GB800969A - Novel 2-hydroxy-benzo [ª‡] quinolizines, acid addition salts thereof and a process for the manufacture of same - Google Patents

Novel 2-hydroxy-benzo [ª‡] quinolizines, acid addition salts thereof and a process for the manufacture of same

Info

Publication number
GB800969A
GB800969A GB3722/57A GB372257A GB800969A GB 800969 A GB800969 A GB 800969A GB 3722/57 A GB3722/57 A GB 3722/57A GB 372257 A GB372257 A GB 372257A GB 800969 A GB800969 A GB 800969A
Authority
GB
United Kingdom
Prior art keywords
hydroxy
benzo
dimethoxy
quinolizine
hexahydro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
GB3722/57A
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Original Assignee
F Hoffmann La Roche AG
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
Application filed by F Hoffmann La Roche AG filed Critical F Hoffmann La Roche AG
Publication of GB800969A publication Critical patent/GB800969A/en
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • C07D455/06—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems

Abstract

This invention comprises compounds of the general formula: <FORM:0800969/IV (b)/1> and acid addition salts thereof, wherein R1 and R2 each represent a hydrogen atom or a hydroxy or alkoxy group or together represent an alkylenedioxy group, and R3 represents an alkyl group, an alkyl group which contains an oxygen atom in the form of a normal or cyclic ether function, or an alkenyl or aralkyl group, and wherein the broken lines denote that the isocyclic ring may contain one or two further double bonds; and a process for the manufacture thereof by reducing a compound of the general formula: <FORM:0800969/IV (b)/2> and, if desired, converting the product into an acid addition salt. Reduction may be effected by hydrogen in the presence of a hydrogenation catalyst, in which case alkenyl groups are also reduced to alkyl groups, by alkali metal in the presence of an alcohol, or by the use of lithium-aluminium hydride or sodium boron hydride. In an example, 2-oxo-3 - ethyl - 9,10 - dimethoxy - 1,2,3,4,6,7 - hexahydro - benzo - [a] - quinolizine is hydrogenated in glacial acetic acid, in the presence of prehydrogenated platinum oxide catalyst at ca. 20 DEG C. to form 2-hydroxy-3-ethyl-9,10-dimethoxy - 1,2,3,4,6,7 - hexahydro - benzo -[a] - quinolizine. The same compound is also prepared in further examples from the same starting material by hydrogenation in methanol, in the presence of Raney-nickel, with hydrogen under pressure at 50 DEG C.; by reaction with metallic sodium in butanol; and by reaction with lithium-aluminium hydride in the presence of a mixture of dioxane and ether (1 : 4), followed by hydrolysis with water. In each case, the hydrobromide, the hydrochloride and the acid sulphate are formed. 2-Hydroxy-3-n-butyl-9,10 - dimethoxy - 1,2,3,4,6,7 - hexahydrobenzo-[a]-quinolizine is prepared from the corresponding 2-oxo-compound by hydrogenation in methanol and in glacial acetic acid, by reduction with metallic sodium and butanol and by reduction with lithium-aluminium hydride, the base being converted into the hydrobromide; and 2,9,10 - trihydroxy - 3 - ethyl - 1,2,3,4,6,7-hexahydrohydro - benzo - [a] - quinolizine hydrobromide is prepared from its corresponding 2-oxo-compound, in the form of its hydrobromide, by hydrogenation in 50 per cent acetic acid in the presence of a platinum oxide catalyst. (The product is identical with that obtained by hydrolysis of the 2-hydroxy-3-ethyl - 9,10 - dimethoxy - 1,2,3,4,6,7 - hexahydro - benzo - [a] - quinolizine, formed above, with 48 per cent hydrobromic acid.) The following may also be prepared by the methods given: 2-hydroxy-3-methyl-, 2-hydroxy-3-isobutyl-, 2-hydroxy-3-amyl-, 2-hydroxy-3-hexyl-, and 2 - hydroxy - 3 - (o - methoxy - butyl) - 9,10-dimethoxy - 1,2,3,4,6,7 - hexahydro - benzo - [a] - quinolizines and their hydrochlorides; 2-hydroxy - 3 - allyl -, and 2 - hydroxy - 3 - (tetrahydro - furfuryl) - 9,10 - dimethoxy - 1,2,3,4,6,7 - hexahydro - benzo - [a] - quinolizines and their hydrobromides; 2-hydroxy-3-ethyl - 9,10 - diethoxy and 2 - hydroxy - 3 - ethyl - 9,10 - methylenedioxy - 1,2,3,4,6,7 - hexahydro-benzo-[a]-quinolizines and their hydrochlorides, 2,9,10 - trihydroxy - 3 - butyl - 1,2,3,4,6,7 - hexahydro - benzo - [a] - quinolizine and its hydrobromide; 2-hydroxy-3-benzyl - 9,10 - dimethoxy - 1,2,3,4,6,7 - hexahydro - benzo - [a] - quinolizine and its picrate; and 2-hydroxy-3-ethyl- and 2-hydroxy-3-butyl-1,2,3,4,6,7,8,9,10,11 - decahydrobenzo - [a] - quinolizines. Starting materials: 2-Oxo-3-ethyl-9,10-dimethoxy - 1,2,3,4,6,7 - hexahydro - benzo - [a]-quinolizine is prepared by reacting 1-ethoxycarbonylmethyl - 6,7 - dimethoxy - 1,2,3,4 - tetrahydro - isoquinoline, paraformaldehyde and dimethyl monoethyl-malonate to form 1-ethoxycarbonylmethyl - 2 - [21,21 - di - (methoxycarbonyl) - butyl] - 6,7 - dimethoxy - 1,2,3,4 - tetrahydro-isoquinoline which is then reacted with sodium ethoxide to effect ring closure, and then with 3-n-hydrochloric acid to effect hydrolysis and decarboxylation. The product is isolated as the base which is converted into the hydrochloride and hydrobromide. 2-Oxo-3-ethyl - 9,10 - dihydroxy - 1,2,3,4,6,7 - hexahydrobenzo-[a]-quinolizine hydrobromide is prepared from the corresponding 9,10-dimethoxy compound or its hydrobromide by hydrolysis with 48 per cent hydrobromic acid. Specification 789,789 is referred to.
GB3722/57A 1956-02-08 1957-02-04 Novel 2-hydroxy-benzo [ª‡] quinolizines, acid addition salts thereof and a process for the manufacture of same Expired GB800969A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CH341161T 1956-02-08

Publications (1)

Publication Number Publication Date
GB800969A true GB800969A (en) 1958-09-03

Family

ID=4505675

Family Applications (1)

Application Number Title Priority Date Filing Date
GB3722/57A Expired GB800969A (en) 1956-02-08 1957-02-04 Novel 2-hydroxy-benzo [ª‡] quinolizines, acid addition salts thereof and a process for the manufacture of same

Country Status (8)

Country Link
AT (1) AT196875B (en)
BE (1) BE554816A (en)
CH (1) CH341161A (en)
DE (1) DE1082912B (en)
DK (1) DK89401C (en)
ES (1) ES233470A1 (en)
FR (1) FR1231641A (en)
GB (1) GB800969A (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010026436A2 (en) * 2008-09-08 2010-03-11 Biovail Laboratories International (Barbados) Srl Pharmaceutical compounds
WO2011019956A2 (en) 2009-08-12 2011-02-17 Biovail Laboratories International (Barbados) S.R.L. Pharmaceutical compositions
WO2018178243A3 (en) * 2017-04-01 2018-12-13 Adeptio Pharmaceuticals Limited Dihydrotetrabenazine for use in the treatment a movement disorder
US10660885B2 (en) 2017-04-01 2020-05-26 Adeptio Pharmaceuticals Limited Pharmaceutical compositions
US10668052B2 (en) 2017-04-01 2020-06-02 Adeptio Pharmaceuticals Limited Combinations of isomers of dihydrotetrabenazine
US11065232B2 (en) 2017-04-01 2021-07-20 Adeptio Pharmaceuticals Limited Dihydrotetrabenazine for the treatment of anxiety and psychoses
US11844786B2 (en) 2017-04-01 2023-12-19 Adeptio Pharmaceuticals Limited Uses of combinations (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine in methods of treating movement disorder

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HU175890B (en) * 1977-06-15 1980-11-28 Chinoin Gyogyszer Es Vegyeszet Process for producing new 1,2,3,4,6,7-hexahydro-11-b-alpha-benzo-square bracket-a-square brecket closed-quinolyzine derivatives

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010026436A2 (en) * 2008-09-08 2010-03-11 Biovail Laboratories International (Barbados) Srl Pharmaceutical compounds
WO2010026436A3 (en) * 2008-09-08 2010-06-24 Biovail Laboratories International (Barbados) Srl 1,3, 4, 6, 7, 11b-hexahydro-benzo[alpha]quinolizines for the treatment of hyperkinetic movement and related disorders
WO2011019956A2 (en) 2009-08-12 2011-02-17 Biovail Laboratories International (Barbados) S.R.L. Pharmaceutical compositions
WO2018178243A3 (en) * 2017-04-01 2018-12-13 Adeptio Pharmaceuticals Limited Dihydrotetrabenazine for use in the treatment a movement disorder
US10660885B2 (en) 2017-04-01 2020-05-26 Adeptio Pharmaceuticals Limited Pharmaceutical compositions
US10668052B2 (en) 2017-04-01 2020-06-02 Adeptio Pharmaceuticals Limited Combinations of isomers of dihydrotetrabenazine
US11065232B2 (en) 2017-04-01 2021-07-20 Adeptio Pharmaceuticals Limited Dihydrotetrabenazine for the treatment of anxiety and psychoses
US11103498B2 (en) 2017-04-01 2021-08-31 Adeptio Pharmaceuticals Limited Pharmaceutical compositions
RU2768738C2 (en) * 2017-04-01 2022-03-24 Адептио Фармасьютикалз Лимитед USE OF (−)-α-DIHYDROTETRABENAZINE OR A COMBINATION THEREOF WITH (+)-α-DIHYDROTETRABENAZINE IN THE TREATMENT OF HYPERKINETIC MOVEMENT DISORDER, AS WELL AS CORRESPONDING METHODS
US11844794B2 (en) 2017-04-01 2023-12-19 Adeptio Pharmaceuticals Limited Pharmaceutical compositions
US11844786B2 (en) 2017-04-01 2023-12-19 Adeptio Pharmaceuticals Limited Uses of combinations (+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine in methods of treating movement disorder

Also Published As

Publication number Publication date
CH341161A (en) 1959-09-30
DE1082912B (en) 1960-06-09
ES233470A1 (en) 1957-10-16
BE554816A (en) 1960-02-12
DK89401C (en) 1960-07-25
AT196875B (en) 1958-03-25
FR1231641A (en) 1960-09-30

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