16750A; PT72595B; EP0035244A3; AU540284B2; AR230638A1

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.

Description

The present invention relates to cycloalka[4,5]pyrrolo[2,3-g]isoquinolines, process and intermediates far their preparation, and medicaments containing them.

The present invention relates to cycloalkat4,5] pyrxolo[2,3-gl isoquinolines of the general formula *1 wherein R^ is hydrogen, lcwer alkyl, lower alkanoyl, arylcarbcmyl, or aryl-lower alkyl; Rg is hydrogen, lower alkyl, lcwer hydroxyalkyl, aryl-lcwer hydroxyalkyl, lower alkoxy-lcwer alkyl, lower alkanoyloxy-lower alkyl, arylcarbonyloxy-lcwer alkyl, lower alkanoyllower alkyl, arylcarbonyl-lower allyl, aryl-lcwer allyl, lower alkenyl, (C3_g) -cycloalkyl-lciwer alkyl, lower alkynyl, thienylower alkyl, furyl-lcwer alkyl, arylcaxbcxamido-lcwer alkyl, aryllower alkenyl, lower alkenyloxy-lower alkyl, aryloxy-lcwer alkyl, aryl-lower alkyloxy-lcwer alkyl or aryl-N-imidazolonyl-lcwer alkyl; X is 0 or S; and n is 3, 4, 5 or 6; optical and geometric isaners of these compounds and their pharmaceutically acceptable acid addition salts.

As used herein, the term lower alkyl denotes a straight or branched chain saturated hydrocarbon containing 1 to 7 carbon atcms, for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, neopentyl, pentyl or heptyl. The tern (Cg_g)-cycloalkyl denotes a cyclic alkyl group of 3 to 6 carbon atcms, for exanple, cyclcprcpyl or cyclohexyl. The tem “lower alkoxy denotes a lower alkyl ether group in which the lower alkyl group is as described above, for example, methoxy, ethoxy, propcoy or pentoxy. The term lower alkenyl denotes a straight or branched chain alkenyl group containing 2 to 7 carbon atons, for example, vinyl or allyl. The term lower alkenyloxy denotes a lcwer alkenyl ether group in which the lawer alkenyl group is as described above, far example, ethenyloxy. The term lower alkynyl denotes a straight or branched chain alkynyl group containing 2 to 7 carbon atoms, for example, ethynyl, propargyl or methylbutynyl. The term halogen or halo denotes all the halogens, i.e., branine, chlorine, fluorine, and iodine. The term aryl denotes phenyl or phenyl bearing one cr more substituents selected from halogen, trifluoranethyl, lcwer alkyl, lower alkoxy, nitro, amino, lcwer alkylamino, and di-lcwar alkyl-amino. The term aryl-lower allyl preferably denotes benzyl. The term aryl-lower alkenyl preferably denotes 3-phenyl-2-propenyl. The term aryl-lower alkyloxy denotes an aryl-lower alkyl ether, for example, benzyloxy.

The term aryloxy denotes an aryl ether group in which the aryl group is as described above, for example, phenoxy.

The term lower alkanoyl denotes a group derived from an aliphatic carboxylic acid of 1 to 7 carbon atoms, for example, formyl, acetyl or propionyl. The term arylcarbonyl denotes a group derived from an aromatic carboxylic acid, such as, for example benzoyl. The term lower alkanoyloxy denotes a group derived from an aliphatic carboxylic acid of 1 to 7 carbon atoms, for example, formyloxy, acetoxy or propionyloxy. The term arylcarbonyloxy denotes a group derived from an aromatic carboxylic acid, such as, for example, benzoyloxy. Exemplary of lower alkanoyl-lower alkyl and arylcarbonyl-lower alkyl are 2-oxo-propyl and 4-(4-fluorophenyl)-4 oxobutyl. Exemplary of lower alkanoyloxy-lower alkyl and arylcarbonyloxy-lower alkyl are 2-acetoxyethyl and 3-benzoyloxypropyl. Exemplary of lower hydroxyalkyl are hydroxyethyl and 2-hydroxy-3,3-dimethylbutyl. Exemplary of (c3_g)-cycloalkyl-lower alkyl are cyclopropylmethyl and cyolobutylmethyl. Exemplary of arylcarboxamido-lower alkyl are benzamidoethyl. Exemplary of aryloxy-lower alkyl are 3-phenoxypropyl. Exemplary of aryl-lower alkyloxy-lower alkyl are 2-benzyloxyethyl and 3-benzyloxypropyl. Exemplary of aryl-N-imidazolonyl-lower alkyl are 2-(2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)ethyl and 3-(2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)propyl. Exemplary of aryl-lower hydroxyalkyl are 2-hydroxy-2-phenylethyl and 2-hydroxy-2-(4-chlorophenyl)ethyl. Exemplary of lower alkoxy-lower alkyl are 2-ethoxyethyl and 3-methoxypropyl. Exemplary of lower alkenyloxy-lower alkyl are 2-ethenyl5 oxyethyl.

Preferred compounds of formula A are those wherein n is 3, 4, 5 or 6, Rj is hydrogen, Rj is lower alkyl, lower hydroxyalkyl, aryl-lower hydroxyalkyl, lower alkoxy-lower alkyl, aryloxy-lower alkyl, lower alkanoyl-lower alkyl, arylcarbonyl-lower alkyl or aryl-lower alkyl; and X is 0 or S.

More preferred compounds of formula A are those wherein n is 3 or 4, Rj is hydrogen, R2 is lower alkyl, lower hydroxyalkyl, aryl-lower hydroxyalkyl, lower alkoxy-lower alkyl, aryloxy-lower alkyl, lower alkanoyl-lower alkyl, arylcarbonyl-lower alkyl or aryl-lower alkyl; and X is 0.

Most preferred compounds of formula A of the invention are; 2-methy1-1,2,3,4,4a,5,7,3,9,10a-decahydro-4a,lOa-trans20 6H-cyclopenta[4,5] pyrrolo i2,3-g]isoquinolin-10(10H)-one; 2-methyl-l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,lOa-trans6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one hydrochloride ·0.5 H20; 2-(2-phenylethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a, 10a-trans-6H-cvclopenfca [4,5]pyrrolo[2,3-gJisoquinolin-10(10B)-one; 2-[4-(4-fluorophenyl)-4-oxobutyl]-l,2,3,4,4a,5,7,8,9, 10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(1OH)-one; (-)-2-methyl-l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,lOa-trans 30 6H-cyclopenta[4,5] pyrrolo [2,3-g]isoquinolin-10(10H)-one; 2-methvl-2.3.4.4a.5.7.8.9.I0.11a-decnhvdro-4a.lla-trans-lH.6H-cyclohexa[4.5jpyrrolo[2,3-g]isoquinolin-n(llH)-one; 2-methyl-2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,na-_trans-lH,CH-cyclohexa[4,5] pyrrolo[2,3-gIisoquinolin-ll(IIH)-one 0.75 -HgO ; 2-(2-phenvlethvl)-2.3.4.4a.5.7.8,9.10.11a-deoahvdro-4a.lla-trans-IH.6H-cvclohexa[4,5j pyrrolo[2,3-g] isoquinoIin-ll(llH)-one; 2-[4-(4-fluorophenvI)-4-oxobutyll-2,3,4,4a,5,7,8,9J0,lla-deeahydro-4a,ll'a-translH,6H-cyclohexa[4,5J pyrrolo[2,3-g] isoquinolin-ll(UH)-one; and 2-methvl-1.2.3.4.4a.5.7.8.9.10a-decahvdro-4a.l0a-trans-6H-cvelopenta[4.51 pyrrolo 10 [2,3-g] isoquinolin-10(10H)-thione.

Exemplary of the compounds of formula A wherein n is 3, i.e., compounds of the formula wherein Rj ι R2and x are ω previously described, are: 2-et))vl-1.2.3.4.4a.5.7.8.9,10a-decal)ydro-4a,10a-ti,ans-6H-cycIopcnta[415] pyrrolo[2,3-g] isoquinolin-lOOOHj-one; 2-(2-hvdfoxvethyl)-I.2.3.4,4a,5,7,8.9,10a-decahydro-4a,I0a-trans-GH-cyclopcnta[4,5] pyrrolo(2,3-g] isoquinolin-10(10H)-one; 2-(2-hydroxy-2-phenylGthyl)-l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6Heyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one; 2-(2-ethoxyethyl)-l,2,3,4,4a,5,718,9,10a-decahydro-4a,10a-_trans-GH-eyclopcnta[4,5] pyrrolo(2,3-g] isoquinolin-10(I0H)-one; 2-(2-aeetoxvethvl)-1.2.3.4,4a.5,7.8,9.I0a-deeahydro-4a,lQa-trans-SH-cyeIopenta“ 10 [4.5J pyrrolo[2,3-g] isoquinolin-10(I0H)-one; 2-[3-(4-fluorophenyl)-3-oxopropyl] -1,2,3,4,4a,5,7,8,9,I0a-decahydro-4a, IQa-trans6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquinoIin-IO(IOH)-one; 2-[2-(4-methoxyphenyl)ethyl]-l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-2trans-6Hcyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(I0H)-one; 2-allvl-1.2.3.4.4a.5.7.8.9.I0a-decahvdro-4a.l0a-trans-6H-cvGlopenta[4^] pyrrolo[2,3-g] isoquinolin-10(10H)-one; 2-cyclopropylmethyl-l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10aHtrans-6H-cyclopsnta [4,5] pyrrolo[2,3-g] isoquinolin-I0(10H)-one; 2-propargyl-l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-transH6H-eyclopenta[4,5]20 pyrrolo[2,3-g] isoquinolin-10(10H)-one; 2-[2-(2-thienvl)ethylI-1,2,3,4,4a,5.7.8.9.10a-deGahvdro-4a.l0a-trans-6H-cvclopenta[4,5] pyrrolo[2,3-gj isoquinolin-10(10H)-one; 2-[2-(2-furyl)etliyl]-l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a'2tvans-6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolln-10(10H)-one; 2-(2-(2,3-diliydro~2-oxo-lH-benzimidazol-l-yl)etliyl] -l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-eycIopenla[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one; 2-r2-fbcnzylQxy1ethvll-1.2.3.4.4a.5.7.8.9.1Qa-dccal)ydro-4a,10n-trans-CH-cyljpenta[4,5] pyrrolo(2,3-g] isoquinolin-10(10H)-one; 2-(3-plK>nyl-2-propenyB-1.2.3.4.4a.5.7.8.9.10a-decahydro-4a,10a-trans-6H-c','cIopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-onc; 2-f2-(4-fluorobenzatnido)cthyl]-1.2,3,4,4a,5,7,8,9,10a-dccahydro-4a,10a-trnns6H-eyclopenta[4,5] pyrrolol2,3-g] isoquinolin-10(10H)-one; ?.-[?.-(pthnny1oxy)ethyn-l,2,3,4.ja.5.7.8.9.I0a-decahvdro-4a.l0a-trans-5H-cyciOpenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one; 2-benzyl-l,2,3,4,4a,5,7,8,9110a-decahydro-4a,10a-££aSS-6H-cyGlopenta[4,5] pyrrolo10 . ’ [2,3-g] isoquinolin-10(10H)-onej l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-oyoiopenta[4,5] pyrrolo[2,3g] isoquinolin-10(lQH)-one; fi-benzoyl-2-methvl-1.2.3.4.4a.5.7.8.9.10a-decabvdro-4a,10a-trans-6H-cyolopc-nta[4,5] pyrrolo[2,3-gl isoquinolin-10(10H)-one; 2.6-dimethy]-l,2.3,4.4a.5,7,8.9,10a-decah.ydro-4a,10a-trans-6K-cyclopenta[4,53 pyrrolo[2,3-g] isoquinolin-10(10H)-one; 6-benzyl-2-methvl-l,2.3.4.4a,5,7.8.9,10a-decahydro-4a.l0a-trans-6H-cvcIopenta[4,5] pyrrolo[2,3-g] isoquinoIin-i0(10H)-one; 6-methyl-2-[4-(4-fluorophenyl)-4-oxobutyl]-l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a 20 trans-6H-cycIopen ta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one; l,2,3,4,4a,5,7)8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo[2,3~g] isoquinolin-10(10H)-thione; 2-(2-hydroxy-3,3-dimethylbutyl)-l,2,3,4,4a,5,7,8,9,10a-deeahydro-4a,10a-trans6H-cyclope.nta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-thione; 2-(2-plienvlethyl)-I.2.3.4.4a.5.7.8.9.1Qa-deoahvdro-4a.l0a-trans-6H-eveIODenta[4,5] pyrrolo[2,3-g] isoquinolin-lQ(10H)-thione; and 2-[4-(4-fluorophenyl)-4-oxobutyi]4,2,3,4,4a, 5,7,8,9,10a-decahydro-4a, lOa-trans6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-thione.

Exemplary of the compounds of formula A wherein n is 4, i.e., compounds of the formula 50883 X wherein Rp Rj and X are as previously described, ' are: 2-f2-hydroxy-3,3-dlmethvlbutyl)-2.3.4,4a.5,7,8,9,10,lla-decahydro-4a,lla-translH,6H-cyclohexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(llH)-one; 2-f2-ethoxyethyl)-2,3,4,4a,5,7f8,9,10.11a-decahvdro-4a.lla-trans-lH.6H-evclohexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(HH)-one; ]_q 2-evclobutvlmethvl-2.3.4.4a.5.7.8.9.10,lla-decalivdro-4a,lla-trans-lH,GII-eyclohexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(UH)’one; 2-[2-(2-thienyl)ethy]J-2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-trans-lH,6Ii-cyclohexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(llH)-one; 2-[2-(2-furyl)ethyl] -2.3.4.4a.5,7.8.9.10.11a-decahvdro-4a.Ua-trans-lH,6H-cycIo15 hexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(llH)-one; 2-[3-(4-fluorophenyl)-3-oxopropyl]-2,3,4,4a,5,7,819,10,lla-decahydro-4a,lla-translH,GH-cyelohexa[4,5] pyrrolp[2,3-g] isoquinolin-ll(HH)-one; 2-(2-propcnyl)-2,3,4,4a,5)7,8,9,19,lla-deeahydro-4a,lla-trans2lH1GH-cyeloliexa[4,5] pyrrolo[2,3-g] isoquinolin-U(UH)-one; 2-(3-phenoxypropyl)-2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-tran£-lH,GH-cyelohexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(UH)-one; . 2-[3-{2,3-dihydro-2-oxo-III-benzin)idazol-l-yl)propyl]-2,3,4,4a,5,7,8,9,10,lIadecahydro-4a,) Ia-trans-lH, 6 H-ey clohexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(HH)-one; 2-benzyl-2,3.4.4a,5,7,8,9,10.11a-decahvdro-4a,Ha-tri)n:;-lII,0H-cycloliexn[4,5] pyrrolo[2,3-g] isoquinolin-ll(llll)-onc; 2,3,4,4a,5,7,8,9,10,lla-deeahydro-4a,lla-trans4H,GH-cyclohexa[4,5] pyrrolo[2,3g] isoquinolin-ll(nil)-one; 2.6-dimethyl-2,3,4,4a,5,7,8,9,10,Ha-deeahydro-4a,ila-traris-IH,6H-cyclohexa[4,5] pyrrolo[2,3-g] isoquinolin-1101H)-one; 6-benzoyl-2-[4-(4-fluorophcnyl)-4-oxobutylJ -2,3,4,4a,5,7,8,9,10,lla-aecahydro4a,lla-trans-lH.6H-cvclohexa[4.5]pyrroIo[2.3-g]isoquinolin-ll(llH)-one; 2-(2-phenylethyl)-2,3,4,4a,5,7,8,9,10,Ila-decaliydro-4a,Ila-trans-lH,SH-cyclo10 hexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(llH)-thione; 2,3,4,4a,5,7,8,9,10,lla-deeahydro-4a,lla-_trans-lH,6H-cyclohexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(HH)-thione; and 2-[4-(4-fluorophenyl)-4-oxobutyl]-2,3,4,4a,5,7,8,9,10Illa-decahydro-4a,lla-transy lH,6H-cyclohexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(HH)-thione.

In the compounds of formula A-2 wherein X is 0, an alternative nomenclature may be employed. Thus, for example, 2-methyl-2,3,4,4a,5,7,8,9,I0,lla-decahydro-4a,lla-trans-lH,6H-cyclohexa[4,5]pyrrolo[2,3-g] isoquinolin-ll(llH)-one; and 2-methyl-2,3,4,4a,5,7,8,9,I0,lla-decahydro-4a,Ila-trans-pyrido[4,3-b] carbazol20 ll(lH,6H)-one are one and the same compound.

Exemplary of lhe compound·' of formula Λ wherein n is 5, i.e., compounds of the formula wherein Rj, R^ and x are as previously described, ares 2-methyl-l, 2,3,4,4a, 5,7,8,9,10.11.12a-dodecahvdro-4a,12a-trans-6H-eycIohepta[4,5]pyrrolo[2,3-g] isoquinolin-12(12H)-one; 2-[4-(4-fluoropher.yl)-4-oxobutyl]-l,2,3,4,4a,5,7,8,9,10,ll,12a-dodecahydro4a,12a-trans-GH-cycleliepta[4,5] pyrrolo[2,3-g] isoquinolin-12(12H)-one; 2-(3-phenoxvpropyl)-1.2,3,4,4a..5,7,8,9,10,ll,12a-dodecahydro-4a112a-trans-6Hcyclohepta[4,5] pyrrolo[2,3-g] isoquinolin-12(12H)-or.e; 2-(2-phenyletiiyl)-l,2,3,4,4a,5,7,8,9,10,ll,12a-dodecahydro-4a,12a-trans-6H-eyclohepta[4,5] pyrrolo[2,3-g] isoquinolin-12(12H)-one; 2-[4~(4-fluorophcnyl)-4-oxobutyl]-l,2,3,4,4a,5,7,8,9,10,ll,12a-dodecahydro-4a,12a15 lEaas-6II-cyclohepta[4,5] pyrrolo[2,3-g] isoquinolin-12(12H)-thione; 2-(3-phenoxypropyl)-l)2,3)4,4a,5,7,819,10Ill,12a-dodecahydro-4a112a-trans-6Hcyclohepta[4,5] pyrrolo[2,3-g] isoquinolin-12(12H)-thione; and 2-(2-phenyletIiyl)-l,2,3,4,4a,5,7,8,9,10,ll,12a-dodecahydro-4a,12a-trans-6H-cycloliepta[4,5] pyrrolo[2,3-g] isoquinolin-12(12Ii)-thione. 5098 Exemplary of the compounds o: formula Λ wherein n is C,i.e., compounds of tl formula X A-4 wherein Rp R2 and X are as previously described, are: 2-[4-(4-fIuorophenyl)-4-oxobutyl]-2,3,4,4a,5,7,8,9,10,ll,12,13a-dodecahydro-4a,13a trans-lH,GH-eycioocta[4,5] pyrrolo[2,3-g] isoquinolin-13(131I)-one; 2-(2-phenylethyl)-2,3,4,4a,5,7,3,9,10,ll,12,13a-dodecahydro-4a,13a-trans-lH> 6Hcyclooeta[4,5] pyrrolo[2,3-g] isoquinolin-13(13H)-cne; lo 2-{2-hydroxy-3,3-di[nethylprupyl)-2,3,4,4a, S, 7,3,9,10,11,12,13a-dodeeahydro-4a, 13atrans-lH,6H-cycloocta[4,53 pyrrolo[2,3-g] isoquinolin-13(13H)-one; 2-mettwl-2.3.4.4a.5.7,8.9.I0.11.12,13a-dodecahydro-4a,13a-trans-lH,6Heycloocta[4,5] pyrrolo[2,3-g] isoquinolin-13(13H)-one; 2-(3-plienoxypropyl)-2,3,4,4a,5,7,8,3,lQ,ll,12,13a-dodecahydro-4a,13a-trans-liI,6H15 cycloocta[4,5] pvrrolo[2,3-g] isoquinolin-13(13H)-one; 2-[4-(4-fluorophenyl)-4-oxobutyl]-2,3,4,4a,5,7,8,9,10,U,12,13a-dodecahydro-4a,13atrans-lH,SH-eyelooota[4,5]pyrrolo[2,3-g] isoquinolin-13(13H)-th:cne; 2-(2-phenylethvl)-2.3.4.4a.5f7,Sf9.10.11.12f13a-dodecahvdro-4a.l3a-trans-lH.SHcycloocta[4,5] pyrrolo[2,3-g] isoquinolin-13(13H)-thione; 2-(2-cUioxyethyl)-2,3,4,4a,5,7,8,9,10,n,12,13n-dodecnhydro-4a,13a-trans-lH,CHcyoloocta[4,5] pyrrolo[2,3-g] isoquinolin-13(I3ilMiiione; and '2-(3-phenoxypropyl)-2,3,4,4a,5,7,8,9.101H.12.13a-dodecahydro-4a,I3a--trar.s-lH,GHcycloocta(4,5] pyrrolo[2,3-g] isoquinolin-13(13il)’thione. 50933 The compounds of the invention wherein n is 3 can exist ns the 4a,10a-trans_or 4a.l0a-eis isomers or mixtures thereof} the 4a,10a-trans isomers are preferred.

The compounds of the invention wherein n is 4 can exist as the 4a,lla-trans or 4a,Ua-cis isomers or mixtures thereof; the 4a,lla-trans isomers are preferred.

The compounds of the invention wherein n is 5 can exist as the 4a,12a-trans or 4a,12a-cis isomers or mixtures thereof; the 4a,l2a-trans isomers are preferred.

The compounds of the invention wherein n is 6 can exist as the 4a.l3a-trans or 4a,13a-cis isomers or mixtures thereof; the 4a.l3a-trans isomers are preferred.

The compounds of the general formula A above, their optical 10 and geometric isomers and their pharmaceutically acceptable acid addition salts can be prepared in accordance with the invention by a process which comprises a) for preparing a compound of the general formula wherein R'^ is lcwer allyl, lcwer alkoxy-lcwer alkyl or (C3_g)cycloalkyl-lower alkyl and n is as previously described, reacting a compound of the general formula H wherein R'j and n are as previously described, with formaldehyde, or b) for preparing a compound of the general formula Ia above, reacting, a compound of the general formula XII wherein R^' is as previously described, with a compound of the general formula in the presence of a reducing agent or with a compound of the general formula VII h2n VIII or a precursor thereof, in which formulae n is as previously described, or c) for preparing a compound of the general formula wherein n is as previously described, N-demethylating a compound of the formula Ia above wherein R1^ is methyl, or lie wherein R^ is hydrogen, lover alkyl or aryl-lover alkyl, R^ is hydrogen, lower alkyl, lower alkoxy-lower alkyl, aryl-lower alkenyl, (C3_6)-cycloalkyl-lawer alkyl, lower alkynyl, thienyl-lower alkyl, furyl-lower alkyl, lower alkenyloxy-lower alkyl, aryl-lower alkenyl, aryloxy-lower alkyl or aryl-lower .alkyloxy-lover alkyl, and n is as previously described, reacting a compound of the general formula wherein R, Ie R2 and n are as previously described, with phosphorus pentasulfide, or e) for preparing a compound of the general formula Wherein R'g is lower alkyl, lower hydroxyalkyl, aryl-lower hydroxyalkyl, lower alkoxy-lower alkyl, lower alkanoyloxylower alkyl, arylcarbonyloxy-lower alkyl, lower alkanoyl-lower alkyl, arylcarbonyl-lower 5 alkyl, aryl-lower alkyl, lower alkenyl, (C3_g)-cycloalkyllower 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 ary1-N-imidazolonyl-lower alkyl and X and n are as previously described, substituting a compound of the general formula H wherein X and n are as previously described at the Isoquinoline nitrogen atom, or f) for preparing a compound of the general formula A'c wherein RJ is lower alkyL, lower alkanoyl, arylcaibcnyl or aryl-lcwer alkyl, R^1 is lcwer alkyl, lcwer alkoxy-lower alkyl, lower alkanoyloxy-lower alkyl, arylcarbonyloxy-lower alkyl, lower alkanoyl-lower alkyl, arylcarbonyl-lower alkyl, aryl-lower alkyl, lower alkenyl, (C3_g)-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 are as previously described, substituting a compound of the general formula X H a ciass wherein R* . x and n are as previously described, at the pyrrole nitrogen atom, or Rj., X and n are as previously described, splitting off the protecting group in a compound of the general formula χ V wherein R2 is 'a lower hydroxyalkyl or aryl-lower_ hydroxyalkyl group protected at the hydroxy group and R£ X and n are as previously described, h) for preparing a compound of the general formula X wherein R2 , X and n are as previously described, reducing the lower alkanoyl-lower alkyl or arylcarbonyllower alkyl group in a compound of the general formula wherein is l°wer alkanoyl-lower alkyl or arylcarbonyl-lcwer alkyl, and X and n are as previously described, or i) for preparing a compound of the general formula and Rj are as previously described, ethoxycaxbcsiyl group in a confound of the general wherein X, n splitting off the formula 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 . 30983 k) if desired, separating the trans isomer from the mixture obtained, and/or l) if desired, resolving a racemic mixture obtained into the optical antipodes and/or ®) if desired, converting a compound obtained or a nonpharmaceutically acceptable acid addition salt into a pharmaceutically acceptable acid addition salt thereof.

More specifically, the compounds of formula A above, their optical and geometric isomers and their pharmaceutically accep10 table acid addition salts as well as various intermediates there for can be prepared as illustrated hereinbelow in more detail.

Thus, for example, the compounds of formula A wherein X is 0 have the formula *1 wherein n, Rj and Rg are as hereinbefore described, and can be prepared as set forth in Schemes I, II, III and IV and further described.

FORMULA SCHEME I IX Ia wherein n is as previously described, and R2 is lower alkyl, lower · alkoxy-lower alkyl, or (C^gJ-cycloalkyl-lower alkyl. 50883 In accordance with Formula Scheme I, compounds of formula Ia are prepared frcm knewn compounds of foimula IV wherein RiJ is lower alkyl, lower alkoxylower alkyl or (C3_g) -cycloalky1-lower alkyl. Birch reduction of the amine of formula IV with lithium, in smrenia containing t-butanol yields the dihydro5 amine of formula V. Other modifications of the Birch reduction may also be snplqyed. Thus, the amine of formula IV may be reacted with an alkali metal, such as sodium, lithium, potassium or cesium, in ammonia or an amine such as methylamine or ethylaraine in the presence of a lewsr alkanol such as ethanol, butanol, or t-butanol. The reaction is generally carried out at the boiling point of the solvent or belcw, for exanple, frcm -78° to 15°C. If ammonia is used, the reaction is run at reflux. Optionally, cosolvents such as diethyl ether or tetrahydrofuran may ,be added.

The hydrolysis of the dihydroamine of formula V is readily accomplished by the usual methods for hydrolysis of enol ethers, for example, with aqueous acid. Exemplary of acids which may be used are hydrochloric acid, hydrobromic acid, formic acid, acetic acid, p-toluenesulfonic acid and perchloric acid. These may be used in aqueous solutions or mixed solvents. Tetrahydrofuran, benzene, diethyl ether, acetone, toluene, dioxane or acetonitrile are exemplary of the solvents which may be employed. For example, hydrolysis of the dihydroamine of formula V wherein It, is methyl in 2N hydrochloric aci(i at room temperature or above or in aqueous acetic acid at between 40° and reflux leads to the diketone of formula VI, wherein Rg is methyl.

The dikctonc of formula VI is condensed in a Knorr condensation to give the methylaminoethyl ketone of formula IX. The Knorr condensation is a well-known method for the preparation of pyrroles and the process may be used in any of the wellknown modifications [see, for exemplary conditions, J. M. Patterson, Synthesis, 281 (197S) and references therein]. For example, the reaction of an isonitrosoketone of formula VII in the presence of a reducing agent, for example with zine in aqueous acetic acid or hydrochloric acid, is thought to proceed via the aminocarbonyl compound of formula VIII which then condenses with the diketone of formula VI to give the product methylaminoethyl ketone of formula IX. Alternatively, the condensation can be carried lo out with an aminocarbonyl compound of formula VIII or precursor thereof, such as an aminoketone hydrochloride salt, or a ketal derivative of an aminoketone. The use of a precursor of the aminoketone is preferred, since such substances are prone to selfcondensation. They may best be utilized in situ where the aminocarbonyl component is liberated in the presence of the diketone of formula VI. The aminocarbonyl component 15 immediately reacts to form the compound of formula IX. It is not necessary to isolate the diketone of formula VI prior to carrying out the Knorr condensation since the reaction conditions employed are sufficient to hydrolyze the dihydroamine of formula V to the diketone of formula VI. The Knorr condensation is best carried out at a pH of from about pH 2 to pH 6. Much above pH 6, there is a considerable loss in yield due to the formation of self-condensation products of the aminocarbonyl compound of formula Vllf.

Preferably, an isonitrosoketone of formula VII and zinc dust in aqueous acetic acid is condensed with a diketone of formula VI wherein R2IS methyl to- give the product methylaminoethyl ketone of formula IX wherein Rf *s methyl.

The Knorr condensation is preferably carried out at a temperature runge of from about room temperature to reflux. The isonitrosoketones of formula VII are known compounds or can readily be prepared by nitrosation of the corresponding 8-ketoester, for example, with sodium nitrite, [see, for example, T. A. Geissman and M. J.

Schlatter, J. Org. Chem., Π, 771 (1946)].

Exemplary of isonitrosoketoncs which can be used in the Knorr condensation are: 2-isonitrosoeyclopentanone; 2-isonitrosocyclohexanone; 2-isonitrosocycloheptanone; and 2-isonitrosocycIooctanone.

Exemplary of aminocarbonyl precursor compounds which can be used in the Knorr condensation are: 2-aminoeyclohexanone, hydrochloride; 2-aminoeyclopentanone, hydrochloride; 2-aminocycloheptanone, hydrochloride,· and 2-aminoeyclooetanone, hydrochloride.

Said compounds are known or may be prepared by reduction of the corresponding isonitrosoketone, for example, by catalytic hydrogenation in the presence of hydrogen chloride.

The amine of the formula IX is converted to the compound of the formula la via an intramolecular Mannich reaction. The Mannich reaction is usually performed starting with a ketone and a dialkylamine salt, for example, dimethylamine hydrochloride and formaldehyde (for example, as an aqueous solution, as paraformaldehyde or as trioxnne) in an alcoholic solvent such as ethanol, at the reflux temperature of the reaction mixture. In the modification herein described, an acid addition salt of the methylaminoethyl-kctone of formula IX is reacted with formaldehyde, added in the form of paraformaldehyde, trioxane, or as aqueous formaldehyde in a solvent. For example, a high boiling hydroxylic solvent, such as amyl alcohol, octanol, ethylene 0 glycol or diethylene glycol monoethyl ether; a high boiling polar aprotic solvent, such as dimethylformamide, N-methylpyrrolidinone or diethylene glycol dimethyl ether; a lower boiling polar solvent, such as ethanol, butanol or 2-propanol, under pressure; or a lower boiling aprotic solvent under pressure, such as dioxane or tetrahydrofuran, may be used at a temperature in the range of from about 135° C. to 200°c. to yield the 5 cycloalka[4,5J pyrrolo[2,3-g] isoquinolines of formula Ia. The reaction, especially when run at temperatures below 150” C. leads to a mixture of cis and trans isomers, i.e., for example, when Rg is methyl, compounds of the formulae trans Η if' Longer heating of the reaction mixture or separate heating of the isomeric mixture of hydrochloride salts of formulas if1 and ig', for example, in ethylene glycol at 5 reflux for 2 hours can be used to equilibrate the cis and trans isomers to a final ratio which comprises predominantly the trans isomer, which is readily isolated by crystallization or by chromatographic separation.

For example, when the hydrochloride salt of the amine of formula IX wherein R2 is methyl is reacted with paraformaldehyde in butanol at 180° for 2 hours, the product is isolated as the trans isomer If'. 2450983 FORMULA SCHEME XI wherein n is us previously described, and ΐγ is lower alkyl, lower alkanoyl, aryl carbonyl or aryl-lower alkyl.

S0S83 In accordance with Formula Scheme II, compounds of formula Ic are prepared by alkylation or acylation of the pyrrole nitrogen of a compound of formula la' and other N-2-alkyl derivatives by formation of the pyrrole anion with a strong base, foe exanple, sodium amide, potassium hydride, sodium methylsulfinyl carbanion, potassium t5 butoxide, or butyllithium, or with an alkali metal, followed by quenching with an alkyl or acyl halide in a solvent such as tetrahydrofuran, dioxane, ethyl ether, dimethylformamide or dimethylsulf oxide. For example, treatment of a compound of formula Ia1, wherein n is 3 with potassium t-butoxide in tetrahydrofuran followed by quenching with methyl iodide affords the 6-methyl derivative, i.e., a compound of formula Ic wherein n is 3 and is methyl. Similarly, reaction of a compound of formula Ia', wherein n is 4 with butyllithium in tetrahydrofuran at -30° followed by quenching with benzoyl chloride affords the 6-benzoyl derivative, i.e., a compound of formula Ic wherein Rj' is benzoyl and n is 4. Similarly, reaction of a compound of formula Ia', wherein n is 3, with sodium methylsulfinyl carbanion in dimethylsulfoxide 15 followed by quenching with benzyl chloride affords the 6-benzyl derivative, i.e., a compound of formula Ic wherein R^' is benzyl and n is'3.

N-Demethylation of the compound of formula la’ can be accomplished by standard N-dealkylation procedures, such as the von Braun method (H.A. Hageman, Org. Reactions, 7,198 (1953)], or via acid or base hydrolysis of a urethane derivative such as those listed in K. C. Rice [J. Org. Chem., 40, 1850 (1975)]. One procedure for the dealkylation of the compound of formula la' is via the urethane of formula xrrra and add hydrolysis to give the secondary amine of formula lb. For example, a compound of formula la', wherein n is 4, when refluxed in dioxane with excess ethyl chloroformate and potassium bicarbonate for 6 hours gives a compound of formula ΧΙΠ, wherein n is 4.

Hydrolysis of the foregoing compound with 30% aqueous sodium hydroxide in ethanoldioxane at reflux for 24 hours gives the compound of formula lb, wherein n is 4.

Urethane darivatives may alas be etpLoyei as starting materials fir the preparation af pyrrole-ring sdoetttuted derivatives by aUgiaeicn cr acylaticn at the pyrrole nitrogen, fallowed iy cleavage of the urethane. The alkylation cr acylaticn is carried out fidlcwing the procedxes given fir the pnepsraticn cf cmpouris cf fimuLa I'c, and the ucethaie derivatives ad prooadxes fix their cleavage are given, as maiticned above, in K.C. Rice (ibid). Br exaiple, in acmKtnce with Ftrnula Shene H, treatment of the ethaocabayl urethane of feanula XTTTa «he- rein n is 4 with sodiun nethylsulfiryl carheion in dimethylsulfisdde, fcilcwai by treatment with bazyl chl.o-id?, affixds the crnpxrd cf fixnuLa XTEDo wharein n is 4 ad R^' is baizyl, fjcfcolysisi with sodiun lycfcodcfe affixds the 6-bai^l derivative, i.e., a cnpcud cf the fctnula Ih «herein R^1 is bmzyl ad n is 4. ih cases «hare R^' is a lewer alkanoyl car arylcarbonyl group which could be hydrolyzed under vigorous alkaline or strongly acidic conditions, a grotp such as 2,2,2,-trichloroethcixycarbcnyl, which xey be cleaved under mild conditions with zinc in aqueous acetic acid, may be employed to give catpounds of formula Ih therein Rj^ ’ is lower alkancyl or arylcarbonyl.

FORMULA SCHEME III wherein n is as previously described, and Rg' is lower alkyl, lower alkanoyl, ary lcarbonyl or aryl-lower alkyl, and Rg' is 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_g)-cycloalkyl-lower alkyl, lower alkynyl, thienyl-lower alkyl, furyl-lower alkyl, arylcarboxamidolower alkyl, aryl-lower alkenyl, lower alkenyloxy-lower alkyl, aryloxy-lower alkyl, aryl-lower alkyloxy-lower alkyl, or ary1-N-imidazolonyl-lower alkyl.

In accordance with Formula Scheme III, the compounds of formulae Id and Ic are prepared from the secondary amine of formula lb, the starting material for the preparation of numerous derivatives encompassed by formula I, by substitution at the basic amine nitrogen (N-2) and/or the pyrrole nitrogen (N-6). For example, treatment of a compound of formula lb with an alkyl halide, such as ethyl bromide, an alkenyl halide, such as allyl bromide, a cycloalkyl-alkyl halide, such as chloromethylcyclopropane, an aralkyl halide, such as benzyl bromide, or an aoylalkyl halide such as γchloro-£-fluorobutyrophenone, in the presence of a base, for example, potassium carbonate, in acetone, 2-propanone or dimethylformamide, yields the correspondingly substituted compound of formula Id, that is, wherein Rg' is lower alkyl, lower alkenyl, (C3_g)-cycloalkyl-lower alkyl, aryl-lower alkyl, or lower alkanoyl or arylcarbonyl-lower alkyl, respectively, With reactive halides, the reaction may be run at room temperature; with less reactive halides, reflux temperatures are used, and in some cases, the reaction rate can be enhanced by the addition of an iodide salt, such as lithium iodide, to the reaction mixture.

Reaction of a compound of formula lb with epoxyalkanes gives the hydroxyalkyl substituted compound of formula Id.

Treatment with a substituted epoxyalkane gives the 2-substituted-2-hydroxyalkyl analogues of a compound of formula Id, for example, reaction of a compound of formula lb with styrene oxide gives a compound of formula Id, wherein Rg' is 2-phenyl2-hydroxyethyl. The reaction is usually carried out in the presence of an alcoholic solvent such as methanol, at fran about roan tanperature to the reflux temperature of the mixture. The epoxyalkanes are either commercially available or are prepared by epoxidation of the corresponding olefins, or by methylenation of a ketone with a sulfonium methylide or sulfoxonium methylide reagent, for example, dimethylsulfonium methylide. Thus, for example, treatment of benzaldehyde with dimethylsulfoniuro methylide gives styrene oxide.

In some cases, where R2' in the compound of formula Id does not contain functional groups capable of undergoing alkylation or acylation, the procedures outlined in Formula Scheme II for the preparation of compounds of formula Ic' can be used directly to prepare N-6 substituted analogues of formula Ic as depicted in Formula Scheme III. Alkylations can occur in compounds wherein R2' is lower hydroxyalkyl or aryl-lower hydroxyalkyl. The hydroxyl groups therein must be protected with a base-stable protecting group, such as tetrahydropyranyl. After N-6 alkylation, the protecting group is removed by acid hydrolysis.

Alternatively, compounds of formula Id, wherein R2' is lower hydroxyalkyl or aryl-lower hydroxyalkyl may be prepared by reduction of the corresponding compounds of formula Id wherein R2' is lower alkanoyl or alylcarbonyl-lower alkyl.

More particularly, the foregoing reduction may be carried out, for example, with an alkali metal borohydride reducing agent, such as sodium borohydride or lithium borohydride. at, for example, room temperature in a solvent, for example, an alkanol, such a.8, for example, ethanol.

In the reactions described in Formula Schemes I, II and III, both the trans isomers of the formula nnd cis isomers of the formula wherein n, Rj and Rg are as previously described, of the compounds of formula I may be formed, with the trans isomer predominating.

The pure trans isomer may be separated by chromatography or crystallization. In addition, the mixture may be isomerized as described for the isomerization of the trans and cis isomers of the oxo compound of formula IE'· and ig', or by base-catalj’zed equilibration, for example, with sodium hydroxide in ethanol.

When the substituent groups Rj and R2 in compounds of the formula I contain 0 additional asymmetric centers, a mixture of diasterecmers may be obtained. For example, the number of isomers possible is 2n wherein n is the total number of asymmetric centers in the compound. Preferred are the enantiomers and/or diastereomers of compound of the formula^. hereinbefore described. 50883 FORMULA SCHEME IV XII VII ΥΙΠ wherein n is as previously described, and Rj is lower alkyl, lower alkoxy-lower alkyl, or (Cj_g)-cycloalkyl-lower alkyl. 3t An alternative synthesis of the compounds of formula la is described in Formula Scheme IV, in which the isoquinoline ring is formed prior to the formation of the pyrrole ring. In accordance with Formula Scheme IV, the (3,5-dimelhoxyphenyl)-etbylaniine of formula IV is refluxed with aqueous formaldehyde to give the letrahydroisoquinoline of formula X. Birch reduction of the tetrohydroisoquinoline of formula X with lithium in liquid ammonia containing t-butanol under conditions substantially the same as described for the Birch reduction of the compound of formula IV yields the hexahydroisoquinoline of formula XI. Hydrolysis of crude hexahydroisoquinoline of formula XI under conditions substantially the same as described for the hydrolysis of the dihydroamine of the formula V yields the diketone of formula ΧΠ. The compound of formula XII is reacted in a Knorr condensation, as described in the preparation of the methylaminoethyl ketone of formula IX with the isonitrosoketone of formula VH or with the aminocarbonyl compound of formula VM to give the cycloalka[4,5] pyrroloisoquinoline of formula la. Preferred is the sequence of reactions in accordance with Formula Scheme IV starting with the amine of formula IV, wherein Rj methyl, giving the corresponding N-methyl-cyeloalka[4,5] pyrroloisoquinoline of formula la, as a mixture containing the trans isomer If'and the cis isomer of formula ig'. · The same procedures for isomerization of the mixture of cycloalka[4,5] pyrrolo20 isoquinolincs of formulae If ad ig as described previously may be employed to yield mainly the trans isomer of formula If' · II The compounds of formula Λ wherein X is S have the formula S wherein n, Rj and Rg are as hereinbefore described, and can be prepared as set forth in Formula Schemes V and VI, and further described hereinafter.

FORMULA SCHEME V wherein n is as previously described; Rj is hydrogen, lower alkyl or aryl-lcwer alkyl; arid Rf 1 is hydrogen., lower alkyl, lower alkoxylcwar alkyl, aryl-lcwer-alkyl, lower alkenyl, arylctxy-lower alkyl, thienyl-lower alkyl, furyl-lower alkyl, lower alkynyl, aryl-lcwer alkenyl, lower alkenyloxy-lower alkyl, aryl-lower alkyloxy-lower alkyl or (C3_g)-cycloalky l-l In accordance v.'itii Formula Scheme V, compounds of formula Heave prepared by heating compounds of formula le with phosphorus pentasulfide in an inert organic solvent. Preferred solvents arc tetrahydrofuran, benzene, toluene or dioxane, and the reaction is generally run at the reflux temperature.

Additional compounds of formula II are prepared as described in Formula Scheme VI. In accordance with Formula Scheme VI, a compound of formula lib is reacted to give a compound of formula lid following Ute procedures detailed in Formula Scheme III for the preparation of the corresponding oxo compounds of formula Id.

FORMULA SCHEME VI wherein n, Rj' and Rj' are as previously described.

Similarly, a compound of formula lid is reacted to give a compound of formula He following the procedures outlined in Scheme III for the preparation of the corresponding oxo compounds of formula ic.

Adhtdcnal aapoutds cf fixnula Π ere papered foUcwinj the pooetres detailed in 5 HxmiLa Shens n fer the p^sraticn cf oaxeepcndiig oo aaipotrds cf fcntula Di.

In those reactions, both the trans isomers of the formula wherein n, Rj and R2 are as previously described, and cis isomers of the formula wherein n, Rj and Rg are as previously described. of the compounds of formula II may be formed, with the trans isomer predominating. The pure tram isomer may be separated by chromatography or crystallization. In addition, the mixture may be isomerized as described for the isomerization of the trans and cis isomers of the oxo compound of formula Ifand ig'.

As described above for compounds of formula I, when substituent groups Rj and R2 in compounds of formula H contain additional asymmetric centers, a mixture of diastereomers may be obtained. Preferred are the enantiomers and/or diastereomers of compounds of the formula nf,hereinbefore described.

The compounds of formula A form acid addition salts with inorganic or organic acids. Thus, they form pharmaceutically acceptable aeid addition salts with both pharmaceutically acceptable organic and inorganic acids, for example, with hydrohalie acid, such as, hydrochloric acid, hydrobromic acid, hydriodic· acid,· other mineral aeid salts, such as, for example, sulfuric acid, nitric acid or phosphoric add, allsyl-and mono-aryl sulfonic acids, such as, for example, ethanesulfanic acid, toluene15 sulfonic acid or benzenesulfonic aoid, other organic acids such as, for example, acetic acid, tartaric acid, maleic acid, citric acid, benzoic acid, salicylic acia and ascorbic acid. Npnnpharmaoentirally acceptable acid addition salts of ooipcunds of formula A can be converted into pharmaceutically acceptable acid addi tion salts via conventional metathetic reactions whereby the non-pharm20 aceutically acceptable anion is replaced by a pharmaceutically acceptable anion? or alternatively, by neutralizing the ηαη-pharmaceutically acceptable.acid addition salt and then reacting the so-obtained free base with a- reagent yielding a pharmaceutically acceptable acid addition salt. The acid addition salts may also form hydrates.

The compounds of the general formulae XX and XIII are novel and also form part of the present invention.

The compounds of formula A and their pharmaceutically acceptable acid addition salts exhibit neuroleptic activity. Accordingly, the compounds of formula A arc useful as antipsychotic agents, for instance, in the treatment of schizophrenia. The activity of the compounds of formula A which makes them useful as antipsychotic agents can be 5 demonstrated in warm-blooded animals, in accordance with known procedures.

For example, by one procedure, trained rats are placed in experimental chambers equipped with a response lever, a steel grid floor for delivery of electric shock and a loudspeaker for presentation of auditory stimuli. Each trial consists of a fifteen-second warning tone, (conditioned stimulus), continuing for an additional fifteen seconds accompanied by electric shock (unconditioned stimulus; 1.0 mA, 350 V.A.C.). The rats can terminate a trial at any point by depression of the response lever. A response during the initial fifteen-second warning tone ends the trial before shock delivery and is considered an avoidance response, while a response occurring during shock delivery is an escape response. Trials are presented every two minutes during a one-hour test session (30 trials per session).

Trained rats maintain a reliable control baseline of avoidance behavior (zero to three avoidance failures per session). Compounds are administered at appropriate pretreatment times to a minimum of three to four rats at each dose level over a range of doses. Rats receive vehicle alone, during control sessions. One control and one experimental session are alternated during each week.

The session is divided into three consecutive twenty minute (ten trial) segments. Response counts are summed over all subjects at a given dose within each segment.

The number oi trials ’.viiich the ;ats failed to exhibit ait avoidance response (uvoidnr.ee block; AU) or failed to exhibit an escape response (escape block; EB) is determined for the segment displaying the maximum such effect nt each dose. This number is expressed as a percentage of the total trials within the segment. The dose calculated to produce a 50% block of avoidance (ABD 50) is obtained from the doseeffect regression line fitted by the Method of Least Squares. The lowest dose which produced a 20% block of escape responding (EBD 20) is read from a graphic dose-cffect plot. In.obtaining these values, percent effect is plotted against the log dose.

Antipsychotic agents can be distinguished from other types of drugs, which 10 affect the behavior of rats in this procedure, by the larger separation between doses which block avoidance responding and doses which block escape responding. The clinical potency of antipsychotic drugs with known therapeutic uses and properties is significantly and highly correlated with their potency in this procedure. Consequently, the compounds of formula A may be used therapeutically in dosage ranges consistent with their potency in the test procedure. 50883 When ?.-ii'.'t:ivl-1.2.3.4.-la.f).7.8.9.10it-tiecnhvdro-4a.l0a-trans-CH-cyclopentn[-l,5] pyrrolo[2,3-g] isoquinolin-10(10U)-one is utilized os the test substance, neuroleptic activity is observed nt an ABD^q of 0.98 mg/kg p.o.

Similarly, when 2-[4-(4-fluorophenyl)-4-oxobutyl] -l,2,3,4,4a,5,7,8,9,10a-deca5 liyaro-4a.l0a-trans-SH-cycIopentn[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one is utilized as the test substance, neuroleptic activity is observed at an ABD5Q of 0.15 mg/kg p.o.

Similarly, when 2-[4-(4-fluorophenyl)-4-oxobutyl] -2,3,4,4a,5,7,8,9,10,lla-dacahydro-4a,lla-trans-IH,6H-cyclolioxa[4,5] pyrrolo[2,3-g] isoquinolin-lI(UH)-one is utilized as the test substance, neuroleptic activity is observed at an ΑΒΟ^θ of 0.73 mg/kg p.o.

Similarly, when 2-methvl-2.3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-trans-lH,6Hcyelohexa[4,5j pyrrolo[2,3-g] isoquinolin-ll(llH)-one, hydrochloride . 0.75 HjO which has demonstrated an ΙΛΙ,θ of, for example, 650 mg/kg p.o. in mice, is utilized as the test substance, neuroleptic activity is observed at an ABDSO of 5.5 mg/kg p.o.

Similarly, when 2-methyl-2,3,4,4a,5,7,8,9, 10,ll,I2,13a-dodeeahydro-4a,13a-trans15 lH,61I-cycloocta[4,3] pyrrolo[2,3-g] isoquinolin-13(13Ii)-one is utilized as the test substance, neuroleptic activity is observed at 8 mg/kg p.o. where the avoidance blockade is 6394.

Similarly, when 2-methyl-l,2,3,4,4a,5,7,8,9,10,ll,12a-dodeoahydro-4a,12a-trans-6Heyelohepta[4,5] pyrro!o[2,3-g] isoquinolin-12(12n)-one is utilized as the test substance, neuroleptic activity’ is observed at 16 mg/kg p.o. where the avoidance blockade is 50%.

The compounds of formula Λ and their pharmaceutically acceptable aeid addition salts have antipsychotic effects which are qualitatively similar to those of haloperidol, and trifluoroperazine, known for their therapeutic uses and properties. Thus, the compounds of formula A demonstrate a pattern of activity associated with anti5 psychotic drugs of known efficacy and safety.

The compounds of formula A and their pharmaceutically acceptable acid addition salts can be used in the form of conventional pharmaceutical preparations. By way of exemplification, suitable oral dosage units comprise or are in the range of from 0.05 to 50 mg., and suitable oral dosage regimens in warm-blooded animals comprise or are in the range of from about 0.001 mg/kg per day to 10 mg/kg per day. However, for any particular warm-blooded animal, the specific dosage regimen may be variable and should be adjusted according to individual need and the professional judgment of the person administering or supervising the administration of a compound of formula A or a pharmaceutically acceptable acid addition salt thereof. Furthermore, the frequency with which any sueh dosage form will be administered will vary, depending upon the quantity of active medicament present therein and the needs and requirements of the pharmacological situation.

For the disclosed use, the compounds of formula A and their pharmaceutically acceptable acid addition salts are formulated, using conventional inert pharmaceutical adjuvant materials, into dosage forms which are suitable for oral or parenteral administration. Such dosage forms Include, for example,, tablets, suspensions and solutions. Furthermore, the compounds of formula A can be embodied into, and administered in the form of, suitable hard or soft capsules. Tlie identity of the inert adjuvant materials which arc used in formulating the compounds of formula A and their pharmaceutically acceptable acid addition salts into oral and parenteral dosage forms will be immediately .apparent to persons skilled in the art. These adjuvant materials, either inorganic or organic in nature, include, for example, water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, and polyalkylene glycols. Moreover, preservatives, stabilisers, wetting agents, emulsifying agents, salts for altering osmotic pressure or buffers, for exanple, can be incorporated, if desired, into such formulations.

Since the compounds of formula A and their pharmaceutically acceptable acid addition salts possess asymmetric carbon atoms, they are ordinarily obtained as racemic mixtures. If desired, diastereomeric mixtures, when obtained, may be separated. The resolution of individual racemates into the optically active isomers can be carried out by known procedures. Alternatively, optically active isomers can be prepared utilizing, in the processes herein described, corresponding optically active starting materials. Some racemic mixtures can be precipitated as eutectics and can thereafter be separated. Chemical resolution is, however, preferred. By this method, diastereomers are formed from the racemic mixture with an optically active resolving agent, for example, an optically active acid, such as μ for example (+)-tartaric acid, (+)dibenzqyl-D-tartaric acid, (+)-d-10-caiiphor-sulfcnic acid and (-) -3<-pinanecarboxylic acid, to form a diastereomeric salt. The formed diastereaners are separated by fractional crystallization and can be converted to the corresponding optical isernar base. Thus,.the invention covers the optically active isaners of the compounds of formula A as well as their racemates.

Furthermore, due to the possible different spatial arrangements of their atoms, it is to bo understood that the compounds of this invention may be obtained in more than one possible geometric isomeric form. The compounds of formula A, as described and claimed, are intended to embrace all such isomeric forms. Accordingly, the examples included herein are to be understood as illustrative of particular mixtures of geometric isomers or single geometric isomers and not as limitations upon the scope of the invention.

The Examples which follow further illustrate the invention. All temperatures are in degrees Centigrade, unless otherwise stated.

Example 1 Preparation of N-methyl-1.5-dimethoxycyclohexn-1.4-dicne-3-ethyIamine 185.2 g. of N-methyl-(3,5-dimethoxyplienyl)-ethylamine hydrochloride was dissolved in 1600 ml. of water and the solution was made alkaline with 160 ml. of ammonium hydroxide. The mixture was extracted with 3 xlOOO ml. of dichloromethane and the combined extracts were washed with 1000 ml. of brine and dried over anhydrous sedium sulfate. Evaporation of the solvent on a rotary evaporator at 35-40° gave 156.0 g. of free base.

In a 12 1. 3-neek flask equipped with a mechanical stirrer and two dry iee condensers, one fitted with a gas inlet and the other with a soda-lime drying tube was condensed 4.0 1. of anhydrous ammonia. To the ammonia was added a solution of 156.0 g. of the free base in 400 ml. of t-butanol and 400 ml. of anhydrous ether over 15 minutes. To the stirred solution was added over 50 min. a total of 32.6 g. of lithium wire cut into6.35 on lengths. The addition rate was controlled so that 12;7cm of wire was added per minute. After all the lithim had been added, the deep blue mixture was stirred under reflux for 2 hours. Than 2.8 1 of anhydrous ether was added to dilute the mixture, the drying tube was removed to allcw the hydrogen to vent, and a total of 280 g. of amnenium chloride pewder was added slcwly over 30 minutes until the blue color had dissipated. The dry ice condenser was removed'and the mixture was stirred and the arimcnia allowed to evaporate overnight. To the residue was added 2.8 1. of ioe water. The mixture was transferred to a separatory funnel, rinsing with 800 ml. of ether, and the layers were separated. The aqueous layer was extracted with 2x1.5 1. of di-chlororaethane and the extracts were oenfoined and washed with 1 1. of brine and dried over anhydrous sodium sulfate. Evaporation of the solvents on a rotary evaporator at 40° and finally at 40°/1.0 urn. (40°/1.0 Torr) for 1.5 hours afforded 150.7 g. of crude product as a yellow oil. The crude oil was distilled through a 30.5 cmGoodloe column (bath 150°) collecting fractions as follows: 50883 Fraction Se wt ggPul 1 40-80°/0.45 mm. 7.9 g. 4.6% 2 80-85e/0.45 to 0.15 mm. 6.2 g. 50% 3 85-866/0.15 mm. 21.2 g. 92% 4 86-87°/0.15 mm. 99.4 g. 100% Fractions 3 and 4 combined afforded 120.6 g. of N-methyl-l,5-dimethoxycyelo hexa-l,4-diene-3-ethylamine as a colorless oil.

Anal. Calcd. for CUH19NO2: C, 66.97; H, 9.71; N, 7.10 Found: C, 66.84; H, 9.62; N, 6.93 4-6 80983 Example 2 Preparation of 1,2,'3,5,6,7.8,9-oetnliydro-2-[2-(incihylnmino)cthyl) -IH-cai-bnzol—1-one Λ mixture of 15.6 g. of N-methyl-l,5-dimcthoxycyclohcxa-l,4-dicne-3-ethylamine (79 mmol), 16.7 g. of 2-isonitrosocyclohexanone (131 mmol), and 19.5 g. of zinc dust (00 mg-atom) in 300 ml. of 70% aqueous acetic aeid heated to reflux for 5 hours, and was cooled and filtered. The filtrate was concentrated in vacuo and excess dioxane was added. The dioxane-acetic aeid azeotrope was distilled off and the process was repented until all the acetic aeid was removed. The residue was chromatographed on Alumina III eluting ivith 10% methanol in dichloromethane to give 10.7 g. of crude l,2,3,5,6,7,8,9-octabydro-2-[2-(inethylamino)ethyl]-4H-carbazol-4-one. The crude product was dissolved in methanol and treated with methanolic HCl and the solvent evaporated to give 12.2 g. of l,2,3,5,6,7,8,9-oetahydro-2-(2-(methylamino)ethyl3-4Hcarbazol-4-one hydrochloride. 50883 Exnmple 3 Preparation of 2-mcthyl-2.3.4,-ln.5,7.8,9,10.Hn-decahydro-4n,Ha-tran5-lH.61I-cyclohcxa[4,5] pyrrolof2.3-g] isoquinolin-ll(llH)-one A mixture of 2.3 g. of l,2,3,5,6,7,8,9-octahydro-2-[2-(methylamino)ethyl] -4H5 carbazol-4-onc hydrochloride (8.14 mmol) and 2.3 g. of paraformaldehyde (75 mmol) in 100 ml. of n-butanol was heated in a pressure bottle immersed in a 180“ C. oil bath to an internal pressure of 5.5 bar. for 1 hour. Hie solution was cooled and the solvent was removed at reduced pressure and the residue was dissolved in water and washed with dichloromethane (discarded). The aqueous solution was made alkaline with ammonium hydroxide and extracted with dichloromethane. The extracts were dried over sodium sulfate, filtered, and evaporated to a 10 ml. volume. The mixture was slurried with 10 g. of alumina, filtered, and evaporated to dryness. The residue was chromatographed on 80 g. of Alumina III eluting with 10% methanol in dichloromethane to give crude 2methyl-2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,Ua-trang.-lH,6H-cyciohexa[4,5]pyrrolo15 [2,3-g] isoquinolin-ll(llll)-one containing a small amount of the corresponding 4a,Ha- cis isomer. Crystallization of the crude product from methanol-dichloromethane-ether gave 2-methyl-2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-trans-lH,6H-cyclohexa[4,5]pyrrolo[2,3-g] isoquinolin-U(UH)-one as an off-white solid. The free base was treated with HCl in methanol and the hydrochloride recrystallized twice from ethanol to give 0.46 g. of pure 2-methyl-2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-trans-lH,6H-cyelohexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(llH)-one, hydrochloride · 0.75 HgO as crystals, mp 217-220° (19% yield).

Anal. Calcd. for C16H22N2O.HC1.0.75 HgO C, 62.33; H, 8.01; N, 9.09; Cl, 11.50 Found: C, 62.56; H, 8.11; N, 9.08; Cl, U.59 50883 Example 4 Preparation of 3,4-dihyflro-ii(-ti.8-dimothoxy-2-methyl-isoquinolinc, hydrochloride A solution of N-methyl-(3,5-dimcthoxyphenyl)othylamine hydrochloride (15.0 g, 64.7 mmol) in 30 ml. of water was treated with 35 ml. of 2N sodium hydroxide and extracted with dichloromethane. The combined extracts were concentrated on a rotary evaporator and mixed with aqueous formaldehyde (65 ml, 37% solution). The mixture was refluxed for 2 hours, made alkaline with 2N sodium hydroxide (15 ml.) and extracted with dichloromethane. The combined extracts were washed with brine and dried over anhydrous magnesium sulfate and concentrated to give the product as a yellow oil (15.5 g). The oil was dissolved in 100 ml. of ethanol and treated with ethanolic hydrogen chloride. Ether (75 ml) was added, and the salt crystallized to give 10.15 g. of 3,4-dihydro-lH-6,8-dimethoxy-2-methylisoquinoline, hydrochloride (64% yield).

S0983 Example 5 Preparation of 1.2.3.4,4a.7-hcxnhydro-6,8-dimcthoxy-2-mctliylisoqui;wline nnd octahydro-2-methvIisoquinolin-6,8-dione Ammonia (150 ml) was condensed in a flask containing t-butanol (9.1 g, 123 mmol) 5 and diethyl ether (50 ml). To the solution was added 3,4-dihydro-lH-G,S-dimethoxy-2methylisoquinoline hydrochloride (1.0 g, 4.1 mmol). After stirring 2-3 minutes, lithium wire (0.57 g, 82 mmol) was added in short pieces over 30 minutes. The blue solution was stirred under reflux for 2.5 hours and solid ammonia chloride (4.5 g) was added until the blue color dissipated. Ether (100 ml) was added and the ammonia was allowed tc< evaporate overnight. Ice water (100 ml) was added and the organic phase was separated. The aqueous layer was extracted with ethyl acetate and chloroform. The combined extracts were washed with brine and dried over anhydrous magnesium sulfate and concentrated to give l,2,3,4,4a,7-hexahydro-6,8-dimethoxy-2-methylisoquinoline (O.SS g, crude) as a yellow oil.

The crude product (1.05 g) in 20 ml. of 70% aqueous acetic acid was refluxed for hours and the acetic acid was removed on a rotary evaporator. The residue was dissolved in water and washed with chloroform. The aqueous phase was concentrated to a 10 ml. volume and chromatographed on Dowex AG 50 WX8 eluting with 2 molar aqueous pyridine to afford 0.11 g. of octahydro-2-methylisoquinolin-6,8-dione (11.6% 20 yield) as a light yellow solid. Treatment with hydrochloric acid in methanol afforded the hydrochloride, mp 193-196°.

Example 6 Preparation of 2-rncthyi-2,3,4.4n.5,7,8,9,10,ll;i-dceahvdro-ia,lia-trnns-lH.6II-cycio!)c\'a[4,5] pvrrolof2,3-gl fcoquinolin-U(HH)-one via oct;iliydro-2-incthylisoquinolin-6.8-dione A mixture of 72 g. of crude ootahydro-2-methylisoquinolin-6,S-dione (about 30% 5 , pure, approximately 0.1 mol), 21.1 g. of crude 2-isonitrosocyclohexanone (about 60% pure, approximately 0.1 mol), and 19.5 g. of zinc dust (0.3 g-atom) in 500 ml. of 70% aqueous acetic acid was heated to reflux for 1 hour. A second 10.5 g. portion of 2isonitrosoeyclohexanone and 6.5 g. of zinc dust was added and the mixture refluxed an additional 2 hours. The solution was cooled, filtered and concentrated in vacuo, and the jq residue was dissolved in water and washed with chloroform (discarded). The aqueous solution was made alkaline with ammonium hydroxide and was extracted with chloroform. The extracts were washed with brine, dried over sodium sulfate, and concentrated. The crude 2-methyl-2,3,4,4a,5,7,8,9,10,Ua-decahydro-4a,Ua-trans-lH,6Hcyclohexa[4,5] pyrrolo[2,3-g] isoquinolin-ll,llH-one was chromatographed on silica gel 15 (dry column) eluting with the organic phase of a mixture prepared by shaking (by volume) 90 parts chloroform, 30 parts methanol, 10 parts water, and 6 parts acetic acid to give 7.8 g. of 2-methyl-2,3,4,4a,5,7,8,9,10,lla-deeahydro-4a,lla-trans-lH,6H-cyclohexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(HH)-one as a white amorphous solid after slurrying with hot ethanol, mp 273-275° C. (dec.).

Anal. Calcd. for C16H22N2O: C, 74.38; H, 8.58; N, 10.84 Found: C, 74.21; H, 8.39; N, 10.61 ,> 50 9 83 Example 7 Following the procedure of Example 6, starting from 2-isonitro$ocyclopcntanone and octahydro-2-methylisoquinolin-6,8-dione, there was obtained 2-methyI-I,2,3,4,4a,5.7,8,9.10a-dceahydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-lO(lOH) -one, mp 295-297° C. (dec.), crystallized from ethanol-methanol.

Anal. Calcd. for C15H2()N2O: C, 73.74; H, 8.25; N, 11.47 Found; C, 73.93) H, 8.41; N, 11.46 The hydrochloride crystallized from water as a hemihydrate, mp 256-258° C. (dec.) Anal. Calcd. for CjgHggNgO.HCl 0.5Η2Ο: C, 62.17; H, 7.65; N, 9.67; Cl, 12.23 Found: C, 62.16; H, 7.71; N, 9.54; Cl, 12.37 50883 Example 8 Following the procedure of Example 6, starting from 2-isonitrosocyclohcptanone and octahydro-2-methylisoquinolin-6,8-dione, there was obtained 2-methyl1,2,3,4,4a,5,7,8,9,i0,HT12a-dodecativdro-4n.l2a-trans-6H-cvcloliePtai4.5] pyrrolo[2,3-g] 5 iso quinolin-12(12il)-one, mp 293-296° C, crystallized from ethanol.

Anal. Calcd. for C17H24N2O: C, 74.96; H, 8.88; N, 10.28 Found: C, 74.79; H, 8.74; N, 10.33 Example 9 Following the procedure of Example 6, starting from 2-isonitrosoeycloocta1 o none and octahydro-2-methylisoquinolin-6,8-dione, there was obtained 2-methyl2,3,4.4a.5.7.8.9.10.11.12.13a-dodecahydro-4a.l3a-trans-lH.6H-cycloocta[4.5] pyrrolo[2,3-g] isoquinolin-13(13H)-one, mp 298-300° C, crystallized from water-dimethyiformamide.

Anal. Calcd. for CjgHgg^O: C, 75.48; H, 9.15; N, 9.78 Founds C, 75.29; K, 9.04; N, 9.70 30983 Example 10 Preparation of 2.3,4.4a,5.7,8,9,10,lla-decnhydro-4a,lla-trnns-lH.6H-cyclohoxn[4,51 pvrγο1ο[2·3-;τ1 isonuinolin-ll(llfl)-one A mixture of 1.9 g. of 2-methyl-2.3.4.4a.5.7.8.9.10.1Ia-decahvdro-4a.lla-trnns5 lH,6H-cyelohexa[4,5] pyrrolo[2,3-gl isoquinolin-U(UH)-one, 2.6 g. of ethyl chloroformate, and 3.2 g. of potassium bicarbonate in 100 ml. of dioxane was heated to reflux for 6 hours, cooled, and filtered. The filtrate was concentrated at reduced pressure, dissolved in chloroform, and extracted with 5% aqueous hydrochloric acid, washed with water, brine, and dried over sodium sulfate. Evaporation of the solvent afforded 1.4 g. of the carbamate, 2-ethoxyearbonyl-2,3,4,4a,5,7,8,9,10,lla-deeahydro-4a,lla-translH,6H-cyclohexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(llH)-one. From the aqueous extracts, 0.45 g. of starting material was recovered by treatment with ammonium hydroxide and chloroform extraction.

The crude carbamate (1.4 g.) was heated to reflux fcr 24 hours with 15 ml. of 30% aqueous sodium hydroxide in a mixture of 15 ml. of ethanol and 5 ml. of dioxane. The mixture was concentrated in vacuo and the residue was dissolved in 5% aqueous hydrochloric acid and washed with chloroform. The aqueous solution was made alkaline with ammonium hydroxide and extracted with chloroform. The extracts were washed with brine, dried, and concentrated to afford 0.65 g. of 2,3,4,4a,5,7,8,9,10,lla-decahydro20 4a,lla-trans-lH,6H-cyclohexa[4,5] pyrroio[2,3-g] isoquinolin-H(llH)-one. 5450983 Example Π Following the procedure of Example 10, starting from 2-methyl-l,2,3,4,4a,5,· 7,8,9,10n-decahydro-4a,10a-trans-GH-cyclopentn[4,5] pyrrolo[2,3-g] isoquinolin-lO(lOII)onc, there was obtained via the carbamate, l,2,3,4,4a,5,7,8,9,I0a-decahydro-4a,10a5 trans-6H-eyclopenta[4,5]pyrroIo[2,3-g) isoquinoiin-10(10H)-one. mp 242-245° C. (dec.), crystallized from ethanol-ethyl acetate.

Anal. Calcd. for C^H^NgO: C, 73.01; H, 7.88; N, 12.16 Found:. C, 72.84; H, 7.78; N, 12.30 Example 12 θ Following the procedure of Example. 10, starting from 2-methyl-2,3,4,4a,5,7, 8.9.10.11.12.13a-dodecahydro-4a,13a-trans-lH,6H-cycloocta[4,5] pyrrolo[2,3-g] isoquinolin13(13H)-one, there was obtained via the carbamate, 1,2,3,4,4a,5,6,7,8,9,10,11,12,13atetradecahydro-4a,13a-trans-cycloocta[4,5] pyrrolo[2,3-g] isoquinolin-4-one, mp 283-5° C.: crystallized from ethanol.

Anal. Calcd. for C^Hg^igO: C, 74.96; H, 6.88; N, 10.28 Found: C, 74.71; H, 8.65; N, 10.24 Example 1 3 Preparation of 2-[4-(4-fluorophcnyl)-4-oxobtityl) -2,3,4,4a,5,7,8.9,lQ,l!a-dccnhydro4n,lla-traris-lH,6H-cvclohcxnf4,5i pyrroto(2.3-gl isonuinoIin-ll(HH)-one A mixture of 0.G8 g. of 2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-trans-lH,6H5 cyclohcxa[4,5] pyrrolo[2,3-g] isoquinolin-U(UH)-one, 1.C8 g. of γ -chloro-p-fluorobutyrophenone, and 1.55 g. of potassium carbonate in 15 ml. of diethylketone was heated to reflux for 24 hours. The mixture was cooled, filtered and concentrated. The residue was chromatographed (dry column) eluting with the organic phase of a mixture prepared fay shaking (by volume) 90 parts chloroform, 30 parts methanol, 10 parts water, and 6 parts acetic acid to afford 0.85 g. of a crude amine, which was recrystallized from ethanol to afford 0.42 g. of pure 2-[4-(4-fluorophenyl)-4-oxobutyll2,3.4.4a.5.7,8,9.10,Ila-deeahydro-4a,lla-trans-lH,6H-cyclohexa[4,5] pyrrolo[2,3-g] isoquinolin -ll(llH)-one as a crystalline solid, mp 220-222®.

Anal. Calcd. for CjgHjgNjOjF: C, 73.50; H, 7.16; li, 6.86; F, 4.65 Found: C, 73.46; H, 7.08; N, 7.16; F, 4.61 Example 14 Following tile procedure of Example 13, alkylation of 2,3,4,la,5,7,8,9,10,lla-deeahydro-4a,lla-trans-lH,61{-cyclohexa[4,5l pyrrolo[2,3-g] isoquinolin-ll(llll)-ono with (2bromocthyl)benzene afforded 2-(2-p))enyletl)yl')-2)3,4,4a,5,7I8,9,10,lla-decahyc'ro-4a,lln5 trans-lH,6H-cyelohcxa[4,5) pyrrolo[2,3-g] isoquinolir.-lKlllD-one, mp 250-256° C. (dec.), as a crystalline solid after rccrystallization from etiianol.

Anal. Calcd. for C23II28N2O! C, 79.27; II, 8.10; N, 8.04 Founds C, 79.29; li, 8.40; N, 7.97 Example 15 Following the procedure of Example 13, alkylation of 2,3,4,4a,5,7,8,9,10,lla--decahydro-4a,lla-trans-lH,6H-cyclohexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(llH)-one with benzyl chloride afforded 2-benzyl-2,3,4,4a,5,7,8,9,10,lla-decahydro-4a)lla-trans-lH,6K-cyclohexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(UH)-one, mp 266-268° C, as a crystalline solid after recrystallization from ethanol.

Anal. Calcd. for C22H26N2O: C, 79.00; H, 7.84; N, 8.38 Found: C, 79.27; H, 8.03; N, 8.60 Example 16 Following the procedure of Example 13, alkylation of l,2,3, !,-!a,5,7,8,9,19a-decahydro-4a.l0a-trans-6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one with benzyl chloride afforded 2-benzyl-l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-eyclcpenta5 [4,5]pyrrolo[2,3-g] isoquinolin-10(10H)-one, mp 258-260’C. (dec.), as a crystalline solid after recrystallization from ethanol.

Anal. Calcd. for C^H^NgO: C, 78.71; H, 7.55; N, 8:74 Found: C, 78.97; H, 7.54; N, 8.53 Example 17 Following the procedure of Example 13, alkylation of l,2,3,4,4a,5,7,8,9,10a-dscahydro-4a,10a-trans-6H-eyclopenta[4,5] pyrrolo(2,3-g] isoquinolin-20(10H)-one with γ chloro-p-fluorobutyrophenone afforded 2-[4-(4-fluorophenyl)-4-oxobutyl] -1,2,3,4,43,5,7,8,9,10a-decahydro-4a,10a-trans-6H-eyclopenta[4,5]pyrrolo[2,3ig]isoquinolin-10(10ii)-one, mp 225-227° C., as a crystalline solid after recrystallization from ethanol.

AnaL Calcd. for C24H27FN2O2: C, 73.07; H, 6.90; N, 7.10; F, 4.82 Found: C, 72.76; H, 6.86; N, 7.24; F, 4.71 Example 13 Following the procedure of Exumplc 13, alkylation of l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one with (2bromocthyDbcnzcne afforded 2-(2-phenylethyl)-l,2,3,4,4a,5,7,8,9,10a-dccahydro-4a,10a5 trans-6H-cyclopenta[4,5] pyrrolo(2,3-g] isoquinolin-10(l0H)-one, mp 251-254° C. (dee.), as a crystalline solid after recrystallization from ethanol.

Anal. Calcd. for C^lI^NgO: C, 79.00; II, 7.84; N, 8.38 Found: C, 78.68; 11, 7.72; N, 8.28 Example 19 Following the procedure of Example 13, alkylation of 1,2,3,4,4a,5,7,8,9,10adecahydro-4a,10a-trans-6H-eyelopenta[4,51 pyrrolo[2,3-g] isoquinoIin-I0(10H)-one with 4methoxybenzyl chloride afforded 2-(4-methoxybenzyl)-l,2,3,4,4a,5,7,8,9,10adecahvdro-4a.l0a-trans-6H-cvclopenta(4,5] pyrrolo[2,3-gl isoquinoh'n-4-one, mp 236-8° (dec.), as a crystalline solid after recrystallization from ethanol.

Anal. Calcd. for C22H2gN2O2: C, 75.40; H, 7.48; N, 7.99 Found: C, 75.39; H, 7.41; N, 8.03 80983 Example 20 Following the procedure of Example 13, alkylation of 1,2,3,4,4a,5,7,8,9,10adecahydro-4a,10a-traiis-6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one with 4chlorobenzyl chloride afforded 2-(4-chlorobcnzyl)-l,2,3,4,4a,5,7,8,9,10a-decahydro5 4a,10a-trans-6H-cyelopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one as a crystalline monohydrate, mp 254-6° after recrystallization from ethanol.

Anal. Calcd. for C21H2;}N2O Cl HgO: C, 67.63; H, 6.22; N, 7.51; Cl, 9.51 Found: C, 67.86; H, 6.38; N, 7.50; Cl, 9.92 Example 21 Following the procedure of Example 13, alkylation of 1,2,3,4,4a,5,7,8,9,10adecahydro-4a,10a-trans-6H-cyelopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one with allyl bromide afforded 2-(2-propenyl)-l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10atrar.s-6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-lO(lOH) -one, mp 257-9° (dee.), after recrystallization from ethyl acetate-ethanol.

Anal. Calcd. for C17H22N2O: C, 75.52; H, 8.20; N, 10.36 Found! C, 75.25; H, 8.17; N, 10.36 50883 Example 22 Following the procedure of Example 12, alkylation of 1,2,3,4,4a,5,7,8,9,10adccahvdro-4a.I0a-trans-6H-cyclopenta[4,5] pyrrolo(2,3-g] isoquinolin-10(10H)~one with 2bromoethyl ether afforded 2-(2-ethoxyethyl)-l,2,3,4,4a,5,7,8,9,10a-decahydros 4a.I0a-trans-6H-cvclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one, mp 236-8° (dee.) as a crystalline solid after recrystallization from ethanol.

Anal. Calcd. for ci8H26N2°2: C» 7L49> H> 8,67; N’ 9,26 Found: C, 71.35; H, 8.47; N, 9.23 Example 23 Following the procedure of Example 13, alkylation of 2,3,4,4a,5,7,8,9,10,11,12,13adodecahydro-4a,13a-trans-lH,6H-cycloocta[4,5] pyrrolo[2,3-g]isoquinolin-13(13H)-one with the ethylene ketal of gamma-chloro-g-fluorobutyrophenone followed by acid hydrolysis afforded 2-[4-(4-fluorophenyl)-4-oxobutyll -1,2,3,4,4a, 5,6,7,8,9,10,11,12,13atetradecahydro-4a.l3a-trans-cvclooctaC4.5] pyrroIo[2,3-g]isoquinolin-I3(I3H)-one.

Example 24 Following the procedure of Example 13, the compounds listed in Table I may be prepared from the indicated cycloalka[4,5] pyrrolo[2,3-g] isoquinoline and the indicated halide. *1 ι-M U. U O CQ CQ CQ CQ «Ί e* S3 $. Λ. £ £ 0—0 '03 £ ? O £ O £ O 'o3 £ O £ O N-CHOCH, ό 0~w TABLE I - cont’d. Ό I δ* o *§“ Ο I—R GJ ho 7« ® 03 O 1,2 °bo t- >> r. Q, ‘Ί--’ ca « ’.Λ *« ·* .3 2| >« JS r—i g a, co 7 03 d'o °° O’ U op S CO w w 0 4 cf «* ,£ P >> t oC O & , £.51 0 0} Ui ϋ oj »n λ 2 «β .£ ££ g 7 F Q *3 £ S’ T 0 i.J3 1 r> T· SL? c? ® “2 0 ,—t 3Ύ »03 8 l'S •o S T “o? «··* »» r· S 5 - U3 a 5« 07. “o “bo ca h g ά 1 §£'3 M* ZL co 5 Λ O f CU « Λ * S, v a «λ 't’O J? >* σ ·, js 0 M a .S3 T 0 0 Xl w j a < ta Ε oj X ω I Μ a n a o o a o ι cq a ? a o II a o ι eq a o cq a V ? a o II cq a o 'cq a cq a o cq a o CO a o oi a o 1 S3 a φ— ο 04 cq S3 a 0—0 i i t u O c ’3 σ o .w >.·§ σ ο ο a> .!2 ο ΖΖ ' έ, Ό 1-^ £ΐ° 1 Ο 1 -ο ό J..2 g? ? rt oT i V ° co <η£Ϊ α) rt S22 V ,2 q rt ,2 ® o οο® w *1 0 0 u *£2 ’“ί. t3 0 5^ «-Μ U * u >» Ol <β ο. S α σ> CZ* •clO Ω* co «—* *»ΙΛ 50883 *1 ra ra =1 TABLE I - cont'd, a o II CX a o •0 , 5-2 f « J2 c* CT £ W„S t» ι—» to1 £2 tS o o ?3 cT CM I *r« X “x G : 0 ! G :'3 1 σ σ .o >8 G5 o cT’o Γ-H L( co Λ tf> xjT •5*3 tt TP 2 tr? o cm 73 ι >> Q u ¢) c c a o O to Q. *C5 Ο Ξ 3 r-ι r-t P*.

CM I >Λ g f» ω « 7cx o 2 ε σ» >» * °* co frTto toS ef S **§ *S< £ « o A o S >>hJ? o «»a [J M Zl Cu*2 5 >i *7*. 3 X ω] i O GG c G PH’S to -j ~i si, m I X| m u e« pq E Cn c| c o o w J CO < EI Z7 ι ο ι >1 V C ο Ό -° > I *c S i-Ss X I o o O —< U „? Ci >>C0 i*> X «. ti C) « A 1 ,2 r o .>» CJ cs a _**F^ o^io » c- ‘‘Ja -io, Μ* ·“ «2 •τ-εΐ uj - · £2 cq 'c * o co >» °s ϋ O o C9 Ο φ cn P Λ U S 2 .5 T3 § ΠΪΑ 3>«ik 3 H UP—’' >> ·» u σ> >> ’3 CP o (Λ T.e. IO *“' ~io ti -2» co£ t— ΙΛ ιθ^ To 1 co g «2 «31* £ co o* C? ti a - “ c £Ti c £ cr o £ o •S £.22 Λ Έ w Q< gtiTo § =J ·§« 4. ν o Tag 2 2 £ n d a I. 2 1 Ό £5 •£3 s.s -g CP O o τ? .22 C4 A *7-2 A ϋ >>& ex 9 gi CXtD >» ι ι w V) I o c « c a c §£ o A I Λ c. ti X «3.2 Λ 5 2 Ό O f'.S a & ° o •g.§ ?¥ “j= « 0 «3 ri >» Λ >3 £S w *£ e o c ti c §bl? A ι Λ Ci ti **ri Λ2« 50883 (. n L. m TABLE I - cont'd. c| a) •s ε as X W a □ OJ a υ o OJ a o M a o Example 49 Preparation of 2-motliyl-1.2,3,4.4n.5,7.8.9.10a-decahydro-4a,10n-trans-6H-cycIopenta[4,5] pyrrolo[2.3-g] isocuinolin-lOGOlD-thione A mixture of 244 mg. (1.0 mmol) of ^-methyl-l^jS^^a^.T^^JOa-decahydro5 4a,I0a-trans-6H-eyeiopenta(4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one and 222 mg. (1.0 mmol) of phosphorus pentasulfide in 15 ml. of dioxane was stirred and refluxed for 17 hours. Tile dioxane solution was decanted off and water (20 ml.) and enough ammonium hydroxide to bring the pH to 8-9 was added to the residue. The mixture was extracted with chloroform, and the extracts were washed with brine, dried and evaporated. The io crude thione was chromatographed as described in Example 13 to afford 65 mg. of pure solid thione which was recrystallized from acetonitrile to give 2-methyl-l,2,3,4,4a,5,7,8.9.10a-decahvdro-4a,10a-trans-6H-cyelopenta[4.5] pyrrolo[2,3-g] isoquinolin-lOflOK) -thione, mp 224-227° C. (dec.).

Anal. Calcd. for CjgH^NgS: C, 69.19; H, 7.74; Ν,ΪΟ.76 Found; C, 68.97; H, 7.59; N, 10.97 50883 Example 50 The procedure of Example 49 is used to prepare 2-methyI-2,3,4,4a,5,7,8,9,I0,Iladccshydro-4a,Iln-trans-lH,6iI-cyclohexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(llH)-thione starting from 2-methyl-2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-tains-lH,GH-eyclohexa5 [4,5] pyrrolo(2,3-g] isoquinolin-ll(UH)-one.

Example 51 The procedure of Example 49 is used to prepare l,2,3,4,4a,5,7,8,9,10a-deeahydro4a,10a-trans-6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-thior>e starting from 1.2.3.4.4a.5.7.8.9.10a-deeahvdro-4a.l0a-trans-6H-cyclopenta[4,5] pyrrolo[2.3-g] isoquino10 lin-JOflOHbone.

Example 52 The procedure of Example 13 is used to prepare 2-[4-(4-fluorophenyl-4-oxobutyl] l12.3.4.4a.5.7.8.9.10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-thione starting from 1.2.3.4.4a.5.7.8.9.10a-decahvdro-4a.I0a-trans-6H-cvelo15 penta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-thione and γ-chloro-p-fluorobutyrdphenone.

Example 53 The procedure of Example 13 is used to prepare 2-(2-phenylethyl)-l,2,3,4,4a,5,7,8,9,10a-deeahydiO-4a,10a-trans-6H-cyelopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)tliione starting from ],2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-lrans-GH-cyclopenta[4,5] 20 pyrrolo[2,3-g] isoquinolin-10(10Il)-thione and (2-bromoethyl)benzene.

Example 54 Preparation of 6-benzoyl-2-mcthyl-1.2.3.4,4a.5.7.3.9.10a-decahvdro-4a.l0a-tr.ansr6Hcyclopentn[4,51 nyrrolof2.3-g] isoquinolin-10(10ti)-one To a mixture of 244 mg. (1.0 mmol) of 2-metliyl-l,2,3,4,4a,5,7,8,3,lOa-decahydro5 4a.l0a-trans-6H-cvelopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one in 10 ml. of dry tetrahydrofuran at -30° is added 0.5 ml. of n-butyllithium (1.1 mmol of 2.2M solution in hexane) over 2-3 minutes via syringe. The solution is stirred for 30 minutes at -30° and 168 mg. of benzoyl chloride (1.2 mmol) is added over 2-3 minutes. The solution is stirred 1 hour at -30° and 30 minutes at room temperature. The mixture is poured onto ice and extracted with chloroform. The extracts are washed with brine, dried (sodium sulfate), concentrated and chromatographed to afford the 6-benzoyl-2-methyll,2,3,4,4a,5,7,8,9,10a-decaliydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo[2,3-g) isoquinolin -10(10H)-one.

Example 55 Following the procedure of Example 54, 2,6-dimethyl-l,2,3,4,4a,5,7,S,9,10a-decahydro-4a,I0a-trans-6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquinoIin-10(10H)-one is prepared using methyl iodide instead of benzoyl chloride. 50883 Example 56 Preparation of ;-(2-hydroxy-3.3-dimcUiylbutyl)-2.3,4.4a,5,7,8.9.1Q.IIa-decaliydro-4a,llalranS.-lH,6H-eyeloliexaf4,5) pyrrolo(2.3-g] isonuinolin-Il(llH)-one A solution of 488 mg. (2.0 mmol) of 2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-tmflS5 llI,6H-cyclohexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(llH)-one and 300 mg. (3.0 mmol) of 3,3dimcthyl-l,2-cpoxybutanc in IS ml. of methanol was refluxed for 24 hours and concentrated. The residue was chromatographed, and the crude product (350 mg.) crystallized from ethanol to give 200 mg. of 2-(2-hydroxy-3,3-dimethylbutyl)-2,3,4,4a,5,7,8,9,10,lla-decaliydro-4a,lla-l£ana-lH,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-ll(UH)10 one, mp 270-278° C. (dec.).

Anal. Calcd. for C, 73.22; H, 9.36; N, 8.13 Found: C, 73.39; H, 9.31; N, 8.15 Example 57 The procedure of Example 55 is used to prepare 2-(2-hydroxy-2-phenylethyl)15 l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-irans-6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one starting from 1.2.3.4.4a,5.7.8.9.10a-decahydro-4a.I0a-trans-6H-evelopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one and styrene oxide.

Example 58 Following the procedure of Example 56, alkylation of 1,2,3,4,4a,5,7,8,9,10a20 decahydro-4a,10a-^/yjs-6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one with ethylene oxide at room temperature afforded 2-(2-hydroxyethyl)-l,2,3,4,4a,5, 7,8,9,I0a-decaliydro-4a,10a-trans-6H-cvclopenta[4.5l pyrrolo[2,3-g] isoquinolin-lO(lOH)one, mp 237-9° (dec.) as a crystalline solid after recrystallization from ethanol.

Anal. Calcd. for C^Il^NgOg! C, 70.04; H, 8.08; N, 10.21 23 Found: C, 69.66; H, 3.17; N, 10.19 50883 Example 59 Following the procedure of Example 56, alkylation of 1,2,3,4,4a,5,7,8,9,10adecahydro-4a,10g-trans-6H-cyclopentaf4.51 pyrrolo[2,3-g] isoquinolin-IQ(10H)-one with 3,3-dimethyl-l,2-epoxybutane afforded 2-(2-hydroxy-3,3-dimethylbutyl)-l,2,3,4,4a, .7.8.9.10a-decahvdro-4a.l0a-trans-6H-ovclopenta[4.5l pyrrolo[2,3-g] isoquinolin10(10H)-one, mp 284-6’ (dee.), as a crystalline solid after recrystallization from ethanol.

Anal. Calcd. for C20H30N2°2s C> 72,69j H’ 9,15; N’ 8,48 Found: C, 72.80; H, 9.02; N, 8.55 Example CO A mixture of 30 mg of sodium hydride dispersion (57%, washed free of oil) and 2 ml of dry dimethyl sulfoxide (DMSO) was heated to 65-70’ for 1.5 hrs. The solution was cooled and a solution of 244 mg of 2-methyl-l,2,3,4,4a,5,7,8,9,10a-deeahydro-4a,10atrnns-6H-cyelopentaf4,5l pyrrolo[2,3-g] isoquinolin-1000H)-one in I ml of dry DRISO was added in portions. The mixture was stirred for 2 hrs. at room temperature. A solution of 160 mg of benzyl chloride in 1 ml of dry DMSO was added, and the mixture was stirred for 2.5 hrs. at room temperature and then poured into ice water. The mixture was extracted with chloroform, the extracts washed with brine, dried and concentrated to give 560 mg crude solid. Chromatography on silica gel using the system given in Example 62 gave 60 mg of 6-benzyl-2-methyl-l,2,3,4,4a,5,7,8,9,10a-deeahydro-4a,10atrans-6H-evclopenta[4.5] pyrrolo[2,3-g] isoquinolin-10(10H)-one as a crystalline solid, mp 169-171’ after recrystallization from ethyl acetate-ethanol.

Anal. Calcd. for CggHjgNjO: C, 79.00; H, 7.84; N, 8.35 Found: C, 78.92; H, 7.84; N, 3.55 Example 61 To a solution of 2.35 g of rac.-2-methyl-l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10atrans-SH-oveIooentaf4.5] pyrrolo[2,3-g] isoquinolin-10(10H)-one in 20 ml of methanol was added a solution of 3.62 g of (+)-dibenzoyl-{D)-tartaric acid monohydrate in 20 ml of methanol. The mixture was concentrated and crystallized from methanol three times and converted to the free base with ammonium hydroxide. Reorystallization of the base from ethanol afforded 0.18 g of (-)-2-methyl-l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10atrans-6H-cyelopenta[4.5] pyrrolo[2,3-g] isoquinolin-10(10II)-one, mp 270-2° (dec.). The hydrochloride salt gave [ a ] D -101.17° in methanol (1%).

Example 62 Preparation of 2-[4-<4-fluorophenyl)-4-hydroxybutyll -l,2,3,4,4a,5,7,8,9,10adecahydro-6H-4a,10a-lEan5.*cyclopcnta[4,5)pyrrolo[2,3-g] isoquinolin-10(10H)-one.

A mixture of 394 mg (1.0 mmol) of 2-[4-(4-fluorophenyl)-4-oxobuiyl] l,2,3,4,4a,5,7,8,9,10a-decahydro-6H-4a,10a-lEana-cyclopenta[4,5] pyrrolo[2,3-g] isoquit, olin10(10H)-one and 151 mg of sodium borohydride (4.0 mmol) in 15 nil of ethanol was stirred at room temperature for 24 hrs. A second portion of sodium borohydride (150 mg, 4.0 mmol) was added, and the mixture was stirred further at room temperature for 24 hrs. The mixture was poured into 50 ml of water and filtered to remove the white solid product containing some starting material. Dry column chromatography on silica gel eluting with the lower phase of a mixture of 90 ml chloroform, 30 ml methanol, ml water and 6 ml acetic acid afforded 220 mg of solid which was recrystallized from aqueous dimethylformamide to give 2-[4-(4-fluorophenyl)-4-hydroxybutyl] l,2,3,4,4a,5,7,8,9,10a-decahydro-6H-4a,10a-lEaDSrcyclopenta[4,5] pyrrolo[2,3-g] isoquinoiin10(10H)-one, mp 243-5’, as a mixture of diastereomers.

Anal. Calcd. for C^H^N^F: C, 72.70; H, 7.37; N, 7.07 Found: C, 72.68; H, 7.56; N, 7.33 Example 63 Following the procedure of Example 62, sodium borohydride reduction of 2-[4-(4fluorophenylH-oxobutyl]-2,3,4,4a,5.7.8.9,10.Ila-decahvdro-4a,lla-trans-lH.6Hcyclohexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(llH)-one afforded 2-[4-{4-fluorophenyl)-4-hy5 droxybutyl] -2,3,4,4a,5,7,8,9,I0,lla-decahydro-4a.IIa-trans-lH.6H-eyclohaxal4,m pyrrolo[2,3-g] isoquinolin-ll(llil)-one, as a mixture of diastereomers, mp 239-41°, crystallized from 1,4-dioxane.

Anal. Calcd. for c25H3iN2°2F: ' C, 73.14; H, 7.61; N, 6.82 Found: C, 73.18, H, 7.72; N, 6.82 Example 64 Following the procedure of Example 62, sodium borohydride reduction of 2-[4(4-fluorophcnyl)-4-oxobutyl]-2,3,4,4a,5,7,8,9,10,H,12,13a-dodecahydro-4a,13a-ii2n2.lH,6H-cyeloocta[4,5] pyrrolo[2,3-g] isoquinolin-13(13H)-one afforded 2-[4-(4-fluorophenyl)4-hydroxybutyl]-2,3,4,4a,5,7,8,9,10,ll,12,13a-dodecahydro-4a,13a-trans-lH,6H-cyclo15 octa[4,5l pyrrolo(2,3-g] isoquinolin-13(13II)-one, as a mixture of diastereomers, mp 249-51°, crystallized from 1,4-dioxane.

Anal. Caled. for C27H,5N2O2F: C, 73.94; H, 8.04; N, 6.39 Found: C, 73.71; H, 8.05; N, 6.37 Example 65 Preparation of 5-[(2-methylamino)ethyl] -cyclohexane-1,3-dione To a stirred solution of N-methyl-l,5-dimethoxycyclohexa-l,4-diene-3-ethylamine (5.5 g, 27.9 mmol) in 20 ml of tetrahydrofuran was added 10 ml of 6N hydrochloric acid in one portion. The warm solution was heated for 15 min. at 50° C and concentrated to give a light yellow oil. The crude oil was dissolved in 25 ml of water, and the solution was mixed with 50 g of Dowex 50X8 resin (previously washed with 2N HCl and deionized water) in a sintered glass funnel. After a few minutes, the aqueous solution was drawn out by suction, and the resin rinsed with four 50 ml-portions of water, and then with eight 35 ml-portions of 2M aqueous pyridine. Pyridine fractions 3-8 were pooled and concentrated to give 3.9 g of 5-[(2-methylamino)ethyl] cyclohexane-1,3-dione. An analytical sample crystallized from water and had mp 171i’C.

Anal. Calcd. for CgIl15NO2! C, 63.88; H, 8.93; N, 8.28 Found; C, 63.50; H, 8.87; N, 8.15 Example 66 Preparation of 6-benzyl-2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,11atcaa&-lH.6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-ll(11H)-one Following the procedure of example 60, 316 mg of 2-ethoxycarbonyl-2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-trans-ΙΗ,6Hcyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-ll(11H)-one was alkylated with 190 mg of benzyl chloride to afford 6-benzyl-2-ethoxy-carbonyl-2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-trans-ΙΗ.6H<^cl

Claims

1. CLAIMS;

1. A cycloalka[4,5]pyrrolo[2,3-g]isoquinoline of the general formula r 2 -n wherein R 1 is hydrogen, lower alkyl, lower alkanoyl, arylcarbonyl or aryl-lower alkyl.; Rg is hydrogen, lower alkyl, lower hydroxyalkyl, aryl-lower hydroxyalkyl, lower alkoxylower alkyl, lower alkanoyloxy-lower alkyl, arylcarbonylcxy- lower alkyl, lower alkanoyl-lower alkyl, arylcarbonyllower alkyl, aryl-lower alkyl, lower alkenyl, (C 3 _ g )oycloalkyl-lower alkyl, lower alkynyl, thienyl-lower alkyl, furyl-lower alkyl, arylcarboxamido-lower alkyl, aryllower alkenyl, lower alkenyloxy-lower alkyl, aryloxylower alkyl, aryl-lower alkyloxy-lower alkyl or aryl-Nimidazolonyl-lower alkyl ; X is 0 or S; and n is 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, or an optical or geometric isomer of said compound or a pharmaceutically acceptable acid addition salt thereof.

2. A compound in accordance with claim 1, wherein Rg is other than hydrogen when R 1 is other than hydrogen.

3. A compound in accordance with claim 1, wherein Rj^ is hydrogen.

4. A compound in accordance with claim 1, wherein R^ is hydrogen and Rg is lower alkyl, lower hydroxyalkyl, aryllower hydroxyalkyl, lower alkoxy-lower alkyl, aryloxy-lower alkyl, lower alkanoyl-lower alkyl, arylcarbonyl-lower alkyl or aryl-lower alkyl.

5. A compound in accordance with any one of claims 1 to 4, wherein n is 3 or 4.

6. a compound in accordance with any- one of claims 1 to 5, wherein X is 0.

7. A oaipoond in accordance with any one of claims 1'to 6, which -is the trans isomer. 5

8. 2-Methyl-l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,lOa-iE^ng.6H-cyclopentaf4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one.

9. 2-Methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,IQa-trans6H-cyclopenta[4,5 ]pyrrolo[2,3-g]isoquinolin-10(10H)-one hydrochloride. 0.5 H 2°·

10. Io. 2-[4-(4-Fluorophenyl)-4-oxobutyl]-l,2,3,4,4a,5,7,8,9,10a decahydro-4a,10a-tr ans-6H-cyclopenta[4,5]pyrrolo[2,3-g3 isoquinolin-10(10H)-one.

11. 2-(2-Phenylethyl)-1,2,3,4,4a,5,7,8,9,lOa-decahydro4a,10a-transj-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin15 10(10H)-one.

12. (-)-2-Methyl-l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10atrans-6H-cyclonentar 4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one.

13. 2-Methyl-2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-transIH,6H-cyclohexa[4,5]pyrrolo[2,3-gJisoquinolin-11(11H)-one. 5098

14. 2-Methyl-2,3.4,4a,5,7,8,9,10,lla-decahydro-4a,lla-transIH,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(1IH)-one . 0.75 H 2 0.

15. 2-[4-(4-Fluorophenyl)-4-oxobutyl1-2,3,4,4a,5,7,8,9,10, 5 lla-decahydro-4a,lla-trans-lH.6H-cvclohexa[4.5]pyrrolo[2.3-q]iso· quinolin-ll(HH)-one.

16. 2-(2-Phenylethyl)-2,3,4,4a,5,7,8,9,10,lla-decahydro4 a,11a-trans-1H,6 H-cyclohexa[4,5]pyrrolo[2,3-g]is oquino1 inll(llH)-one. 10

17. 2-Methyl-l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10atrans-6H-cvclopenta[4.5]pyrrolo[2,3-g.l isoquinolin-10(10H)thione.

18. A compound of the general formula H 15 wherein R 2 is lower alkyl, lower alkoxy-lower alkyl or (C 3 _ g )-cycloalkyl-lower alkyl and n is 3, 4, 5 or 6, whereby the residues denoted as lower contain up to 7 carbon atoms.

19. A compound in accordance with claim 18, wherein R 2 20. Is methyl. 50883

20. A compound of the general formula wherein X is S or Ο, n is 3, 4, 5 or 6, Sj is hydrogen, lower alkyl, lower alkanoyl, arylcarbonyl or aryl5 lower alkyl, 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 akylamino or di(lower alkyl)amino.

21. A compound in accordance with any one of claims 1 to 17 for use as a pharmaceutically active substance.

22. A compound in accordance with any one of claims 1 to 17 for use as an antipsychotic agent.

23. A process for the manufacture of a compound in accord15 ance with any one of claims 1 to 17, which process comprises a) for preparing a compound of the general formula R 2 -l la wherein is lower alkyl, lower alkoxy-lcwer alkyl or (C 3 _g)- cycloalkyl lower alkyl and n is as defined in claim 1, 20 reacting a canpound of the general formula I wherein Rg and n are as defined above, with formaldehyde, or b) for preparing a compound of the general formula la above, reacting a compound of the general formula with a compound of the general formula VII HOM in the presence of a reducing agent or with the general formula o a compound of h 2 n < CH 2>n VIII or a precursor thereof, in which formulae n is as defined above, or c) for preparing a compound of the general formula wherein n is as defined above, N-demethylating a compound of the formula la above wherein RJ is methyl, or wherein RJ is hydrogen, lower alkyl or aryl-lower alkyl, Rj' is hydrogen, lower alkyl, lower alkoxy-lower alkyl, aryl-lower alkyl, lower alkenyl, (Cg_g)-cycloalkyl-lower alkyl, lower alkynyl, thienyl-lower alkyl, furyl-lower 10 alkyl, lower alkenyloxy-lower alkyl, aryl-lower alkenyl, aryloxy-lower alkyl or aryl-lower alkyloxy-lower alkyl, and n is as defined above, reacting a compound of the general formula 15 wherein RJ, RJ* and n are as defined above, with phosphorus pentasulfide, or e) for preparing a compound of the general formula X H wherein Rj is lower alkyl, lower hydroxyalkyl, aryllower hydroxyalkyl, lower alkoxy-lower alkyl, lower alkanoyloxy-lower alkyl, arylcarbonyloxy-lower alkyl, lower alkanoyl-lower alkyl, arylcarbonyl-lower alkyl, aryl-lower alkyl, lower alkenyl, (C 3 _ g )-cycloalkyllower alkyl, lower alkynyl, thienyl-lower alkyl, furyllower alkyl, arylcarboxamido-lower alkyl, aryl-lower alkenyl, lower alkenyloxy-lower alkyl, aryloxy-lower alkyl, aryl-lower alkyloxy-lower alkyl or aryl-Nimidazolonyl-lower alkyl and X and n are as defined in Claim 1, substituting a compound of the general formula wherein X and n are as defined above, at the isoquinoline nitrogen atom, or f) for preparing a compound of the general formula wherein R’^ is lower alkyi, lower alkanoyl, arylcarbonyl or aryl-lower alkyl, R^ 1 is 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, (C 3 _ g )-cycloalkyllower alkyl, thienyl-lower alkyl, lower alkynyl, furyllower 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 are as defined above, A d' wherein R^ 1 , X and n are as defined above, at the pyrrole nitrogen atom, or g) for preparing a compound of the general formula X < CS A AC wherein R^ is lower hydioxyalkyl or aryl-lower hydroxyalkyl, and R^, X and n are as defined above, splitting off the protecting group in a compound of the hydroxyalkyl group protected at the hydroxy group andJR|, X and n are as defined above, h) for preparing a compound of the general formula X wherein Rg , X and n are as defined above, reducing the lower alkanoyl-lower alkyl or arylcarbonyl-lower alkyl group in a compound of the general formula wherein Rg is lower lower alkyl and X and n H alkanoyl-lower alkyl or arylcarbonylare as defined above, or i) for preparing a compound of the general formula wherein X, n and R^' are as defined above, splitting off the ethoxycarbonyl group in a compound of the general and j) if desired, isomerizing a mixture of the cis and trans isomers obtained to a final ratio which comprises predominantly the trans isomers, and/or k) if desired, separating the trans isomer from the mixture 2 obtained, and/or 1 ) if desired, resolving a racemic mixture obtained into the optical antipodes and/or m ) if desired, converting a compound obtained or a nonpharmaceutically acceptable acid addition salt into a pharma 1Q ceutically acceptable acid addition salt thereof.

24. A process in accordance with claim 23, wherein process embodiments a), b), c), d), e), f), g), j), ^), jJ and m ) are performed.

25. A process in accordance with claim 23, wherein process 15 embodiment h) is performed.

26. A medicament containing a compound in accordance with any one of claims 1 to 17 .in association with a pharmaceutically acceptable carrier or diluent therefor.

27. A neuroleptic/antipsychotic medicament containing 2q a compound in accordance with any one of claims 1 to 17 in association with a pharmaceutically acceptable carrier or diluent therefor.

28. A compound in accordance with any one of claims 1 to 17 for use in the treatment of schizophrenia.

29. A compound in accordance with any one of claims 1 to 17, whenever prepared according to the process as claimed in any one of 5 claims 23 to 25 or by an obvious chemical equivalent thereof.

30. A cycloalka[4,5]pyrrolo[2,3-g]isoquinoline of the general formula A given and defined in Claim 1 or an optical or geometric isomer of said compound or a pharmaceutically acceptable acid addition salt thereof, substantially as hereinbefore described and 10 exemplified.

31. A process for the manufacture of a cycloalka[4,5]pyrrolo[2,· 3-g]isoquinoline of the general formula A given and defined in Claim 1 or an optical or geometric isomer of said compound or a pharmaceutically acceptable acid addition salt thereof, substan15 tially as hereinbefore described and exemplified.

32. A cycloalka[4,5]pyrrolo[2,3-g]isoquinoline of the general formula A given and defined in claim 1 or an optical or geometric isomer of said compound or a pharmaceutically acceptable acid addition salt thereof, whenever manufactured by a process claimed 20 in Claim 31.

33. A compound of the general formula IX given and defined in 'claim 18, substantially as hereinbefore described and exemplified.

34. A compound of the general formula XIII given and defined in Claim 20, substantially as hereinbefore described and 25 exemplified.

35. A medicament according to Claim 26, substantially as hereinbefore described with particular reference to Examples