NZ191830A - 4,4a,5,6,7,8,8a,9-octahydro-1h-pyrrolo(2,3-g)-isoquinolin-4-(thi)ones - Google Patents

4,4a,5,6,7,8,8a,9-octahydro-1h-pyrrolo(2,3-g)-isoquinolin-4-(thi)ones

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Publication number
NZ191830A
NZ191830A NZ191830A NZ19183079A NZ191830A NZ 191830 A NZ191830 A NZ 191830A NZ 191830 A NZ191830 A NZ 191830A NZ 19183079 A NZ19183079 A NZ 19183079A NZ 191830 A NZ191830 A NZ 191830A
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NZ
New Zealand
Prior art keywords
alkyl
hydroxyalkyl
octahydro
pyrrolo
trans
Prior art date
Application number
NZ191830A
Inventor
L Berger
G L Olsen
Original Assignee
Hoffmann La Roche
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=26754910&utm_source=***_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=NZ191830(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from US06/073,813 external-priority patent/US4260762A/en
Application filed by Hoffmann La Roche filed Critical Hoffmann La Roche
Publication of NZ191830A publication Critical patent/NZ191830A/en

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Description

New Zealand Paient Spedficaiion for Paient Number 1 91 830 Priority Dat^o): . .W.yVWi Complete Spsci^oation Filed: C lass: P.f7 .v.*•>.< Jft,T5 Publication Date: ..... .9. SEP. 1984 P.O. Journal, Wo: ....
P=tM» m. m <§5 No.: Date: NEW ZEALAND PATENTS ACT, 1953 1 J $nr^.
COMPLETE SPECIFICATION ISOQUIMOLINE DERIVATIVES if? We, P. HOFFMANN-LA ROCHE & CO. AXTIENGESELLSCHAFT, 124-184 Grenzacherstrassa, Basle, Switzerland, a Swiss Company hereby declare the invention for which 30V we pray that a patent may be granted toXKSB^us, and the method by which it is to be performed, to be particularly described in and by the following statement: - - 1 - (followed by page la) The present invention relates to octahydro-lH-pyrrolo[2,3-g]isoquinolines of the general formula X A 1 wherein R^ is hydrogen, alkyl, alkanoyl, aroyl or aralkyl; Rg and R^, independently, are hydrogen, alkyl, cycloalkyl, alkenyl, acyl, aryl or aralkyl; R^ is hydrogen, alkyl, hydroxyalkyl, phenyl-hydroxyalkyl, halophenyl-hydroxyalkyl, alkylphenyl-hydroxyalkyl, alkoxy-phenyl-hydroxyalkyl, alkoxyalkyl, aryloxy-hydroxyalkyl, alkoxy-hydroxy-alkyl, acyloxyalkyl, arylcarbonylalkyl, alkoxycarbonylalkyl, aralkyl, alkenyl, alkyl-cycloalkyl,alkynyl, thienyl-alkyl, furyl-alkyl, aryl-carboxamidoalkyl, acylalkyl, cyclic- alkyloxyalkyl, cyclic-alkyl-hydroxy-alkyl, alkenyloxyalkyl, aralkenyl, aryloxyalkyl, N-alkyl-pyrrolidinyl-alkyl, trifluoroalkyl of 2 to 6 carbon atoms, f or N-alkyl, wherein Rg and R^, independently, are hydrogen or R 7 2 NOV 1982 > 1 2 3 4 -6 7. 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 !'911®3CB30i alkyl, or taken together with the nitrogen, are a 5- or 6-membered saturated j heterocyclic ring; and X is O or S, j \ optical and geaiietric isomers of these oatrpounds and pharmaceutically acceptable acid addition salts thereof.
As used herein, the term "alkyl" preferably denotes "lower alkyl", which denotes j a straight or branched chain saturated hydrocarbon containing 1 to 7 carbon atoms, for i ' I example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, neopentyl, pentyl, heptyl, and . the like. The term "alkoxy" preferably denotes "lower alkoxy", which denotes an alkyl j ether group in which the lower alkyl group is as described above, for example, methoxy, j ethoxy, propoxy, pentoxy, and the like. The term "alkenyl" preferably denotes "lower j alkenyl", which denotes a straight or branched chain unsaturated hydrocarbon containing j i 2 to 7 carbon atoms, for example, vinyl, allyl, and the like. The term "alkynyl" J I preferably denotes "lower alkynyl", which denotes a straight or branched chain i unsaturated hydrocarbon containing 2 to 7 carbon atoms, for example, ethynyl, j propargyl, methylbutynyl, and the like. The term "halogen" or "halo" denotes the ! ! halogens, bromine, chlorine, fluorine, and iodine. The term "trifluoroalkyl of 2 to 6 ! carbon atoms" preferably denotes 2,2,2-trifluoroethyl and the like. The term "aryl" ; denotes phenyl or phenyl bearing one or more substituents selected from the group ! j consisting of halogen, trifluoromethyl, lower alkyl, lower alkoxy, nitro, amino, lower j 1 \ alkylamino, and di-lower alkylamino. The term "aralkyl" preferably denotes benzyl and , I I the like. The term "aryloxy" denotes an aryl ether group in which the aryl group is as \ j described above, for example, phenoxy and the like. The term "acyl" denotes an i i "alkanoyl" group derived from an aliphatic earboxylic acid of 1 to 7 carbon atoms, for ! i example, formyl, acetyl, propionyl, and the like; and an "aroyl" group derived from an i i aromatic carboxylic acid, such as benzoyl and the like. The term "acyloxy" denotes an i "alkanoyloxy" group derived from an aliphatic carboxylic acid of 1 to 7 carbon atoms, i for example, formyloxy, acetoxy, propionyloxy, and the like; and an "aroyloxy" group • 2NOVI98Z i 1 2 3 4 6 7 S 9 11 12 13 14 16 17 18 19 .21 22 23 24 26 27 191830 derived from an aromatic carboxylic acid, such as benzoyloxy and the like. The term "cyclie-alkyl" denotes a cycloalkyl group of 3 to 6 carbon atoms, that is, cyelopropyL, cyclobutyl, cyclopentyl and cyclohexyl, or a bicycloalkyl group such as bornyl or a saturated tricycloalkyl group such as adamantyl. The 5-membered or 6-membered/heterocyclic ring is derived from a saturated heterocyclic compound comprising one or two nitrogen atoms or one nitrogen atom and one oxygen atom where the second nitrogen atom may be substituted by alkyl or hydroxyalkyl, for example, morpholino, N-methyl-piperazino. piperazino, pyrrolidino, and the like.
Preferred compounds of formula A are those wherein R^ is hydrogen, R? and R„ are alkyl; R^ is alkyl, hydroxyalkyl, phenyl-hydroxyalkyl, halophenyl-hydroxy alkyl, alkoxyalkyl, aryloxyalkyl, arylcarbonylalkyl, or aralkyl; and X is O. i Most preferred compounds of formula A of the invention wherein X is O are: 3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo-[2,3—g] isoquinolin-4-one; ' j (-)-3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo-[2,3—gj isoquinolin-4-one; i (-)-3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo-[2,3-g] isoquinolin-4-one, hydrochloride, 0.25 molar hydrate; j 2-methyl-3-ethyl-6-(2-hydroxy-2-phenylethyl)-4,4a,5,6,7,8,8a,9-octahydro- i 4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one; i | 2,3,6-trimethyl-4,4a,5,.6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g]- isoquinolin-4-one; ! | 2,3,6-trimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] - ; isoquinolin-4-one, hydrochloride; ; t i I I i I j j, ,i,r 1 | -3- 2NOV 1982 ^ ! RECSVED ' i ' « 1 2 3 4 6 7 « 9 11 12 13 14 16 17 IS 19 21 22 23 24 26 27 1 ^ 1 B 3 0 2-methyl-3-ethyl-6-benzyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-IH- pyrrolo[2,3-g] isoquinolin-4-one; 2-methyl-3-ethyl-6-benzyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one, hydrochloride; 2-methyl-3-ethyl-6-{2-phenylethyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one; 2-methyl-3-ethyI-6-(2-ethoxyethyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one; 2-methyl-3-ethyl-6-{2-ethoxyethyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one,hydrochloride; 2-methyl-3-ethyl-6-[4-{4-fluorophenyl)-4-oxobutyl] -4,4a,5,S,7,8,8a,9-octahydro-4a,8a-trajis-lH-pyrrolo[2,3-g] isoquinolin-4-one; 2-methyl-3-ethyl-6-[3-(4-fluorophenyl)-3-oxopropyl] -4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one; 2-methyl-3-ethyl-6-(3-phenoxypropyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans- lH-pyrrolo[2,3-g] isoquinolin-4-one; 2-methyl-3-ethyl-6-(2-hydroxy-3-methylbutyl)-4,4a,5,6,7,8,8a,9-octahydro- 4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one; 2-methyl-3-ethyl-6-(2-hydroxy-3,3-dimethylbutyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one; and 2,6-dimethyl-3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] -isoquinolin-4-one, hydrochloride, dihydrate. -.4 - 1 2 3 4 6 7 9 11 12 13 14 16 17 IS 19 21 22 23 24 26 27 191830 Exemplary of the Compounds of formula A wherein X is O are: 2-methyl-3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g] isoquinolin- 4-one; 3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g] isoquinolin- 4-one; 3-ethyl4,2,6-trimethyl-4,4a,5,6,7,8,8a,9-oetahydro-lH-pyrrolo[2,3-g] isoquinolin- 4-one; 1-benzoyl-2,6-dimethyl-3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g]-isoquinolin=4-one; ■ 3-ethyl-2-methyl-6-{2-propynyl)-4,4a,5,6,7,8,8a,9-octahydro-4af 8a-trans-lH-pyrrolo-[2,3-g]isoquinolin-4-one; (+)-3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-LH-pyrrolo-[2,3-g] isoquinolin-4-one; (+}-3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo-[2,3-g] isoquinolin-4-one, hydrochloride, 0.25 molar hydrate; 3,6-dimethyl-2-(2-propyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-IH-pyrrolo-[2,3-g] -isoquinolin-4-one, hydrochloride; 3,6-dimethyl-2-(2-propyl)-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g] -isoquinolin-4-one; 2,6-dimethyl-3-butyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g] isoquinolin- 4-one; 2-methyl-3-ethyl-6-[2-hydroxy-2-{4-chlorophenyl)ethyl] -4,4a,5,6,7,8,8a, 9-octahydro-lH-pyrrolo[2,3-g] isoquinolin-4-one; 2-methyl-3-ethyl-6-(2-hydroxyethyl)-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo-[2,3-g] isoquinolin-4-one; 2-methyl-3-ethyl-6-(2-propenyl)-4,4a,5,6,7,8,8a,9-octahydro -4a,8a-trans-XH-pyrrolo[2,3-g]isoquinolin-4-one; I 2 NOV 1982 received 1 2 3 4 6 7 *S 9 11 12 13 14 16 17 IS 19 21 22 23 24 26 27 1918 • -4a,8a-trans- 2-methyl-3-ethyl-6-(2-propenyl)^4,4a,5,6,7,8,8a,9-octahydro/iH-pyTrolo- 12,3-g] isoquinolin-4-one, hydrochloride, 0.5 molar hydrate; -4a,8a-trans- 2-methyl-3-ethyl-6-{cyclopropylmethyl)-4,4a,5,6,7,8,8a,9-octahyclro/lH-pyrrolo[2,3-g] isoquinolin-4-one; -4a,8a-trans- 2-methyl-3-ethyl-6-<cyclopropylmethyl)-4,4a,5,6,7,8,8a, 9-octahydro/lH- pyrrolo[2,3-g] isoquinolin-4-one, hydrochloride, 0.2 molar hydrate; 49. ^3— I i 2,6-dimethyl-3-ethyl-l-(2,2-dimethyl-l-oxopropyl)-4,4a,5,6,7,8,8a,9-octah; lH-pyrrolo[2,3-g] isoquinolin-4-one; -4a,8a-trans- 2,6-dimethyl-3-cyclopropyl-4,4a,5^6;7,8,8a,9-octahydro-4H-pyrrolo[2,3-g] - isoquinolin-4-one; 3-ethyl-2-methyl-6-(2-dinlethylaminoethyl)-4,4a,5,6,7,8,8a,9-oct'ahy pyrrolo[2,3-g] isoquinolin-4-one; isoquiiiolin-4-one; -4a,8a-trans- 3-ethyl-2-methyl-4,4a,5,6,7,8,8a,9-octahydrc/lH-pyrrolo[2,3-g] isoquinolin-4-oxo-6-acetic acid, ethyl ester; 4a,8a-trans-' " drc/lH- l-beiizyl-2,6-dImethyl-3-ethyl-4,4a,5,6,7,8,8a,9-oeta$iyc§a/fi!r^?yrrolo[2,3-g]- -4a,8a-trans- 2-benzyl-3,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro/j.H-pyrrolo[2,3-g] isoquinolin- 4-one; 3,6-dimethyl-2-{2-propenyl)-4,4a,5,6,7,8,8a,9-octahy^roSf^rrrolo[2,3-g] -isoquinolin-4-one; -4a,8a—trans- 2,6-dimethyl-3-<2-propyl)-4,4a,5,6,7,8,8a,9-octahydro/4H-pyrrolo[2,3-g] -isoquinolin-4-one; 3-ethyl-2-methyl-6-[2-hydroxy-3-(4-chlorophenoxy)propyl] -4,4a,5,6,7,8,8a,9--4a,8a-trans- octahydrc/lH-pyrrolo[2,3-g] isoquinolin-4-one; -4a,8a-trans- 3,6-diethyl-2-methyl^4,4a,5,6,7,8,8a,9-octahydro/IH-pyrrolo[2,3-g] isoquinolin- 4-one; - 6 2 NOV 1982 deceived -4 ■ V 1 ? 3 4 • 7 a 9" #10 li 12 13 14 16 17 18 19 £20 21 22 23 •« 26 27 ■1 91 830 -4a,8a-trans- ' 2-methyl-3-ethyl-6-propyl-4,4a,5,6,7,3,8a,9-octahydro/lH-pyrrolo-[2,3-g] isoquinolin-4-one; -4a,8a-;trans- 2-methyl-3-ethyl-6-butyl-4,4a,5,6,7,8,8a,9-octahydro/lH-pyrrolo- 12,3-g] isoquinolin-4-one; 2-methyI-3-ethyl-6-pentyl-4,4a,5,6,7,8,8a,9-octahydro/iH-pyrrolo[2,3-g] -isoquinolin-4-one; -4a,8a-trans-rc/ll -4a,8a-trans- 3,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydrc/lH-pyrrolo[2,3-g] -isoquinolin- 4-one; -4a,8a-trans- " "6=methyl-4,4a,5,6,7,87&a,a-octahydro/lH-pyrPoIo[2,3rg] isoquineIin-4-one; 6-benzyl-4,4a,5,6,7,8,8a,9-octahyciro/iW-^^rrolo[2,3-g] isoquinolin-4-one; -4a,8a-trans- 2,6-dimethyl-3-propyl-4,4a,5,6,7,8,8a,9-octahydro/LH-pyrrolo[2,3-g] -iso-quinolin-4-one; 3-ethyl-2-methyl-6-E2-hydroxy-3-(4-t-butylphenoxy)-propyl)-4,4aj5,6,7,8,8£,9--4a,8a-trans- octahydro/lH-pyrroIc[2,3-g] isoquinolin-4-one; " 3-ethyl-2-methyl-6-[2-hydroxy-2-(4-chloro-3-trifluoromethylphenyl)ethyl]- 4,4a,5,6,7,8,8a,9-octatyfiro/®ipyrrolo[2,3-g] isoquinolin-4-one; 3-ethyl-2-methyl-6-(2-hydroxy-2-adamant 7elhyl)-4,4a,5,6,7,8,8a,9-octa--4a,8a-trans- hydro/lH-pyrrolo[2,3-g] isoquinolin-4-one; _4a ■3-ethyl-2-methyI-6-[2-(4-morphoIino)ethyl]-4,4a,5,6,7,8,8a,9-octahydrb/TK-pyrrolo[2,3-g] isoquinolin-4-one; 3-ethyl-2-methyl-6-[2-oxo-2-{4-fluorophenyl)ethyl] -4,4a,5,S,7,8,8a,9-octa- -4a,8a-trans-hydro/lH-pyrrolo[2,3-g] isoquinolin-4-one; Mi PATE.VT omce 7 _ j 2 NOV 1982 I RECEIVED 1 2 3 4 4 7 '£ 11 12 13 14 16 17 IS 19 21 22 23 24 26 27 n/no 3-e thyl-2-rn ethyl-6-(2-methy lpropyl)-4,4a,5,6,7,8,8 a, 9-octahydro-4a, 8a-trans-Ih-; pyrrolo[2,3-g] isoquinolin-4-one; -ethyl-2-methyl-5-cyclobutylmethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH- pyrrolo[2,3-g]isoquinolin-4-one; -4a,8a-trans- 3-ethyI-2-methyl-6-hexyl-4j4a,5,6,7,8,0a,9-octahydro/lH-pyrrolo[2,3-g]-isoquinolin-4-one; ■ " -4a,8a-trans- 3-ethyl-2-m ethyl-6-heptyl-4,4a,5,6,7,8,8a, 9-octahydro/lH-pyrrolo [ 2,3-g ] - isoquii'iolin-4-one; -4a,8a-trans- 3-ethvl-2-methvl-6-[2-(l-pyrrolidinyl)ethyl] -4,4a,5,6.7.8.8a.9-octahydro/lH-pyrrolo[2,3-g] isoquinolin-4-one; -4a,8a-trans- 3-ethyl-2-methyl-6-(4-methoxy-2-phenylethyl)-4,4a,5,6,7,8,8a,9-cctahydro/lH-pytrolo[2,3-g] isoquinoIin-4-one; ' -4a,8a-trans- 2,6-dimethyl-3-ethyl-l-(l-oxobutyl)-4,4a,5,6,7,8,8a,9-octahydro/!H-pyrrolo-[2,3-g] isoquinolin-4-one; -4a,8a-trans- 3-ethyl-2-methyl-S-(4-l chloro-2-phenyle thyl)-4,4a,5,6,7,8,8a,9-octahydro/lii-pyrrolo[2,3-gJ isoquinolin-4-one; 2,6-dimethyl-3-propyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one; 2,3-dlmethyl-6-(2-phenylethyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinoIin-4-one; 2,3-dimethyl-6-[4-{4-fluorophenyl)-4-oxobutyl] -4,4a,5,6,7,8,8a,9-octa- I hydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one; ■3-ethyl-2-methyl-6-<2,2,2-trifluoroethyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one; 2,6-dimethyl-3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-cis-lH-pyrrolo[2,3-g] - ; isoquinolin-4-one; tic^civuu C5SSC.IUI 1 1 2 3 4 0 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 1 V 183 0 are as previously described, i.e. a compound of the general formula 'la wherein R^" is alkyl, alkoxyalkyl or alkylcycloalkyl and R2 and are as previously describedj treating a compound of the general formula IX wherein Ft,, and R^" are as previously described, with formaldehyde, or b) for preparing a carrpound of the formula la above, treating a ocarpourd of the general formula III wherein R^" is as previously described, with a compound of the general formula 191. "83 0 HON^ R3 1 vii wherein and R^ are as previously described, in the presence of a reducing agent or with a compound of the general formula- h2n vie wherein R^ and R^ are as previously described, or a precursor thereof, or c) for preparing a ccmpound of the formula A above wherein R^ and are hydrogen and X is 0 and and R^ are as previously described, i.e. a ocrrpound of the general formula lb wherein R2 and are as previously described, N-demethylating a ccrrpound of the formula la above wherein R^" is methyl, or .
PA7£?, 1 • iV0V»9g2 d) for preparing a compound of the formula A above wherein R^ and R^, independently, are hydrogen, alkyl, cycloalkyl, alkenyl, aryl or aralkyl, R^ is hydrogen, alkyl, alkoxy alky 1, aralkyl, alkenyl, alkyl-cycloalkyl, 1 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 19 1830 alkynyl, thienyl-alkyl, furyl-alkyl, alkenyloxyalkyl, aralkenyl, aryloxyalkyl or trifluoroalkyl of 2 to 6 carbon atoms and X is S and R^ is as previously described, i.e. a ocmpound of the general formula s R R 3 TT " lie 2 R. 1 wherein R^1 and ', independently, are hydrcgen, alkyl, cyclo-alkvl, alkenyl, aryl or aralkyl, R^" is hydrogen, alkyl, alkoxyalkyl, aralkyl, alkenyl, alkyl-cycloalkyl, alkynyl, thienyl-alkyl, furyl-alkyl, alkenyloxyalkyl, aralkenyl, aryloxyalkyl or trifluoroalkyl of 2 to 6 carbon atoms and R^ is a previously described, treating a compound of the general formula 0 Ic ii R. '1 wherein R-^, R^, R3' and R^"' are as previously described, with phosphorus pentasulfide,. or 1 2 3 4 S 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 191830 for preparing a compound of the formula A above, wherein Rj is hydroxyalkyl, phenyl-hydroxyalkyl, halophenyl-hydroxvalkyl, alkyl-phenyl-hydroxyalkyl, alkoxypheriyl-hydroxy alkyl, arylaxy-hydroxy-alkyl, alkoxyhylroxyalkyl, acy loxyalkyl, arylcarbonylalkyl, alkoxycarbonylalkyl, arylcarboxamidoalkyl, acylalkyl, cyclic- N-alkyl-pyrrolidinylalkyl, alkyloxyalkyl, cyclic-alky 1-hydroxyalkyl, R, or ^6^p:N-alkyl, wherein Rg and , i independently, are hydrogen or alkyl or taken together with the nitrogen, ■ ■ saturated - " are a 5- or 6-membered/heterocyclic ring and X is S and R^, and R^ are as previously described,- i.e. a ccnpound of the general formula s lie wherein is hydroxyalkyl, phenyl-hydrocyalkyl, halophenyl-hydroxv alkyl alkyIpheny 1-hydroxyalky 1, alkoxyphenyl-hydroxyalkyl, aryloxy-hylroxyalkyl, alkoxyhydroxy alkyl, acy loxyalkyl, arylcarbonylalkyl, alkoxy carbonylalkyl, arylcarboxamidoalkyl, acylalkyl, cyclic-alky 1- j oxyalkyl, cyclic-alkyl-hydraxyalkyl, N-alkyl-pyrrolidinylalkyl, or alkyl, wherein Rg and R?, independently^ are hydrogen or alkyl or taken together with the nitrogen, are a 5- or 6-memboS^iei<lrocyclic ring and R^, R£ and R^ are as previously described, splitting off the protecting group or groups in a compound of the general "14 2 MOV 4982 i RECSV'SD 1 2 3 4 3 6 7 8 9 11 12 13 14 16. 17 18 19 21 22 23 24 26 27 191830 formula r V.
Ilf or wherein R-," and. R^"_have the same meaning as ani R^^cept in -the. case where^ and are acyl, R^" and R^" are acyl in a protected form, 1 ; r and R^ has the sane meaning as but in a protected form and R^ is as previously described., f) for preparing a compound of the formula A above, wherein R-^ is alkyl, alkanoyl, aroyl or aralkyl and R^ is alkyl, alkoxyalkyl or alkyl-cycloalkyl and , R^ and X are as previously described, i.e. a ccrrpound of the general formula r Ac wherein R^' is alkyl, alkanoyl, aroyl or aralkyl and R^, R^, R^" and X are as previously described, substituting a compound of the general formula 2 NOV 1982 1 2 3 4 9 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 1918JO Aa wherein R^, Rj" and X are as previously described, at the pyrrole nitrogen atom, or # g) for preparing a compound of the formula. A above, wherein R^ is hydrogen and R^ is alkyl, hydroxyalkyl, phenyl-hydroxy alkyl, halo- ; phenyl-hydroxyalkyl, alkylphenyl-hydroxyalkyl, alkoxyphenyl-hydroxy- \ alkyl, alkoxyalkyl, aryloxy-hydroxyalkyl, alkoxy-hydroxy alkyl, ■ acy loxyalkyl, arylcarbonylalkyl, alkoxycartonylalkyl, aralkyl, alkenyl, = alkyl, cycloalkyl, alkynyl, thienyl-alkyl, furyl-alkyl, arylcarboxamidoalkyl, acylalkyl, cyclic-alkyloxyalkyl, cyclic-alkyl-hydroxyalkyl, alkenyloxyalkyl, aralkenyl, aryloxyalkyl, N-alkyl-pyrro-lidinyl-alkyl, trifluoroalkyl of 2 to 6 carbon atcms. dently, are hydrcgen or alkyl, or taken together with the nitrogen, saturated are a 5- or 6-membered/heterocyclic ring and R^, R^ ani X are as previously described, i.e. a compound of the general formula x Ad 16 - 2 !vOV 1982 j BECETVEQ ' 1 2 3 4 S 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 191830 wherein R^' is alkyl, hydroxyalkyl, phenyl-hydroxyalkyl, halo-pheryl-hydroxy alkyl, alkylphenyl-hydroxyalkyl, alkoxyphenyl-hy- -droxyalkyl, alkoxyalkyl, aryloxy-hydroxyalkyl, alkoxy-hydroxy-alkyl, acyloxyalkyl, arylcarbonylalkyl, alkoxycarfconylalkyl, aralkyl, alkaiyl, alkyl-cycloalkyl, alkynyl, thienyl-alkyl, furyl- alkyl, arylcarboxamidoalkyl, acylalkyl, cyclic-alkyloxyalkyl, cyclic- I alkyl-hydroxyalkyl, alkenyloxy alkyl, ar alkenyl, ary loxyalkyl, N-alky1-pyrrolidinyl-alkyl, trifluoroalkyl of 2 to 6 carbon atoms, or ^6^1-alkyl, wherein Rg and R^, independently, are hydrogen or alkyl, or taken together with the nitrogen, saturated are a 5- or 6-membered/heterocyclic ring and R^ R^ and X are as previously described, substituting a ocnpound of the general formula H-N lb wherein R^, R^ and X are as previously described, at the isoquinoline nitrogen atan, or h) for preparing a compound of the formula A above, wherein R^ is alkyl, alkanoyl, aroyl or aralkyl and R^ is alkyl, hydroxyalkyl, phenyl-hydraxyalkyl, halqphenyl-hydroxyalkyl, alkylphenyl-hydroxyalkyl, alkoxyphenyl-hydroxyalkyl, alkoxyalkyl, aryloxy-hydroxyalkyl, alkoxy-hydroxy alkyl , acy loxyalkyl, arylcarbonylalkyl, alkoxycarbonylalkyl, Kr- „ .PAT^rdiFPlCS (' 2 NOV 1982 ^ Sl'-CSW 1 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 '191830 aralkyl, alkenyl, alkyl-cycloalkyl, alkynyl, thienyl-alkyl, furyl-alkyl, arylcarboxamidoalkyl, acylalkyl, cyclic-alky loxyalkyl, cyclic-alky 1-hydroxyalkyl,'alkenyloxyalkyl, aralkenyl, aryloxyalkyl, N-alky1-pyrrolidinyl-alkyl, trifluoroalkyl of 2 to 6 carbon atoms, R,- —'. or 6^N-alkyl, wherein Rg and Ry, independently, are hydrogen or alkyl, or taken together with the nitrogen, ape a 5- or 6-rrerberS^neterocy clic ring ard R-,, R^ and X are as previously described, i.e. a compound of the general formula Af wherein R^1 , , R^, R^1 and X are as previously described, substituting a compound of the formula Ae hereinbelow at the isoquinoline nitrogen atom, or i) for preparing a compound of the formula A above, wherein R^ is alkyl, alkanoyl, aroyl or aralkyl and R^ is hydrogen ard R^, R^ and X are as previously described, i.e. a oornpound of the general formula H—N Ae 18 - *i2.FAT CiTt-?j£ f received 1 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 191850 wherein R^1, R2, and X are as previously described, splitting off the protecting group in a compound of the general formala wherein Z is a protecting group and R^'rR^, ^3 and X are as previously described, or j) for preparing a confound of the formula A above, wherein R^ is alkyl, alkancyl, arcyl or aralkyl and R^ is hydrogen, alkyl, alkoxyalkyl, acy loxyalkyl, alkylcarbonylalkyl, alkoxycarbonylalkyl, aralkyl, alkenyl, alkylcycloalkyl, alkynyl, thienyl-alkyl, furyl-alkyl, arylcarboxamidoalkyl, acylalkyl, cyclic-alky loxyalkyl, alkenyloxyalkyl, aralkenyl, aryloxyalkyl, N-alky 1-pyrrolidinyl-alkyl or jtrifluoroalkyl of 2 to 6 carbon atans —. .- and R^, R-j and X are as previously described, i.e. a compound of the general fontula 19 - ,1 JUL PATENT urirri 2 NOV 1982 received 1 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 wherein R^1 is hydrogen, alkyl, alkoxyalkyl, acy loxyalkyl, alkyl-. carbonylalkyl, alkoxycarbonylalkyl, aralkyl, alkenyl, alkyl-cycloalkyl, alkynyl, thienyl-alkyl, furyl-alkyl, arylcarboxamidoalkyl, acylalkyl, cyclic-alky loxyalkyl, alkeny loxyalkyl, aralke-nyl, ary loxyalkyl, N-alkyl-pyrrolidinylalkyl or .trifluoroalkyl: of 2 to 6 carbon atons — — ——r~~—-rr—; and R^1 , R^, R^ and X are as previously described, substituting a compound of the general formala .. .
VI l4\ Ad „VI wherein R^, R^, R^ and X are as previously described , at the pyrrole nitrogen atom, or k) for preparing a ccnpound of the formula A above^ wherein is alkyl, alkancyl, aroyl or aralkyl and R^ is hydroxyalkyl, phenyl-hydroxy- alkyl, halophenyl-hydroxyalkyl, alkylphenyl-hydroxyalkyl, alkoxy- phenyl-hydroxyalkyl, aryloxy-hydroxyalkyl, alkoxyhydroxy alkyl, ' R cyclic-alkyl-hydroxyalkyl or alkyl, wherein Rg and R^, inde pendently, are hydrogen or alkvl, or taken together with the saturated nitrogen, are a 5- or 6-merribered/heterocyclic ring and R^, R^ and X are as previously described, i.e. a compound of the general formula -20- f 2 NOV 1982 «ECEiVt;f 1 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 191830 "VII Af1 wherein is hydroxyalkyl, phenyl-hydroxyalkyl, halophenyl- hydroxyalkyl, alkylphenyl-hydroxyalky 1, alkoxyphenyl-hydroxy- alkyl, aryloxy-hydroxyalkyl, alkoxyhydroxvalkyl, cyclic-alkyl-r hydroxyalkyl or alkyl, wherein Rg and R-j, independently, are hydrogen or alkyl, or taken together with the nitrogen, are a 5- or e-mEmb^^^etarocyclic ring and R^', R£, R^ and. X are as previously described, splitting of the protecting group in a corresponding oonpound of the 4 formula Af" above, but wherein rY11 is protected, i.e. in a ocmpound of the general formala VIII R4\ Af or wherein R^"^ has the same meaning as but in a protected form, and R^', R^, R^ and X are as previously described, 1) isanerizing the mixture of the cis and trans isomers obtained * f 2 NOV 1982 RECEIVED 1 2 3 4 S 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 to a final ratio which comprises predominantly the trans isomer, or m) separating the trans isaner frcm the mixture obtained, or n) resolving a racemic. mixture obtained into the optical antipodes and o) if desired, converting a^oompound obtained or a non-pharniaceutically acceptable acid addition salt thereof into a pharmaceutical^. acceptable acid addition salt thereof.
More specifically, the compourris of formula A above, their optical and geometric isaners and their pharmaceutically acceptable acid addition salts as well as various intermediates therefor can be prepared as illustrated hereinbelow in more detail.
NX PATe&T&:v!S3 2 NOV S982 • 1 2 3 4 6 7 8 3 11 12 13 14 16 17 IS 19 21 22 23 24 26 27 1 9 18 3 0 Thus, for exarple, the compounds of formula A wherein X is O are characterized by the formula R 4\ wherein R£, R3 and are as hereinbefore described, and can be prepared as set forth in Schemes I, n, in and IV and further described.
FORMULA SCHEME I wherein Rg , aid R^" are as previously described.
PATENT OFHCS £<!■■- — £ 2 NOV 1982 RECEIVED 1 2 3 4 6 7 8 9 11 12 13 If 16 17 18 19 21 22 23 2k 26 27 191830 In accordance with Formula Scheme I, compounds of formula IV wherein R^" is methyl, are prepared by reacting the primary amine of formula XIV with ethyl chloroformate to yield the urethane of formula III, which is reduced with lithium aluminum hydride to yield the N-methylamine of formula IV. In a broader aspect, the oonpounds of the formula IV can be prepared by reductive alkylation of the compound of formula XIV, utilizing the corresponding aldehyde, for—-j example, acetaldehyde, and the like, and sodium cyanoborohydride under known j conditions [see, for example, R. F. Borch, J. Am.. Chem. Soc., 9j3, 2897 (1971)]. 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 of 1 to 7 carbon atcms methylamine or ethylamine in the presence of a lower alkanol/such as ethanol, butanol, or t-butanol. The reaction is generally carried out at the boiling point of the solvent or below, for example, from -78° to 15° C. If ammonia is used, the reaction is run at reflux. Optionally, cosolvents such as diethyl ether or tetrahydrofuran may be added.
The hydrolysis of the dihydroamine of formula V is readily accomplished by the usual methods for hydrolysis of enol ethers, for example, with aqueous acid. Exemplary j 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. At least two equivalents of water per mole of dihydroamine and more than 1 equivalent of acid are needed. Tetrahydrofuran, benzene, diethyl ether, acetone, toluene, dioxane or acetonitrile are exemplary of the solvents which may be employed. For example, hydrolysis of the dihydroamine of formula V wherein R^" is methyl in 2N hydrochloric acid at room temperature or above or in'aqueous acetic acid at between 40°Cand reflux leads to the dikctone of formula VI, wherein R^" is methyl. r;2M0N/W82 .1 1 2 3 4 •6 7 ' 8 • 11 12 13 14 16 17 18 0 21 22 • 24 .26 27 1 91830 The diketone of formula VI is condensed in a Knorr condensation to give the ; dihydroindolone-ethylamine of formula IX. The Knorr condensation is a well-known : • ! method for the preparation of pyrroles and the process may be used in any of the well- i known modifications [see, for exemplary conditions, J. M. Patterson, Synthesis, 281 (1976) and references therein]. For example, the reaction of an isonitrosoketone of - ! formula VII in the presence of a reducing agent, for example with zinc in aqueous acetic i acid or hydrochloric acid, is thought to proceed via the aminocarbonyl compound of • _ • -form ula. VIII whicii—then condenses - wi t-h-the diketone;-:of-formula VI" to" give -therproduct • ' - i dihydroindolone-ethylamine of formula IX. Alternatively, the condensation can be ; carried out with an aminocarbonyl" compound of formula VIII or precursor thereof, such as an aminoketone hydrochloride salt, or an acetal derivative of an aminoketone or : • aminoaldehyde. The use of a precursor of the aminoketone or aminoaldehyde is • preferred, since such substances are prone to seilf-condensation. They may best be f 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 | dihydroindolone-ethylamine of formula IX. It is not necessary to isolate the diketone of ^ formula VI prior to carrying out the Knorr condensation since the reaction conditions • : ; employed are sufficient to hydrolyze the dihydroamine of formula V to the diketone of formula VI. The Knorr condensation is best carried out at a pH of from about pH 2 to • pH 6. Much above pH 6, there is a considerable loss in yield due to the formation of self-condensation products of the aminocarbonyl compound of formula VIII. j j Preferably, an isonitrosoketone of formula VII and zinc dust in aqueous acetic . ; acid is condensed with a diketone of formula VI wherein RV' is methvl to ffive the i product dihydroindolone-ethylamine of formula IX wherein R^" is methyl. j 26 - gjJLBWfjK? C" 2 NOV 1982 1 2 3 4 3 6 7 is 9 il 12 13 16 17 IS 19 21 22 23 24 2'6 27 1.91/830 The Knorr condensation is preferably carried out at a temperature range of from j •- - " » about room temperature to reflux. The isonitrosoketones of formula VET are known ' ' l ' compounds [see, for instance, Eerris, J. Org. Chem., 24, 1726 (1959)] or can readily be • prepared by nitrosation of the corresponding ketones, for example, with an alkyl nitrite, i or in the case of highly acidic 0-diketones or g-ketoesters, with sodium nitrite.
Exemplary of isonitrosoketones which may be used in the Knorr condensation are: ! 2-isonitroso-3-pentanone; 2,3-butanedione monoxime; - • . 2-isonitroso-4-methyl-3-pentanone; 2-isonitroso-3-hexanone; 2-isonitroso-3-heptanone; 3-isonitroso-4-methyl-2-pentanone; 2-isonitroso-l-cyclopropyl-l-propanone; 3-isonitroso-5-hexen-2-one; and 3-isonitroso-4-phenyl-2-butanone.
Exemplary of aminocarbonyl precursor compounds which may be used in the Knorr condensation are: aminoacetaldehyde dimethyl acetal; and 2-amino-3-pentanone hydrochloride. 27 _ 3 2 NOV 1982 RECEIVED - .1 1 2 3 4 • g 7 8 •- 11 12 13 14 16 17 18 ®19 21 22 ^23 24 26 27 I The amine of the formula IX is converted to the compound of the formula la via | an intramolecular Mannich reaction. The Mannich reaction is usually performed ! ! starting with a ketone and a dialkylamine salt, for example, dimethylamine hydro- ; • • " i chloride and formaldehyde (for example, as an aqueous solution, as paraformaldehyde or ; j as trioxane) in an alcoholic solvent such as ethanol, at reflux. In the modification : :- ■ "1 herein described, an acid addition salt of the dihydroindolone-ethylamine of formula IX ; j is reacted with formaldehyde, added in the form of paraformaldehyde, trioxane, or as j aqueous formaldehyde in'a.solvent. For example, a high'boiling"IiydroxyIi"c solvent, such ; i as amyl alcohol, octanol, ethylene glycol or diethylene glycol monoethyi ether, a high : boiling polar aprotic solvent, such as dimethylformamide, N-methyIpyrrolidir*6ne or I I diethylene glycol dimethyl ether; a lower boiling polar solvent, such as ethanol, butanol i j 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 ' I 135° to about 200tto yield the pyrrolo[2,3-g] isoquinolines of formula la. The reaction, ' i especially when run at temperatures below 150°c leads to a mixture of cis and trans \ i isomers, i.e., for example, when RV is methyl, compounds of the formulas 1 1 2 3 4 • . 6 7 • 11 . 12 13 14 17 18 #19 21 22 ^23 24 26 27 cii3-n trans ch3 — N I'a I"al Longer heating of the reaction mixture or separate heating of the isomeric mixture of hydrochloride salts of formulas I'a and I"a, 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 predominantly the trans isomer, which is readily isolated by crystallization or by chromatographic separation.
Preferred is the reaction of the hydrochloride salt of the dihydroindolone-ethylamine of formula IX whereinR^" is methyl with paraformaldehyde in octanol at 180°cfor 2 hours, wherein the product is isolated as almost exclusively, the trans isomer I'a. - 1 2 3 4 • 6 7 8 0 11 12 13 14 16 17 18 i# 21 % 23 24 26 27 i formula scheme ii ch3-n 2%°"^ h-n lb wherein Rg and R^ are as previously described, and Rj' is alkyl, alkanoyl, aroyl or aralkyl. 1 2 3 <f 6 7 8 9 11 12 13 If 16 17 18 19 21 22 23 2<i 26 27 IS 1830 In accordance with Formula Scheme II, compounds of formula Ic1 are prepared by alkylation or acylation of the pyrrole nitrogen of a compound of formula la' and other N-6-alkyl derivatives by formation of the pyrrole anion with strong base, for example, sodium amide, potassium hydride, sodium methylsulfinylcarbanion, or butyl-; lithium, or with an alkali metal followed by quenching with an alkyl or acyl halide in a solvent such as tetrahydrofuran, dioxane, ethyl ether, dimethylforrnamide or dimethyl-sulfoxide. For example, treatment of a compound of formula la', wherein R2 is methyl and Rg. is ethyl, with sodium in liquid ammonia followed by quenching with methyl j iodide affords the 1-methyl derivative, i.e., a compound of formula Ic* wherein R^- is - j methyl, is ethyl, and R^' is methyl. Similarly, reaction of a compound of formula la' , wherein R2 is methyl and R3 is ethyl, with butyllithium in tetrahydrofuran at -30°c followed by quenching with benzoyl chloride affords the 1-benzoyl derivative, i.e., a i compound of formula Ic* wherein R^' is benzoyl, Rg is methyl and R^ is ethyl.
N-Demethylation of the compound of formula la'can be accomplished by standard j N-dealkylation procedures, such as the von Braun method [H. A. Hageman, Org. Reactions, 7, 198 (1953)], or via acid or base hydrolysis of a urethane derivative such as those listed in K. C. Rice [J. Org. Chem., 40, 1850 (1975)]. One procedure for the dealkylation of the compound of formula la' is via the urethane of formula XIII and i I acid hydrolysis to give the secondary amine of formula lb. For example, a compound of j formula la1 ,wherein R2 is methyl and R^ is ethyl is refluxed in diethyl ketone with i excess ethyl chloroformate and potassium bicarbonate for 3 hours to give a compound of { formula XIII, wherein Rg is metiiyl and R^ is ethyl. Hydrolysis of the foregoing ! i compound with concentrated hydrochloric acid in acetic acid at reflux for 24 hours gives! i a compound of formula lb, wherein R„ is methyl and R„ is ethyl. The same compound j It I is obtained by hydrolysis of the urethane of formula XIII with sodium hydroxide in I refluxing ethanol. 31 2 MOV 1982 1 -2 3 « 6 7 S 9 11 12 13 14 16 17 IS 19 21 22 23 24 26 27 28 FORMULA SCHEME III 1 p. X -V_i/ H-n Ie ' Id wherein R^', R2, R3 and R41 are as previously described. • 1 2 = 3 4 6 7 S 9 11 12 13 U 16 17 18 19 21 22 23 24 26 27 19 1830 In accordance with Formula Scheme HI, the compounds of formulas Ic, Id and Ie j are prepared from the secondary amine of formula lb, the starting material for the j f preparation of numerous derivatives encompassed by formula I, by substitution at the • l -basic amine nitrogen (N-6) and/or the pyrrole nitrogen (N-l). For example, treatment of a compound of formula lb with an alkyl halide, such as ethyl bromide, an alkenyl halide, : such as allyl bromide, a cycloalkyl-halide, such as chloromethylcyclopropane, or an ; aralkyl halide, such as benzyl bromide, in the presence of a base, for example, r i potassium carbonate, in acetone, 2-propanone or dimethylformamide, yields the i correspondingly substituted compound of formula Id, that is, wherein R^' is alkyl, alkenyl, cycloalkyl-alkyl or aralkyl, respectively. With reactive halides, the reaction i j may be run at room temperature; with less reactive halides, reflux temperatures are i used, and in some cases, the reaction rate can be enhanced by the addition of an Iodide salt, such as lithium iodide, to the reaction mixture.
Reaction of a compound of formula lb with epoxyalkanes gives the hydroxy alkyl < i substituted compound of formula Id. Treatment with a substituted epoxyalkane gives j j the 2-substituted-2-hydroxyalkyl analogs of a compound of formula Id, for example, | [ reaction of a compound of formula lb with styrene oxide gives a compound of formula ! Id, wherein R^' is 2-phenyl-2-hydroxyethyl. The reaction is usually carried out in the j presence of an alcoholic solvent such as methanol, at from about room temperature to : | the reflux temperature of the mixture. The expoxyalkanes are either commercially ' ; available or are prepared by epoxidation of the corresponding olefins, or by j I methylenation of a ketone with a sulfoniummethylide or sulfoxonium methylide reagent, ; i for example, dimethylsulfonium methylide. Thus, for example, treatment of benzalde- f hyde with dimethylsulfonium methylide gives styrene oxide. 1 2 3 4 6 7 8 9 11 12 13 14 16 17 IS 19 21 22 23 24 26 27 191850 The compound of formula lb may be converted to the compound of formula Ie by a process in which, successively, the basic amine nitrogen (N-G) of the compound of formula lb is protected with a hydrolyzable or hydrogenolyzable protecting group, substituted at the pyrrole nitrogen (N-l), and deprotected. Typical protecting groups are acetyl, t-butoxycarbonyl, benzenesulfonyl, or benzyl. The reaction of the protected intermediate is carried out substantially as described for the conversion of the compound of formula la to the compound of formula Ic'. The substituted intermediate is deprotected by base or acid hydrolysis or hydrogenolysis methods appropriate to the protecting group. For example, the compound of formula lb where ^ is methyl and . is ethyl, is treated with formic acetic anhydride to yield the 6-formyl derivative. Treatment of the derivative with sodium hydride in dimethylsulfoxide followed by treatment with methyl iodide and acid hydrolysis yields the compound of formula Ie where R^' is methyl, R£'s methyl, and R^ is ethyl.
Treatment of a compound of formula lb with a haloalkylamine in the presence of a base, for example, potassium carbonate, or an aziridine yields amine-substituted^ analogs of a compound of formula Id, respectively. The reaction conditions are as described for the preparation of alkyl derivatives.
In some cases, where R^' in the compound of formula Id does not contain functional groups capable of undergoing alkvlation or acylation, the procedures outlined in Formula Scheme III can be used directly to prepare N-l substituted analogs of formula Ic. Alkylations can occur in compounds wherein R^1 is hydroxyalkyl, phenyl- hydroxyalkyl, halophenyl-hydroxyalkyl, alkylphenyl-hydroxyalkyl, alkoxyphenyl-hgjroxy- alkyl, aryloxy-hydroxyalkyl, alkoxy-hydroxvalkyl, cyclic-alkylhydroxyalkyl, or ^N- R7 alkyl, wherein Rg and R^, independently, are hydrogen or alkyl, or taken together with saturated the nitrogen, are a 5- or 6-membered/fieterocyclic ring. The functional groups therein, HZ. PATENT QHtCg < 2 NOV 1982 received 1 • 1 2 3 f 6 7 8 9 11 12 13 If 16 17 18 19 21 22 23 24 26 27 28 29 ? 9 183 0 for example, hydroxyl or secondary amino, must be protected with a base-stable j protecting group, such as tetrahydropyranyl. After N-l alkylation, the protecting group is removed by acid hydrolysis.
The compound of formula Ie is converted to the compound of formula Ic using j substantially the same procedure used in the conversion of the compound of formula lb j to the compound of formula Id.
In the reactions described in Formula Schemes I, II and IE, both the trans isomers • 7 t of the formula wherein R^ R^, R^ and R4 are as previously described, and cis isomers of the formula wherein R^, R2, R^ and R^ are as previously described, of the compounds of formula I may be formed, with the trans isomer predominating, j The pure trans isomer may be separated by chromatography or crystallization. In ! I addition, the mixture may be isomerizedas described for the isomerization of the trans and cis isomers of the oxo compound of formula I'af and I"al % 1 2 3 4 • 6 7 8 • 11 12 13 14 16 17 18 • 21 22 f 24 26 27 1-9:8 3 0 FORMULA SCHEME IV R4 h2n- ^-r2 h wherein R2 r ^3 ^4" are previously described. 91 830 1 2 3 f 6 7 8 9 11 12 13 If 16 17 18 19 21 22 23 2 f 26 27 An alternative synthesis of the compounds of formula la is described in Formula Scheme IV, in which the isoquinoline ring is formed prior to the formation of the pyrrole ring. In accordance with Formula Scheme IV, the (3,5-dimethoxyphenyl)-ethylamine of formula IV is refluxed with aqueous formaldehyde to give the tetrahydroisoquinoline of formula X. Birch reduction of the tetrahydroisoquinoline of formula X with lithium in liquid ammonia containing t-butanol under conditions substantially the same as described for the Birch reduction of the compound of formula IV yields the hexa- hydroisoquinoline of formula XI. Hydrolysis of crude hexahydroisoquinoline of formula XI under conditions substantially the same as described " for the'hydrolysis of the dihydroamine of the formula V yields the diketone of formula XE. The compound of formula XII is reacted in a Knorr condensation, as described in the preparation of the dihydroindolone-ethylamine of formula IX with the isonitrosoketone of formula VII or or precursor thereof with the aminocarbonyl compound of formula VIE/to give the pyrroloisoquinoline of formula la. 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-pyrroloisoquinoline of formula Ia\ as a mixture containing the trans isomer I'a1 and the cis isomer of formula I"al.
The same procedures for isomerization of the mixture of pyrroloisoquinolines of formulas I'a1 and I"a'as described previously may be employed to yield mainly the trans isomer of formula I'a1. 37 - FiZ. PATtiXT ■ } 2^QVi982 i ?3VED 1 2 3 f 6 7 8 9 11 12 13 If 16 17 18 19 21 22 23 2f 26 27 T •I '% 0 The compounds of formula A wherein X is S are characterized by the formula S II R 2 3 R. '1 wherein Rj, R2, R3 and R4 are as hereinbefore, described, and can be prepared as set forth hereinafter.
Thione compounds of formula II are generally prepared by reaction of phosphorus ; pentasulfide on keto compounds of formula I. When the compound of formula I has no j i functional groups capable of reacting with phosphorus pentasulfide besides the 4-oxo j group, then the compound of formula I may be converted to the compound of formula II j directly by heating with phosphorus pentasulfide in an inert organic solvent. On the j other hand, when the compound of formula I does contain functional groups capable of j I reacting with phosphorus pentasulfide, for example, when R^ is other than hydrogen, j alkyl, alkoxyalkyl, aralkyl, alkenyl, alkyl-cycloalkyl, alkynyl, thienyl-alkyl, furyl-alkyl, j alkenyloxyalkyl, aralkenyl, aryloxyalkyl, or trifluoroalkyl of 2 to 6 carbon atoms or when! R2 or is acyl, these groups must be protected before the reaction and de- J as ethylene ketal arid alcohol groups may be protected as an ether derivative, such as a benzyl ether. Alternatively, thiones of formula II may be made by suitable procedures described in Formula Schemes V and VI. protected thereafter. For example, keto groups may be protected as a ketal such ; 38 - i 1 2 3 f 6 7 8 9 11 12 13 If 16 17 18 19 21 22 23 2f 26 27 FORMULA SCHEME V wherein R^1, , Rg and R^" are as hereinbefore described. * 1 2 3 f 6 7 8 9 II 12 13 If 16 17 18 19 21 22 23 2 f 26 27 1 9 1S 3 0 In Formula Scheme V, the compound of formula la is converted to the compound of formula Ila by heating in an inert organic solvent with pliosphorus pentasulfide. i j Preferred solvents are tetrahydrofuran, benzene, and dioxane, and the reaction is ■ j generally run at reflux temperature. The compound of formula Ila may then be j alkylated or acylated to the compound of formula He1 in the same manner described in Formula Scheme II for the conversion of the compound of formulala'to the compound of formula lei VI: Additional compounds of formula II can be made as described in Formula Scheme l 1 . 2 3 4 3 6 7 8 9 II 12 13 If 16 17 18 19 21 22 23 2f 26 27 19 18 3 0 FORMULA SCHEME VI wherein R2, Rg, R^ and R^'are as previously described. 1 2 3 ft £ 7 2 9 11 12 13 lft 16 17 IS 19 21 22 23 2ft 26 27 I *f7 O > " d J In Formula Scheme VI, the compound of formula lb is reacted with phosphorus pentasulfide as above described, to afford the thione of formula lib. Subsequent transformations of the compound of formula lib to the compounds of formulas Uc, IIdand lie i are performed in the same manner as described in Formula Scheme HI for the analogous ! oxo compound lb in its conversions to the compounds of formulas Ic, Id and Ie.
#• In these reactions, both the trans isomers of the formula m wherein Rp Rg, Rj and R^ are as previously described, and cis isomers of the formula IF wherein Rj, R£f Rj and R^ are as previously described, 1 2 3 4 :5 6 7 3 9 11 12 13 If 16 17 18 19 21 22 23 2U 26 27 ii S 0 of the compounds of formula II may be formed, with the trans isomer predominating. I Toe pure trans isomer may be separated by chromatography or crystallization. In addition, the mixture may be isomerized as described for the isomerization of the trans and cis isomers of the oxo compound of formula I'a1 and I"a'. 1 2 3 A • 7 8 9 •So 11 12 13 14 16 17 18 19 21 22 ,^23 w 24 26 27 850- The compounds of formula A form acid addition salts with inorganic or organic I acids- Thus, they form pharmaceutical^ acceptablc acid addition salts with both j pharmaceutical^ acceptable organic and inorganic acids, for example, with hydrohalic ; ! acid, such as, hydrochloric acid, hydrobromic acid, hydroiodic acid, other mineral acids,; i —:— such as sulfuric acid, nitric acid, phosphoric acid, or the like, alkyl- and mono-aryl ; .1 - i ! sulfonic acids, such as ethanesulfonicacia,p-toluenesulfonic acid, benzenesulfonic acid, j - - " i or the like, other organic acids such as acetic acid, tartaric acid, maleic acid, citric ■: » acid, benzoic acid, salicylic acid, ascorbic acid, and the like. Non-pharmaceutically ■ acceptable acid addition salts of compounds of formula Ac&n be converted into pharma- '■ i i ceutically acceptable acid addition salts via conventional metathetic reactions whereby ; ! the non-pharmaceutically acceptable anion is replaced by a pharmaceutical^ accept- ' j able anion; or alternatively, by neutralizing the non-pharmaceutically acceptable acid ■ \ j addition salt and then reacting the so-obtained free base-with a reagent yielding a j . . ' ■ i pharmaceutical^ acceptable acid addition salt. The acid addition salts may also form j hydrates.
The compounds of formula Aand their pharmaceutical^ acceptable acid addition ; | salts exhibit neuroleptic activity. Significantly, however, they lack hypotensive ; i i activity, and demonstrate only weak cataleptic activity. Accordingly, the compounds of , formula A are useful as antipsychotic agents, for instance, in the treatment of ' schizophrenia. The activity of the compounds of formulaA which makes them useful as • i i antipsychotic agents can be demonstrated in warm-blooded animals, in accordance ' with known procedures. * 1 2 3 4 ♦ 7 8 • 11 12 13 14 16 17 18 4s 21 22 •» 24 26 27 1 9 ! 8 3.0 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 j loudspeaker for presentation of auditory stimuli. Each trial consists of a fifteen-second j warning tone, (conditioned stimulus), continuing for an additional fifteen seconds j accompanied by electric shock (unconditioned stimulus; 1.0 mA, 350 V.A.C.). The rats j can terminate a trial at any point by depression of the response lever. A response ' * ' I during the initial fifteen-second warning tone ends the trial before shock delivery and is j considered an avoidance response, while a response occurring during shock delivery is an j escape response. Trials are presented every two minutes during a one-hour test session \ (30 trials per session).
Trained rats maintain a reliable control baseline of avoidance behavior (zero to three avoidance failures per session). Compounds are administered at appropriate j pretreatment times to a minimum of three to four rats at each dose level over a range : I j of doses. Rats receive vehicle alone, during control sessions. One control and one ! experimental session are alternated during each week; each animal serves as his own control.
The session is divided into three consecutive twenty minute (ten trial) segments, j Response counts are summed over all subjects at a given dose within each segment. I • 1 2 3 6 K 7 8 9 II 12 13 U 16 17 18 19 21 22 23 2 26 27 f D CEJ^ . ^ The number of trials in which the rats failed to exhibit an avoidance response (avoidance 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. This number is expressed as a percentage of the total trials within the segment. The dose calculated to produce a 50% block of avoidance (AB 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 (EB 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 procedure. Consequently, the compounds of formula A may be used therapeutically in dosage ranges consistent with their potency in the test procedure.
When 3-ethyl-2,6-dimethyl-4>4a,5,6,7,8,Sa,9-octahydro-4a,8a-trans-lH-pyrrolo-[2,3-g] isoquinolin-4-one, hydrochloride, which has demonstrated an LD,q of, for example, 350 mg/kg p.o. in mice, is utilized as the test substance, neuroleptic activity is observed at an AB5Q of 0.7 mg/kg p.o. and 0.095 mg/kg s.c. In the (-)-enantiomer of the foregoing compound, neuroleptic activity is observed at an AB5q of 0.48 mg/kg p.o.
Similarly, when 2,3,6-trimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyr-rolo[2,3-g] isoquinolin-4-one, hydrochloride is utilized as the test substance, neuroleptic activity is observed at an AB50 of 0.48 mg/kg p.o. 1 2 3 4 6 7 '8 3 11 12 13 Ik 16 17 18 19 21 22 23 2H 26 27 28 29 T 9 is 3 o I Similarly, when N-[2(3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-2-methyl-4-oxo-4a,8a- j trans-lH-pyrrolo[2,3-g] isoquinolin-6-yl)ethyl] -4-fluorobenzamide is utilized as the test \ suDstance, neuroleptic activity is observed at an AB^q of 3.5 mg/kg p.o.
Similarly, when 3-ethyl-2-methyl-6-[4-(4-fIuorophenyl)-4-oxobutyl] -4,4a,5,6,7,- ! 8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one is utilized as the test ; substance, neuroleptic activity is observed at an AB^g of 0.19 mg/kg p.o.
Similarly, when 3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH- i pyrrolo[2,3-g] isoquinolin-4-thione is utilized as the test substance, neuroleptic aetivity is observed at an ABgg of 0.94 mg/kg p.o.
The compounds of formula A and their pharmaceutically acceptable acid addition ■ i I salts have antipsychotic effects which are qualitatively similar to those of haloperidol.
. ' I trifluoroperazine and molindone, known for their therapeutic uses and properties. Thus, | the compounds of formula A demonstrate a pattern of activity associated with ; antipsychotic drugs of known efficacy and safety.
The compounds of formula A and their pharmaceutically acceptable acid addition I salts can be used in the form of conventional pharmaceutical preparations. By way of ; exemplification, suitable oral dosage units comprise or are in the range of from 0.05 to 50; | mg., and suitable oral dosage regimens in warm-blooded animals comprise or are in the ' i range of from about 0.001 mg/kg per day to about 10 mg/kg per day. However, for anv I particular warm-blooded animal, the specific dosage regimen may be variable and ! i should be adjusted according to individual need and the professional judgment of the j person administering or supervising the administration of a compound of formula A or a I pharmaceutically acceptable acid addition salt thereof. Furthermore, the frequency j I | with which any such dosage form will be administered will vary^ depending upon the j quantity of active medicament present therein and the needs and requirements of the pharmacological situation. ■ - 47 - ' 19183 0 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 tablets, suspensions, solutions, and the like. Furthermore, the compounds of formula Acan be embodied 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 formulaA 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, preservatives, stabilizers, wetting agents, emulsifying agents, salts for altering osmotic pressure, buffers, or the like, can be incorporated, if desired, into such formulations. 4 4 * 1 2 3 4 I 6 7 i 9 11 12 13 14 16 17 I 21 • 23 24 26 27 1 ^18 3 0 Since the compounds of formula A and their pharmaceutically acceptable acid ; i addition salts possess an asymmetric carbon atom, they are ordinarily obtained as i j racemic mixtures. The resolution of such racemates into the optically active isomers , can be carried out by known procedures. Some racemic mixtures can be precipitated as j j eutectics and can thereafter be separated. Chemical resolution is, however, preferred. • ' i h i By this method, diastereomers are formed from the racemic mixture with an optically i active resolving agent, for example, an optically active acid, such as (+)-tartaric acid to j 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.
Furthermore, due to the possible different spatial arrangements of their atoms, ; j it is to be understood that the compounds of this invention may be obtained in mere 1 than one possible geometric isomeric form. The compounds of formula A,as described i and claimed, are intended to embrace all such isomeric forms. Accordingly, the ' i. examples included herein are to be understood as illustrative of particular mixtures of i geometric isomers or single geometric isomers and not as limitations upon the scope of the invention.
The Examples which follow further illustrate the invention. All temperatures are in degrees Centigrade, unless otherwise stated. - 9 1830 Example 1 i preparation of N-2-(3.5-dimethoxyphcnyl)-ethyl carbamic acid, ethyl ester In a 5 I. 3-neck round-bottom flask fitted with a mechanical stirrer and addition funnel were placed 32.63 g. of (3,5-dimethoxyphenyl)-ettiylamine hydrochloride, 600 ml. of water, 600 ml. of dichloromethane and 150 ml. of IN sodium hydroxide solution.
The mixture was stirred and cooled in an ice bath while 16.28 g. of ethyl chloroformate ♦ in 60 ml. of dichloromethane was added dropwise over 30 min. During the addition, a total of 150 ml. of IN sodium hydroxide solution was added in 8 portions tc keep the pH between 8 and 9. After the addition was complete, the mixture was stirred in the ice bath for 1 hour. The mixture was transferred to a separatory funnel and the organic layer was separated. The aqueous solution was extracted with 200 ml. of dichloromethane and the organic solutions were combined and washed with 100 ml. of water and 100 ml. of brine and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated on a rotary evaporator to give 37.1 g. of crude N-2-(3,5-dimethoxyphenyl)-ethyl carbamic acid, ethyl ester as a colorless oil. 9 1830 Example la Preparation of N-methyl-(3,5-dimethoxyphenyl)-ethylamine hydrochloride In a 3 L 3-neck round-bottom flask equipped with a mechanical stirrer, addition J i funnel, and condenser were placed 180 ml. of 70% sodium dihydrobis(2-metlioxyethoxy>- j aluminate solution and 700 ml. of dry tetrahydrofuran. The solution was cooled in an f ice bath and a solution of 37.1 g. of crude N-2-(3,5-dimethoxyphenyl)-ethyl carbamic | i acid, ethyl ester in 100 ml. of dry tetrahydrofuran was added over 15 minutes. After the ! .1 addition, the mixture was heated to reflux for 1 hour and then was cooled in an ice bath. ! Excess hydride was decomposed by the dropwise addition of 100 mL of 5% sodium | hydroxide solution. After all the base had been added, the organic layer was separated and the aqueous extracted with 100 ml. of ether. The combined organic solutions were i concentrated to an oil on a rotary evaporator and the oil was dissolved in 300 ml. of ; t ether. The ether solution was washed with 50 ml. of water, 50 ml. of brine, dried over j anhydrous sodium sulfate, and filtered. To the filtrate was added 70 ml. of ethereal j hydrogen chloride to precipitate the amine hydrochloride. The solid was collected on a Buchner funnel and was crystallized from 180 ml. of absolute ethanol and 270 ml. of ether to give 28.9 g. of N-methyH3,5-dimethoxyphenyl)-ethylamine hydrochloride as a white, crystalline solid, mp 160-164°. 1 9 1830 Example 2 Preparation of N-methyl-l,5-dimethoxycycIohexa-I,4-diene-3-ethylamine 185.2 g. of N-methyl-(3,5-dimethoxyphenyl)-ethylamine hydrochloride was dissolved in 1600 ml. of water and the solution was made alkaline with 160 ml. of ammonium hydroxide. The mixture was extracted with 3 x 1000 ml. of dichloromethane and the combined extracts were washed with 1000 ml. of brine and dried over anhydrous sodium sulfate. Evaporation of the solvent on a rotary evaporator at 35-40° gave 156.0 g.» of free base.
In a 12 1. 3-neck flask equipped with a mechanical stirrer and two dry ice condensers, one fitted with a gas inlet and the other with a soda-lime drying tube was condensed 4.0 1. of anhydrous ammonia. To the ammonia was added a solution of 156.0 g. of the free base in 400 ml. of t-butanol and 400 ml. of. anhydrous ether over 15 minutes. To the stirred solution was added over 50 min. a total of 33.6 g. of lithium wire cut into 2.5 in. lengths. The addition rate was controlled so that 5 in. of wire was added per minute. After all the lithium 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 the layers were separated. The aqueous layer was extracted with 2 x 1.5 1. of dichloromethane and the extracts were combined and washed with 1 1. of brine and dried over anhydrous sodium sulfate. Evaporation of the solvents on a rotary evaporator at 40° and finally at 40°/1.0 mm. for 1.5 hours afforded 150.7 g. of crude product as a yellow oil. The crude oil was distilled through a 12-in. Goodloe column (bath 150°) collecting fractions as follows: • 1 2 3 4 • 7 8 • 11 12 13 14 16 17 18 19 # 21 22 2^ 24 26 27 1 9 18 30 Fraction b£ 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°/0.15 mm. 21.2 g. 92% 4 86-87°/0.15 mm. 99.4 g. 100% Fractions 3 and 4 combined afforded 120.6 g. of N-methyl-l,5-dimethoxycyclo- » l h9xa-l,4-diene-3-ethylamine as a colorless oil. j ! I I 2 3 11 6 7 8 9 11 12 13 l(f 16 17 18 19 21 22 23 2<f 26 27 191830 v Example 3 Preparation of 6-[2-(N-methvlamino)ethyI] -2-methyl-3-ethyl-5,6,7,8-tetrahydro-lH- - j lndol-4-one j - In a 1 1. 3-neck round-bottom flask equipped with a mechanical stirrer and con- ! . I denser was placed a solution of 60.0 g. of distilled N-methyl-l,5-dimethoxycyclohexa- j l,4-diene-3-ethylamine in 700 ml. of 70% aqueous acetic acid. The reaction mixture i was refluxed for 15 minutes and 59.5 g. of zinc dust was added in five portions over 10 minutes and then the mixture was refluxed for another 15 minutes. To the refluxing I i solution wasTadded a solution of 42.1 g. of 2-isonitroscf-3-pentanone in TTa ml. of 70% aqueous acetic acid over a period of 1 hour. After the addition, the mixture was refluxed for 2.5 hours and cooled to room temperature. The precipitated zinc acetate was removed by filtration and the filter cake was washed with 500 mL of dichloromethane. The filtrate was concentrated on a rotary evaporator and the residue heated at 100°/1.0 mm. for 30 minutes to remove last traces of acetic acid. The residue was dissolved in 500 ml. of water and the solution was extracted with 2 x 150 ml. of dichloromethane. The dichloromethane extracts were discarded and the aqueous layer was made basic (pH 8-9) with 165 ml. of ammonium hydroxide and 500 ml. of brine was - added. The mixture was extracted with 3 x 200 mL of dichloromethane and the i i combined extract was washed with 100 ml. of brine and was dried over anhydrous sodium J sulfate. Evaporation of the solvent afforded 56.0 g. of crude tetrahydroindolone which j was dissolved in 90 ml. of 2:1 toluene-ethyl acetate. The solution was stirred I magnetically and was seeded and allowed to crystallize overnight with stirring. The j first crop of 20.8 g. was collected by filtration and the mother liquor was concentrated and crystallized again from a stirred solution to give 10.0 g. in the second crop. The mother liquor was dissolved in 75 ml. of methanol and a solution of 15.0 g. of oxalic acid in 50 ml. of methanol was added. The mixture was warmed 10 minutes on the steam bath and cooled. The solid oxalate salt was filtered off and washed with 10 ml. of RECEIVED i 91830 1 2 3 H 6 7 8 9 11 12 13 if 16 17 18 19 21 22 23 24 26 27 methanol and dissolved in 50 mL of water. The solution was made basic with ammonium hydroxide and extracted with 2x50 ml. of dichloromethane. The extracts were washed with 1 x 20 ml. of brine and dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give 4.5 g. of additional crude product. Crystallization from 2:1 toluene-ethyl acetate afforded 2.6 g. of additional crystalline product. The two crops and oxalate-derived crystals were combined and dried at 25°/l mm. for 2 hours to give 33.4 g. of 6-[2-{N-'methylamino)ethyl] -2-methyl-3-ethyl- 5,6,7,8-tetrahydro-lH-indol-4-one as a light yellow.solid, mp 114-120°> which was homogenous by TLC. . - 55 - .?4z?.u-.;;i"£vvsg 2 MOV 1982 mm . . c—. ' i 1 2 3 4 • 5 6 7 8 • 9 11 • 12 13 14 16 17 18 • l9 21 22 ^ 23 24 26 27 *91.830 Example 4. frgparation of 3-ethyI-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo-[2,3-gl -isoquinolin-4-one, hydrochloride .
In a 500 ml. round-bottom flask was placed 17.0 g. of 6-[2-(N-methylamino)ethyl] 2-methyl-3-ethyl-5,6,7,8-tetrahydro-lH-indol-4-one' aricl 170 ml. of itethanol. To the solution was added 20 ml. of 4N hydrogen chloride in diethyl ether (made by bubbling HC1 gas into diethyl ether in an ice bath and titrating). The solvent was removed on a rotary - evaporatoFand the residual solta was dried at 50°/lTnm'for 2 hours to give 19.7 g. of crude hydrochloride salt.
In a 3-1. 3-neck round-bottom flask equipped with a mechanical stirrer, thermometer and distilling head were placed the 19.7 g. of hydrochloride salt, 21.8 g. of paraformaldehyde and 1000 ml. of octanol. The reaction mixture was heated to reflux and water which was liberated was removed by distillation until the temperature of the octanol solution in the flask reached 175-180°, whereupon the distilling head was removed and replaced by a reflux condenser. The reaction mixture was heated at 175-180° for 1 hour and 6.54 g. of paraformaldehyde was added in three portions over 5 minutes. Water was distilled out as before until the temperature reached 175-180° and the mixture was heated at 175-180° for an additional 1 hour. The dark brown solution was cooled and poured into 1000 ml. of water. The layers were separated and the organic layer was extracted with 2 x 400- ml. of 5% hydrochloric acid. The combined aqueous extract was washed with 2 x 150 ml. of chloroform and the chloroform solutions were discarded. To the aqueous layer were added 120 ml. of ammonium hydroxide and 400 ml. of chloroform. The layers were separated and the aqueous solution was ! extracted with 4 x 200 ml. of chloroform. The combined chloroform extracts were I washed with 200 ml. of brine and dried over anhydrous sodium sulfate. Evaporation of l the solvent afforded 12.0 g. of crude pyrrolo[2,3-g] isoquinoline as a 4a,8a-trans, 4a,8a- i cis mixture (about 8:1) as a dark tan solid. The crude solid was dissolved in 100 ml. of 9:1 1 i 56 - 2 MOV 1982 ' •S,-C?sV£D 1 2 3 t 6 7 8 9 11 12 13 if 16 17 18 19 21 22 23 2f 26 27 19 1830 dichloromethane-methanol and 300 ml. of diethyl ether was added. The fine solid j precipitate, predominantly the 4a,8a-trans isomer, was collected by filtration and the j filtrate was concentrated and crystallized to give second and third crops of tan solid. j J The combined material was dried at 25°/I mm. for 1 hour to give 8.20 g. of a'light grey j solid, 3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] - ! ! isoquinolin-4-one, mp 203-226°. The partially-purified grey solid was j suspended in 80 ml. of methanol and 12 ml. of 4N hydrogen chloride in diethyl ether was i added. The solvent was removed and the residue was crystallized from 25 ml. of hot j absolute ethanol. The first crop was collected by filtration and the mother liquid was . j concentrated and crystallized to give second and third crops of crystals. The combined j i solid was dissolved in 120 ml. of methanol and 2.4 g. of activated carbon (Darco-G-60) was I i added. The mixture was warmed on a steam bath for 10 minutes and the carbon filtered off through celite. The filtrate was concentrated and recrystallized from 15 ml. of ethanol to give three crops of white crystals. The combined solid was dried under vacuum at 80°/0.05 mm. for 18 hours to give 5.4 g. of 3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,- j 8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one, hydrochloride as a white ! solid, mp 196-198° ; Oxime, semihydrate, mp 131-133° . 1 9 t£ 3 0 Examples 4a-c Following the procedures of Examples 3 and 4, the compounds listed in Table I were prepared from the appropriate isonitrosoketone with variations as noted. Each compound displayed spectral characteristics which were consistent with the described structure. Melting points are for the free base or hydrochloride salt (.HC1) as indicated. Isonitrosoketones were prepared as described in the literature [e.g., Ferris et al., Org. Chem., 24, 1726 (1959)] by nitrosation of the appropriate ketone. The isolated compounds are the 4a,8a-trans isomers. - 58 to -j to o to Cn to »u to to to o Table I 0%:5i-;/''r3 ch3nh ] + hon'/^'r„ Knorr Reaction OCH„ CH3NH Mannich >Clf Reaction ul vo Example 4a 3,6-dimethyl-2-(2-propyl)-4,4a,5, 6,7,8,8a, 9-oc tahydro-1 H-pyr rolo-[2,3-g] isoquinolin-4-one CH(CH3)2 CHg Analysis Calcd.
(-HC1) Found c 64.74 c 64.53 H 8.49 H 8.38 N 9.44 N 9.36 Cl" 11.94 Cl" 12.16 mp (.HC1) > 280°,d Crystallized from methanol Variation in procedure 4b 2,6-dimethyl-3-phenyl-4,4a,5,6,7, 8,8a,9-octahydro-lH-pyrrolo[2,3-g]- isoquinolin-4-one CH, ^ / C 77.23 C 77.23 > 240° ,d ethanol- H 7.53 H 7.50 ethyl N 9.52 N 9.54 acetate Mannich reaction in diethylene glycol monoethyl ether, 155°, 1 hour vO Co ■J o to to to ■o o> tn to to to to, to H4 O ] oo -o o> tn 4* to to op cr>^^ut CJ to H* Table I - cont'd.
Example 4c 2,3,6-trimethyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g] iso-quinolin-4-one 2 CH, %L CH, Analysis Calcd. Found (.hc1) C 62.56 C 62.19 H 7.88 H 7.97 N 10.42 N 10.20 Cl" 13.19 Cl~ 13.41 mg Crystallized from 275-80°,d ethanol-ether Variation in procedure Knorr reaction in n-butanol at 170°/50 psi ■ —t% . 00 1 2 3 4 • 6 7 8 0 11 12 13 14 16 17 18 • 21 » 24 26 27 28 91 °57 Example 5 Preparation of 2-raethyl-3-cthyl-4,4a,5T6,7,3,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one A mixture of 3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrroIo[2,3- g] isoquinolin-4-one prepared as in Example 4 (4.92 g., 20 mmol), ethyl chloroformate [ ! (19.55 g., 180 mmol)-, and potassium bicarbonate (6.0 g., 60 mmol) in diethyl ketone (100 • i ml.) was heated to reflux for 3 hours. The mixture was cooled, filtered, and the filtrate ! concentrated on a rotary evaporator to dryness and the residue was dissolved in •i chloroform. The chloroform solution was washed with 5% aqueous hydrochloric acid, ] brine, and was dried over anhydrous sodium sulfate. Evaporation of the solvent afforded : | 4.90 g. of crude carbamate which was purified by chromatography on alumina III to give 1 i 3.70 g. of pure 6-ethoxycarbonyI-3-ethyI-2-methyl-4,4a,5,6,7,8,8a,9-oetahydro-lH-pyr- ; rolo[2,3-g] isoquinolin-4-one.
The carbamate (3.7 g., 12.2 mmol), glacial acetic acid (45 ml.) and concentrated hydrochloric acid (60 ml.) were heated to reflux for 24 hours, cooled, and concentrated on a rotary evaporator. The residue was dissolved in water and extracted with chloroform (discarded) and the aqueous layer was made alkaline with ammonium hydroxide and was extracted with chloroform. The combined extracts were washed with brine and dried over anhydrous sodium sulfate and concentrated to give 2.72 g. of crude secondary amine. Treatment of the crude amine in ethanol with ethanolic hydrogen chloride gave the hydrochloride salt, which was crystallized, from hot ethanol to afford 2.18 g. (47% yield) of 2-methyl-3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,Sa-trans-lH-pyrrolo[2,3-g] iso-quinolin-4-one, hydrochloride as white crystals, mp > 250°.
Anal. Calcd. for C14H2QN20.HC1: C, 62.56; H, 7.88; N, 10.42; Cl", 12.19 Found: C, 62.50; H, 7.90; N, 10.19; Cl~, 13.33 • 1 2 3 4 S 9 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 19 1830 In an analogous manner, 2,3-d±methyl-4,4a,5,6,7,8,8a,9-octahydro-4a, 8a-trans-IH-pyrrolo [2,3-g]iscquinolirr4-one can be prepared frcm 2,3,6-trimethyl-4,4a,5,6,7,8,8a,3-octahydro- lH-pyrrolo[2,3-a]iso-quinolin-4-one.
Example 6 Preparation of 3,4-dihydro-lH-6,8-dimethoxy-2-methyl-isoquinoline, hydrochloride A solution of N-methyl-(3,5-dimethoxyphenyl)ethyla.mine hydrochloride (15.0 g, 64.7 mmol) in 30 ml. of water was treated with 35 ml. of 2N sodium hydroxide and extracted with dichloromethane. The combined extracts were concentrated on a rotary evaporator and mixed with aqueous formaldehyde (65 ml, 37% solution). The mixture was refluxed for 2 hours, made alkaline with 2N sodium hydroxide (15 ml.) and extracted with dichloromethane. The combined extracts were washed with brine and dried over anhydrous magnesium sulfate and concentrated to give the product as a yellow oil (15.5 g). The oil was dissolved in 100 ml. of ethanol and treated with ethanolic hydrogen chloride. Ether (75 ml.) was added, and the salt crystallized to give 10.15 g. of 3,4-dihydro-lH-6,8-dimethoxy-2-methylisoquinoline, hydrochloride (64% yield). t 9 18 3 0 Example 7 Preparation of I,2,3,4,4a,7-hexahydro-S,8-dimetIio.\-y-2-methyIisoquinoline and octa-hydrD-2-methylisoouinoIin-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-methylisoquinolir.e hydrochloride (1.0 g, 4.1 mmol). After stirring 2-3. minutes, lithium wire (0.57 g, 82 mmol) was added in short pieces over 30 minutes. The blue solution was stirred under reflux for 2.5 hours and solid ammonia chloride (4.5 g) was added until the . blue color dissipated. Ether (100 ml) was added and the ammonia was allowed to evaporate overnight. Ice water (100 ml) was added and the organic phase was separated. The aqueous layer was extracted with ethyl acetate and chloroform. The combined extracts were washed with brine and dried over anhydrous magnesium sulfate and concentrated to give l,2,3,4,4a,7-hexahydro-6,8-dimethoxy-2-methylisoquinoline (0.58 g, 68% yield) as a yellow oil.
The crude product (1.05 g) in 20 ml. of 70% aqueous acetic acid was refluxed for 5 hours and the acetic acid was removed on a rotary evaporator. The residue was dissolved in water and washed y/ith chloroform. The aqueous phase was concentrated to a 10 ml. volume and chromatographed on Dowex AG 50WX 8 eluting with 2 molar aqueous pyridine to afford 0.11 g. of octahydro-2-methylisoquinolin-6,8-dione (1L696 yield) as a light yellow solid. Treatment with hydrochloric acid in methanol afforded the hydrochloride, mp 193-196°. . - 63 - 1 2 3 4 • 7 8 9 % 11 12 13 14 16 17 18 19 m 21 .22 24 - 2G 27 W v'V ■ • ' • ■ • • ■ ■■ / j 9 j 830 Example 8 —4a , Rg—t-rans- Preparation of 3-ethyl-2,6-dImethyI-.4',4a,5.G,7,8,8n,9-octnhyaro/lH-pyrrolo[2>3-?I iso-quir7Jlin-4-one via- octnhydro-2-mcthvIisoquinolin-6,S-dione lJ2,3,4,4a,7-Hexahydro-6,8-dimethox7-2-methylisoquinoline (0.56 gf 2.63 mmol) was heated to 90-100" in 70% aqueous acetic acid (10 ml) to hydrolyze the bis(enolether) to the octahydro-2-methylisoquinolin-6,8-dione. To the hot solution was added zinc dust (0.6 g, 9.25 mmol)*and 2-isonitroso-3-pentanone (0.7 g, 6.1 mmol). The mixture was refluxed for 3 hours, cooled and filtered to remove zinc and zinc acetate. The filtrate was concentrated to dryness on a rotary evaporator and the residue'Vivas' dissolved in dichloromethane. To the solution was added ammonium hydroxide and the layers were separated. The organic layer was washed with brine and dried over anhydrous sodium sulfate ana concentrated to give the crude product. Chromatography of the crude -4a,8a-trans- product on Alumina III afforded 3-ethyl-2,6-dimethyl-4,'4a,5,5,7,8,8a,9-oetahydro/lH-pyrrolo[2,3-g] isoquinolin-4-one as a white solid (0.19 g, 29% yield). luipatlsrcracs 2 NOV 3982 .
«SCSVED i 2 3 k 6 7 S 9 11 12 13 1« 16 17 IS 19 21 22 23 24 26 27 19 1330 Example 9 Preparation of 2,6-dimethyl-3-isopropyl-4,4a,5,6,7,8,Sa,9-octahydro-4a,8a-trans-IH-pyr- j roIo[2,3-g] isoquinolin-4-one A solution of crude octahydro-2-methyl-isoquinolin-6,8-dione (approximately 12.5 j mmol) and 2.4 g. (18 mmol) of 2-isonitroso-4-methyl-3-pentanone in 40 ml. of 70% j aqueous acetic acid was treated with 2.6 g. (40 mmol) of zinc dust and slowly heated to i ' • i reflux. After 1 hour the mixture was cooled slightly and an additional 0.4 g. of iso- I nitrosoketone and 1.0 g. of zinc were added and the mixture stirred for 1.5 hours at J i reflux. The mixture was then cooled and filtered, and the filtrate concentrated at j 50°/20 mmHg to give a yellow oil which was diluted with 50 ml. of water and made j t alkaline (pH 8-9) with ammonium hydroxide. The mixture was extracted with chloro- j form and the extracts were washed with brine and dried over sodium sulfate and j ! concentrated to give 2.6 g. of crude product. The material was chromatographed (dry j column) on 100 g. of silica gel eluting with the organic phase of a mixture prepared by equilibrating (by volume) 90 parts chloroform, 30 parts methanol, 10 parts water, and 6 parts acetic acid. The eluate fractions containing the product were evaporated, diluted with water, made alkaline (pH 8-9) with ammonium hydroxide, and extracted with chloroform. The extracts were dried over sodium sulfate and evaporated to give 1.0 g. of solid product which was recrystallized twice from ethyl acetate to give 470 mg. of i pure 2,6-dimethyl-3-isopropyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one as a crystalline solid, mp 244-247°. 1 = 3 4 .5 € 7 * 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 518i.o Example 10 .
Preparation of 3,6-dimethvl-2-(2-proDenyl)-4,4a,5,6,7,8,8a,9-octahydro-4a.8a-trans-lH-pyrroio[2,3-g] isoquinolin-4-one In a similar manner to that described in Example 9, 3-isonitroso-5-hexen-2 -one .and 2-methyl-octahydroisoquinolin-6,8-dione afforded 3,6-dimethyl-2-(2-propenyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one, mp 221— 223°, Example 11 ■ " •' Preparation of 3-cyeloDropyl-2,6-dimethyI-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one In a similar manner to that described in Example 9, l-cyclopropyl-2-isonitroso-l-propanone and 2-methyl-octahydroisoquinolin-6,8-dione afforded 3-cyclopropyl-2,6-dimethyl-4.4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one, mp 258-259° (dec.).
Example 12 Preparation of 2-benzyl-3,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyr-rolo[2,3-g;] isoquinolin-4-one In a similar manner to- that described in Example 9, 3-isonitroso-4-phenyl-2-butanone and 2-methyl-octahydroisoquinolin-6,8-dione afforded 2-benzyl-3,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one, mp 234-235°. 2 NOV 3982 - 66 - RECEIVED $ 1 Example 13 2 Preparation of 6-methyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2.3-gl iso- 3 quinolin-4-one In a similar manner to that described in Example 9, except that no zinc was used, aminoacetaldehyde dimethyl acetal and 2-methyl-octahydroisoquinolin-6,8-dione afforded 6-methyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one, mp 208-210° 11 12 13 if 16 17 18 19 21 22 23 24 26 27 • 4 ( 1 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 1-91830 Example J4 Preparation of 3-ethyl-I,2,6-trimethyl-4.4a,5,6,7,S,8a.9-octahydro-4a.8a-trans-lH-pyr- rolo[2,3-g] isoqufnolin-4-one Liquid ammonia (80 ml) was condensed into a flask containing a suspension of -4a,8a-trans- 2,6-dimethy'l-3-ethyl-4,4a,5,6,7,8,8a,9-octahydro/lH-pyrrolo[2,3-g] isoquinolin-4-one (0.984 g, 4.0 mmol) in'ether (24 ml). Sodium metal (0.138 g, 6.0 mmol) was added and the solution stirred until all the sodium had dissolved. A solution of methyl iodide (1.28 2 NOV 1982 yy'wfved 68 - g, 9.0 mmol) in ether (16 ml) was added and the mixture was stirred at room temperature until the ammonia evaporated. Water and chloroform were added and the aqueous layer was separated and extracted with chloroform. The combined extracts were washed with brine and dried over anhydrous sodium sulfate and concentrated to give 1.14 g. of crude product which was chromatographed on Alumina m to give 0.572 g. of white solid product. The chromatographed free base was converted to the hydrochloride salt with, ethereal hydrogen chloride and crystallized from ethyl acetate-ethanol and ethanol to give pure 3-ethyl-l,2,6-trimethyl-4,4a,5,6,7,8,8a,9-oct2hydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one, hydrochloride (0.33 g, 28% yield) as white crystals, mp 241-243° .
Anal. Calcd. for C^H^f^O.HCl: C, 64.74; H, 8.49; N, 9.44; Cl", 11.94 Found: C, 64.72; H, 8.63; N, 9*.29; Cl", 12.03 ■ I J i 2 3 4 6 7 3 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 WQ30 Example 15 Preparation of l-benzoyl-2,6-dimethyl-3-ethyl-4.4a,5,6,7,S,8a,9-octahydro-4a,3a-trans-IH-pyrrolof2,3-g] isoquinolin-4-one ^ To a suspension of 3-ethyl-2,6-dimethyi-4,4a,5,6,7,8,8a,9-oc -pyrrolo- [2,3-g] isoquinolin-4-one (492.7 mg, 2.0 mmol) in dry tetrahydrofuran (10 ml) at -30° was added butyllithium *(1.6 ml, 2.4 mmol, 1.5 M solution in hexane) over 2-3 minutes via syringe. The solution was stirred at -30° for 1 hour and benzoyl chloride (336 mg, 2.4 mmol) was added over 2-3 minutes. The resulting solution was stirred for 1 hour at -25 to -35° and for 0.5 hours at room temperature. The solution was poured into ice water (30 ml) and extracted with chloroform. The combined extracts were washed with brine and dried over anhydrous sodium sulfate. Evaporation of the solvent afforded the crude product (0.9 g), which was chromatographed (dry column, silica gel, eluting with a chloroform-aqueous methanol-acetic acid solution). Column fractions were treated with ammonium hydroxide and extracted with chloroform and washed with water and dried over anhydrous sodium sulfate. Evaporation of the solvent gave l-benzoyl-2,6-dimethyl-3-ethyl-4,4a,5,G,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] -isoqu;nolin-4- -one as a solid which was recrystallized from cyclohexane to give the pure product, mp 144-146°.
Anal. Calcd. for C22H26N2C>2: C, 75.40; H, 7.48; N, 7.'99 ■a* -Sa—trans- Found: C, 75.63; H, 7.79; N, 8.01 . « 1 2 3 4 • 5 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 191830 Utilizing the procedure of Example 15, the following compounds were prepared. | The isolated compounds are the 4a,8a-ti:ans isomers. -4a,8a-trans- From 2,6-dimethyl-3-cthyl-4,4a,5,6,7,8,Sa,9-octahydro/lH-pyrrolo[2,3-g] isoquin- i i olin-4-one and benzyl chloride, there was obtained l--benzyl-2,6-dimethyl-3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g] isoquinoIin-4-one. — ..— . -4a, 8^-trans- ■ From . 2,6-dimethyl-3-ethyl-4,4a,5,6,7,S,8a,9-octahydro/lH-pyrrolo[2,3-g]- ' i isoquinolin-4-one and 1-trimethylacetyl chloride, there was obtained 2,6-dimethyl-3- j ethyl-l-(2,2-dimethyl-l-oxopropyl)-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g] isoquinolin--4-one, mp 110°-112°. - , , ' -4a,8a-trans- From 2-methyl-3-ethyl-6-(2-phenylethyl)-4,4a,5,6,7,8,8a,9-octahydrc/lH-pyrrolo- [2,3-g] isoquinolin-4-one and methyl iodide, there was obtained 3-ethyl-l,2-dimethyl-6- (2-phenylethyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4- one, mp 180-181°. "w. rarest eyes ' 2 NOV 1982 " 70 ~ '91830 j Example 16 2 Preparation of 3-ethyl-2-methyl-6-(2-propcnyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans- 3 lH-pyrrolo[2,3-g] isoquinolin-4-one -4a,8a-trans- 4 A mixture of 3-ethyl-2-methyl-4,4a,5,6,7,S,8a,9-octahydro/lH-pyrrolo[2,3-g] iso- quinolin-4-one (0.470g, 2.03 mmol), allyl bromide (0.5 g, 4.13 mmol) and potassium 6 carbonate (0.85 g, 6.16 mmol) in acetone (35 ml) was stirred, at room temperature for 2 7 hours and was filtered. The filtrate was concentrated and the residue (0.53 g) chroma- 8 tographed on Alumina III to give the product (0.40 g). This product was treated with 9 ethereal hydrogen chloride to form the hydrochloride salt, which was recrystallized from ethanol-ethyl acetate to give 3-ethyl-2-methyl-6-(2-propenyl)-4,4a,5,6,7,8,8a,9- 11 octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one hydrochloride as a white solid, 12 ; mp 214-217°. 13 " Anal. Calcd. for C17H24N20.HC1. 0.5H20 14 C, 64.24; H, 8.25; N, 8.81; Cl" 11.15 Found: C, 64.50; H, 8.48; N, 8.96; Cl", 11.37 16 !; 17 Examples I6a-dd 18 Following the procedure of Example 16, the compounds listed in Table II were 19 prepared from the indicated . 4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g]-isoquino- lin-4-one and the indicated halide. Each compound displayed spectral characteristics 21 : consistent with the described structure. Melting points are for the free base or 22 hydrochloride salt (.HC1) as indicated. Compounds isolated are the 4a,8a-trans isomers. 23 24 26 27 "Hz. pAitiffr c.vin- »i 1'" | 2 MOV 1982 iw.seivr L, 1 to to to to <•4 o> cn £* If to to to to I-* O * tS oo -a o> cn »p> co . to h-* o OO -O O rf* CO to Table II k co* + r4x 2_3 > -j to Example 16a 2 -m ethy l-3-ethyl-6-(cyclo-propylmethyl)-4,4a,5,6,7,8, 8 a, 9-oc tahydro-lH-py rrolo-[2,3-g] isoquinolin-4-dne, HCl, 0.2 molar hydrate rl. r2 r3 h ch, R. X _jl — ch2oh3 [>-CHJ Calcd.
(.HCl) Analysis Found mp Crystallized from Reaction conditions temp. time Cl C 66.22 C 66.24 215-9° Ethmol- reflux 16 hours H 8.15 H 8.35 ethyl in acetone N 8.58 N 8.36 acetate Cl" .85 cf .51 16b 2-methyl-3-ethyl-6-benzyl-4., 4a, 5,6,7,8, 8a,~9-oc tahy dro-lH-pyrrolo[2,3-g] isoquino-lin-4-one 1IC1 h ch, ch2ch3 ch 2 cl (.HCl) C 70.27 C 70.49 H 7.58 H 7.33 N 7.81 N 7.72 Cl" 9.88 Cl" .03 193-7° Ethanol reflux 2 hours in acetone Table II - cont'd.
Reaction Analysis Crystallized conditions Example Rj R2 Rg R4 — Calcd. Found mp from temp. time 16c * . rac. 2-methyl-3-ethyl- H CH, CH„CH„ (CIIJ-NCH.CH. Cl C 71.25 C 71.03 " 184-5° ethyl reflux 20 hours in 6-[2-(dimethylamino)ethyl]- ' • 1 s o* H 9.63 H 9.73_ acetate 3-pentanone 4,4a,5,6,7,8,8a,9-octahydro- .N.. 13.85 N 13.66 ^ 4a,8a-trans-lH-oyrroIo[2,3-g] - . . i _/ isoquinolin-4-one rac. 2-methyl-3-ethyl-6-[4- H CH, CH„CH„ CCH2CH2CH2 Cl C 72.70 C 72.47 210-12° Ethyl acetate reflux 24 hours (4-fluorophenyl)-4-oxobutyl] - • II H 7.37 H 7.47 in 3- 4,4a,5,6,7,8,8a,9-octahydro- N 7.07 N 7.09 pentanone 4a,8a-trans-lH-pyrrolo[2,3- F 4.79 F 4.75 g] isoquinolin-4-one a rac. 2-methyl-3-ethyl-6-(2- H CH, CH„CH, CH„CH„ Br C 78.53 C 78.53 239-40° ethyl reflux 2 hours phenylethyl)-4,4a,5,6,7,8,8a,9- 15 " H 8.39 H 8.40 acetate- in 3- octahydro-4a,8a-trans-lH-pyrrolo- N 8.33 N 8.35 ■ ethanol pentanone : -a [2,3-g] isoquinolin-4-one 16f ■ rac. 2-methyl-3-ethyl-6-(2- H CH„ CH„CH„ CH,CH„OCH„CH2Br C 63.42 C 63.13 213-5° ethanol. reflux 2 hours in ethoxyethyl)-4,4a,5,6,7,8,8a,9- 0 0 H 8.57 H 8.71 ethyl acetate 3-pentanonev. octahydro-4a,8a-trans-lH-pyrrolo N 8.21 ft 8.17 QO. [2,3-g] isoquinolin-4-one hydro- C1"10.40 Cl" 10.64 7 t chloride ; - ■ , o k> ui k> k> n) n) k) k) »— o vo 00 *s| c\ ' v* -p \>> to Table II - cont'd.
Example 16g r1 r2 rac. 3,6-diethyl-2-methyl-4,4a,5,6,7,8,8a,9-octa-hydro-4a,8a-trans-lH-pyrrolo-[2,3-g] isoquinolin-4-one h ch.
R, ch2ch3 R.
'GH3CH2 x Br Analysis Calcd.
C 73.81 h 9.29 N 10.76 Found c 73.91 h 9.30( n 10.84 mp Reaction Crystallized conditions from temp. time 228-30 ethanol reflux 3 hours in acetone 16h rac. 3-ethyl-2-methyl-6-propyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one h ch, ch2ch3 CH3CH2CH2 Br c h N 74.41 9.55 10.21 C h N 74.29 . 9.40 10.21j 226-8° ethanol reflux 13 hours in 3-pentanone 16i - 4a,8a-trans-3-ethyl-4-oxo- h 4,4a,5,6,7,8,8a,9-octahydro-2-rnethyl-IH-pyrrolo- [2,3-g] -isoquinoline-6-acetic acid ethyl ester ch3 ch2ch3 ch3ch2oocch2 Br C 67.90 C 68.09 h . 8.23 h 8.28 N 8.80 N 8.80 \ 215-6° ethanol- reflux 2 hours In ethyl acetate 3-pentanone 16j 4a, 8a-trans-l- [3-ethyl-4, 4a,-fj 5,6,7,8,8a,9-octahydro-2- irethyl-4-oxo-lH-pyrrolo-[2,3-g]isoguinolin-6-yl]-2-propanone ch3 ch2ch3 h3cjjch2 cl C 70.80 C 71.10 h 8.39 h 8.30 N 9.71 N 9.93: 19 2-5 ethanol . reflux 2 hours in 3-pentanone ' ; CO c■ ■ o ■ Table II - cont'd.
Example 16k R, Rn R.
Analysis Calcd.
Found mp Reaction Crystallized conditions from temp. time ul rac. 2-methyl-3-ethyl-6-[2- H (4-fluorophenyl)-2-oxoethyl] -4,4a,5,6,7,8,83,9-oct3hydro-4a,8a-trans-lH-pyrrolo[2,3-g] -isoquinolin-4-one 16-1 rac. 2-methyl-3-ethyl-6-[3- H (4-fluorophenyl)-3-oxo- propyl] -4,4a,5,6,7,8,8a,9- octahydro-4a,8a-trans-l.H- pyi rolo[2,3-g] isoquinolin- 4-one CH3 CH2CH3j^y^CH2 01 P ch3 ch2ch3 |<^fxch2ch2 cl C 71.72 c 71.44 h 6.84 h 6.80 N 7.60 N 7.47 c h n 72.23 7.12 7.32 c h n 72.24 7.00 7.19 ' 209-13 ethanol reflux 208-10 ethanol reflux 3 hours in 3-pentanone 3 hours in 3-pentanone 16 m rac. 3-ethyl-2-methyl-6-(3- h phenoxypropyl)-4,4a,5,6,7,8,-8a,9-octahydro-lH-4a,8a-trans-pyrrolo[2,3-g] iso-quinolin-4-one 16n rac. 6-{3-diphenylpropyl)- h 3-ethyl-2-methyl-4,4a,5,6,-7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin- 4-one ch3 ch2ch3 v /; Br och2ch2ch2 C6H5 ch3 ch2ch3 . \:hch2ch2 cl C6H5 c h n 75.37 8.24 7.64 c 81.65 H N 8.03 6.57 c h n 75.64 8.18 7.52 H N 81.60 7.85 6.72 202-3° ethanol 220-2" reflux 2 hours in 3-pentanone reflux 17 hours in Qq 3-pentanone n) n) ON s> vji k> 45* k) k3 k) k) m m m.m'm m m m m m vjj is) . o so w m on'^i •(? u kj h-' o m>06"sjo\ljt4p\«)tsj Table II - cont'd. -j o-1 Example Rj 16o rac. 3-ethyl-6-[2-(4-methoxy- H phenyl)-ethyl] -2-methyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] -isoquinolin-4-one 16p 3-ethyl-4,4a,5,6,7,8,8a,9- H octahydro-2-methyl-6-[2-[tricyclo[3.3.1.1/3,7/] decan- 1-yl] -2-oxoethyl] -4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin- 4-one R2 R3 R, analvsf? Calcd. Found Reaction Crystallized conditions mp from temp. time CH, CHxCH, CH,0-fVcH„CH0 Cl C 75.37 C 75.65 255-7° ethanol 3 W 2 2 H 8,25 H 8.41 N 7.64 N 7.73 reflux 24 hours In 3-pentanone ch3. ch2ch3 1-chr Br C 76.43 C 76.34 237-40° ethanol H 8.88 H 8.75. N 6.86 N 6.62' reflux ' 3 hours in 3-pentanone 16q rac. 3-ethyl-2-methyl-6-(2-methylpropyl)-4,4a,5,6,7,8-8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one h CH, ch2ch3 h3^\ / h3c ch-chr Br C 74.96 fl 9.79 N 9.71 c H N 75.24 9.89 9.70 213-15° ethanol reflux hours In 3-pentan<5ne 16 r rnc. 3-ethyl-G-[2-(4-cliloro-phenyl)-ethyl] -2-methyl-4,4u,5,6,7,8,8u,l)-oetuhydro-4o,8n-trnn.s-lII-pyrro]o[2,3-g] isoquinolin-4-one H ch3 ch2ch3 cl -^V-CH.CH, Cl c 71.24 C 71.25 264-7° 1,4-dioxane .reflux 1 * H 7.34 H 7.16 N 7.55 N 7.63 hours in 3-pontunone -. n Table II - cont'd.
Example 16s rac. 3-ethyl-6-[2-(ethenyl-oxy)ethyl] -2-methyl-4,4a,5,-6,7,8,8a,9-octahydro-4a,8a-transTlH-pyrrolo[2,3-g] iso-quinolin-4-one 16t r, r, r„ r, x h ch3 ch2ch3 Ch2=choch2ch2 cl Analysis Calcd. ,c h N 71.49 8.67 9.26 Found c h N 71.31 8.59 9.25 mp Reaction Crystallized conditions from temp. time 174-7° acetonitrile reflux 10 hours in 3-pentanone rac. 3-ethyl-2-methyl-6-(3-phenyl-2-propenyl)-4,4a,5,6,-7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one h ch, ch2ch3 cgh5ch=chch2 Br C 79.27 h 8.10 N 8.04 C 79.10 h 8.04 N 8.10' 218-20° ethanol .. reflux" 4 hours in 3-pentanone -16u rac.4a,8a-trans-3-ethyl- h 4,4a,5,6,7,8,8a,9-octa-hydro-2-methyl-4-oxo-lH-pyrrolo[2,3-g]isoquinoline-6-propanoic acid ethyl ester 16v rac.-6-(cyclobutylmethyl)- h 3-ethyl-2-m ethyl-4,4a, 5,6,7,-8,8n,9-octahydro-4n,8a-trans-lH-pyrrolol2,3-g] isoquinolin- 4-ouo cii3 ch2ch3, ch3ch2oocch2ch2 ch3 ch2ch3 h2c.
/CH2\ i chch- \ / 2 CH2 Br c h N cl C h N 68.65 8.49 8.43 75.96 9.39 9.32 c h n C h N 68:59 8.50 8.55 75.70 9.34 9.23 180-4° acetonitrile reflux 222-4 ethanol reflux 3 hours in 3-pentanone 18 hours in 3-pentanone vo co lv. o Is) k) o> K) V-n ts> •p- k) NJ nj fo fs) o vd 00 vj OS ' \Ji . u> k) ►— o vd 00 si on v* - «f> . v* k> ►— Table II - cont'd* Example ' Rj' Rg 16w rac.-6-(4-diphenylbutyl)- H CH, 3-ethyl-2-methyl-4,4a,5,6," vjsjfia^-octahydr^a^a-trans-lH-pyrrolo[2,3-g]-isoquinolin-4-one R4 R Analysts Calcd.
Found c6h!k chgchg ^,chch2ch2ch2 C6H5 mp Reaction Crystallized conditions from temn. time cl c 81.78 C 81.88 I 236-8° ethanol reflux 18 hours in H 8.24 H 8.16 3-pentanone N 6.36 N 6.36 -j oo 16x 4a,8a-trans-[2-[3-ethyl-_ 4,4a,5,6,7,8,8a,9-kx:ta-hydro-2-methyl-4-oxo-lH-pyrrolo[2,3-g]isoquinolin-6-yl]ethyl]benzoic acid ester 16y • h ch„ ch2ch3 cooch2ch2 Br c h n 72.60 7.42 7.36 c h N 72.31 7.58 7.22 ' 206-8° ethanol ■ ' reflux 6 hours in 3-pentanone rac. 3-ethyl-2-methyl-6-[2-(N-metliyl-2-pyrrolidinyl)-ethyl] -4,4a,5,6,7,8,8a',9-oeta-hydro-4n,8ft-trflns-iri-pyrrolo-[2,3-g] isoquinolin-4-one h ch, ch2ch3 ^Tp~CH->< ch, 2C«2 cl c h n 73.43 9.68 12.23 c h N 73.25 9.54 12.41 192-4® ethyl acetate reflux hours in 3-pentanone IGz 4a,8a-trans-[3-[3-ethyl-4,4a,5,6,7,8,8a,9-octa-hydro-2-methyl-4-oxo-lH-pyrrolo[2,3-g]-isoquinolin-6-yl]propyl]benzoate H CH, ch2ch3 ooch2ch2ch2 Br c h n 73.07 7.67 7.10 c h N 73.12 7.63 7.07 189-90,5 ethanol . reflux 8 hours in 3-pentnnone vo CO L.< Example 16aa R„ R, r.
Analysis Calcd.
Found mp Reaction Crystallized conditions from temp. time <1 lis rac.-3-ethyl-2-methyl-6-(2,3-dihydroxypropyl)-4,48,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one h ch, ch2ch2 ch2ch-ch2 oh oh A, ci c h n 66.64 8.55 9.14 c h n 66.32 9.07 9.07 210-12° ethanol reflux hours in 3-pentanone 16bb rac. 3-ethyl-6-[2-(4-morpholinyl)ethyl] -2-methyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8u-trans-lH-pyrrolo-[2,3-g] isoquinolin-4-one h ch, ch2ch3 o n-ch2-ch2 cl c 69.53 h 9.04 n 12.16 c h n 69.59 9.12 12.12 206-8° ethanol reflux 8 hours in 3-pentanone vo oo c-;-- o m w m w w w m ^1 on ul •<=■ v>) k» i— k) o vo 00 vj os ' \_n 4=- v» nj »— o .vo 00, vj on Kji ■ -t? u» k> »— Table II - cont'd.
Example ll R„ R, R, X .Anatols..
Calcd.
Found HIE Reaction Crystallized condition from temp. time 16 cc rac. 6-benzyl-2,3-di-m(jthyl-4)4a,5,6,7,8,8a,9-octahydro-lH-4a,8a-trans-pyrrolo[2,3-g] isoquinolin-4-one H CH, CH, \ ~ ch2 cl C H N 77.89 C 7.84 H 9.08 N 77.61 7.63 9.13 245.5-6" ethanol reflux 3 hours in acetone s 0'"r!! : IS) ' 8! i; SO oo k) l vo CO o * * 1 2 3 4 6 7 8. 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 T91830 Example 17 : ' i Preparation of 3-ethyl-2-methyl-6-(2-hydroxy-2-phenyIethyI)-4.43.5,6,7,8.Sa.S-octa-- hydro-4a,8a-trans-lH-pyrrolo[2?3-g3 isoquinolin-4-one J -4a,8a-trans- | A mixture of 3-ethyl-2-methyl-4,4a,5,6,7,8,8a,9-octahydrc/lH-pyrrolo[2,3-g] iso- quinolin-4-one (0.83 g, 3.58 m mol) and styrene oxide (0.51 g, 4.22 mmol) in methanol (25 ml) was refluxed for 2.5 hours, cooled, and filtered. The filtrate was concentrated and * the residue chromatographed on Alumina III to give 0.69 g. of crude product. Re-crystallization from ethyl acetate-ethanol afforded 0.195 g. of 3-ethyl-2-methyl-s-(2-hydroxy-2-phenylethyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,3a-trans-lH-pyrrolo[2,3-g] isoquinoiin - 4-one as a white solid, mp 218.5-220°. j t Anal. Calcd. for ! C, 74.97; H, 8.01; N, 7.95 j r Found: C, 74.87; H, 7.S2; N, 7.95 j 1 Examples 17a-17f Following the procedure of Example 1-7,- the compounds listed in Table. HI were -4a,8a-trans- prepared from 3-ethyl-2-methyl-4,4a,5,6,7,3,8a,9-octahydroaH-pyrrolo[2,2-<r] iscquino-' lin-4-one and the indicated epoxide. Each compound displayed spectral characteristics consistent with the described structure. Melting points are for the free base Gr hydrochloride salt (.HCl) as indicated. The compounds isolated are the 4a,8a-trans isomers. 81 ~ 17 NOV 1982 tO to to tO -J o> in to to to to O co -j OS tn co to 00 -4 C5 .to. O tO >-• Table 111 >—<>3 H N Reaction CO to Example 17a 2-methyl-3-ethyl-6-[2-hydi'oxy-2-(4-chloro phenyD-ethyl] -4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g] -iso'quinolin-4-one 17b 2-m ethy l-3-ethyl-6-(2-hydroxyethyl)-4,4a,5,6,7,8, 8a,9-octahydro-lH-pyrrolo-[2,3-g] isoquinolin-4-one h. h.
Sl X Calcd.
Found m from temp. time H CH, CH„CH, ci-0 _ C 68.29 C 68.11 214-5° Ethanol- reflux 3 hours 0 Z i) H 7.03 H 7.03 ethyl in methanol N 7.24 N 7.18 acetate Cl 9.16 Cl 9.38 H CH, CH,CH, H C 69.53 C 68.93 215-8° Ethanol ° 2 hours 0 L 0 H 8.75 H 8.78 in methanol N .14 N 9.96 s0 o NJ vi KJ ON h) Vji nj •p- ro Vji k) kj nj h- k> o 00 on v* Table III - cont'd Example r, rn rfl Re Analysis Calcd.
Found rnc Reaction Crystallized Condi t Ions from temp. time 00 u> Ex. 17 c rac. 2-methyl-3-:ethyl-6-[2- H CH, hydroxy-3-[4-(l,l-dimethyl-ethyl)phenoxy] propyl] -4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] -isoquinolin-4-one 17d rac. 2-methyl-3-ethyl-6-(2- H CH, hydroxy-3-m ethylbutyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo-[2,3-g] isoquinolin-4-one ch2ch3 ''a OCH„ CH, CH2CH3 CH^ CH„ c 73.94 c 73.83 225-7° ethyl reflux 2 hours H 8.73 H 8.84 acetate- in methanol N 6.39 N 6.30 ethanol C 71.66 C 71.49 197-9° ethanol- reflux hours in H 9.50 H 9.72 ethyl acetate ethanol N 8.80 N 8.77 17e rac. 2-methyl-3-ethyl-6-(2- H CH, hy droxy-3,3-di m e thylbu tyl)— 4,4a,5,6,7,8,8a,9-oetahydro-4 a, 8a-1 rans-lH-py rrolo-[2,3-g] isoquinolin-4-one 17 f rac. 2-methyl-3-ethyl-6-[2- H CH, hydroxy-3-(4-ehlorophenoxy)- propyl] -4,4a,5,6,7,8,8a,9- octahydro-4a,8a-trans-lH- pyrrolo[2,3-g] isoquinolin-4-one CH2CH3 h3c.
CH, \/CHa /\ CH2CH3 C 72.25 C 72.31 232-4° ethanol- reflux H 9.70 H 9.73 ethyl acetate N 8.43 N 8.20 och2- in methanol C 66.26 C 66.11 211-13° ethanol reflux 3 hours in H 7.01 H 7.05 ethanol N 6.72 N 6.81 Cl 8.50 Cl 8.26 vO O 9 1830 11 12 13 14 16 . 17 18 * 21 22 •> 24 26 27 Example 18 Resolution of racemic 3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,83-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one The racemic free base (prepared as in Example 4) (1.20 g.) was dissolved in methanol and a solution of d-(+)-tartaric acid (0.74 g.) in methanol was added. The solution was concentrated and recrystallized twice from methanol. The crystalline d-(+)-tartrate salt was treated with ammonium hydroxide to liberate the free base, and the free base was treated with anhydrous ethereal hydrogen chloride to give the hydrochloride salt. After two recrystallizations from ethanol and drying at 80°/0.005 mm, there was obtained 0.15 g. of the (-)-enantiomer as a white crystalline solid, mp 240-245°. rotation: [a ] ^ -120.78° (c 0.81%, water) Anal. Calcd. for C15H22N20.HC1. 0.25H2Q Found: C, 62.70; H, 8.24; N, 9.75 C, 62.44; H, 8.33; N, 9.67 The mother liquors from the crystallization of the d-(+)-tartrate salt were treated with ammonium hydroxide to liberate the free base which was treated with a solution of H-)-tartaric acid (0.46 g.) in methanol. The solution was concentrated and recrystallized twice from methanol, converted to the free base and hydrochloride salt as described above to give 0.10 g. of the (+)-enantiomer as a white crystalline solid, mp 240-244°. rotation: [a] + 121.38° (c 0.44%, water) Anal. Calcd. for C^H22N2O.HC1.0.25H20 C, 62.70; H, 8.24; N, 9.75 Found: C, 63.02; H, 8.20; N, 9.88 1 2 3 4 8 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 191830 Example 19 Preparation of N-[2-(3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-2-methy1-4-oxo- 4a,8a-trans-IH-pyrrolo[2,3-g]isoguinolin-6-yl)ethyl]-4-fluorobenzamide N-[2-(3-ethyl-4,4a,5,6,7,8,3a,9-octahydro-2-methyl-4-oxo-4a,8a-trans-lH- pyrrolo[2,3-g] isoquinolin-6-yl)ethyl] -4-£luorobenzamide was prepared by heating 3- -4a,8a-trans- ethyl-2-methyl-4,4a,5,6,7,8,8a,9-octahyar(y'lH-pyrrolo[2,3-g] isoquinolin-4-one and l-(4-fluorobenzoyD-aziridine in a mixture of benzene and methanol for 2 hours. The crude product crystallized from ethanol as a white solid, mp 252-253°. The starting * aziridine was prepared from aziridine and p-fluorobenzoyl chloride and sodium bicarbonate in water.
Example 20 Preparation of 3-ethyl-2,6-dimethvI-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-Dyr- rolo[2,3-g] isoquinolin-4-thione A mixture of 2.48 g. (0.01 mol) of 3-ethyl-2,6-dimethyl-4,4a,5,S,7,3,8a,9-octa--4a,8a-trans- hydro/iH-pyrrolo[2,3-g] isoquinolin-4-one and 2.44 g. (0.008 mol) of in 100 ml. of dioxane was stirred and refluxed for 17 hours. The dioxane was evaporated at reduced pressure and 150 ml. of water and enough ammonium hydroxide were added to bring the pH to 8-9. The mixture was extracted with chloroform and the extracts were washed with water and dried over sodium sulfate. Evaporation of the solvent gave the crude thione (3.3 g.) as a gummy material. Dry column chromatography gave 1.2 g. solid thione which was recrystallized twice from acetonitrile to give pure 3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-thione, mp 194-196° (dec.). 85 - t&l k.*-w V ^ 17 NOV S982 ' °'830 1 2 3 4 6 7 8 9 11 12 13 14 16 17 IS 19 21 22 23 24 26 27 Example 21 .-4a,8a-trans- Preparation of 3-ethvl-2-methvl-4.4a.5,6.7,8.8a.9-octahydr(y-IH-Dyrrolof2.3-g3 -iso-quinolin-4-thione -4a, 8a—trans- • A mixture of 1.45 g. (6 mmol) of 3-ethyl-2-methyl-4,4a,5,6,7,8,8a,9-octahydro-/ lH-pyrrolo[2,3-g] isoquinolin-4-one and 1.77 g. (4 mmol) of phosphorus pentasulfide in 60 ml. of dioxane was stirred and refluxed for 10 hours. The mixture was cooled and the dioxane solution was decanted from a dark residue which was dissolved in 75 ml. of ! i i water. The solution was made alkaline (pH_8-9) with ammonium hydroxide and the [ aqueous mixture was extracted with chloroform. The extracts were washed with water and dried over sodium sulfate. Evaporation of the solvent gave 420 mg. of crude thione which was chromatographed (dry column, silica gel) together with 100 mg. of additional crude product obtained by hot water treatment of the residues from the initial isolation followed by the same chloroform extraction procedure. Elution of the dry column with the organic phase of a mixture - prepared by equilibrating (by volume) 90 parts chloroform, 30 parts methanol, 10 parts water, and 6 parts acetic acid gave purified thione after evaporation, dissolution in water, neutralization to pH 8-9 with ammonium hydroxide, and extraction with chloroform. After washing with water, and drying over sodium sulfate, evaporation of the chloroform afforded 250 mg. of 3-ethyl-2-methyl--4a.8a-trans- 4,4a,5,6,7,8,8a,9-octahydro'lH-pyrrolo[2,3-g] isoquinolin-4-thione as a yellow solid, mp 190-194°. Recrystallization from acetonitrile gave the pure 4a,8a-trans isomer, mp 203-205°. • .hz.r& XT 2 NOV $82 1 2 3 4 6 7 8 9 ii 12 13 if 16 17 18 19 21 22 23 2f 26 27 1s>1830 Example 22 Preparation of 3-ethyl-2-methyl-6-(2-phenyIethyl)-4,4a,5.6,7,8,8a,9-octahvdro-4a.8a-trans-lH-pvrrolo[2,3-g] isoauinolin-4-thione A mixture of 248 mg. (1 mmol) of 3-ethyl-2-methyl-4,4a,5,6,7,8,8a,9-ofc^ahy§ro^7 lH-pyrrolo[2,3-g] isoquinolin-4-thione, 276 mg. of potassium carbonate, and 222 mg. of 2-bromoethylbenzene in 15 ml. of 3-pentanone was stirred and refluxed for 3 hours. The solvent was removed on a rotary evaporator, 25 ml. of water was added, and the j mixture was extracted with chloroform. Purification by dry column chromatography as i i detailed in Example 21 gave 100 mg. of purified product, which gave 50 mg. of 3-ethyl-2- j i methyl-6-(2-phenylethyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoqui -4-thione, mp 164-166° , (dec.) upon recrystallization from acetonitrile. " 87 ~ ia&pateotoiryft5g 2 NOV 1982 «iecsved to to to to to . -q 0> U% 1CO | to to i— o loo o> </» h-» »-* h-» »-• CD . CO tO H-* O I . «U U 14 M Example 23 . Capsule Formulation 00 CO Ingredients 3-ethyl-2,6-dimethyI-4,4a5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one hydrochloride Lactose Starch Talc Magnesium Stearate Total 220 mg. mg/capsule 0.5 .0 .0 0.5 .0 .0 183.5 179.0 218.0 .0 .0 50.0 .0 .0 .0 1.0 1.0 2.0 220 mg. 200 mg.
C Procedure: Mix the active ingredient, lactose and starch in a suitable mixer. Mill through a suitable mill. Mix with talc and magnesium stearate and fill on capsule machine. © o fO to to -3 o> tn , to to I to I— Example 24 Tablet Formulation (Direct Compression) mg/tablet Ingredients - (K5 .0 3-ethyl-2,6-dimethyl-tf,fa,5,6,7,8,8a,9-octahydro-'»a,8a- trans-lH-pyrrolo C2,3-g] isoquinolin-f-one, hydrochloride 0.5 .0 .0 Lactose 85.5 E1.0 103.0 Avicel .0 .0 it 5.0 Modified Starch " > . 7.5 7.5 .0 Magnesium Stearate 1.5 1.5 • 2.0 Total 125 mg. 125 mg. 170 mg.
Procedure: Mix the active ingredient, lactose, avicel and modified starch in a suitable mixer for 10-15 minutes. Add the magnesium stearate as a premix and mix for f minutes. Compress on a suitable press. o Example 25 - Tablet Formulation (Wet Granulation) mg/tablet Ingredients - . 0.5 M .0 3-ethyl-2,6-dimethyl-4,fa,5,6,7,8,8a,9-octahydro-'fa,8a- trans-lH-pyrroloC2,3-{Q isoquinolin-t-one, hydrochloride 0.5 .0 .0 Lactose Modified Starch Pregelatinized Starch , Magnesium Stearate 103.5 10.0 • 10.0 1.0 99.0 10.0 10.0 1.0 lfS.O 20.0 20.0 2.0 .
Total 125 mg. ' 125 mg. 200 mg.
Procedure; Mix the active ingredient, lactose, modified starch and pregelatinized starch in a suitable mixer, granulate with water. Dry, mill. Mix with the magnesium stearate and compress on a suitable press.
O v ( 1 i 2 • 3 4 • . 6 7 8 9 11 12 13 14 0 15 16 17 #U ■ 19 '91830

Claims (24)

WHAT WE CLAIM IS:
1. An octahydro-IH-pyrrolo[2,3-g]isoquiri9line of the general formula wherein R^ is hydrogen, alkyl, alkanoyl, aroyl or aralkyl; and Rg, independently, are hydrogen, alkyl, cycloalkyl, alkenyl, acyl, aryl or aralkyl; and R^ is hydrogen, alkyl, hydroxyalkyl, phenyl-hydroxyalkyl, halophenyl-hydroxyalkyl, alkylphenyl-hydroxyalkyl, alkoxyphenyl-hydroxyalkyl, alkoxyalkyl, aryloxy-hydroxyalkyl, alkoxy-hydroxyalkyl, acyloxyalkyl, arylcarbonylalkyl, alkoxycarbonylalkyi, aralkyl, alkenyl, alkyl-cycloalkyl, alkynyl, thienyl-alkyl, furyl-alkyl, arylcarboxamidoalkyl, acylalkyl, cyclic-alkyloxyalkyl, cyclic-alkyl-hydroxyalkyl, alkenyloxyalkyl, aralkenyl, aryloxyalkyl, N-alkyl-pyrrolidinylalkyl, trifluoroalkyl of 2 to 6 carbon atoms, or R6 \ ^1-alkyl, wherein Rg and R^, independently, are hydrogen or R7 alkyl, or taken together with the nitrogen, are a 5- or 6-membered saturated heterocyclic ring, and X is 0 or S, an optical isomer, a geometric isomer, or a pharmaceutically acceptable acid addition salt thereof. - 91 - .t^romcg 2 NOV 1982 3ECE5VED 1 2 3 4 5 6 7 8 9 10 11 12 13 14 1 2 3 1 2 3 ,9'850
2. A compound as claimed in claim 1, wherein is hydrogen, alkyl, alkanoyl, aroyl or aralkyl; R2 and Rj, independently, are hydrogen, alkyl, cycloalkyl, alkenyl, or aralkyl; and is hydrogen, alkyl, hydroxyalkyl, phenyl-hydroxyalkyl, halophenyl-hydroxyalkyl, alkylphenyl-hydroxyalkyl, alkoxyphenyl-hydroxyalkyl, alkoxyalkyl, aryloxy-hydroxyalkyl, alkoxy-hydroxyalkyl, acyloxyalkyl, arylcarbonylalkyl, alkoxycarbonylalkyl, aralkyl, alkenyl, alkyl-.. cycloalkyl, alkynyl, thienyl-alkyl, furyl-alkyl or R6 \ -alkyl, wherein Rg and R?, independently, are hydrogen or r7 alkyl, or taken together with the nitrogen, are a 5- or 6-membered saturated heterocyclic ring, and X is 0( an optical isomer, a geometric isomer, or a pharmaceutically acceptable acid addition salt thereof.
3. A cctipound as claimed in claim 1 or 2 (wherein is hydrogen. in,
4. A compound as claimed farcy one of claims 1 to 3, wherein R2 and are alkyl.
5. A caipound as claimed in any one of claims 1 to 4, wherein R^ is alkyl, hydroxyalkyl, phenyl-hydroxyalkyl, halophenyl-hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, arylcarbonylalkyl or aralkyl. - 92 - .. fatefjt otfesdsf 2 NOV 1982 1 deceived 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 3 4 EC 4085yQ
6. A aaipound as claimed in any one of claims 1 and 3 to 5^wherein X is 0.
7. A ccnpound as claimed in any one of claims 1 to 6^which is the trans isomer.
8. 3-Ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g]isoquinoiin-4-one.
9. 2-Methyl-3-ethy1-6-(2-phenylethyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g]isoquinoiin-4-one.
10. 2-Msthyl-3-ethyl-6-(2-ethoxyethyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-piyrrolo[2,3-g]isoquinoiin-4-one.
11. 2-Methyl-3-eth.yl-6- [4- (4-fluorophenyl)-4-cocobutyl] -4,4a, 5,6,7,8, 8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g]isoquinolin-4-one.
12. 3-Ethy1-2-methy1-6-(2-hydroxy-3,3-dimethylbutyl)-4,4a,5,6,7,8,8a,9-octahydro- IH-pyrrolo[2,3-g]isoquinolin-4-one.
13. 2-Methy1-3-ethy1-6-(2-hvdroxy-2-phenylethyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8artrans-iH-pyrrolo[2,3-g]isoquinolin-4-one, 2,3,6-trimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-IH-pyrrolo[2,3-g]-isoquinoiin-4-one, 2-methy1-3-ethy1-6-benzy1-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-1H- - 93 - I 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 191830 ■ --.ok 5? 2: pyrrolo[2,3-g]isoquinoiin-4-one, 2-inethy1-3-ethy1-6-[3-(4-fluorophenyl)-3- oxopropyl]-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans- IH-pyrrolo[2,3-g]iso- quinolin-4-one, 2-methyl-3-ethy1-6-(3-phenoxypropyl)-4,4a,5,6,7,8,8a,9- octahydro-4a,8a-trans-IH-pyrrolo[2,3-g]isoquinoiin-4-one, 2-methyl-3- ethy1-6-(2-hydroxy-3-methylbutyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a- trans-lH-pyrrolo[2,3-g]isoquinoiin-4-one, l-benzoyl-2,6-dirnethyl-3-ethy 1- -4a, 3a-trans- -— . ... .—-—-... — 4,4a,5,6,7,8,8a,9-octahydrc/lH-pyrrolo[2,3-g]isoquinoiin-4-one, 2-methvl- -4a,8a-trans- 3-ethy 1- 6- (2-hydroxyethyl) - 4,4a,5,6,7,8,8a, 9-octahydro ^IH-pyrrolo [2,3- g]isoquinoiin-4-one, 2-methyl-3-ethyl-6-(2-propenyl)-4,4a,5,6,7,8,8a,9--4a,8a-trans- octahydro/lH-pyrrolo[2,3-g]isoquinoiin-4-one, 2-methyl-3-ethyl-6-(cyclo- -4a,8a-trans- propy lrrethyl) - 4, 4a, 5,6,7,8, 8a, 9-octahydro/lH-pyrrolo [ 2,3-g] isoquinolin- -4a,8a-trans- 4-one, 2,6-dirrethy 1- 3- ey c loprcpy 1- 4, 4a, 5,6,7,8, 8a, 9-octahydro /lH- pyrrolo [2,3-g]isoquinolin-4-one, 2,6-dimethyl-3-{2-propyl)-4,4a,5,6,7,8,8a,9-■-4a,8a-trans- octahydro/lH-pyrrolo[2,3-g]isoquinoiin-4-one, 3,6-diethyl-2-methyl- -4a,8a-trans- 4,4a,5,6,7,8,8a,9-octahydro /lH-pyrrolo[2,3-g]isoquinolin-4-one, 6-methyl- -4a,8a-trans- 4,4a,5,6,7,8,8a,9-octahydro/lH-pyrrolo[2,3-g]isoquinolin-4-one, 2,6- -4a,8a-trans- dimethyl-3-propy1-4,4a,5,6,7,8,8a,9-octahydro- /lH-pyrrolo[2,3-g]iso- quinolin-4-one, 3-ethy1-2-methy1-6-[2-oxo-2-(4-fluorcphenyl)ethyl]- -4a,8a-trans- 4,4a,5,6,7,8,8a,9-octahydro/lH-pyrrolo[2,3-g]isoquinoiin-4-one, 2,3-dimethyl-6-(2-phenylethyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrxolo[2,3-g]isoquinoiin-4-one, 2,3-dimethyl-6-[4-(4-fluorophenyl)-4-oxobutyl]-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g]isoquinoiin- 4-one, 2-methyl-3-ethy1-6-(2-phenylethyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-IH-pyrrolo[2,3-g]iscquinolin-4-thione, 2,6-dimethyl-3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a^trans-lH-pyrrolo[2,3-g]iso-quinolin-4-thione, 2-methyl-3-ethy1-6-[4-(4-fluorophenyl)-4-oxobutyl]- f m.ii r i ^ PATENT 0Ef3C£j_ 2 NOV 3982 .tcsved 4,4a,5,6,7,8,8a, 9-octahydro-4a, 8a-trans-M-pyrxolo [2,3-g] isoquinolin- 4-thione and 2-methyl-3-ethy1-6-(2-hydroxy-3,3-dirrethylbutyl)- 4,4a,5,6,7,8,8a, 9-octahydro- 4a, 8artrans- IH-pyrrolo [ 2,3-g] isoquinolin- 4-thione.
14. An octahydro-lH-pyrrolo[2,3-g]isoquinoline according to any one jo£. claims 1 to 13 suitable for use as-a pharmaceutically-active --j substance.
15. An octahydro-lH-pyrrolo[2,3-g]isoquinoline according to any one of claims 1 to 13 suitable for use as a neuroleptic/antipsychotic agent.
16. 3-Ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2.3-g]isoquinolin-4-one suitable for use as a pharmaceutically active substance.
17. 3-Ethyl-2,6-dimethyl-4,4a,5,6, 7, 8,8a,9-octahydro-4a,8a-trans-IH-pyrrolo[2,3-g]isOquinolin-4-one suitable for use as a neuroleptic/ antipsychotic agent. . ^ patent ck-o.':" _ 95 - — -- 2 NOV 1982 secejvsd 1 2 3 4 5 6 7 8 9 10 11 12 '9185C 18- A process for the preparation of the corrpounds of the formula A given in claim 1, optical and geometric isoners of these oonpounds and pharmaceutically acceptable acid addition salts thereof which comprises a) for preparing a oonpound of the formula A above wherein R^ is hydrogen, R^ is alkyl, alkoxyalkyl or alkylcycloalkyl and X is 0 and R2 and R^ are as described in claim 1, i.e. a compound of the general formula rV 4\ la wherein R4" is alkyl, alkoxyalkyl or alkylcycloalkyl and R^ and R3 are as described in claim 1, treating a compound of the general formula r IX - 96 - 2 NOV 1982 ■' deceived 191830 wherein R^/ R^ and R^" are as previously described, with formaldehyde, or b) for preparing a compound of the formula la above, treating a oonpound of the general formula xii wherein R^" is as previously described, with a compound of the general formula ho / r„ ho vii wherein R^ and are as previously described, in the presence of a reducing agent or with a compound of the general formula 0 h2n 'r, viii wherein and are as previously described, or a precursor thereof, or c) for preparing a compound of the formula A above wherein R^ and R^ are hydrogen and X is 0 and R2 and R-, are as previously described, i.e. a compound of the general formula 97 - 2 NOV 1982 DECEIVED 1 2 3 4 5 6 7 8 9 10 11 12 13 14 191830 wherein and are as previously described, N-dernethylating a compound of the formula la above wherein R^" is methyl, or. d) for preparing a oonpound of the formula A above wherein and R^, independently, are hydrogen, alkyl, cycloalkyl, alkenyl, aryl or aralkyl, R4 is hydrogen, alkyl, alkoxyalkyl, aralkyl, alkenyl, alkyl-cycloalkyl, alkynyl, thienyl-alkyl, furyl-alkyl, alkenyloxyalkyl, aralkenyl, aryloxyalkyl or trifluoroaJJ-cyl of 2 to 6 carbon atoms and X is S and R^ is as described in claim 1, i.e. a compound of the general formula S wherein ' and R,1, independently, are hydrogen, alkyl, cycloalkyl, alkenyl, aryl or aralkyl, R^"' is hydrogen, alkyl, alkoxyalkyl, aralkyl, alkenyl, alkyl-cycloalkyl, alkynyl, thienyl-alkyl, furyl- _ 98 - 2 NOV 1982 • ■ i 'iceived '■■■ 1 2 3 4 5 6 7 8 9 1( 11 12 13 14 15 16 17 ,9'8:O" alkyl, alkenyloxyalkyl, aralkenyl, aryloxyalkyl or trifluoroalkyl of 2 to 6 carbon atoms and R^ is as described in claim 1, treating a oampotind of the general formula i o R Ml 4\ ic wherein R^, R^', R^' and R^"1 are as previously described, with phosphorus pentasulfide,' or e) for preparing a compound of the formula A above, wherein R^ is hydroxyalkyl,phenyl-hydroxyalkyl, halophenyl-hydroxyalkyl, alkyl-phenyl-hyiroxyalkyl, alkoxyphenyl-hydroxyalkyl, aryloxy-hydroxyalkyl, alkoxyhyiroxyalkyl, acyloxyalkyl, arylcarbonylalkyl, alkoxy carbonylalkyl, arylcarboxamidoalkyl, acylalkyl, cycli chalky loxjalkyl, cyclic-alkyl-hydroxyalkyl, N-aJkyl-pyrrolidinylalkyl, R, inde- or alkyl, wherein Rg and R^, i pendently, are hydrogen or alkyl or taken together with the nitrogen, saturated are a 5- or 6-membered/heterocyclic ring and X is S ard R^, R2 and R^ are as previously described, i.e. a coirpound of the general formula - 99 - • -- 1 1 " j" 2 NOV 1982 RECEIVED 6 7 8 9 ID 11 12 13 I°I8jQ lie III wherein R^ is hydroxyalkyl, phenyl-hydroxyalkyl, halophenyl-hydroxyalkyl,^ alkylpheny1-hydroxyalkyl, alkoxyphenyl-hyiroxyalky1," aryloxy-hydroxyalkyl, alkoxyhydroxy alkyl, acyloxyalkyl, arylcarbonylalkyl, • alkoxy carbonylalkyl, arylcarboxamidoalkyl, acylalkyl, cyclic-alkyl- oxyalkyl, cyclic-alkyl-hydroxy alkyl, N-alkyl-pyrrolidinylalkyl, £ or alkyl, wherein Rg and R^, independently^ are hydrogen or alkyl or taken together with the nitrogen, saturated are a 5- or 6-membered/heterocyclic ring and R^, R^ and R^ are as previously described, splitting off the protecting group or groups in a compound of the general formula S R V Ilf - 1001- 2 MOV 398Z ' 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 '9I83C wherein R^" and R^" have the same meaning as R, and R, except in the case where and are acyl, R," and R^" are acyl in a protected fom( and R^ has the same meaning as R^^ but in a protected forrr^and is as previously described, or f) for preparing a oonpound of the formula A above, wherein R^ is alkyl, alkanoyl, aroyl or aralkyl and R^ is alkyl, alkoxyalkyl or alkyl-cycloalkyl and R2, R3 and X are as previously described, i.e. a compound of the general formula R 4\ Ac wherein R^' is alkyl, alkanoyl, aroyl or aralkyl and R^, R,, R^" and X are as previously described, substituting a ccrtpourd of the general formula X R Aa wherein I<2' ^3' **4" ^ x 3X6 33 previously described, at the pyrrole nitrogen atom, or • ; vowcs 2 NOV 1982 received 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 ' ° /8j0 g) for preparing a compound of the formula A above, wherein R^ is hydrogen and R^ is alkyl, hydroxyalkyl, phenyl-hydroxyalkyl, halophenyl-hydroxyalkyl, alkylphenyl-hydroxyalkyl, alkoxyphenyl-hydroxy-alkyl, alkoxyalkyl, aryloxy-hydroxyalkyl, alkoxy-hydroxyalkyl, acy loxyalkyl, arylcarbonylalkyl, alkoxy carbonylalkyl, aralkyl, alkenyl, alkyl,cycloalkyl, alkynyl, thienyl-alkyl, furyl-alkyl, arylcarboxa-midoalkyl, acylalkyl~cyclic-alkyloxya±kyl, cyclic-alkylhydroxy- . alkyl, alkeny loxyalkyl, ar alkenyl, ary loxyalkyl, N-alkyl-pyrxo- lidinyl-alkyl, trifluoroalkyl of 2 to 6 carbon atcms, _ or ^Sj^rN-alkyl, wherein Rg and R-,, independently, are hydrogen or alkyl, or taken together with the nitrogen, saturated are a 5- or 6-merbered/heterocyclic ring and R^, R^ and X are as previously described, i.e. a compound of the general formula Ad wherein R^' is alkyl, hydroxyalkyl, phenyl-hydroxyalkyl, halo-phenyl-hydroxyalkyl, alkylphenyl-hydroxyalkyl, alkoxyphenvl-hy-droxyalkyl, alkoxyalkyl, aryloxy-hydroxyalkyl, alkoxy-hydrojty-alkyl, acy loxyalkyl, arylcarbonylalkyl, aLkoxycarbcnylalkyl, aralkyl, alkenyl, alkyl-cycloalkyl, alkynyl, thienyl-alkyl, furyl-alkyl, arylcarboxamidoalkyl, acylalkyl, cyclic-alkyloxyalkyl, cyclic-alkyl-hydroxy alkyl, alkerry loxy alkyl, aralkenvl, ary loxyalkyl, N-alky 1-pyrrolidinyl-alkyl, trifluoroalkyl of 2 to 6 carbon atcms, .or-ao?; 2 NOV 3982" 1 *• \ COVED -4 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 I 91330 — or ^^N-alkyl, wherein Rg and R^, independently, are hydrogen or alkyl, or taken together with the nitrogen, saturated are a 5- or 6-menbered/heterocyclic ring and an^ x 3X0 32 previously described, substituting a compound of the general formula H-N Ab wherein R^, R^ and X are as previously described, at the iscquinoline nitrcgen aton, or h) for preparing a compound of the formula A above, wherein is alkyl, alkanoyl, aroyl or aralkyl and R^ is alkyl, hydroxyalkyl, phenyl-hydroxyalkyl, halophenyl-hydroxyalkyl, alkylphenyl-hydroxyalkyl, alkoxyphenyl-hydroxyalkyl, alkoxyalkyl, aryloxy-hydroxyalkyl, alkoxyhydroxy alkyl , acyloxyalkyl, arylcarbonylalkyl, alkoxycarbonylalkyl, aralkyl, alkenyl, alkyl-cycloalkyl, alkynyl, thienyl-alkyl, furyl-alkyl, arylcarboxamidoalkyl, acylalkyl, cyclic-alkyloxyalkyl, cyclic-alkyl-hydroxyalkyl, alkeny loxyalkyl, aralkenyl, ary loxyalkyl, N-alkyl-pyrrolidinyl-alkyl, trifluoroalkyl of 2 to 6 carbon atoms,■ or 6^rN-alkyl, wherein n Rg and R^, Independently, are hydrogen or alkyl, or taken together saturated with the nitrogen, are a 5- or 6-irembered/heterocyclic ring and 1 2 3 4 5 6 7 8 9 10 11 12 I 5' 1850 1*2/ R3 and X are as previously described, i.e. a oonpound of the general formula r '4\ Af wherein R^1, P^, R^, R^' and X are as previously described, substituting a oonpound of the formula Ae hereinbelow at the isoquinoline nitrogen aton, or i) for preparing a compound of the formula A above, wherein is alkyl, alkanoyl, aroyl or aralkyl and R^ is hydrogen ard R2, R^ and X are as previously described, i.e. a compound of the general formula h—n ae N R, ■r. wherein R^', R^, R^ and X are as previously described, splitting off the protecting group in a compound of the general formula - 104 - Jm)VI982 .ichved ^ 1 2 3 4 5 6 7 8 9 10 11 12 13 14 wherein Z is a protecting group and R^1, P^, and X are as previously described, or j) for preparing a compound of the formula A above, wherein is alkyl, alkanoyl, aroyl or aralkyl and R^ is hydrogen, alkyl, alkoxyalkyl, acy loxyalkyl, alkylcarbonylalkyl, alkoxycarbcnylalkyl, aralkyl, alkenyl, alkylcycloalkyl, alkynyl, thienyl-alkyl, furyl-alkyl, arylcarboxamidoalkyl, acylalkyl, cyclic-alkyloxyalkyl, alkeny loxyalkyl, aralkenyl, ary loxyalkyl, N-alkyl-pyrrolidinyl-^lkyl or trifluoroalkyl of 2 to 6 carbon atoms and R^, R^ and X are as previously described, i.e. a oonpound of the general formula - 105 - jig. 2 IjOV 1932 jsshvsr i 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 '9' 850" wherein is hydrogen, alkyl, alkoxyalkyl, acy loxyalkyl, alkylcarbonylalkyl,. alkoxycarbonylalky 1, aralkyl, alkenyl, alkyl-cycloalkyl, alkynyl, thienyl-alkyl, furyl-alkyl, arylcarboxamidoalkyl, acylalkyl, cyclic-alky loxyalkyl, alkenyloxyalkyl, aralke-nyl, ary loxy alkyl, N-alkyl-pyrrolidinylalkyl or-trifluoroalkyl of 2 to 6 carbon atoms ——- 'and R^' , R^ R^ and X are as previously described, substituting a oonpound of the general—formula... - — s x ■vi ii h ■ wherein R^, R^, R^ and X are as previously described , at the pyrrole nitrogen atom, or k) for preparing a oonpound of the formula A above^ wherein R^ is alkyl, alkanoyl, arcyl or aralkyl and is hydroxyalkyl, phenyl-hydroxy-alkyl, halophenyl-hydroxyalkyl, alkylphenyl-hydroxyalkyl, alkoxy-phenyl-hydroxyalkyl, aryloxy-hydroxyalkyl, alkoxyhydroxy alkyl, cyclic-alkyl-hydroxyalkyl or alkyl, wherein Rg and R^, inde pendently, are hydrogen or alkyl, or taken together with the saturated nitrogen, are a 5- or 6-membered/heterocyclic ring and R^ R^ and X are as previously described, i.e. a compound of the general formula - 106 ~ " gr cfomce 2 NOV 1982 ^ pschvid , Minuj) i 1 2 3 '4 s 6 7 8 9 10 11 12 13 14 15 16 17
18 19 20 21 22 23 24 25 26 27 1 9 1 8 "5 0 r VII ■4\ Af1 . wherein is hydroxyalkyl, phenyl-hydroxyalkyl, halophenyl- hydroxyalkyl, alkylphenyl-hydroxyalkyt7 alkoxyphehyl-hydroxy- alkyl, aryloxy-hydroxyalkyl, alkoxyhydroxyalkyl, cyclic-alkyl- hydroxyalkyl or alkyl, wherein Rg and R^, independently, are hydrogen or alkyl, or taken together with the nitrogen, are saturated a 5- or 6-memfcered/heterocyclic ring and R^', R£, R_j and X are as previously described, splitting of the protecting group in a corresponding oonpound of the formula Af" above, but wherein R^"1 is protected, i.e. in a canpound of the general formula R VIII 4\ Af or wherein has the same meaning as but in a protected form, and R^', R^, R^ and X are as previously described, 1) iscanerizing the mixture of the cis and trans isomers obtained - 107 - to a final ratio which comprises predominantly the trans iscnier, or. separating the trans isomer fron the mixture obtained, or resolving a racemic mixture obtained into the optical antipodes and if desired, converting a compound obtained or a non-pharmaceutically acceptable acid addition salt thereof into a pharmaceutically acceptable acid addition salt thereof. - 108 - %2 1 2 3 1 2 3 4 ' 1 2 1 2 3 '9' Gio
19. A medicament containing an octahydro-lH-pyrrolo[2,3-g]isoquinoline of formula A given in claim 1^ an optical or geometric isomer or a pharmar-ceutically acceptable acid addition salt thereof. _ l '
20. A neuroleptic/antipsychotic meiicarment containing an octahydro- i IH-pyrrolo[2,3-g]isoquinoline of formula A given in claim 1, an optical or geometric isoner or a pharmaceutically acceptable acid addition salt thereof.
21. A medicament containing 3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a—trans-lH-pyrxolo[2,3-g]isoquinoiin-4-one.
22. A neuroleptic/antipsychotic medicament containing 3-ethy1-2,6-dimethyl-4, 4a, 5,6,7,8, 8a, 9-octahydro-4a, 8a-trans-lH-pyrrolo [2,3-g] isoquinoiin-4-one. 109 ~ 3*- patt&7 tvjcjp 2 NOV 1982 ' seesva> 121330
23. A process for the preparation of the compounds of the formula A given in claim 1, optical and geometric iscmers of these compounds and pharmaceutically acceptable acid addition salts thereof, substantially as hereinbefore described with particular reference to any one of the foregoing Examples 1 to 22.
24. A medicament containing a compound of the formala A given in claim 1, an optical or geometric isoier or a pharmaceutically acceptable acid addition salt thereof, substantially as hereinbefore described with particular reference to any one of the foregoing Examples 23 to 25. oateo this £» DAY OF ^ A jENTS FOft THE APPLICANTS - 112 -
NZ191830A 1978-10-13 1979-10-11 4,4a,5,6,7,8,8a,9-octahydro-1h-pyrrolo(2,3-g)-isoquinolin-4-(thi)ones NZ191830A (en)

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US4732902A (en) * 1986-05-23 1988-03-22 Hoffmann-La Roche Inc. Pyrroloisoquinolinyl-dimethyloxoalkyl alkonoates and their use as antipsychotic agents
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