Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1984-08-14
1987-02-24
Lesmes, George F.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546 48, 546 71, 514284, C07D47122, C07D49122, A61K 31435
Patent
active
046457720
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to the levorotatory enantiomers of derivatives of tetrahydro-5,6,13,13a-8H-dibenzo[a,g]quinolizine. It also relates to the preparation of the said enantiomers. The invention also provides the therapeutic use of these novel compounds and the pharmaceutical compositions containing them.
5,6,13,13a-tetrahydro-8H-dibenzo[a,g]quinolizine, whose non-proprietary name is "Berbine", has the formula I below: ##STR3##
"Berbine" reverses the hypertensive effects of adrenalin in the dog (Raymond Hamet, Bulletin de l'Academie Nationale de Medecine 1952, 22 and 23, 408; Raymond Hamet, C. R. Acad. Sci. 1953, 236, 1916). L-Berbine has in the cat, as in the dog, a strong sympatholytic activity (Raymond Hamet, C. R. Acad. Sci. Paris, t 259 1964, p. 4397-4399). Berbine has hypotensive activity in hypertensive patients (Faquet, Lisles and Combaz, Gazette Medicale de France, 1954, 61, 1615). The separation of the enantiomers of Berbine as described by Wolfgang Leithe, Berichte 63 2343 (1930) is by successive crystallizations of certain of its salts with optically active acids, according to a conventional method.
The patent No. EP-A-0028959 describes the synthesis of a racemic mixture of certain derivatives of tetrahydro-5,6,13,13a-8H-dibenzo[a,g]quinolizine, as well as its use in the treatment of cardiovascular disorders, but the separation of the enantiomers, and/or their possible remarkable therapeutic properties are not suggested.
In the publication: Heterocycles (1974) 2(5) 625-30 the preparation of certain derivatives of Berbine is described from each of the distinct enantiomers, of the corresponding isoquinolines. The preparation process for each enantiomer is completely different from that according to the invention since the latter involves a stereospecific synthesis starting from each appropriately substituted isomer of isoquinoline. The tests described prove that the compounds thus obtained, which have the formula Ib below, do not have dopaminergic activity. ##STR4## in which if R.sub.4 is H, R.sub.2 and R.sub.3 represent OH or OCH.sub.3 and if R.sub.2 is H, R.sub.3 and R.sub.4 represent OH.
Finally, the patent GB No. 1,004,077 provides compositions comprising dibenzoquinolizines which have tranquilizing, antidepressant and antiemetic activity. It is indicated that these dibenzoquinolizines can be in the racemic form or in d- or l-forms but the isolation of these latter forms is not described and their respective properties remain unknown.
These dibenzoquinolizines have the general formula below: ##STR5## in which R.sub.1 and R.sub.2 represent hydrogen, hydroxy, methoxy or ethoxy;
It should be noted that by the synthetic process described in this patent GB No. 1,004,077, it is not possible to obtain derivatives hydroxylated in position 3, that is to say the compounds of formula Ia above in which R.sub.1 is hydroxy.
Indeed the operative conditions of the process mentioned on page 2, lines 59 to 64 of this patent GB No. 1,004,077 are too strong (acidity and heat) to avoid the decomposition of the benzyloxy group (protector of the hydroxy functional group) during the course of the cyclization reaction of the N-substituted phenylacetamides to 3,4 dihydroisoquinolines, carried out in the presence of phosphorus oxychloride and with heating.
In the patent application No. FR-A-2,469,413 in the name of the applicant, there was described derivatives of Berbine which have an interesting pharmacological activity, in particular in the cardiovascular area for the treatment of rhythm disorders and cardiac and coronary insufficiencies.
The derivatives of Berbine described in said patent application No. FR-A-2,469,413 have the general formula II: ##STR6## in which: R.sub.3 is --OR or --SR in which R is hydrogen, an aryl or alkyl group or a group of formula ##STR7## in which R' is an aryl or alkyl group: ##STR8## R.sub.10 and R.sub.11 are identical or different, and hydrogen or an aryloxy or lower alkoxy group provided that, when ##STR9## R.sub.10 and R.sub.11 are hydrogen or a lower alkoxy group, R.sub.3
REFERENCES:
patent: 3426027 (1969-02-01), Muller et al.
Spath, E. et al, Chem. Ber., (1930) pp. 3007-3012.
Chem Abs., vol 82, 43626 u (p. 460) 1975.
Berichte der Deutschen Chemischen Gesellschaft, vol. 63, No. 358, pp. 2343-2347 (1930).
Heitz Christiane
Jung Louis
Schott Claire
Schutz Fabienne
Stambach Jean-Francois
Gibson S. A.
Lesmes George F.
Urpha
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