IE48965B1 - Isoquinoline derivatives,process for their preparation,medicaments containing them and their pharmaceutical use - Google Patents

Isoquinoline derivatives,process for their preparation,medicaments containing them and their pharmaceutical use

Info

Publication number
IE48965B1
IE48965B1 IE1944/79A IE194479A IE48965B1 IE 48965 B1 IE48965 B1 IE 48965B1 IE 1944/79 A IE1944/79 A IE 1944/79A IE 194479 A IE194479 A IE 194479A IE 48965 B1 IE48965 B1 IE 48965B1
Authority
IE
Ireland
Prior art keywords
alkyl
hydroxy
phenyl
compound
alkylamino
Prior art date
Application number
IE1944/79A
Other versions
IE791944L (en
Original Assignee
Hoffmann La Roche
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=26754910&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=IE48965(B1) "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 IE791944L publication Critical patent/IE791944L/en
Publication of IE48965B1 publication Critical patent/IE48965B1/en

Links

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

Abstract

1. Claims for the Contracting States : BE, CH, DE, FR, GB, IT, LU, NL, SE. An octahydro-1H-pyrrolo[2,3-g]isoquinoline of the general formula see diagramm : EP0010661,P42,F2 wherein R1 is hydrogen, (C1 -C7 )-alkyl, (C1 -C7 )-alkanoyl or benzoyl or phenyl-(C1 -C7 )-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C1 -C7 )-alkyl, (C1 -C7 )-alkoxy, nitro, amino, (C1 -C7 )-alkylamino or di-(C1 -C7 )-alkylamino, R2 and R3 independently of each other are hydrogen, (C1 -C7 )-alkyl, (C3 -C6 )-cycloalkyl, (C2 -C7 -alkenyl, (C1 -C7 )-alkanoyl or benzoyl, phenyl or phenyl-(C1 -C7 )-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C1 -C7 )-alkyl, (C1 -C7 )-alkoxy, nitro, amino, (C1 -C7 )-alkylamino or di-(C1 -C7 )-alkyl-amino and R4 is hydrogen, (C1 -C7 )-alkyl, hydroxy-(C1 -C7 )-alkyl, phenyl-hydroxy-(C1 -C7 )-alkyl, halophenyl-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkylphenyl-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxyphenyl-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxy-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkanoyloxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxycarbonyl-(C1 -C7 )-alkyl, (C2 -C7 )-alkenyl, (C3 -C6 )-cycloalkyl-(C1 -C7 )-alkyl, (C2 -C7 )-alkynyl, thienyl-(C1 -C7 )-alkyl, furyl-(C1 -C7 )-alkyl, (C1 -C7 )-alkanoyl-(C1 -C7 )-alkyl, (C3 -C6 )-cycloalkoxy-(C1 -C7 )-alkyl, (C3 -C6 )-cycloalkyl-hydroxy-(C1 -C7 )-alkyl, (C2 -C7 )-alkenyloxy-(C1 -C7 )-alkyl, N-(C1 -C7 )-alkyl-pyrrolidinyl-(C1 -C7 )-alkyl, trifluoroalkyl with 2 to 6 carbon atoms or phenoxy-hydroxy-(C1 -C7 )-alkyl, benzoyloxy-(C1 -C7 )-alkyl benzoyl-(C1 -C7 )-alkyl, phenyl-(C1 -C7 )-alkyl, phenylcarboxamido-(C1 -C7 )-alkyl, phenyl-(C2 -C7 )-alkenyl, phenoxy-(C1 -C7 )-alkyl or phenyl-N-imidazolonyl-(C1 -C7 )-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C1 -C7 )-alkyl, (C1 -C7 )-alkoxy, nitro, amino, (C1 -C7 )-alkylamino or di-(C1 -C7 )-alkylamino, or see diagramm : EP0010661,P43,F2 wherein R6 and R7 independently of each other are hydrogen or (C1 -C7 )-alkyl or together with the nitrogen atom are a 5- or membered saturated heterocyclic ring which can further contain as a ring member an oxygen atom or a nitrogen atom optionally substituted by (C1 -C7 )-alkyl or hydroxy-(C1 -C7 )-alkyl, and X is O or S, an optical or geometric isomer thereof or a pharmaceutically acceptable acid addition salt thereof. 1. Claims for the Contracting State : AT. A process for the manufacture of octahydro-1H-pyrrolo[2,3-g]isoquinolines of the general formula see diagramm : EP0010661,P47,F3 wherein R1 is hydrogen, (C1 -C7 )-alkyl, (C1 -C7 )-alkanoyl or benzoyl or phenyl-(C1 -C7 )-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C1 -C7 )-alkyl, (C1 -C7 )-alkoxy, nitro, amino, (C1 -C7 )-alkylamino or di-(C1 -C7 )-alkylamino, R2 and R3 independently of each other are hydrogen, (C1 -C7 )-alkyl, (C3 -C6 )-cycloalkyl, (C2 -C7 )-alkenyl, (C1 -C7 )-alkanoyl or benzoyl, phenyl or phenyl-(C1 -C7 )-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C1 -C7 )-alkyl, (C1 -C7 )-alkoxy, nitro, amino, (C1 -C7 )-alkylamino or di-(C1 -C7 )-alkylamino and R4 is hydrogen, (C1 -C7 )-alkyl, hydroxy-(C1 -C7 )-alkyl, phenyl-hydroxy-(C1 -C7 )-alkyl, halophenyl-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkylphenyl-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxyphenyl-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxy-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkanoyloxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxycarbonyl- (C1 -C7 )-alkyl, (C2 -C7 )-alkenyl, (C3 -C6 )-cycloalkyl-(C1 -C7 )-alkyl, (C2 -C7 )-alkynyl, thienyl-(C1 -C7 )-alkyl, furyl-(C1 -C7 )-alkyl, (C1 -C7 )-alkanoyl-(C1 -C7 )-alkyl, (C3 -C6 )-cycloalkoxy-(C1 -C7 )-alkyl, (C3 -C6)-cycloalkyl-hydroxy-(C1 -C7 )-alkyl, (C2 -C7 )-alkenyloxy-(C1 -C7 )-alkyl, N-(C1 -C7 )-alkyl-pyrrolidinyl-(C1 -C7 )-alkyl, trifluoroalkyl with 2 to 6 carbon atoms or phenoxy-hydroxy-(C1 -C7 )-alkyl, benzoyloxy-(C1 -C7 )-alkyl, benzoyl-(C1 -C7 )-alkyl, phenyl-(C1 -C7 )-alkyl, phenylcarboxamido-(C1 -C7 )-alkyl, phenyl-(C2 -C7 )-alkenyl, phenoxy-(C1 -C7 )-alkyl or phenyl-N-imidazolonyl-(C1 -C7 )-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C1 -C7 )-alkyl, (C1 -C7 )-alkoxy, nitro, amino, (C1 -C7 )-alkylamino or di-(C1 -C7 )-alkylamino, or see diagramm : EP0010661,P47,F2 wherein R6 and R7 independently of each other are hydrogen or (C1 -C7 )-alkyl or together with the nitrogen atom are a 5- or 6-membered saturated heterocyclic ring which can further contain as a ring member an oxygen atom or a nitrogen atom optionally substituted by (C1 -C7 )-alkyl or hydroxy-(C1 -C7 )-alkyl, and X is O or S, the optical and geometric isomers of these compounds and their pharmaceutically acceptable acid addition salts, characterized by a) for the manufacture of a compound of the general formula see diagramm : EP0010661,P47,F4 wherein R"4 is (C1 -C7 )-alkyl, (C1 -C7 )-alkoxy-(C1 -C7 )-alkyl or (C3 -C6 )-cyclo-alkyl-(C1 -C7 )-alkyl and R2 and R3 are as described previously, treating a compound of the general formula see diagramm : EP0010661,P48,F1 wherein R2 , R3 and R"4 are as described previously, with formaldehyde, or b) for the manufacture of a compound of formula Ia above, treating a compound of the general formula see diagramm : EP0010661,P48,F2 wherein R"4 is as described previously, with a compound of the general formula see diagramm : EP0010661,P48,F3 in the presence of a reducing agent, or with a compound of the general formula see diagramm : EP0010661,P48,F5 wherein R2 and R3 are as described previously, or a precursor thereof, or c) for the manufacture of a compound of the general formula see diagramm : EP0010661,P48,F7 wherein R2 and R3 are as described previously, N-demethylating a compound of formula Ia above wherein R"4 is methyl, or d) for the manufacture of a compound of the general formula see diagramm : EP0010661,P48,F8 wherein R'2 and R'3 independently of each other are hydrogen, (C1 -C7 )-alkyl, (C3 -C6 )-cycloalkyl, (C2 -C7 )-alkenyl or phenyl or phenyl-(C1 -C7 )-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C1 -C7 )-alkyl, (C1 -C7 )-alkoxy, nitro, amino, (C1 -C7 )-alkyl-amino or di-(C1 -C7 )-alkylamino, R'"4 is hydrogen, (C1 -C7 )-alkyl, (C1 -C7 )-alkoxy-(C1 -C7 )-alkyl, (C2 -C7 )-alkenyl, (C3 -C6 )-cycloalkyl-(C1 -C7 )-alkyl, (C2 -C7 )-alkynyl, thienyl-(C1 -C7 )-alkyl, furyl-(C1 -C7 )-alkyl, (C2 -C7 )-alkenyloxy-(C1 -C7 )-alkyl or phenyl-(C1 -C7 )-alkyl, phenyl-(C2 -C7 )-alkenyl or phenoxy-(C1 -C7 )-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoro-methyl, (C1 -C7 )-alkyl, (C1 -C7 )-alkoxy, nitro, amino, (C1 -C7 )-alkylamino or di-(C1 -C7 )-alkylamino, or trifluoroalkyl with 2 to 6 carbon atoms and R1 is as described previously, treating a compound of the general formula see diagramm : EP0010661,P48,F4 wherein R1 , R'2 , R'3 and R'"4 are as described previously, with phosphorus pentasulphide, or e) for the manufacture of a compound of the general formula see diagramm : EP0010661,P48,F6 wherein R4-IV is hydroxy-(C1 -C7 )-alkyl, phenyl-hydroxy-(C1 -C7 )-alkyl, halophenyl-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkyl-phenyl-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxyphenyl-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxy-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkanoyloxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxycarbonyl-(C1 -C7 )-alkyl, (C1 -C7 )-alkanoyl-(C1 -C7 )-alkyl, (C3 -C6 )-cycloalkoxy-(C1 -C7 )-alkyl, (C3 -C6 )-cycloalkyl-hydroxy-(C1 -C7 )-alkyl, N-(C1 -C7 )-alkyl-pyrrolidinyl-(C1 -C7 )-alkyl or phenyl-N-imidazolonyl-(C1 -C7 )-alkyl, phenoxy-hydroxy-(C1 -C7 )-alkyl, benzoyloxy-(C1 -C7 )-alkyl, benzoyl-(C1 -C7 )-alkyl or phenylcarboxamido-(C1 -C7 )-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C1 -C7 )-alkyl, (C1 -C7 )-alkoxy, nitro, amino, (C1 -C7 )-alkylamino or di-(C1 -C7 )-alkylamino, or see diagramm : EP0010661,P48,F9 and R1 , R2 , R3 , R6 and R7 are as described previously, cleaving off the protecting group or protecting groups in a compound of the general formula see diagramm : EP0010661,P49,F1 wherein R"2 and R"3 have the same significance as R2 and R3 except when R2 and R3 are (C1 -C7 )-alkanoyl or benzoyl optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C1 -C7 )-alkyl, (C1 -C7 )-alkoxy, nitro, amino, (C1 -C7 )-alkyl-amino or di-(C1 -C7 )-alkylamino, R"2 and R"3 are in protected form, R4-V has the same significance as R4-IV , but in protected form, and R1 is as described previously, or f) for the manufacture of a compound of the general formula see diagramm : EP0010661,P49,F2 wherein R'1 is (C1 -C7 )-alkyl, (C1 -C7 )-alkanoyl or benzoyl or phenyl-(C1 -C7 )-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C1 -C7 )-alkyl, (C1 -C7 )-alkoxy, nitro, amino, (C1 -C7 )-alkylamino or di-(C1 -C7 )-alkylamino and R2 , R3 , R"4 and X are as described previously, substituting a compound of the general formula see diagramm : EP0010661,P49,F5 wherein R2 , R3 , R"4 and X are as described previously, at the pyrrole nitrogen atom, or g) for the manufacture of a compound of the general formula see diagramm : EP0010661,P49,F7 wherein R'4 is (C1 -C7 )-alkyl, hydroxy-(C1 -C7 )-alkyl, phenyl-hydroxy-(C1 -C7 )-alkyl, halophenyl-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkylphenyl-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxyphenyl-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxy-hydroxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkanoyloxy-(C1 -C7 )-alkyl, (C1 -C7 )-alkoxycarbonyl-(C1 -C7 )-alkyl, (C2 -C7 )-alkenyl, (C3 -C6 )-cycloalkyl-(C1 -C7 )-alkyl, (C2 -C7 )-alkynyl, thienyl-(C1 -C7 )-alkyl, furyl-(C1 -C7 )-alkyl, (

Description

This invention relates to isoquinoline derivatives, a process for their preparation, medicaments containing them and their pharmaceutical use. The present invention provides octahydro-lH-pyrrolo/2,3-g7isoquinolines of the general formula wherein is hydrogen, (C^-Cy)-alkyl, (C^-Cy)-alkanoyl or benzoyl or phenyl-(C^-Cy)-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C^-Cy)-alkyl, (C^-Cy)-alkoxy, nitro, amino, (C^-Cy)-alkylamino or di-(C^-Cy)-alkylamino, R2 and Rj independently of each other are hydrogen, (Cy-Cy)-alkyl, (C3~Cg)-cycioalkyl, (C2~Cy)-alkenyl, (C-j^-Cy)-alkanoyl or benzoyl, phenyl or phenyl-(C^-Cy)15 alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C^-Cy)-alkyl, (C^-Cy)alkoxy, nitro, amino, (C^-Cy)-alkylamino or di-(C^-Cy)alkylamino and R4 is hydrogen, (Cj^-Cy)-alkyl, hydroxy(Cj-Cy)-alkyl, phenyl-hydroxy-(C^-Cy)-alkyl, halophenyl48365 hydroxy-(C^-Cy)-alkyl, (C^-Cy)-alkylphenyl-hydroxy-(C^-Cy)alkyl, (C^-Cy)-alkoxyphenyl-hydroxy-(C^-Cy)-alkyl, (C^-Cy)alkoxy-(C^-Cy)-alkyl, (C^-Cy)-alkoxy-hydroxy-(C^-Cy)alkyl, (C^-Cy)-alkanoyloxy-(C^-Cy)-alkyl, (C^-Cy)-alkoxycarbonyl- (C^-Cy) -alkyl, (C2-Cy)-alkenyl, (C^-Cg)-cycloalkyl- (C^-Cy)-alkyl, (C2~Cy)-alkynyl, thienyl-(Cj-Cy)alkyl, furyl-(C^-Cy)-alkyl, (C^-Cy)-alkanoyl-(C^-Cy)alkyl, (C^-Cg)-cycloalkoxy-(C-j^-Cy)-alkyl, (C3-Cg)-cycloalkyl-hydroxy- (C^-Cy)-alkyl, (C2-Cy)-alkenyloxy-(C^-Cy)alkyl, N-(Cj-CyJ-alkyl-pyrrolidinyl-iC^-Cy)-alkyl, trifluoroalkyl with 2 to 6 carbon atoms or phenoxyhydroxy(C^-Cy)-alkyl, benzoyloxy-(C^-Cy)-alkyl, benzoyl-(C^-Cy)alkyl, phenyl-(C^-Cy)-alkyl, phenylcarboxamido-(C1-Cy)alkyl, phenyl-(Cj-Cy)-alkenyl, phenoxy-(C-j-Cy)-alkyl or pheny1-N-imidazolony1-(C^-Cy)-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C1~Cy)-alkyl, (C^-Cy)-alkoxy, nitro, amino, Rg (Cj^-Cy)-alkylamino or di-(C^-Cy)-alkylamino, N(C^-Cy)-alkyl, wherein Rg and Ry independently of each other are hydrogen or (C^-Cy)-alkyl or together with the nitrogen atom are a 5- or 6-membered saturated heterocyclic ring which can further contain as a ring member an oxygen atom or a nitrogen atom optionally substituted by (C^-Cy)-alkyl or hydroxy-(Cj-Cy)-alkyl, and X is 0 or S, optical and geometric isomers of these compounds and pharmaceutically acceptable acid addition salts thereof.
As used herein, the term (C^-Cy)-alkyl denotes a straight or branched chain saturated hydrocarbon containing 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, neopentyl, pentyl or heptyl. The term (Ci-Cy)-alkoxy denotes an alkyl ether group in which the alkyl group is as described above, for example, methoxy, ethoxy, propoxy or pentoxy. The term (C2-Cy)alkenyl denotes a straight or branched chain unsaturated hydrocarbon containing 2 to 7 carbon atoms, for example, vinyl or allyl. The term (C2~Cy)-alkynyl denotes a straight or branched chain unsaturated hydrocarbon containing 2 to 7 carbon atoms, for example, ethynyl, propargyl or methylbutynyl. The term halogen or halo denotes the halogens, bromine, chlorine, fluorine and iodine. The term trifluoroalkyl with 2 to 6 carbon atoms prefer10 ably denotes, for example, 2,2,2-trifluoroethyl. The term aryl denotes phenyl or phenyl bearing one or more substituents selected from halogen, trifluoromethyl, lower alkyl, lower alkoxy, nitro, amino, lower alkylamino, and di-lower alkylamino. The terms (C^-Cy)-alkanoyl and (C^-Cy)15 alkanoyloxy are derived from aliphatic carboxylic acids of 1 to 7 carbon atoms, for example, formyl, acetyl, propionyl, formyloxy, acetoxy or propionyloxy. The 5membered 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 (C^-Cy)alkyl or hydroxy-(C^-Cy)-alkyl, for example, morpholino, Nmethyl-piperazino, piperazino or pyrrolidino.
Preferred compounds of formula A are those wherein R^ is hydrogen, R2 and R3 are (C^-Cy)-alkyl; R^ is (C-^-Cy)alkyl, hydroxy-(C^-Cy)-alkyl, phenyl-hydroxy-(C^-Cy)-alkyl, halophenyl-hydroxy-(C^-Cy)-alkyl, (C^-Cy)-alkoxy-(C^-Cy) alkyl or phenoxy-(C^-Cy)-alkyl, benzoyl-(C^-Cy)-alkyl or phenyl-(C^-C?)-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C1~C7)-alkyl, (C^-C?)-alkoxy, nitro, amino, (C1~C7)alkylamino or di-(C^-C·^-alkylamino; and X is 0.
Most preferred compounds of formula A of the invention wherein X is 0 are: 3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro4a,8a-trans-lH-pyrrolo-/2,3-g7isoquinolin-4-one; (-)-3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octa10 hydro-4a,8a-trans-lH-pyrrolo-/2,3-q7 isoquinolin-4-one; (-)-3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo-/2,3-q7 isoquinolin-4-one, hydrochloride, 0.25 molar hydrate; 2-methy1-3-ethy1-6-(2-hydroxy-2-phenylethyl)-4,4a, 15 5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo/2,3-g7 isoquinolin-4-one; 2,3,6-trimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8atrans-lH-pyrrolo/2,3-q7-isoquinolin-4-one; 2,3,6-trimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a20 trans-lH-pyrrolo/2,3-g7-isoquinolin-4-one, hydrochloride; 48963 2-methyl-3-ethyl-6-benzyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-Uipyrrolo[2,3-g] isoquinolin-4-one; 2-methyl-3-ethyl-6-benzyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lHpyrrolo[2,3-g] isoquinolin-4-one, hydrochloride; 2-methyl-3-ethyl-6-(2-phenylethyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8atrans-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-translH-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-trans10 lH-pyrrolo[2,3-g] isoquinolin-4-one,hydrochloride; 2-methyl-3-ethyl-6-[4-(4-fluorophenyl)-4-oxobutyl]-4,4a,5,8,7,8,8a,9-oetahydro4a,8a-trans-lH-pyrrolof2,3-g·] isoquinolin-4-one; 2-methyl-3-ethyl-6-[3-(4-fluorophenyl)-3-oxopropyl]-4,4a,5,6,7,8,8a,9-octahydro4a,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-translH-pyrrolo[2,3-g] isoquinolin-4-one; 2-methyl-3-ethyl-6-(2-hydroxy-3-methylbutyl)-4,4a,5,6,7,8,8a,9-octahydro4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one; 2-methyl-3-ethyI-6-(2-hydroxy-3,3-dimethylbutyl)-4,4a,5,6,7,8,8a,9-octahydro20 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.
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] isoquinolin4-one; 3- ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-glisoquinolin4-one; 3-ethyl4^,6-trimethyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g]isoquinolin4-one; 1- benzoyl-2,6-dimethyl-3-ethyl-4,4a,5,6,7,8,8a,9-oetahydro-lH-pyrrolo[2,3-gJisoquinolin-4-one; 3-ethyl-2-methyl-6-(2-propynyl)-4,4a,5,6,7,8,8a,9-octahydro*IH-pyrrolo[2,3-gl isoquinolin-4-one; (+)-3-ethyl-2,6-dimethyl-4,4a,S,6,7,8,8a,9-octahydr<>-4a,8a-trans-lH-pyrroIo[2,3-gI isoquinolin-4-one; (+)-3-ethyI-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrro2o[2,3-gl isoquinolin-4-one, hydrochloride, 0.25 molar hydrate; 3.6- dimethyl-2-(2-propyl)-4,4a,5,6,7,8,8a,9-octahydro-lH-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] isoquinolin4-one; 2- methyl-3-ethyl-6-[2-hydroxy-2-(4-chlorophenyl)ethyl]-4,4a,5,6,7,8,8a,9octahydro-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-lH-pyrrolo[2,3-g] isoquinolin-4-one; 48365 2-methyl-3-ethyl-6-(2-propenylb4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo(2,3-g3 isoquinolin-4-one, hydrochloride, 0.5 molar hydrate; 2- methyl-3-ethyl-6-{eyclopropylmethyD-4,4a,5,6,7,8,8a,9-oetahydro-lHpyrrolo[2,3-g] isoquinolin-4-one; 2-methyl-3-ethyl-6-{eyclopropylmethyl)-4,4a,5,6,7,8,8a,9-octahydro-lHpyrrolo[2,3-g] isoquinolin-4-one, hydrochloride, 0.2 molar hydrate; 2.6- dimethyl-3-ethyl-l-(2,2-dimethyl-l-oxopropyl)-4,4a,5,6,7,8,8a,9-oetahydrfrlH-pyrrolo[2,3-g] isoquinolin-4-one; 2.6- dimethyl-3-cyclopropyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g] 10 isoquinolin-4-one; 3- ethyl-2-methyl-6-(2-dimethylaminoethyl)-4,4a,5,6,7,8,8a,9-octahydro-lHpyrrolo[2,3-g] isoquinolin-4-one; 1- benzyl-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-4,4a,5,6,7,8,8a,9-oetahydro-lH-pyrrolo[2,3-g] isoquinolin4-oxo-6-acetic acid, ethyl ester; 2- benzyl-3,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrroIo[2,3-g]isoquinolin 4-one; 3.6- dimethyI-2-{2-propenyl)-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-gJ20 isoquinolin-4-one; 2.6- dimethyl-3-(2-propyl)-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g]isoquinolin-4-one; 3- ethyl-2-methyl~6-[2-hydroxy-3-(4-chlorophenoxy)propyII-4,4a,5,6,7,8,8a,9oetahydro-lH-pyrrolo[2,3-g] isoquinolin-4-one; 3,6-diethyl-2-methyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrroIo[2,3-g] isoquinolin4-one; 2-methyl-3-ethyl-6-propyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g] isoquinolin-4-one; 2- methyl-3-ethyl-6-butyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo12,3-g] isoquinolin-4-one; 2-methyl-3-ethyl-S-pentyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrroloi2,3-g]isoquinolin-4-one; 3)6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g]-isoquinolin4-one; 6-methyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g]isoquinolin-4-one; 6-benzyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g]isoquinolin-4-one; 2,6-diraethyl-3-propyl-4,4a,5,6,7,8,8a,9-ootahydro-lH-pyrrolo[2,3-g]-isoquinolin-4-one; 3- ethyl-2-methyl-6-[2-hydroxy-3-(4-t-butylphenoxy)-propyl}-4,4a, 5,6,7,8,8a, 9octahydro-lH-pyrrolo[2,3-g]isoquinolin-4-one; 3-ethyl-2-methyl-6-t2-hydroxy-2-{4-chloro-3-trifluoroniethylphenyl)ethyl] 4,4a,5,6,7,8,8a,9-2ctahydro-lH-pyrrolo[2,3-g]iqoquinolin-4-one; 3-ethyl-2-methyl-6-{2-hydroxy-2-adamantylethyl)-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g]isoquinoIin-4-one; 3-ethyl-2-methyI-6-[2-(4-morphoIino)ethyI] -4,4a,5,6,7,8,8a,9-octahydr0-IH20 pyrrolo[2,3-g] isoquinolin-4-one; 3-ethyl-2-methyl-6-{2-oxo-2-(4-fluorophenyl)ethyl]-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g] isoquinolin-4-one; 3-ethyl-2-methyl-6-(2-methylpropyI)-4,4a,5,6,7,8,8a,9-octahydro-lHpyrrolo[2,3-g] isoquinolin-4-one; 3-ethyI-2-methyI-S-eycIobutyIme£hyl-4,4a,5,S,7I8,8a,9-oetahydro-lHpyrrolo[2,3-g] isoquinolin-4-one; 3-ethyl-2-methyl-6-hexyl-4,4a,5,6,7,8,8a,9-oetahydro-IH-pyrrolo[2,3-g] isoquinolin-4-one; 3-ethy 1-2-m ethy 1-6- heptyl-4,4a, 5,6,7,8, 8a, 9-oc±ahydro-lH-pyrrolo [2,3-g ] isoquinolin-4-one; 3-ethyl-2-methyl-6-[2-G-pyrrolidinyl)ethyl]-4,4a,5,6,7,8,8a,9-octahydro-lH10 pyrrolo[2,3-g]isoqainolir.-4-one; 3-ethyl-2-niethyl-6-(4-methoxy-2-phenylethyl)-4,4a,5J6,7,8,8a,9-oetahydro-!Hpyrrolo[2,3-g] isoquinolin-4-one; 2.6- diraethyl-3-ethyl-l-(l-oxobutyl)-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g] isoquinolin-4-one; 3-ethy l-2-methyl-6-(4-l chloro-2-phenylethyl)-4,4a,5,6,7,8,8a,9-ootahydro-lHpyrrolo[2,3-g] isoquinolin-4-one; 2.6- dimethyl-3-propyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lHpyrrolo[2,3-g] isoquinolin-4-one; 2.3- dimethyl-6-{2-phenylethyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a20 trans-lH-pyrrolo[2,3-g] isoquinolin-4-onej 2.3- dimethyl-6-[4-{4-fluorophenyl)-4-oxobutyl]-4,4a,5,6,7,8,8a,9-oetahydro-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-oetahydro4a,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-eis-lH-pyrrolo[2,3-g]isoquinolin-4-one; 2- acetyl-3,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-IH-pyrrolo[2,3-gl isoquinolin-4-one; 3- ethyl-2-methyl-6-[2-{2-thienyl)ethyl]-4,4a,5,6,7,8,8a,9-oetahydro-4a,8atrans-lH-pyrrolo[2,3-g] isoquinolin-4-one; 3-ethyl-2-methyl-6-[2-(2-furyI)ethyl]-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-translH-pyrrolo[2,3-g] isoquinolin-4-one; and 3-ethyl-2-methyl-6-[2- Most preferred compounds of formula A of the invention wherein X is S are: 2-methyl-3-ethyl-6-{2-phenylethyl)-4,4a,5,6,7,8,8a,9-oetahydro-4a,8a-translH-pyrrolo[2,3-g] isoquinolin-4-thione; 2,6-dimethyl-3-ethyl-4,4a,5,6,7,8,8a,9-oetahydro-4a,8a-trans-lH-pyrroloi2,3gl isoquinolin-4-thione; 2-methyl-3-ethyl-6-[4-(4-fluorophenyl)-4-oxobutyl]-4,4a,5,6,7,8,8a>9-octahydro4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-thione; and 2-methyl-3-ethyl-8-(2-hydroxy-3,3-dimethylbutyl)-4,4a,5,6,7,8,8a,9-octahydro4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-thione.
Exemplary of compounds of formula A wherein X is S are: 2-methyl-3-ethyl-5-(2-hydroxy-2-phenylethyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8atrans-lH-pyrrolo[2,3-g] isoquinolin-4-thione; 2,3,S-trimethyl-4,4a,5,6,7,3,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g]iso5 quinolin-4-thione; 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-thione; 2-methyl-3-ethyl-6-(2-ethoxyethyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-translH-pyrrolo[2,3-g] isoquinolin-4-thione; 2-methyl-3-ethyl-6-[3-(4-fluorophenyl)-3-oxopropyl]-4,4a,5,8,7,8,8a,9-octahydro4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-thione; 2-methyl-3-ethyl-6-(3-phenoxypropyI)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-translH-pyrrolo[2,3-g] isoquinolin-4-thione; 2-methyl-3-ethyl-S-{2-hydroxy-3-methylbutyl)-4,4a,5,6,7,8,8a,9-octahydro1-5 4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-thione; and 2-methyl-3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g]isoquinoIin-4thione.
The compounds of the invention may exist as the 4a,8a-trans or 4a,8a-cis isomers 20 or mixtures thereof; the 4a,8a-trans isomers are preferred.
The ccnpounds of the formula A above, their optical and geometric isomers and their pharmaceutically acceptable add addition salts can be prepar red in accordance with the invention by a process which ocnprises a) for preparing a ccnpound of the general formula . 48965 la , wherein R4 is (CpCy)-alkyl, (C^-Cy)-alkoxy-(C^-Cy)-alkyl or (Cj-Cg)-cycloalkyl-(Cj-Cy)-alkyl and Ry and Ry are as previously described, reacting a ccnpound of the general formula wherein R^ Ry and R4 are as previously described, with formaldehyde, or' b) for preparing a ccnpound of the formula Ia above, reacting a ccnpound 10 of the general fontula r4»-n XII , 489 65 wherein R4 is as previously described, with a ccnpound of the general formula in the presence of a reducing agent or with a oonpound of the general formula wherein Ry and Ry are as previously described, or a precursor thereof, or c) for preparing a ccnpound of the general formula Ih wherein Ry and Ry are as previously described, N-danethylating a ccnpound of the formula Ia above wherein R4 is methyl, Or d) for preparing a ccnpound of the general formula wherein Ry' and Ry', independently of each other are hydrogen, (Cy-Cy)-alkyl, (Cy-Cg)-cycloalkyl, (Cy-Cy)-alkenyl or phenyl or phenyl-(Cy-Cy)-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (Cy-Cy)alkyl, (Cy-Cy)-alkoxy, nitro, amino, (Cy-Cy)-alkylamino or di-(Cy-Cy)-alkylamino, R^' is hydrogen, (Cy-Cy)-alkyl, (Cy-Cy)-alkoxy-(Cy-Cy)-alkyl, (Cy-Cy)-alkenyl, (Cy-Cg)-cycloalkyl-(Cy-Cy)-alkyl, (Cy-Cy)-alkynyl, thienyl-(Cy-Cy)-alkyl, furyl(Cy-Cy)-alkyl, (Cy-Cy)-alkenyloxy-(Cy-Cy)-alkyl or phenyl-(Cy-Cy)-alkyl, phenyl-(Cy-Cy)-alkenyl or phenoxy-(Cy-Cy)-alkyl each of which is option15 ally substituted on the phenyl ring by halogen, trifluoromethyl, (Cy-Cy)-alkyl, (Cy-Cy)-alkoxy, nitro, amino, (Cy-Cy)-alkylamino or dl-(Cy-Cy)alkylamino, or trifluoroalkyl with 2 to 6 carbon atoms and Ry is as previously described, reacting a compound of the general formula wherein R^, Rj1, Rj' and R^’" are as previously described, with phosphorus pentasulfide, or wherein R^ is hydroxy-(C^-Cy)-alkyl, phenylhydroxy- (C^-Cy)-alkyl, halophenyl-hydroxy-(C^-Cy) alkyl, (C^-Cy)-alkylpheny1-hydroxy-(C^-Cy)-alkyl, (C^-Cy)-alkoxyphenyl-hydroxy-(C^-Cy)-alkyl, (C^-Cy) -alkoxy hydr oxy- (C^-Cy)-alkyl, (C^-Cy) alkanolyloxy-fe^-Cy) -alkyl, (C^-Cy) -alkoxycarbonyl(C^-Cy) -alkyl, (C^-Cy) -alkanoyl-(C^-Cy) -alkyl, (C^-Cg)-cycloalkoxy-(C^-Cy)-alkyl, (Cg-Cg)-cyclo15 alkylhydroxy- (Cj^-Cy) -alkyl, N- (C-j-Cy) -alkyl48965 pyrrolidinyl-(Cy-Cy)-alkyl or phenyl N-imidazolonyl(Cy-Cy)-alkyl, phenoxy-hydroxy-(Cy-Cy)-alkyl, benzoyloxy-(Cy-Cy)-alkyl, benzoyl-(Cy-Cy) alkyl or phenyl-carboxamido-(Cy-Cy) -alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluorcmethyl, (Cy-Cy)-alkyl, (Cy-Cy)-alkoxy, nitro, amino, (Cy-Cy)-alkylamino or di-(Cy-Cy)-alkylamino, or ^N-(Cy-Cy)-alkyl and Ry, Ry, Ry, Ry^ Rg and Ry are as previously described, splitting off a protecting group or protecting groups in a compound of the general formula wherein Ry'' and Ry have the same meanings as Ry and Ry except when Ry and Ry are (Cy-Cy)-alkanoyl or benzoyl optionally substituted on the phenyl ring by halogen, trifluoromethyl, (Cy-Cy)-alkyl, (Cy-Cy)-alkoxy, nitro, amino, (Cy-Cy)-alkylamino or di-(Cy-Cy)-alkylamino, Ry and Ry are in a protected form, rJ has the same meaning as 2o R4V but in a protected form, and Ry is as previously described, or wherein Ry1 is (Cy-Cy)-alkyl, (Cy-Cy)-alkanoyl or benzoyl or phenyl-(Cy-Cy)-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (Cy-Cy)-alkyl, (Cy-Cy)alkoxy, nitro, amino, (Cy-Cy)-alkylamino or di(Cy-Cy)-alkylamino and R2, Ry, R^ and X are as previously described, substituting a compound of the general formula wherein R2, Ry, R^ and X are as previously described, at the pyrrole nitrogen atom, or g) for preparing a compound of the general formula Ad, wherein R4' is (Cj-Cy)-alkyl, hydroxy-(C^-Cy) alkyl, phenyl-hydroxy-(C^-Cy)-alkyl, halophenyl-hydroxy- (C^-Cy)-alkyl, (C^-Cy)-alkylphenylhydroxy-(C^-Cy)-alkyl, (C^-Cy)-alkoxyphenylhydroxy- (C^-Cy)-alkyl, (C^-Cy)-alkoxy-(C^-Cy) alkyl, (C^-Cy)-alkoxy-hydroxy-(C^-Cy)-alkyl, (C^-Cy)-alkanoyloxy-(C^-Cy)-alkyl, (Cj-Cy)alkoxycarbonyl-(C^-Cy)-alkyl, (Cy-Cy)-alkenyl, (C^-Cg)-cycloalkyl-(C-^-Cy)-alkyl, (Cy-Cy)-alkynyl, thienyl-(C^-Cy)-alkyl, furyl-(C-^-Cy)-alkyl, (Cy-Cf)alkanoyl-(C^-Cy)-alkyl, (C^-Cg)-cycloalkoxy-(C^-Cy) alkyl, (C-j-Cg)-cycloalkylhydroxy-(C^-Cy)-alkyl, (Cy-Cy)-alkenyloxy-(C^-Cy)-alkyl, N-(C^-Cy) alkyl-pyrrolidinyl-(C^-Cy)-alkyl, trifluoroalkyl with 2 to 6 carbon atoms or phenoxy-hydroxy-(C^-Cy)alkyl, benzoyloxy-(Cj-Cy)-alkyl, benzoyl-(C^-Cy)alkyl, phenyl-(C^-Cy)-alkyl, phenylcarboxamido(Cj^-Cy)-alkyl, phenyl- (C2~Cy) -alkenyl, phenoxy(Ci-Cy)-alkyl or phenyl-N-imidazolonyl-(Cj-Cy)alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C^-Cy)alkyl, (C-j-Cy)-alkoxy, nitro, amino, (C^-Cfalkylamino or di-(C^-Cy)-alkylamino, or N-(C-j-Cy) -alkyl and R-,, R3 , Rg, Ry and X R7 are as previously described, substituting a compound of the general formula 489 65 Ab, wherein R2, R3 and X are as previously described, at the isoquinoline nitrogen atom, or h) for preparing a compound of the general formula R4\ Af, wherein R^', R2, R^, R4' and X are as previously described, substituting a compound of the following formula Ae at the isoquinoline nitrogen atom, or 1) for preparing a compound of the general formula Ae, wherein Ry’, Ry, Ry and X are as previously described, splitting off the protecting group in a compound of the general formula wherein Z is a protecting group and Ry’, Ry, Ry and X are as previously described, or j) for preparing a compound of the general formula wherein R^ is hydrogen, (Cy-Cy)-alkyl, (Cy-Cy)alkoxy-(Cy-Cy)-alkyl, (Cy-Cy)-alkanoyloxy (Cy-Cy)alkyl, (Cy-Cy)-alkoxycarbonyl-(Cy-Cy)-alkyl, (Cy-Cy)alkenyl, (Cy-Cg)-cycloalkyl-(Cy-Cy)-alkyl, (Cy-Cy)-alkynyl, thienyl(Cy-Cy)-alkyl, furyl-(Cy-Cy)-alkyl, (Cy-Cy)-alkanoyl48965 (C^-Cy)-alkyl, (Cj-Cg)-cycloalkyloxy-(C^-Cy)-alkyl, (C2~Cy) -alkenyloxy- (C-j-Cy) -alkyl, N- (Cy^-Cy) -alkylpyrrolidinyl-(C^-Cy)-alkyl, trifluoroalkyl with 2 to 6 carbon atoms or pheny1-N-imidazolonyl5 (C^-Cy)-alkyl, benzoyloxy-(C^-Cy)-alkyl, phenyl(C^-Cy)-alkyl, phenylcarboxamido-(C^-Cy)-alkyl, benzoyl-(C^^-Cy)-alkyl, phenyl-^-Cy)-alkenyl or phenoxy-(C^-Cy)-alkyl each of which is optionally substituted on the phenyl ring by halogen, tri10 fluoromethyl, (C^-Cy)-alkyl, (C-j-Cy)-alkoxy, nitro, amino, (C-^-Cy)-alkylamino or di- (C^-Cy) -alkylamino and , R2' R3 an^ x are as Previously described, substituting a compound of the general formula wherein R2, R^, R^ and X are as previously described, at the pyrrole nitrogen atom, or k) for preparing a compound of the general formula wherein R* is hydroxy-(C^-Cy)-alkyl, phenylhydroxy- (C-^-Cy)-alkyl, halophenylhydroxy-(C^-Cy)alkyl, (C^-Cy)-alkylphenyl-hydroxy-(C^-Cy)-alkyl, (C^-Cy)-alkoxyphenyl-hydroxy-(C^-Cy)-alkyl, (C^-Cy)alkoxyhydroxy-(C1~Cy)-alkyl, (C3~Cg)-cycloalky1hydroxy-(C-|-C7)-alkyl, 6^N-(C, -C_)-alkyl or phenoxyRy·^ x ' hydroxy-(C^-Cy)-alkyl optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C^-Cy,-alkyl, (Cj^-Cy)-alkoxy, nitro, amino, (C^-Cy)-alkylamino or di(C^-Cy)-alkylamino and R^', R2, R3, Rg, Ry and X are as previously described, splitting of the protecting group in a compound of the general formula VIII Af wherein R^111 has the same meaning as R^·11, hut in a protected form, and Rj', R2» R3 and x are as previously described, 1) isomerizing the mixture of cis and trans isomers obtained to a final ratio which comprises predominantly the trans iscmer, or m) separating the trans isansr frcm the mixture obtained, or n) resolving a racemic mixture obtained into the optical antipodes and o) if desired, converting a ocatpound obtained or a non-pharmaceutieally acceptable acid addition salt thereof into a pharmaceutically acceptabl acid addition salt thereof.
More specifically, the aonpounds of formula A above, their optical and geometric isanars and their pharmaceutically acceptable acid addition salts as well as various intermediates therefor can be prepared as illustrated hereinbelow in more detail. 48865 Thus, for exanple, the ccnpounds of formula A wherein X is 0 nave the formula wherein Bj, Rg, Rg and B^ are as hereinbefore described, and can be prepared as set forth in Schemes I to IV and further described.
FORMULA SCHEME I wherein R2 , R^ aid R^ are as previously described It /48965 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 cdtpounds of the fonnula IV can be prepared hy reductive alkylation of the compound of formula XIV, utilizing the corresponding aldehyde, for exanple, acetaldehyde, and sodiun cyanoborohydride under known conditions [see, for example, R. F. Borch, J. Am. Chem. Soc., 93, 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 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 of acids which may be used are hydrochloric acid, hydrobromic aeid, 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 aeid are needed. Tetrahydrofuran, benzene, diethyl ether, acetone, toluene, dioxan 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" and reflux leads to the dikotone of formula VI, wherein R/ is methyl. 469 6 5 The diketone of formula VI is condensed in a Iinorr condensation to give the dihydroindolone-ethylamine of formula IX. The Iinorr condensation is a well-known method for the preparation of pyrroles and the process may be used in any of the wellknown modifications [see, for exemplary conditions, J. M. Patterson, Synthesis, 281 (1976) and references therein]. For example, the reaction of an isonitrosoketone of formula VII in the presence of a reducing agent, for example with zine in aqueous acetic acid or hydrochloric acid, is thought to proceed via the aminocarbonyl compound of formula VIII which then condenses with the diketone of formula VI to give the product dihydroindolone-ethylamine of formula IX. Alternatively, the condensation can be carried out with an aminocarbonyl canpound of formula VIII or precursor thereof, such as an aminoketone hydrochloride salt, or an acetal derivative of an aminoket or aminoaldehyde. The use of a precursor of the aminoketone or aminoaldehyde is preferred, since such substances are prone to self-condensation. They may best be utilized in situ where the aminocarbonyl component is liberated in the presence of the lb 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.
Preferably, an isonitrosoketone of formula VII and zine dust in aqueous acetic acid is condensed with a diketone of formulu VI wherein R^ is methvl to eive the product dihydroindolone-ethylamine of formula IX wherein R^ is methyl.
The Knorr condensation is preferably carried out at a temperature range of from about room temperature to reflux. The isonitrosoketones of formula VE are known compounds [see, for instance, Ferris, J. Qrg, Chem., 24, 1726 (1959)] or can readily be prepared by nitrosation of the corresponding ketones, for example, with an alkyl nitrite, or in the ease of highly acidic β-diketones or β-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-cyelopropyl-l-propanone; 3- isonitroso-5-hexen-2-one; eyclopropyl-2-isonitroso-l-propanone; and 3-isonitroso-4-phenyI-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.
The amine of the formula IX is converted to the compound of the formula Ia via an intramolecular Mannich reaction. The Mannich reaction is usually performed starting- with a ketone and a dialkylamine salt, for example, dimethylamine hydrochloride and formaldehyde (for example, as an aqueous solution, as paraformaldehyde or as trioxane) in an alcoholic solvent such as ethanol, at reflux. In the modification herein described, an acid addition salt of the dihydroindolone-ethylamine of formula IX is reacted with formaldehyde, added in the form of paraformaldehyde, trioxane, or as aqueous formaldehyde in a solvent. For example, a high boiling hydroxylie solvent, such as amyl alcohol, octanol, ethylene glycol or diethylene glycol monoethyl ether, a high boiling polar aprotic solvent, such as dimethylformamide, N-methylpyrrolidinone or diethylene glyeol dimethyl ether; a lower boiling polar solvent, such as ethanol, butanol or 2-propanol under pressure, or a lower boiling aprotic solvent under pressure, such as dioxan ox tetrahydrofuran, may be used at a temperature in the range of from about 135° to 203° to yield, the pyrrolo/2,3-g7isoquiiiolines of formula Xa. The react especially when run at temperatures below 150° leads to a mixture of cis and trans isomers, i.e., for example, when is methyl, compounds of the formulae Ia‘ Longer heating of the reaction mixture or separate heating of the isomeric mixture of hydrochloride salts of formulae I'a and Ia, 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° for 2 hours, wherein ‘he product is isolated as almost exclusively the trans isomer I'a. , 48965 FORMULA SCHEME II wherein R^', Rg and R3 are as previously described, 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 butyl5 lithium, or with an alkali metal followed by quenching with an alkyl or acyl halide in a solvent such as tetrahydrofuran, dioxan, ethyl ether, dimethylformamide or dimethylsulfoxide. For example, treatment of a compound of formula Ia} wherein R2’s methyl and Rg. is ethyl, with sodium in liquid ammonia followed by quenching with methyl iodide affords the 1-methyl derivative, i.e., a compound of formula Ie'wherein R2 is methyl, Rg is ethyl, and R^ is methyl. Similarly, reaction of a compound of formula Ia', wherein R2 is methyl and Rg is ethyl, with butyllithium in tetrahydrofuran at -30° followed by quenching with benzoyl chloride affords the 1-benzoyl derivative, i.e., a compound of formula Ic* wherein R^' is benzoyl, R2 is methyl and Rg is ethyl.
N-Demethylation of the compound of formula Ia'can be accomplished by standard N-dealkylation procedures, such as the von Braun method [H. A. Hageman, Org. Reactions, 7, 198 (1953)], or via acid or base hydrolysis of a urethane derivative such as those listed in K. C. Rice [J. Org. Chem., 40, 1850 (1975)]. One procedure for the dealkylation of the compound of formula la* is via the urethane of formula XIII and acid hydrolysis to give the secondary amine of formula lb. For example, a compound of formula la',wherein R2 is methyl and Rg is ethyl is refluxed in diethyl ketone with excess ethyl chloroformate and potassium bicarbonate for 3 hours to give a compound of formula XIII, wherein R2 is methyl and Rg is ethyl. Hydrolysis of the foregoing compound with concentrated hydrochloric acid in acetic acid at reflux for 24 hours gives a compound of formula lb, wherein R2 is methyl and Rg is ethyl. The same compound is obtained by hydrolysis of the urethane of formula ΧΙΠ with sodium hydroxide in refluxing ethanol.
FORMULA SCHEME III Ic lb wherein R/ , R2, R3 and R/ are as previously described. 489 6 5 Xn accordance with Formula Scheme XXI, the compounds of formulae Ic, Id and Ie are prepared from the secondary amine of formula Ib, the starting material for the preparation of numerous derivatives encompassed by formula I, by substitution at the basic amine nitrogen (N-6) and/or the pyrrole nitrogen (N-l). For example, treatment of a compound of formula Ib with an alkyl halide, such as ethyl bromide, an alkenyl halide, such as allyl bromide, a cycloalkyl-alkyl-halide, such as chloromethylcyclopropane, or an aralkyl halide, such as benzyl bromide, in the presence of a base, for example, potassium carbonate, in acetone, 2-propanone or dimethylformamide, yields the correspondingly substituted compound of formula Id, that is, wherein R^' is alkyl, (C2~C7)-alkenyl, (C3-Cg)-cycloalkyl-(C^-C·?)-alkyl or phenyl-(C^-C7)-alkyl which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C1~C7)alkyl, (C1~C7)-alkoxy, nitro, amino, (Cj-C-y)-alkylamino or di-(C^-C7)-alkylamino. With reactive halides, the reaction may be run at room temperature; with less reactive halides, reflux temperatures are used, and in seme 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 Ib with epoxyalkanes gives the hydroxyalkyl substituted compound of formula Id. Treatment with a substituted epoxyalkane gives the 2-substituted-2-hydroxyalkyl analogs of a compound of formula Id, for example, reaction of a compound of formula Ib with styrene oxide gives a compound of formula Id, wherein R^' is 2-phenyl-2-hydroxyethyl. The reaction is usually carried out in the presence of an alcoholic solvent such as methanol, at from about room temperature to the reflux temperature of the mixture.
The epoxyalkanes are either commercially available or are prepared by epoxidation of the corresponding olefins, or by methylenation of a ketone with a sulfoniummethylide or sulfoxonium methylide reagent, for example, dimethy1sulfonium methylide. Thus, for example, treatment of benzaldehyde with dimethylsulfonium methylide gives styrene oxide.
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-6) of the compound of formula lb is protected with a hydrolyzable or hydrogenolyzable protecting group, substituted at the pyrrole nitrogen (N-1), and deprotected. Typical protecting groups are acetyl, t-butoxyearbonyl, benzenesulfonyl, or benzyl. The reaetion of Hie protected intermediate is carried out substantially as described for the conversion of the compound of formula Ia 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 Rg is methyl and Rg 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 le where R^' is methyl, Rg is methyl, and Rg is ethyl.
Treatment of a compound of formula lb with a haloalicylamine in the presence of a base, for example, potassium carbonate, or an aziridine yields amine-substituted analogues of a canpound of formula Id. 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 alkylation or acylation, the procedures outlined 2o in Formula Scheme III can be used directly to prepare N-1 substituted analogues of foxmu Ic. Alkylations can occur in compounds wherein R^' is hydraxy-(Cg-Cy)-alkyl phenyIhydroxy-tC^-C^)-alkyl, halophenyl-hydroxy-(C^-Gy)-alkyl, (C-^-C^)-alkylphenyl-hydroxy- (Cj-Gy) -alkyl, (C^-Gy) -alkoxyphenyl-hydroxy- (C^-Gy) alkyl, (C^-Cy)-alkoxy-hydroxy-(Cj-Cy)-alkyl, (Cj-Cg)-cycloalkylhydrojy-(C-^-Cy)25 alkyl, R6 N-fCj-Gy)-alkyl or phenoxy-hydroxy-(C^-Gy)-alkylamino which is optionally substituted on the phenyl ring by halogen, trifluorcmethyl, (C^-Gy) alkyl, (C-j-Cy)-alkoxy, nitro, amino, (C^-C^)-alkylamino or di-(C-^-Cy)-alkylamin The functional groups therein, for exanple, hydroxyl or secondary amino, must be protected with a base-stable protecting group, such as tetrahydropyranyl After N-1 alkylation, the protecting group is removed by acid hydrolysis.
The compound of formula Ie is converted to the compound of formula Ic using substantially the same procedure used in the conversion of the compound of formula lb to the compound of formula Id.
In the reactions described in Formula Schemes I, II and ΙΠ, both the trans isomers of the formula wherein Rj, Rg, Rg and R^ are as previously described, and cis isomers of the formula wherein Rj, Rg, Rg and R4 are as previously described, of the compounds of formula I may be formed, with the trans isomer predominating.
The pure trans isomer may be separated by chromatography or crystallization. In addition, the mixture may be isomerized as described for the isomerization of the trans and cis isomers of the oxo compound of formulae I’a’ and la'.
FORMUL;! SCHEME IV VH or VIH H wherein R2 , ard R4 are as previously described.
An alternative synthesis of the compounds of formula Ia is described in Formulu 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 hexahydroisoquinoline of formula XI. Hydrolysis of crude hexahydroisoquinoline of formula XI under conditions substantially the same as described for the hydrolysis of the dihydroamine of the formula V yields the diketone of formula ΧΠ. The compound of formula XII is reacted in a Knorr condensation, as described in the preparation of the dihydroindolone-ethylamine of formula IX with the isonitrosoketone of formula VII or with the aminoearbonyl compound of formula VIH to give the pyrroloisoquinoline of formula Ia. Preferred is the sequence of reactions in accordance with Formula Scheme IV starting with the amine of formula IV, wherein R^ is methyl, giving the corresponding N-methyl-pyrroloisoquinoline of formula Ia', as a mixture containing the trans isomer I’a'and the cis isomer of formula Ia* The same procedures for isomerization of the mixture of pyrroloisoquinolines of formulae I'a* and Ia*as described previously may be employed to yield mainly the trans isomer of formula Pal The ocnpounds of formula A wherein x is S have the formula wherein Rg, Rg, Rg and R4 are as hereinbefore described, and can be prepared as set forth hereinafter.
Thione compounds of formula Π are generally prepared by reaction of phosphorus pentasulfide on keto compounds of formula I. When the compound of formula I has no functional groups capable of reacting with phosphorus pentasulfide besides the 4-oxo group, then the compound of formula I may be converted to the compound of formula Π directly by heating with phosphorus pentasulfide in an inert organic solvent. On the lo other hand, when the compound of formula I does contain functional groups capable of reacting with phosphorus pentasulfide, for example, when R4 is other than hydrogen, (Cj-cp-alkyl, (C^—C-,)-alkoxy-(Cg-Cy)-alkyl, (Cg-Cy)-alkenyl, (Cg-Cg)-cycloalkyl-(C1"C?)-alkyl, (Cg-Cy)-alkynyl, thienyl-(Cg-Cy)-alkyl, furyl-(C^-Cy)-alky (Cg-Cy)-alkenyloxy-(C^-Cy)-alkyl or phenyl-(Cg-Cy)-alkyl, phenyl-(Cg-Cy)15 alkenyl or phenoxy-(Cg-Cy)-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (Cg-Cy)-alkyl, (Cg-Cy)-alkoxy, nitro, amino, (Cg-Cy)-alkylamino or di-(Cg-Cy)-alkylamino or trifluoroalkyl with 2 to carbon atans or when Rg or Rg is (Cg-Cy)-alkanoyl benzqyl which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (Cg-Cy)-alkyl, (Cg-Cy)-alkoxy, nitro, amino, (Cg-Cy)alkylamino or di-(Cg-Cy)-alkylamino, these groups must be protected before the reaction and de-protected thereafter. Por exanple, keto groups may be protected as a ketal such as ethylene ketal and 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.
FORMULA SCHEME V wherein R^, Rg , Rg and R^ are as hereinbefore described.
In Formula Scheme V, the compound of formula Ia is converted to the compound of formula Ila by heating in an inert organic solvent with phosphorus pentasulfide. Preferred solvents are tetrahydrofuran, benzene and dioxan, and the reaction is generally run at reflux temperature. The compound of formula Da may then be alkylated or acylated to the compound of formula He'in the same manner described in Formula Scheme U for the conversion of the compound of formulala'to the compound of formula Ic1.
Additional compounds of formula II can be made as described in Formula Scheme VI: 48865 FORMULA SCHEME VI wherein Rj, Rj, Rj' and R^'are as previously described.
In Formula Scheme VI, the compound of formula lb is reacted with phosphorus, pentasulfide as above described, to afford the thione of formula Hb. Subsequent transformations of the compound of formula Hb to the compounds of formulae He, Hdand Ife 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 formulae Ic, Id and Ie.
In these reactions, both the trans isomers of the formula I *1 wherein Rj, Rg, Rg and are as previously described, and cis isomers of the formula wherein Rj, Rg, Rg and R^ are as previously described, of the compounds of formula Π may be formed, with the trans isomer predominating. Tne 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 formulae I'a' and Ia'. ι The compounds of formula A form acid addition salts with inorganic or organic acids. Thus, they form pharmaceutically acceptable acid addition sa with both pharmaceutically acceptable organic and inorganic acids, for exanple, with hydrohalie acid, such as, hydrochloric acid, hydrobronic acid, hydro5 iodic acid, other mineral acid salts, such as, for exanple, sulfuric acid, nitr acid or phosphoric acid, alkyl- and mono-aryl sulfonic acids, such as, for exanple ethanesulfanic acid, toluenesulfonic acid or benzenesulfcnic acid, other organic acids such as, for exanple, acetic acid, tartaric acid, maleic ac citric acid, benzoic acid, salicylic acid or ascorbic acid. Noa-pharmaceutical 10 acceptable acid addition salts of compounds of formula A^an be converted into pharmaceutically acceptable acid addition salts via conventional metathetic reactions whereby the non-pharmaceutically acceptable anion is replaced by a pharmaceutically acceptable anion; or alternatively, by neutralizing the non-pharmaceutically acceptable acid addition salt and then reacting the so-obtained free base.with a reagent yielding a pharmaceutically acceptable acid addition salt. The acid addition salts may also form hydrates.
The compounds of formula Aand their pharmaceutically acceptable aeid addition salts exhibit neuroleptic activity. Significantly, however, they lack hypotensive activity, and demonstrate only weak cataleptic activity. Accordingly, the compounds of 2o 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 antipsychotic agents can be demonstrated in warm-blooded animals, . in accordance with known procedures.
For example, by one procedure, trained rats are placed in experimental chambers equipped with a response lever, a steel grid floor for delivery of electric shock and a loudspeaker for presentation of auditory stimuli. Each trial consists of a fifteen-second warning tone, (conditioned stimulus), continuing for an additional fifteen seconds accompanied by electric shock (unconditioned stimulus; 1.0 mA, 350 V.A.C.). The rats can terminate a trial at any point by depression of the response lever. A response during the initial fifteen-second warning tone ends the trial before shock delivery and is considered an avoidance response, while a response occurring during shock delivery is an escape response. Trials are presented every two minutes during a one-hour test session (30 trials per session).
Trained rats maintain a reliable control baseline of avoidance behavior (zero to three avoidance failures per session). Compounds are administered at appropriate pretreatment times to a minimum of three to four rats at each dose level over a range of doses. Rats receive vehicle alone, during control sessions. One control and one 15 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. Response counts are summed over all subjects at a given dose within each segment.
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 doseeffect 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 10 affect the behavior of rats in this procedure, by the larger separation between doses which block avoidance responding and doses which bloek 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,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one, hydrochloride, which has demonstrated an LDS() 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 2o the foregoing compound, neuroleptic activity is observed at an ΛΒ^θ of 0.48 mg/kg p.o.
Similarly, when 2,3,S-trimethyl-4,4a,5,G,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo(2,3-g] isoquinolin-4-one, hydrochloride is utilized as the test substance, neuroleptic activity is observed at an ABgg of 0.48 mg/kg p.o. 48865 Wien N-/2(3-ethyl-4,4a,5,6,7,8,8a,9-ocrt^hydro-2-nii2thyl-4-oxo-4a,batrans-lH-pyrrolo[2,3-g] isoquinolin-6-yl)ethyl] -4-fluorobenzamide is utilized as the test suDstance, neuroleptic activity is observed at an AB5(} of 3.5 mg/kg p.o.
When 3-ethy1-2-metby1-6-/4-(4-fluorophenyl)-4-axobutyl7-4,4a,5,6,75 8,8a,9-oetahydro-4a,8a-trans-lH-pyrrolo[2,3-g]isoquinolin-4-one is utilized as the test substance, neuroldptic activity is observed at an ABS0 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-lHpyrrolo[2,3-g] isoquinolin-4-thione is utilized as the test substance, neuroleptic activity is observed at an AB5(J of 0.94 mg/kg p.o.
The compounds of formula A and their pharmaceutically acceptable acid addition salts have antipsychotic effects which are qualitatively similar to those of haloperidol, 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 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.Q5 to 50 mg., and suitable oral dosage regimens in warm-blooded animals comprise or are in the range of fran about O.OOl mg/kg per day to 10 ng/kg per day. However, for any particular warm-blooded animal, the specific dosage regimen may be variable and should be adjusted according to individual need and the professional judgment of the person administering or supervising the administration of a compound of formula A or a pharmaceutically acceptable acid addition salt thereof. Furthermore, the frequency with which any such dosage form will be administered will vary, depending upon the quantity of active medicament present therein and the needs and requirements of the pharmacological situation.
For the disclosed use, the cctipounds of foimula A and their pharmaceutically acceptable acid addition salts are formulated, using conventional inert pharmaceutical adjuvant materials, into dosage forms which are suitable for oral or parenteral administration. Such dosage forms include, for exanple tablets, suspensions and solutions.
Furthermore, the compounds of formula A can be embodied into, and administered in the form of, suitable hard or soft capsules. The identity of the inert adjuvant materials which are used in formulating the compounds of formula A and their pharmaceutically acceptable acid addition salts into oral and parenteral dosage forms will be immediately apparent to persons skilled in the art. These adjuvant materials, either inorganic or organic in nature, include, for exanple, water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums and polyalkylene glycols. Moreover, preservatives, stabilizers, wetting agents, emulsifying agents, salts for altering oamotic pressure or buffers, for example, can be incorporated, if desired, into such formulations.
Since the compounds of formula A and their pharmaceutically acceptable acid addition salts possess an asymmetric carbon atom, they are ordinarily obtained as 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 eutectics and can thereafter be separated. Chemical resolution is, however, preferred. By this method, diastereomers are formed from the racemic mixture with an optically active resolving agent, for example, an optically active acid, such as (+)-tartarie acid to form a diastereomeric salt. The formed diastereomers are separated by fractional crystallization and can be converted to the corresponding optical isomer base. Thus, the invention covers the optically active isomers of the compounds of formula A as well as their racemates.
Furthermore, due to the possible different spatial arrangements of their atoms, it is to be understood that the compounds of this invention may be obtained in mere than one possible geometric isomeric form. The compounds of formula A, as described 15 and claimed, are intended to embrace all such isomeric forms. Accordingly, the examples included herein are to be understood as illustrative of particular mixtures of geometric isomers or single geometric isomers and not as limitations upon the scope of the invention.
The Examples which follow further illustrate the invention. All temperatures are in degrees Centigrade, unless otherwise stated) Example 1 Preparation of N-2-(3.5-dimethoxyphenyI)-ethyI 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)-ethylamine hydrochloride, 600 ml. of water, 600 ml. of dichloromethane and 150 ml. of IN sodium hydrosade 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 pK 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 diehloromethane 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)15 ethyl carbamic acid, ethyl ester as a colorless oil.
Example Ia Preparation of N-methyH3,5-dimethoxyphenyl)-ethylamine hydrochloride In a 3 L 3-neck round-bottom flask equipped with a mechanical stirrer, addition funnel, and condenser were placed 180 ml. of 70% sodium dihydrobis(2-me thoxye thoxy)5 aluminate solution and 700 mt of dry tetrahydrofuran. The solution was cooled in an ice bath and a solution of 37.1 g. of crude N-2-(3,5-dimethoxyphenyl)-ethyl carbamic acid, ethyl ester In 100 mt of dry tetrahydrofuran was added over 15 minutes. After the 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 mt of ether. The combined organic solutions were concentrated to an oil on a rotary evaporator and the oil was dissolved in 300 mt of ether. The ether solution was washed with 50 mt of water, 50 mt of brine, dried over anhydrous sodium sulfate, and filtered. To the filtrate was added 70 mt of ethereal hydrogen chloride to precipitate the amine hydrochloride. The solid was collected on a Buchner funnel and was crystallized from 180 mt of absolute ethanol and 270 mt of ether to give 28.9 g. of N-methyl-(3,5-dimethoxyphenyl)-ethylamine hydrochloride as a white, crystalline solid, mp 160-164°.
Example 2 Preparation of N-methyl-l,5-dimethoxycyclohexa-l,4-diene-3-ethylamine 185.2 g. of N-methy 1-(3,5-dim ethoxy phenyl)-e thy lamine 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-neek 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 6.35 cm (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 2.81. 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 2o 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 11. 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 30.5 an (12-in.) Goodloe aolunm (bath 150°) collecting fractions as follcws: • 488 Fraction & wt gc puri 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-dim ethoxy cyclo hexa-l,4-diene-3-ethyIamine as a colorless oil.
Example 3 Preparation of 6-[2-(N-methylamino)ethyl] -2-methyl-3-ethyl-6,7-dihydro-(5H)-4(lH,5H)indolone In a 1 L 3-neek round-bottom flask equipped with a mechanical stirrer and eon5 denser was placed a solution of 60.0 g. of distilled N-methyl-l,5-dimethoxyeyclohexal,4-diene-3-ethylamine in 700 mb of 70% aqueous acetic acid. The reaction mixture 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 solution was added a solution of 42.1 g. of 2-isonitroso-3-pentanone in 175 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 zine 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 combined extract was washed with 100 ml. of brine and was dried over anhydrous sodium sulfate. Evaporation of the solvent afforded 56.0 g. of crude tetrahydroindolone which was dissolved in 90 ml. of 2d toluene-ethyl acetate. The solution was stirred magneticaUy and was seeded and aHowed to crystallize overnight with stirring. The 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 methanol and dissolved in 50 mL of water. The solution was made basic with ammonium hydroxide and extracted with 2 X 50 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 2sl toluene-ethyl acetate afforded 2.6 g. of additional crystalline product. The two crops and oxalate-derived crystals were combined and dried at 25’ fl mm. for 2 hours to give 33.4 g. of 6-[2-(N-'methylamino)ethyl] -2-methyl-3-ethyl-6,7-dihydro-(5H)-4(lH,5H)-indolone as a light yellow solid, mp 114-120’, which was homogenous by TLC.
Example 4 Preparation of 3-ethyI-2.6-dimeth,vI-4,4a,5,6,7,8.8a,9-oetahydro-4a,8a-trans-lH-pyrroIo(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-6,7-dihydro-(5H)-4(lH,5H)-indolone and 170 mL of methanol. To the solution was added 20 mL of 4N hydrogen chloride in diethyl ether (made by bubbling HCl gas into diethyl ether in an ice bath and titrating). The solvent was removed on a rotary evaporator and the residual solid was dried at 50°/l mm 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 175180° 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 mi. of chloroform. The layers were separated and the aqueous solution was extracted with 4 x 200 ml. of chloroform. The combined chloroform extracts were washed with 200 ml. of brine and dried over anhydrous sodium sulfate. Evaporation of the solvent afforded 12.0 g. of crude pyrrolo[2,3-g] isoquinoline as a 4a,8a-trans, 4a,Sacis mixture (about 8:1) as a dark tan solid. The crude solid was dissolved in 100 ml. of 9:1 • 48965 dichloromethane-methanol and 300 ml. of diethyl ether was added. I’he fine solid precipitate, predominantly the 4a,8a-trans isomer, was collected by filtration and the filtrate was concentrated and crystallized to give second and third crops of tan solid.
The combined material was dried at 25" /1 mm. for 1 hour to give 8.20 g. of a light grey solid, 3-ethyi-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 suspended in 80 ml. of methanol and 12 ml. of 4N hydrogen chloride in diethyl ether was added. The solvent was removed and the residue was crystallized from 25 ml. of hot absolute ethanol. The first crop was collected by filtration and the mother liquid was concentrated and crystallized to give second and third crops of crystals. The combined solid was dissolved in 120 ml. of methanol and 2.4 g. of activated carbon (Darco-G-60) was added. The mixture was warmed on a steam bath for 10 minutes and the carbon filtered off through Celite. The filtrate was concentrated and reerystallized 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,5,6,7,8,8a,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’ . - 48965 6θ 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 (.HCl) as indicated. Isonitrosoketones were prepared as described in the literature [e.g., Ferris et al., J. Org. Chem., 24, 1726 (1959)] by nitrosation of the appropriate ketone. The isolated compounds are the 4a,8a-trans isomers.
Table I Ο φ b e t, ο Φ φ * 2 c c & >.5 Ό V M •—4 a ε a o K o c CO JZ 4-> . Φ E ϋ ffi CM Λ , C? C? w U co oi ei O ffi d« s o S3 o S_4 ffi o CL ε CO κ W oszu S' os Ί -.
S "m a oszu "lo « o ’Φ U >,►1 φ cl~ e ο I o o L Cb Ε Φ I Ό I «Μ & C ««° >, o 3 sz I cr +-» CD O CJ « (Λ c « 22 ho V CO 1 1 *CJ , ω h m CO »» *· CM «cf co «Ο -—ι O £ c ·—« n Ο O fe .- u f tt ^-5 «ο ω φ •g £ " 5?S t e J? o □ § « o£ S3Eh Λ φ o *i C w Φ ,β JS Φ 4-» 4-» Ο Φ Φ CO OffiZ υκζ co ffi Q •» J. CM "lo « § tj« o A fc4 tp C *7* o fj Si ό I t- C2 CO Ό Q Λ >» X λ 2 c φ Ο ΐ=ί E?g ·- °1.·3 T a o’ η 'R'R.o (Ν co Ά 48065 Co v t3 c ·σ ο φ *□ ϋ « 2 A Q Λ o C L<3 0) x; x: cn t» o ·-; cn ¢9 S’ c·^ © co OSZO £»n m co «a* 2 N t^o M IS Φ H ε cd X w υ S3 OKZO co ffi O I °1 ι β o co w co ή ·. qa t- A n< t« I >1 7ί Ql ? ι φ •c ac c »X3 ^•s g Example 5 Preparation of 2-methyl-3-ethyl-4,4a,5,6,7.3,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2.3g] isoquinolin-4-one A mixture of 3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-oetahydro-lH-pyrrolo[2,3g] isoquinolin-4-one prepared as in Example 4 (4.92 g., 20 mmol), ethyl chloroformate (19.55 g., 180 mmol), and potassium bicarbonate (8.0 g., 60 mmol) in diethyl ketone (100 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 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 3,70 g. of pure 6-ethoxycarbonyl-3-ethyl-2-methyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[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-ethyI-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one, hydrochloride as white crystals, mp > 250°.
Anal. Calcd. for c14II20N2°-HCl! C, 62.56; H, 7.88; N, 10.42; Cl", 12.19 C, 62.50; H, 7.90; N, 10.19; Cl, 13.33 Found: In an analogous manner, 2,3-dimsthyl-4,4ar5,6,7,8,8a,9-ocfcahyd£o4a,8ar-trans-lH-pyrrolo[2,3-gJisoquinolirr4-one can be prepared fron 2,3,6-trimetbyl-4,4a, 5,6,7,8, 8a, S-octahydro-lH-pyrrolo [2,3-a] isoquinolin-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)ethylamine hydrochloride (15.0 g 64.7 mmol) in 30 ml. of water was treated with 35 ml. of 2N sodium hydroxide ant extracted with dichloromethane. The combined extracts were concentrated on arotan 10 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 ovei anhydrous magnesium sulfate and concentrated to give the product as a yellow oil (15.: g). The oil was dissolved in 100 ml. of ethanol and treated with ethanolic hydrogei chloride. Ether (75 ml.) was added, and the salt crystallized to give 10.15 g. of 3,4dihydro-lH-6,8"dimethoxy-2-methylisoquinoline, hydrochloride (64% yield).
Example 7 Preparation of l,2,3,4,4a,7-hexahydro-6,8-dimethoxy2-methylisoquinoline and octahydro-2-methylisoquinolin6,8-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-6,8dimethoxy-2-methylisoquinoline hydrochloride (1.0 g, 4.1 mmol). After stirring 2-3 minutes, lithium wire (0.57 g, 82 mmol) was added in short pieces over 30 minutes. The blue solution was stirred under reflux for 2.5 hours and solid 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-dimethoxy20 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 with 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-methylisoguinolin-6,8-dione (11.6% 489 65 yield) as a light yellow solid. Treatment with hydrochloric acid in methanol afforded the hydrochloride, mp 193-196°.
Example 8 Preparation of 3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9octahydro-IH-pyrrolo/2,3-q7isoquinolin-4-one via octahydro-2-methylisoquinolin-6,8-dione 1,2,3,4,4a,7-Hexahydro-6,8-dimethoxy-2methylisoquinoline (0.56 g, 2.68 mmol) was heated to 90-100° in 70% aqueous acetic acid (10 ml) to hydrolyze the bis(enolether) to the octahydro-2-methylisoquinolin6,8-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 was 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 and concentrated to give the crude product. Chromatography of the crude product on Alumina III afforded 3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo/2,3-g7isoquinolin-4-one as a white solid (0.19 g, 29% yield).
Example 9 Preparation of 2.6-dimethyl-3-isopropyl-4.4a,5,6,7,8,8a.9-oetahydro-4a,8a-trans-IH-pyrrolo[2,3-gl isoquinolin-4-one A solution of crude octahydro-2-methyl-isoquinolin-6,8-dione (approximately 12.5 5 mmol) and 2.4 g. (18 mmol) of 2-isonitroso-4-methyl-3-pentanone in 40 ml. of 70% aqueous acetic acid was treated with 2.6 g. (40 mmol) of zinc dust and slowly heated to reflux. After 1 hour the mixture was cooled slightly and an additional 0.4 g. of isonitrosoketone and 1.0 g. of zinc were added and the mixture stirred for 1.5 hours at reflux. The mixture was then cooled and filtered, and the filtrate concentrated at 50°/20 mmHg to give a yellow oil which was diluted with 50 mL of water and made alkaline (pH 8-9) with ammonium hydroxide. The mixture was extracted with chloroform and the extracts were washed with brine and dried over sodium sulfate and concentrated to give 2.6 g. of crude product. The material was chromatographed (dry 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 reerystallized twice from ethyl acetate to give 470 mg. of pure 2,6-dimethyl-3-isopropyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3g] isoquinolin-4-one as a crystalline solid, mp 244-247°. Τ 48965 Example 10 Preparation of 3,S-dimethyl-2-(2-proDenyl)-4,4a.5.6,7,8,8a,9-octahydro-4a.8a-trans-lHpyrrolo[2.3-g] isoquinolin-4-one In a similar manner to that described in Example 9, 3-isonitroso-5-hexen-2 -or 5 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 221223° Example 11 Preparation of 3-cyclopropyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lHpyrrolo[2,3-g] isoquinolin-4-one In a similar manner to that described in Example 9, cyclopropyl-2-isonitroso-lpropanone and 2-methyl-octahydroisoquinolin-6,8-dione afforded 3-cyclopropvl-2,6dimethyl-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-dimethyI-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinoIin-4-one In a similar manner to that described in Example 9, 3-isonitroso-4-phenyl-2butanone and 2-methyl-octahydroisoquinolin-6,8-dione afforded 2-benzyl-3,6-dimethyl20 4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one, mp 234235' Example 13 Preparation of 6-methyl-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, except that no zinc was used, 5 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’ 2(1 Example 14 Preparation of 3-ethyl-l,2,S-trimethyl-4.4a,5,6,7,3,Sa.9-octahydro-4a,8a-trans-IH-pyrrolo[2,3-g] isoquinolin-4-one Liquid ammonia (80 ml) was condensed into a flask containing a suspension of 5 2,6-dimethyl-3-ethyl-4,4a,5,6,7,8,8a,9-oetahydro-lH-pyrrolo[2,3-g]lsoquinoIin-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 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 10 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 HI 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 acetate19 ethanol and ethanol to give pure 3-ethyl-l,2,6-trimethyl-4,4a,5,6,7,8,8a,S-oetahydro4a,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 CjgHg^NgO.HCl: C, 64.74; H, 8.49; N, 9.44; Cl', U.94 C, 64.72; H, 8.63; N, 9.29; Cl, 12.03 Found: 8965 Example 15 Preparation of l-benzoyl-2,6-dimethyl-3-ethyI-4.-in.5.6,7,S,8a.9-octahydro-4a,3a-translH-pyrrolo[2,3-g]isoguinolin-4-one To a suspension of 3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,3a,9-oetahydro-lH-pyrroIo5 [2,3-g] isoquinolin-4-one (492.7 mg, 2.0 mmol) in dry tetrahydrofuran GO ml) at -30° was added butyllithium ‘G.6 ml, 2.4 mmol, 1.5 M solution in hexane) over 2-3 minutes via syringe. The solution was stirred at -30° for I 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 j0 (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-benzovl-2,6dimethyl-3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g]-isoquinolin-4-one as a solid which was recrystallized from cyclohexane to give the pure product, mp 144-146°.
Anal. Calcd. for C22H26N2°2! C, 75.40; H, 7.48; N, 7.‘99 C, 75.63; H, 7.79; N, 8.01 Found: 489 65 Utilizing tlie procedure of Example 15, the following compounds were prepared. The isolated compounds are the 4a,8a-trans isomers.
From 2,6-dimethyl-3-ethyl-4,4a,5,6,7,8,Sa,9-octahydro-lH-pyrrolo[2,3-g]isoquinolin-4-one and benzyl chloride, there was obtained l-benzyl-2,S-dimethyl-3-ethyl5 4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g] isoquinolin-4-one.
From 2,6-dimethyl-3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g] isoquinolin-4-one and 1-trimethylacetyl chloride, there was obtained 2,6-dimethyl-3ethyl-l-(2,2-dimethyl-l-oxopropyl)-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolot2,3-g]isoquinolin -4-one, mp 110°-112°.
From 2-methyl-3-ethyl-6-(2-phenylethyl)-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-gI 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-4one, mp 180-181°.
Example is Preparation of 3-ethyl-2-methvl-6-(2-propcnyI)-4,4a,5,6,7,8,Sa,9-oc tahvdro-4a,8a-translH-pyrrolo(2,3-gl isoauinoiin-4-one A mixture of 3-ethyl-2-methyl-4,4a,5,S,7,S,8a,9-octahydro-lH-pyrrolo[2,3-g3 iso5 quinolin-4-one (0.470g, 2.03 mmol), allyl bromide (0.5 g, 4.13 mmol) and potassium carbonate (0.85 g, 6.16 mmol) in acetone (35 ml) was stirred, at room temperature for 2 hours and was filtered. The filtrate was concentrated and the residue (0.53 g) chromatographed on Alumina III to give the product (0.40 g). This product was treated with ethereal hydrogen chloride to form the hydrochloride salt, which was reerystallized from ethanol-ethyl acetate to give 3-ethyl-2-methyl-6-(2-propenyl)-4,4a,5,6,7,8,8a,9octahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one hydrochloride as a white solid, mp 214-217°.
Anal. Calcd. for C^H^N/.IICI. 0.511/ 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 Examples ISa-dd Following the procedure of Example 16, the compounds listed in Table II were prepared from the indicated 4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g]-isoquinolin-4-one and the indicated halide. Each compound displayed spectral characteristics consistent with the described structure. Melting points are for the free base or hydrochloride salt (.HCl) as indicated. Compounds isolated are the 4a,8a-trans isomers.
C c Ο C ’ΰ £· · ϋ £ α ® c Ε ® Ο 5 05 *' -*τ? φ Ν 6 cd ο zb «I 2—oi «1 pTi pT| φ c ο § φ C a £s Α ο ο -μ C Λ χ: £ φ +i £ ο W «υ β co co © 52 co co © © R* OHZO irt °° © 3©« Ο | osz3 « w o CQ S3 O « S3 O 7Ϊ c- o o' Ύ> 2 © o3 » | Ό 1. M* SC β J» Λ I Ο O cc cd ? >»Έ.Ί o «X cr C ο ε >> £ ti ·- 2 « >. ? " ° ε o -«.S CS LliOO «_· fcM XJ © 2-methyl-3-ethvl-6-benzyl- H CH, CH„CH, xii\xCH2 Cl C 70.27 C 70.49 193-7° Ethanol reflux 2 hours 4(4a,5,6,7,3,8a,9-ootahydro- * IJ H 7·58 11 7·33 in acetone lH-pyrrolo[2,3-g] isoquino- N_ 7.81 N_ 7.72 Ιίη-4-one IIC1 Cl 9.88 Cl 10.08 O :g <0 ft) c Pi §1 •σ β, N c ft) *3 rt £ ft, 4-» O . ft) (0 * OS a t- (-4 M4 r- O ©ft £ CL eft T «ί r- o io • t> ©ft · t>. · OSSto ® t- » Oi ©» CO © tφ c « 2 t« 5 □ ι 5 2 «*5 c - ft) K CL eft .
J, 4-> O -« rt C >>ti * Λ Φ Λ w y 4j ft) CO ft) £2 © © "5 co ?o co co OE55 c C o •=3 c «2 g s Cft CO κ c ft) ft) • CJ ο rt c *3 a >i £ £ 4·* 4-» ft) ft) w *. 3* «-j t- 53 co co co oo © to W qS l^_, OS25 O Table II - cont'd. *1 «* Pt Md et OK2 OEZPn © © CO 09 «»« OKZ £3 t» r-« © " m ©ft oj 52 co co © © r-t OK55 O a. a e o □ a M cq o c a a o o a a cq cq a o ^~co o <—/ a ϋ=Ο /-\ o a o ϋ Λ&ΐ° "co i3 2?»-* ΛΪ·§2 >»*rt 3 o £ 2 o o fc* fc ? > o « 5 01 ? c I 2 £ *3 co w) ** rn - — ft, S c* g.5 Z3 «ι· ’ m ι · «ft c = 2'S Ύ.2 Λ 3 σ ο CQ cq a o cq a □ o CC a o CS a o n a o cq a o co a o cq a o co a o cq a o co co co a a a o o o I 3 Λ ο >»κ J= 9 w ι b CO •Q r» ►ieft 2?»—» £ Q rt · ι £ ι rt dt co co ι Yoo ? to W «3 4-» O O t- ft, 1 £ I Λα> Q-? CO r-4 — I jl 2>α a 7 •a, c oo a λ 2» c .„ c e- ·-* *3£ ft) CX ε £ I o CM 3 co tn ί ~ c r. CJ Q ¢3 co tn ·* ft, e o >»© £ . in 2 ? <0 v.s 7 θ j c >» I Co — ·* 3 or ό S' cs i w eft in £ bo . rt rt ‘ a, o £ tl co rt ·£ 2 eft (m Or Ο I—· I « o. , : I 00 ►— «3 ' Λ *-'>> ! >,» c 5« S' ω «V ι « · Λ 7 >»A. rt ·, £ L ft, £ O . £ *j e- I ft, Ό · Λ >» 2»ί *4 κ £ 1 . O rt , Η ° Λ tl Λ ±ί 2 c u ft) O *.
I 8 9 6 5 α? C •Ε g 2 2 g S -= ? CJ ο α> c •Sg S3 § § χ: ο. ι CJ CQ *1 κ J3 Φ u «·’ c Φ b κ 3 G • φ b κ 3 r-< Φ b -© aj . ® O c *3 § ,. Ci O 3 C β 5o *o c «3 <0 Λ 4= JZ JZ +* JZ +* Φ © Φ Φ Φ o © o o 0 eo * © © ΙΛ 1 00 to © 03 03 03 rM © 03 03 03 j-4 O °5 co co s ° -O< OJ 2 co a ® 03 CO g CO 00 β © «Ο S 05 05 *? © © t- ( Z* 05 © fc· «—1 *5 CO © t— USX USX USX OE5! :3 © to. * Wt· B « h ~ Ift 03 ® co © °J 03 CO ®«S S2 05 © 0- .—1 2* © © ε»® ® com USX USX OBZ. osz b CQ b m b CQ o ϋ «Ί ¢3 Β Ο Β Ο « Β ϋ Β Ο Ο Ο ο Β Ο Μ Β ϋ Β Ο .0=0 ο *Ί Μ Β Ο cj Β Ο η Β Ο Β Ο « Β' Ο ο» Β Ο Β Ο Β Ο Β ρΓ ? >> « Β I = ηι Ο Λ Ο ε -S S 4. Λ ° £ s Λ ®« 3 >» « Ε 2 £ο° γ.Ξ Τ ·β) οο « Η. .2 .α σ Ό e- ~ Ο • ,λ ® 52 to co rr ··· co «J _r 5?ea fc, -q· X.^1 i . 5 s V α» T B Λ m w o · x® §.s f»$g· C O" 1* □ c -,5 « V ia d 'to j >»<2 L eo JZ O * ¢3 - 1- 03 OJ V '□‘ΟΙ Λ >»5 «ο >,χ; ο Φ • Qj Φ b C ο Ο u Ο S fc ϋ >: ι ί; αο cl^ ο κ ι ο ρ ι — I ο> ο « 4-5-3 ? 2» t, <ο ι _ i-H 2$ «£Β Φ Λ C Ο φ ff w »4'2 OT B 3 2» :3, *-» _+j co io £ eo S "* *" I ei *’ cr o ·>. tn i viy «£? o Λ Λ ό.Ξ eo cr Sco ' ο φ ¢ώ®Λ~§ "--ti " o 35 E£i a.
Table II - cont’d, a a a c o c a 0) e o G a s (0 e o c a .s tn ta a ta • 3 4-> c ta 3 4-» C 3 o <5 o Φ O a A a i JS p· £ tf4 a t co t*· ci « «Ί pTI o c CO £ g a x: eo e OKZ cOffiZ a o I Ϊ® >* L, eo u-* J3 »□ * Λ £*03 eo v 2**_L ο — o *3« a *a ί 9 o u 9 ? >> co -- Sg §>/a ? , C CO r-l 2, ω * ’ T X oo tn > •5 * d e g"> a S 2®h g => "I aj '3 ΓΊ Cd 00 o’ as g ,J2 088 088 0=1 K <0 A CO » S co o· 03555 <· ’r " n to 0358 » O M a o I o e> c o c eo +J c 4> a.
O BJ 8 tO to CO o « a o CS a o . o a o CS a o a co Ο \ in a co O rt a o cs a o rt μ « a a a o o o a a a eo ( Xi 23 X o 5 «λ o £ ? « 2 ‘3 λ) co c* t* 5* j I * ’ 0 21½ gg-γ^£ 2 ' ·ο*χ I O S3 >»5 03 3 >>-C O I 00 i I. ·» 3. - a . = <5 ρ 03 . Ν >, £ " Λ a<, ·= a « - , τ £2 " |<£ £ g glsO bo Jos ->>O ° :.T £ a ι U*3.S I «ο « o τζ to co .2 a a « 2 o -Λ *5- j— j. c £?Έ, bo #3¾ " CJ <3 . a g· ·«-» e<4 7 ι ο o rt V A O Ύ’ « £· » gg o a co ' ο a ι i ta <*7 t— 23 *j· §4 8 9 6 5 m c 5 _o .ο xs *β c Q> O « ϋ no o> N ie 4-» O n t ίο «Ί d> Q £ e3 X W ω £§ £ § g £ f 8.
E? —«co <° -a· t£: m * cs co UKZ a o cs a o ό a Q -cs a o Μ Ο JS c *-» ' To a f c o I . 7 w 1 . ^_ C C _ Q <0 οΛ® h θ «ο „ Λ >» ££ Λ >,·Λ . c <η ό ω ά *3 CO θ' G ο ^.«2 0) O o c r- C e c o .5 o •5 O c co 3 ¢3 2 β ti sj 4-» c g c 3 E O — a> 2 J= 3 cu Λ Q, Z 9* I co 2 A © J 04 CO S ιΛ « fr- CO g « CO oaa S2 «Ό .«θ’» ® »«5 oaa ra o= co Ε Ο c I I <3 04 Ο ηΓΤ ® ® ώ ό -Λτ; *7.5 « CO 0) >ufSfr ea Λ « 2* δ« Λ 'G ° £££ Μ β ϋ ί ο is co Ο*—« <Λ I C rca .£ £-. S o c I _ ca .3 CO 3 «§ ω 04 So ? 2 04 U I >» ,Λ ? S»O °2 co e* £ 05 05 c· o a a 05 — fr- Cgoe' a o«a o: OE2 ra cs a o ώ Zxo CO w co E co e o a □ co ffl O ’ a) E e 7 o ϋ s? Λ V o ?Ti.s eq «—«· >» 5*©: eo ο o t: «. +3 u « 04 V CX co P • *3 05 « OS rr ® ε « O I , js x: -3 c 0*3 _ o t) a «Λά δ° «=<§=: Λ 1 ·5 ® 2 *3 5 φν.- c ο Λ.«» is ‘3 Λ E.uo » σ’ « >> »c ο d S 2 " .2 a -C c —« u Οι·** 'T hD e £ o 0 *-» _ 2 ’*□ β c φ o tf § •σ v N !i ί* o Λ O ~ c £ ca i? w § -= Q* SA φ c C O ·** c S3 § X O ® £ O· C φ § £ Φ A tSS'® •"5 o t-t ® co oo « 1 OT ® S c o φ Σ Ω. « « M C 4) ft. ® o io yl «j ο gw® 4) £ o E§ *= cu 00 ' o c ce «c ® co Γζ f5 N i2 o5 o> Table II - cont'd. *1 P? col « 033 55 C» CO <0 CM 33 55 (JHZ C- _ «So « W W OBZ ozz o ZZ Offifc ® Oi oo °J co eo "2 03 cn 6» ΟΖΖ ϋ cc Z O cc Z o o z ϋ II cc Z Ό co Z ϋ cc Z ϋ cc z □ Z o II Z o m Z co ϋ Z o cc z o n cc Z o cc z ϋ ϋ ο ο cc ζ ο CO ζ ϋ co Ζ ϋ cc Ζ ο \ CC Ζ ο cc Ζ co Ζ ϋ CC Ζ Ο co Ζ ϋ O ι « «) i 3.3 °°-.2 «Ί. «ϋ » ό1 ν ω X! I. L· ι «5 >»2^ ’«τ-· Δ Ό co «ίο α ε 3 ? « ϋ >» χ: j* ·*» 1 Qi-L 03 | ? ο 2* X ε * C Ο to *-» ι ®Β.5 co -V a ·. ·τά 2 «ο cd οο .5 I Μ* 9 w » « σ &Τ Τ ο Ζ Α. 6 » Φ «?§>ϊ° A λ-S «Ί 4·2«« ί θ' η Ο JS | y <-μ ti CM · Ο Φ I 03 u 1 «Γ tc co g c S£«i ? u Oct- Z Ί· Λ «o v M 4-5 . O . OT I i ® oo g —« ·* CQ *J· 4) .— ρ·3 I 7 « X bo. £S « ?A I xs · <0 β ι ζ ι <5 ® ® ΣΞ 2 oo 33 Z3 I ΕΛ | c- g = Λ- £8 ·— <°5 2 2·® L = • 43 _« Φ *3« ε ?>>2 hO J J= 43 Γ 1 Φ C' * ; e «5 n , e S7O4 ϋ ·9 •3a ο 2 ί ί >. a . 4-» ς- Q. « φ Φ CO I Ο ¢9 1 1 u CO 00 ’Γ ο Φ c 2 Ο Ρμ Φ •ο © •S ο η u ο <*5 «Ί s" s pT ♦— σ c o3 c V) u aJ +j 03 ¢4 Oj «-> 3 c 3 C O © O © 4— a JS a CO t 03 CO co © ·£ ο C b CJ 3 ο c 45 Φ _ Ο< β I 04 βθ κ C φ . M © 0 O 4-J c 3 wx cd 0 £ OS JZ +* >»** λ 2 W © © O © © co <ί ο I » co£ 00 <Ο Λ » «Ο οκζ ϋ SZ « s □ oi s □ oi S □ s s □ • oi s □ s □ I 1 2* 2 ® □ ^7 Λ 27 geT >»Λ £ ‘λ Φ C £= ο _ I t, b Si eL® « CO fl I 'T' —» ,A , CO c- *4 ·— □ sa ? οι to "ϊ ν< « g^e- □ sa ei S □ Ol S □ O o ·□ s □ . oi S □ o to £ © » TS? ο I *τζ Ό 5* >» is ά§ I I 04 03 1« x2"CO *# ΟΧ.2 OT ° ~ n co ,« F·^ £2 >> o £ ο φ £4 Zw >» >» a ‘ .
S’*" w □ sa· a-u ι 1 Λθ4 >» 1 £ j? f 5 " E « ®ά _„® 2 ? Hb •=i ·— © ‘ 0 £32«-,}, i 2 " M P t· *1 5 S3 5* =° s' v s .2 V ,2 ? £ >>" N 0 £ Ei 2 ^A^^.^GOOCTI PH PH trans-[3-[3-e thyl-4,4a,5,6- H CH, CH„CH, K |P 2 "2 2 C 73.07 C 73.12 189-90,5® ethanol reflux 8 hours In 7,8,8a,9-octnhydro-2-methyl- Br H 7.67 H 7.63 3-pentnnone 4-oxo-lU-pyrrolol2,3-gl iso- N ' 7.10 N 7.07 qubiolbi-6-yl) propyl) bonzonto CO Ό C o Φ Φ c £ c o o c « c as u 3 «-» 3 ♦-» c O c Φ 45 Φ CL 1 e Cl 1 CO cs co X c Φ o c ed <21-12 © © Oi —I g ®" V c £ g S-2 SS Λ O. 00 CO X c Φ »4 o c β 4= λΝΝ , Η H Se5o3 Table II - eont'd, usz orc 55 033 2; tft _M ® «3 2 co © Π e- © "2® , © w goioi g aj co g® s USZ 033 23 033 23 r>4 ϋ Cm CC u «Ί CQ S3 O S3 S3 O—O CQ S3 S3 o—o CQ s: o ώ v33 O— CO S3 ^O CS SC ϋ I cs SC V 23.
S3 O S3 O « S3 O CQ S3 o co SC O cs SC □ ¢4 pT co se ϋ sc co SC o Φ *S ε ed X W cd cd © A >»£1 ι , λ o >>£3-3 £ >· o u a> « §1 '!"-Ia ..i g1 o"3 " ed ij-j rr tt ofl es Ss i iT "Γ^ C t- C c I cd ·» aj m 5 ·3 ί· " g«f-§ f° ι Ts i CQ Λ >. h CQ S®§^2§ a> £ O r .5 ί5 o >> « co Ό >> 0 CL^r ®·§. ε .c ι cd ι cs +Α ι Φ Ύξ? L ** ed 1 2 2§ Ο ι gT £.5 A o -=- c « i , ύ s3 es e * ® cs Cm S ΤΓ rp to rt t-« 0) c o rt o o] O PS c c o o Im Φ u o c S3 Δ cn o © I in in *3 CM •σ c O b «η «0 C < TJ V rt tt ® Ss © ©» OKZ ®° ®® co o usz —4 o «3*! tt ! eo s ϋ I V ± © c .£ • O —4 rt u o j.« T ,S Ό βθ rt 3 ‘ S' e° ~ βΓ o ©r«t®.2 |-s? c 7. i " 4, O’ u CM ,1. ; o cw Example 17 Preparation of 3-ethyl-2-methvI-6-(2-hydroxy-2-phenyIethyl)-4,43.5,6,7,8,8a,9-octahydro-4a,Sa-trans-lH-pyrrolo[2,3-g] isoquinolin-4-one A mixture of 3-ethyl-2-methyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g] iso5 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. Recrystallization from ethyl acetate-ethanol afforded 0.195 g. of 3-ethyl-2-methyl-6-(2hydroxy-2-phenylethyl)-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g3isoquinolin10 - 4-one as a white solid, mp 218.5-220°.
Anal. Calcd. for C22H28N2°2: C, 74.97; H, 8.01; N, 7.95 Found: C, 74.87; H, 7.92; N, 7.95 Examples 17a-17f Following the procedure of Example 17/ the compounds listed in Table DI were prepared from 3-ethyl-2-methyI-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g] isoquinolin-4-one and the indicated epoxide. Each compound displayed spectral characteristics consistent with the described structure. Melting points are for the free base or hydrochloride salt (.HCl) as indicated. The compounds isolated are the 4a,8a-trans isomers. [2,3-g] isoquinolin-4-one 48963 © ·σ e «eg © ·© © Λ3 I 4-« O o c « © J= = 1 OE CM .Ξ □ 5 o © p £ Ζ Ό «44 © C >** © JS © JS *3 © £3 © © © s © 4m* . © Λ © o © C —t © >» β β *-» 4-» © V g ·* © °® 00 «ο co co Ρ· CM P· •Φ t- eϋ WB «Ο 03 O? t- CO f? CO CO -I -β © ω£ *2 © ίύ ε §.ξ κ ΰ © . © C —4 0 5» 4= -C ♦* »-» © © — MO " t- M g oi « ο § § ·=£ Ο © κ C © u io co — © 00 M "eito w Table III - cont'd oil a £ a x « oaz OKZ co o e co io oo CO P· o wa osa OS32 osa O S — n <= o t— LO ϋ •S " 2·Ε2 sc o. z °\ « xs m O S Q « S o M yr \r o M o M a o O 3 ' £ .
A < ο.» ? e I © tC r siϊs'f -T ·φ "’-c p-3—4 +* a e * e c« » 8 *„ S 3 £ £ 2 ( X Cu * 1 ζ cm Ο O ij ’3 • J- >» co co σ’ © js μ* * ο © >»*f w • o y 3 jo Ό * © >»*i _«r © w pW fc« ^4 © ©» ©* *« »"» Y I » , © I TC 45 Ο P >> fl — Ό o » £ 2 © h ** A £ m- P·? 1 S ? ε U;2.2 Α δ "ΐ « To 2.= £1 • >>·ο +· Έ 3 >> V c £ rt* «3 =» £' I Δ 45 TiS. * 2» >»4-» £ Ο r γ ♦* *4 rt W I ®«5 ? >> = A //? 4. £’e0 co* ώ 57»τ| S| in iV © M SI » >» CM ι tIa 7 4 TC *5 oo >» Cu _ O ai © 0 I Α Ξ "= A 7«. 2··» « 57* ««? -a· E >» ’ A g’g ¢3 ·σ o > 2.= nJ S.s V> O 5-§ v ir 5w co ·— •sr t- CM 7,° © ε Example 18 Fssclution of racemic 3-ethyI-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-translH-pyrrolo[2,3-g] isoquinolin-4-one The racemic free base (prepared as in Example 4) (1.20 g.) was dissolved in 5 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 10 mm, there was obtained 0J5 g. of the (-)-enantiomer as a white crystalline solid, mp 240-245°. oc rotation: [a ] -120.78° (c 0.81%, water) Anal. Calcd. for CjgHggNgO.HCl. 0.2SH2O C, 62.70; H, 8.24; N, 9.75 15 Found: 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 l-(-)-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) D Anal. Calcd. for C15H22N2O.HC1.0.25H2O C, 62.70; H, 8.24; N, 9.75 C, 63.02; H, 8.20; N, 9.88 Found: Exanple 19 Preparation of N-[2-(3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-2-inethyl-4-axo4a, 8a-trans-lH-pyrrolo[2,3-g]isoquinolln-fr-yl)ethyl]-4-fluorcbenzanide N-(2-(3-ethyl-4,4a, 5,5,7,8,8a, 9-octahydro-2-methyl-4-oxo-4a, 8a-trans-lHpyrrolo[2,3-g] isoquinolin-6-yI)ethyI] -4-fluorobenzamide was prepared by heating 3ethyl-2-methyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g] isoquinolin-4-one and 1-(4fluorobenzoyl)-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-dimethyl-4,4a,5,6,7,8,8a,9-oetahydro-4a,8a-trans-lH-pyr?olo[2,3-g] isoquinolin-4-thione A mixture of 2.48 g. (0.01 mol) of 3-ethyl-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3-g] isoquinolin-4-one and 2.44 g. (0.008 mol) of Ρ^θ 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-2,6dimethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo[2,3-g]isoquinolin-4-thione, mp 194-196’ (dec.).
Example 21 Preparation of 3-ethyl-2-methvl-4.4a,5,6,7,8,8a,9-octahydro-lH-pyrrolo[2.3-g1 -isoquinolin-4-thione A mixture of L45 g. (6 mmol) of 3-ethyl-2-methyl-4,4a,5,6,7,8,8a,9-octahydro3 lH-pyrrolo[2,3-gl 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 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-methyl4,4a,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°.
Example 22 Preparation of 3-ethyl-2-methyl-6-(2-phenylethyl)-4,4a,5,6,7,8,8a,9-octahydro-4a.8atrans-lH-pyrrolo[2,3-gl isoquinolin-4-thione A mixture of 248 mg. (I mmol) of 3-ethyl-2-methyl-4,4a,5,6,7,8,8a,9-octahydro5 lH-pyrrolo[2,3-gIisoquinoIin-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 mt of water was added, and the mixture was extracted with chloroform. Purification by dry column chromatography as detailed in Example 21 gave 100 mg. of purified product, which gave 50 mg. of 3-ethyl-2, o methyl-6-(2-phenylethyl)-4,4a,5,6,7,8,8a,9-oetahydro-4a,8a-trans-lH-pyrrolo[2,3-g] isoquinolin -4-thione, mp 164-166°, (dec.) upon recrystallization from acetonitrile. © ® β ο 22°« bo ε Ο ιό bo ε ο Cft Cft ο σ ο So«Ι-Μ « bo ε ω eo 2 4° Μ ]?·ο *5 β ΓΤ *-» ** Ο φ 4? *7 » C CO £ -:s ω '3 ιη σ' 0 ο ^jT*rn Χψ* ?>»©> 5 CM .5 ο £ Cft * ι X 5rtrf £ ω ·*-» c ψ « > cCO •a 4-» £ ·& L 4- □ w tn .72 Ο* £ 3 • C2 Ε* Ο σ 2L κ Ξ2 3§ φ 4J 4-* •μ 75 3 g » « <8 Φ Ε3 *« ϋ (0 c •ο S’ § ε φ *σ « c <ϋ u α) φ *-» (Λ ε ‘55 φ c υ fj c ~ 2 V ho α 2 « 5 w Η ** φ u •α φ ο ο U Λ «3 rt fc4-» c5 ^•g •σ ω κ gS S3 S Ε § ο ω 3 <2 Λ 5" <-> ,·£ £ κ σ 2 .□ tn rt £ as ε © ©I © © © © «η © γμ © 4t- —< :ample 24 κ Ul © Ο «Λ Ά «η ο «ΛΟ ΙΛΙΛ ε ο Η Zi V IU -^2 2 £ ο θ ο ® Ο CM ΧΓ\ m «Λ . υ ci 2 oo U, <α£ •a- X ι υ Ρ ο !*£ Ο 2 ο § °lJΙβ I ©Ο °° ο Ώ. Ο <β J2 J. Α _e οΓ iu U ο Ε ο ϊ L >? 1 X «η « § ί*\ +3 ΐΐ <3 ο «Η C V) ΒΟ u ε £ο C χ ·£ -Η 22 -C £ 4-* >» VI U -σ Ω . · £2 t* «Λ ego. c ο ·» f· 4, -ρ X w X <α ο 5 +*· jtf nJ ♦J □ C C C Ο ο m /; u (Λ •a ω? <λ „-Κ "« g. .5 κ Ε « Ε 8 •ijo-g ura § «j <0 Λ, 4J.t^ X □ nJ 4-» V) t•δ .£

Claims (30)

1. CLAIMS:1. An octahydro-lH-pyrrolo/2,3-g7isoquinoline of the general formula 5 wherein Ry is hydrogen, (Cy-Cy)-alkyl, (Cy-Cy)alkanoyl or benzoyl or phenyl-(Cy-Cy)-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (Cy-Cy)-alkyl, (Cy-Cy)-alkoxy, nitro, amino, (Cy-Cy)-alkylamino or di-(C^-Cy)-alkyl10 amino, R 2 and R 3 independently of each other are hydrogen, (C^-Cy)-alkyl, (C 3 -Cg)-cycioalkyl, (Cj-Cy)-alkenyl, (C^-Cy)-alkanoyl or benzoyl, phenyl or phenyl-(Cy-Cy) alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (Cy-Cy)-alkyl, 15 (Cy-Cy)-alkoxy, nitro, amino, (Cy-Cy)-alkylamino or di(Cj-Cy)-alkyl-amino and R^ is hydrogen, (Cy-Cy)-alkyl, hydroxy-(Cy-Cy)-alkyl, phenyl-hydroxy-(Cy-Cy)-alkyl, halophenyl-hydroxy-(Cy-Cy)-alkyl, (Cy-Cy)-alkylphenylhydroxy- (Cy-Cy)-alkyl, (Cy-Cy)-alkoxypheny1-hydroxy20 (Cy-Cy)-alkyl, (Cy-Cy)-alkoxy-(Cy-Cy)-alkyl, (Cy-Cy)alkoxy-hydroxy-(Cy-Cy)-alkyl, (Cy-Cy)-alkanoyloxy(Cy-Cy)-alkyl, (Cy-C?)-alkoxycarbonyl-(Cy-Cy)-alkyl, (C 2 ~Cy)-alkenyl, (C 3 ~Cg)-cycioalkyl-(Cy-Cy)-alkyl. (Cg-Cy)-alkynyl, thienyl-(Cg-Cy)-alkyl, furyl- (Cg-Cy) alkyl, (Cg-Cy)-alkanoyl-(Cg-Cy)-alkyl, (Cg-Cg)cycloalkoxy- (Cg-Cy) -alkyl, (Cg-Cg) -cycloalkyl-hydroxy- (Cg-Cy) alkyl, (Cg-Cy)-alkenyloxy-(Cg-Cy)-alkyl, N-(Cg-Cy)-alkylpyrrolidinyl-(Cg-C-y)-alkyl, tri fluoroalkyl with 2 to 6 carbon atoms or phenoxyhydroxy-(Cg-Cy)-alkyl, benzoyloxy(Cg-C 7 )-alkyl, benzoyl-(Cg-Cy)-alkyl, phenyl-(Cg-Cy) alkyl, phenylcarboxamido-(Cg-Cy)-alkyl, phenyl-(Cg-Cy)alkenyl, phenoxy-(Cg-Cy)-alkyl or phenyl-N-imidazolonyl(Cg-Cy)-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (Cg-Cy)alkyl, (Cg-Cy)-alkoxy, nitro, amino, (Cg-Cy)-alkylamino Rg or di-(Cg-Cy)-alkylamino, or ^N-(Cg-Cy) -alkyl, Ry wherein Rg and Ry independently of each other are hydrogen or (Cg-Cy)-alkyl or together with the nitrogen atom are a 5 or 6-membered saturated heterocyclic ring which can further contain as a ring member an oxygen atom or a nitrogen atom optionally substituted by (Cg-Cy)-alkyl or hydroxy-(Cg-Cy)-alkyl, and X is 0 or S, an optical or geometric isomer thereof or a pharmaceutically acceptable acid addition salt thereof.
2. A compound as claimed in claim 1, wherein Rg is hydrogen, (Cg-Cy)-alkyl, (Cg-Cy)-alkanoyl or benzoyl or phenyl-(Cg-Cy)-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (Cg-Cy)-alkyl, (Cg-Cy)-alkoxy, nitro, amino, (Cg-Cy)alkylamino or di-(Cg-Cy)-alkylamino, Rg and Rg independently of each other are hydrogen, (Cg-Cy)-alkyl, (Cj-Cg) -cycloalkyl, (Cy-Cy)-alkenyl or phenyl-(C^-Cy)alkyl optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C^-Cy)-alkyl, (C^-Cy)-alkoxy, nitro, amino, (C^-Cy)-alkylamino or di-(C^-Cy)-alkylamino and r 4 5 is hydrogen, (C^-Cy)-alkyl, hydroxy-(C^-Cy)-alkyl, phenylhydroxy- (Cj-Cy)-alkyl, halophenyl-hydroxy-(C^-Cy)-alkyl, (C^-Cy)-alkylphenyl-hydroxy-(C^-Cy)-alkyl, (C^-Cy)-alkoxyphenyl-hydroxy- (C^-Cy)-alkyl, (Cj-Cy)-alkoxy-(C^—Cy)alkyl, (C^-Cy)-alkoxy-hydroxy-(C^-Cy)-alkyl, (C^-Cy)10 alkanoyloxy-(Cj^-Cy)-alkyl, (C^-Cy)-alkoxycarbonyl-(C 1 ~Cy)alkyl, (Cy-Cy)-alkenyl, (Cy-Cg)-cycloalkyl-(C^-Cy)-alkyl, (Cy-Cy)-alkynyl, thienyl-(Cj-Cy)-alkyl, furyl-(C^-Cy)alkyl or phenoxy-hydroxy-(C^-Cy)-alkyl, benzoyloxy-(C^-Cy)alkyl, phenyl-(C^-Cy)-alkyl or benzoyl-(C^-Cy)-alkyl each 15 of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C^-Cy)-alkyl, (Cj-Cy)-alkoxy, nitro, amino, (C.-Cy)-alkylamino or di-(C^-Cy)-alkylamino, Hg___ or ' N-(C 1 -C 7 )-alkyl and X is 0, an optical or geometric Ry^ isomer thereof or a pharmaceutically acceptable acid addition 20 salt thereof.
3. A compound as claimed in Claim 1 or 2, wherein R^ is hydrogen.
4. A compound as claimed in any one of Claims 1 to 3, wherein R2 and R^ are (C^-Cy)-alkyl. 489 65
5. A compound as claimed in any one of claims 1 to 4, wherein is (Cy-Cy)-alkyl, hydroxy-(Cy-Cy)-alkyl, phenylhydroxy- (Cy-Cy ) -alkyl, halophenyl-hydroxy-(Cy-Cy)-alkyl, (Cy-Cy)-alkoxy-(Cy-Cy)-alkyl, or phenoxy-(Cy-Cy)-alkyl, 5 benzoyl-(Cy-Cy)-alkyl or phenyl-(Cy-Cy)-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (Cy-Cy)-alkyl, (Cy-Cy)-alkoxy, nitro, amino, (Cy-Cy)-alkylamino or di-(Cy-Cy)-alkylamino. 10
6. A compound as claimed in any one of claims 1 and 3 to 5, wherein X is 0.
7. A compound 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-octahydro15 4a,8a-trans-lH-pyrrolo/2,3-g/isoquinolin-4-one,
9. 2-Methyl-3-ethyl-6-(2-phenylethyl)-4,4a,5,6,7,8,8a 9-octahydro-4a,8a-trans-lH-pyrrolo/2,3-g7isoquinolin-4-one.
10. 2-Methyl-3-ethyl-6-(2-ethoxyethyl)-4,4a,5,6,7,8,8a 9-octahydro-4a,8a-trans-lH-pyrrolo/2,3-g7isoquinolin-4-one. 20
11. 2-Methy1-3-ethy1-6-/4-(4-fluorophenyl)-4-oxobuty1/-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lHpyrrolo/2,3-g/isoquinolin-4-one.
12. 3-Ethyl-2-methyl-6-(2-hydroxy-3,3-dimethylbutyl)97 4,4a,5,6,7,8,8a,9-octahydro-ΙΗ-pyrrolo/2,3-g/isoquinolin-4-one.
13. A compound as claimed in claim 1, wherein Rg is hydrogen, Rg is methyl, Rg is ethyl, X is 0 and R 4 is 2- hydroxy-2-phenylethyl, benzyl, 3- (4-fluorophenyl)-3-oxo-propyl, 3-phenoxypropy1, 2-hydroxy-3-methylbutyl, 2-hydroxy-ethyl, 2 propenyl, cyclopropylmethyl, ethyl, 2-oxo-2-(4-fluorophenyl)-ethyl.
14. A compound as claimed in claim 1, wherein Rg is hydrogen, Rg and Rg are methyl, X is 0 and R 4 is methyl, 2-phenethyl, 4-(4-fluorophenyl)-4oxobutyl.
15. An octahydro-lH-pyrrolo/2,3-g/isoquinoline according to any one of claims 1 to 14 as a pharmaceutically active substance.
16. An octahydro-lH-pyrrolo/2,3-g/isoquinoline according to any one of claims 1 to 14 as a neuroleptic/ antipsychotic substance.
17. 3-Ethyl-2,6-dimethy1-4,4a,5,6,7,8,8a,9-octahydro4a,8a-trans-lH-pyrrolo/2,3-g/isoquinolin-4-one as a pharmaceutically active substance.
18. 3-Ethyl-2,6-dimethy1-4,4a,5,6,7,8,8a,9-octahydro4a,8a-trans-lH-pyrrolo/2,3-g/isoquinolin-4-one as a neuroleptic/antipsychotic agent.
19. A process for the preparation of a compound of the formula A given in claim 1, or an optical or geometric isomer thereof or a pharmaceutically acceptable acid 5 addition salt thereof which comprises a) for preparing a compound of the general formula R 4 la wherein R 4 is (Cy-Cy)-alkyl, (C^-Cy) -alkoxy(C^-Cy)-alkyl or (Cg-Cg)-cycloalkyl-(C^-Cy)10 alkyl and Rg and Rg are as defined in claim 1 reacting a compound of the general formula wherein R 2 , Rg and R 4 are as previously described, with formaldehyde, or b) for preparing a compound of the formula la above, reacting a compound of the general formula wherein R 4 is as previously described, with a compound of the general formula VIX in the presence of a reducing agent, or with a compound of the general formula VIII h 2 n R 2 wherein R 2 and R^ are as previously described, or a precursor thereof, or c) for preparing a compound of the general formula 4 8 9 6 5 100 wherein ί? 2 and are as previously described, N-demethylating a compound of the formula Ia above wherein R^ is methyl, or 5 d) for preparing a compound of the general formula S wherein R 2 1 and 1 , independently of each other are hydrogen, (Cj-C 7 ,-alkyl, (C^-Cg)-cycloalkyl, (C 2 C 7 )-alkenyl or phenyl or pheny110 (Ο-^-Ογ)-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C- L ~C 7 )-alkyl, (C-^-C·?)-alkoxy, nitro, amino, (C 3 ~C 7 )-alkylamino or di-)alkylamino, R^' is hydrogen, (C^-C 7 )-alkyl, 15 (C 1 ~C 7 )-alkoxy-(C^-C 7 )-alkyl, (C 2 ~C 7 )-alkenyl, (C^-Cg) -cycloalkyl- (C^—C 7 ) -alkyl, (C 2 -C 7 ) alkynyl, thienyl-(C^-C 7 )-alkyl, furyl-(C^-C 7 )48965 Ιοί alkyl, (C 2 “Cy)-alkenyloxy-(C^-Cy)-alkyl or phenyl-(C^-Cy)-alkyl, phenyl-(Cy-Cy)-alkenyl or phenoxy-(C^-Cy)-alkyl each of which is optionally substituted on the phenyl ring by 5 halogen, trifluoromethyl, (C^-Cy)-alkyl, (C^-Cy)-alkoxy, nitro, amino, (C^-Cy)-alkylamino or di-(Cj^-Cy)-alkylamino, or trifluoroalkyl with 2 to 6 carbon atoms and R^ is as defined in claim 1, reacting a compound of the general 10 formula wherein R^, Ry'» Rg' and Rj are as previously described, with phosphorus pentasulfide, or e) for preparing a compound of the general formula wherein R^ is hydroxy-(C^-Cy)-alkyl, phenylhydroxy- (C-^-Cy) -alkyl, halophenyl-hydroxy- (C-^-Cy)48965 102 alkyl, (C^-Cy)-alkylphenyl-hydroxy-(C^-Cy)-alkyl, (C-^-Cy)-alkoxyphenyl-hydroxy-(C^-Cy)-alkyl, (C^-Cy) -alkoxyhydroxy- (C^-Cy) -alkyl, (.C-^-Cf alkanoyloxy- (C-^-Cy) -alkyl, (C^-Cy) -alkoxy5 carbonyl-(C^-Cy)-alkyl, (C^-Cy)-alkanoyl(Cg-Cy)-alkyl, (Cg-Cg)-cycloalkoxy-(C^-Cy)-alkyl, (Cg-Cg)-cycloalkyl-hydroxy-(C^-Cy)-alkyl, N(C-^-Cy) -alkyl-pyrrolidinyl- (C^-Cy) -alkyl or phenyl-N-imidazolonyl-(C^-Cy)-alkyl, phenoxy10 hydroxy-(C^-Cy)-alkyl, benzoyloxy-(C^-Cy)-alkyl, benzoyl-(Cy-Cy)-alkyl or pheny1-carboxamido(C^-Cy)-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C^-Cy)-alkyl, (C-j-Cy)-alkoxy, nitro, amino, 15 (C^-Cy)-alkylamino or di-(C^-Cy)-alkyl-amino, or R 6 ' N-(C,-C 7 )-alkyl, wherein R fi and R- are as Ry ' o / defined in claim 1, and R^, Rg and Rg are as previously described, splitting off a protecting group or protecting groups in a 20. Compound of the general formula S Ilf 103 4 8 9 6 5 wherein R 2 and Ry have the same meanings as R 2 and Ry except when R 2 and Ry are (Cy-Cy)-alkanoyl or benzoyl optionally substituted on the phenyl ring by halogen, trifluoromethyl, (Cy-Cy)-alkyl, 5 (Cy-Cy)-alkoxy, nitro, amino, (Cy-Cy)-alkylamino or di-(Cy-Cy)-alkylamino, R 2 and Ry are V in a protected form, R^ has the same meaning as R™, but in a protected form, and Ry is as previously described, 10 ° r f) for preparing a compound of the general formula X wherein Ry' is (Cy-Cy)-alkyl, (Cy-Cy)-alkanoyl or benzoyl or phenyl-(Cy-Cy)-alkyl each of which is 15 optionally substituted on the phenyl ring by halogen, trifluoromethyl, (Cy-Cy)-alkyl, (Cy-Cy)-alkoxy, nitro, amino, (Cy-Cy)-alkylamino or di-(Cy-Cy)alkylamino, Ry, Ry, R^ are as previously described and X is as defined in claim 1, 20 substituting a compound of the general formula 489 6 5 104 wherein Rg , Rg, R^ and X are as previously described, at the pyrrole nitrogen atom, or g) for preparing a compound of the general formula wherein R 4 ' is (Cg-Cg)-alkyl, hydroxy-(Cg-Cg)alkyl, phenyl-hydroxy-(Cg-Cg)-alkyl, halophenylhydroxy- (Cg-Cg) -alkyl, (Cg-Cg)-alkylphenyl-hydroxy(Cg-Cg)-alkyl, (Cg-Cg)-alkoxyphenyl-hydroxy-(Cg-Cg) 10 alkyl, (Cg-Cg)-alkoxy-(Cg-Cg)-alkyl, (Cg-Cg)-alkoxy hydroxy-(Cg-Cg)-alkyl, (Cg-Cg)-alkanoyloxy-(Cg-Cg)alkyl, (Cg-Cg)-alkoxycarbonyl-(Cg-Cg)-alkyl, (C 2 -Cg)-alkenyl, (Cg-Cg)-cycloalkyl, (Cg-Cg)-alkyl, (C 2 -Cg)-alkynyl, thienyl-(Cg-Cg)-alkyl, furyl15 (Cg-Cg)-alkyl, (Cg-Cg)-alkanoyl-(Cg-Cg)-alkyl, (Cg-Cg)-cycloalkyoxy-(Cg-Cg)-alkyl, (Cg-C g )-cycloalky lhydroxy- (Cg-Cg)-alkyl, (Cg-Cg)-alkenyloxy105 (C^-Cy)-alkyl, N-(C^-Cy)-alkyl-pyrrolidinyl(C^-Cy)-alkyl, trifluoroalkyl with 2 to 6 carbon atoms or phenoxy-hydroxy-fC^-Cy)-alkyl, benzoyloxy-iC^-Cy)-alkyl, benzoyl-(C^-Cy)-alkyl, phenyl5 (Cj-C?)-alkyl, phenylcarboxamido-( 2 -Cy)-alkenyl, phenoxy-(Cj-Cy)-alkyl or pheny1-N-imidazolony1-(C^-Cy)-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (C^-Cy)-alkyl, (C^-Cy)10 alkoxy, nitro, amino, (C-^-Cy)-alkylamino or di(C^-Cy)-alkylamino, or R 6—N-(C^-Cy)-alkyl and Ry R 2 , R 3 , Rg, Ry and X are as previously described, substituting a compound of the general formula 15 wherein R 2 , R 3 and X are as previously described, at the isoguinoline nitrogen atom, or h) for preparing a compound of the general formula Af 106 wherein Ry', R o' R 3 Z R 4' an< ^ x are as previously described, substituting a compound of the following formula Ae at the pyrrole nitrogen atom, or· i) for preparing a compound of the general formula wherein Ry', R 2 , R 3 ant ^ x are as P re viously described, splitting off the protecting group in a compound of the general formula 10 wherein Z is a protecting group and Ry', R 2 , Ry and X are as previously described, or j) for preparing a compound of the general formula 107 wherein R^ is hydrogen, (C^-Cy)-alkyl, (C^-Cy)alkoxy-(Cj—Cy)-alkyl, (C^-Cy)-alkanoyloxy-(C^-Cy)alkyl, (C^-Cy)-alkoxycarbonyl-(C^-Cy)-alkyl, 5 (C 2 -Cy)-alkenyl, (C^-Cg)-cycloalkyl-(C-^-Cy)-alkyl, (Cy-Cy)-alkynyl, thienyl-(C^-Cy)-alkyl, furyl(Cj-Cy)-alkyl, (C-^-Cy) -alkanoyl(C^-Cy)-alkyl, (Cy-Cg)-cycloalkyloxy-(C^-Cy)-alkyl, (Cy-Cy) -alkenyloxy- (C-^-Cy) -alkyl, N- (C^-Cy) -alkyl10 pyrrolidinyl-(C^-Cy)-alkyl, trifluoroalkyl with 2 to 6 carbon atoms or phenyl-N-imidazolonyl(C^-Cy)-alkyl, benzoyloxy-(C^-Cy)-alkyl, phenyl(Cj^-Cy)-alkyl, phenylcarboxamido-(C^-Cy)-alkyl, benzoyl-(Cj-Cy)-alkyl, phenyl-(Cy-Cy)-alkenyl or 15 phenoxy-(C^-Cy)-alkyl each of which is optionally substituted on the phenyl ring by halogen, trifluoromethyl, (Cj^-Cy) -alkyl, (C^-Cy)-alkoxy, nitro, amino, (C^-Cy)-alkylamino or di-iC^-Cy)alkylamino and R^J, R 2 ' R3 and x are as previously 20 described, substituting a compound of the general formula 108 wherein Rg, Rg, R^ and X are as previously described, at the pyrrole nitrogen atom, or k) for preparing a compound of the general formula X VII wherein R 4 is hydroxy-(Cg-Cg)-alkyl, phenylhydroxy- (Cg-Cg)-alkyl, halophenylhydroxy-(Cg-Cg)alkyl, (Cg-Cg)-alkylphenyl-hydroxy-(Cg-Cg)-alkyl, (Cg-Cg)-alkoxyphenyl-hydroxy-(Cg-Cg)-alkyl, 10 (Cg-Cg)-alkoxyhydroxy-(Cg-Cg)-alkyl, (Cg-Cg)Rg cycloalkylhydroxy-(C.-C?)-alkyl, N-(C.-C_) 17 Rg 1 7 alkyl or phenoxy-hydroxy-(Cg-Cg)-alkyl optionally substituted on the phenyl ring by halogen, trifluoromethyl, (Cg-Cg)-alkyl, (Cg-Cg)-alkoxy, nitro, amino, (Cg-Cg)-alkylamino or di-(Cg-Cg)-alkylamino 109 and Rj' ι R 2 , R-j, Rg, R? and X are as previously described, splitting of the protecting group in a compound of the general formula or VIII wherein Rj has the same a protected form, and R^', previously described, meaning as R^ , but in R 2 , R 3 and X are as l) isomerizing the mixture of cis and trans isomers 10 obtained to a final ratio which comprises predominantly the trans isomer, or m) separating the trans isomer from the mixture obtained, or n) resolving a racemic mixture obtained into the 15 optical antipodes and o) if desired, converting a compound obtained or a non-pharmaceutically acceptable acid addition salt thereof into a pharmaceutically acceptable acid addition salt thereof. ΠΟ
20. A medicament containing an octahydro-lHpyrrolo/2,3-g/isoquinoline of formula A given in claim 1, an optical or geometric isomer or a pharmaceutically acceptable acid addition salt thereof in association 5 with a pharmaceutically acceptable carrier or diluent therefor.
21. A neuroleptic/antipsychotic medicament containing an octahydro-lH-pyrrolo/2,3-g/isoquinoline of fonnula A given in claim 1, an optical or geometric isomer or a 10 pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutically acceptable carrier or diluent therefor.
22. A medicament containing 3-ethy1-2,6-dimethy14,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-lH-pyrrolo 15 /2,3-q/isoquinolin-4-one in association with a pharmaceutically acceptable carrier or diluent therefor.
23. A neuroleptic/antipsychotic medicament containing 3-ethyl-2,6-dimethy1-4,4a,5,6,7,8,8a,9-octahydro-4a,8atrans-lH-pyrrolo/2,3-g/isoquinolin-4-one in association 20 with a pharmaceutically acceptable carrier or diluent therefor.
24. An octahydro-lH-pyrrolo/2,3-g/isoquinoline of formula A given in claim 1, an optical or geometric isomer or a pharmaceutically acceptable acid addition 25. Salt thereof for use in the treatment of schizophrenia.
25.5. 3-Ethy1-2,6-dimethyl-4,4a,5,6,7,8,8a,9-octahydro4a,8a-trans-lH-pyrrolo/2,3-g7isoquinolin-4-one for use in 111 the treatment of schizophrenia.
26. An octahydro-lH-pyrrolo/2,3-g/isoquinoline of the general formula A given and defined in claim 1 or an optical or geometric isomer thereof or a pharmaceutically acceptable acid addition salt thereof, which is any one of those specifically hereinbefore mentioned.
27. An octahydro-lH-pyrrolo/2,3-g/ isoquinoline of the general formula A given and defined in claim 1 or an optical or geometric isomer thereof or a pharmaceutically acceptable acid addition salt thereof, substantially as hereinbefore described with particular reference to Examples 1-22 of the accompanying Examples.
28. A process for the preparation of an octahydrolH-pyrrolo/2,3-g7 isoquinoline of the general formula A given and defined in claim 1 or an optical or geometric isomer thereof or a pharmaceutically acceptable acid addition salt thereof, substantially as hereinbefore described with particular reference to Examples 1-22 of the accompanying Examples.
29. An octahydro-lH-pyrrolo/2,3-g/ isoquinoline of the general formula A given and defined in claim 1 or an optical or geometric isomer thereof or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by a process claimed in a preceding claim.
30. A medicament according to any one of claims 20 112 to 23, substantially as hereinbefore described with particular reference to Examples 23-25 of the accompanying Examples.
IE1944/79A 1978-10-13 1979-10-12 Isoquinoline derivatives,process for their preparation,medicaments containing them and their pharmaceutical use IE48965B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US95094778A 1978-10-13 1978-10-13
US06/073,813 US4260762A (en) 1979-09-10 1979-09-10 Octahydro-1H-pyrrolo[2,3-g]isoquinolines

Publications (2)

Publication Number Publication Date
IE791944L IE791944L (en) 1980-04-13
IE48965B1 true IE48965B1 (en) 1985-06-26

Family

ID=26754910

Family Applications (1)

Application Number Title Priority Date Filing Date
IE1944/79A IE48965B1 (en) 1978-10-13 1979-10-12 Isoquinoline derivatives,process for their preparation,medicaments containing them and their pharmaceutical use

Country Status (18)

Country Link
EP (1) EP0010661B1 (en)
AR (2) AR228244A1 (en)
AU (1) AU528685B2 (en)
CA (1) CA1132553A (en)
CS (1) CS242858B2 (en)
DE (1) DE2967215D1 (en)
DK (1) DK430579A (en)
ES (2) ES8104805A1 (en)
FI (1) FI67548C (en)
HU (1) HU181883B (en)
IE (1) IE48965B1 (en)
IL (1) IL58438A (en)
MC (1) MC1285A1 (en)
NO (1) NO152873C (en)
NZ (1) NZ191830A (en)
PH (1) PH14835A (en)
PT (1) PT70310A (en)
SU (3) SU1109052A3 (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MC1377A1 (en) * 1980-02-28 1982-01-19 Hoffmann La Roche ISOQUINOLEIN DERIVATIVES
EP0091565B1 (en) * 1982-03-29 1986-04-23 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Process for the manufacture of isoquinoline diones
US4732902A (en) * 1986-05-23 1988-03-22 Hoffmann-La Roche Inc. Pyrroloisoquinolinyl-dimethyloxoalkyl alkonoates and their use as antipsychotic agents
GB8828669D0 (en) * 1988-12-08 1989-01-11 Lilly Industries Ltd Organic compounds
EP1131284A1 (en) * 1998-11-20 2001-09-12 Basf Aktiengesellschaft Method and intermediate products for producing bis(oxim)monoethers

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS51118799A (en) * 1975-04-10 1976-10-18 Sankyo Co Ltd Method for preparing pyridindole derivatives

Also Published As

Publication number Publication date
CS242858B2 (en) 1986-05-15
PT70310A (en) 1979-11-01
EP0010661A3 (en) 1980-10-01
DK430579A (en) 1980-04-14
ES493014A0 (en) 1981-05-16
SU1109052A3 (en) 1984-08-15
IE791944L (en) 1980-04-13
FI67548B (en) 1984-12-31
AR228244A1 (en) 1983-02-15
EP0010661A2 (en) 1980-05-14
ES8104806A1 (en) 1981-05-16
PH14835A (en) 1981-12-16
FI793183A (en) 1980-04-14
EP0010661B1 (en) 1984-09-12
MC1285A1 (en) 1980-07-22
SU1048985A3 (en) 1983-10-15
CS694579A2 (en) 1985-08-15
NZ191830A (en) 1984-09-28
NO793301L (en) 1980-04-15
AU5169779A (en) 1980-04-17
NO152873B (en) 1985-08-26
ES493015A0 (en) 1981-05-16
HU181883B (en) 1983-11-28
ES8104805A1 (en) 1981-05-16
CA1132553A (en) 1982-09-28
AR229096A1 (en) 1983-06-15
DE2967215D1 (en) 1984-10-18
IL58438A0 (en) 1980-01-31
FI67548C (en) 1985-04-10
AU528685B2 (en) 1983-05-12
SU1014474A3 (en) 1983-04-23
IL58438A (en) 1982-12-31
NO152873C (en) 1985-12-04

Similar Documents

Publication Publication Date Title
JP4197650B2 (en) Pyrido (2,1-a) isoquinoline derivatives as DPP-IV inhibitors
JP3180344B2 (en) Indole derivatives
EP0487071A1 (en) Condensed heterocyclic compounds, their production and use
JPH10510247A (en) Dihydropyrimidines and uses thereof
EP0937077A1 (en) Pyridone-fused azabicyclic- or cytisine derivatives, their preparation and their use in addiction therapy
NO140589B (en) ANALOGICAL PROCEDURE FOR PREPARING NEW THERAPEUTICALLY ACTIVE 3,4-DIHYDROCARBOSTYRIL DERIVATIVES
MXPA00007058A (en) Novel beta-carboline derivatives, process for their preparation and pharmaceutical compositions containing them.
HU177408B (en) Process for preparing new tetrahydrofurfuryl-6,7-benzomorphans
EP0677046B1 (en) Piperazine derivatives as 5-ht antagonists
EP0734387B1 (en) Hiv protease inhibitors
HU176479B (en) Process for preparing new n-/methoxymethyl-furyl-methyl/-6,7-benzomorphans and -morphians further acid addition snlts thereof
HU202842B (en) Process for producing new isoquinolinone derivatives and pharmaceutical compositions containing them
US20080214542A1 (en) Arylpiperazine Derivatives and their Use as Selective Dopamine D3 Receptor Ligands
IE48965B1 (en) Isoquinoline derivatives,process for their preparation,medicaments containing them and their pharmaceutical use
US4260762A (en) Octahydro-1H-pyrrolo[2,3-g]isoquinolines
SK68090A3 (en) 1,2-etanediole derivatives and their salts, and method of their production
JPS63277665A (en) Ketone derivative
EP0040990B1 (en) Antiallergic imidodisulfamides, their preparation and pharmaceutical compositions containing them
US4334070A (en) Cycloalka[4,5]pyrrolo[2,3-g]isoquinolines
JP3545332B2 (en) Novel camptothecin analogues, methods for their preparation, and pharmaceutical compositions containing them
US4442291A (en) 1,2,3,4,4a,7-Hexahydro-6,8-dimethoxy-2-methyl isoquinoline
US4349678A (en) Octahydro-2-methyl-isoquinoline-6,8-dione
CZ308494A3 (en) Derivatives of epi-epibatidin, process of their preparation and pharmaceutical compositions containing thereof
HU207069B (en) Process for producing 3-(3-indolyl)-quinuclidine derivatives and pharmaceutical compositions comprising same as active ingredient
US6699876B2 (en) Camptothecin analogue compounds