CA1160228A - Cycloalka¬4,5|pyrrolo¬2,3-g|isoquinolines - Google Patents
Cycloalka¬4,5|pyrrolo¬2,3-g|isoquinolinesInfo
- Publication number
- CA1160228A CA1160228A CA000371766A CA371766A CA1160228A CA 1160228 A CA1160228 A CA 1160228A CA 000371766 A CA000371766 A CA 000371766A CA 371766 A CA371766 A CA 371766A CA 1160228 A CA1160228 A CA 1160228A
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- Prior art keywords
- alkyl
- trans
- pyrrolo
- decahydro
- isoquinolin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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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
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- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Abstract The novel cycloalka[4,5]pyrrolo[2,3-g]isoquinolines of the general formula wherein R1 is hydrogen, alkyl, acyl or aralkyI; R2 is 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 O or S; and n is 3, 4, 5 or 6;
and their optical and geometric isomers as well as their pharma-ceutically acceptable acid addition salts exhibit neuroleptic activity and are useful antipsychotic agents for the treatment of schizophrenia. These compounds can be prepared by various processes starting from partlynovel intermediates.
and their optical and geometric isomers as well as their pharma-ceutically acceptable acid addition salts exhibit neuroleptic activity and are useful antipsychotic agents for the treatment of schizophrenia. These compounds can be prepared by various processes starting from partlynovel intermediates.
Description
~6~2~8 The present invention relates to cycloalka[4,5]pyrrolo-~2,3-g]isoquinolines of the general formula A
R -N ~ ~
R -N ~ ~
2 ~ ~ CH2)n Rl wherein Rl is hydrogen, alkyl, alkanoyl, arylcarbonyl or aryl-alkyl; R2 is hydrogen, alkyl, hydroxyalkyl, arylhydroxyalkyl, alkoxyalkyl, alkanoyloxyalkyl, arylcarbonyloxyalkyl, alkanoyl-alkyl, arylcarbonylalkyl, arylalkyl, alkenyl, cycloalkyl~
alkyl, alkynyl, thienyl-alkyl, furyl-alkyl, arylcarboxamido-alkyl, arylalkenyl, alkenyloxyalkyl, aryloxyalkyl, arylalkyl-oxyalkyl or aryl-N imidazolonylalkyl; X is O or S; and n is
alkyl, alkynyl, thienyl-alkyl, furyl-alkyl, arylcarboxamido-alkyl, arylalkenyl, alkenyloxyalkyl, aryloxyalkyl, arylalkyl-oxyalkyl or aryl-N imidazolonylalkyl; X is O or S; and n is
3, 4, 5 or 6;
with alkyl, alkoxy and alkanoyl having 1 to 7 carbon atoms, alkenyl and alkinyl having 2 to 7 carbon atoms, cycloalkyl having 3 to 6 carbon atoms and with aryl being phenyl or phenyl bearing one or more substituents selected from the group con-sisting of halogen, txifluoromethyl, alkyl, alkoxy, nitro~
amino, alkylamino and dialkylamino;
optical and geometric isomers of these compounds and their pharmaceutically acceptable 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, ~.
22~
.
methyl, ethyl, propyl, isoprop~l, 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 cyclo-propyl, cyclohexyl, and the like. The term "alkoxy1', 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 - la -., ..~
2f~8 denotes an alkenyl ether group in which the lower alkenyl group is as described above, for example, ethenyloxy, and the like.
The term "alkynyl" preferably denotes "lower alkynyl", which denotes a straight or branched chain unsaturated hydrocarbon con-taining 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 acid 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, 4-3Z2~
. ~
fluorobenzoyl and the like. ~he term ~acyloxy~' denot~san "alkanoyloxy" group derived from an aliphatic carboxylic acid of 1 to 7 carbon atoms, for example, formyloxy, acetoxy, propionyloxy, and the like; and an "arolyloxy" group deri~ed from an aromatic carboxylic acid, such as benzoyloxy and the like. Exemplary of "acylalkyl" are 2-oxo-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 "cycloaLkyl-alkyl" are cyclopropylmethyl, cyclobutylmethyl ~nd the like. Exemplary of "arylcarboxamidoalkyl" are benzamidoethyl and the like.
~xemplary of "aryloxyalkyl" are 3-phenoxypropyl and the like.
Exemplary of "aralkyloxyalkyl" are 2-benzyloxyethyl, 3-benzyloxypropyl and the like. Exemplary of "aryl-N-imida-zolonylalkyl" are 2-(2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)ethyl, 3-(2,3-dihydro-2-oxo-lH~benzimidazol-l-yl)propyl and the like. ~xemplary 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 nalkenyloxyalkyl" are 2-ethenyloxyethyl and the like.
Preferred compounds of formula A are those wherein n is 3, 4, 5 or 6, Rl is hydrogen, R2 is alkyl, hydroxyalkyl arylhydroxyalkyl, alkoxyalkyl, aryloxyalkyl, acylalkyl, or aralkyl; and X is O or S.
More preferred compounds of formula A are those wherein n is 3 or 4, Rl is hydrogen, R2 is alkyl, hydroxyalkyl, arylhydroxyalkyl, alkoxyalkyl, aryloxyalkyl, acylalkyl~ or aralkyl; and X is O.
Most preferred compounds of formula A of the inventi~n are:
2-me~hyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-~a,lOa-trans-6H-cyclopenta[4,5]pyrrolo [2,3-g] i~inolin-10(10~)-one;
~L~613Z~
2-methyl-1,2,3,4/4a,5,7,8,9,10a-decahyaro-4a,10a-trans-6EI-cyclopenta l4,51 pyrrolo [2~3-g]iSOqllinolin-lo(loH)-one hydrochloride, 0.5 molar hydrate;
2-(2-phenylethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta ~4,5~pyrrolo 12,3-g] isoquinolin-lO(lOH)-one;
2- [4-(4-fluorophenyl)-4-oxobutyll-1,2,3,4,4a,5,7,8,9, lOa-decahydro-4a-lOa-trans-6H-cyclopenta 4,5 pyrrolo 2,3 isoquinolin-lO(lOH)-one;
- (-)-2-methyl-1,2,3,4,4a,5,7,8,9 ,lOa-decahydro-~a,lOa-trans-6H-cyclopenta [4,5) pyrrolo 12,3-gl tso~uinolin-lO~lOH)-one;
2-methyl-2,3,4,42-5,7,8,9,10,11a-decahydro-4a,11a-tranq-lH ,6H-cyclohexa [4,5] pyrrolo [2,3-g~ isog~nol~n-ll(l~H)ffne;
2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa [4,5]pyrrolo 12,3-g] isoquin~lin-H~llH)-one, 0.75 molar hydrate;
2-~2-phenylethyl)2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa [4,5] pyrrolo 12,3-g] isoquinolin-ll (llH~-one;
2-[4- (4-fluorophenyl)-4-oxobutyl] -2,3,4,4a,5,7,B,9,10, lla-decahydro-.~a,lla-trans-lE~,6H-cyclohexa[4,5] pyrrolo ~2,3~g 3 isoquinolin-ll(llH)-one; and 2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,~0a~trans-6H-cyclopenta[4,5] pyrrolo ~2,3-g] isoquinolin-lOllOH)-thione.
Exemplary of the compounds of formula A wherein n is 3, i.e., compounds of the fo~nula . X
R~ ~ i,L~ '~ 1~-1 wherein Rl, R2 and X are as previously described arP-` 2-ethyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin lO(lO~t-one;
2-(2-hydroxyethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5~pyrrolo[2,3-glisoquinolin-lO(lOH)-one;
2-(2-hydroxy-2-phenylethyl)-1,2,3,4,4a,5,7y8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5~pyrrolo`[2,3-g]isoquinolin~10(10H)-one;
2-(2-ethoxyethyl~-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta~4,5]pyrrolo~2,3-g]isoquinolin-lO(lOH)-one;
2-(2-acetoxyethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo~2,3-glisoquinolin-lO(lOH)-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-g]isoquinolin-lO(lOH~-one;
2-[2-(.4-methoxyphenyl)ethyl]-1,2r3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5~pyrrolor2,3-g]isoquinolin-lO(lOH)-one;
2-allyl-1,2,3,4,4a,5, 7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta~4,5]pyrrolo[2,3-g~isoquinolin-lO(lOH)-one;
2-cyclopropylmethyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta [4,5]pyrrolo[2,3-g]isoquinolin-lO(lOH)-one;
2-propargyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-lO(lOH)~one;
2-[2-(2-thienyl?ethyl~-1,2,3,4,4a~5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5Jpyrrolo[2,3-g]isoquinolin-lO(lOH)-one;
2-[2-(2-furyl)ethyl]-1,2,3,4,4a,5,~,8,9,10a-decahydro-4a, lOa-trans-6H-cyclopental4,5]pyrrolo~2,3-g]isoquinolin-lO(lOH)-one;
~ 2-r2-(2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)ethyl]-1,2,3, ¦ 4,4a,5,7,8,9,10a-decahydro-4a,1Qa-trans-6H-cyclopenta[4,5]
¦ pyrrolol2,3-g]isoquinolin-lOllOH)-one;
2,[2-(benzyloxy)ethyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-lO(lOH)-one;
~ .
Z2~
, ~
- ~~ 2-(3-phenyl-2-propenyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g~isoquinolin-lO(lOH)-one;
2-~2-(4 fluoro`benzamido)ethyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolol2,3-g]isoquinolin-lO(lOH)-one;
2-[2-(ethenyloxy) ethyl]-1,2,3,4,4a,5,7 r~, 9,10a-decahy~4a,10a-tranS-6~~
cyclopenta[4,5~pyrrolo[2,3-g~ inolin-lO(lOH)-one~
2-benzyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-lO(lOH)-one;
1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclo-penta[4,5]pyrrolo[2,3-g]isoquinolin-lO(lOH)-one;
6-benzoyl-2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-lO(lOH)-one;
2,6-dimethyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolol2,3-g]isoquinolin-lO(lOH)-one;
6-benzyl-2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo~2,3-g]isoquinolin-lO(lOH)-one;
6-methyl-2-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,4,4.a,5,7,8, 9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]-isoquinolin-lO(lOH)-one;
1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta-14,5]pyrrolo 12,3-g]isoquinolin-lO(lOH)-thione;
¦ 2-(2-hydroxy-3,3-dimethylbutyl)-1,2,3,4,4a,5,7,8,9,10a-~ decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolol2~3-glisoquinolin-t lO(lOHl-thione;
j 2-(2-phenylethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-.4a,10a-trans-6H-cyclopenta~4,5]pyrrolo[2,3-g]isoquinolin-lO(lOH)-thione; :-and 2-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,4,4a,5,7,8,9,10a-d~cahydro-4a,10a-trans-6H-cyclopenta~4,5]pyrrolo[2,3-g]isoquinolin-lO(lOH)-thione ~ .
Z2~3 Exemplary of the compounds of formula A wherein n is 4, i.e., compounds of the formula l~ A-2 R2 N~
wherein Rl, R2 and X are as previously described, are:
2-~2-hydroxy-3,3-dimethylbutyl)-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a~trans-lH,6H-cyGlohexa[4,5]pyrrolo[2,3-g3isoquinoi'in-ll(llH~-one;
2-(2-ethoxyethyl)-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa[4,5].pyrrolol2,3-g]isoquinolin-ll(llH)-one;
2-cyclo~utylmethyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,~H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-ll(llH)-one;
2-[2-(2-thienyl)ethyl~-2,3,4,4a,5,7,8,9,10,11a-decahydro- ~.
4a,11a-trans-lH,6H-cyclohexa[4,5~pyrrolo[2,3-g]isoquinolin-ll(llH)-one;
2-[2-(2-furyl)ethyl~-2,3,4,4a,5,7,8,9,10,11a~decahydro-4a,11a-trans-lH,6H-cyclohexa[4,5]pyrrolol2,3-g]isoquinolin-ll(llH~-one;
2-[3-(4-fluorophenyl)-3-oxopropyl]-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa[4,5]pyrrolol2,3-g]i.soquinolin-ll(llH)-one;
2-(2-propenyl) 2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa~4,5]pyrrolo[2,3-g]isoquinolin~ llH)-one;
2-(3-phenoxypropyl~-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa~4,5]pyrxolo[2,3-g]isoquinolin-ll(llH)-one;
2-[3-(2,3-dihydro 2-oxo-lH-benzimidazol-l-yl~propyl]-2,3,4,4a, 5,7,8,9,10,11a decahydro-4a,11a-trans-lH,6H-cyclohexa[4,5]pyrrolo-[2,3-g]isoquinolin-ll(llH)-one;
2-benzyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH, 6H-cyclohexa~4,5]pyrxolo[2,3-g]isoquinolin-ll~llH)-one;
2,3,4,4a,5,7,8,9,10,11a-decahydrp-4a,11a-trans-lH,6H-cyclo-hexa[4,5]pyrrolo[2,3-g]isoquinolin-ll(llH)-one;
Y~ .
;22~ `
2,6 dimethyl-2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-trans-~H,6H-~yclohexaE4,5~pyrrolo[2~3-g1isoquinolin-ll(llH)-one;
6-benzoyl-2-~4 (4-fluorophenyl~-4-oxobutyl]-2,3,4,4a,5,7,8,9, lO,lla-decahydro-4a,11a-trans-lH,6H-cyclohexa~4,5]pyrrolo[2,3-g]-isoquinolin-ll(llH)-one; `s 2-(2-phenylethyl~-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-ll(llH)-thione;
2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclo- .
hexa[4,5pyrroloE2,3-g]isoquinolin-ll(llH)-thione; and -~
2-[4-(4-fluorophenyl)-4-oxobutyl]-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-~
ll(llH)-thione~ y In the compounds o formula A-2 wherein X is O, an alternative nomenclature may be employed. Thus, for example, 2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans~ H-cyclohexa~4,5~pyrrolo [2,3-g]isoquinolin-ll(llH)-one; and -~
2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-pyrido~4,3-b]carbazol-ll(lH,6H~-one are one and the same compound.
Exemplary of the compounds of formula A wherein n is 5, s i.e~, compounds of the formula R2 ~ ) A-3 wherein Rl, R2 and X are as previously described, are:
2-methyl-1,2,3,4,4a,5,7,8,9,10,11,12a-dodecahydro-4a,12a-trans-6H-cyclohepta[4,5]pyrrolo~2,3-g]isoquinolin-12(12H~-one;
, 2-[4-(4-fluorophenyl,~-4-oxobutyl]-1,2,3,4t4a,5,7,8,9,10,11, 12a-dodecahydro-4a,12a-trans-6H-cyclohepta[4,5]pyrrolol2,3-g]-isoquinolin-12(12H)-one;
2-(3-phenoxypropyl)-1,2~3,4,4a,5,7,8,9,10~11,12a-dodecahydro-4a,12a-trans-6H-cycloheptal4,5]pyrrolo[2,3-g]isoquinolin-12(12H)-one;
~t~ - 8 2-(2-phenylethyl~-1,2,3,4,4a,5,7,8,9,10,11,12a-dodecahydro-4a,12a-trans-6H-cycloheptaE4,5~pyrrolol2,3-g~isoquinolin~12(12H)-one;
2-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,3,4,4a,5,7,8,9.10,11, 12a,-dodecahydro-4a,12a-trans-6H-cyclohepta[4,5]pyxrQlo[2,3-g]i quinolin-12(12H)-thione;
2-(3-phenoxypropyl2-1,213,4,4a,5,7,8,9~10,11,12a-dodecahydro-4a,12a-trans-6H-cyclohepta[4,5]pyrrolo[2,3-g]isoquinolin-12(12H)-thione; and 2-(2-phenylethyl~-lf2,3,4,4a,5,7,8,9,10/11/12a-dodecahydro-4a, 10 12a-trans-6H-cycloheptal4/5]pyrrolo~2/3-glisoquinolin~12(12H)-thione.
Exemplary of the compounds of formula A wherein n is 6, i.e., compounds of the formula X
R2 N ~ ~ A-4 wherein Rl, R2 and X are as previously described, are:
2-~4-(4-fluorophenyl)-4-oxobutyl]-2l3,4l4a,5,7,8,9,10,11,12, 13a-dodecahydro-4a,13a-trans-lH,6H-cycloocta[4,5]pyrrolo[2,3-g]iso-quinolin-13(13H)-one;
2-(2-phenylethyl~-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;
2-(2-hydroxy-3,3-dimethylpropyl)-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]iso-quinolin-13(13H)-one;
2-methyl-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-lH,6H-cycloocta[4,5]pyrrolo[2,3-g]isoquinolin-13(13H)-one;
2-(3-phenoxypropyl~-2,3,4,4a,5,7,8,9,10,11,12,13a dodecahydro-4a,13a-trans-lH,6H-cyclooctal4,5]pyrrolo[2~3-g]isoquinolin-13(13H)-one;
2-[4-(4-fluorophenyl)-4-oxobutyl]-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]iso-quinolin-13(13H)-thione;
.
2~(2-phenylethyl)-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-lH,6H-cyclooctal4,5]pyrrolo[2,3-g]isoquinolin-13(13H)-thione;
2-(2-ethoxyethyl)-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)-thione; and 2-(3-phenoxypropyl)-2,3,4,~a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-lH,6H-cycloocta[4,5]pyrrolo[2,3-g]isoquinolin-13(13H)-thione.
The compounds of the invention wherein n is 3 can exist as the 4a,10a-trans or 4a,10a-cis isomers or mixtures thereof; the 4a,10a-trans isomers are preferred.
The compounds of the invention wherein ~ is 4 can exist as the 4a,11a-trans or 4a,11a-cis isomers or mixtures thereof; the 4a,11a-trans isomers are preferred.
The compounds of the invention wherein n is 5 can exist as the 4a,12a-trans or 4a,12a-cis isomers or mixtures thereof; the 4a,12a-trans isomers are preferred.
The compounds of the invention wherein n is 6 can exist as The 4a,13-trans or 4a,13a-cis isomers or mixtures thereof; the ; 4a,13a-trans isomers are preferred.
~ The compounds of the general formula A above, theix optical and geometric isomers and their pharmaceutically acceptabl~ 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 R "- ~ (CH2)n Ia 3~
~l~6~Z;2~3 wherein R"2 is alkyl, alkoxyalkyl or cycloalkylalkyl and n is as previously described, treating a compound of the general formula 2~N I i (C1~2)n I'~
X /~
~ z~
1 wherein R'2 and n are as previously described, 2 with formaldehyde, or
with alkyl, alkoxy and alkanoyl having 1 to 7 carbon atoms, alkenyl and alkinyl having 2 to 7 carbon atoms, cycloalkyl having 3 to 6 carbon atoms and with aryl being phenyl or phenyl bearing one or more substituents selected from the group con-sisting of halogen, txifluoromethyl, alkyl, alkoxy, nitro~
amino, alkylamino and dialkylamino;
optical and geometric isomers of these compounds and their pharmaceutically acceptable 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, ~.
22~
.
methyl, ethyl, propyl, isoprop~l, 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 cyclo-propyl, cyclohexyl, and the like. The term "alkoxy1', 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 - la -., ..~
2f~8 denotes an alkenyl ether group in which the lower alkenyl group is as described above, for example, ethenyloxy, and the like.
The term "alkynyl" preferably denotes "lower alkynyl", which denotes a straight or branched chain unsaturated hydrocarbon con-taining 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 acid 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, 4-3Z2~
. ~
fluorobenzoyl and the like. ~he term ~acyloxy~' denot~san "alkanoyloxy" group derived from an aliphatic carboxylic acid of 1 to 7 carbon atoms, for example, formyloxy, acetoxy, propionyloxy, and the like; and an "arolyloxy" group deri~ed from an aromatic carboxylic acid, such as benzoyloxy and the like. Exemplary of "acylalkyl" are 2-oxo-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 "cycloaLkyl-alkyl" are cyclopropylmethyl, cyclobutylmethyl ~nd the like. Exemplary of "arylcarboxamidoalkyl" are benzamidoethyl and the like.
~xemplary of "aryloxyalkyl" are 3-phenoxypropyl and the like.
Exemplary of "aralkyloxyalkyl" are 2-benzyloxyethyl, 3-benzyloxypropyl and the like. Exemplary of "aryl-N-imida-zolonylalkyl" are 2-(2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)ethyl, 3-(2,3-dihydro-2-oxo-lH~benzimidazol-l-yl)propyl and the like. ~xemplary 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 nalkenyloxyalkyl" are 2-ethenyloxyethyl and the like.
Preferred compounds of formula A are those wherein n is 3, 4, 5 or 6, Rl is hydrogen, R2 is alkyl, hydroxyalkyl arylhydroxyalkyl, alkoxyalkyl, aryloxyalkyl, acylalkyl, or aralkyl; and X is O or S.
More preferred compounds of formula A are those wherein n is 3 or 4, Rl is hydrogen, R2 is alkyl, hydroxyalkyl, arylhydroxyalkyl, alkoxyalkyl, aryloxyalkyl, acylalkyl~ or aralkyl; and X is O.
Most preferred compounds of formula A of the inventi~n are:
2-me~hyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-~a,lOa-trans-6H-cyclopenta[4,5]pyrrolo [2,3-g] i~inolin-10(10~)-one;
~L~613Z~
2-methyl-1,2,3,4/4a,5,7,8,9,10a-decahyaro-4a,10a-trans-6EI-cyclopenta l4,51 pyrrolo [2~3-g]iSOqllinolin-lo(loH)-one hydrochloride, 0.5 molar hydrate;
2-(2-phenylethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta ~4,5~pyrrolo 12,3-g] isoquinolin-lO(lOH)-one;
2- [4-(4-fluorophenyl)-4-oxobutyll-1,2,3,4,4a,5,7,8,9, lOa-decahydro-4a-lOa-trans-6H-cyclopenta 4,5 pyrrolo 2,3 isoquinolin-lO(lOH)-one;
- (-)-2-methyl-1,2,3,4,4a,5,7,8,9 ,lOa-decahydro-~a,lOa-trans-6H-cyclopenta [4,5) pyrrolo 12,3-gl tso~uinolin-lO~lOH)-one;
2-methyl-2,3,4,42-5,7,8,9,10,11a-decahydro-4a,11a-tranq-lH ,6H-cyclohexa [4,5] pyrrolo [2,3-g~ isog~nol~n-ll(l~H)ffne;
2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa [4,5]pyrrolo 12,3-g] isoquin~lin-H~llH)-one, 0.75 molar hydrate;
2-~2-phenylethyl)2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa [4,5] pyrrolo 12,3-g] isoquinolin-ll (llH~-one;
2-[4- (4-fluorophenyl)-4-oxobutyl] -2,3,4,4a,5,7,B,9,10, lla-decahydro-.~a,lla-trans-lE~,6H-cyclohexa[4,5] pyrrolo ~2,3~g 3 isoquinolin-ll(llH)-one; and 2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,~0a~trans-6H-cyclopenta[4,5] pyrrolo ~2,3-g] isoquinolin-lOllOH)-thione.
Exemplary of the compounds of formula A wherein n is 3, i.e., compounds of the fo~nula . X
R~ ~ i,L~ '~ 1~-1 wherein Rl, R2 and X are as previously described arP-` 2-ethyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin lO(lO~t-one;
2-(2-hydroxyethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5~pyrrolo[2,3-glisoquinolin-lO(lOH)-one;
2-(2-hydroxy-2-phenylethyl)-1,2,3,4,4a,5,7y8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5~pyrrolo`[2,3-g]isoquinolin~10(10H)-one;
2-(2-ethoxyethyl~-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta~4,5]pyrrolo~2,3-g]isoquinolin-lO(lOH)-one;
2-(2-acetoxyethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo~2,3-glisoquinolin-lO(lOH)-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-g]isoquinolin-lO(lOH~-one;
2-[2-(.4-methoxyphenyl)ethyl]-1,2r3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5~pyrrolor2,3-g]isoquinolin-lO(lOH)-one;
2-allyl-1,2,3,4,4a,5, 7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta~4,5]pyrrolo[2,3-g~isoquinolin-lO(lOH)-one;
2-cyclopropylmethyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta [4,5]pyrrolo[2,3-g]isoquinolin-lO(lOH)-one;
2-propargyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-lO(lOH)~one;
2-[2-(2-thienyl?ethyl~-1,2,3,4,4a~5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5Jpyrrolo[2,3-g]isoquinolin-lO(lOH)-one;
2-[2-(2-furyl)ethyl]-1,2,3,4,4a,5,~,8,9,10a-decahydro-4a, lOa-trans-6H-cyclopental4,5]pyrrolo~2,3-g]isoquinolin-lO(lOH)-one;
~ 2-r2-(2,3-dihydro-2-oxo-lH-benzimidazol-l-yl)ethyl]-1,2,3, ¦ 4,4a,5,7,8,9,10a-decahydro-4a,1Qa-trans-6H-cyclopenta[4,5]
¦ pyrrolol2,3-g]isoquinolin-lOllOH)-one;
2,[2-(benzyloxy)ethyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-lO(lOH)-one;
~ .
Z2~
, ~
- ~~ 2-(3-phenyl-2-propenyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g~isoquinolin-lO(lOH)-one;
2-~2-(4 fluoro`benzamido)ethyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolol2,3-g]isoquinolin-lO(lOH)-one;
2-[2-(ethenyloxy) ethyl]-1,2,3,4,4a,5,7 r~, 9,10a-decahy~4a,10a-tranS-6~~
cyclopenta[4,5~pyrrolo[2,3-g~ inolin-lO(lOH)-one~
2-benzyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-lO(lOH)-one;
1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclo-penta[4,5]pyrrolo[2,3-g]isoquinolin-lO(lOH)-one;
6-benzoyl-2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-lO(lOH)-one;
2,6-dimethyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolol2,3-g]isoquinolin-lO(lOH)-one;
6-benzyl-2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo~2,3-g]isoquinolin-lO(lOH)-one;
6-methyl-2-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,4,4.a,5,7,8, 9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]-isoquinolin-lO(lOH)-one;
1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta-14,5]pyrrolo 12,3-g]isoquinolin-lO(lOH)-thione;
¦ 2-(2-hydroxy-3,3-dimethylbutyl)-1,2,3,4,4a,5,7,8,9,10a-~ decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolol2~3-glisoquinolin-t lO(lOHl-thione;
j 2-(2-phenylethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-.4a,10a-trans-6H-cyclopenta~4,5]pyrrolo[2,3-g]isoquinolin-lO(lOH)-thione; :-and 2-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,4,4a,5,7,8,9,10a-d~cahydro-4a,10a-trans-6H-cyclopenta~4,5]pyrrolo[2,3-g]isoquinolin-lO(lOH)-thione ~ .
Z2~3 Exemplary of the compounds of formula A wherein n is 4, i.e., compounds of the formula l~ A-2 R2 N~
wherein Rl, R2 and X are as previously described, are:
2-~2-hydroxy-3,3-dimethylbutyl)-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a~trans-lH,6H-cyGlohexa[4,5]pyrrolo[2,3-g3isoquinoi'in-ll(llH~-one;
2-(2-ethoxyethyl)-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa[4,5].pyrrolol2,3-g]isoquinolin-ll(llH)-one;
2-cyclo~utylmethyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,~H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-ll(llH)-one;
2-[2-(2-thienyl)ethyl~-2,3,4,4a,5,7,8,9,10,11a-decahydro- ~.
4a,11a-trans-lH,6H-cyclohexa[4,5~pyrrolo[2,3-g]isoquinolin-ll(llH)-one;
2-[2-(2-furyl)ethyl~-2,3,4,4a,5,7,8,9,10,11a~decahydro-4a,11a-trans-lH,6H-cyclohexa[4,5]pyrrolol2,3-g]isoquinolin-ll(llH~-one;
2-[3-(4-fluorophenyl)-3-oxopropyl]-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa[4,5]pyrrolol2,3-g]i.soquinolin-ll(llH)-one;
2-(2-propenyl) 2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa~4,5]pyrrolo[2,3-g]isoquinolin~ llH)-one;
2-(3-phenoxypropyl~-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa~4,5]pyrxolo[2,3-g]isoquinolin-ll(llH)-one;
2-[3-(2,3-dihydro 2-oxo-lH-benzimidazol-l-yl~propyl]-2,3,4,4a, 5,7,8,9,10,11a decahydro-4a,11a-trans-lH,6H-cyclohexa[4,5]pyrrolo-[2,3-g]isoquinolin-ll(llH)-one;
2-benzyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH, 6H-cyclohexa~4,5]pyrxolo[2,3-g]isoquinolin-ll~llH)-one;
2,3,4,4a,5,7,8,9,10,11a-decahydrp-4a,11a-trans-lH,6H-cyclo-hexa[4,5]pyrrolo[2,3-g]isoquinolin-ll(llH)-one;
Y~ .
;22~ `
2,6 dimethyl-2,3,4,4a,5,7,8,9,10,lla-decahydro-4a,lla-trans-~H,6H-~yclohexaE4,5~pyrrolo[2~3-g1isoquinolin-ll(llH)-one;
6-benzoyl-2-~4 (4-fluorophenyl~-4-oxobutyl]-2,3,4,4a,5,7,8,9, lO,lla-decahydro-4a,11a-trans-lH,6H-cyclohexa~4,5]pyrrolo[2,3-g]-isoquinolin-ll(llH)-one; `s 2-(2-phenylethyl~-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-ll(llH)-thione;
2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclo- .
hexa[4,5pyrroloE2,3-g]isoquinolin-ll(llH)-thione; and -~
2-[4-(4-fluorophenyl)-4-oxobutyl]-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-~
ll(llH)-thione~ y In the compounds o formula A-2 wherein X is O, an alternative nomenclature may be employed. Thus, for example, 2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans~ H-cyclohexa~4,5~pyrrolo [2,3-g]isoquinolin-ll(llH)-one; and -~
2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-pyrido~4,3-b]carbazol-ll(lH,6H~-one are one and the same compound.
Exemplary of the compounds of formula A wherein n is 5, s i.e~, compounds of the formula R2 ~ ) A-3 wherein Rl, R2 and X are as previously described, are:
2-methyl-1,2,3,4,4a,5,7,8,9,10,11,12a-dodecahydro-4a,12a-trans-6H-cyclohepta[4,5]pyrrolo~2,3-g]isoquinolin-12(12H~-one;
, 2-[4-(4-fluorophenyl,~-4-oxobutyl]-1,2,3,4t4a,5,7,8,9,10,11, 12a-dodecahydro-4a,12a-trans-6H-cyclohepta[4,5]pyrrolol2,3-g]-isoquinolin-12(12H)-one;
2-(3-phenoxypropyl)-1,2~3,4,4a,5,7,8,9,10~11,12a-dodecahydro-4a,12a-trans-6H-cycloheptal4,5]pyrrolo[2,3-g]isoquinolin-12(12H)-one;
~t~ - 8 2-(2-phenylethyl~-1,2,3,4,4a,5,7,8,9,10,11,12a-dodecahydro-4a,12a-trans-6H-cycloheptaE4,5~pyrrolol2,3-g~isoquinolin~12(12H)-one;
2-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,3,4,4a,5,7,8,9.10,11, 12a,-dodecahydro-4a,12a-trans-6H-cyclohepta[4,5]pyxrQlo[2,3-g]i quinolin-12(12H)-thione;
2-(3-phenoxypropyl2-1,213,4,4a,5,7,8,9~10,11,12a-dodecahydro-4a,12a-trans-6H-cyclohepta[4,5]pyrrolo[2,3-g]isoquinolin-12(12H)-thione; and 2-(2-phenylethyl~-lf2,3,4,4a,5,7,8,9,10/11/12a-dodecahydro-4a, 10 12a-trans-6H-cycloheptal4/5]pyrrolo~2/3-glisoquinolin~12(12H)-thione.
Exemplary of the compounds of formula A wherein n is 6, i.e., compounds of the formula X
R2 N ~ ~ A-4 wherein Rl, R2 and X are as previously described, are:
2-~4-(4-fluorophenyl)-4-oxobutyl]-2l3,4l4a,5,7,8,9,10,11,12, 13a-dodecahydro-4a,13a-trans-lH,6H-cycloocta[4,5]pyrrolo[2,3-g]iso-quinolin-13(13H)-one;
2-(2-phenylethyl~-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;
2-(2-hydroxy-3,3-dimethylpropyl)-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]iso-quinolin-13(13H)-one;
2-methyl-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-lH,6H-cycloocta[4,5]pyrrolo[2,3-g]isoquinolin-13(13H)-one;
2-(3-phenoxypropyl~-2,3,4,4a,5,7,8,9,10,11,12,13a dodecahydro-4a,13a-trans-lH,6H-cyclooctal4,5]pyrrolo[2~3-g]isoquinolin-13(13H)-one;
2-[4-(4-fluorophenyl)-4-oxobutyl]-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]iso-quinolin-13(13H)-thione;
.
2~(2-phenylethyl)-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-lH,6H-cyclooctal4,5]pyrrolo[2,3-g]isoquinolin-13(13H)-thione;
2-(2-ethoxyethyl)-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)-thione; and 2-(3-phenoxypropyl)-2,3,4,~a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-lH,6H-cycloocta[4,5]pyrrolo[2,3-g]isoquinolin-13(13H)-thione.
The compounds of the invention wherein n is 3 can exist as the 4a,10a-trans or 4a,10a-cis isomers or mixtures thereof; the 4a,10a-trans isomers are preferred.
The compounds of the invention wherein ~ is 4 can exist as the 4a,11a-trans or 4a,11a-cis isomers or mixtures thereof; the 4a,11a-trans isomers are preferred.
The compounds of the invention wherein n is 5 can exist as the 4a,12a-trans or 4a,12a-cis isomers or mixtures thereof; the 4a,12a-trans isomers are preferred.
The compounds of the invention wherein n is 6 can exist as The 4a,13-trans or 4a,13a-cis isomers or mixtures thereof; the ; 4a,13a-trans isomers are preferred.
~ The compounds of the general formula A above, theix optical and geometric isomers and their pharmaceutically acceptabl~ 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 R "- ~ (CH2)n Ia 3~
~l~6~Z;2~3 wherein R"2 is alkyl, alkoxyalkyl or cycloalkylalkyl and n is as previously described, treating a compound of the general formula 2~N I i (C1~2)n I'~
X /~
~ z~
1 wherein R'2 and n are as previously described, 2 with formaldehyde, or
4 b) for preparing a compound of the general formula Ia above, S treating a compound of the general formula a E2"- ~ Xll wherein R2' is as previously described, 11 with a compound of the general formula 12 0 ~
13 H0~` ~ H2)n VII
in the presence of a reducing agent or with a compound of 17 the gen al formula i2)n 19 VI~
or a precursor thereof, in which formulae n is as previously 21 described, or 23 c) for preparing a compound of the general formula 24 l ~2)n Ib ~ 22~a 1 wherein n is as previously described, 2 N-demethylating a compound of the formula Ia above wherein 3 R'2 is methyl, or d) for preparing a compound of the general formula 7 I H2)n IIe wherein R'i is hydrogen, alkyl or aralkyl, R"` is hydrogen, 11 alkyl, alkoxyalkyl, aralkyl, alkenyl, cycloalkyl-alkyl, 12 alkynyl, thienyl-alkyl, furyl-alkyl, alkenyloxyalkyl, 13 aralkenyl, aryloxyalkyl or aralkyloxyalkyl, and n is 14 as previously described, 1~ treating a compound of the general formula ~ ¦ J / 2)n Ie wherein R'i , R'2' and n are as previously described, 21 with phosphorus pentasulfide, or 22 .
23 e) for preparing a compound of the general formula 26 B2 ~ - ~ CH2) zz8 ~ wherein R'2 is alkyl, hydroxya.lkyl, arylhydroxyalkyl, 2 ¦l alkoxyalkyl, acyloxyalkyl, acylalkyl, aralkyl, alkenyl, 3 1l cycloalkyl-alkyl, thienyl-alkyl, alkynyl, :Euryl-alkyl, 4 l! arylcarboxamidoalkyl, aralkenyl, alkenyloxyalkyl,
13 H0~` ~ H2)n VII
in the presence of a reducing agent or with a compound of 17 the gen al formula i2)n 19 VI~
or a precursor thereof, in which formulae n is as previously 21 described, or 23 c) for preparing a compound of the general formula 24 l ~2)n Ib ~ 22~a 1 wherein n is as previously described, 2 N-demethylating a compound of the formula Ia above wherein 3 R'2 is methyl, or d) for preparing a compound of the general formula 7 I H2)n IIe wherein R'i is hydrogen, alkyl or aralkyl, R"` is hydrogen, 11 alkyl, alkoxyalkyl, aralkyl, alkenyl, cycloalkyl-alkyl, 12 alkynyl, thienyl-alkyl, furyl-alkyl, alkenyloxyalkyl, 13 aralkenyl, aryloxyalkyl or aralkyloxyalkyl, and n is 14 as previously described, 1~ treating a compound of the general formula ~ ¦ J / 2)n Ie wherein R'i , R'2' and n are as previously described, 21 with phosphorus pentasulfide, or 22 .
23 e) for preparing a compound of the general formula 26 B2 ~ - ~ CH2) zz8 ~ wherein R'2 is alkyl, hydroxya.lkyl, arylhydroxyalkyl, 2 ¦l alkoxyalkyl, acyloxyalkyl, acylalkyl, aralkyl, alkenyl, 3 1l cycloalkyl-alkyl, thienyl-alkyl, alkynyl, :Euryl-alkyl, 4 l! arylcarboxamidoalkyl, aralkenyl, alkenyloxyalkyl,
5 1 aryloxyalkyl, aralkyloxyalkyl or aryl-N-imidazolonylalkyl
6 and X and n are as previously described, substituting a compound of the general formula 10 ~ H - ~ CH2)n A b 11 wherein X and n are as previoùsly described, 12 at the isoquinoline nitrogen atom, or 14 f) for preparin~ a compound of the general formula VT ~ ~
16 ~2- ~ ~ CH2)n A'c 18 1' 19 wherein R'1 is alkyl, acyl or aralkyl, RV2I is alkyl, alkoxyalkyl, acyloxyalkyl, acyl, aralkyl, alkenyl, 21 cycloalkyl-alkyl, thienylalkyl, alkynyl, furylalkyl, 22 arylcarboxamidoalkyl, aralkenyl, alkenyloxyalkyl, 23 aryloxyalkyl, aralkyloxyallcyl or aryl-N-imidazolonylalkyl 24 and X and n are as prevlously described, substituting a compound of the general formula 26 VI ~ CH2~ d' . .
-l~ , wherein R2 ~ X and n are as previously described, 2 I at the py.rrole nitrogen atom, or ~ l l 4 I g) for preparing a xcompound of the general formula 6 I (CH2ln Ac"
9 wherein R2V is hydroxyalkyl or arylhydroxyalkyl, and Ri, X and n are as previously described, ll splitting off the protecting group in a compound of the general formula X
12 R2 ~ CH2)n XIV
Rl 16 wherein R2 is an O-protected hydroxyalkyl- or aryl-17 hydroxyalkyl-group and Ri, X and n are as previously 18 described, 19 or .
21 h) for preparing a compound of the general formula 22 Rz~ 2)n Ad 26 wherein R2 ~ X and n are as previously described, I
28 r ucing the acylalkyl group in a compound of the general for~ula 3 ~
j2 , . ~ - 15 _ I
Z~
~ ~! X
2 ~ VII~ ~ ~)n ~d ll 4 ! I
.
6 ¦ wherein R2II is acylalkyl, and X and n are as previously
16 ~2- ~ ~ CH2)n A'c 18 1' 19 wherein R'1 is alkyl, acyl or aralkyl, RV2I is alkyl, alkoxyalkyl, acyloxyalkyl, acyl, aralkyl, alkenyl, 21 cycloalkyl-alkyl, thienylalkyl, alkynyl, furylalkyl, 22 arylcarboxamidoalkyl, aralkenyl, alkenyloxyalkyl, 23 aryloxyalkyl, aralkyloxyallcyl or aryl-N-imidazolonylalkyl 24 and X and n are as prevlously described, substituting a compound of the general formula 26 VI ~ CH2~ d' . .
-l~ , wherein R2 ~ X and n are as previously described, 2 I at the py.rrole nitrogen atom, or ~ l l 4 I g) for preparing a xcompound of the general formula 6 I (CH2ln Ac"
9 wherein R2V is hydroxyalkyl or arylhydroxyalkyl, and Ri, X and n are as previously described, ll splitting off the protecting group in a compound of the general formula X
12 R2 ~ CH2)n XIV
Rl 16 wherein R2 is an O-protected hydroxyalkyl- or aryl-17 hydroxyalkyl-group and Ri, X and n are as previously 18 described, 19 or .
21 h) for preparing a compound of the general formula 22 Rz~ 2)n Ad 26 wherein R2 ~ X and n are as previously described, I
28 r ucing the acylalkyl group in a compound of the general for~ula 3 ~
j2 , . ~ - 15 _ I
Z~
~ ~! X
2 ~ VII~ ~ ~)n ~d ll 4 ! I
.
6 ¦ wherein R2II is acylalkyl, and X and n are as previously
7 I described, or
8 ~ i) for preparing a compound of the general formula 11 ~ ~"~
13~
5 l wherein X, n and Ri are as previously described, 16 ¦ splitting off the urethane group in a compound of the general 17 ~ ,formula ~ .
19 ~ y ~ ~ CH~) XIII
22 ~ 11 23 wherein X, n and Ri are as previously described and Y
is a urethane group, 24 and j) if desired, isomerizing the mixture of the cis and trans 26 isomers obtained to a final ratio which comprises predominantly 27 ~ the trans isomer , andfor .
~3L61~ZZ~}
~ l k) if desired, separating the trans isomer from the mixture 2 ~ obtained, and/or 3 i ~ l l) if desired, resolving a racemic mixture obtained into the ¦ optical antipodes and/or 7 ~) if desired, converting a compound obtained or a non-8 pharmaceutically acceptable acid addition salt into a pharma-
13~
5 l wherein X, n and Ri are as previously described, 16 ¦ splitting off the urethane group in a compound of the general 17 ~ ,formula ~ .
19 ~ y ~ ~ CH~) XIII
22 ~ 11 23 wherein X, n and Ri are as previously described and Y
is a urethane group, 24 and j) if desired, isomerizing the mixture of the cis and trans 26 isomers obtained to a final ratio which comprises predominantly 27 ~ the trans isomer , andfor .
~3L61~ZZ~}
~ l k) if desired, separating the trans isomer from the mixture 2 ~ obtained, and/or 3 i ~ l l) if desired, resolving a racemic mixture obtained into the ¦ optical antipodes and/or 7 ~) if desired, converting a compound obtained or a non-8 pharmaceutically acceptable acid addition salt into a pharma-
9 ceutically acceptable acid addition salt thereof.
11 More specifically, the compounds of formula A above, their 12 optical and geometric isomers and their pharmaceutically accep-table acid addition salts as well as various intermediates there-13 for can be prepared as illustrated hereinbelow in more detail.
Thus, for example, the compounds of formula A wherein X
16 is O are characterized by the ~ormula 19 J~
21 R2 - N ~ ~ C~2)n 22 .~ Rl wherein n, R1 and R2 are as hereinbefore described, 26 and can be prepared as set forth in Schemes I, II, III and 27 IV and further described.
3l - ~6~Z~8 FORMULA-SCHEME I
2 \ N ~ ~
R ~ ~ HON ~ ~ H2~n , VI VIII
/
R '' (CH2~ CH2)n IX Ia H
wherein n is as previously de~cribed, and R2" is alkyl, alkoxyalky, or cycloalkyl-alkyl.
/~
X
%~
In accordance with Formula Scheme I, c~mpounds of formula Ia are prepared from known compounds of formula IV wherein R2" is alkyl, alkoxyalkyl or cycloalkylalkyl. Birch reduction of the amine of formula IV with lithium in ammonia containing t-butanol yields the dihydroamine of formula V. Other modifications of the Birch reduction may also be employed. Thus, the amine of formula IV may be reacted with an alkali metal, such as sodium, lithium, potassium or cesium, in ammonia or an amine such as methylamine or ethylamine in the presence of a lower alkanol such as ethanol, ¦ 10 butanol, or t-butanol. The reaction is generally carried out at ! the boiling point of the solvent or below, for example, from -78 to 15C. If ammonia is used, the reaction is run at reflux.
Optionally, cosolvents such as diethyl ether or tetrahydrofuran may be added.
The hydrolysis of the dihydroamine of formula V`is readily accomplished by the usual methods for hydrolysis of enol ethers, for example, with aqueous acid. Exemplary of acids which may be used are hydrochloric acid, hydrobromic acid, formic acid, acetic acid, p-toluenesulfonic acid and-perchloric acid. These may be used in aqueous solutions or mixed solvents. Tetrahydrofuran, benzene, ~ diethyl ether, acetone, toluene, dioxane or acetonitrile are j exemplary of the solvents which may be employed. For example, i, -hydrolysis of the dihydroamine of formula V wherein R2" is methyl in d 2N hydrochloric acid at room temperature or above or in aqueous ~` 25 acetic acid at between 40 and reflux leads to the diketone of formula VI, wherein R2" is methyl.
i .
, ,~
f~2~ .
The diketone of formula VI is condensed in a Knorr condensation to give the methylaminoethyl ketone o~ formula IX. The Knorr condensation is a well-known method ~or 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, 281 ~1976) and references therein~. For example, the reaction of an isonitrosoketone of formùla VII ln the presence of a reducing agent, for example with zinc in aqueous acetic acid of hydrochloric acid, is thought to proceed via t~e 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 amino-aarbonyl 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 K~orr condensation is best carried out at a pH of from about pH 2 to pH6. 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 R~" is methyl to give the product methylaminoethyl ketone of formula IX ~herein R2" is methyl.
~0 The Knorr condensation is preferably carried out at a temperature range of from about room temperature to reflux.
The isoitrosoketones of formula VII are known ~unds or can readily be prepared by nitrosation of the corresponding ~ -ketoester, for example, with sodium nitritè. [see, for example, T.A.
Geissman and M. J. Schlatter, J.- Org. _em., 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-i~onitrosocyclooctanone.
Exemplary of aminocarbonyl precursor compounds of formula VIII which can be used in the Knorr condensation are:
2-aminocyclohexanone, hydrochloride;
2-aminocyclopentanone, hydrochloride;
2-aminocycloheptanone, hydrochloride; and 2-aminocyclooctanone, hydrochloride.
Said o~x~nds are known or may be prepared by reduction of the corresponding isonitrosoketone, for example, by catalytic hydrogenation in the presence of hydrogen chloride.
2Zt3 The amine of the formula IX is converted to the compound of the formula Ia via an intramolecular Mannich reaction. The Mannich reaction is usually performed starting with a ketone and a dialkylamine salt, for example, dimethylamine hydrochloride and formaldehyde (for example, as an a~ueous solution, as paraformalde-hyde 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 methylaminoethyl-ketone 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-methylpyrrolidinone or diethylene glycol dimethyl ether, a lower boiling polar solvent, such as ethanol, butanol or 2-propanol, under pressure; or a lower boiling aprotic solvent under pressure, such as dioxane or tetrahydrofuran, may be used at a temperature in the range of from about 135C. to about 200C. to yield the cycloalka[4,5~pyrrolo~2,3-g]isoquinolines of formula Ia. The reaction, especially when run at temperatures below 150C. leads to a mixture of cis and trans isomers, i.e., for example, when R2" is methyl, compounds of the formulas L ~ Z~8 CH3 ~ )n tranS H
If' C~3~ ~ (C~2)n N
H H
Ig.~ cis Longer heating of the reaction mixture o~ separate heating of the isomeric mixture of hydrochlori~e salts of formulas If' and Ig', 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 isomers, which is readily isolated by crystallization or by chromatographic separation.
For example, when the hydrochloride salt o the amine of formula IX wherein R2" is methyl is reacted with paraformaldehyde in butanol at 180 for 2 hours, the product is isolated as.the trans isomer If'.
z~
FORMULA SCHEME I I
.
~ ~ ~ r;l,c~l2)n Ia C2350-C-N ~ ~ ~ (C}~2)n ~ ¦ 1" )n ~ - c2H50 g ~ ~ r, ~-2)n Ib H 11 3-~ ~2 ) n Ih wherein n is as previously described, and Rl' is alkyl, acyl or aralkyl.
/ ~ 2 4 -22~
In accordance with Formula Scheme II, compounds of formul~
Ic are prepared by alkylation or acylation of the pyrrole nitrogen of a compound of formula Ia' and other N-2-alkyl derivatives by forma-tion of the pyrxole anion with strong base, for example, sodium 1 5 amide, potassium hydride, sodium methylsulf~nyl carbanion, potassium j t-butoxide, or butyllithium, or with an alkali metal, followed by quenching with an alkyl or acyl halide in a solvent such as tetra-hydrofuran, dioxane, ethyl ether, dimethylformamide or dimethylsul-foxide. For example, treatment of a compound of formula Ia', wherein lQ n is 3 with potassium t-butoxide in tetrahydrofuran followed by quenching with methyl iodide affords the 6-methyl derivative, i.e., a compound of formula Ic wherein n is 3 and Rl' is methyl. Similarly, reaction of a compound of formula Ia', wherein n is 4 with butyl-lithium in tetrahydrofuran ab -30 followed by quenching with benzoyl chloride affords the 6-benzoyl derivative, i.e., a compound of formula Ic wherein Rl' is benzoyl and n is 4. S;milarly, reaction of a compound of formula Ia', wherein n is 3, w;th sodium methylsulfinyl carbanion in dimethylsulfoxide followed by quenching with benzyl chloride affords the 6-benzyl derivative, i.e., a compound of formula Ic wherein R1' is benzyl and n is 3.
N-Demethylation of the compound of formula Ia' can be accom-plished by standard N~dealkylation procedures, such as ~he von Braun method ~H.A. Hageman, Org. Reactiohs, 7, 198 (1953)], or via acid or base hydrolysis of a urethane derivative such as those listed in K. C. Rice [J. Org. Chem., 40, 1850 ('1975)]. One procedure for the dealkylation of the compound of formula Ia' is via the urethane of formula XIIIa and acid hydrolysis to give the secondary amine of formula Ib. For example, a compound of formula Ia', 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. Hydrolysis of the foregoing compound with 30%
aqueous sodium hydroxide in ethanol-dioxane at reflux for 24 hours gives the compound of formula Ib, wherein n is 4.
zz~
Urethane derivatives may also be employed as star~ing materials for the preparation of pyrrole-ring substituted derivatives by alkyla-tion or acylation at the pyrrole nitrogen, followed by cleavage of the urethane. The alkylation or acylation is carried out following the pro~res givan for the preparation of compounds of formula I'c, and the urethane derivatives and procedures for their cleavage are g.~ven, as mentioned above, in K.C. Rice (ibid). For example, in accordance with Formula Scheme II, treatment of the ethoxycarbonyl urethane of formula XIIIa wherein n is 4 with sodium methylsulfinyl carbanion in dimethylsulfoxide, followed by treatment with benzyl chloride, affords the compound of formula XIIIb wherein n is 4 and Rl' is benzyl. Hydrolysis with sodium hydroxide affords the 6-benzyl derivative, i.e., a compound of the formula Ih wherein ~! is benzyl and n is 4. In cases ~here ~' is an acyl group which could be hydrolyzed under vigorous alkaline or strongly acidic conditions, a urethane group such as 2,2,2,-trichloroethyoxycarbonyl, which may be cleaved under mild conditions with zinc in aqueous acetic acid, may be ~,~loyed to give compounds of formula m wherein ~' is acyl.
FORMULA SCHEME III
N-N ~ H ~ H2)n Ib R ' 2 \ (CH2)n Id ¦ H
2 \ N ~ ! (C~2)n Ic ; - 26 -z~
wherein n is as previously described, and Rl' is alkyl, acyl, or aralkyl, and R2' is alkyl, hydroxy-alkyl, arylhydroxyalkyl, alkoxyalkyl, acyloxyalkyl, acylalkyl, aralkyl, alkenyl, cycloalkyl-alkyl, thienyl-alkyl, alkynyl, furyl-alkyl, arylcarboxamido-alkyl, aralkenyl, alkenyloxyalkyl, aryloxyalkyl, aralkyloxyalkyl, or aryl-N-im;dazolonylalkyl.
In accordance with Formula Scheme III, the compounds of formulas Id and Ic are prepared from the secondary amine of formula Ib, the s~ting material for the preparation of numerous derivatives encom-passed by formula I, by substitution at the basic amine nitrogen (N-2) andfor the pyrrole n;~trogen ~N~6). For example, treatment of a compound of formula Ib with an alkyl halide, such as ethyl bromide, an alkenyl halide, such as allyl bromide, a cycloalkyl-alkyl halide, such as chloromethylcyclopropane, an aralkyl halide, such as benzyl bromide, or an acylalkyl halide such as ~ -chloro-p-fluorobutyro-phenone, in the presence of a base, for example, potassium carbonate, in acetone, 2-propanone or dimethylformamide, yields the correspond-ingly substituted compound o formula Id, that is, wherein R2' is alkyl, alkenyl, cycloalkyl-alkyl, aralkyl, or acylalkyl, respectively.
With reactive halides, the reaction may be run at room temperature;
with less reactive halides, refulx temperatures are used, and in - some cases, the reaction rate can be enhanced by the addition of an iodide salt, such as l;thium iodide, to the reaction mixture.
Reaction of a compound of formula Ib with epoxyalkanes gives the hy~roxyalkyl substituted compound of formula Id. Treatment with a substituted epoxyalkane gives the 2-substituted-2-hydroxyalkyl analogs of a compound of formula Id, for example, reaction of a compound of formula Ib with styrene oxide gives a compound of formula Id, wherein ~2' is 2-phenyl-2-hydroxyethyl. The reaction is usually carried out in the presence o an alcoholie solvent such as methanol, at from about room temperture to the reflux temperature of the zz~
mixture. The epoxyalkanes are either commercially available or are prepared by epaxidation 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 cases, where R2' in the compound of formula Id does not contain functional groups capable of undergoing alkylation or acylation, the procedures outlined in Formula Scheme II for the preparation of compoundsof formula Ic can be used directly to prepared N-6 substituted analogs of formula Ic as depicted in Formula Scheme III. Alkylations can occur in compounds wherein R2' is hydroxyalkyl or arylhydroxyalkyl. The hydroxyl groups therein must be protected with a base-stable protecting group, such as tetrahydropyranyl.
After N-6 alkylation, the protecting group is removed by acid hydrolysis.
Alternatively, compounds of formula Id, wherein R2' is hydroxyalkyl or aryl hydroxyalkyl may be prepared by reduction of the corresponding compounds of formula Id where~n R2' is acylalkyl.
More particularly, the foregoing reduction may be carried out, for example, with an alkali metal borohydride reducing agent, such as sodium borohydride or lithium borohydride at, for example, room temperture in a solvent, for example, an alkanol, such as ethanol, or~the like.
In the reactions described in Formula Schemes I, II and III, both the trans isomers of the formula \ ~ 2)n If H ~1 wherein n, Rl and R2 are as previously described, and cis isomers of the formula ~2\ 2)~ Ig Rl wherein n, Rl and R2 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 chromato-graphy or crystallization. In addition, the mixture may beisomerized as descrlbed for the isomerization of the trans and cis isomers of the-oxo compound of formula If' and Ig', or by base-catalyzed equilibration, for example, with sodium hydroxide in ethanol.
When the substituent groups Rl and R2 in compounds of the formula:I contain additional asymmetric centers, a m~xture of diastereomers may be obtained. For example, the number of isomers possible is 2n wherein n is the t~tal number of asymmetric centers in the compound. Preferred are the enantlomers and/or diasteromers of compound of the formula If, hereinbefore described.
~6~;228 - FO~MULA SCHEME IV
R2 ~ OC ~ R " - ~ OCH3 IV / X
TH3 ~/
R " N ~ XI
/
R2 ~ N ~ ,~
~ O HON or ~ 2)n R " N ~ ~ H2)n Ia wherein n is as previously described, and R2" is alkyl, alkoxy-alkyl, or cycloalkyl-alkyl.
2~1~
An alternative synthesis of the compounds of formula Ia is described in Formula Scheme IV, in which the isoquinoline ring is formed prior to the formation of the pyrrole ring. In accordance with Formula Scheme IV, the (3,5-dimethoxyphenyl)-ethylamine of formula IV is refluxed with aqueous formaldehyde to giv~ the tetra-hydrosioquinoline of formula X. Birch reduction of the tetrahydro-isoquinoline 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 hexahydro-isoquinoline of formula XI. Hydrolysis of crude hexahydroisoquinolineof 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 ~he preparation of the methyl-aminoethyl ketone of formula IX with the isonitrosoketone of formulaVII or with the aminocarbonyl o~x~nd of formula VIII to give the cycloalka[4,5]pyrroloisoquinoline of formula Ia. Preferred is the sequence of reactions in accordance with Formula Scheme IV starting with the amine of formula IV, wherein R~" is methyl, giving the corresponding N-methyl-cycloalka[4,5]pyrroloisoquinoline of formula Ia, as a mixture containing the trans isomer If' and the cis isomer of formula Ig'.
The same procedures for isomerization of the mixture of cyclo-alka[4,5]pyrroloisoquinolines of formulas If and Ig as described previously may be employed to yield mainly the trans isomer of formula If'.
X ~/
Z215~
The compounds of formula A wherein X is S are characterized by the formula N 1 ~ 2)n ~ II
Rl wherein n, Rl and R2 are as hereinbefore described, and can be prepared as set forth in Formula Schemes V and VI, and further described hereinafter.
ZZ~
FORMULA SCHEME V
\ N ~
~ N / ~ Ie ~ 23n Iie wherein n is as previously descriked; Rl" is hydrogen, alkyl, or aralkyl; and R2"' is hydrogen, alkyl, alkoxyalkyl, aralkyl, alkenyl, aryloxyalkyl, thienylalkyl, furyl-alkyl, alkynyl, aralkenyl, alkenyloxyalkyl, aralkyloxyalkyl or cycloalkyl-alkyl.
22~3 In accordance with Formula Scheme V, compounds of formula IIe are prepared by heating compounds of formula Ie with phosphorus pentasulfide 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 VI. In accordance with Formula Scheme VI, a compound of formula IIb is reacted to give a compound of formula IId following the procedures detailed in Formula Scheme III for the preparation of the corresponding oxo compounds o~ ormula Id.
~.~L~Z28 FO~MULA SCHEME VI
S~2)n IIb H
r ' IId 2 ~ ~--~ 2 ~ n I I c wherein n, Rl' and R21 are as previously described.
X ~
Z2~3 Similarly, a compound of formula IId is reacted to give a compound of formula IIc following the procedures outlined in Scheme III for the preparation of the corresponding oxo compounds of formula Ic.
Additional compounds of formula II are prepared following the procedures detailed in Formula Scheme II for the preparation of corresponding oxo compounds of formula Ih.
In these reactions, both the trans isomers of the formula 2 (CN2)n IIf wherein n, Rl and R2 are as previously described, and cis isomers of the formula Rl IIg wherein n, Rl and R2 are as previously described, - 3~
~L~6(~Z8 of the compounds of formula II may be formed, with the trans isomer predominating. The pure trans isomer may be separated by chromato-graphy 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 Igl.
As described above for compounds of formula I, when substituent groups Rl and R2 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 IIf, hereinbefore described.
The compounds of formula A form acid addition salts with inorganic or organic acids. Thus, they form pharmaceutically accept-able acid addition salts with both pharmaceutically acceptable organic and inorganic acids, for example, with hydrohalic acid, such as, hy~x~
lS chloric acid, hydrobromic acid, hydroiodic acid, other mineral acid salts, such as sulfuric acid, nitric acid, phosphoric acid, or the like, alkyl- and mono-aryl sulfonic acids, such as ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acidr 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 accep~able acid addition salts ol compounds of for~ula A can be converted into pharmaceutically accept-able acid addition salts via conventional metathetic reactions wherehy the non-pharmaceutically acceptable anion is replaced by a pharmaceutically acceptable anion, or alternatively, by neutraliz-ing 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 form hydrates.
The compounds of the general formulae IX and XIII are novel and also form part of the present invention.
~6~213 The compounds of ~ormula A and their pharmaceu~ically acceptable acid addition salts exhibit neuroleptic activity. Accordingly, -the compounds of formula ~ are use~ul as antipsychotic agents, for instance, in the treatment of schizophrenia. The activity of the compounds of formula A which makes them use~ul as antipsychotic agents can be demonstrated in warm-blooded animals, in accordance with known procedures.
For example, by one procedure, trained rats are placed in experimental chambers equipped with a response lever, a steel grid floor for delivery of electric shock and a loudspeaker for presenta-tion of auditory stimuli. Each trial consists of a fifteen-second warning tone, (conditioned stimulus), continuing for an additional fifteen seconds accompanied by electric shock (unconditioned stimulus;
1.0 mA, 35~ ~.A.C.). The rats can terminate a trial at any point by depression of the response lever. A response during the initial fifteen-second warning tone ends the trial before shock delivery and is considered an avoidance response, while a response occurring during shock delivery is an escape response. Trials are pres~nted every - two minutes during a one-hour test session (30 trials per session).
Trained rats maintain a xeliable control baseline of avoidance - behavior (zero to three avoidance failures per session). Compounds are administered at appropriate pretreatment times to a minimum o~
three to four rats at each dose level over a range of doses. ~ats receive ~ehicle alone, during control sessions. One control and one experimental session are alternated during each weekD
The session is divided into three consecutive twenty minute ~ten trial) segments. Response counts are summed over all subjects at a given dose within each segment.
)~ ~8 ~ 16~D2Z8 The number of trials in which the rats failed to exhibit an avoidance response (avoidanse block; AB) or failed to exhibit an escape response (escape block; EB) is determined for the segment displaying the maximum such effect at each dose. Thi~ number is expressed as a percentage of the total trials within the segment.
The dose calculated to produce a 50% block of avoidance (A~D 50) is obtained from the dose effect regression line fitted by the Method of Least Squares. The lowest dose which produced a 20~ block of escape responding (EBD 20) is read from a graphic dose-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 affect the behavior of rats in this procedure, by the larger separation between doses which block avoidance responding and doses which block escape responding. The clinical potency of antipsychotic drugs with known therapeutic uses and properties is significantly and highly correlated with their potency in this pro-cedure. Consequently, the compounds of formula A may be used therapeutically in dosage ranges consistent with their potency in the test procedureO
X ~
~:~6~Z~8 When 2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5~pyrrolo[2,3-g~isoquinolin-lO(lOH)-one is utilized as the test substance, neuroleptic activity is observed at an ABD50 of 0.98 mg/kg p.o.
Similarly, when 2-[4-(4-fluorophenyl~-4-oxobutyl]-1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta~4,5]pyrrolot2,3-g]-isoquinolin-lO(lOH)-one is utilized as the test substance, neuroleptic activity is observed at an ABD50 of 0.15 mg/kg p.o.
Similarly, when 2-[4-(4-fluorophenyl)-4-oxobutyl]-2,3,4,4a,5, 7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa[4,5]pyrroloE2,3-g]-isoquinolin-ll(llH)-one is utilized as the test substance, neuroleptic activity is observed at an ABD50 o 0.73 mg/kg p.o.
Similarly, when 2-methyl-2,3,4,-4a,5,7,8,9,10,1la-decahydro-4a,11a-trans-lH,6H-cyclohexar4,5]pyrrolo[2,3-g]isoquinolin-ll,(llH)-one, hydrochloride, Q.75 molar hydrate, which has demonstrated an LD50 of~ for example, 650 mg/kg p~o. in mice, is utilized as the test substance, neuroleptic activity is observed at an ABD50 f 5.5 mg/kg p.o.
Similarly, when 2-methyl-2,3,4,4a,5,7,8,9,10,11,12,13a-dod~ca-- 20 hydro-4a,13a-trans-lH,6H-cyclooctal4,5]pyrrolo[2,3-g]isoquinolin-13(13H)-one is utilized as the test substance, neuroleptic activity is observed at 8 mg/kg p.o~ where the avoidance blockade is 63%o Similarly, when 2-methyl-1,2,3,4,4a,5,7,8,9,10,11, 12a-dodeca-hydro-4a,12a-trans-6H-cyclohepta~4,5]pyrrolo~2,3-g~isoquinolin-12(12H)-one is utilized as the test substance, neuroleptic activity is observed at 16 mg/kg p.oO where ~he avoidance blockade is 50~0 -The compounds of formula A and their pharmaceutically accept-able acid addition salts have antipsychotic effects which are quali-tatively similar to those of haloperidol, and trifluoroperazine, h~ for their therapeutic uses and properties~ Thus, the compounds of formula A demonstrate a pattern of activity associated with anti-psychotic drugs of known ef~icacy and safety~
The compounds of formula A and their pharmaceutically acceptable acid sddition salts can be used in the form of conventional pharma-ceutical preparations. By way of exemplification, suitable oral dosage units comprise or are in the range of from 0.05 to 50 mg., and suitable oral dosage regimens in warm-blooded animals comprise or are in the range o~ 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 should be adjusted according to individual need and the professional judgment of the person administering or supervising the administration of a compound of formula A or a pharmaceutically acceptable acid addition salt thereof. Furthermore, the frequency with which any such dosage form will be administered will vary, depending upon the quantity of active -20 medicament present therein and the needs and requirements of the pharmacological situation.
X Y~
" ~:L6~Z;~8 For the disclosed use, the compounds of formula A and their pharmaceutically acceptable acid addition salts are formulated, using conventional inert pharmaceutical adjuvant materials, into dosage forms which are suitable for oral or parenteral administration. Such dosage forms include tabletsl suspensions, solutions, and the like.
Furthermore, the compounds of formula A can be embodiecl into, and administered in the form of, suitable hard or soft capsules. The identity of the inert adjuvant materials which are used in formulating the compounds of formula A and their pharmaceutically acceptable acid addition salts into oral and parenteral dosage forms will be immediately apparent to persons skilled in the art. These adjuvant materials, either inorganic or organic in nature, include, for example, water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols, etc. Moreover, perservatives, stabilizers, wetting agents, emulsifying agents, salts for altering osmotic pressure, buffers, or the like, can be incorporated, if desired, into such formulations.
Since the compounds of formula A and their pharmaceutically acceptable acid addition salts possess asymmetric carbon atoms, they are ordinarily obtained as racemic mixtures. I~ desired, diastereomeric mixtures, when obkained, may be separated. The resalution of individual racemates into the optically active isomers can be carried out by known procedures. Alternatively, optically active isomers can be prepared utilizing, in the processes herein described, corresponding optically active starting materials. Some racemic mixtures can be precipitated as eutectics and can thereafter be separated. Chemical resolution is, howe~er, preferred. By this method, diasbereomers are formed from the racemic mixture with an optically active resolving agent, for example, an optically active acid, such as t~)-tartaric acid, ~+~-dibenzoyl-D-tartaric acid, (~)-d-10-camphor-sulfonic acid, ~ 3-pinanecarboxylic acid, and the like, to form a diastereomeric salt. The formed diastereomers are separated by fractional crystallization and can be converted to the corresponding optical isomer base. Thus, the invention covers the optically active isomers of the compounds of formula A as well as their racemates.
22~
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 than one possible geometric isomeric form. The compounds of formula A, as described and claimed, are intended to embrace all such isomeric forms. Accordingly, the examples included herein are to be understood as illustrative of particular mixtures of geometric isomers or single geometric isomers and not as limitations upon the scope of the invention.
The Examples which follow further illustrate the invention.
All temperatures are in degrees Centigrade, unless otherwise stated.
~6~28 Example 1 Preparation of N-methyl-1,5-dimethoxycyclohexa-lr4-diene-3-ethylamine 185.2 g. of N-methyl-(3,5-dimethoxyphenyl)-ethylamine hydro-chloride 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 condensersr one fitted with a gas inlet and th~ othe~
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 minutes.
After all the lithium had 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 280 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 layers were separated. The aqueous layer was extracted with 2 x 1.5 1. of di-chloromethane and the extracts were combined and washed with 1 1.
of brine and dried over anhydrous sodium su1fate. 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:
~e 2;2~3 Fraction _ wt gc purity 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/~.15 mm. 21.2 g. 92%
4 ~6-87/~.15 mm. 99.4 g. 100%
Fractions 3 and 4 combined afforded 120.6 g. of N-methyl-1,5-dimethoxycyclohexa-1,4-diene-3-ethylamine as a colorless oil.
Anal. Calcd. for CllHlgNO2: C, 66.97; H, 9.71; N, 7.10 Found: C, 66.84; H, 9.62; N, 6.93 ~L6~Z2~3 Example 2 Prepara~ion of 1,2,3,5,6,7,8,9-octahydro-20[2 (methylamino)ethyl]-4H-carbazol-4-one A mixture of 15.6 g. of N-methyl~1,5-dimethoxycyclohexa-1,4-diene-3-ethylamine (79 mmol), 16.7 g. of 2-isonitrosocyclohexanone (131 mmol), and 10.5 g. of zinc dust (300 mg-atom) in 300 ml. of 70~
aqueous acetic acid heated to reflux for 5 hours, and was cooled and filtered. The filtrate was concentrated in vacuo and excess dioxane was added. The dioxane-acetic acid azeotrope was distilled off and the process was repeated until all the acetic acid was re-moved. The residue was chromatographed on Alumina III eluting with
11 More specifically, the compounds of formula A above, their 12 optical and geometric isomers and their pharmaceutically accep-table acid addition salts as well as various intermediates there-13 for can be prepared as illustrated hereinbelow in more detail.
Thus, for example, the compounds of formula A wherein X
16 is O are characterized by the ~ormula 19 J~
21 R2 - N ~ ~ C~2)n 22 .~ Rl wherein n, R1 and R2 are as hereinbefore described, 26 and can be prepared as set forth in Schemes I, II, III and 27 IV and further described.
3l - ~6~Z~8 FORMULA-SCHEME I
2 \ N ~ ~
R ~ ~ HON ~ ~ H2~n , VI VIII
/
R '' (CH2~ CH2)n IX Ia H
wherein n is as previously de~cribed, and R2" is alkyl, alkoxyalky, or cycloalkyl-alkyl.
/~
X
%~
In accordance with Formula Scheme I, c~mpounds of formula Ia are prepared from known compounds of formula IV wherein R2" is alkyl, alkoxyalkyl or cycloalkylalkyl. Birch reduction of the amine of formula IV with lithium in ammonia containing t-butanol yields the dihydroamine of formula V. Other modifications of the Birch reduction may also be employed. Thus, the amine of formula IV may be reacted with an alkali metal, such as sodium, lithium, potassium or cesium, in ammonia or an amine such as methylamine or ethylamine in the presence of a lower alkanol such as ethanol, ¦ 10 butanol, or t-butanol. The reaction is generally carried out at ! the boiling point of the solvent or below, for example, from -78 to 15C. If ammonia is used, the reaction is run at reflux.
Optionally, cosolvents such as diethyl ether or tetrahydrofuran may be added.
The hydrolysis of the dihydroamine of formula V`is readily accomplished by the usual methods for hydrolysis of enol ethers, for example, with aqueous acid. Exemplary of acids which may be used are hydrochloric acid, hydrobromic acid, formic acid, acetic acid, p-toluenesulfonic acid and-perchloric acid. These may be used in aqueous solutions or mixed solvents. Tetrahydrofuran, benzene, ~ diethyl ether, acetone, toluene, dioxane or acetonitrile are j exemplary of the solvents which may be employed. For example, i, -hydrolysis of the dihydroamine of formula V wherein R2" is methyl in d 2N hydrochloric acid at room temperature or above or in aqueous ~` 25 acetic acid at between 40 and reflux leads to the diketone of formula VI, wherein R2" is methyl.
i .
, ,~
f~2~ .
The diketone of formula VI is condensed in a Knorr condensation to give the methylaminoethyl ketone o~ formula IX. The Knorr condensation is a well-known method ~or 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, 281 ~1976) and references therein~. For example, the reaction of an isonitrosoketone of formùla VII ln the presence of a reducing agent, for example with zinc in aqueous acetic acid of hydrochloric acid, is thought to proceed via t~e 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 amino-aarbonyl 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 K~orr condensation is best carried out at a pH of from about pH 2 to pH6. 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 R~" is methyl to give the product methylaminoethyl ketone of formula IX ~herein R2" is methyl.
~0 The Knorr condensation is preferably carried out at a temperature range of from about room temperature to reflux.
The isoitrosoketones of formula VII are known ~unds or can readily be prepared by nitrosation of the corresponding ~ -ketoester, for example, with sodium nitritè. [see, for example, T.A.
Geissman and M. J. Schlatter, J.- Org. _em., 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-i~onitrosocyclooctanone.
Exemplary of aminocarbonyl precursor compounds of formula VIII which can be used in the Knorr condensation are:
2-aminocyclohexanone, hydrochloride;
2-aminocyclopentanone, hydrochloride;
2-aminocycloheptanone, hydrochloride; and 2-aminocyclooctanone, hydrochloride.
Said o~x~nds are known or may be prepared by reduction of the corresponding isonitrosoketone, for example, by catalytic hydrogenation in the presence of hydrogen chloride.
2Zt3 The amine of the formula IX is converted to the compound of the formula Ia via an intramolecular Mannich reaction. The Mannich reaction is usually performed starting with a ketone and a dialkylamine salt, for example, dimethylamine hydrochloride and formaldehyde (for example, as an a~ueous solution, as paraformalde-hyde 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 methylaminoethyl-ketone 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-methylpyrrolidinone or diethylene glycol dimethyl ether, a lower boiling polar solvent, such as ethanol, butanol or 2-propanol, under pressure; or a lower boiling aprotic solvent under pressure, such as dioxane or tetrahydrofuran, may be used at a temperature in the range of from about 135C. to about 200C. to yield the cycloalka[4,5~pyrrolo~2,3-g]isoquinolines of formula Ia. The reaction, especially when run at temperatures below 150C. leads to a mixture of cis and trans isomers, i.e., for example, when R2" is methyl, compounds of the formulas L ~ Z~8 CH3 ~ )n tranS H
If' C~3~ ~ (C~2)n N
H H
Ig.~ cis Longer heating of the reaction mixture o~ separate heating of the isomeric mixture of hydrochlori~e salts of formulas If' and Ig', 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 isomers, which is readily isolated by crystallization or by chromatographic separation.
For example, when the hydrochloride salt o the amine of formula IX wherein R2" is methyl is reacted with paraformaldehyde in butanol at 180 for 2 hours, the product is isolated as.the trans isomer If'.
z~
FORMULA SCHEME I I
.
~ ~ ~ r;l,c~l2)n Ia C2350-C-N ~ ~ ~ (C}~2)n ~ ¦ 1" )n ~ - c2H50 g ~ ~ r, ~-2)n Ib H 11 3-~ ~2 ) n Ih wherein n is as previously described, and Rl' is alkyl, acyl or aralkyl.
/ ~ 2 4 -22~
In accordance with Formula Scheme II, compounds of formul~
Ic are prepared by alkylation or acylation of the pyrrole nitrogen of a compound of formula Ia' and other N-2-alkyl derivatives by forma-tion of the pyrxole anion with strong base, for example, sodium 1 5 amide, potassium hydride, sodium methylsulf~nyl carbanion, potassium j t-butoxide, or butyllithium, or with an alkali metal, followed by quenching with an alkyl or acyl halide in a solvent such as tetra-hydrofuran, dioxane, ethyl ether, dimethylformamide or dimethylsul-foxide. For example, treatment of a compound of formula Ia', wherein lQ n is 3 with potassium t-butoxide in tetrahydrofuran followed by quenching with methyl iodide affords the 6-methyl derivative, i.e., a compound of formula Ic wherein n is 3 and Rl' is methyl. Similarly, reaction of a compound of formula Ia', wherein n is 4 with butyl-lithium in tetrahydrofuran ab -30 followed by quenching with benzoyl chloride affords the 6-benzoyl derivative, i.e., a compound of formula Ic wherein Rl' is benzoyl and n is 4. S;milarly, reaction of a compound of formula Ia', wherein n is 3, w;th sodium methylsulfinyl carbanion in dimethylsulfoxide followed by quenching with benzyl chloride affords the 6-benzyl derivative, i.e., a compound of formula Ic wherein R1' is benzyl and n is 3.
N-Demethylation of the compound of formula Ia' can be accom-plished by standard N~dealkylation procedures, such as ~he von Braun method ~H.A. Hageman, Org. Reactiohs, 7, 198 (1953)], or via acid or base hydrolysis of a urethane derivative such as those listed in K. C. Rice [J. Org. Chem., 40, 1850 ('1975)]. One procedure for the dealkylation of the compound of formula Ia' is via the urethane of formula XIIIa and acid hydrolysis to give the secondary amine of formula Ib. For example, a compound of formula Ia', 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. Hydrolysis of the foregoing compound with 30%
aqueous sodium hydroxide in ethanol-dioxane at reflux for 24 hours gives the compound of formula Ib, wherein n is 4.
zz~
Urethane derivatives may also be employed as star~ing materials for the preparation of pyrrole-ring substituted derivatives by alkyla-tion or acylation at the pyrrole nitrogen, followed by cleavage of the urethane. The alkylation or acylation is carried out following the pro~res givan for the preparation of compounds of formula I'c, and the urethane derivatives and procedures for their cleavage are g.~ven, as mentioned above, in K.C. Rice (ibid). For example, in accordance with Formula Scheme II, treatment of the ethoxycarbonyl urethane of formula XIIIa wherein n is 4 with sodium methylsulfinyl carbanion in dimethylsulfoxide, followed by treatment with benzyl chloride, affords the compound of formula XIIIb wherein n is 4 and Rl' is benzyl. Hydrolysis with sodium hydroxide affords the 6-benzyl derivative, i.e., a compound of the formula Ih wherein ~! is benzyl and n is 4. In cases ~here ~' is an acyl group which could be hydrolyzed under vigorous alkaline or strongly acidic conditions, a urethane group such as 2,2,2,-trichloroethyoxycarbonyl, which may be cleaved under mild conditions with zinc in aqueous acetic acid, may be ~,~loyed to give compounds of formula m wherein ~' is acyl.
FORMULA SCHEME III
N-N ~ H ~ H2)n Ib R ' 2 \ (CH2)n Id ¦ H
2 \ N ~ ! (C~2)n Ic ; - 26 -z~
wherein n is as previously described, and Rl' is alkyl, acyl, or aralkyl, and R2' is alkyl, hydroxy-alkyl, arylhydroxyalkyl, alkoxyalkyl, acyloxyalkyl, acylalkyl, aralkyl, alkenyl, cycloalkyl-alkyl, thienyl-alkyl, alkynyl, furyl-alkyl, arylcarboxamido-alkyl, aralkenyl, alkenyloxyalkyl, aryloxyalkyl, aralkyloxyalkyl, or aryl-N-im;dazolonylalkyl.
In accordance with Formula Scheme III, the compounds of formulas Id and Ic are prepared from the secondary amine of formula Ib, the s~ting material for the preparation of numerous derivatives encom-passed by formula I, by substitution at the basic amine nitrogen (N-2) andfor the pyrrole n;~trogen ~N~6). For example, treatment of a compound of formula Ib with an alkyl halide, such as ethyl bromide, an alkenyl halide, such as allyl bromide, a cycloalkyl-alkyl halide, such as chloromethylcyclopropane, an aralkyl halide, such as benzyl bromide, or an acylalkyl halide such as ~ -chloro-p-fluorobutyro-phenone, in the presence of a base, for example, potassium carbonate, in acetone, 2-propanone or dimethylformamide, yields the correspond-ingly substituted compound o formula Id, that is, wherein R2' is alkyl, alkenyl, cycloalkyl-alkyl, aralkyl, or acylalkyl, respectively.
With reactive halides, the reaction may be run at room temperature;
with less reactive halides, refulx temperatures are used, and in - some cases, the reaction rate can be enhanced by the addition of an iodide salt, such as l;thium iodide, to the reaction mixture.
Reaction of a compound of formula Ib with epoxyalkanes gives the hy~roxyalkyl substituted compound of formula Id. Treatment with a substituted epoxyalkane gives the 2-substituted-2-hydroxyalkyl analogs of a compound of formula Id, for example, reaction of a compound of formula Ib with styrene oxide gives a compound of formula Id, wherein ~2' is 2-phenyl-2-hydroxyethyl. The reaction is usually carried out in the presence o an alcoholie solvent such as methanol, at from about room temperture to the reflux temperature of the zz~
mixture. The epoxyalkanes are either commercially available or are prepared by epaxidation 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 cases, where R2' in the compound of formula Id does not contain functional groups capable of undergoing alkylation or acylation, the procedures outlined in Formula Scheme II for the preparation of compoundsof formula Ic can be used directly to prepared N-6 substituted analogs of formula Ic as depicted in Formula Scheme III. Alkylations can occur in compounds wherein R2' is hydroxyalkyl or arylhydroxyalkyl. The hydroxyl groups therein must be protected with a base-stable protecting group, such as tetrahydropyranyl.
After N-6 alkylation, the protecting group is removed by acid hydrolysis.
Alternatively, compounds of formula Id, wherein R2' is hydroxyalkyl or aryl hydroxyalkyl may be prepared by reduction of the corresponding compounds of formula Id where~n R2' is acylalkyl.
More particularly, the foregoing reduction may be carried out, for example, with an alkali metal borohydride reducing agent, such as sodium borohydride or lithium borohydride at, for example, room temperture in a solvent, for example, an alkanol, such as ethanol, or~the like.
In the reactions described in Formula Schemes I, II and III, both the trans isomers of the formula \ ~ 2)n If H ~1 wherein n, Rl and R2 are as previously described, and cis isomers of the formula ~2\ 2)~ Ig Rl wherein n, Rl and R2 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 chromato-graphy or crystallization. In addition, the mixture may beisomerized as descrlbed for the isomerization of the trans and cis isomers of the-oxo compound of formula If' and Ig', or by base-catalyzed equilibration, for example, with sodium hydroxide in ethanol.
When the substituent groups Rl and R2 in compounds of the formula:I contain additional asymmetric centers, a m~xture of diastereomers may be obtained. For example, the number of isomers possible is 2n wherein n is the t~tal number of asymmetric centers in the compound. Preferred are the enantlomers and/or diasteromers of compound of the formula If, hereinbefore described.
~6~;228 - FO~MULA SCHEME IV
R2 ~ OC ~ R " - ~ OCH3 IV / X
TH3 ~/
R " N ~ XI
/
R2 ~ N ~ ,~
~ O HON or ~ 2)n R " N ~ ~ H2)n Ia wherein n is as previously described, and R2" is alkyl, alkoxy-alkyl, or cycloalkyl-alkyl.
2~1~
An alternative synthesis of the compounds of formula Ia is described in Formula Scheme IV, in which the isoquinoline ring is formed prior to the formation of the pyrrole ring. In accordance with Formula Scheme IV, the (3,5-dimethoxyphenyl)-ethylamine of formula IV is refluxed with aqueous formaldehyde to giv~ the tetra-hydrosioquinoline of formula X. Birch reduction of the tetrahydro-isoquinoline 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 hexahydro-isoquinoline of formula XI. Hydrolysis of crude hexahydroisoquinolineof 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 ~he preparation of the methyl-aminoethyl ketone of formula IX with the isonitrosoketone of formulaVII or with the aminocarbonyl o~x~nd of formula VIII to give the cycloalka[4,5]pyrroloisoquinoline of formula Ia. Preferred is the sequence of reactions in accordance with Formula Scheme IV starting with the amine of formula IV, wherein R~" is methyl, giving the corresponding N-methyl-cycloalka[4,5]pyrroloisoquinoline of formula Ia, as a mixture containing the trans isomer If' and the cis isomer of formula Ig'.
The same procedures for isomerization of the mixture of cyclo-alka[4,5]pyrroloisoquinolines of formulas If and Ig as described previously may be employed to yield mainly the trans isomer of formula If'.
X ~/
Z215~
The compounds of formula A wherein X is S are characterized by the formula N 1 ~ 2)n ~ II
Rl wherein n, Rl and R2 are as hereinbefore described, and can be prepared as set forth in Formula Schemes V and VI, and further described hereinafter.
ZZ~
FORMULA SCHEME V
\ N ~
~ N / ~ Ie ~ 23n Iie wherein n is as previously descriked; Rl" is hydrogen, alkyl, or aralkyl; and R2"' is hydrogen, alkyl, alkoxyalkyl, aralkyl, alkenyl, aryloxyalkyl, thienylalkyl, furyl-alkyl, alkynyl, aralkenyl, alkenyloxyalkyl, aralkyloxyalkyl or cycloalkyl-alkyl.
22~3 In accordance with Formula Scheme V, compounds of formula IIe are prepared by heating compounds of formula Ie with phosphorus pentasulfide 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 VI. In accordance with Formula Scheme VI, a compound of formula IIb is reacted to give a compound of formula IId following the procedures detailed in Formula Scheme III for the preparation of the corresponding oxo compounds o~ ormula Id.
~.~L~Z28 FO~MULA SCHEME VI
S~2)n IIb H
r ' IId 2 ~ ~--~ 2 ~ n I I c wherein n, Rl' and R21 are as previously described.
X ~
Z2~3 Similarly, a compound of formula IId is reacted to give a compound of formula IIc following the procedures outlined in Scheme III for the preparation of the corresponding oxo compounds of formula Ic.
Additional compounds of formula II are prepared following the procedures detailed in Formula Scheme II for the preparation of corresponding oxo compounds of formula Ih.
In these reactions, both the trans isomers of the formula 2 (CN2)n IIf wherein n, Rl and R2 are as previously described, and cis isomers of the formula Rl IIg wherein n, Rl and R2 are as previously described, - 3~
~L~6(~Z8 of the compounds of formula II may be formed, with the trans isomer predominating. The pure trans isomer may be separated by chromato-graphy 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 Igl.
As described above for compounds of formula I, when substituent groups Rl and R2 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 IIf, hereinbefore described.
The compounds of formula A form acid addition salts with inorganic or organic acids. Thus, they form pharmaceutically accept-able acid addition salts with both pharmaceutically acceptable organic and inorganic acids, for example, with hydrohalic acid, such as, hy~x~
lS chloric acid, hydrobromic acid, hydroiodic acid, other mineral acid salts, such as sulfuric acid, nitric acid, phosphoric acid, or the like, alkyl- and mono-aryl sulfonic acids, such as ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acidr 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 accep~able acid addition salts ol compounds of for~ula A can be converted into pharmaceutically accept-able acid addition salts via conventional metathetic reactions wherehy the non-pharmaceutically acceptable anion is replaced by a pharmaceutically acceptable anion, or alternatively, by neutraliz-ing 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 form hydrates.
The compounds of the general formulae IX and XIII are novel and also form part of the present invention.
~6~213 The compounds of ~ormula A and their pharmaceu~ically acceptable acid addition salts exhibit neuroleptic activity. Accordingly, -the compounds of formula ~ are use~ul as antipsychotic agents, for instance, in the treatment of schizophrenia. The activity of the compounds of formula A which makes them use~ul as antipsychotic agents can be demonstrated in warm-blooded animals, in accordance with known procedures.
For example, by one procedure, trained rats are placed in experimental chambers equipped with a response lever, a steel grid floor for delivery of electric shock and a loudspeaker for presenta-tion of auditory stimuli. Each trial consists of a fifteen-second warning tone, (conditioned stimulus), continuing for an additional fifteen seconds accompanied by electric shock (unconditioned stimulus;
1.0 mA, 35~ ~.A.C.). The rats can terminate a trial at any point by depression of the response lever. A response during the initial fifteen-second warning tone ends the trial before shock delivery and is considered an avoidance response, while a response occurring during shock delivery is an escape response. Trials are pres~nted every - two minutes during a one-hour test session (30 trials per session).
Trained rats maintain a xeliable control baseline of avoidance - behavior (zero to three avoidance failures per session). Compounds are administered at appropriate pretreatment times to a minimum o~
three to four rats at each dose level over a range of doses. ~ats receive ~ehicle alone, during control sessions. One control and one experimental session are alternated during each weekD
The session is divided into three consecutive twenty minute ~ten trial) segments. Response counts are summed over all subjects at a given dose within each segment.
)~ ~8 ~ 16~D2Z8 The number of trials in which the rats failed to exhibit an avoidance response (avoidanse block; AB) or failed to exhibit an escape response (escape block; EB) is determined for the segment displaying the maximum such effect at each dose. Thi~ number is expressed as a percentage of the total trials within the segment.
The dose calculated to produce a 50% block of avoidance (A~D 50) is obtained from the dose effect regression line fitted by the Method of Least Squares. The lowest dose which produced a 20~ block of escape responding (EBD 20) is read from a graphic dose-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 affect the behavior of rats in this procedure, by the larger separation between doses which block avoidance responding and doses which block escape responding. The clinical potency of antipsychotic drugs with known therapeutic uses and properties is significantly and highly correlated with their potency in this pro-cedure. Consequently, the compounds of formula A may be used therapeutically in dosage ranges consistent with their potency in the test procedureO
X ~
~:~6~Z~8 When 2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5~pyrrolo[2,3-g~isoquinolin-lO(lOH)-one is utilized as the test substance, neuroleptic activity is observed at an ABD50 of 0.98 mg/kg p.o.
Similarly, when 2-[4-(4-fluorophenyl~-4-oxobutyl]-1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta~4,5]pyrrolot2,3-g]-isoquinolin-lO(lOH)-one is utilized as the test substance, neuroleptic activity is observed at an ABD50 of 0.15 mg/kg p.o.
Similarly, when 2-[4-(4-fluorophenyl)-4-oxobutyl]-2,3,4,4a,5, 7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa[4,5]pyrroloE2,3-g]-isoquinolin-ll(llH)-one is utilized as the test substance, neuroleptic activity is observed at an ABD50 o 0.73 mg/kg p.o.
Similarly, when 2-methyl-2,3,4,-4a,5,7,8,9,10,1la-decahydro-4a,11a-trans-lH,6H-cyclohexar4,5]pyrrolo[2,3-g]isoquinolin-ll,(llH)-one, hydrochloride, Q.75 molar hydrate, which has demonstrated an LD50 of~ for example, 650 mg/kg p~o. in mice, is utilized as the test substance, neuroleptic activity is observed at an ABD50 f 5.5 mg/kg p.o.
Similarly, when 2-methyl-2,3,4,4a,5,7,8,9,10,11,12,13a-dod~ca-- 20 hydro-4a,13a-trans-lH,6H-cyclooctal4,5]pyrrolo[2,3-g]isoquinolin-13(13H)-one is utilized as the test substance, neuroleptic activity is observed at 8 mg/kg p.o~ where the avoidance blockade is 63%o Similarly, when 2-methyl-1,2,3,4,4a,5,7,8,9,10,11, 12a-dodeca-hydro-4a,12a-trans-6H-cyclohepta~4,5]pyrrolo~2,3-g~isoquinolin-12(12H)-one is utilized as the test substance, neuroleptic activity is observed at 16 mg/kg p.oO where ~he avoidance blockade is 50~0 -The compounds of formula A and their pharmaceutically accept-able acid addition salts have antipsychotic effects which are quali-tatively similar to those of haloperidol, and trifluoroperazine, h~ for their therapeutic uses and properties~ Thus, the compounds of formula A demonstrate a pattern of activity associated with anti-psychotic drugs of known ef~icacy and safety~
The compounds of formula A and their pharmaceutically acceptable acid sddition salts can be used in the form of conventional pharma-ceutical preparations. By way of exemplification, suitable oral dosage units comprise or are in the range of from 0.05 to 50 mg., and suitable oral dosage regimens in warm-blooded animals comprise or are in the range o~ 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 should be adjusted according to individual need and the professional judgment of the person administering or supervising the administration of a compound of formula A or a pharmaceutically acceptable acid addition salt thereof. Furthermore, the frequency with which any such dosage form will be administered will vary, depending upon the quantity of active -20 medicament present therein and the needs and requirements of the pharmacological situation.
X Y~
" ~:L6~Z;~8 For the disclosed use, the compounds of formula A and their pharmaceutically acceptable acid addition salts are formulated, using conventional inert pharmaceutical adjuvant materials, into dosage forms which are suitable for oral or parenteral administration. Such dosage forms include tabletsl suspensions, solutions, and the like.
Furthermore, the compounds of formula A can be embodiecl into, and administered in the form of, suitable hard or soft capsules. The identity of the inert adjuvant materials which are used in formulating the compounds of formula A and their pharmaceutically acceptable acid addition salts into oral and parenteral dosage forms will be immediately apparent to persons skilled in the art. These adjuvant materials, either inorganic or organic in nature, include, for example, water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols, etc. Moreover, perservatives, stabilizers, wetting agents, emulsifying agents, salts for altering osmotic pressure, buffers, or the like, can be incorporated, if desired, into such formulations.
Since the compounds of formula A and their pharmaceutically acceptable acid addition salts possess asymmetric carbon atoms, they are ordinarily obtained as racemic mixtures. I~ desired, diastereomeric mixtures, when obkained, may be separated. The resalution of individual racemates into the optically active isomers can be carried out by known procedures. Alternatively, optically active isomers can be prepared utilizing, in the processes herein described, corresponding optically active starting materials. Some racemic mixtures can be precipitated as eutectics and can thereafter be separated. Chemical resolution is, howe~er, preferred. By this method, diasbereomers are formed from the racemic mixture with an optically active resolving agent, for example, an optically active acid, such as t~)-tartaric acid, ~+~-dibenzoyl-D-tartaric acid, (~)-d-10-camphor-sulfonic acid, ~ 3-pinanecarboxylic acid, and the like, to form a diastereomeric salt. The formed diastereomers are separated by fractional crystallization and can be converted to the corresponding optical isomer base. Thus, the invention covers the optically active isomers of the compounds of formula A as well as their racemates.
22~
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 than one possible geometric isomeric form. The compounds of formula A, as described and claimed, are intended to embrace all such isomeric forms. Accordingly, the examples included herein are to be understood as illustrative of particular mixtures of geometric isomers or single geometric isomers and not as limitations upon the scope of the invention.
The Examples which follow further illustrate the invention.
All temperatures are in degrees Centigrade, unless otherwise stated.
~6~28 Example 1 Preparation of N-methyl-1,5-dimethoxycyclohexa-lr4-diene-3-ethylamine 185.2 g. of N-methyl-(3,5-dimethoxyphenyl)-ethylamine hydro-chloride 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 condensersr one fitted with a gas inlet and th~ othe~
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 minutes.
After all the lithium had 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 280 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 layers were separated. The aqueous layer was extracted with 2 x 1.5 1. of di-chloromethane and the extracts were combined and washed with 1 1.
of brine and dried over anhydrous sodium su1fate. 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:
~e 2;2~3 Fraction _ wt gc purity 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/~.15 mm. 21.2 g. 92%
4 ~6-87/~.15 mm. 99.4 g. 100%
Fractions 3 and 4 combined afforded 120.6 g. of N-methyl-1,5-dimethoxycyclohexa-1,4-diene-3-ethylamine as a colorless oil.
Anal. Calcd. for CllHlgNO2: C, 66.97; H, 9.71; N, 7.10 Found: C, 66.84; H, 9.62; N, 6.93 ~L6~Z2~3 Example 2 Prepara~ion of 1,2,3,5,6,7,8,9-octahydro-20[2 (methylamino)ethyl]-4H-carbazol-4-one A mixture of 15.6 g. of N-methyl~1,5-dimethoxycyclohexa-1,4-diene-3-ethylamine (79 mmol), 16.7 g. of 2-isonitrosocyclohexanone (131 mmol), and 10.5 g. of zinc dust (300 mg-atom) in 300 ml. of 70~
aqueous acetic acid heated to reflux for 5 hours, and was cooled and filtered. The filtrate was concentrated in vacuo and excess dioxane was added. The dioxane-acetic acid azeotrope was distilled off and the process was repeated until all the acetic acid was re-moved. The residue was chromatographed on Alumina III eluting with
10% methanol in dichloromethane to give 10.7 g. o~ crude 1,2,3,5,6, 7,8,9-octahydro-2-[2-(methylamino)ethyl]-4H-carbazol-4-one. The crude product was dissolved in methanol and treated with methanolic HCl and the solvent evaporated to ~ive 12.2 g. of 1,2,3,5,6,7,8,9-octahydro-2-~2-(methylamino)ethyl]-4H-carbazol-4-one hydrochloride.
X ~ .
~6~3Z~3 Preparation of 2-methyl-2,3,4,4a,5,7,8,9,10 t lla-decahydro-4a,11a-trans-lH,6H-cyclohexa-[4,5]pyrrolo[2,3-~isoquinolin- (llH)-one A mixture of 2.3 g. of 1,2,3,5,6,7,8,9~x~hy~x~2-[2-(methylamino)ethyl]-4H-carbazol-4-one hydrochloride (8.14 mmol) and 2.3 g. of parafonE~dehyde (76 mmol) in 100 ml. of n-butanol was heated in a pressure bottle immersed in a 180C. oil bath to an internal pressure of 80 psi for 1 hour. The solution was cooleddand the sol-vent was removed at reduced pressure and the residue was dissolved in water and washed with dichloromethane (discarded). The aaueous solution was made alkaline with ammonium hydroxide and extracted with dicichlon~e. The extracts were dried over sodium sulfate, filtered, and evaporated to a 10 ml. v~lume; The mixture was slurried with 10 g. of alumina, filteredr 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, lO,lla-decahydro-4a,11a-trans-lH,6H-cyclohexa~4,5]pyrrolo[2,3-g]
isoquinolin-ll(llH)-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,lO,lla-decahydrO-4a,11a-trans-lH,6H-cyclohexa[4,5~pyrrolo[2,3-g]
- isoquinolin-ll(llH)-one as an off-white solid. The free base was treated with ~Cl in methanol and the hydnx~loride r~ystallized twice from ethanol to give 0.46 g. of pure 2-methyl-2,3,4,4a,5,7,8, 9~10~11a-decahydro-4a~11a-trans-lH~6H-cyclohexa[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 C16H22N2-HCl--75 H20 C, 62.33; H, 8.01; ~, 9.09; Cl, 11.50 Found: C, 62.56; H, 8.11; N, g.08; Cl, 11.59 . )~ 'Y~
~7 _ ~6~
Example 4 Preparation of ~3,4-dihydro-lH-6,8-dimethoxy-2-methyl-isoquinoline, hydrochloride A solution of N-methyl-(3,5-dimethoxyphenyl)ethylamine hydro-chloride (15.0 g., 64.7 mmol) in 30 ml. of water was treated with 35 ml. of 2N sodium hydroxide and extracted with d~ichloromethane. The combined extracts were concentrated on a rotary evaporator and mixed with a~ueous formaldehyde (65 ml, 37~ solution). The mixture was refluxed for 2 hours, made alkaline with 2N sodium hydroxide (15 ml.) and extracted with dichloromethane~ The combined extracts were washed with brine and dried over anhydrous magnesium sulfate and concentrated to give the product as a yellow oil (lS.5 g.) The oil was dissolved in lOQ mi. of ethanol and treated with ethanolic hydrogen chloride.
~ther (75 ml) was added, and the salt crystallized to give 10.15 g.
of 3,4-di-hydro-lH-6,8-dimethoxy-2-methylisoquinoline, hydxochloride (64~ yield).
X ~
~6(~2Z8 Example 5 Preparation of 1,2,3,4,4a,7-hexahydro-6,8-dime~hoxy-2-methyliso-quinoline -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 3,4-dihydro-lH-6,8-dimethoxy-2-methylisoquinoline 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 am~onia 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-methyl-isoquinoline (0.58 g, crude) as a yellow oil.
The crude product (1.05 g) in 20 ml. of 70~ aqueous aceticacid 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. ~reatment with hydrochloric acid in methanol afforded the hydrochloride, mp 193-196.
_ ~9 _ X
Example 6 Preparation of 2-methyl--2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa~4 ! 5]pyrrolo~2~3-g]isoquinolin-ll(llH)-one via oc~ahydro-2-methyli~soquinolin-6~,'8-'dione A mixture of 72 g. of crude octahydro-2-methyli~Lnolin-6,8-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 relfuxed 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,11a-trans-lH,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquin-olin-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,5,7,8,9,10,11a-deca-~ hydro-4a,11a-trans-lH,6H-cylohexa~4,5]pyrrolo[2,3-g]isoquinolin-ll(llH)-one as a white amorphous solid after slurrying with hot ethanol, mp 273-275C.(dec.).
Anal. Calcd. for C16H22N2O: C, 74.38; H, 8.58; N, lOo 84 Found: ~, 74.21, H, 8.39; N, 10061 Example 7 Following the procedure of Example 6, starting from 2-isonitro-socyclopentanone and octahydro~2-methylisoquinolin-6,8-dione, there was obtained 2-methyl-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, mp 296-297C
(dec.), crystalized from ethanol-methanol.
Anal. Calcd. for C15H20N20: C, 73 74; H, 8.25; N, 11.47 Found: C, 73.93; H, 8.41; N, 11.46 The hydrochloride crystallized from water a~ a hemihydrate, mp 256-258C. (dec.).
Anal. Cal~d. for C15H20N20.HC1 0.5H20:
C, 62.17; H, 7.65; N, 9.67; Cl, 12.23 Found: C, 62.16, H, 7.71; N, 9.54; Cl, 12.37 .X ~
- . - -Example 8 Following the procedure of Example 6, starting from 2-isonitro-socycloheptanone and octahydro-2-methylisoquinolin-6,8-dione, there was obtained 2-methyl-1,2,3,4,4a,5,7,8,9,10,11,12a-dodecahydro-4a,12a-trans-6H-cycloheptal4,5]pyrrolol2,3-g]isoquinolin-12~12H)-one, mp 293-296C, crystallized from ethanol.
Anal. Calcd. for C17H24N20: C, 74.96; H, 8.88; N, 10.28 Found: C, 74.79; H, 8.74; N, 10.33 Example 9 Following the procedure of Example 6, starting from 2-isonitro-socyclooctanone and octahydro-2-methylisoquinolin-6,8-dione, there was obtained 2-methyl-2,3,4~4a,5,7,8,9,10~11,12,13a-dodecahydro-4a,13a-trans-lH,6H-cycloocta[4,5]pyrrolo[2,3-g~isoquinolin-13(13H~-one, mp 298-300C, crystallized from water-dimethylformamide.
Anal- Calcd. for C18H26N2O: C, 75,48; H, 9.15; N, 9.78 Found: C, 75.2~; H, 9.04; N, 9.70 Example '10 Preparation of 2,-3,4 ! 4a ~ 5,7,8,9,10,11a'-decahydro-4a,11a-trans-lH,~H-cyclohexaE4~5]pyrrolo[2~3-g]iso~uinolin-ll(llH)-one A mixture of 1.9 g. of 2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexaE4,5]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 5% aqueous hydrochloric acid, washed with water, brine, and dried over sodium sulfate. Evaporation of the solvent afforded 1.4 g. of the carbamate, 2-ethoxycarbonyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-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 extractionO
The crude carbamate ~1.4 g.) was heated to reflux for 24 hours with 15 ml. of 30% aqueous sodium hydroxide in a mixture of 15 ml.
of e~hanol and 5 ml~ of dioxane. The mixture was concentrated in vacuo and the residue was dissolved in 5~ aqueous hydrochloric acid and washed with chloroform. The aqueous solution was made alkaline with ammonium hydroxide and extracted with chloroform. ~he extracts were washed with brine, dried, and concen~rated to afford 0.65 g.
of 2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa-l4~5]pyrrolo[2~3-g]isoquinolin-ll(llH)-one~
$;~
;22~
Example 11 Following the prooK~re of Example io, starting from 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-lO(lOH)-one~ there was obtained via the carbamate, 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclo-penta[4,5]pyrrolor2,3-g]isoquinolin-lO(lOH)-one, mp 242-245C.(dec.), crystallized from ethanol-ethyl acetate.
Anal- Calcd. for C14H18N20; C, 73.01; H, 7.88; N, 12.16 Found: C, 72,84: H, 7.78; N, 12.30 E ~
Following the procedure of Example 10, starting from 2 methyl-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-lH,6H~cyclo-octa[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,iO~ 2,~3a-tetradecahydro-4a,13a-trans-cycloocta[4,5]pyrrolo[2,3-g]isoquinolin-4-one, mp 283-5C., crystallized from ethanol.
Anal. Calcd. for C17H24N20: C, 74.96; H, 8.88; N, 10.28 Found: C, 74.71; H, 8.65: N, 10.24 ~6C~2215 Exa~ple 13 Preparation of 2-[4-(4--fluorophenyl)-4-oXobutyl]-2,3,4,4a,5,7,8,9,10, lla-decahydro-4a,11a-trans-lH,6H-cyc'lohexa[4,5]pyrrolo[2,3-g]iso-quinolin-ll(llH)-one -A mixture of 0.68 g. of 2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa[4,5]pyrrolo~2,3-g]isoquinolin-ll(llH)-one, 1.68 g. of ~-chloro-p-fluorobutyrophenone, and 1.55 g. of potassium carbonate in 15 ml. of diethylketone was heated ~o reflux for 24 hours. The mixture was cooled, filtered and concentrated.
The residue was chromatographed (dry column) eluting with the organic phase of a mixture prepared by shaking ~by volume) 90 parts chloro-form, 30 parts methanol, 10 parts water, and 6 parts acetic acid to afford 0.85 g. of a crude amine, which was recrystalli2edfrom ethanol to afford 0.42 g. of pure 2-[4-(4-fluorophenyl)-4-oxobutyl~-2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa[4,S~pyrrolo [2,3-g]isoquinolin-ll(llH~- one as a crystalline solid, mp 220-222.' Anal. Calcd. for C25H29N2O2F: 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 :~~S,~
~6t~ZZ~
- Example 14 Following the prooK~re of Example 13, alkylation of 2,3,4,4a, 5,7,8,9,10,11a-dPcahydro-4a,11a-trans-lH,6H-cyclohexa[4,5]pyrrolo-[2,3-g]isoquinolin-ll(llH) one with (2-bromoethyl)benzene afforded 2-(2-phenylethyl)-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-ll(llH)-one, mp 250-256C. (dec.),as a crystalline solid after recyrstallization from ethanol.
Anal. Calcd~ for C23H28N20: C, 79.27; H, 8.10; N, 8~04 Found: C, 79;29; H, 8.40; N, 7.97 Example 15 Following the procedure of Example 13, alkylation of 2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa[4,5]pyrrolo-[2,3-g]isoquinolin-ll(llH)-one with benzyl chloride afforded 2-benzyl-2,3,4,4a,5,7,8~9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclo-hexa~4,5]pyrrolo~2,3-g]isoquinolin-ll(llH)-one, mp 266-268C, as a crystalline solid after recrystallization from ethanol.
Anal. Calcd. for C22H26N2O: C, 79.00; H, 7.84; N, 8.38 Found: C, 79.27; ~, 8.03; N, 8.60 Example 16 Following the procedure of Example 13, alkylation of 1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopentaE4,5]pyrrolo[2,3-g]-isoquinolin-lO(lOH~-one with benzyl chlorid~ afforded 2-benzyl-1,2~3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]-pyrrolo[2,3-g]isoquinolin-lO~lOH)-one, mp 258-260C.(dec~), as a crystalline solid after recrystalli~ation from ethanol.
Anal. Calcd. for C21H2~N20: C, 78.71r H, 7.55; N, 8.74 Found: C, 78.97; H, 7.54; N, 8.63 Example 17 Following the procedure of Example ~3, alkylation of 1,2,3,4, 4a,5,7,8,9,1Oa-decahydro-4a,1Oa-trans-6H-cyclopenta[4,5]pyrrolo-[2,3-g]isoquinolin-lO(lOH)-one with r -chloro-p-fluorobutyrophenone afforded 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-lO(lOH)-one, mp 225-227~C., as a crystalline solid ater recrystalli-zation from ethanol.
Anal. Calcd- for C24H27FN202: C,73.07; H,6.90; N,7-10; F,4~82 Found: C,72~76; H,6.86; N,1.24; PJ4.71 -S ~L
~6V;~ZI~
Example 18 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-lO~lOH)-one with (2-bromoethyl)benzene afforded 2-(2-phenylethyl)-1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,1Oa-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-lO(lOH)-one, mp 251-254C.
(dec.), as a crystalline solid after recrystallization from ethanol.
Anal. Calcd. for C22H26N20: C, 79.00; H, 7.84; N, 8.38 Found: C, 78.68; H, 7.72; N, 8.28 Example 19 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-lO(lOH)-one with 4-methoxybenzyl chloride afforded 2-(4-methoxybenzyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g~isoquinolin-4-one, mp 236-8 (dec.) r as a crystalline solid after recrystallization from ethanol.
Anall Calcd. for C22H26N202 Found: C, 75.39; H, 7.41; N, 8.03 .
X ~
~3~6~;2;;28 Example 20 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-lO(lOH)-one with 4-chlorobenzyl chloride afforded 2-(4-cXlorobenzyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g~isoquinolin-lO(lOH)-one as a crystalline monohydrate, mp 254-6 after recrystallization from etha-nol.
~nal. Calcd. for C21H23N20 Cl H20: C,67.63; H,6.22; N,7~51; Clf9.51 Found: C,67.86; H,6.38; N,7.50; C1,9.92 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-cyclopental4,5]pyrrolo[2,3-g]-isoquinolin-lO(lOH)-one with allyl bromide afforded 2-(2-propenyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]-pyrrolo[2,3-g]isoquinolin-lO(lOH)-one, mp 257-9~ ~dec.), after recrystallization from ethyl acetate-ethanol.
Anal. Calcd. for C17H22N20: C, 75.52; H, 8.20; N, 10.36 Found: C, 75.25; H, 8.17; ~, 10.36 -S-~
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'Exampl'e''22 Following the procedure of Example 13 alkylation of 1,2,3,4, 4a,5,7,8,9,10a-decahydro-4a,10a-trans-S~-cyclopenta[4,5]pyrrolo-[2,3-g]isoquinolin-lO(lOH)-one with 2-bromoethyl ether afforded 2-(2-ethoxyethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a~10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3~g]isoquinolin-lO~lOH)-one, mp 236-B
(dec.~ as a crystalline solid after recrystallization from ethanol.
Anal. Calcd. for C18H26N202: ' Found: C, 71.35; H, 8.47; N, 9~23 E~
Following the procedure of Exampl~ 13, alkylation of 2,3,4, 4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-lH,6~-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-oxobutyl]-1,2,3,4,4a,$, 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]iso~uinolin and the indicated halide.
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Z;~8 Example 49 Pre~aration of 2-methyl-~1,2,-3,4,4a,5,7,8,9,10a-decahydro-4_,1Oa-- trans--6H-cycl-openta[-4,5]pyrrolo[2,3-g]isoquinolin-lO(lOH)-thione A mixture of 244 mg. (1.0 mmol) of 2-methyl-1,2,3,4,4a,5,7,8, 9,lOa-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquino-lin-lO(lOH)-one and 222 mg. ~1.0 mmol) of phosphorus pentasulfide in 15 ml. of dioxane was stirred and refluxed for 17 hours. The dioxane solution was decanted off and water (20 ml,~' and enough ammDnium hydroxide bo brLng the pH to 8-9 was added ~o the residue.
The mixture was extracted with chloroform, and the extracts were washed with brine, dried and evaporated. The 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-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta-[4,5]pyrrolo[2,3-g]isoguinolin-lO(.lOH)-thione, mp 224-227C(dec.).
Anal. Calcd. for C15H20N2S: C, 69~19; H, 7.74; N, 10.76 Found: C, 68.97; H, 7.59; N, 10.97 .~ .j..
~6~
-Example 50 The procedure of Example 49 is u~ed to prepare 2-methyl-2,3, 4,4a,5,7,8~9,10llla-decahydro-4a,1la-trans-lH,6H-cyclohexa[4,5]
pyrrolo[2,3~g]isoquinolin~ llH)-~hione starting from 2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-~rans-lH,6H~cyclohexa-[4,5]pyrrolo[2,3-g]isoquinolin-ll(llH)-one.
Example Sl The procedure of Example 4g is used to prepare 1,2,3,4f4a, 5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta~4,5]pyrrolo[2,3-g]-isoquinolin-lO(lOH)-thione starting from 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo~2,3-g~isoquinolin-lO(lOH)-one.
Example '52 The procedure of Example 13 is used to prepare 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-glisoguinolin-lO'(lOH)-thione starting from 1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,1Oa-tr~ns-6H-cyclopenta[4,5]pyrrolo [2,3-g]isoquinolin-lO(lOH~-thione Y-chloro-p-fluorobutyrophenone.
fluorobutyrophenone.
~xample 53 The procedure of Example 13 i5 used to prepare 2-~2-phenyl-ethyl)-1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,1Oa-trans-6X-cyclopenta-~4,5]pyrrolo[2,3-g]isoquinolin-lO(lOHI-thione starting from 1,2,3,4, 4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopentat4,5]pyrrolo--~2,3~g~isoquinolin-lO(lOH)-thione and (2-bromoethyl)benzene.
~( 6~
~L6~221~1 Example 54 Preparation of 6-benzoyl-2-methyl-1,2,3,4,4a,5,7,8,9!1Oa-decahydro-4a lOa-trans-6H-c cl-o enta[4 5~ yrrolo~2 3- ]iso uino-l.in-lO(lOH)-one Y P _ ~ P ~ g q . . . _..
To a mixture of 244 mg. (1.0 mmol~ of 2-methyl-1,2,3,4,4a,5,7, 8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo:r2,3-g]iso-quinolin-lO:(lOH)-one in 10 ml. of dry tetrahydrofuran at -30 is added 0.5 ml. of n-butyllithium ~1.1 mmol of 2.2M solution in hexane) over 2-3 minutes via syringe. The solution is stirred for 30 minutes at -30 and 168 mg. of benzoyl chloride (1.2 mmol~ is added over 2-3 minutes. The solution is stirred 1 hour at -30 and 30 minutes at room temperature. The mixture is poured onto ice and extracted with chloroform. The extracts are washed with brine, dried (sodium sulfate), concentrated and chromatographed to afford the 6-ben20yl-2-methyl-1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,1Oa-trans-6H-cyclopenta-[4,5]pyrrolo:l2,3-g]isoquinolin-lO~lOH)-one.
Exampl-e 55 Following the procedure of Example 54, 2,6-dimethyl-1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4~5~pyrrolo-~2,3-g]-isoquinolin-lO(lOH)-one is prepared using methyl iodide instead of benzoyl chloride.
,Y
~6~ZZ8 Example 56 -Preparation of 2-(2-~ydroxy-3l3-dimethylbut;~l)-2 ! 3,4,4a,5,7,8,9,10 lla-decahydro-4a,11a-trans lH,6H-cyclohexa~4,5]pyrro-10[2-,3-g]iso-quino~lin-ll(llH)-one A solution of 488 mg. (200 mmol) of 2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa~4,5]pyrrolo[2,3-g]isoquinolin-ll(llH)-one and 300 mg. (3.0 mmol) of 3,3-dimethyl-1,2-epoxybutane in 15 ml. of methanol was refluxed for 24 hours and concentrated.
The residue was chromatographed, and the crude product ~350 mg.) crystallized from ethanol to give 200 mg. of 2-(2-hydroxy-3,3-dimethyl-butyl~-2~3~4~4a~5~7~8~9~lo~lla-decahydro-4a~lla-trans-lHr6H-cyclo-hexa[4,5]pyrrolo[2,3-g]isoquinolin-ll~llH~-one, mp 276-278C(dec.~.
Anal- Calcd- for C21H32N22 C, 73-22; H~ 9-36; N~ 8-13 Found: C, 73.39; H, 9.31; N, 8.15 Examp'l'e 57 The procedure of Example 56 is used to prepare 2-(2-hydroxy~
2-phenylethyl)-l~2~3~4~4a~5~7~8~9~loa-decahydro-4a~loa-trans-6~-cylopentar4,5]pyrrolo[2,3-g]isoquinolin-lO~lOH)-one starting from 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]-pyrrolo[2,3-g]isoquinolin-lO(lOH~-one and styrene oxide ~Example ~58 Following the procedure of Example 56, alkylàtion of 1,2,3,4, 4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolor2,3-g]isoquinolin-lO(lOH)-one with ethylene oxide at room temperature aforded 2-(2-hydroxyethyl)-1,2,3,4,4a,5,7,8,9,10a-d~cahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]iso~uinolin-lO(lOH~-one, mp 237-9 (dsc.) as a crystalline solid af~e~ recrystalliza~ion from ethanol~
Anal- CalCd~ for C16H22N22 C, 70.04, H~ ~08; N~ 10-21 Found; C, 69.66; H, 8017; N, 10.19 X ~
(J Z28 Example 59 Following the procedure of Example 56, alkylation of 1,2,3,4, 4a,5,7,8,9,1Oa-decahydro-4a,1Oa-trans-6H-cyclopenta[4,5~pyrrolo-~2,3-g]isoquinolin-lO(lOH)-one with 3,3-dimethyl-1,2-epoxybutane afforded 2-(2-hydroxy-3,3-dimethylbutyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-lO(lOH)-one, mp 284-6 (dec.), as a crystalline solid after recrystal-lization from ethanol.
20 30N202: C, 72,69; EI, 9715; N, 8.48 Found: C, 72.80; H, 9.02; N, 8.55 ~xample 60 A mixture of 30 mg of sodium hydride dispersion (57%, washed free of oil~ and 2 ml of dry dimethyl sulfoxide (Dr~SO) was heated to 65-70 for 1.5 hrs. The solution was cooled and a solution of 244 mg of 2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-lO~lOH)-one in 1 ml of dry 15- D~ISO 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-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a~10a-trans-6H-cyclopenta~
[4~5~pyrrolo[2~3-g]isoquinolin-lO[lOH)-one as a crystalline solid, ` mp 169-171 after recrystallization from ethyl acetate~ethanol.
Anal~ Calcd. Eor C22H26N20: C, 79.00; H, 7,84; N, 8.35 Found~ C, 78.~2; H, 7,84; N, 8.55 ~1 '~6VZZ8 Example 61 To a solution of 2.35 g of rac.-2-methyl-1,2,3,4,4a,5,7,8,9, lOa-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g~isoquino-lin-lO(lOH)-one in 20 ml o~ methanol was added a solution of 3.62 g of (+)'~dibenzoyl-(D)-tartaric acid monohydrate in 20 ml of methanol.
The mixture was concentrated and crystallized from methanol three times and converted to the free base with ammonium hydroxide. Recry-stallization of the base from ethanol afforded 0.18 g of 1-)-2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,1Da-trans-6H-cyclopenta[4,5]-pyrrolo[2,3-g]isoquinolin-lO~lOH~-one, mp 270-2 (dec.). The hydrochloride salt gave [~]~5- 101.17 in methanol (1~).
'Exa~p'l'e'`62 Preparation of 2-[4-(4-fluorophenyl)-4-hydxoxybutyl]-1,2,3,4, 4a,5,7,8,9,10a-decahydro-6H-4a,10a-trans-cyclopenta[4,5]pyrrolo-[2,3-g]isoquinolin-lO~lOH)-one.
A mixture of 394 mg (l.Ommol) of 2-[4-(4-fluorophenyl)-4 oxobuty]-1,2,3,4,4a,5,7,8,9,1Oa-decahydro-6H-4a,1Oa-trans-cyclopenta-[4,5]pyrrolo[2,3-g]isoquinolin-lO(lOH)-one and 151 mg of sodium borohydride (4.0 mmol) in 15 ml of ethanol was stirred at room tem-perature for 24 hrs. A second portion of ~odium borohydride (150 mg, 4.0 mmol) was added, and the mixture was stirred further at room temperature for 24 hrs. The mixture was poured into 50 ml of water and`filtered to remove the white solid product containing some starting material. Dry column chromatoyraphy 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~-5-hydroxybutyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-6H-4a,10a-trans-cyclopenta~4,5]pyrrolo[2,3-g]isoquinolin-lO~lOH)-one, mp 243-5, as a mixture of diastereomers.
Anal. Calcd- for C24H29 2 2 30Found: C, 72~68; H, 7.56; N, 7.33 72 ~
~s ., - -~6~Z2~
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,11a-trans-lH,6H-cyclohexa[4,5]pyrrolo[2,3-g]iso-quinolin-ll(llH)-one afforded 2-~4~4-fluorophenyl)-4-hydroxybutyl]
2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa[4,5]-pyrrolo r2,3-g]isoquinolin-ll(llH)-one, as a mixture of diastereomers, - mp 239-41, crystallized from 1,4-dioxane, cd- for C25H31N2O2F: C, 73.14; H, 7.61; N, 6.82 Found: C, 73~18: H, 7.72; N, 6.82 Example 64 Followingthe procedure of Example 62, sodium borohydride reduction of 2-[4-(4-fluorophenyl)-4-oxobutyl]-2,3,4,4a,5,7,8,9,10,
X ~ .
~6~3Z~3 Preparation of 2-methyl-2,3,4,4a,5,7,8,9,10 t lla-decahydro-4a,11a-trans-lH,6H-cyclohexa-[4,5]pyrrolo[2,3-~isoquinolin- (llH)-one A mixture of 2.3 g. of 1,2,3,5,6,7,8,9~x~hy~x~2-[2-(methylamino)ethyl]-4H-carbazol-4-one hydrochloride (8.14 mmol) and 2.3 g. of parafonE~dehyde (76 mmol) in 100 ml. of n-butanol was heated in a pressure bottle immersed in a 180C. oil bath to an internal pressure of 80 psi for 1 hour. The solution was cooleddand the sol-vent was removed at reduced pressure and the residue was dissolved in water and washed with dichloromethane (discarded). The aaueous solution was made alkaline with ammonium hydroxide and extracted with dicichlon~e. The extracts were dried over sodium sulfate, filtered, and evaporated to a 10 ml. v~lume; The mixture was slurried with 10 g. of alumina, filteredr 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, lO,lla-decahydro-4a,11a-trans-lH,6H-cyclohexa~4,5]pyrrolo[2,3-g]
isoquinolin-ll(llH)-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,lO,lla-decahydrO-4a,11a-trans-lH,6H-cyclohexa[4,5~pyrrolo[2,3-g]
- isoquinolin-ll(llH)-one as an off-white solid. The free base was treated with ~Cl in methanol and the hydnx~loride r~ystallized twice from ethanol to give 0.46 g. of pure 2-methyl-2,3,4,4a,5,7,8, 9~10~11a-decahydro-4a~11a-trans-lH~6H-cyclohexa[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 C16H22N2-HCl--75 H20 C, 62.33; H, 8.01; ~, 9.09; Cl, 11.50 Found: C, 62.56; H, 8.11; N, g.08; Cl, 11.59 . )~ 'Y~
~7 _ ~6~
Example 4 Preparation of ~3,4-dihydro-lH-6,8-dimethoxy-2-methyl-isoquinoline, hydrochloride A solution of N-methyl-(3,5-dimethoxyphenyl)ethylamine hydro-chloride (15.0 g., 64.7 mmol) in 30 ml. of water was treated with 35 ml. of 2N sodium hydroxide and extracted with d~ichloromethane. The combined extracts were concentrated on a rotary evaporator and mixed with a~ueous formaldehyde (65 ml, 37~ solution). The mixture was refluxed for 2 hours, made alkaline with 2N sodium hydroxide (15 ml.) and extracted with dichloromethane~ The combined extracts were washed with brine and dried over anhydrous magnesium sulfate and concentrated to give the product as a yellow oil (lS.5 g.) The oil was dissolved in lOQ mi. of ethanol and treated with ethanolic hydrogen chloride.
~ther (75 ml) was added, and the salt crystallized to give 10.15 g.
of 3,4-di-hydro-lH-6,8-dimethoxy-2-methylisoquinoline, hydxochloride (64~ yield).
X ~
~6(~2Z8 Example 5 Preparation of 1,2,3,4,4a,7-hexahydro-6,8-dime~hoxy-2-methyliso-quinoline -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 3,4-dihydro-lH-6,8-dimethoxy-2-methylisoquinoline 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 am~onia 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-methyl-isoquinoline (0.58 g, crude) as a yellow oil.
The crude product (1.05 g) in 20 ml. of 70~ aqueous aceticacid 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. ~reatment with hydrochloric acid in methanol afforded the hydrochloride, mp 193-196.
_ ~9 _ X
Example 6 Preparation of 2-methyl--2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa~4 ! 5]pyrrolo~2~3-g]isoquinolin-ll(llH)-one via oc~ahydro-2-methyli~soquinolin-6~,'8-'dione A mixture of 72 g. of crude octahydro-2-methyli~Lnolin-6,8-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 relfuxed 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,11a-trans-lH,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquin-olin-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,5,7,8,9,10,11a-deca-~ hydro-4a,11a-trans-lH,6H-cylohexa~4,5]pyrrolo[2,3-g]isoquinolin-ll(llH)-one as a white amorphous solid after slurrying with hot ethanol, mp 273-275C.(dec.).
Anal. Calcd. for C16H22N2O: C, 74.38; H, 8.58; N, lOo 84 Found: ~, 74.21, H, 8.39; N, 10061 Example 7 Following the procedure of Example 6, starting from 2-isonitro-socyclopentanone and octahydro~2-methylisoquinolin-6,8-dione, there was obtained 2-methyl-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, mp 296-297C
(dec.), crystalized from ethanol-methanol.
Anal. Calcd. for C15H20N20: C, 73 74; H, 8.25; N, 11.47 Found: C, 73.93; H, 8.41; N, 11.46 The hydrochloride crystallized from water a~ a hemihydrate, mp 256-258C. (dec.).
Anal. Cal~d. for C15H20N20.HC1 0.5H20:
C, 62.17; H, 7.65; N, 9.67; Cl, 12.23 Found: C, 62.16, H, 7.71; N, 9.54; Cl, 12.37 .X ~
- . - -Example 8 Following the procedure of Example 6, starting from 2-isonitro-socycloheptanone and octahydro-2-methylisoquinolin-6,8-dione, there was obtained 2-methyl-1,2,3,4,4a,5,7,8,9,10,11,12a-dodecahydro-4a,12a-trans-6H-cycloheptal4,5]pyrrolol2,3-g]isoquinolin-12~12H)-one, mp 293-296C, crystallized from ethanol.
Anal. Calcd. for C17H24N20: C, 74.96; H, 8.88; N, 10.28 Found: C, 74.79; H, 8.74; N, 10.33 Example 9 Following the procedure of Example 6, starting from 2-isonitro-socyclooctanone and octahydro-2-methylisoquinolin-6,8-dione, there was obtained 2-methyl-2,3,4~4a,5,7,8,9,10~11,12,13a-dodecahydro-4a,13a-trans-lH,6H-cycloocta[4,5]pyrrolo[2,3-g~isoquinolin-13(13H~-one, mp 298-300C, crystallized from water-dimethylformamide.
Anal- Calcd. for C18H26N2O: C, 75,48; H, 9.15; N, 9.78 Found: C, 75.2~; H, 9.04; N, 9.70 Example '10 Preparation of 2,-3,4 ! 4a ~ 5,7,8,9,10,11a'-decahydro-4a,11a-trans-lH,~H-cyclohexaE4~5]pyrrolo[2~3-g]iso~uinolin-ll(llH)-one A mixture of 1.9 g. of 2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexaE4,5]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 5% aqueous hydrochloric acid, washed with water, brine, and dried over sodium sulfate. Evaporation of the solvent afforded 1.4 g. of the carbamate, 2-ethoxycarbonyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-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 extractionO
The crude carbamate ~1.4 g.) was heated to reflux for 24 hours with 15 ml. of 30% aqueous sodium hydroxide in a mixture of 15 ml.
of e~hanol and 5 ml~ of dioxane. The mixture was concentrated in vacuo and the residue was dissolved in 5~ aqueous hydrochloric acid and washed with chloroform. The aqueous solution was made alkaline with ammonium hydroxide and extracted with chloroform. ~he extracts were washed with brine, dried, and concen~rated to afford 0.65 g.
of 2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa-l4~5]pyrrolo[2~3-g]isoquinolin-ll(llH)-one~
$;~
;22~
Example 11 Following the prooK~re of Example io, starting from 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-lO(lOH)-one~ there was obtained via the carbamate, 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclo-penta[4,5]pyrrolor2,3-g]isoquinolin-lO(lOH)-one, mp 242-245C.(dec.), crystallized from ethanol-ethyl acetate.
Anal- Calcd. for C14H18N20; C, 73.01; H, 7.88; N, 12.16 Found: C, 72,84: H, 7.78; N, 12.30 E ~
Following the procedure of Example 10, starting from 2 methyl-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-lH,6H~cyclo-octa[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,iO~ 2,~3a-tetradecahydro-4a,13a-trans-cycloocta[4,5]pyrrolo[2,3-g]isoquinolin-4-one, mp 283-5C., crystallized from ethanol.
Anal. Calcd. for C17H24N20: C, 74.96; H, 8.88; N, 10.28 Found: C, 74.71; H, 8.65: N, 10.24 ~6C~2215 Exa~ple 13 Preparation of 2-[4-(4--fluorophenyl)-4-oXobutyl]-2,3,4,4a,5,7,8,9,10, lla-decahydro-4a,11a-trans-lH,6H-cyc'lohexa[4,5]pyrrolo[2,3-g]iso-quinolin-ll(llH)-one -A mixture of 0.68 g. of 2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa[4,5]pyrrolo~2,3-g]isoquinolin-ll(llH)-one, 1.68 g. of ~-chloro-p-fluorobutyrophenone, and 1.55 g. of potassium carbonate in 15 ml. of diethylketone was heated ~o reflux for 24 hours. The mixture was cooled, filtered and concentrated.
The residue was chromatographed (dry column) eluting with the organic phase of a mixture prepared by shaking ~by volume) 90 parts chloro-form, 30 parts methanol, 10 parts water, and 6 parts acetic acid to afford 0.85 g. of a crude amine, which was recrystalli2edfrom ethanol to afford 0.42 g. of pure 2-[4-(4-fluorophenyl)-4-oxobutyl~-2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa[4,S~pyrrolo [2,3-g]isoquinolin-ll(llH~- one as a crystalline solid, mp 220-222.' Anal. Calcd. for C25H29N2O2F: 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 :~~S,~
~6t~ZZ~
- Example 14 Following the prooK~re of Example 13, alkylation of 2,3,4,4a, 5,7,8,9,10,11a-dPcahydro-4a,11a-trans-lH,6H-cyclohexa[4,5]pyrrolo-[2,3-g]isoquinolin-ll(llH) one with (2-bromoethyl)benzene afforded 2-(2-phenylethyl)-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-ll(llH)-one, mp 250-256C. (dec.),as a crystalline solid after recyrstallization from ethanol.
Anal. Calcd~ for C23H28N20: C, 79.27; H, 8.10; N, 8~04 Found: C, 79;29; H, 8.40; N, 7.97 Example 15 Following the procedure of Example 13, alkylation of 2,3,4,4a, 5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa[4,5]pyrrolo-[2,3-g]isoquinolin-ll(llH)-one with benzyl chloride afforded 2-benzyl-2,3,4,4a,5,7,8~9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclo-hexa~4,5]pyrrolo~2,3-g]isoquinolin-ll(llH)-one, mp 266-268C, as a crystalline solid after recrystallization from ethanol.
Anal. Calcd. for C22H26N2O: C, 79.00; H, 7.84; N, 8.38 Found: C, 79.27; ~, 8.03; N, 8.60 Example 16 Following the procedure of Example 13, alkylation of 1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopentaE4,5]pyrrolo[2,3-g]-isoquinolin-lO(lOH~-one with benzyl chlorid~ afforded 2-benzyl-1,2~3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]-pyrrolo[2,3-g]isoquinolin-lO~lOH)-one, mp 258-260C.(dec~), as a crystalline solid after recrystalli~ation from ethanol.
Anal. Calcd. for C21H2~N20: C, 78.71r H, 7.55; N, 8.74 Found: C, 78.97; H, 7.54; N, 8.63 Example 17 Following the procedure of Example ~3, alkylation of 1,2,3,4, 4a,5,7,8,9,1Oa-decahydro-4a,1Oa-trans-6H-cyclopenta[4,5]pyrrolo-[2,3-g]isoquinolin-lO(lOH)-one with r -chloro-p-fluorobutyrophenone afforded 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-lO(lOH)-one, mp 225-227~C., as a crystalline solid ater recrystalli-zation from ethanol.
Anal. Calcd- for C24H27FN202: C,73.07; H,6.90; N,7-10; F,4~82 Found: C,72~76; H,6.86; N,1.24; PJ4.71 -S ~L
~6V;~ZI~
Example 18 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-lO~lOH)-one with (2-bromoethyl)benzene afforded 2-(2-phenylethyl)-1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,1Oa-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-lO(lOH)-one, mp 251-254C.
(dec.), as a crystalline solid after recrystallization from ethanol.
Anal. Calcd. for C22H26N20: C, 79.00; H, 7.84; N, 8.38 Found: C, 78.68; H, 7.72; N, 8.28 Example 19 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-lO(lOH)-one with 4-methoxybenzyl chloride afforded 2-(4-methoxybenzyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g~isoquinolin-4-one, mp 236-8 (dec.) r as a crystalline solid after recrystallization from ethanol.
Anall Calcd. for C22H26N202 Found: C, 75.39; H, 7.41; N, 8.03 .
X ~
~3~6~;2;;28 Example 20 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-lO(lOH)-one with 4-chlorobenzyl chloride afforded 2-(4-cXlorobenzyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g~isoquinolin-lO(lOH)-one as a crystalline monohydrate, mp 254-6 after recrystallization from etha-nol.
~nal. Calcd. for C21H23N20 Cl H20: C,67.63; H,6.22; N,7~51; Clf9.51 Found: C,67.86; H,6.38; N,7.50; C1,9.92 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-cyclopental4,5]pyrrolo[2,3-g]-isoquinolin-lO(lOH)-one with allyl bromide afforded 2-(2-propenyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]-pyrrolo[2,3-g]isoquinolin-lO(lOH)-one, mp 257-9~ ~dec.), after recrystallization from ethyl acetate-ethanol.
Anal. Calcd. for C17H22N20: C, 75.52; H, 8.20; N, 10.36 Found: C, 75.25; H, 8.17; ~, 10.36 -S-~
X
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'Exampl'e''22 Following the procedure of Example 13 alkylation of 1,2,3,4, 4a,5,7,8,9,10a-decahydro-4a,10a-trans-S~-cyclopenta[4,5]pyrrolo-[2,3-g]isoquinolin-lO(lOH)-one with 2-bromoethyl ether afforded 2-(2-ethoxyethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a~10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3~g]isoquinolin-lO~lOH)-one, mp 236-B
(dec.~ as a crystalline solid after recrystallization from ethanol.
Anal. Calcd. for C18H26N202: ' Found: C, 71.35; H, 8.47; N, 9~23 E~
Following the procedure of Exampl~ 13, alkylation of 2,3,4, 4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-lH,6~-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-oxobutyl]-1,2,3,4,4a,$, 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]iso~uinolin and the indicated halide.
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Z;~8 Example 49 Pre~aration of 2-methyl-~1,2,-3,4,4a,5,7,8,9,10a-decahydro-4_,1Oa-- trans--6H-cycl-openta[-4,5]pyrrolo[2,3-g]isoquinolin-lO(lOH)-thione A mixture of 244 mg. (1.0 mmol) of 2-methyl-1,2,3,4,4a,5,7,8, 9,lOa-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquino-lin-lO(lOH)-one and 222 mg. ~1.0 mmol) of phosphorus pentasulfide in 15 ml. of dioxane was stirred and refluxed for 17 hours. The dioxane solution was decanted off and water (20 ml,~' and enough ammDnium hydroxide bo brLng the pH to 8-9 was added ~o the residue.
The mixture was extracted with chloroform, and the extracts were washed with brine, dried and evaporated. The 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-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta-[4,5]pyrrolo[2,3-g]isoguinolin-lO(.lOH)-thione, mp 224-227C(dec.).
Anal. Calcd. for C15H20N2S: C, 69~19; H, 7.74; N, 10.76 Found: C, 68.97; H, 7.59; N, 10.97 .~ .j..
~6~
-Example 50 The procedure of Example 49 is u~ed to prepare 2-methyl-2,3, 4,4a,5,7,8~9,10llla-decahydro-4a,1la-trans-lH,6H-cyclohexa[4,5]
pyrrolo[2,3~g]isoquinolin~ llH)-~hione starting from 2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-~rans-lH,6H~cyclohexa-[4,5]pyrrolo[2,3-g]isoquinolin-ll(llH)-one.
Example Sl The procedure of Example 4g is used to prepare 1,2,3,4f4a, 5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta~4,5]pyrrolo[2,3-g]-isoquinolin-lO(lOH)-thione starting from 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo~2,3-g~isoquinolin-lO(lOH)-one.
Example '52 The procedure of Example 13 is used to prepare 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-glisoguinolin-lO'(lOH)-thione starting from 1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,1Oa-tr~ns-6H-cyclopenta[4,5]pyrrolo [2,3-g]isoquinolin-lO(lOH~-thione Y-chloro-p-fluorobutyrophenone.
fluorobutyrophenone.
~xample 53 The procedure of Example 13 i5 used to prepare 2-~2-phenyl-ethyl)-1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,1Oa-trans-6X-cyclopenta-~4,5]pyrrolo[2,3-g]isoquinolin-lO(lOHI-thione starting from 1,2,3,4, 4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopentat4,5]pyrrolo--~2,3~g~isoquinolin-lO(lOH)-thione and (2-bromoethyl)benzene.
~( 6~
~L6~221~1 Example 54 Preparation of 6-benzoyl-2-methyl-1,2,3,4,4a,5,7,8,9!1Oa-decahydro-4a lOa-trans-6H-c cl-o enta[4 5~ yrrolo~2 3- ]iso uino-l.in-lO(lOH)-one Y P _ ~ P ~ g q . . . _..
To a mixture of 244 mg. (1.0 mmol~ of 2-methyl-1,2,3,4,4a,5,7, 8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo:r2,3-g]iso-quinolin-lO:(lOH)-one in 10 ml. of dry tetrahydrofuran at -30 is added 0.5 ml. of n-butyllithium ~1.1 mmol of 2.2M solution in hexane) over 2-3 minutes via syringe. The solution is stirred for 30 minutes at -30 and 168 mg. of benzoyl chloride (1.2 mmol~ is added over 2-3 minutes. The solution is stirred 1 hour at -30 and 30 minutes at room temperature. The mixture is poured onto ice and extracted with chloroform. The extracts are washed with brine, dried (sodium sulfate), concentrated and chromatographed to afford the 6-ben20yl-2-methyl-1,2,3,4,4a,5,7,8,9,1Oa-decahydro-4a,1Oa-trans-6H-cyclopenta-[4,5]pyrrolo:l2,3-g]isoquinolin-lO~lOH)-one.
Exampl-e 55 Following the procedure of Example 54, 2,6-dimethyl-1,2,3,4,4a, 5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4~5~pyrrolo-~2,3-g]-isoquinolin-lO(lOH)-one is prepared using methyl iodide instead of benzoyl chloride.
,Y
~6~ZZ8 Example 56 -Preparation of 2-(2-~ydroxy-3l3-dimethylbut;~l)-2 ! 3,4,4a,5,7,8,9,10 lla-decahydro-4a,11a-trans lH,6H-cyclohexa~4,5]pyrro-10[2-,3-g]iso-quino~lin-ll(llH)-one A solution of 488 mg. (200 mmol) of 2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa~4,5]pyrrolo[2,3-g]isoquinolin-ll(llH)-one and 300 mg. (3.0 mmol) of 3,3-dimethyl-1,2-epoxybutane in 15 ml. of methanol was refluxed for 24 hours and concentrated.
The residue was chromatographed, and the crude product ~350 mg.) crystallized from ethanol to give 200 mg. of 2-(2-hydroxy-3,3-dimethyl-butyl~-2~3~4~4a~5~7~8~9~lo~lla-decahydro-4a~lla-trans-lHr6H-cyclo-hexa[4,5]pyrrolo[2,3-g]isoquinolin-ll~llH~-one, mp 276-278C(dec.~.
Anal- Calcd- for C21H32N22 C, 73-22; H~ 9-36; N~ 8-13 Found: C, 73.39; H, 9.31; N, 8.15 Examp'l'e 57 The procedure of Example 56 is used to prepare 2-(2-hydroxy~
2-phenylethyl)-l~2~3~4~4a~5~7~8~9~loa-decahydro-4a~loa-trans-6~-cylopentar4,5]pyrrolo[2,3-g]isoquinolin-lO~lOH)-one starting from 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]-pyrrolo[2,3-g]isoquinolin-lO(lOH~-one and styrene oxide ~Example ~58 Following the procedure of Example 56, alkylàtion of 1,2,3,4, 4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolor2,3-g]isoquinolin-lO(lOH)-one with ethylene oxide at room temperature aforded 2-(2-hydroxyethyl)-1,2,3,4,4a,5,7,8,9,10a-d~cahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]iso~uinolin-lO(lOH~-one, mp 237-9 (dsc.) as a crystalline solid af~e~ recrystalliza~ion from ethanol~
Anal- CalCd~ for C16H22N22 C, 70.04, H~ ~08; N~ 10-21 Found; C, 69.66; H, 8017; N, 10.19 X ~
(J Z28 Example 59 Following the procedure of Example 56, alkylation of 1,2,3,4, 4a,5,7,8,9,1Oa-decahydro-4a,1Oa-trans-6H-cyclopenta[4,5~pyrrolo-~2,3-g]isoquinolin-lO(lOH)-one with 3,3-dimethyl-1,2-epoxybutane afforded 2-(2-hydroxy-3,3-dimethylbutyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-lO(lOH)-one, mp 284-6 (dec.), as a crystalline solid after recrystal-lization from ethanol.
20 30N202: C, 72,69; EI, 9715; N, 8.48 Found: C, 72.80; H, 9.02; N, 8.55 ~xample 60 A mixture of 30 mg of sodium hydride dispersion (57%, washed free of oil~ and 2 ml of dry dimethyl sulfoxide (Dr~SO) was heated to 65-70 for 1.5 hrs. The solution was cooled and a solution of 244 mg of 2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-lO~lOH)-one in 1 ml of dry 15- D~ISO 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-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a~10a-trans-6H-cyclopenta~
[4~5~pyrrolo[2~3-g]isoquinolin-lO[lOH)-one as a crystalline solid, ` mp 169-171 after recrystallization from ethyl acetate~ethanol.
Anal~ Calcd. Eor C22H26N20: C, 79.00; H, 7,84; N, 8.35 Found~ C, 78.~2; H, 7,84; N, 8.55 ~1 '~6VZZ8 Example 61 To a solution of 2.35 g of rac.-2-methyl-1,2,3,4,4a,5,7,8,9, lOa-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g~isoquino-lin-lO(lOH)-one in 20 ml o~ methanol was added a solution of 3.62 g of (+)'~dibenzoyl-(D)-tartaric acid monohydrate in 20 ml of methanol.
The mixture was concentrated and crystallized from methanol three times and converted to the free base with ammonium hydroxide. Recry-stallization of the base from ethanol afforded 0.18 g of 1-)-2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,1Da-trans-6H-cyclopenta[4,5]-pyrrolo[2,3-g]isoquinolin-lO~lOH~-one, mp 270-2 (dec.). The hydrochloride salt gave [~]~5- 101.17 in methanol (1~).
'Exa~p'l'e'`62 Preparation of 2-[4-(4-fluorophenyl)-4-hydxoxybutyl]-1,2,3,4, 4a,5,7,8,9,10a-decahydro-6H-4a,10a-trans-cyclopenta[4,5]pyrrolo-[2,3-g]isoquinolin-lO~lOH)-one.
A mixture of 394 mg (l.Ommol) of 2-[4-(4-fluorophenyl)-4 oxobuty]-1,2,3,4,4a,5,7,8,9,1Oa-decahydro-6H-4a,1Oa-trans-cyclopenta-[4,5]pyrrolo[2,3-g]isoquinolin-lO(lOH)-one and 151 mg of sodium borohydride (4.0 mmol) in 15 ml of ethanol was stirred at room tem-perature for 24 hrs. A second portion of ~odium borohydride (150 mg, 4.0 mmol) was added, and the mixture was stirred further at room temperature for 24 hrs. The mixture was poured into 50 ml of water and`filtered to remove the white solid product containing some starting material. Dry column chromatoyraphy 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~-5-hydroxybutyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-6H-4a,10a-trans-cyclopenta~4,5]pyrrolo[2,3-g]isoquinolin-lO~lOH)-one, mp 243-5, as a mixture of diastereomers.
Anal. Calcd- for C24H29 2 2 30Found: C, 72~68; H, 7.56; N, 7.33 72 ~
~s ., - -~6~Z2~
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,11a-trans-lH,6H-cyclohexa[4,5]pyrrolo[2,3-g]iso-quinolin-ll(llH)-one afforded 2-~4~4-fluorophenyl)-4-hydroxybutyl]
2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa[4,5]-pyrrolo r2,3-g]isoquinolin-ll(llH)-one, as a mixture of diastereomers, - mp 239-41, crystallized from 1,4-dioxane, cd- for C25H31N2O2F: C, 73.14; H, 7.61; N, 6.82 Found: C, 73~18: H, 7.72; N, 6.82 Example 64 Followingthe procedure of Example 62, sodium borohydride reduction of 2-[4-(4-fluorophenyl)-4-oxobutyl]-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 afforded 2-r4-(4-fluorophenyl)-4-hydroxy-butyl]-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, as a mixture of diastereomersl mp 249-51, crystallized from 1,4-dioxane.
27 35 2 2 ' . ; , . ; N, .39 Found: C, 73.71; H, 8~05; N, 6.37 X ~3 ~ 6~Z~
Example 65 Preparation of 5-;[(2-~ethylamino?eth~l]-cyclohexane-l~3-dione To a stirred solution of N-methyl-1,5-dimethoxycyclohexa-1,4-diene-3-ethyl-amine(5.5g, 27.9 mmol) in 20 ml of tetrahydrofuran was added 10 ml of 6N hydrochloric acid in one por~ion. The warm solution was heated for 15 min. at 50C and concentxated 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 50X~ resin (previously washed with 2N HCl and deionized water) in a sintered glass funnel.
After a few minutes, the aqueous solution was drawn out by suction, and the resin rinsed with four 50 ml-portions of water, and then with eight 35 ml-portions''of 2M aqueous pyridine. Pyridine fractions 3-8 were pooled and concentrated to give 3.9 g of 5-[(2-methylamino)-ethyl~-cyclohexane-1,3-dione, An analytical sample crystallized from water and had mp 171-4C~
Anal. Calcd. for C~H15NO2: C, 63~88; H, 8.93; N, 8.28 Found: C, 63.50; H, 8.87; N, 8.15 xa'mpl'e''66 .. .. . . . .. .. .. . . . . . . .. . . . .
Prepar'ation of 6-~enzyl'-2,3,4~4'a,'5,7',8,9,10','11'a-decahydro-4a,11a-trans-lH,6H-cyclo~exa[4,5]pyrrolo[2,3-g]isoquinoli~-ll(llH)-one Following the procedure of example 60, 316 mg of 2-ethoxy-carbonyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoguinolin-ll(llH~-one was alkylated with 190 mg of benzyl chloride to afford 6-benzyl-2-ethoxy-carbonyl-2,3, 4~4a~5~7~8~9~lo~lla-decahydro-4a~lla-txans-lH,6H-cyclohexaf4~s~pyr rolo[2,3-g]isoquinolin-ll(llH)-one (220 mg~, mp 54-60C which was hydrolyzed following the procedure of example 10 with sodium hydroxIde to ~f ford 6-benzyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa[4,53pyrrolof2,3-g3isoquinolin-ll(llH)-one~
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Example 65 Preparation of 5-;[(2-~ethylamino?eth~l]-cyclohexane-l~3-dione To a stirred solution of N-methyl-1,5-dimethoxycyclohexa-1,4-diene-3-ethyl-amine(5.5g, 27.9 mmol) in 20 ml of tetrahydrofuran was added 10 ml of 6N hydrochloric acid in one por~ion. The warm solution was heated for 15 min. at 50C and concentxated 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 50X~ resin (previously washed with 2N HCl and deionized water) in a sintered glass funnel.
After a few minutes, the aqueous solution was drawn out by suction, and the resin rinsed with four 50 ml-portions of water, and then with eight 35 ml-portions''of 2M aqueous pyridine. Pyridine fractions 3-8 were pooled and concentrated to give 3.9 g of 5-[(2-methylamino)-ethyl~-cyclohexane-1,3-dione, An analytical sample crystallized from water and had mp 171-4C~
Anal. Calcd. for C~H15NO2: C, 63~88; H, 8.93; N, 8.28 Found: C, 63.50; H, 8.87; N, 8.15 xa'mpl'e''66 .. .. . . . .. .. .. . . . . . . .. . . . .
Prepar'ation of 6-~enzyl'-2,3,4~4'a,'5,7',8,9,10','11'a-decahydro-4a,11a-trans-lH,6H-cyclo~exa[4,5]pyrrolo[2,3-g]isoquinoli~-ll(llH)-one Following the procedure of example 60, 316 mg of 2-ethoxy-carbonyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoguinolin-ll(llH~-one was alkylated with 190 mg of benzyl chloride to afford 6-benzyl-2-ethoxy-carbonyl-2,3, 4~4a~5~7~8~9~lo~lla-decahydro-4a~lla-txans-lH,6H-cyclohexaf4~s~pyr rolo[2,3-g]isoquinolin-ll(llH)-one (220 mg~, mp 54-60C which was hydrolyzed following the procedure of example 10 with sodium hydroxIde to ~f ford 6-benzyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-lH,6H-cyclohexa[4,53pyrrolof2,3-g3isoquinolin-ll(llH)-one~
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Claims (32)
1. A process for the manufacture of cycloalka[4,5]-pyrrolo[2,3-g]isoquinolines of the general formula A
wherein R1 is hydrogen, alkyl, alkanoyl, arylcarbonyl or aryl-alkyl; R2 is hydrogen, alkyl, hydroxyalkyl, arylhydroxyalkyl, alkoxyalkyl, alkanoyloxyalkyl, arylcarbonyloxyalkyl, alkanoyl-alkyl, arylcarbonylalkyl, arylalkyl, alkenyl, cycloalkyl-alkyl, alkynyl, thienyl-alkyl, furyl-alkyl, arylcarboxamido-alkyl, arylalkenyl, alkenyloxyalkyl, aryloxyalkyl, arylalkyl-oxyalkyl or aryl-N-imidazolonylalkyl; X is O or S; and n is 3, 4, 5 or 6;
with alkyl, alkoxy and alkanoyl having 1 to 7 carbon atoms, alkenyl and alkinyl having 2 to 7 carbon atoms, cycloalkyl having 3 to 6 carbon atoms and with aryl being phenyl or phenyl bearing one or more substituents selected from the group con-sisting of halogen, trifluoromethyl, alkyl, alkoxy, nitro, amino, alkylamino and dialkylamino;
optical and geometric isomers of these compounds and pharmaceuti-cally acceptable acid addition salts thereof, which process com-prises a) for preparing a compound of the general formula Ia wherein R? is alkyl, alkoxyalkyl or cycloalkylalkyl and n is as previously described, treating a compound of the general formula IX
wherein R? and n are as previously described, with formaldehyde, or b) for preparing a compound of the general formula Ia above, treating a compound of the general formula XII
wherein R? is as previously described, with a compound of the general formula VII
in the presence of a reducing agent or with a compound of the general foxmula VIII
or a precursor thereof, in which formulae n is as previously described, or c) for preparing a compound of the general formula Ib wherein n is as previously described, N-dimethylating a compound of the formula Ia above wherin R? is methyl, or d) for preparing a compound of the general formula IIe wherein R? is hydrogen, alkyl or arylalkyl, R? is hydrogen, alkyl, alkoxyalkyl, arylalkyl, alkenyl, cycloalkyl-alkyl, alkynyl, thienyl-alkyl, furyl-alkyl, alkenyloxyalkyl, arylalkenyl, aryloxyalkyl or arylalkyloxyalkyl, and n is as previously described, treating a compound of the general formula Ie wherein R?, R? and n are as previously described with phos-phorus pentasulfide, or e) for preparing a compound of the general formula A d wherein R is alkyl, hydroxyalkyl, arylhydroxyalkyl, alkoxy-alkyl, alkanoyloxyalkyl, arylcarbonyloxyalkyl, alkanoylalkyl, arylcarbonylalkyl, arylalkyl, alkenyl, cycloalkyl-alkyl, thienyl-alkyl, alkynyl, furyl-alkyl, arylcarboxamidoalkyl, arylalkenyl, alkenyloxyalkyl, aryloxyalkyl, arylalkyloxyalkyl or aryl-N-imidazolonylalkyl and X and n are as previously described, substituting a compound of the general formula A b wherein X and n are as previously described, at the isoquinoline nitrogen atom, by treating with a halide or epoxide, or f) for preparing a compound of the general formula A ' C
wherein Rl is alkyl, alkanoyl, arylcarbonyl or arylalkyl, is alkyl, alkoxyalkyl, alkanoyloxyalkyl, arylcarbonyloxy-alkyl, alkanoyl, arylcarbbnylalkyl, arylalkyl, alkenyl, cycloalkyl-alkyl, thienylalkyl, alkynyl, furylalkyl, aryl-carboxamidoalkyl, arylalkenyl, alkenyloxyalkyl, aryloxyalkyl, arylalkyloxyalkyl or aryl-N-imidazolonylalkyl and X and n are as previously described, substituting a compound of the general formula wherein RV2I, X and n are as previously described, at the at the pyrrole nitrogen atom, by formation of the pyrrole anion with a strong base followed by quenching with a halide, or g) for preparing a compound of the general formula Ac"
wherein RI2V is hydroxyalkyl or arylhydroxyalkyl, and Rl, X and n are as previously described, splitting off the protecting group in a compound of the general formula XIV
wherein R2 is an O-protected hydroxyalkyl- or aryl-hydroxy alkyl-group and Ri, X and n are as previously.described, or h) for preparing a compound of the general formula Ad"
wherein R?, X and n are as previously described, reducing the alkanoylalkyl or arylcarbonylalkyl group in a com-pound of the general formula Ad''' wherein R? is alkanoylalkyl or arylcarbonylalkyl, and X and n are as previously described, or i) for preparing a compound of the general formula Ah wherein X, n and R? are as previously described, splitting off the urethane group in a compound of the general formula XIII
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 isomers, and/or k) if desired, separating the trans isomer from the mixture obtained, and/or l) if desired, resolving a racemic mixture obtained into the optical antipodes and/or m) if desired, converting a compound obtained or a non-pharmaceutically acceptable acid addition salt into a pharma-ceutically acceptable acid addition salt thereof.
wherein R1 is hydrogen, alkyl, alkanoyl, arylcarbonyl or aryl-alkyl; R2 is hydrogen, alkyl, hydroxyalkyl, arylhydroxyalkyl, alkoxyalkyl, alkanoyloxyalkyl, arylcarbonyloxyalkyl, alkanoyl-alkyl, arylcarbonylalkyl, arylalkyl, alkenyl, cycloalkyl-alkyl, alkynyl, thienyl-alkyl, furyl-alkyl, arylcarboxamido-alkyl, arylalkenyl, alkenyloxyalkyl, aryloxyalkyl, arylalkyl-oxyalkyl or aryl-N-imidazolonylalkyl; X is O or S; and n is 3, 4, 5 or 6;
with alkyl, alkoxy and alkanoyl having 1 to 7 carbon atoms, alkenyl and alkinyl having 2 to 7 carbon atoms, cycloalkyl having 3 to 6 carbon atoms and with aryl being phenyl or phenyl bearing one or more substituents selected from the group con-sisting of halogen, trifluoromethyl, alkyl, alkoxy, nitro, amino, alkylamino and dialkylamino;
optical and geometric isomers of these compounds and pharmaceuti-cally acceptable acid addition salts thereof, which process com-prises a) for preparing a compound of the general formula Ia wherein R? is alkyl, alkoxyalkyl or cycloalkylalkyl and n is as previously described, treating a compound of the general formula IX
wherein R? and n are as previously described, with formaldehyde, or b) for preparing a compound of the general formula Ia above, treating a compound of the general formula XII
wherein R? is as previously described, with a compound of the general formula VII
in the presence of a reducing agent or with a compound of the general foxmula VIII
or a precursor thereof, in which formulae n is as previously described, or c) for preparing a compound of the general formula Ib wherein n is as previously described, N-dimethylating a compound of the formula Ia above wherin R? is methyl, or d) for preparing a compound of the general formula IIe wherein R? is hydrogen, alkyl or arylalkyl, R? is hydrogen, alkyl, alkoxyalkyl, arylalkyl, alkenyl, cycloalkyl-alkyl, alkynyl, thienyl-alkyl, furyl-alkyl, alkenyloxyalkyl, arylalkenyl, aryloxyalkyl or arylalkyloxyalkyl, and n is as previously described, treating a compound of the general formula Ie wherein R?, R? and n are as previously described with phos-phorus pentasulfide, or e) for preparing a compound of the general formula A d wherein R is alkyl, hydroxyalkyl, arylhydroxyalkyl, alkoxy-alkyl, alkanoyloxyalkyl, arylcarbonyloxyalkyl, alkanoylalkyl, arylcarbonylalkyl, arylalkyl, alkenyl, cycloalkyl-alkyl, thienyl-alkyl, alkynyl, furyl-alkyl, arylcarboxamidoalkyl, arylalkenyl, alkenyloxyalkyl, aryloxyalkyl, arylalkyloxyalkyl or aryl-N-imidazolonylalkyl and X and n are as previously described, substituting a compound of the general formula A b wherein X and n are as previously described, at the isoquinoline nitrogen atom, by treating with a halide or epoxide, or f) for preparing a compound of the general formula A ' C
wherein Rl is alkyl, alkanoyl, arylcarbonyl or arylalkyl, is alkyl, alkoxyalkyl, alkanoyloxyalkyl, arylcarbonyloxy-alkyl, alkanoyl, arylcarbbnylalkyl, arylalkyl, alkenyl, cycloalkyl-alkyl, thienylalkyl, alkynyl, furylalkyl, aryl-carboxamidoalkyl, arylalkenyl, alkenyloxyalkyl, aryloxyalkyl, arylalkyloxyalkyl or aryl-N-imidazolonylalkyl and X and n are as previously described, substituting a compound of the general formula wherein RV2I, X and n are as previously described, at the at the pyrrole nitrogen atom, by formation of the pyrrole anion with a strong base followed by quenching with a halide, or g) for preparing a compound of the general formula Ac"
wherein RI2V is hydroxyalkyl or arylhydroxyalkyl, and Rl, X and n are as previously described, splitting off the protecting group in a compound of the general formula XIV
wherein R2 is an O-protected hydroxyalkyl- or aryl-hydroxy alkyl-group and Ri, X and n are as previously.described, or h) for preparing a compound of the general formula Ad"
wherein R?, X and n are as previously described, reducing the alkanoylalkyl or arylcarbonylalkyl group in a com-pound of the general formula Ad''' wherein R? is alkanoylalkyl or arylcarbonylalkyl, and X and n are as previously described, or i) for preparing a compound of the general formula Ah wherein X, n and R? are as previously described, splitting off the urethane group in a compound of the general formula XIII
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 isomers, and/or k) if desired, separating the trans isomer from the mixture obtained, and/or l) if desired, resolving a racemic mixture obtained into the optical antipodes and/or m) if desired, converting a compound obtained or a non-pharmaceutically acceptable acid addition salt into a pharma-ceutically acceptable acid addition salt thereof.
2. A process in accordance with claim 1, wherein process embodiments a), b), c), d), e), f), g), j), k), l) and m) are performed.
3. A process in accordance with claim 1 wherein process embodiment h) is performed.
4. A process in accordance with claim 1 wherein Rl is hydrogen.
5. A process in accordance with claim 4, wherein R2 is alkyl, hydroxyalkyl, arylhydroxyalkyl, alkoxyalkyl, aryloxyalkyl, alkanoylalkyl, arylcarbonylalkyl or arylalkyl.
6. A process in accordance with claim 5, wherein n is 3 or 4.
7. A process in accordance with claim 6, wherein X is O.
8. A process in accordance with claim 7, wherein there are prepared the trans isomers of compounds of the general formula A given in claim 1.
9. A process in accordance with claim 2, wherein there is prepared 2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-glisoquinolin-10(10H)-one by reacting octahydro-2-methylisoquinolin-6,8-dione with l-isonitrosocyclo-pentanone in the presence of zinc.
10. A process in accordance with claim 2, wherein there is prepared 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]iso-quinolin-10(10H)-one by substituting 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5Jpyrrolo[2,3-g]isoquinolin-10(10H)-one at the isoquinoline nitrogen atom with .gamma.-chloro-p-fluorobutyrophenone.
.
.
11. A process in accordance with claim 2, wherein there is prepared 2-(2-phenylethyl)-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 by substituting 1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-gJisoquinolin-10(10H)-one at the iso-quinoline nitrogen atom with (2-bromoethyl)benzene.
12. A process in accordance with claim 2, wherein there is prepared (-)-2-methyl-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 by resolving the corresponding racemic mixture with (+)-dibenzoyl(D)-tartaric acid monohydrate.
13. A process in accordance with claim 2, wherein there is prepaxed 2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one by treating 1,2,3,5,6,7,8,9-octahydro-2-[2-(methylamino)ethyl]-4H-carbazol-4-one hydrochloride with paraformaldehyde or by reacting octahydro-2-methylisoquinolin-6,8-dione with 2-isonitrosocyclo-hexanone in the presence of zinc.
14. A process in accordance with claim 2, wherein there is prepared 2-[4-(4-fluorophenyl)-4-oxobutyl]-2,3,4,4a,5,7,8,9,10, 11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]iso-quinolin-11(11H)-one by substituting 2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]iso-quinolin-11(11H)-one at the isoquinoline nitrogen atom with .gamma.-chloro-p-fluorobutyrophenone.
15. A process in accordance with claim 2, wherein there is prepared 2-(2-phenylethyl)-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H-one by substituting 2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one at the isoquinoline nitrogen atom with (2-bromoethyl)benzene.
16. A process in accordance with claim 2, wherein there is prepared 2-methyl-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)-thione by treating 2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-y]isoquinolin-10(10H)-one with phosphorus pentasulfide.
17. Cycloalka[4,5]pyrrolo[2,3-g]isoquinolines of the general formula A
wherein R1 is hydrogen, alkyl, alkanoyl, arylcarbonyl or arylalkyl; R2 is hydrogen, alkyl, hydroxyalkyl, arylhydroxy-alkyl, alkoxyalkyl, alkanoyloxyalkyl, arylcarbonyloxyalkyl, alkanoylalkyl, arylcarbonylalkyl, arylalkyl, alkenyl, cyclo-alkyl-alkyl, alkynyl, thienyl-alkyl, furyl-alkyl, arylcarboxy--amidoalkyl, arylalkenyl, alkenyloxyalkyl, aryloxyalkyl, arylalkyloxyalkyl, or aryl-N-imidazolonylalkyl; X is O or S;
and n is 3, 4, 5 or 6;
with alkyl, alkoxy and alkanoyl having 1 to 7 carbon atoms, alkenyl and alkinyl having 2 to 7 carbon atoms, cycloalkyl having 3 to 6 carbon atoms and with aryl being phenyl or phenyl bearing one or more substituents selected from the group con-sisting of halogen, trifluoromethyl, alkyl, alkoxy, nitro, amino, alkylamino and dialkylamino;
optical and geometric isomers of these compounds and pharmaceuti-cally acceptable acid addition salts thereof, whenever prepared according to the process as claimed in claim 1 or by an obvious chemical equivalent thereof.
wherein R1 is hydrogen, alkyl, alkanoyl, arylcarbonyl or arylalkyl; R2 is hydrogen, alkyl, hydroxyalkyl, arylhydroxy-alkyl, alkoxyalkyl, alkanoyloxyalkyl, arylcarbonyloxyalkyl, alkanoylalkyl, arylcarbonylalkyl, arylalkyl, alkenyl, cyclo-alkyl-alkyl, alkynyl, thienyl-alkyl, furyl-alkyl, arylcarboxy--amidoalkyl, arylalkenyl, alkenyloxyalkyl, aryloxyalkyl, arylalkyloxyalkyl, or aryl-N-imidazolonylalkyl; X is O or S;
and n is 3, 4, 5 or 6;
with alkyl, alkoxy and alkanoyl having 1 to 7 carbon atoms, alkenyl and alkinyl having 2 to 7 carbon atoms, cycloalkyl having 3 to 6 carbon atoms and with aryl being phenyl or phenyl bearing one or more substituents selected from the group con-sisting of halogen, trifluoromethyl, alkyl, alkoxy, nitro, amino, alkylamino and dialkylamino;
optical and geometric isomers of these compounds and pharmaceuti-cally acceptable acid addition salts thereof, whenever prepared according to the process as claimed in claim 1 or by an obvious chemical equivalent thereof.
18. Compounds in accordance with claim 17 wherein R2 is other than hydrogen when R1 is other than hydrogen, whenever pre-pared according to the process as claimed in claim 2 or by an obvious chemical equivalent thereof.
19. Compounds in accordance with claim 17 wherein R1 is hydrogen and R2 is hydroxyalkyl or arylhydroxyalkyl, whenever prepared according to the process as claimed in claim 3 or by an obvious chemical equivalent thereof.
20. Compounds in accordance with claim 17, wherein R1 is hydrogen, whenever prepared according to the process as claimed in claim 4 or by an obvious chemical equivalent thereof.
21. Compounds in accordance with claim 17, wherein R1 is hydrogen and R2 is alkyl, hydroxyalkyl, arylhydroxyalkyl, alkoxy-alkyl, aryloxyalkyl, alkanoylalkyl, arylcarbonylalkyl or arylalkyl, whenever prepared according to the process as claimed in claim 5 or by an obvious chemical equivalent thereof.
22. Compounds in accordance with claim 17, wherein R1 is hydrogen, R2 is alkyl, hydroxyalkyl, arylhydroxyalkyl, alkoxyalkyl, aryloxyalkyl, alkanoylalkyl, arylcarbonylakyl or arylalkyl and n is 3 or 4, whenever prepared according to the process as claimed in claim 6 or by an obvious chemical equivalent thereof.
23. Compounds in accordance with claim 17, wherein R1 is hydrogen, R2 is alkyl, hydroxyalkyl, arylhydroxyalkyl, alkoxyalkyl, aryloxyalkyl, alkanoylalkyl, arylcarbonylalkyl or arylalkyl, n is 3 or 4 and X is 0, whenever prepared according to the process as claimed in claim 7 or by an obvious chemical equivalent thereof.
24. Compounds in accordance with claim 17 wherein R1 is hydrogen, R2 is alkyl, hydroxyalkyl, arylhydroxyalkyl, alkoxyalkyl, aryloxyalkyl, alkanoylalkyl, arylcarbonylalkyl or arylalkyl, n is 3 or 4 and X is 0 and which are the trans isomers, whenever pre-pared according to the process as claimed in claim 8 or by an obvious chemical equivalent thereof.
25. 2-Methyl-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, whenever prepared according to the process claimed in claim 9 or by an obvious chemical equivalent thereof.
26. 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]iso-quinolin-10(10H)-one, whenever prepared according to the process as claimed in claim 10 or by an obvious chemical equivalent thereof.
27. 2-(2-Phenylethyl)-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, whenever prepared according to the process as claimed in claim 11 or by an obvious chemical equivalent thereof.
28.(-)-2-Methyl-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, whenever prepared according to the process as claimed in claim 12 or by an obvious chemical equivalent thereof.
29. 2-Methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one, whenever prepared according to the process as claimed in claim 13 or by an obvious chemical equivalent thereof.
30. 2-[4-(4-Fluorophenyl)-4-oxobutyl]-2,3,4,4a,5,7,8,9,10, 11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]iso-quinolin-11(11H)-one, whenever prepared according to the process as claimed in claim 14 or by an obvious chemical equivalent thereof.
31. 2-(2-Phenylethyl)-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one, whenever prepared according to the process as claimed in claim 15 or by an obvious chemical equivalent thereof.
32. 2-Methyl-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)-thione, whenever prepared according to the process as claimed in claim 16 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US12560480A | 1980-02-28 | 1980-02-28 | |
| US125,604 | 1980-02-28 | ||
| US21611680A | 1980-12-15 | 1980-12-15 | |
| US216,116 | 1980-12-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1160228A true CA1160228A (en) | 1984-01-10 |
Family
ID=26823740
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000371766A Expired CA1160228A (en) | 1980-02-28 | 1981-02-26 | Cycloalka¬4,5|pyrrolo¬2,3-g|isoquinolines |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0035244B1 (en) |
| AR (2) | AR230638A1 (en) |
| AU (1) | AU540284B2 (en) |
| CA (1) | CA1160228A (en) |
| DE (1) | DE3170368D1 (en) |
| DK (1) | DK87981A (en) |
| HU (1) | HU185407B (en) |
| IE (1) | IE50983B1 (en) |
| IL (1) | IL62223A (en) |
| MC (1) | MC1377A1 (en) |
| NO (1) | NO156371C (en) |
| NZ (1) | NZ196363A (en) |
| PH (1) | PH16750A (en) |
| PT (1) | PT72595B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0091565B1 (en) * | 1982-03-29 | 1986-04-23 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | Process for the manufacture of isoquinoline diones |
| US4732902A (en) * | 1986-05-23 | 1988-03-22 | Hoffmann-La Roche Inc. | Pyrroloisoquinolinyl-dimethyloxoalkyl alkonoates and their use as antipsychotic agents |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1132553A (en) * | 1978-10-13 | 1982-09-28 | Gary L. Olson | Isoquinoline derivatives |
-
1981
- 1981-02-24 MC MC811502A patent/MC1377A1/en unknown
- 1981-02-26 EP EP81101406A patent/EP0035244B1/en not_active Expired
- 1981-02-26 IL IL62223A patent/IL62223A/en unknown
- 1981-02-26 DE DE8181101406T patent/DE3170368D1/en not_active Expired
- 1981-02-26 CA CA000371766A patent/CA1160228A/en not_active Expired
- 1981-02-26 NZ NZ196363A patent/NZ196363A/en unknown
- 1981-02-26 DK DK87981A patent/DK87981A/en not_active Application Discontinuation
- 1981-02-27 IE IE430/81A patent/IE50983B1/en unknown
- 1981-02-27 PT PT72595A patent/PT72595B/en unknown
- 1981-02-27 NO NO810683A patent/NO156371C/en unknown
- 1981-02-27 PH PH25280A patent/PH16750A/en unknown
- 1981-02-27 AU AU67909/81A patent/AU540284B2/en not_active Ceased
- 1981-02-27 AR AR284479A patent/AR230638A1/en active
- 1981-02-27 HU HU81487A patent/HU185407B/en not_active IP Right Cessation
-
1982
- 1982-02-22 AR AR288509A patent/AR231640A1/en active
Also Published As
| Publication number | Publication date |
|---|---|
| MC1377A1 (en) | 1982-01-19 |
| EP0035244B1 (en) | 1985-05-08 |
| DK87981A (en) | 1981-08-29 |
| AR231640A1 (en) | 1985-01-31 |
| EP0035244A3 (en) | 1981-10-28 |
| AR230638A1 (en) | 1984-05-31 |
| IE810430L (en) | 1981-08-28 |
| EP0035244A2 (en) | 1981-09-09 |
| HU185407B (en) | 1985-02-28 |
| PH16750A (en) | 1984-02-10 |
| PT72595B (en) | 1982-10-21 |
| IL62223A0 (en) | 1981-03-31 |
| IE50983B1 (en) | 1986-09-03 |
| NO810683L (en) | 1981-08-31 |
| IL62223A (en) | 1984-01-31 |
| AU6790981A (en) | 1981-09-17 |
| AU540284B2 (en) | 1984-11-08 |
| NZ196363A (en) | 1984-03-30 |
| NO156371B (en) | 1987-06-01 |
| NO156371C (en) | 1987-09-09 |
| DE3170368D1 (en) | 1985-06-13 |
| PT72595A (en) | 1981-03-01 |
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