NZ196363A - Cycloalka (4,5) pyrrolo (2,3-g) isoquinolin (ones or thiones) - Google Patents

Cycloalka (4,5) pyrrolo (2,3-g) isoquinolin (ones or thiones)

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Publication number
NZ196363A
NZ196363A NZ196363A NZ19636381A NZ196363A NZ 196363 A NZ196363 A NZ 196363A NZ 196363 A NZ196363 A NZ 196363A NZ 19636381 A NZ19636381 A NZ 19636381A NZ 196363 A NZ196363 A NZ 196363A
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NZ
New Zealand
Prior art keywords
trans
pyrrolo
alkyl
compound
isoquinolin
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Application number
NZ196363A
Inventor
L Berger
G L Olson
Original Assignee
Hoffmann La Roche
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Application filed by Hoffmann La Roche filed Critical Hoffmann La Roche
Publication of NZ196363A publication Critical patent/NZ196363A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Description

New Zealand Paient Spedficaiion for Paient Number 1 96363 1 96'3 6 PrioHty Dstc{9)-Ag:?.'^Pi..i'?. ■ ' Como!st@ Specification Fiisd: <&.'?;?l Eass: .... ...3P.MAR.M .jasfc .
Pu&iSCcl^C-n 0£ .0. f«> m 3s«?B5! gl A NEW ZEALAND PATENTS ACT, 1953 No.: Date: COMPLETE SPECIFICATION ISOQUINOLINE DERIVATIVES H^We, F. HOFFMANN-LA ROCHE & CO. AKTIENGESELLSCHAFT, 124-184 Grenzacherstrasse, Basle, Switzerland, a Swiss company, hereby declare the invention for which X / we pray that a patent may be granted to HK/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - (followed by la) 1 2 3 4 6 7 -S 9 II 12 13 14 16 17 18 19 21 22 23 2H 26 27 1 %J The presort invention relates to cycloaIka[-l,5] pyrrolo[2,3-g] isoquinolines of the general formula wherein is hydrogen, alkyl, acyl or aralkyl; Ej 's hydrogen, alkyl, hydroxyalkyl, arylhydroxyalkyl, alkoxyalkyl, acyloxyalkyl, acylalkyl, aralkyl, alkenyl, cycloalkyl-alkyl, alkynyl, thienyl-alkyl, furyl-alkyl, arylcarboxamidoalkyl, ar-alkenyl, alkenyloxyalkyl, aryloxyalkyl, aralkyloxyalkyl, or aryl-N-imidazolonylalkyl; X is 0 or S; and n is 3, 4, 5 or 6] optical and geometric iscmos of tinese enrpxrrfs ard tiisir jjnanteceutically acoaptsiale acid addition salts.
As used herein, the term "alkyl" preferably denotes "lower alkyl", which denotes a straight or branched chain saturated hydrocarbon containing 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, neopentyl, pentyl, heptyl, and the like. The term "cycloalkyl" denotes a cyclic alkyl group of 3 to 6 carbon atoms, for example, cyclopropyl, cyelohexyl, and the like. The term "alkoxy", preferably denotes "lower alkoxy", which denotes an alkyl ether group in which the lower alkyl group is as described above, for example, methoxy, ethoxy, propoxy, pentoxy. and the like. The term "alkenyl" preferably denotes "lower alkenyl", which denotes a straight or branched chain unsaturated hydrocarbon containing 2 to 7 carbon atoms, for example, vinyl, allyl, and the like. The term "alkenyloxy", preferably denotes "lower alkenyloxy", which ■M-t /11.1 .-84 X A R, 1 - la- • 1 2 3 4 6 7 8 9 II 12 13 14 16 17 IS 19 21 22 23 24 26 27 *1 96 3 & 3 denotes an alkenyl ether group in which the lower alkenyl group is as described ubove, for example, ethenyloxy, and the like. The term "alkynyl" preferably denotes "lower alkynyl", which denotes a straight or branched chain unsaturated hydrocarbon containing 2 to 7 carbon atoms , for example, ethynyl, propargyl, methylbutynyl, and the like. The term "halogen" or "halo" denotes all the halogens, i.e., bromine, chlorine, fluorine, and iodine. The term "aryl" denotes phenyl or phenyl bearing one or more substituents selected from the group consisting of halogen, trifluoromethyl, lower alkyl, lower . alkoxy, nitro, amino, lower alkylamino, and di-lower alkylamino. The term "aralkyl" preferably denotes an aryl group linked to an alkylene chain of 1 to 4 carbon atoms, such ; as, 2-phenylethyl, 4-chlorobenzyl, benzyl and the like. The term aralkenyl preferably denotes 3-phenyl-2-propenyl, and the like. The term "aralkyloxy" denotes an aralkyl ether, for example, benzyloxy, and the like. The term "aryloxy" denotes an aryl ether group in which the aryl group is as described above, for example, phenoxy, and the like. : The term "acyl" denotes an "alkanoyl" group derived from an aliphatic carboxylic aeid of 1 to 7 carbon atoms, for example, formyl, acetyl, propionyl, and the like; and an "aroyl" group derived from an aromatic carboxylic acid, such as benzoyl, 4- : fluorobenzoyl and the like. The term "acyloxy" denotes an "alkanoyloxy" group derived j from an aliphatic carboxylic acid of 1 to 7 carbon atoms, for example, formyloxy, j acetoxy, propionyloxy, and the like; and an "aroyloxy" group derived from an aromatic ; carboxylic acid, such as benzoyloxy and the like. Exemplary of "acylalkyl" are 2-oxo- j i propyl, 4-(4-fluorophenyl)-4 oxobutyl and the like. Exemplary of "acyloxyalkyl" are 2- [ acetoxyethyl, 3-benzoyloxypropyl and the like. Exemplary of "hydroxyalkyl" are : hydroxyethyl, 2-hydroxy-3,3-dimethybutyl and the like. Exemplary of "cycloakyl-alkyl" are cyclopropylmethyl, cyclobutylm ethyl and the like. Exemplary of "arylcarboxamidoalkyl" are benzamidoethyl and the like. Exemplary of "aryloxyalkyl" are 3-phenoxypropyl and the like. Exemplary of "aralkyloxyalkyl" are 2-benzyloxyethyl, 3-benzyloxypropvl and the like. Exemplary of "aryl-N-imidazolonylalkyl" are 2-(2,3- j 1 2 3 4 6 7 S 9 11 12 13 14 16 17 18 19 21 22 23 2 4 26 27 963 S3 dihydro-2-oxo-lH-benzimidazol-l-yl)ethyl, 3-(2,3-dihydro-2-oxo-lH-ben7,!T.id£Zol-I- yl)propyl and the like. Exemplary of "arylhydroxyalkyl" are 2-hydroxy-2-phenylethyl, 2-hydroxy-2-(4-chlorophenyl)ethyl and the like. Exemplary of "alkoxyalkyl" are 2-ethoxyethyl, 3-methoxypropyl and the like. Exemplary of "alkenyloxyalkyl" are 2-ethenyloxyethyl and the like.
Preferred compounds of formula A are those wherein n is 3, 4, 5 or G, R^ is hydrogen, R2 is alky], hydroxyalkyl, arylhydroxyalkyl, alkoxyalkyl, aryloxyalkyl, acylalkyl, or aralkyl; and X is 0 or S.
More preferred compounds of formula A are those wherein n is 3 or 4, R^ is hydrogen, Rg is alkyl, hydroxyalkyl, arylhydroxyalkyl, alkoxyalkyl, aryloxyalkyl, acylalkyl, or aralkyl; and Xis O.
;; Most preferred compounds of formula A of the invention are: ii - 2-methyl-l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyelcpenta[4,5j pvrrolo- • 1 [2,3-g] isoquinolin-10(10H)-one; ij .j 2-methyl-l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopentaL4,5] pyr- :j rolo[2,3-g] isoquinolin-10(10H)-one hydrochloride, 0.5 molar hydrate; 2-(2-phenylethylH,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta-i, [4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one; - - 2-[4-(4-fluorophenyl)-4-oxobutyl] -l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,lGa-trans-: 6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)~one; (-)-2-metliyl-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; - 3 • 1 2 3 4 6 7 .8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 < ;7 2-methyl-2,3,4,4a,5,7,8,9)lQ,lla~decnhydro-4a,lla-trans-lH,GIi-cyclohexa['i,:3] -pyrrolo[2,3-g] isoquinolin-ll(llH)-one; 2-methyl-2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-trans-lH,GH-cyclohexal4,5] -pyrrolo[2,3-g] isoquinolin-ll(llIl)-one, 0.75 molar hydrate; 2-(2-phenylethyl)-2,3,4)4a,5,7,8,9,10,lla-decahydro-4a,lla-trans-lH,6H-cyclo-hexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(llH)-one; 2-[4-(4-fluorophenyl)-4-oxobutyl] -2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-trans-lH,6H-cyclohexa[4,5] pyrrolo[2,3-gJ isoquinolin-ll(llH)-one; and 2-methyH,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.
Exemplary of the compounds of formula A wherein n is 3, i.e., compounds of the formula X A-1 R. 1 wherein , Rj an^ X are as previously described, are: 1 96 3 6 3 2-etliyl-l,2,3,4,4a,5,7,S,9,10a-decahydro-4a,10a-trans-6H-cyciopenta[4,5] pyrrolo-[2,3-g] isoquinolin-10(10H)-one; 2-{2-hydro\yethylH,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-GH-cyclopenla-[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one; 2-(2-hydroxy-2-phenylethyl)-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; 2-(2-ethoxyethylH,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-GH-cyclopenta-[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one; 2-(2-acetoxyethyl)-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; 2-[3-(4-fluorophenyl)-3-oxopropyl] -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; 2-[2-(4-methoxyphenyl)ethyl] -l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-GH-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(l0H)-one; 2-allyH,2,3,4,4a,5,7,S,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,.5] pyrrolo-[2,3-g] isoquinolin-10(10H)-one; 2-cyclopropylmethyH,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyelopenta-[4,5] pyrrolo[2,3-g] isoquinolin-10(lDH)-one; 2-propargyH,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,y] -pyrrolo[2,3-g] isoquinolin-10(10H)-one; 2-[2-(2-thienyl)ethyl] -l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-GH-eyelo-penta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)~one; 2-[2-(2-furyl)ethyl] -l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta-[4,5] pyrrolo[2,3-g] isoquinoliu-10(10H)-one; 2-[2-(2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)ethyl] -l,2,3,4,4n,5,7,8,9,10a-deca-hydro-4a,10a-trans-GH-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10II)-one; 1 W/ 2-[2-(benzyloxy)ethyl] -l^S^^a.SJ.SAlOa-decahydi-o^la^Ofi-truns-GH-cyiOa-penta[4,5] pyrrolo(2,3-g] isoquinolin-10(10II)-one; 2-(3-phenyl-2-propenyl)-l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclo-penta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one; 2-[2-(4-fluorobenzamido)ethyl]-l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-GH-cycIopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one; 2-[2-(ethenyloxy)ethyl] -l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclo-penta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one; 2-benzyl-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; 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; 6-benzoyl-2-methyH,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopc;nta-[4,5] pyrrolo[2,3-g] isoquinoIin-10(I0H)-one; 2,6-dimethyl-l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopsnta[4,5] -pyrrolo[2,3-g] isoquinolin-10(10H)-one; 6-benzyl-2-methyH,2,3,4,4a,5,7,8,9,10a-deeahydro-4a,10a-trans-6H-cyclopenta-[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one; 6-methyl-2-[4-(4-fluorophenyl)-4-oxobutyl] -l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6II-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10Ii)-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-decahydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-thione; 2-(2-phenylethylH,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; and 2-[4-(4-fluorophenyl )-4-oxobutylH,2,3,4,4a,5,7,8,9,10a-decaliydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-thione.
J 96 3 6 3 Exemplary of the compounds of formula A wherein n is 4, i.e., compound;; of the formula wherein R^ Rg and X are as previously described, are: 2-(2-hydroxy-3,3-dimethylbutyl)-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(llII)-one; 2-(2-ethoxyethyl)-2l3,4,4a,517,8,9,l0,lla-decahydro-4a,lla-trans-lH,BH-cyclo-hexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(llH)-one; 2-cyclobutylmethyl-2,3,4,4a,5,7,8,9,lQ,lla-decaliydro-4a,lla-trans-lH,CH~eyclo-hexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(llH)-one; 2-[2-(2-thienyl)ethyl] -2,3,4,4a,5,7,S,9,10,lla-decahydro-4a,lla-trans-lH,6H-cyclo-hexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(IlH)-one; 2-[2-(2-furyl)ethyl] -2)3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-trans-lH,6H-cyclo- hexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(llH)-one; 2-[3-(4-fluorophenyl)-3-oxopropyl] -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(lHI)-one; 2-(2-propenyl)-2,3,4,4a,5,7,S,9,lp,lla-decahydro-4a,lla-traiis-lH,GH-cyclohexa-[4,5] pyrrolo[2,3-g] isoquinolin-ll(llH)-one; 2-(3-phenoxypropyl)-2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-trans-lH,6H-cyelo-hexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(llH)-one; _ 2-[3-(2,3-dihydro-2-oxo-llI-benzimidazol-l-yl)propyl] -2,3,4,4a,5,7,8,9,10.11a-dec;ahydro-4a,}la-trans-lH,6H-cyclohexa[4)5] pyrrolo[2,3-g] isoquinolin-ll(llH)-one; X A-2 R. t ' • 1 2 3 if 6 7 8 9 11 12 13 x- If 16 17 IS 19 21 22 23 24 26 27 i ^ o <- ^ - 2-benzyl-2,3,4,4a,5,7,8,9)10,lla-decahydro-4a)Ha-trano-!I!,GH-cyclohcxn[4,5j -pyrrolo[2,3-g] isoquinolin-ll(HH)-one; 2,3,4,4a,5,7,8,9l10,lla-decahydro-4a,lla-trans-lH,6H-cyclohexa[4,o] pyrrolo[2,3-g] isoquinolin-ll(HH)-one; 2,6-dimethyl-2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-traris-lH,6H-cyclohexa-[4,5] pyrrolo[2,3-g] isoquinolin-ll(llH)-one; 6-benzoyl-2-[4-(4-fluorophenyl)-4-oxobutyl] -2,3,4,4a,5,7,8,9,10,]la-d2cahydro-4a,lla-trans-lH,6Ii-cyclohexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(IlH)-one; 2-(2-phenylethyl)-2,3,4,4a,5)7)8)9,10,lla-decahydro-4a,lla-trans-lH,SH-cyclo-' hexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(llH)-thione; 21314,4a,5,7,8,9,10,lla-decahydro-4a,lla-trans-lH,6H-cyclohexa[4,5] pyrrolo-[2,3-g] isoquinolin-ll(llH)-thione; and 2-[4-{4-fluorophenyl)-4-oxobutyl]-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)-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,5,7,8,9,10,lla-decahydro-4a,lla-trans-lH,GH-cyck>hexa[4,5] -pyrrolo[2,3-g] isoquinolin-ll(UH)-one; and 2-methyl-2,3,4,4a,5,7,8,9)10,lla-decahydro-4a,lla-trans-pyrido[4,3-b] carbazol-ll(lH,6H)-one are one and the same compound. 1 96 3 £ Exemplary of tho compound"' r>i' formulu A wherein n is 5, i.e., compounds of the wherein R^, R^ and X are as previously described, are: 2-methyl-l,2,3,4)4a,5,7,8,9,I0)ll,12a-dodecahydro-4a,12a-trans-6H-cyclohepta[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-dodecahydro-4a,12a-trans-6H-cyclohepta[4,5] pyrrolo[2,3-g] isoquinolin-12(I2H)-one; 2-(3-phenoxypropylH,2,3,4,4a,,5,7,8,9,10,ll,12a-dodecahydro-4a,12a-trans-6H-cyeloheptat4,53 pyrrolo[2,3-g] isoquinolin-12(12H)-one; 2-(2-phenylethylM,2,3,4,4a,5,7,B,9,10,ll,12a-dodecahydro-4a,12a-trans-6H-cyclo-hepta[4,5] pyrrolo[2,3-gj isoquinolin-12(12H)-one; 2-[4-(4-fluorophenyl)-4-oxobutyl] -l,2,3,4,4a,5,7,8,9,lQ,ll,12a-dodecahydro-4a,12a-trans-6H-eyclohepta[4,5] pyrrolo[2,3-g] isoquinoIin-12(12II}-thione; 2-(3-phenoxypropyl)-l,2,3,4,4a,5,7,8,9,10,ll,12a-dodecahydro-4a,12a-trans-6H-cyclohepta[4,5] pyrrolo[2,3-g] isoquinolin-12(12H)-thione; and 2-(2-phenylethyl)-l,2,3,4,4a,5,7,S,9,10,ll,12a-dodecahydro-4a,12a-trans-6H-cyclo-hepta[4,5] pyrrolo[2,3-g] isoquinolin-12(12H)-thione. formula A-3 1 1 Exemplary of the compounds of formula A wherein n is G,i.e., compounds of t!ic wherein Rj, Rg arid X are as previously described, are: 2-[4-(4-fluorophenyl)-4-oxobutyl] -2,3,4,4a,5,7,8,9,10,ll,12,13a-dodecahydro-4a,13a-trans-lH,6H-cycloocta[4,i>] pyrrolo[2,3--g] isoquinolin-13(13H)-one; 2-(2-phenylethyl)-2,3,4,4a,5,7j 3,9,10jll,12,13a-dodecahydro-4a,13a-trans-lH,6H-cyeloocta[4,5] pyrrolo[2,3-g] isoquinoJin-I3(13H)-one; 2-(2-liydroxy-3,3-dirnethylpropyl)-2,3,4,4a,5,7,8,9,10,ll,12,13a-dodecahydro-4a>13a-trans-lH,6H-cycloocta[4,5j pyrrolo [2,3-g] isoquinolin-13(13H)-oue; 2-methyl-2,3,4,4a,5,7,8,9,10,ll:12,13a-dodecahydro-4a,13a-trans-lH,6H-cycloocta[4,5] pyrrolo[2,3-g] isoquinolin-13(13H)-one; 2-(3-phenoxypropyl)-2,3,4,4a,5,7,8,9,10,ll,12,13a-dodecahydro-4a,13a-trans-lH,6H-cycloocta[4,5] pyrrolo[2,3-g] isoquinolin-13(13H)-one; 2-[4-(4-fluorophenyl)-4-oxobutyl] -2,3,4,4a,5,7,8,3,10,ll,12,13a-dodecahydro-4a,13a-trans-lII,6H-cycloocta[4,5] pyrrolo[2,3-g] isoquinolin-13(13H)-thione; 2-(2-phenylethyl)-2,3,4,4a,5,7,S,9,lQ,!l,12,13a-dcdecahydro-4a,13a-trans-lH,GH-cyeloocta[4,5] pyrrolo[2,3-g] isoquinolin-13(13H)-thione; 2-(2-clhoxyethyl)-2,3,4,4a,5,7,8,9,10,ll,12,13n-dodecfihydro-4a,13a-trans-lH,GH-cycloocta[4,5] pyrrolo[2,3-g] isoquinolin-13(13H)-thione; and '2-(3-phenoxypropyl)-2,3,4,4a,5,7,8,9,10,ll,12,13a--dodecahydro-4a)13a--trans-]H,6H-cycloocta[4,5] pyrrolo[2,3-g] isoquinolin-13(13H)-thione. formula A-4 R. • 1 2 3 4 6 7 S 9 11 12 13 - 14 16 17 18 19 21 22 23 24 26 27 1 96 3 6 3 [ i i i i I ! The compounds of the invention wherein n is 3 can exist as the 4a,10a-trans or j i 4a,10a-cis isomers or mixtures thereof; the 4a,10a-trans isomers are preferred. j The compounds of the invention wherein n is 4 can exist as the 4a,lla-trans or ] 4a,lla-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 \ j 4a,32a-cis isomers or mixtures thereof; the 4a,12a-trans isomers are preferred. j The compounds of the invention wherein n is Gcan exist as the 4a,13a-trans or 4a,13a-cis isomers or mixtures thereof; the 4a,13a-trans isomers are preferred.
The compounds of the general formula A above, their optical 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 O wherein R'^ is alkyl, alkoxyalkyl or cycloalkylalkyl and n is as previously described, treating a compound of the general formula O H IX I • 1 2 3 4 S 7 8 9 11 12 13 14 19 17 18 19 21 22 23 24 26 27 wherein R'^ and n are as previously described, with formaldehyde, or b) for preparing a compound of the general formula la above, treating a compound of the general formula 0 r2"-n o wherein R^' is as previously described, with a compound of the general formula XII HO n VII in the presence of a reducing agent or with a compound of the general formula q h2n VIII or a precursor thereof, in which formulae n is as previously described, or c) for preparing a compound of the general formula 0 H-N lb 1 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 wherein n is as previously described, N-demethylating a compound of the formula la above wherein R'i, is methyl, or d) for preparing a compound of the general formula S ~ ®H2»„ lie wherein R'| is hydrogen, alkyl or aralkyl, R1* is hydrogen, alkyl, alkoxyalkyl, aralkyl, alkenyl, cycloalkyl-alkyl, alkynyl, thienyl-alkyl, furyl-alkyl, alkenyloxyalkyl, aralkenyl, aryloxyalkyl or aralkyloxyalkyl, and n is as previously described, treating a compound of the general formula (CII2>„ le wherein R'« , R'£ and n are as previously described, with phosphorus pentasulfide, or e) for preparing a compound of the general formula X (CH2)n A d X 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 23 29 31 / j (y 3> f) wherein R' is alkyl, hydroxyalkyl, arylhydroxyalkyl, alkoxyalkyl, acyloxyalkyl, acylalkyl, aralkyl, alkenyl, cycloalkyl-alkyl, thienyl-alkyl, alkynyl, furyl-alkyl, arylcarboxamidoalkyl, aralkenvl, alkenyloxyalkyl, aryloxyalkyl, aralkyloxyalkyl or aryl-N-imidazolonylalkyl and X and n are as previously described, substituting EJ> for H^t the isoquinoline nitrogen atcm in a compound of the general H -N A b wherein X and n are as previously described, or for preparing a compound of the general formula X (CIV„ A' c wherein R is alkyl, acyl or aralkyl, R^1 is alkyl, alkoxyalkyl, acyloxyalkyl, acyl, aralkyl, alkenyl, cycloalkyl-alkyl, thienylalkyl, alkynyl, furylalkyl, arylcarboxamidoalkyl, aralkenvl, alkenyloxyalkyl, aryloxyalkyl, aralkyloxyalkyl or aryl-N-imidazolonylalkyl and X and n are as previously described, substituting!^'for H at the pyrrole nitrogen atom in a compound i ' of the general X formula <CH2>n A d' .4 - n.z. patent office 3 I AUG 1983 RPCEIV^r X 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 28 29 31 '6363 wherein , X and n are as previously, -described, or ... • for preparing a . compound of the general- formula X <CH2»„ "-'Ac" wherein is hydroxyalkyl or arylhydroxyalkyl,1 and , X and n are as previously described, splitting off the protecting group in a compound of the general formula or <CH2>„ XIV wherein R£ is an O-protected hydroxyalkyl- or aryl- hydroxyalkyl-group and R^, X and n are as previously described, h) for preparing a compound of the general formula X <CH2>n . M" IV H wherein R£ , X and n are as previously described, reducing the acylalkyl group in a compound"- of the general formula « X 2 3 4 6 7 8 9 n 12 13 14 16 17 18 19 21 22 23 24 26 27 28 29 31 32 1 98363 I I <CH2)» M" N' u ■ VII wherein R2 is acylalkyl, and X and n are as previously described, or i) for preparing a compound of the general formula X h -N wherein X, n and R^ are as previously described, splitting off the urethane group in a compound of the general formula y —N <CIVn XI11 wherein X, n and R| are as previously described and Y is a urethane group, and j) if desired, isomerizing the mixture of the cis and trans isomers obtained to a final ratio which comprises predominantly the trans isomer , and/or 1 2 3 4- 6 7 8 9 n 12 13 14 16 17 18 19 21 22 23 24 26 27 28 29 31 32 i ! -196363 i . . ..
I k) if desired,- separating.the trans isomer from the mixture' J obtained, and/or '■ ■ • ■ .. . . : . '. i 1) if■desired, resolving a racemic mixture■obtained into the■ optical antipodes and/or ■ , . . - ;. m) if desired, converting a compound obtained or a nor.-pharmaceutically acceptable acid addition salt thereof into a pharmaceutically acceptable acid addition salt thereof. ■ More specifically, the compounds of formula A above, their optical and geometric isomers and their pharmaceutically acceptable acid addition salts as well as various intermediates therefor can be prepared as illustrated hereinbelow in more detail.
Thus, for example, the compounds of formula A wherein X is 0 are characterized by the formula i f I ! i i ' wherein n, RJL and R^are as hereinbefore described, and can be prepared as set forth in Schemes I, II, HI and IV and further described. i i i i 2 3 4 6 7 ■8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 1 963 6 3 FOR ML'I, A SCHEME I wherein n is as previously described, and R9" is alkyl, alkoxyalkyl, or cycloalkyl-alkyl. 196363 1 In accordance with-'Formula Scheme I, compounds, of .formula. Ia"are prepared 2 from known compounds of formula IV wherein Rg" is alkyl, alkoxyalkyl or 3 " cycloalkylalkyl. Birch reduction of the amine of formula IV with lithium in ammonia : k containing t-butanol yields the dihvdroamine'of formula V. Other modifications of the ' Birch reduction may also be employed. Thus, the amine of .formula IV may be reacted 6 with an alkali metal, such as.sodium, lithium, potassium or cesium, in ammonia cr an 7 amine such as rncthylamine or ethylamine in the presence of a lower alkanol contain-25 ing 1 to 7 carbon atoms such as ethanol, butanol, or t-butanol. Hie reaction is 9 generally carried out at the boiling-point of the solvent or below, for example, jq frcm -78° to 15°C. If aitmonia is used, the reaction is run at reflux. Optionally j j cosolvents such as diethyl ether or tetrahydrofuran may be added. 12 13 The hydrolysis of the dihydroamine of formula V is readily accomplished by the 14 : 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, acctic 16 - acid, p-toluenesulfonic acid and perchloric acid. These may be used in aqueous solutions [I 17 or mixed solvents. Tetrahydrofuran, benzene, diethyl ether, acetone, toluene, dioxane 18 or acetonitrile are exemplary of the solvents which may be employed. For example, 19 .' hydrolysis of the dihydroamine of formula V wherein R9" is methyl in 2N hydrochloric acid at room temperature or above or in aqueous acetic acid at between 40° C and 2] reflux leads to the diketone of formula VI, wherein is methyl. 22 : 23 24 1 9636 3 The dikctonc of formula VI is condcnscd 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 well-known modifications [see, for exemplary conditions, J. M. Patterson, Synthesis, 231 (197G) and references therein] • For example, the reaction of an isonitrosoketone of formula VII in the presence of a reducing agent, for example with zinc 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 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 self-condensation. 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 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 pll 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 VIII.
Preferably, an isonitrosoketone of formula VII and zinc dust in aqueous acetic acid is condensed with a diketone of formula VI wherein Rg" is methyl to- give the product methylaminoethyl ketone of formula IX wherein I^" is methyl. i 1 2 3 4 6 7 -8 9 11 12 13 If 16 17 IS 19 21 22 23 24 26 27 1 €>/:'. ^ I f J" ' o ' '— I The Knorr condensation is preferably carricd out at a temperature range of from i about room temperature to reflux. The isonitrosoketones of formula VII are known j compounds or can readily be prepared by nitrosation of the corresponding 3-ketoester, for example, with sodium nitrite, [see, for example, T. A. Geissman and M. J. Schlatter, J. Org. Chem., 11, 771 (1946)]. «> Exemplary of isonitrosoketones of formula VII which can be used in the Knorr condensation are: 2-isonitrosocyclopentanone; 2-isonitrosocyclohexanone; 2-isonitrosocycloheptanone; and 2-isonitrosocyclooctanone.
Exemplary of aminocarbonyl precursor compounds of formula VIII which can be used in the Knorr condensation are: 2-aminocyclohexanone, hydrochloride; 2-aminoeyclopentanone, hydrochloride; 2-aminocycloheptanone, hydrochloride; and 2-aminocyclooctanone, 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. 196363 The amine of the formula IX is converted to the-eonipound of the formula la via an intramolecular Mannich reaction. The Mannich reaction is usually performed j starting with a ketone and a dialkylamine salt, for example, dimethylamine hydrochloride and formaldehyde (for example, as an aqueous solution, as paraformaldehyde or as trioxane) 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 J 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 glycol or diethylene glycol monoethyl ether; a high boiling polar aprotic solvent, such as dimethylformamide, N-methy 1-2-pyrro 1 idinorie 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 about 200°C. to yield the>,cycloalka[4,5]pyrro]o[2,3-9]isoquinolines of formula la. The reaction, especially when run at temperatures below 150°C. leads to a mixture of cis and trans isomers, i.e. for exairple, when R2" is methyl, compounds of the formulas 196363 if ■ cis Ig.' Longer heating of the reaction mixture or separate heating of the isomeric mixture of hydrochloride salts of formulas If'and ]g', for example, in ethylene glycol at reflux for 2 hours can be used to equilibrate the cis and trans isomers to a final ratio which comprises predomonantly 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°c. for 2 hours, the product is isolated as. the trans isomer If'. • 1 2 3 4 6 7 8 9 11 12 13 14 16 17 IS 19 21 22 23 24 26 27 FORMULA SCHEME II wherein n is as previously described, and R 1 is alkyl, acyl or aralkyl. 196363 / 1 In accordance with Formula Scheme II, compounds of formula Ic are prepared by 2 alkylation or acylation of the pyrrole nitrogen of a compound of formula la' and other 3 N-2-alkyl derivatives by formation of the pyrrole anion with strong base, for example, (» sodium amide, potassium hydride, sodium methylsulfinyl carbanion, potassium t- butoxide, or butyllithium, or with an alkali metal, followed by quenching with an alkyl 6 or acyl halide in a solvent such as tetrahydrofuran, dioxane, ethyl ether, 7 dimethylformamide or dimethylsulfoxide. For example, treatment of a compound of • 8 formula la', wherein n is 3 with potassium t-butoxide in tetrahydrofuran followed by 9 quenching with methyl iodide affords the 6-methyl derivative, i.e., a compound of i formula Ic wherein n is 3 and R^' is methyl. Similarly, reaction of a compound of 11 formula la', wherein n is 4 with butyllithium in tetrahydrofuran at -30° C. followed 12 by quenching with benzoyl chloride affords the 6-benzoyl derivative, i.e., a 13 compound of formula Ii wherein ' is benzoyl and n is 4. Similarly, reaction 14 of a compound of formula la', wherein n is 3, with sodium methylsulfinyl carban- ion in dimethylsulfoxide followed by quenching with benzyl chloride affords the 16 6-benzyl derivative, i.e., a coirpound of formula Ii wherein .R^1 is benzyl and n 17 is 3.
IS N-Demethylation of the compound of formula la' can be accomplished by 19 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 21 those listed in K. C. Rice [J. Org. Chem., 40, 1850 (1975)]. One procedure for the 22 dealkylation of the compound of formula la' is via the urethane of formula XEHa ari acid 23 hydrolysis to give the secondary amine of formula lb. For example, a compound of 2^ 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 XIII, wherein n is 4. 26 Hydrolysis of the foregoing compound with 3096 aqueous sodium hydroxide in ethanol- 27 dioxane at reflux for 24 hours gives the compound of formula lb, wherein n is 4. ^patentoffice 18 JUL 1983 I 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 28 29 31 32 1 Urethane derivatives also fce eipLc^d as starting iratfcg.iAL.s far tte prefaraticn of p/rrole^nrg substituted derivatives by aUylation or acylatim at the pyrrole nitrogen, followed by cleavage of the urethane. The alkylatim or acylatim is carried out following the procedures guran for the pcFpraticn cf aaipcurris a£ fbnruLa I'c, ard the urethaie derivatives aid pxcaiires far their cleavage are given, as rratticned abous, in K.C. Rios (ibid). Fbr exatpLe, in aocm^me with PornuLa S±ene n, treaUitaiL of the ethOQcarfccr^l urethane of fonrula XHIa whereon n is 4 with sodiun msthylsiilfiryl carfcanim in diirethylsiflfcKide, follcwad ty treatmaiL with fcaizyl chloride, dTToit-b the cntpxrd of fonniLa XLUb wherein n is 4 and R^1 is ba^yl. F^drol^sis with sodiun hr^draxids affords the 6-baizyl (Privative, i.e., a cnrpcurd of the fbrnula Ih wtarein R^1 is baizyl ad n is 4. In cases vhare R^1 is an acyl groip which crnLd be t^dmLyzed urdsr vigorous alkalire car strcrgly iridic arrditicns, a urethaie grtxp sixh as 2,2,2,-tridiLaxethcKicar-bcr^l, vhich ma/ fce cleaved ureter mild gyriitions with zinc in aquaxs acetic acid, be ait-pLq,ed to give aatpcunds af fomula Ih vterein R^1 is acyl.
FORMULA SCHEME III (C-II2)n lb (CHo)n u n Id (C"A Ic 3, 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 28 29 31 32 1 /C wherein n is as previously described, and R^1 is alkyl, acyl, or aralkyl, nnd is alkyl, hydroxyalkyl, arylhydroxyalkyl, alkoxyalkyl, acyloxyalkyl, acylalkyl, aralkyl, alkenyl, cycloalkyl-alkyl, thienyl-alkyl, alkynyl, furyl-alkyl, arylcarboxamidoalkyl, aralkenyl, alkenyloxyalkyl, aryloxyalkyl, aralkyloxyalkyl, or aryl-N-imidazo-lonylalkyl.
In accordance with Formula Scheme III. the compounds of formulas Id and Ic arc prepared from the secondary amine of formula lb, the starting material for tiie 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 chloromethylcyclopro-pane, an aralkyl halide, such as benzyl bromide, or an acylalkyl halide such as y -chloro-p-fluorobutyrophenone, in the presence of a base, for example, potassium carbonate, in acetone, 2-propanone or dimothylformamide, yields the correspondingly substituted compound of form.ula Id, that is, wherein is alkyl, alkenyl, cycloalkyl-alkyl, aralkyl, or acylalkyl, 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-hydroxyalkyI analogs 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 's 2-phenyl-2-hydroxyethyl. The reaction is usually carried out in the presence of an alcoholic solvent such as methanol, at from about room temperature to i I 2 3 4 6 7 8 9 ii 12 13 14 16 17 18 19 21 22 23 24 26 27 28 29 31 32 c-s-9 the reflux temperature of the mixture. The epoxyalkanes are either commercially available or are prepared by epoxidation of the corresponding olefins,- or by methylen-ation of a ketone with a sUlfonium methylide or sulfoxonium methylide reagent, for example, dimethylsulfonium methylide. Thus, for example, treatment of benzaldehyde with dimethylsulfonium methylide gives styrene oxide.
In some cuscs, where K,^' in the compound of formula Id docs not contain functional groups capable of undergoing alkylation or ncylation, the procedures outlined in Formula Scheme II for the preparation of compounds of formula Ic' can be used directly to prepare N-Guubstituted analogs of formula*0 as depicted in Formula Scheme III. Alkylations can occur in compounds wherein is hydroxyalkyl or arylhydroxyalkyl. The hydroxyl groups therein must be protected with a base-stable protecting group, such as tctrahydropyranyl. After N-^alkylation, the protecting group is removed by acid hydrolysis.
Alternatively, compounds of formula Id, wherein R^' is hydroxyalkyl or aryl hydroxyalkyl may be prepared by reduction of the corresponding compounds of formula Id wherein I^' is acyl^Mo're 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 alkanoi, such as ethanol, or the like.
In the reactions described in Formula Schemes I, II and III, both the trans isomers of the formula * (CHA 11 wherein n, Rj and R^ arc as previously described, - 28 196363 1 2 3 ii 6 7 S 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 find cis isomers of the formula (0Ho) ig wherein n, Rj and 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 If' and Tg', or by base-catalyzed equilibration, for example, with sodium hydroxide in ethanol.
When the substituent groups Rj and R£ in compounds of the formula I contain 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 enan'ciomers and/or diasterecmers of compounds of the formula If, hereinbefore described.
"T OFFICE 18 JUL 1983 ':cr£iV'~ "> I 1 2 3 k 6 7 8 9 11 12 13 If 16 17 18 19 . 21 22 23 2f 26 27 1 QA 1 A 3 I ^ '■=/ FORMULA SCHKMF IV OCH OCH R2" —NH R2"- N XII OCH, H0.*A_yH2,n or \r VII H2N (CIVn vin o v-N v (C,H9>n l n la •N I H wherein » is as previously described, and It2" is alky], alkoxyalkyl, or cycloalkyl-alkyl.
[ An alternative synthesis of the compounds of formula Ja is described in Formula i Scheme IV, in which the isoquir.olinc ring is formed prior to the formation of the pyrrole i ring. In accordance with Formula Scheme IV, the (3,5-dimethoxyphenyl)-ethylamine of formula IV is refluxed with aqueous formaldehyde to give the tetrahydroisoquinoline of formula X. Birch reduction of the tetrahydroisoquinoline 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 XII. 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 VII or with the aminocarbonyl compound of formula VIII 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 R2" is methyl, giving the corresponding N-methyl-cycloalka[4,5] pyrroloisoquinoline of j 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] pyrrolo- isoquinolincs of formulas if and Ig as described previously may be employed to yield mainly the trans isomer of formula if' • • 1 2 3 k 6 7 8 9 11 12 13 ' If 16 17 18 19 21 22 23 2f 26 27 1 OA 1 The compounds of formula A wherein X is S are characterised by the formula j II (CH2>n wherein n, and are as hereinbefore described, and can be prepared as set forth in Formula Schemes V and VI, and further described hereinafter. > I 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 1 963 6 3 ! FORMULA SCilKME V R 2 X (CH2}n le (CH2)n He wherein n is as previously described; Rj" is hydrogen, alkyl, or aralkyl; and R^'" is hydrogen, alkyl, alkoxyalkyl, aralkyl, alkenyl, aryloxyalkyl, thienylalkyl, furyl-alkyl,, alkynyl, aralkenyi, alkenyloxyalkyl, aralkyloxyalkyl or cycloalkyl-alkyl. j In accordance with Formula Scheme V, compounds of formula He arc prepared by heating compounds of formula le with phosphorus pcntasulfide in an inert organic solvent. Preferred solvents are 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 j VI. In accordance with Formula Scheme VI, a compound of formula lib is reacted to ; i give a compound of formula lid following the procedures detailed in Formula Scheme III for the preparation of the corresponding oxo compounds of formula Id. 9 1 2 3 it 6 7 '8 9 11 12 13 It 16 17 IS 19 21 22 23 2<4 2G 27 1 <W; > W FORMULA SCHEME VI lib lid lie wherein n, R ' and R0' are as previously described. i M I 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 28 29 31 32 1 963 63 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.
Prtti.tjqial crnpxrris of fbmuLa H ace p^ared following tte proosiires ctetailad in Ftanula Setae H for the p^aratiai af aarre^pentog ckd aarpxmds af famuLa Ih.
In these reactions, both the trans isomers of the formula S wherein n, R^ and R2 are as previously described, and cis isomers of the formula wherein n, R^ and R^ are as previously describedj i 196363 of the compounds of formula II■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 isomerizatioii.of the trans and cis isomers of the oxo compound of formula If1 and Ig1.
As described above for compounds of "formula I, when substitutuent groups and in compounds of formula II contain additional asymmetric centers, a mixture of diastereomers may be obtained. Preferred are the enantiomers and/or.diastereomers of compounds of the formula Ilf, hereinbefore described.
The compounds of formula A form acid addition salts with inorganic or organic acids. Thus, they form pharmaceutically acceptable acid addition salts with both pharmaceutically acceptable organic and inorganic acids, for example, with hydrohalic acids, such as hydrochloric acid, hydrobromic acid or hydroiodic acid, other mineral acids, such as sulfuric acid, nitric acid, phosphoric acid, or the like, alkyl- and mono-aryl sulfonic acids, such as ethanesulfonic acid, p-toluenesulfonic acid, benzene-sulfonic acid, or the like, other organic acids such as acetic acid, tartaric acid, maleic acid, citric acid, benzoic acid, salicylic acid, ascorbic acid, and the like. Non-pharmaceutically acceptable acid addition salts of compounds of formula A can be converted into pharmaceutically acceptable, acid addition salts via conventional metathetic reactions whereby the non-pharmaceutically acceptable anion is .replaced by a pharmaceutically acceptable anion; or alternatively, by neutralizing the non-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 rm hydrates. ' N.Z. PA'i r f° 18 JUL 1983 RECE^Vf-) 1 T^e comPoun<^s of t*1® general formulae IX and XIII are novel and also form part of the present invention. 1 2 3 4 6 7 8 9 11 12 13 / 14 16 17 18 19 21 22 23 2t 26 27 /- ' - 7 v "77 The compounds of formula A and their pharmaccutically acceptable acid addition i salts exhibit neuroleptic activity. Accordingly, the compounds of formula A are 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 j demonstrated in warm-blooded animals, in accordance with known procedures. j | 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 j warning tone, (conditioned stimulus), continuing for an additional fifteen seconds i i accompanied by electric shock (unconditioned stimulus; 1.0 mA, 350 V.A.C*). The rats j j can terminate a trial at any point by depression of the response lever. A response ; i during the initial fifteen-second warning tone ends the trial before shock delivery and is I i j considered an avoidance response, while a response occurring during shock delivery is an I 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 ; i three avoidance failures per session). Compounds are administered at appropriate j pretreatment times to a minimum of three to four rats at each dose level over a range ; i of doses. Rats receive vehicle alone, during control sessions. One control and one ! experimental session are alternated during each week. j l The session is divided into three consecutive twenty minute (ten trial) segments. 1 | Response counts are summed over all subjects at a given dose within each segment. • 1 2 3 6 7 8 9 11 12 13 If 16 17 18 19 21 22 23 2k 26 27 The number of trials In which the rats failed to exhibit tin avoidance response (avoidance block; Ali) or failed to exhibit an escape response (escape block; E!3) is determined for the segment displaying the maximum such effect at 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 (ADD 50) is obtained from the dose-effect regression line fitted by the Method of Least Squares. The lowest dose which i produced a 20% block of eseapc responding (BED 20) is read from a graphic dose-effect plot. In.obtaining these values, percent effect is plotted against the log dose. { Antipsychotic agents can be distinguished from other types of drugs, which ; j affect the behavior of rats in this procedure, by the larger separation between doses : i which block avoidance responding and doses which block escape responding. The clinical ; I potency of antipsychotic drugs with known therapeutic uses and properties is ; I significantly and highly correlated with their potency in this procedure. Consequently, ; t the compounds of formula A may be used therapeutically in dosage ranges consistent i with their potency in the test procedure.
I 1 2 3 6 7 •S 9 11 12 13 It 16 17 IS 19 21 22 23 2Jt 26 27 1 96363: ! j | When 2-ino;;iyl-l,2,3,-v!a,f),7,8,9,10;i-dccahydro~la,10a-trans-6II-eyclopentn[4,5] " pv:Tolo[2,3-jj] isoquinolin-10(10II)-one is utilized as the test substance, neuroleptic f activity is observed at an ABD_Q of 0.98 mg/kg p.o. i Similarly, when 2-[4-(4-fluorophenyl)-4-oxobutyl] -l,2,3,4,4a,5,7,8,9,10a-deca-hydro-4a,10a-trans-SH-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one is utilized as j the test substance, neuroleptic activity is observed at an ABD^^ of 0.15 mg/kg p.o. j j Similarly, when 2-[4-(4-fluorophenyl)-4-oxobutyl] -2,3,4,4a,5,7,8,9,10,lla-deca- ; i hydro-4a,lla-trans-lH,6H-cyclohexa[4,5] pyrrolo[2,3-g] isoquinolin-lI(llH)-one is utilized ; j as the test substance, neuroleptic activity is observed at an ABD^q of 0.73 mg/kg p.o. ; Similarly, when 2-methyl-2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-trans-lH,6H-cyelohexa[4,5] pyiTclo[2,3-g] isoquinolin-ll(llH)-one, hydrochloride,' 0.75 molar hydrate, which has demonstrated an LD-n of, for example, 650 mg/kg p.o. in mice, is utilized as ■ 0 U j the test substance, neuroleptic activity is observed at an ABD^^ of 5.5 mg/kg p.o. j Similarly, when 2-methyl-2,3,4,4a,5,7,8,9, 10,11,12,13a-dodecahydro-4a,13a-trans- ' ! lH,GH-cyclooeta[4,5] pyrrolo [2,3-g] isoquinolin-13(13H)-one is utilized as the test sub- | i stance, neuroleptic activity is observed at 8 mg/kg p.o. where the avoidance blockade is 6396.
Similarly, when 2-inethyl-l,2,3,4,4a,5,7,8,9,10,ll,12a-dodecahydro-4a,12a-trans-6H- ! ! cyclohcuta[4,5] pyrrolo[2,3-gj isoquinolin-12(12H)-one is utilized as the test substance, j i neuroleptic activity is observed at 16 mg/kg p.o. where the avoidance blockade is 5 0 96.
• I 2 3 it 6 7 8 9 11 12 13 If 16 17 18 19 21 22 23 2<f 26 27 The compounds of formula A and their pharmaccutically acccptable acid addition salts have antipsychotic effects which are qualitatively similar to those of haloperidol, and trifluoroperazine, known for their therapeutic uses and properties. Thus, the 1 compounds of formula A demonstrate a pattern of activity associated with ariti- ; I 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 i 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 about 10 mg/kg per day. However, for any particular warm-blooded animal, the specific dosage regimen may be variable and ; i i should be adjusted according to individual need and the professional judgment of the ! I person administering or supervising the administration of a compound of formula A or a pharmaceutically acceptable acid addition salt thereof. Furthermore, the frequency i with which any such dosage form will be administered will vary, depending upon the i quantity of active medicament present therein and the needs and requirements of the | pharmacological situation. 95 3 6 3 Fur Urn disclosed use, the compounds of formula A and their pharmaecutically Acceptable acid addition salts arc formulated, using conventional inert pharmaceutical adjuvant materials, into dosage forms which arc suitable for oral or parenteral U administration. Such dosage forms include tablets, suspensions, solutions, and the like.
Furthermore, the compounds of formula A can be embodied into, and administered in 6 the form of, suitable hard or soft capsules. The identity of the inert adjuvant materials 7 which are used in formulating the compounds of formula A and their pharmaceutically S acceptable acid addition salts into oral and parenteral dosage forms will be immediately 9 .apparent to persons skilled in the art. These adjuvant materials, either' inorganic or organic in nature, include, for example, water, gelatin, lactose, starch, magnesium 11 stearale, talc, vegetable oils, gums, polyalkylene glycols, etc. Moreover, preservatives, 12 stabilizers, wetting agents, emulsifying agents, salts for altering osmotic pressure,- 13 buffers, or the like, can be incorporated, if desired, into such formulations.
If Since the compounds of formula A and their pharmaceutically acceptable acid 16 addition salts possess asymmetric carbon atoms, they are ordinarily obtained as racemic 17 mixtures. If desired, diastereomeric mixtures, when obtained, may be separated. The 13 resolution of individual raeemates into the optically active isomers can be carried out 19 by known procedures. Alternatively, optically active isomers can be prepared utilizing, in the processes herein described, corresponding optically active starting materials. 21 Some racemic mixtures can be precipitated as eutectics and can thereafter be 22 separated. Chemical resolution is, however, preferred. By this method, diastereomers 23 are formed from the racemic mixture with an optically active resolving agent, for 2f example, an optically active acid, such as (+)-tartaric acid, (+)-dibenzoyl-D-tartarie acid, (+)-d-10-camphor-sulfonic acid, (-)-3-pinanecarboxylic acid, and the like, to form a 26 diastcreomeric salt. The formed diastereomers are separated by fractional 27 crystallization and can be converted to the corresponding optical isomer base. Thus, 28 the invention covers the optically active isomers of the compounds of formula A as well 20 as their raeemates. (ry ^ °t7 /" " j Furthermore, due to the possible different spatial arrangements of their atoms, it is to be understood that the compounds of this invention may be obtained in more j than one possible geometric isomeric form. The compounds of formula A, as described ! and claimcd, are intended to embrace all such isomeric forms. Accordingly, the ! examples included herein are to be understood as illustrative of particular mixtures of i 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. ) 1 2 3 <i 6 7 -8 9 11 12 13 14 16 17 18 19 21 22 23 2'i 26 27 Example 1 Preparation of N-methvl-I.5-ciimethoxycyclohexa-l,4-dicne-3-cthvIamine 185.2 g. of N-methyl-(3,5-dimethoxyphenyl)-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 x 1000 ml. of dichloromethane and the combined extracts were washed with 1000 ml. of brine and dried over anhydrous sodium sulfate. Evaporation of the solvent on a rotary evaporator at 35-40° gave 156.0 g. of free base.
In a 12 1. 3-neck flask equipped with a mechanical stirrer and two dry ice 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 33.6 g. of lithium wire cut into 2.5 in. lengths. The addition rate was controlled so that 5 in. of wire was added per minute. After all the lithium Jiad been added, the deep blue mixture was stirred under reflux for 2 hours. Then 2.8 1. of anhydrous ether was added to dilute the mixture, the drying tube was removed to allow the hydrogen to vent, and a total of 230 g. of ammonium chloride powder was added slowly over 30 minutes until the blue color had dissipated. The dry ice condenser was removed and the mixture was stirred and the ammonia allowed to evaporate overnight. To the residue was added 2.8 1. of ice 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 2 x 1.5 1. of dichloromethane and the extracts were combined 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 mm. for 1.5 hours afforded 150.7 g. of crude product as a yellow oil. The crude oil was distilled through a 12-in. Goodloe column (bath 150°) collecting fractions as follows: I ■< Fraction wt gc puriU 1 40-80°/0.45 mm. 7.9 g. 4.6% 2 80-85°/0.45 to 0.15 mm. 6.2 g. 50% 3 85-86°/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-dimethoxycyclo-hexa-l,4-diene-3-ethylamine as a colorless oil.
Anal. Calcd. for CuH19N02: C, 66.97; H, 9.71; N, 7.10 Found: C, 66.84; H, 9.62; N, 6.93 I 1 2 3 4 6 7 8 9 II 12 13 14 16 17 18 19 21 22 23 24 26 27 1 963 6 3 Example 2 J X j Preparation of l,2,3,5.G,7,8>9-octnhydro-2-[2-(ine.thylamino)othyl] -4H-carbnzol—l-onc j A mixture of 15.G g. of N-methyl-l,5-diinethoxycyclohcxa-l,4-diene-3-ethv!arnine ! j (79 mmol), 16.7 g. of 2-isonitrosocyclohexanonc (131 mmol), and 19.5 g. of zinc dust (300 i i mg-atom) in 300 ml. of 70% aqueous acetic acid heated to reflux for 5 hours, and was j cooled and filtered. The filtrate was concentrated in vacuo and excess dioxane was | J I added. The dioxane-acetic acid azeotrope was distilled off and the process was j repented until all the acetic acid was removed. The residue was chromatographsd on j Alumina III eluting with 10% methanol in dichloromethane to give 10.7 g. of crude i l,2,3,5,G,7,8,9-octahydro-2-[2-(methylamino)ethyI] -4H-carbazoI-4-one. The crude j product was dissolved in methanol and treated with methanolic HCI and the solvent j I evaporated to give 12.2 g. of l,2,3,5l6,7l8,9-oetahydro-2-[2-(methylamlno)ethylj -411-carbazol-4-one hydrochloride. 1 2 3 H 6 7 J8 9 11 12 13 14 16 17 IS 19 21 22 23 2H 26 27 .. 1 | I ! Example 3 j Preparation of 2-mcthyl-2.3.4,-ln.5.7.3,9.!0.Hn-decahvdro-4n.lla-trans-llI,l)H-cvelo]iCxa-[4,5] pyrrolof2.3-ft] isoquinolin-Il(illi)-one A mixture of 2.3 g. of l,2,3,5,6,7,8,9-octahydro-2-[2-(methylamino)ethyl] -4H- j I carbazol-4-onc hydrochloride (8.14 mmol) and 2.3 g. of paraformaldehyde (7S mmol) in i 100 ml. of n-butanol was heated in a pressure bottle immersed in a 180° C. oil bath to an j i internal pressure of 80 psi for 1 hour. The solution was cooled and the solvent was j removed at reduced pressure and the residue was dissolved in water and washed with ! dichloromethane (discarded). The aqueous solution was made alkaline with ammonium j 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 2-methyl-2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-trans-lH,6H-cyciohexa[4,5] pyrrolo-[2,3-g] isoquinolin-ll(llII)-one containing a small amount of the corresponding 4a,11a- 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-IH,6H-cyclohexa[4,5] -pyrrolo[2,3-g] isoquinolin-ll(llH)-one as an off-white solid. The free base was treated with HC1 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-cyclo-hexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(llH)-one, hydrochloride, 0.75 molar hydrate as crystals, mp 217-220° (19% yield).
Anal. Calcd. for C16H22N2C).HC1.0.75 H20 C, 62.33; II, 8.01; N, 9.09; CI, 11.50 Found: C, 62.56; II, 8.11; N, 9.08; CI, 11.59 1 : 2 3 4 6 7 S 9 11 12 13 ' 14 16 17 IS 19 21 22 23 24 26 27 96363 Examole 4 Preparation of l,2,3,4-tetrahydro-6,8-dimethQxy-2-methyl-isoquinolirie, hydrochloride A solution of N-mcthyl-(3,5-dimethoxyphenyl)ethylamine- hydrochloride (15.0 g, 64.7 mmol) in 30 ml. of water" was treated'With'35 ml.- of 2N "sodium " hydroxide, ana extracted with dichloromethane. The combined extracts were concentrated on a rotary evaporator and mixed, with aqueous formaldehyde (G5 ml, 37% solution).. The mixture was refluxed for 2 hours, made alkaline with 2N sodium hydroxide (15 mi.) 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 . ' 1,2,3,4-tetrahydro-6,8-dimethbxy-2-methyl-isoquinoline, hydrochloride (64% yield). . 48 - N.Z. PATENT OFFICE 18 JUL1983 RECE'V^L) .196363 Example 5 -' Preparation of 1,2,3,4a,7-hexahyd.ro-6,8-dimethoxy-2-methylisoquinoline and octahydro-2-methylisoquinolin-6,8-dione ". - Ammonia (150 ml) was condensed in a flask containing t-butanol (9.1 g, 123 mmol) and diethyl"ether (50 ml). .To the solution was: added 1,2,3, 4-tetrahydro-6 , 8-dimeth6xy-2-methyr-isoquin"oiine 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 to 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 . 1,2,3 , 4 , 4a,' 7-hexahydro-6,8-dimethoxy-2-methylisoquinoline (0.58 g, crude) as a yellow oil.
The crude product (1.05 g) in 20 ml. of 70% aqueous acetic acid was refluxed for 5 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% yield) as a light yellow solid. Treatment with hydro- . chloric acid in methanol afforded the hydrochloride, mp 193-196°.
N.Z. PATENT OFFICE 1S J ' .M 1933 1 96 3 6 3 Example G Preparation of 2-mcthyl-2,3,4.4n.5,7,8,9,10.11a-dccahydro-4n,lla-trflns-lH.GH-cyclohcxa-[4,5) pvrroIof2,3-d isoc;umoIin-Il(H!i)-one via oetahvdro-2-methvlisoquinoIin-G.8-dionc A mixture of 72 g. of crude octahydro-2-methylisoquinolin-6,S-dione (about 30% 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 2-isonitrosocyclohexanone 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 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,lla-decahydro-4a,lla-trans-lH,6H-cyclohexa[4,5] pyrrolo[2,3-g] isoquinolin-ll,llH-one was chromatographed on silica gel (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-decahydro-4a,lla-trans-lH,GH-cyclo-hexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(llH)-one as a white amorphous solid after slurrying with hot ethanol, mp 273-275° C. (dec.).
Anal. Calcd. for C16H22N20: c, 74.38; H, 8.58; N, 10.84 Found: C, 74.21; H, 8.39; N, 10.61 - 50' - 1 ^'O Jf ,r-\ 1 Example 7 2 Following the procedure of Example G, starting from 2-isonitrosocyclopcntanone 3 and octahydro-2-methylisoquinolin-6,8-dione, there was obtained 2-methyl-1,2,3,4,-k 4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cycIopenta[4,5] pyrrolo[2,3-g] isoquinoIin-IO(lOH)- -one, mp 293-237° C. (dec.), crystallized from ethanol-methanol. 6 Anal. Calcd. for C15H2QN20: C, 73.74; H, 8.25; N, 11.47 7 Found; C, 73.93; H, 8.41; N, 11.46 9 11 12 13 ■IH 16 17 18 19 21 22 23 2k 26 27 The hydrochloride crystallized from water as a hemihydrate, mp 256-258° C. (dec.) Anal. Calcd. for C^H^^O.HCl 0.5H20: Found: C, 62.17; Ii, 7.65; N, 9.67; CI, 12.23 C, 62.16; H, 7.71; N, 9.54; CI, 12.37 /? 7 8 9 11 12 13 ' It 16 17 18 19 21 22 23 2k 26 27 Example 8 Following the procedure of Example S, starting1 from 2-isonitrosocycloliepta-none and octahydro-2-methylisoquinolin-6,S-dione, there was obtained 2-methyl-1,2,3, 4,4a,5,7,S,9,10,n,12a-dodeeahydro-4a,12a-trans-6H-cyclohepta[4,5] pyrro!o[2,3-g] -iso quinolin-12(12II)-cne, mp 293-296° C, crystallized from ethanol.
Anal. Calcd. for C^H^NgO: C, 74.96; H, 8.88; N, 10.28 Found: C, 74.79; Ii, 8.74; N, 10.33 Example 9 Following the procedure of Example 6, starting from 2-isonitrosocyclooeta-none and octahydro-2-methylisoquinolin-6,8-dione, there was obtained 2-methyl-2,3, 4,4a,5,7,8,9,10,ll,12,13a-dodecahydro-4a,13a-trans-lH,6H-eyclooeta[4,5] pyrrolo[2,3-g] -isoquinolin-13(13H)-one, mp 298-300° C, crystallized from water-dimethylformamide.
Anal. Calcd. for C^IiggNgO: C, 75.48; H, 9.15; N, 9.78 Found: C, 75.29; K, 9.04; N, 9.70 1 2 3 4 6 7 8 9 11 12 13 It 16 17 18 19 21 22 23 2H 26 27 196363 Example 10 Preparation of 2,3,4,4n,5,7,3,9,10,lla-dccflhvdro-4a.lla-trnns-lH,6H-cyclohcxa[4.5] pyr-rolo[2.3-rr] i?oquinolin-ll(lltl)-one A mixture of 1.9 g. of 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-ll(llH)-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 596 aqueous hydrochloric acid, washed with water, brine, and dried over sodium sulfate. Evaporation of the solvent afforded 1.4 g. of the carbamate, 2-ethoxycarbonyl-2,3,4,4a,5,7,8,9,10,lla-decahydi'o-4a,lla-trans-lH,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 crudc 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 596 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-decahydro-4a,lla-trans-lH,6H-cyclohexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(llH)-one.
/ I 1 2 3 ti 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 2<* 26 27 t 963 63 Exnmnlc II Following the procedure of Example 10, starting from 2-methyl-l,2,3,4,4a,5,-7,8,9,10a-decahydro-4a,10a-trans-GH-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-lG(lOH)-one, there was obtained via the carbamate, 1,2,3,4,4a,5,7,3,9,10a-decahydro-4a,10a-trans-GH-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one, mp 242-245° C. (dec.), crystallized from ethanol-ethyl acetate.
Anal. Calcd. for C, 73.01; H, 7.88; N, 12.16 Found:. C, 72.84; H, 7.78; N, 12.30 Example 12 Following the procedure of Example. 10, starting from 2-methyl-2,3,4,4a,5,7, 8,9,10,ll,12,13a-dodecahydro-4a,13a-trans-lH,6H-eyeloocta[4,5] pyrrolo[2,3-g] isoquinolin-13(13H)-one, there was obtained via the carbamate, 1,2,3,4,4a,5,6,7,8,9,10,11,12,13a-tetradecahydro-4a,13a-trans-cycloocta[4,5] pyrrolo[2,3-g] isoquinolin-4-one, mp 283-5° C., crystallized from ethanol.
Anal. Calcd. for C^H^NgO: C, 74.96; H, 8.88; N, 10.28 Found: C, 74.71; H, 8.65; N, 10.24 1 9^ 6 3 s 9 11 12 13 It 16 17 IS •19 21 22 23 2 '4 26 27 Example 1 3 Preparation of 2-[4-(4-fluoronhcnvl)-4-oxobiitvl] -2,3,4,'iR.5,7.8.9,I0,ila-decnhydro- 4a,lla-trans-lH.6H-cvcIohcxn[4.5l r>yrroIo[2.3-g] isoouinolin-]l(IlH)-one A mixture of 0.68 g. of 2,3,4,4a,5,7,8,9)10,lla-deeahydro-4a,llc-trans-lH,6H-cyclohexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(llll)-one, 1.G8 g. of y-chloro-p-fluorobutyro-phenone, 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 concentratcd. The residue was chromatographed (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 afford 0.85 g. of a crude amine, which was recrystallized from ethanol to afford 0.42 g. of pure 2-[4-(4-fIuorophenyl)-4-oxobutylj -2,3,4,4a,5,7,8)9,10,lla-decahydro-4a,lla-trans-lH,6H-cyclohexa[4,5] pyrrolo[2,3-gJ isoquinclin--ll(llH)-one as a crystalline solid, mp 220-222°.
Anal. Calcd. for C25H2gN202F: C, 73.50; H, 7.16; N, 6.86; F, 4.65 Found: C, 73.46; H, 7.08; N, 7.16; F, 4.61 196363 Exam pic 14 Following the procedure of Example 13, alkylntion of 2,3,4,4a,5,7,8,9,10,Ilu-deca-hydro~4a,lla-trans-lH,6H-cyclohexa[4,5] pyrrolo[2,3-[j] isoquinolin-Il(llH)-onc with (2-bromoethyl)benzene afforded 2-(2-phenylethyl-)-2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-trans-lH,6H-cyclohcxa[4,5] pyrrolo[2,3-g] isoquinolin-ll(llll)-one, mp 250-255° C. (dec.), as a crystalline solid after recrystallization from ethanol.
Anal. Calcd. for C23IT28N20: C, 79.27; II, 8.10; N, 8.04 Found: C, 79.29; H, 8.40; N, 7.97 Example 15 Following the procedure of Example 13, alkylatior. of 2,3,4,4a,5,7,8,9,10,lla-deea-hydro-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,GH-eyelo-hexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(llH)-one, mp 26G-2G80 C, as a crystalline solid after recrystallization from ethanol.
Anal. Calcd. for C22H26N20: C, 79.00; H, 7.S4; N, 8.38 Found: C, 79.27; H, 8.03; N, 8.60 j a ✓ .o 1 Example ig 2 Following the procedure of Example 13, alkylntion of l,2,3,4,4a,5,7,8,!},l0a-dcca- 3 hydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-!0(10H)-one with benzyl t chloride afforded 2-benzyl-l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-eyc!cpenta- [4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one, mp 25S-2G0°C. (dec.), as a crystalline solid 6 after recrystallization from ethanol. ! 7 Anal. Calcd. for C21H24N20: C, 78.71; H, 7.55; N, 8.74 | 8 Found: C, 78.97; H, 7.54; N, 8.60 j 9 I i Example 17 j 11 Following the procedure of Example 13, alkylation of 1,2,3,4,4a,5,7,8,9,lOa-deca- 12 hydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one with y- ; 13 chloro-p-fluorobutyrophenone afforded 2-[4-(4-fluorophenyl)-4-oxcautyl] -1,2,3,4,4a,5,- ; It 7,8,9,10a-decahydro-4a,lGa-trans-6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolln-10(10H)-one, : t mp 225-227° C., as a crystalline solid after recrystallization from ethanol. j I 16 Anal. Calcd. for C24H97FN202: C, 73.07; H, 6.90; N, 7.10; F, 4.82 j 17 Found: C, 72.76; H, 6.86; N, 7.24; F, 4.71 18 • 19 21 22 23 24 26 27 Example 13 1 Following the procedure of Example 13, alkylation of l.S^^^a.S^jS^^Oa-deca- 2 hydro-4a,10a-trans-GH-cyclopenta(4,5! pyrrolo[2,3-g] isoquinolin-10(10H)-one with (2- 3 bromocthyllbcnzcne afforded 2-{2-phenylethyl)-l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-^ trnns-6II-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(101I)-one, mp 251-254° C. (dec.), as ' a crystalline solid after recrystallization from ethanol. 6 Anal. Calcd. for C^H^^O: C, 79.00; II, 7.84; N, 8.38 7 Found: C, 78.68; H, 7.72; N, 8.28 8 9 Example 19 11 Following the procedure of Example 13, alkylation of 1,2,3,4,4a,5,7,8,9,10a- 12 decahydro-4a,10a-trans-6H-cyelopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one with 4- 13 methoxybenzyl chloride afforded 2-(4-methoxybenzyl)-l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-4-one, mp 236-8° '5 (dec.), as a crystalline solid after recrystallization from ethanol. '6 Anal. Calcd. for C22H2gN202: C, 75.40; H, 7.48; N, 7.99 17 Found: C, 75.39; H, 7.41; N, 8.03 IS 19 21 22 23 ' 24 26 27 > 1 2 3 4 6 7 8 9 11 12 13 14 16 17 is 19 21 22 23 24 26 27 1 96 3 6 3 Example 20 Following the procedure of Example 13, alkylation of 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-GH-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one with 4-chlorobenzyl chloride afforded 2-(4-chlorobenzyl)-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 as a crystalline monohydrate, mp 254-G° after recrystallization from ethanol.
Anal. Calcd. for C21H23N20 CI HgO: C, 67.63; H, 6.22; N, 7.51; CI, 9.51 Found: C, 67.86; H, 6.38; N, 7.50; CI, 9.92 Example 21 Following the procedure of Example 13, alkylation of 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one with allyl bromide afforded 2-(2-propenyl)-l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6I-I-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H) -one, mp 257-9° (dec.), after recrystallization from ethyl acetate-ethanol.
Anal. Calcd. for C1?H22N20: C, 75.52; H, 8.20; N, 10.36 Found: C, 75.25; H, 8.17; N, 10.36 1 2 3 4 6 7 S 9 11 12 13 14 16 17 IS 19 21 22 23 24 26 27 Example 22 Following the procedure of Example 13, alkylation of 1,2,3,4,4a,5,7,8,9,10a-dceahydro-4a,10a-trans-6H-cyelopenta[4,5] pyrrolo[2,3-g,J isoquinolin-10(10il)-one with 2-brcirsoethyl ethyl ether afforded 2-(2-ethoxyethyl)-l,2,3,4,4a,5,7,8,9,10a-deca-"/ hydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one, I mp 236-8° (dec.) as a crystalline solid after recrystallization frcm ethanol. Anal. Calcd. for C^H^N^: C, 71.49; H, 8.67; N, 9.2G Found: C, 71.35; H, 3.47; N, 9.23 Example 23 Following the procedure of Example 13, alkylation of 2,3-,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-lH,6H-cycloocta[4,5] pyrrolo[2,3-g] isoquinolin-13(13H)-one with the ethylene ketal of gamma-chloro-p-fluorobutyrophenone followed by acid hydrolysis afforded 2-[4-(4-fluorophenyl)-4-oxobuiyl] -1,2,3,4,4a, 5,6,7,8,9,10,11,12,13a-tetradecahydro-4a,13a-trans-cycloocta[4,5] pyrrolo[2,3-g] isoquinolin-13(13H)-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.
I PiMF.MT OFFICE IG 1983 ^C^V^-^^^^OMDC>0\lcr\,^/i-Cr-V0N)>--O,v0C<3~vJCr\V»-f::*V-0N3 TABLE i (CH2'n +K2-X <ch2>„ Example Name 24 2-ethyH.,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 R, ch3ch2- X Br 26 2-(2-acetoxyethyl)-l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5] pyrroIo[2,3-g) isoquino-lin-10(10H)-one 2-[3-(4-fluorophenyl)-3-oxopropyl] -1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo-[2,3-^j isoquinolin-lG(iOII)-one O ,$< ch3coch2ch2- -ch2cH2- Br Cl L*J s ! 1 2 3 4 6 7 .8 9 11 12 13 It 16 17 18 19 21 22 23 24 26 27 1 96363 x| o u CO ra to c- « c<J X 0 1 X ■ A CO CM ffi K O —O c o y ►J m E- <u £ a 55 o u ( jC 1 o to a3 O Q; bD T3 1 i CO c3 c-f o O cT o co" SL-. t>< >> Cl LO cT tr? ■i»» G 0) a. 1 o >> a a) JZ >> c 4-1 o o i j E ® JZ to S >, j o a. in o c cj o u Oi o L. 4-1 1 1 c 13 >i C3 O 'o .s o 1 cd 3 rr cr « e o .5 • r—I « c ^ .S 1 3 P o* *o ^ >>.£ jc, Cl to O I a> co Y c-T C3 o O f-t i—j O cT b °C a C- f—> u," J2 ^ 03 ^ C "2. o T ? o c >1 u fcD ' — <- ^ 9 oi = L. CO Cl( c3 U o bX> t o t- T3 >> J ►C o cS (A O —« O — V T 2 ^ CO g ^ >> in D> ® "i r?2L « 5 7* a, J o «——» ,—I p >> ^ t: V o c — A T^o £? I ra 3 !2 d 2 52 i v S. a ^ 2 a) o |H csT o u .s >> /—1 o *5 c V 3 cr o to o r—< fcx> o> 1 CO CO* o m o <£ u C-. >> CL IT) S T CO C a JZ Cu 4-J 0) *>> "3 >> c ? cq o c T C3 3 a1 3 - ^ ij ST ■:■ Ago ' U o W r-t O i * V r—I J>> £V +-» H* <y £ Ch i >, £ *< 5- - 2 2^ o V 2 0 c ? S 13 o i2 o 2 g sT .S .S ^ r* Sgl £ o a .£2 ^ r— ■s *° d ^ j i o X 0 1 CO M o cf ' o > \ 0 i-A TJ CO i?-; <ru u'l 1 cl c!j T " CN ^-T o C-» C-, >> CL Tn rr" C3 C GJ a aj a. £ rJ x W s i i 2 3 4 6 7 -s 9 II 12 13 14 16 17 18 19 21 22 23 24 26 27 f 96 3 ' x| CO u m u m CQ CQ c o Cl w J CQ <: o E 2; •a .C 3 03 O O W <y ^ L i O *N *"2, ^ °C o ^ £ m ^ ^ 10 -tt4 C~ I c O Cb «.2 >• a D t >iC £ V ? p^X cr &Q>- O I o I—' to •—< G (—) « a 2 c (D £ "T CM T ^ 3 (N ^ CT r .s o! i ■o e >».5 ,c 3 aj cr 0 o <D 7- 1 V°- 2 eo <y[Si CO o -:s to t-» cT cu ■^Tuo CO S CvT V c if 0) o a, >i o V c_ l a.S J r^ < CM ri( « c* 2' 0 £ -G } Cu rt • 1 o CO ^ I cl cm £ o •§ | o o <D W 'a ^ ^ v0 O CO 00 -2 f" p a) a, r—i •#"1 c-T «2 ,-T C I CJ a, >.£ -c o JSS1 >1J^ o o c >5 'A O G G I O C3C U — s rs t CJ c^J ^ ; -o _L, £"?° ctf co 82 7 S cj O 2 & c^l« in x « a O ^■3 CO >2 - o c CM i o ASA >^-3 V I ^ >> W I X c G o x: o 4-> 1 G 0) 1 CM >->4 a1 T' CM cT a IA I ° I T3 ° j?" !? o C» ? *T 03 >> CO r—. - ijo t- ^ - to ^ r- <3 g3 ^ ^ d> -:■§ ".o cm >1 i cj >.i. $> JZ wi-. c 4_» to o C) r A c X O >> (A r-L "t: c ^ 3 CD v O V .G rH i V C3 o >> ^ C V cT"3 CM -3* u* a G aj X W CM CO <o to CO I 1 2 3 k 6 7 8 9 11 12 13 lft 16 17 IS 19 21 22 23 7k 26 27 1 963 6 3 ca O I-, CQ CQ = 1 • ^ P «*-> c o c w hJ CQ < o E Cj t O t-, % . ? o <33 •*-< O r-, 0 X> ' 1 ^ « N !•> o °° Dj csS ^ C3 - S co x: of .2 I V r—. >» Si § o o o "r—« >-r< /—> >>£ :n C I ^ <D co r~t — C Z* -q cd i . ^ C CM I ^ Y«2 cm i—j trj I C3* 3 ^ cy i o u -a o y) x: _ C3 o ¥> c> CO 'O i CM" cd o 23 —H o o t_ r—■H u. aT >> a.
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| Example Name n R 2 o 46 2-(2-p'nenylethyl)-2,3,4,4a,5,7,8,9,10,11.12,13a-dodeca hydro-4a,13a-trans-lH,6H-cycloocta[4,5] pyrrolo- // \\r„ [2,3-g] isoquinolin-13(13H)-one 6 \ / 2 2. Br 47 2-(2-ethoxyethyl)-2,3,4,4a,5,7,8,9,lD,ll,12)13a-dodeca-hydi-o-4a,13a-trans-lH,61i-cyclooeta[4,5] pyrrolo- [2,3-g] isoquinolin-13(13H)-one 6 CHjCl^OCHgCl^— Br 48 2-(3-phenoxypropyl)-2,3,4,4a,5,7,8,9,10,ll,12,13a-do- decahydro-4a,13a-trans-lH,6fI-cycloocta[4,5]- // \\_nrH pti pyrrolo[2,3-g] isoquinolm-13(13H)-one 6 V / 2 2 2 Br G': 1 © /f "9 - 76,3 s 1 2 3 k 6 7 8 9 11 12 13 " lk 16 17 18 19 21 22 23 2k 26 27 Example 49 Preparation of 2-mothvH.2,3,4,4a.5,7,8.9,10a-decahvdro-4n. lOa-trans-Gri-cvclopen tu-[4,5] pyiTolo[2.3-<tj isoci:inolin-lO(IOH)-thione A mixture of 244 mg. (1.0 mmol) of ^-methyl-l^jS^^a^^jSjS.lOa-decahydro- j 4a,10a-trans-GH-cyclopenta[4,5] pyrrolo[2,3-g] isoauinolin-10(10H)-one and 222 mg. (1.0 ; I mmol) of phosphorus pcntasulfide in 15 ml. of dioxane was stirred and refluxed for 17 j hours. The dioxane solution was decanted off and water (20 ml.) and enough ammonium | i 1 hydroxide to bring the pH to 8-9 was added to the residue. The mixture was extracted ! i with chloroform, and the extracts were washed with brine, dried and evaporated. The i j 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-decahydro-4a,10a-trans-GH-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H) -thione, mp 224-227° C. (dec.).
C, 69.19; H, 7.74; N, 10.76 Found: C, 68.97; H, 7.59; N, 10.97 Anal. Calcd. for _ 67 - / 1 o 3 1 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 j I 2k 26 27 Example 50 The procedure of Example 49 is used to prepare 2-methyl-2,3,4,4a,5,7,8,9,10,lla- ] l decahydro-4a,lla-trans-lH,GH-cyelohexa[4,5] pyrrolo[2,3-g] isoquinolin-ll(llH)-thione j starting from 2-methyl-2)3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-trans-lH,GH-cyclohexa- j [4,5] pyrro!o[2,3-g] isoquinolin-ll(llH)-one.
Example 51 The procedure of Example 49 is used to prepare 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 starting from l)2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquino-lin-10(10H)-one.
Example 52 The procedure of Example 13 is used to prepare 2-[4-(4-fluorophenyl-4-oxobutyl] -l}2,3,4,4a,5,7,8,9,10a-decaliydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo[2,3-g] isccuino-lin-10(10H)-thione starting from l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclo-penta[4,5] pyrrolo[2,3-g] isoquinolin-10(I0H)-thione and y-chloro-p-fluorobutyrophenone.
Example 53 The procedure of Example 13 is used to prepare 2-(2-phenylethyl)-l,2,3,4,4a.5,7,-8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-lO(lOH)-thione starting from l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4;5] -pyrrolo[2,3-g] isoquinolin-10(10Ii)-thion6 and (2-bromoethyl)benzene. 1 963 6 3 j Example 54 I Preparation of 6-bcn7.ovl-2-methvM.2.3.4.4a.5.7,3.9.10a-decalivdro-4a.l0a-trans-6H- | cvclopcnta[4,5] ovrro!of2,3-cr] isoauinolin-10(10t£)-one j ! To a mixture of 244 mg. (1.0 mmol) of 2-methyl-l,2,3,4,4a,5,7,8,9,10a-decahydro- ! j 4a,10a-trans-6H-cyclopenta[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 2.2.M solution in ! | hexane) over 2-3 minutes via syringe. The solution is stirred for 30 minutes at -30° and i 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 ! 1 extracted with chloroform. The extracts are washed with brine, dried (sodium sulfate), i i concentrated and chromatographed to afford the 6-benzoyl-2-m ethyl- i l,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-1 -10(10H)-one.
Example 55 Following the procedure of Example 54, 2,6-dimethyl-l,2,3,4,4a,5,7,S,9,10a-deca-hydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one is prepared ' using methyl iodide instead of benzoyl chloride. f 96 3 6 3 Example 56 Preparation of 2-(2-hydroxy-3,3-dim elhv1butyl)-2.3,4,4 a,5,7,8.9.10.11a-decahydro-4a,lla-trans-lH,GH-cvcloliexa[4.5] nvrrolo[2.3-^1 i?oouinolin-Il(llH)-one A solution of 488 mg. (2.0 mmol) of 2,3,4,4a,3,7,8,9,10,lla-decahydro-4a,lla-trans-lH,6H-cyclohexa[4,5] pyrrolo!2,3-g] isoquinolin-ll(llH)-one and 300 mg. (3.0 mmol) of 3,3-dimethyl-l,2-cpoxybutane in 15 ml. of methanol was refluxed for 24 hours and con- j ccntrated. The residue was chromatographed, and the crude product (350 mg.) crystal- ' lized from ethanol to give 200 mg. of 2-(2-hydroxy-3,3-dimethylbutyl)-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, mp 27G-27S0 C. (dec.).
Anal. Calcd. for C^H^N^: 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 56 is used to prepare 2-(2-hydroxy-2-phenylethyl)-l,2,3,4,4a,5,7,S,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin--10(10H)-one starting from 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 and styrene oxide.
Example 58 Following the procedure of Example 56, alkylation of 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one with ethylene oxide at room temperature afforded 2-(2-hydroxyethyl)-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, mp 237-9° (dec.) as a crystalline solid after recrystallization from ethanol.
Anal. Calcd. for Cjgli^N^: C, 70.04; H, 8.08; N, 10.21 Found: C, 69.66; H, 8.17; N, 10.19 X 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 28 29 31 32 I 96 Example 59 Following the procedure of Example 56, alkylation of 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one with 3,3-dimethyl-l,2-epoxybutane afforded 2-(2-hydroxy-3,3-dimethylbutyl)-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, mp 284-6° (dec.), as a crystalline solid after recrystallization from ethanol. Anal. Calcd. for C2QH30N2O2: C, 72.69: H, 9.15; N, 8.48 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-decahydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10II)-one in 1 ml of dry DMSO 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-decahydro-4a,10a-trans-6H-cyclopenta[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 C22H2gN20: C, 79.00; II, 7.84; N, 8.35 Found: C, 72.80; H, 9.02; N, 8.55 Example 60 Found: C, 78.92; H, 7.84; N, 8.55 X 2 3 4 6 7 8 9 n 12 13 14 i6 17 18 19 21 22 23 24 26 27 28 29 31 32 1 96353 | 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,10a- trans-6H-eyclopenta[4,5] pyrrolo [2,3-g] isoquinolin-10(10H)-one in 20 ml of methanol was j i 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. Recrystallization of the base from ethanol afforded 0.18 g of (-)-2-methyl-l,2,3,4,4a,5,7j8,9,10a-deeahydro-4a,10a- trans-6H-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one, mp 270-2° (dec.). The hydrochloride salt gave [ a ] ^ -101.17° in methanol (1%).
Example 62 Preparation of 2-[4-(4-nuorophenyl)-4-hydroxybutyl] -1,2,3,4,4a,5,7,8,2,10a-decahydro-6H-4a,10a-trans-cyclopenta[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one.
A mixture of 394 mg (1.0 mmol) of 2-[4-(4-fluorophenyl)-4-oxobutyl] -l,2,3,4,4a,5,7,8,9,10a-decahydro-6H-4a,10a-trans-cyclopenta[4,5] pyrrolo [2,3-g] isoquino.lin-10(10H)-one and 151 mg of sodium borohydride (4.0 mmol) in 15 ml of ethanol was stirred at room temperature for 24 hrs. A second portion of sodium borohydride (150 mg, 4.0 j 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, 10 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-trans-cycIopenta[4,5] pyrrolo[2,3-g] isoqutnolin-10(10H)-one, mp 243-5°, as a mixture of diastereomers.
Anal. Calcd. for C24H29N2°2F: C' 72,7°5 H' 7'37' N' 7,07 Found: C, 72.68; H, 7.56; N, 7.33 • X 2 3 4 6 7 8 9 11 12 13 14 i6 17 18 19 21 22 23 ,24 26 27 28 29 31 32 1 963 53 Example 63 Following the procedure of Example 62, sodium borohydride reduction of 2-[4-(4-fluorophenyl)-4-oxobutyl] -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 afforded 2-[4-(4-fluorophenyl)-4-hy-droxybutyl] -2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-trans-lK,6H-cyclohexa[4,5] pyrrolo-[2,3-g] isoquinolin-ll(llH)-one, as a mixture of diastereomers, mp 239-41°, crystallized from 1,4-dioxane.
Anal. Calcd. for C^H^N^F: 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-fluorophenyl)-4-oxobutyl] ^S^^a.S^S^lO.lUS.na-dodecahydro^aJSa-trans-lH,6H-cycioocta[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-cyclo-octa[4,5] pyrrolo[2,3-g] isoquinolin-13(13H)-one, as a mixture of diastereomers, mp 249-51°, crystallized from 1,4-dioxane.
Anal. Calcd. for Cn„H,,No0oF: C, 73.94; H, 8.04; N, 6.39 it I wD u L Found: C, 73.71; H, 8.05; N, 6.37 X 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 28 29 31 32 19633 3 Example 65 Preparation of 5-[(2-methylamino)ethyl] -cyclohexane-l,3-dione i To a stirred solution of N-methyl-l,5-dimethoxycyclohexa-l,4-diene-3-ethyl- j amine (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 HC1 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-l,3-dione. An analytical sample crystallized from water and had mp 171— 4° C.
Anal. Calcd. for CgH15N02: C, 63.88; H, 8.93; N, 8.28 Found: C, 63.50; H, 8.87; N, 8.15 Example 66 I j Preparation of 6-benzyl-2,3,4,4a,5,7,8.9,10,1la-decahydro-4a, 11a- j trans-IH. 6H-cyclohexa[ 4 . 5 ]pyrrolo[ 2 . 3-q]isocrulnolin-l 1 (11H) -one j Following the procedure of example 60, 316 mg of 2-ethoxy-carbonyl-2,3,4,4a,5,7,8,9,10,1la-decahydro-4a,1la-trans-IH,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquino1in-1l(llH)-one was alkylated with 190 mg of benzyl chloride to afford 6-benzyl-2-ethoxy-car-bonyl-2,3,4,4a,5,7,8,9,10,1la-decahydro-4a,1la-trans-IH,6H-Oyclchexa[4,5]pyrrolo[2,3-g]iscquirolin-ll(llHl-cre (220 irg), up 54°-60°C, vfoich was frycfcolyzed fcllcwing the procedure of exatple 10 with SDdiuti hySrcxicte to a£fcrd 6-tenzyl-2,3,4,4a,5,7, 8,9,10, lla-dscahyari^la, lla-trans-lH, 6H-cy=lchexa[ 4,5]pyrrolo[ 2, 3ng]i9oquinDlin-ll (11H) -ere.
-J ui fvj fO N) N) vj ON <-/> •G' K) N> ro V^O K> >— N) O vo 0O U> K> ►— ON V*i K> Example A Capsule Formulation Mix 2-[4-(4-fluorophenyl)-4-oxobutyl]~l,2,3,4?4a,5,7?8,9,lGa-decahydro-4a,10a-trans-6H-cyclopenta-[4,5] pyrrolo[2,3-g] isoquinolin-10(10H)-one, lactose and starch in a suitable mixer. Mill through a suitable mill. Mix with tulc and magnesium stearate and fill on capsule machine.
Ingredients 0.1 0.5 .0 .0 .0 2-[4-(4-fluorophenyl)-4-oxobutyl] -1,2,3,4,4a,5,7,8,9,10a-decaftydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo-[2,3-g] isoquinolin-10(10H)-one 0.1 0.5 .0 .0 .0 Lactose Starch Talc Magnesium Stearate 183.9 30.0 5.0 1.0 183.5 30.0 5.0 1.0 179.0 30.0 5.0 1.0 218.0 50.0 10.0 2.0 257.0 70.0 15.0 3.0 Total 220 mg. 220 mg. 220 mg. 290 mg. 370 mg Procedure: 0^ C4 Ps) VI M ON K) V-n N) 4=* LO K) NJ N3 O ON Example B i Tablet Formulation (Direct Compression) mg/capsule Ingredients oa 0.5 .0 .0 .0 2-[4-(4-fluorophenyl)-4-oxobutyl] -1,2,3,4,4a,5,7,8,9,10a- decahvdro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo- [2,3-gj isoquinolin--10(10H)-one 0.1 0.5 .0 .0 .0 Lactose 85.4 85.5 81.0 103.0 112.5 Avicel .0 .0 .0 45.0 60.0 Modified Starch 8 7.5 7.5 .0 .0 Magnesium Stearate 1.5 1.5 1.5 2.0 2.5 Total 125 mg. 125 mg. 125 mg. 170 mg. 215 mg. -<■4 en 1 Procedure: . .
Mix 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(10H)-one, lactose, avicel and modified starch in a suitable mixer for 10-15 minutes. Add the magnesium stearate as a premix and mix for 4 minutes. Compress on a suitable press.
WWMWWtONW vg C\ ■ Wi -t? IjJ N> ►— O Example C Tablet Formulation (Wet Granulation) mg/tablet -J -J Ingredients OA 0.5 .0 .0 .0 2-[4-(4-fluorophenyl)-4-oxobutyl] -1,2,3,4,4a,5,7,8,9,10a- - decahydro-4a,10a-trans-6H-cyclopenta[4,5] pyrrolo[2,3-g] - isoquinolin-10(10H)-one 0.1 0.5 .0 .0 .0 Lactose 103.9 103.5 99.0 148.0 197.0 Modified Starch .0 .0 .0 .0 .0 Pregelatinized Starch .0 .0 .0 .0 .0 Magnesium Stearate 1.0 1.0 1.0 2.0 3.0 Total 125 mg. 125 mg. 125 mg. 200 mg. 285 mg, Procedure: Mix 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(10H)-one, lactose, modified starch and pregelatinized starch in a suitable mixer, granulate with water. Dry, mill. Mix with the magnesium stearate and compress on a suitable press. 1 2 3 4 6 7 8 9 .0 .1 1 2 1 i 2 1 196363 ' . i

Claims (23)

WHAT WE CLAIM IS: -
1. Cycloalka[4,5]pyrrolo[2,3-g]isoquinolines of the general formula wherein is hydrogen, alkyl, acyl or aralkyl; is hydrogen, alkyl, hydroxyalkyl, arylhydroxyalkyl, alkoxyalkyl, • acyloxyalkyl, acylalkyl, aralkyl, alkenyl, cycloalkyl-alkyl, alkynyl, thienyl-alkyl, furyl-alkyl, arylcarboxamidoalkyl, aralkenyi, alkenyloxyalkyl, aryloxyalkyl, aralkyloxyalkyl, or 'aryl-N-imidazolonylalkyl; X is 0 or S; and n is 3, 4, 5 or 6j optical and geometric isomers of these compounds and pharmaceutically acceptable acid addition salts thereof.
2 . Qupxrds in accordance with claim 1 vha^in is otha: thai fa,drcgm vten is other t±m h^drogsi.
3. Ctnpcurds in aooardanas with claim 1, wherein F_^ is hydrogen.
4. GSrpourls in accordance with ar^ cne of claims 1 to 3, whenain is alkyl, fadraxyalkyl, arylhy±r!xyalkyl, alkoxyalkyl, aryloxyalkyl, acylalkyl or aralkyl.
5. CHicaTds in accordance with any cne of claims 1 to 4, whsBin n is 3 or 4. 1 2 1 2 1 2 1 2 3 1 2 3 1 2 3 1 2 1 2
6. Compounds in accordance with any one of claims 1 to 5, wherein X is 0.
7. Compounds in accordance with any one of claims 1 to 6, which are the trans isomers.
8 . 2-Methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,lOa-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one.
9 . 2-Methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,lOa-trans-6H-cyclopenta[4,5 ]pyrrolo[2,3-g]isoquinolin-10(1 OH)-one hydrochloride, 0.5 molar hydrate.
10.. 2 — [4 —(4-Fluorophenyl)-4-oxobutvl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,lOa-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]iso-quinolin-10(1 OH)-one.
11. 2-(2-Phenylethyl)-1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,lOa-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin- 10(1 OH)-one.
12. (-)-2-Methvl-l,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a ,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquino1 in-10(1 OH)-one.
13. 2-Methyl-2,3,4,4a,5,7,8,9,10,l1a-decahydro-4a,lla-trans-lH,6H-cvclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(1IH)-one. 79 196303
14. 2-Methyl-2,3,4,4a,5,7,8,9,10,1la-decahydro-4a,1la-trans-IH,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(1lH)-one, 0.75 molar hydrate.
15. 2-[4-(4-Fluorophenyl)-4-oxobutyl]-2,3,4,4a,5,7,8,9,10, lla-decahydro-4a,11a-trans-lH,6H-cyclohexa[4,5]pyrrolo[2,3-g]iso-quinolin-ll(11H)-one.
16. 2-(2-Phenylethyl)-2,3,4,4a,5,7,8,9,10,1la-decahydro-4a,lla-trans-lH,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one.
17. 2-Methyl-l,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-thione.
18. Compounds of the general formula X Y -N (CH2)n XIII wharein X is S or 0, n is 3, 4, 5 or 6, is hy±ogai, alkyl, acyl car aralkyl and Y is a urethsne grtxp.
19. Compounds in accordance with any one of claims 1 to 17 in a form suitable for use as pharr aceutically active substances.
20. Compounds in accordance with any one of claims 1 to 17 in a form suitable for use as antipsychotic agents. N.2.P,- tX -2DEC - 80 - C ' - •- ? ^ ^ ^ O J
21. A process for the manufacture of cycloalka[4,5]-pyrrolo[ 2 , 3-g] isoquinolines of the general formula . .. a <C,IA wherein R^ is hydrogen, alkyl, acyl or aralkyl; R2 is hydrogen, alkyl, hydroxyalkyl, arylhydroxyalkyl, alkoxyalkyl, acyloxyalkyl, acylalkyl, aralkyl, alkenyl, cycloalkyl-alkyl, alkynyl, thienyl-alkyl,.furyl-alkvl, arylcarboxamidoalkyl, aralkenyi, alkenyloxyalkyl, aryloxyalkyl, aralkyloxyalkyl or aryl-N-imidazolonylalkyl; X is 0 or S; and n is 3, 4, 5 or 6; - 81 - M.Z. PATENT QEFinp 18 JUL 1983 RECEIVED 1 96 3 6 3 . ■SS='PSg5^3: 23 optical and geometric isomers of these compounds and pharma-^4 ceutically acceptable acid addition salts thereof, which 25 process comprises 1.6 17 19 20 21 a) for preparing a compound of the general formula 0 (C.H9>n ■ 2 n . Ia wherein R'^ is alkyl, alkoxyalkyl or cycloalkylalkyl and n is as previously described, treating a compound of the general formula O (C1I2)n ix - 82 - 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 1-963 63 wherein R'^ and n are as previously described, with formaldehyde, or b) for preparing a compound of the general formula la above, treating a compound of the general formula xii wherein R^' is as previously described, with a compound of the general formula ho* (CH2 \l vii in the presence of a reducing agent or with a compound of the general formula -q h2n (CK2)n vin or a precursor thereof, in which formulae n is as previously described, or c) for preparing a compound of the general formula 0 ii-n ' lb 1 _ 83 _ 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 1 6 as -4frfr5/3- wherein n is as previously described, N-demethylating a compound of the formula la above wherein R2 is methyl, or d) for preparing a compound of the general formula S - - (Cti2>n He wherein R'^ is hydrogen, alkyl or aralkyl, R1^ is hydrogen, alkyl, alkoxyalkyl, aralkyl, alkenyl, cycloalkyl-alkyl, alkynyl, thienyl-alkyl, furyl-alkyl, alkenyloxyalkyl, aralkenyi, aryloxyalkyl or aralkyloxyalkyl, and n is as previously described, treating a compound of the general formula <CIV„ le; wherein R'J , R'™ and n are as previously described, with phosphorus pentasulfide, or e) for preparing a compound of the general formula X <CHA 4 _ 84 _ 196363 wherein R' is alkyl, hydroxyalkyl, arylhydroxyalkyl, alkoxyalkyl, acyloxyalkyl, acylalkyl, aralkyl, alkenyl, cycloalkyl-alkyl, thienyl-alkyl, alkynyl, furyl-alkyl,■ arylcarboxamidoalkyl, aralkenyi, alkenyloxyalkyl, aryloxyalkyl, aralkyloxyalkyl or aryl-N-imidazolonyl-alkyl, and X and n are as previously described, substituting R^ for H at the isoquinoline nitrogen atom in a compound of the general formula ■ • X H —N (CHA *b wherein X and n are as previously described or f) for preparing a compound of the general formula X <CH2>n A* c wherein R1^ is alkyl, acyl or aralkyl, R^ is alkyl, alkoxyalkyl, acyloxyalkyl, acyl, aralkyl,•alkenyl, cycloalkyl-alkyl, thienylalkyl, alkynyl, furylalkyl, arylcarboxamidoalkyl, aralkenyi, alkenyloxyalkyl, aryloxyalkyl, aralkyloxyalkyl or aryl-N-imidazolonyl-alkyl, and X and n are as previously described, substituting R| for H at the pyrrole nitrogen, atom in a compound of the general formula (CH2}n A d' - 85 76 77 78 79 80 81 82 83 84 85 86 87 88 89 196363 wherein R^1 , X and n are as previously described, or for preparing a compound of the general formula X <CH2>n AC" IV 1 wherein is hydroxyalkyl or arylhydroxyalkyl, ~and R^, X and n are as previously described, splitting off the protecting group in a compound of the general formula ^ XIV „V 1 wherein R^ is an O-protected hydroxyalkyl- or aryl-hydroxyalkyl-group and R|, X and n are as previously described. or h) for preparing a compound of the general formula x (CH2)n M- IV H wherein R^ , X and n are as previously described, reducing the acylalkyl group in a compound of the general formula. _86 _ 1 C 9C 91 92 E3- '10 85/-9- ,VII wherein is acylalkyl, and X and n are as previously described, or 93 i) for preparing a compound of the general formula h -n 94 I I] (CH2)n ah n' 95 96 97 wherein X, n and R^1 are as previously described, splitting off the urethane .group in a compound of the general formula Y —N 98 ccn2)n "I" 99 100 wherein X, n and ' are as previously described and Y is a urethane group, and 17 - i©63$3 j) if desired, isomerizing the 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 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 non- pharmaceutically acceptable acid addition salt thereof into a pharmaceutically acceptable acid addition salt thereof.
22. A process in accordance with claim 21, wherein process embodiments a), b), c), d), e), f) or g) and, if desired, process embodiments j), k), 1) and/or m) are performed. 23. A process in accordance with claim 21 wherein process embodiment h) is performed. 24. A medicament containing a compound in accordance with any one of claims 1 to 17. 25. A neuroleptic/antipsychotic medicament containing a compound in accordance with any one of claims 1 to 17. - 88 - 196363 26. A process for the manufacture of a compound in accordance with claim 1, substantially as hereinbefore described with particular reference to any one of the foregoing Examples 1 to 66. 27. Compounds in accordance with any one of claims 1 to 17, whenever prepared according to the process as claimed in any one of claims 21 to 23 and 26.
23. A medicament containing a compound in accordance with claim 1, substantially as hereinbefore described with particular reference to any one of the foregoing Examples A to C. A. J. j per agietits f6r the applicants
NZ196363A 1980-02-28 1981-02-26 Cycloalka (4,5) pyrrolo (2,3-g) isoquinolin (ones or thiones) NZ196363A (en)

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