Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-05-31
1998-05-26
Richter, Johann
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
549400, 549402, 549403, A61K 3135, C07D31130, C07D31132, C07D31126
Patent
active
057565384
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB94/01803 filed Aug. 17, 1994.
FIELD OF THE INVENTION
The present invention relates to certain flavonoids which have been found to have anxiolytic properties (i.e. anxiety reducing) without corresponding depression of the central nervous system which is commonly also found in known sedatives such as benzodiazepines.
BACKGROUND OF THE INVENTION
Some compounds of the invention are novel; other compounds are known but no pharmaceutical uses have previously been described.
Flavone is a known compound which is described in the Merck Index (entry 4030). Chrysin (2261) and apigenin (763) are other known flavonoids. Chrysin has been described as having binding properties for benzodiazepine receptors and anticonvulsant properties in Medina J. H. et al. Biochem. Pharmacol; 40:2227-2232, 1990. This reference also suggests that chrysin may possess myorelaxant (i.e. muscle relaxant) action.
Flavone, 2-phenyl-4H-1-benzopyran-4-one has the formula ##STR1##
Chrysin is 5,7-dihydroxyflavone
Apigenin is 4', 5,7- trihydroxyflavone.
SUMMARY OF THE INVENTION
The present invention relates to a method of treatment of anxiety in a patient which comprises administering to the patient an effective non-toxic amount of a flavonoid compound of general formula (I): ##STR2## where R.sup.1, R.sup.2, R.sup.3 and R.sup.4, R.sup.5 and R.sup.8 are independently selected from H, OH, R, NO.sub.2, halo, OR, NH.sub.2, NHR, NR.sub.2, COOR, COOH, CN, or a sugar group;
R.sup.6 and R.sup.7 are both H, or R.sup.6 and R.sup.7 together form a single bond;
R is C.sub.1-6 alkyl or alkenyl; which is a dimer of a compound of general formula (I) and wherein R.sup.1 to R.sup.8 and R have the meanings given for general formula (I).
It is found that the compounds of the present invention have anxiolytic properties without the associated depression of the central nervous system (e.g. sedative and muscle relaxant effects) commonly found with benzodiazepines. This may allow patients to be treated for anxiety without inducing sedative or myorelaxant side-effects.
It is found further that compounds of the present invention may not show an anti-convulsant activity commonly found with benzodiazepines.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph illustrating ambulatory locomotor activity counts in mice during a five minute test session, twenty minutes after intraperitoneal (i.p.) injection with diazepam (DZ) or chrysin (CHRY);
FIG. 2 is a graph illustrating test results of mice given a five minute test in the elevated plus-maze, twenty minutes after i.p. injection with DZ or CHRY;
FIG. 3 is a graph illustrating test results of mice given a five minute test in the elevated plus-maze, twenty minutes after i.p. injection with vehicle (VEH), CHRY or CHRY plus RO 15-1788 administered ten minutes before chrysin;
FIG. 4 is a graph illustrating the test results of mice given a five minute test in a holeboard, twenty minutes after i.p. injection with DZ or CHRY;
FIG. 5 is a graph illustrating test results of mice in a wire test, twenty minutes after i.p. injection with DZ or CHRY;
FIG. 6 is a graph illustrating test results of mice given a five minute test in the elevated plus-maze and ambulatory activity in mice given a five minute test, twenty minutes after i.p. injection with vehicle and apigenin;
FIG. 7 is a graph illustrating test results of mice given a five minute test in the holeboard, and performance to grasping the wire test, twenty minutes after i.p. injection with vehicle and apigenin;
FIG. 8 is a graph illustrating noradrenaline levels in locus coeruleus nucleus after a session of immobilization stress alone or with pre-treatments;
FIG. 9 is a graph illustrating test results of mice given a five minute test in the elevated plus-maze and ambulatory activity in mice given a five minute test, twenty minutes after i.p. injection with vehicle and flavone;
FIG. 10 is a graph illustrating test results of mice given a five minute test in the elevated plus-maze, twenty minutes after i.p. injection with vehicle and a mixt
REFERENCES:
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J.H. Medina et al; Chrysin (5,7-di-oh-flavone), a Naturally-occurring Ligand for Benozodiazepine Receptors, with Anticonvulsant Properties, Biochemical Pharmacology, 40 No. 10, pp. 2227-2231 (1990).
M. Nielsen et al; High Affinity of the Naturally-occurring Biflavonoid, Amentoflavon, to Brain Benzodiazepine Receptors in Vitro, Biochemical Phamacology, 37 No. 17, pp. 3285-3287 (1988).
B. K. Chakravarthy et al; Isolation of Amentoflavone from Selaginella rupestris and its Pharmacological activity on Central Nervous System, Smooth Muscles and Isolated Frog Heart Preparations; Planta Medica 43, pp. 64-70 (1981).
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Cassels Bruce Kennedy
Dajas Federico Jose
Medina Jorge Horacio
Paladini Alejandro Constantino
Silveira Rodolfo Horacio
Richter Johann
Stockton Laura L.
University of Strathclyde
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